BACKGROUND: Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells. METHODS: We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression. RESULTS: RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer. CONCLUSIONS: This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.

BACKGROUND: Tuberculosis (TB) may facilitate carcinogenesis. We performed a case-control study of the association between TB and cancer in Xinjiang, a high TB endemic area of China. METHODS: From January 2016 to December 2018, a total of 45,455 patients hospitalized in Xinjiang Cancer Hospital were consecutively enrolled and divided into a malignant tumor group (n = 32,539) and a benign tumor group (n = 12,916). Patients with active and previous TB before the diagnosis of cancer were retrospectively identified in the two groups. RESULTS: A significantly higher proportion of TB was found in the malignant tumor group (n = 1776, 5.46%) than in the control (benign tumor) group (n = 175, 1.35%) (p < 0.0001). The highest and lowest proportions of TB in the malignant group were in patients with non-Hodgkin's lymphoma (16.74%) and thyroid cancer (0.77%), respectively. In multivariate analysis adjusting for age, sex, and ethnicity, TB remained an independent risk factor for all cancers (odds ratio (OR) 1.68; 95% confidence interval (CI) 1.43-1.97). Furthermore, TB was associated with a significantly higher risk of non-Hodgkin's lymphoma, cervical cancer, esophageal cancer, "other" cancers, ovarian cancer, and breast cancer. Moreover, females with TB were more likely to develop cancer than males (p < 0.0001), except for esophageal cancer and lymphoma. CONCLUSION: TB patients have an elevated cancer risk. A screening strategy for TB should be taken into consideration before treatment in patients with some cancer types that are associated with a high proportion of TB.

BACKGROUND: Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. METHODS: We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. RESULTS: In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. CONCLUSIONS: Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.

BACKGROUND: Malignant melanoma of the female genital tract is relatively uncommon and accounts for 3-7% of all melanoma localizations. This study aimed to identify driver genes in melanoma of the female genital tract with the purpose of enhancing understanding of disease pathogenesis and identifying potential new therapeutic targets to develop effective therapies. METHODS: KIT (CD117) and BRAF expression were detected immunohistochemically. Polymerase Chain Reaction (PCR) and Sanger sequencing techniques were performed to identify the mutational status of BRAF, NRAS, KRAS, NF1, KIT, PDGFRA and SF3B1 on 19 melanomas of the female genital tract, paired with 25 cutaneous melanomas, 18 acral melanomas and 11 melanomas of nasal cavity. RESULTS: Somatic variant analysis identified KRAS (6/19; 32%) as the most commonly mutated gene, followed by KIT (4/19; 21%), SF3B1 (3/19; 16%) and NRAS (1/19; 5%). None of the cases were found to harbor BRAF, NF1 and PDGFRA mutations in melanomas of the female genital tract. However, none of the cases were found to harbor SF3B1 and KIT mutations in cutaneous melanomas, acral melanomas and melanomas of nasal cavity. Recurrent KIT mutations, as well as mutations in the less frequently mutated genes NRAS and SF3B1, were exclusively detected in vulvovaginal melanomas, but not in tumors arising in the cervix. However, recurrent KRAS mutations were detected in similar frequencies in tumors of the vulva, vagina, and cervix. Additionally, recurrent KRAS and KIT mutations occurred predominantly in polygonal and epithelioid cell types of melanoma in the female genital tract. Immunohistochemistry revealed moderate or strong cytoplasmic CD117 expression in 6 of the 19 cases (31.6%). CONCLUSIONS: We observed that gynecologic melanoma harbored distinct mutation rates in the KIT, BRAF, SF3B1, KRAS, and NRAS genes. Our findings support the notion that gynecologic melanoma is a distinct entity from non-gynecologic melanoma, and these findings offer insights into future therapeutic options for these patients.

BACKGROUND: Nitric oxide (NO) plays an important role in lung cancer. However, the results of previous studies about NO in the occurrence, progress and therapy were not consistent. Therefore, we conducted a meta-analysis to evaluate the relationship between NO and lung cancer. METHOD: We carried out comprehensive search in the databases, and collected related studies. The data of fraction of exhaled nitric oxide (FeNO) or blood NO in different populations (lung cancer patients and control subjects) and different time points (before therapy and after therapy) were extracted by two investigators. A random effect model was applied to analyze the differences of FeNO and blood NO in different populations and different time points. To further compare NO level of each subgroup with different pathological types and different stages, a network meta-analysis (NMA) was performed. RESULTS: Fifty studies including 2551 cases and 1691 controls were adopted in this meta-analysis. The FeNO (SMD 3.01, 95% CI 1.89-4.13, p < 0.00001) and blood NO (SMD 1.34, 95% CI 0.84-1.85, p < 0.00001) level in lung cancer patients was much higher than that in control subjects. NMA model indicated blood NO level in each cancer type except SCLC was higher than that in control patients. There was no significant difference of blood NO level among four kinds of lung cancer patients. Blood NO level in LCC patients (SUCRA = 83.5%) was the highest. Blood NO level in advanced stage but not early stage was higher than that in control subjects. Patients in advanced stage (SUCRA = 95.5%) had the highest blood NO level. No significant difference of FeNO (SMD -0.04, 95% CI -0.46-0.38, p > 0.05) and blood NO level (SMD -0.36, 95% CI -1.08-0.36, p > 0.05) was observed between pretreatment and posttreatment in all patients. However, FeNO level elevated (SMD 0.28, 95% CI 0.04-0.51, p = 0.02) and blood NO level decreased in NSCLC patients (SMD -0.95, 95% CI -1.89-0.00, p = 0.05) after therapy. CONCLUSION: FeNO and blood NO level would contribute to diagnosis of lung cancer and evaluation of therapy effect, especially for NSCLC patients.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that lack of effective therapeutic drugs. K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced PDAC. METHODS: In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3 + 3 design. K-001 was administered twice daily in four-week cycles, and dose escalation from 1350 mg to 2160 mg was evaluated twice daily. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed while tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST). RESULTS: Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and hemorrhoid bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%. CONCLUSIONS: K-001 manifests satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted. TRIAL REGISTRATION: NCT02720666 . Registered 28 Match 2016 - Retrospectively registered.

BACKGROUND: The association between SOX14 and cancer has been reported. The aim of this study was to identify and validate the potential value of SOX14 methylation in the early detection of cervical cancer. METHODS: First, we extracted the data for SOX14 methylation and expression within cervical cancer from The Cancer Genome Atlas (TCGA) database and analysed them via UALCAN, Wanderer, MEXPRESS and LinkedOmics. Subsequently, according to the bioinformatics findings, primers and probes were designed for the most significantly differentiated methylation CpG site and synthesized for methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP) to verify SOX14 methylation in both cervical tissuses and liquid-based cell samples. Eventually, the clinical diagnostic efficacy of SOX14 methylation in the normal, cervical intraepithelial neoplasia, and cancer groups was analysed by ROCAUC. RESULTS: Pooled analysis demonstrated that SOX14 methylation levels were significantly increased in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) compared to normal tissues (P < 0.001). Both the verification and validation cohorts indicated that the methylation level and the positive rate of SOX14 gradually increased with increasing severity from normal to cancer samples (P < 0.01). When the cut-off value was set as 128.45, the sensitivity and specificity of SOX14 hypermethylation in the diagnosis of cervical cancer were 94.12 and 86.46%, respectively. When taken as a screening biomarker (>CINII), the sensitivity was 74.42% and the specificity was 81.48%, with a cut-off value of 10.37. CONCLUSION: SOX14 hypermethylation is associated with cervical cancer and has the potential to be a molecular biomarker for the screening and early diagnosis of cervical cancer.

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.

Erratum in BMC Cancer. 2021 Aug 26;21(1):956.

BACKGROUND: miRNAs and lncRNAs can regulate cellular biological processes both under physiological and pathological conditions including tumour initiation and progression. Interactions between differentially expressed diverse RNA species, as a part of a complex intracellular regulatory network (ceRNA network), may contribute also to the pathogenesis of HPV-associated cancer. The purpose of this study was to investigate the global expression changes of miRNAs, lncRNAs and mRNAs driven by the E6 and E7 oncoproteins of HPV16, and construct a corresponding ceRNA regulatory network of coding and non-coding genes to suggest a regulatory network associated with high-risk HPV16 infections. Furthermore, additional GO and KEGG analyses were performed to understand the consequences of mRNA expression alterations on biological processes. METHODS: Small and large RNA deep sequencing were performed to detect expression changes of miRNAs, lncRNAs and mRNAs in primary human keratinocytes expressing HPV16 E6, E7 or both oncoproteins. The relationships between lncRNAs, miRNAs and mRNAs were predicted by using StarBase v2.0, DianaTools-LncBase v.2 and miRTarBase. The lncRNA-miRNA-mRNA regulatory network was visualized with Cytoscape v3.4.0. GO and KEEG pathway enrichment analysis was performed using DAVID v6.8. RESULTS: We revealed that 85 miRNAs in 21 genomic clusters and 41 lncRNAs were abnormally expressed in HPV E6/E7 expressing cells compared with controls. We constructed a ceRNA network with members of 15 lncRNAs - 43 miRNAs - 358 mRNAs with significantly altered expressions. GO and KEGG functional enrichment analyses identified numerous cancer related genes, furthermore we recognized common miRNAs as key regulatory elements in biological pathways associated with tumorigenesis driven by HPV16. CONCLUSIONS: The multiple molecular changes driven by E6 and E7 oncoproteins resulting in the malignant transformation of HPV16 host cells occur, at least in part, due to the abnormal alteration in expression and function of non-coding RNA molecules through their intracellular competing network.

BACKGROUND: Mutations in TP53 not only affect its tumour suppressor activity but also exerts oncogenic gain-of-function activity. While the genome-wide mutant p53 binding sites have been identified in cancer cell lines, the chromatin accessibility landscape driven by mutant p53 in primary tumours is unknown. Here, we leveraged the chromatin accessibility data of primary tumours from The Cancer Genome Atlas (TCGA) to identify differentially accessible regions in mutant p53 tumours compared to wild-type p53 tumours, especially in breast and colon cancers. RESULTS: We identified 1587 lost and 984 gained accessible chromatin regions in breast, and 1143 lost and 640 gained regions in colon cancers. However, only less than half of those regions in both cancer types contain sequence motifs for wild-type or mutant p53 binding. Whereas, the remaining showed enrichment for master transcriptional regulators, such as FOX-Family TFs and NF-kB in lost and SMAD and KLF TFs in gained regions of breast. In colon, ATF3 and FOS/JUN TFs were enriched in lost, and CDX family TFs and HNF4A in gained regions. By integrating the gene expression data, we identified known and novel target genes regulated by the mutant p53. CONCLUSION: This study reveals the direct and indirect mechanisms by which gain-of-function mutant p53 targets the chromatin and subsequent gene expression patterns in a tumour-type specific manner. This furthers our understanding of the impact of mutant p53 in cancer development.

BACKGROUND: Patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) intermediate stage hepatocellular carcinoma (HCC) encompass a broad clinical population. Kinki criteria subclassifications have been proposed to better predict prognoses and determine appropriate treatment strategies for these patients. This study validated the prognostic significance within the Kinki criteria substages and analyzed the role of liver resection in patients with intermediate stage HCC. METHODS: Patients with intermediate stage HCC (n = 378) were retrospectively subclassified according to the Kinki criteria (B1, n = 123; B2, n = 225; and B3, n = 30). We analyzed the overall survival (OS) and treatment methods. RESULTS: The OS was significantly different between adjacent substages. Patients in substage B1 who underwent liver resection had a significantly better prognosis than those who did not, even after propensity score matching (PSM). Patients in substage B2 who underwent liver resection had a significantly better prognosis than those who did not; however, there was no difference after PSM. There was no difference in prognosis based on treatments among patients in substage B3. CONCLUSIONS: The Kinki criteria clearly stratify patients with intermediate stage HCC by prognosis. For substage B1 HCC patients, liver resection provides a better prognosis than other treatment modalities. In patients with substage B2 and B3, an alternative approach is required.

BACKGROUND: Cervical cancer is one of the most common malignancies among women. Appropriate and timely treatment of these patients can reduce the complications and increase their survival. The objective of this study was to compare neoadjuvant chemotherapy plus radical hysterectomy (NACTRH) and chemo-radiotherapy (CRT) in patients with bulky cervical cancer (stage IB3 & IIA2). MATERIAL AND METHODS: The medical records of patients with bulky cervical cancer (stage IB3 & IIA2) that received NACTRH or CRT between 2007 and 2017 were evaluated for therapeutic effects. Demographic characteristics, complications of chemo-radiotherapy and neoadjuvant chemotherapy, were collected in a researcher-made questionnaire. Our primary outcome was comparison of overall survival (OS), and disease-free survival (DFS) between two groups receiving NACTRH and CRT modalities. RESULTS: One-hundred and twenty three patients were enrolled in the study. The median age and the proportion of patients with stage IIA2 were higher in the CRT group compared to the NACTRH group (p < 0.05). The medians (95% CI) OS were 3.64 (3.95-6.45) and 3.9 (3.53-4.27) years in the NACTRH and CRT groups, respectively (P = 0.003). There were 16 (34.8%) and 22 (43.1%) recurrences in the NACTRH and CRT group, respectively (P = 0.4). The median (95% CI) DFS was 4.5 (3.88-5.12) years in the NACTRH group and 3.6 (2.85-4.35) years in the CRT group (P = 0.004). The 3-year OS rate in NACTRH and CRT groups were 97 and 90% respectively. The 3-year DFS rate in NACTRH and CRT groups were 88 and 66% respectively. CONCLUSIONS: NACTRH is associated with a higher OS and DFS compared to CRT.

BACKGROUND: Integrated social care may help to mitigate social risk factors in order to achieve more equitable health outcomes. In cancer centers certified according to the criteria set out by the German Cancer Society, every patient must be given low-threshold access to qualified social workers at the center for in-house social service counseling (SSC). Previous analyses have demonstrated large variation in the utilization of these services across individual centers. Therefore, this research aims at investigating whether SSC utilization varies regarding breast cancer patient characteristics and center characteristics presenting a unique approach of using routine data. METHODS: Multilevel modeling was performed using quality assurance data based on 6339 patients treated in 13 certified breast cancer centers in Germany in order to investigate whether SSC utilization varies with patient sex, age, and disease characteristics as well as over time and across centers. RESULTS: In the sample, 80.3% of the patients used SSC. SSC use varies substantially between centers for the unadjusted model (ICC = 0.24). Use was statistically significantly (P < .001) more likely in women, patients with invasive (in comparison to tumor in situ/ductal carcinoma in situ) diseases (P < .001), patients with both breasts affected (P = .03), patients who received a surgery (P < .001), patients who were diagnosed in 2015 or 2017 compared to 2016 (P < .001) and patients older than 84 years as compared to patients between 55 and 64 years old (P = .002). CONCLUSION: The analysis approach allows a unique insight into the reality of cancer care. Sociodemographic and disease-related patient characteristics were identified to explain SSC use to some extent.

BACKGROUND: The second most common cancer among females in Bangladesh is cervical cancer. The national strategy for cervical cancer needs monitoring to ensure that patients have access to care. In order to provide accurate information to policymakers in Bangladesh and other low and middle income countries, it is vital to assess current service availability and readiness to manage cervical cancer at health facilities in Bangladesh. METHODS: An interviewer-administered questionnaire adapted from the World Health Organization Service Availability and Readiness Assessment Standard Tool was used to collect cross-sectional data from health administrators of 323 health facilities in Bangladesh. Services provided were categorized into domains and service readiness was determined by mean readiness index (RI) scores. Data analysis was conducted using STATA version 13. RESULTS: There were seven tertiary and specialized hospitals, 118 secondary level health facilities, 124 primary level health facilities, and 74 NGO/private hospitals included in the study. Twenty-six per cent of the health facilities provided services to cancer patients. Among the 34 tracer items used to assess cancer management capacity of health facilities, four cervical cancer-specific tracer items were used to determine service readiness for cervical cancer. On average, tertiary and specialized hospitals surpassed the readiness index cutoff of 70% with adequate staff and training (100%), equipment (100%), and diagnostic facilities (85.7%), indicating that they were ready to manage cervical cancer. The mean RI scores for the rest of the health facilities were below the cutoff value, meaning that they were not prepared to provide adequate cervical cancer services. CONCLUSION: The health facilities in Bangladesh (except for some tertiary hospitals) lack readiness in cervical cancer management in terms of guidelines on diagnosis and treatment, training of staff, and shortage of equipment. Given that cervical cancer accounts for more than one-fourth of all female cancers in Bangladesh, management of cervical cancer needs to be available at all levels of health facilities, with primary level facilities focusing on early diagnosis. It is recommended that appropriate standard operating procedures on cervical cancer be developed for each level of health facilities to contribute towards attaining sustainable developmental goals.

BACKGROUND: Early-stage non-small lung cancer patients may survive long enough to develop second primary lung cancers. However, few studies have accurately described the therapeutic method, evaluation or prognostic factors for long-term survival in this complex clinical scenario. METHODS: Patients who had first and second primary non-small lung cancer in the Surveillance, Epidemiology, and End Results database between 2004 and 2015 were evaluated. Patients were included when their tumors were pathologically diagnosed as non-small lung cancer and in the early-stage (less than 3 cm and with no lymph node metastasis). Therapeutic methods were categorized as lobectomy, sublobectomy or no surgery. The influence of different therapeutic methods on the overall survival rate was compared. RESULTS: For the first primary tumor, patients who underwent lobectomy achieved superior survival benefits compared with patients who underwent sublobectomy. For the second primary tumor, long-term survival was similar in patients who underwent lobectomy and those who underwent sublobectomy treatment. The multivariate analysis indicated that age, disease-free time interval, sex, and first and second types of surgery were independent prognostic factors for long-term survival. Our results showed that the 5-year overall survival rate was 91.9% when the disease-free interval exceeded 24 months. CONCLUSION: Lobectomy for the first primary tumor followed by sublobectomy for the second primary tumor may be a beneficial therapeutic method for patients. If the disease-free interval exceeds 24 months, the second primary tumor will have no influence on the natural course for patients diagnosed with a first primary non-small lung cancer.

BACKGROUND: International differences in survival among colorectal cancer (CRC) patients may partly be explained by differences in emergency presentations (EP), waiting times and access to treatment. METHODS: CRC patients registered in 2015-2016 at the Cancer Registry of Norway were linked with the Norwegian Patient Registry and Statistics Norway. Multivariable logistic regressions analysed the odds of an EP and access to surgery, radiotherapy and systemic anticancer treatment (SACT). Multivariable quantile regression analysed time from diagnosis to treatment. RESULTS: Of 8216 CRC patients 29.2% had an EP before diagnosis, of which 81.4% were admitted to hospital with a malignancy-related condition. Higher age, more advanced stage, more comorbidities and colon cancer were associated with increased odds of an EP (p < 0.001). One-year mortality was 87% higher among EP patients (HR=1.87, 95%CI:1.75-2.02). Being married or high income was associated with 30% reduced odds of an EP (p < 0.001). Older age was significantly associated with increased waiting time to treatment (p < 0.001). Region of residence was significantly associated with waiting time and access to treatment (p < 0.001). Male (OR = 1.30, 95%CI:1.03,1.64) or married (OR = 1.39, 95%CI:1.09,1.77) colon cancer patients had an increased odds of SACT. High income rectal cancer patients had an increased odds (OR = 1.48, 95%CI:1.03,2.13) of surgery. CONCLUSION: Patients who were older, with advanced disease or more comorbidities were more likely to have an emergency-onset diagnosis and less likely to receive treatment. Income was not associated with waiting time or access to treatment among CRC patients, but was associated with the likelihood of surgery among rectal cancer patients.

BACKGROUND: Eribulin mesylate (ERI; Halaven®) is a microtubule inhibitor approved in the United States for metastatic breast cancer patients with at least two prior chemotherapy regimens for metastatic breast cancer, and in the European Union in locally advanced breast cancer or metastatic breast cancer patients who progressed after at least one chemotherapy for advanced disease. This network meta-analysis compared the efficacy and safety of ERI versus other chemotherapies in this setting. METHODS: Systematic searches conducted in MEDLINE, Embase, and the Cochrane Central Register of Clinical Trials identified randomized controlled trials of locally advanced breast cancer/metastatic breast cancer chemotherapies in second- or later-line settings. Efficacy assessment included pre-specified subgroup analysis of breast cancer subtypes. Included studies were assessed for quality using the Centre for Reviews and Dissemination tool. Bayesian network meta-analysis estimated primary outcomes of overall survival and progression-free survival using fixed-effect models. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician's choice (TPC), and vinorelbine (VIN). RESULTS: The network meta-analysis included seven trials. Results showed that second- or later-line patients treated with ERI had statistically longer overall survival versus TPC (hazard ratio [HR]: 0.81; credible interval [CrI]: 0.66-0.99) or GEM+VIN (0.62; 0.42-0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64-0.90), but statistically shorter progression-free survival versus CAP+IXA (1.40; 1.17-1.67) and CAP+UTI (1.61; 1.23-2.12). In triple negative breast cancer, ERI had statistically longer overall survival versus CAP (0.70; 0.54-0.90); no statistical differences in progression-free survival were observed in triple negative breast cancer. CONCLUSIONS: This network meta-analysis suggests that ERI may provide an overall survival benefit in the overall locally advanced breast cancer/metastatic breast cancer populations and triple negative breast cancer subgroup compared to standard treatments. These findings support the use of ERI in second- or later-line treatment of patients with locally advanced breast cancer/metastatic breast cancer.

BACKGROUND: Chemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. However, most patients with advanced pancreatic cancer die within the first 2 years after diagnosis, even when treated with standard of care chemotherapy. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients. METHODS: In this study, we used PV-10, a 10% solution of rose bengal, to induce the death of human pancreatic tumor cells in vitro. Murine in vivo studies were carried out to examine the effectiveness of the direct injection of PV-10 into syngeneic pancreatic tumors in causing lesion-specific ablation. Intralesional PV-10 treatment was combined with systemic gemcitabine treatment in tumor-bearing mice to investigate the control of growth among treated tumors and distal uninjected tumors. The involvement of the immune-mediated clearance of tumors was examined in immunogenic tumor models that express ovalbumin (OVA). RESULTS: In this study, we demonstrate that the injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation. We show that the combination of intralesional PV-10 with the systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of distal uninjected tumors. We observed that this treatment strategy was markedly more successful in immunogenic tumors that express the neoantigen OVA, suggesting that the combination therapy enhanced the immune clearance of tumors. Moreover, the regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. CONCLUSIONS: These results demonstrate that intralesional therapy with PV-10 in combination with gemcitabine can enhance anti-tumor activity against pancreatic tumors and raises the potential for this strategy to be used for the treatment of patients with pancreatic cancer.

BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in females worldwide. Formin-like protein 2 (FMNL2) is a member of formin family that governs cytokinesis, cell polarity, morphogenesis and cell division. To our knowledge, the function of FMNL2 in breast cancer proliferation still remains uncovered. METHODS: Tumor immune estimation resource (TIMER) analysis was used to detect the correlation between FMNL2 and Ki67 in breast cancer tissues. Quantitative real-time transcription polymerase chain reaction (qRT-PCR) and western blotting were performed to analyze the expression in human breast cancer cells. Moreover, RNA interference (RNAi) and plasmids were performed to silence and overexpress FMNL2 and p27. The CCK8, MTT, cell counting, colony formation, and 5-ethynyl-2-deoxyuridine (EdU) incorporation assays were used to detect cell proliferation, respectively. Flow cytometry analysis was used to detect cell cycle distribution. Further, the distribution of p27 was examined using immunofluorescence. RESULTS: We found that FMNL2 expression was positively associated with Ki67 among collected breast cancer tissues and in TCGA database. Compared to lower proliferative cells MCF7 and T47D, FMNL2 was overexpressed in highly proliferative breast cancer cells MDA-MB-231, BT549 and SUM159, accompanied by reduced levels of p27 and p21, and elevated CyclinD1 and Ki67 expression. FMNL2 silencing significantly inhibited the cell proliferation of MDA-MB-231 and BT549 cells. Meanwhile, FMNL2 overexpression distinctly promoted the cell proliferation of MCF7 cells. Furthermore, FMNL2 suppressed the nuclear levels of p27 and promoted p27 proteasomal degradation in human breast cancer cells. The ubiquitination of p27 was inhibited by FMNL2 silencing in BT549 cells. Besides, p27 silencing markedly elevated Ki67 expression and cell viability, which could be blocked by additionally FMNL2 silencing in MDA-MB-231 and BT549 cells. Furthermore, overexpression of p27WT significantly reversed the increased levels of FMNL2 and Ki67, cell viability and cell cycle progression induced by FMNL2 overexpression in MCF7 cells. More importantly, compared to p27WT group, those effects could be significantly reversed by p27△NLS overexpression. CONCLUSIONS: These results demonstrated that FMNL2 promoted cell proliferation partially by reducing p27 nuclear localization and p27 protein stability in human breast cancer cells, suggesting the pivotal role of FMNL2 in breast cancer progression.

BACKGROUND: The Swedish healthcare is decentralised to 21 regions. Detailed information on all delivered care in the southernmost region, Skåne, is prospectively collected in the Skåne Healthcare Register (SHR). The data is updated daily and hence a good source for epidemiological studies. However, the diagnostic codes used to identify cancer patients in SHR have not yet been validated. METHODS: We conducted a validation study including 1,473,204 residents in Skåne region during 2005-2014, with at least one physical consultation in SHR. Newly diagnosed cancer from the Swedish Cancer Register was considered the 'gold standard' reference. We estimated the positive predictive value (PPV), sensitivity, and area under the curve (AUC) of a cancer diagnosis based on SHR by level of consultation, for any cancer, and for different cancer types. RESULTS: There were 61,693 cancers from the Swedish Cancer Register, and 87,650 cancers from SHR. The PPV of SHR-based diagnosis of any cancer was 63.76% (95% confidence interval (CI): 63.44-64.08%) with a sensitivity of 90.58% (95% CI: 90.35-90.81%). The AUC was 0.94, for any cancer. The measures of PPV, sensitivity and AUC varied across levels of care and were higher in specialized care than in primary care. The highest PPV was observed for specialist inpatient care in SHR (89.17, 95% CI 88.89-89.45%) whereas the highest sensitivity was observed for specialized outpatient care in SHR (86.39, 95%CI 86.12-86.66%). Robust validity was noted among most cancers, except for cancers of soft tissues, central nervous system and eye, and endocrine glands. CONCLUSIONS: Our study supports that SHR is a valid and robust healthcare register for cancer diagnosis, with varying validities across levels of care and cancer types. This makes SHR a useful data source for cancer epidemiological studies, especially because the data covers the entire cancer care pathways without time lags for further linkage.

BACKGROUND: Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. METHODS: In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. RESULTS: For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. CONCLUSIONS: Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

BACKGROUND: Patients with locally advanced oral cavity cancer sometimes stopped treatment after neoadjuvant chemotherapy. There are no guidelines of the management for these patients. Before designing clinical trials, we conducted this study to investigate their characteristics, reasons of dropout, and the follow-up information. METHODS: Medical records were consecutively reviewed of patients with locally advanced oral cavity cancer who underwent neoadjuvant chemotherapy from Jan 2017 to Dec 2019.Variables were compared between patients stopped treating after chemotherapy and completed treatments by student t-test and Chi-square test. Logistic regression model was used to calculate the odd rations of potential predictors of dropout. The dropout patients were followed up for reasons and results of their decision. RESULTS: A total of 171 patients were included with 23 not undergoing surgery after chemotherapy. The odd ratios of age over 65 and single marital status were 3.11 (95%CI: 1.1, 8.7) and 4.935 (95%CI: 1.5, 16.1), respectively, for the dropout. The median survival of patients without surgery was 7.4 months. Believing that chemotherapy would be effective and being afraid of the consequence of surgery were the main reasons of refusing surgery. CONCLUSIONS: The prognosis was poor of these dropout patients. Symptom relief and fear of surgery were the reasons of dropout. Age and marital status affected their decision. Clinical trials are needed to be designed for these patients.

BACKGROUND: An important number of breast and ovarian cancer cases is due to a strong genetic predisposition. The main tool for identifying individuals at risk is recognizing a suggestive family history of cancer. We present a prospective study on applying three selected clinical guidelines to a cohort of 1000 Slovenian women to determine the prevalence of at-risk women according to each of the guidelines and analyze the differences amongst the guidelines. METHODS: Personal and family history of cancer was collected for 1000 Slovenian women. Guidelines by three organizations: National Comprehensive Cancer Network (NCCN), American College of Medical Genetics in cooperation with National Society of Genetic Counselors (ACMG/NSGC), and Society of Gynecologic Oncology (SGO) were applied to the cohort. The number of women identified, the characteristics of the high-risk population, and the agreement between the guidelines were explored. RESULTS: NCCN guidelines identify 13.2% of women, ACMG/NSGC guidelines identify 7.1% of women, and SGO guidelines identify 7.0% of women from the Slovenian population, while 6.2% of women are identified by all three guidelines as having high-risk for hereditary breast and ovarian cancer. CONCLUSIONS: We identified 13.7% of women from the Slovenian population as being at an increased risk for breast and ovarian cancer based on their personal and family history of cancer using all of the guidelines. There are important differences between the guidelines. NCCN guidelines are the most inclusive, identifying nearly twice the amount of women as high-risk for hereditary breast and ovarian cancer as compared to the AGMG/NSCG and SGO guidelines in the Slovenian population.

BACKGROUND: Terminal differentiation-induced ncRNA (TINCR) plays an essential role in epidermal differentiation and is involved in the development of various cancers. METHODS: qPCR was used to detect the expression level of TINCR in tissues and cell lines of laryngeal squamous cell carcinoma (LSCC). The potential targets of TINCR were predicted by the bioinformation website. The expression of miR-210 and BTG2 genes were detected by qPCR, and the protein levels of BTG2 and Ki-67 were evaluated by western blot. CCK-8 assay, scratch test, and transwell chamber were used to evaluate the proliferation, invasion, and metastasis ability of LSCC cells. The relationships among TINCR, miR-210, and BTG2 were investigated by bioinformatics software and luciferase reporter assay. The in vivo function of TINCR was accessed on survival rate and tumor growth in nude mice. RESULTS: We used qRT-PCR to detect the expression of TINCR in laryngeal squamous cell carcinoma (LSCC) tissues and cells and found significantly lower levels in cancer tissues compared with adjacent tissues. Additionally, patients with high TINCR expression had a better prognosis. TINCR overexpression was observed to inhibit the proliferation and invasion of LSCC cells. TINCR was shown to exert its antiproliferation and invasion effects by adsorbing miR-210, which significantly promoted the proliferation and invasion of laryngeal squamous cells. Overexpression of miR-210 was determined to reverse the tumour-suppressive effects of TINCR. BTG2 (anti-proliferation factor 2) was identified as the target gene of miR-210, and BTG2 overexpression inhibited the proliferation and invasion of LSCC cells. BTG2 knockdown relieved the inhibitory effects of TINCR on the proliferation and invasion of LSCC. Finally, TINCR upregulation slowed xenograft tumour growth in nude mice and significantly increased survival compared with control mice. CONCLUSION: The results of this study suggest that TINCR inhibits the proliferation and invasion of LSCC by regulating the miR-210/BTG2 pathway, participates in cell cycle regulation, and may become a target for the treatment of LSCC.

BACKGROUND: Corticosteroid therapy (CST) prior to biopsy may hinder histopathological diagnosis in primary central nervous system lymphoma (PCNSL). Therefore, preoperative CST in patients with suspected PCNSL should be avoided if clinically possible. The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST. METHODS: A multicenter retrospective study including all immunocompetent patients diagnosed with PCNSL between 1/2004 and 9/2018 at four neurosurgical centers in Austria was conducted and the results were compared to literature. RESULTS: A total of 143 patients were included in this study. All patients showed visible contrast enhancement on preoperative MRI. There was no statistically significant difference in the rate of diagnostic surgeries with and without preoperative CST with 97.1% (68/70) and 97.3% (71/73), respectively (p = 1.0). Tapering and pause of CST did not influence the diagnostic rate. Including our study, there are 788 PCNSL patients described in literature with an odds ratio for inconclusive surgeries after CST of 3.3 (CI 1.7-6.4). CONCLUSIONS: Preoperative CST should be avoided as it seems to diminish the diagnostic rate of biopsy in PCNSL patients. Yet, if CST has been administered preoperatively and there is still a contrast enhancing lesion to target for biopsy, surgeons should try to keep the diagnostic delay to a minimum as the likelihood for acquiring diagnostic tissue seems sufficiently high.

BACKGROUND: Advanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B-cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL. METHODS: COUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life. The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019. DISCUSSION: The COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03474744 . Registration date: 03/23/2018.

BACKGROUND: Radiofrequency ablation (RFA) is an effective treatment option for hepatocellular carcinoma (HCC). This study aimed to analyze the prognostic factors of HCC patients treated with RFA and to develop nomograms for outcome prediction. METHODS: A total of 3142 HCC patients treated with RFA were recruited, and their data were collected from the Surveillance, Epidemiology, and End Results database. Univariate and multifactor Cox analyses were performed to identify independent prognostic factors. These factors were integrated into a nomogram to predict 3- and 5-year cancer-specific survival (CSS) and overall survival (OS). Consistency indices and calibration plots were used to assess the accuracy of the nomograms in both the internal and external cohorts. RESULTS: The median follow-up periods for HCC patients treated with RFA were 27 and 29 months for OS and CSS, respectively. Marital status, age, race, histological grade of differentiation, tumor size, T stage, and serum alpha-fetoprotein levels at the time of diagnosis were identified as prognostic factors for OS and CSS. Additionally, M stage was identified as risk factors for OS. These risk factors are included in the nomogram. The calibration plots of the OS and CSS nomograms showed excellent consistency between actual survival and nomogram predictions. The bootstrap-corrected concordance indices of the OS and CSS nomograms were 0.637 (95% CI, 0.628-0.646) and 0.670 (95% 0.661-0.679), respectively. Importantly, our nomogram performed better discriminatory compared with 8th edition tumor-node-metastasis (TNM) stage system for predicting OS and CSS. CONCLUSIONS: We identified prognostic factors for HCC patients treated with RFA and provided an accurate and personalized survival prediction scheme.

BACKGROUND: This study aimed to explore the risk factors for lymph node metastasis (LNM) in patients with endometrial cancer (EC) and develop a clinically useful nomogram based on clinicopathological parameters to predict it. METHODS: Clinical information of patients who underwent staging surgery for EC was abstracted from Qilu Hospital of Shandong University from January 1st, 2005 to June 31st, 2019. Parameters including patient-related, tumor-related, and preoperative hematologic examination-related were analyzed by univariate and multivariate logistic regression to determine the correlation with LNM. A nomogram based on the multivariate results was constructed and underwent internal and external validation to predict the probability of LNM. RESULTS: The overall data from the 1517 patients who met the inclusion criteria were analyzed. 105(6.29%) patients had LNM. According the univariate analysis and multivariate logistic regression analysis, LVSI is the most predictive factor for LNM, patients with positive LVSI had 13.156-fold increased risk for LNM (95%CI:6.834-25.324; P < 0.001). The nomogram was constructed and incorporated valuable parameters including histological type, histological grade, depth of myometrial invasion, LVSI, cervical involvement, parametrial involvement, and HGB levels from training set. The nomogram was cross-validated internally by the 1000 bootstrap sample and showed good discrimination accuracy. The c-index for internal and external validation of the nomogram are 0.916(95%CI:0.849-0.982) and 0.873(95%CI:0.776-0.970), respectively. CONCLUSIONS: We developed and validated a 7-variable nomogram with a high concordance probability to predict the risk of LNM in patients with EC.

BACKGROUND: Considerable evidence has indicated an association between the immune microenvironment and clinical outcome in ccRCC. The purpose of this study is to extensively figure out the influence of immune-related genes of tumors on the prognosis of patients with ccRCC. METHODS: Files containing 2498 immune-related genes were obtained from the Immunology Database and Analysis Portal (ImmPort), and the transcriptome data and clinical information relevant to patients with ccRCC were identified and downloaded from the TCGA data-base. Univariate and multivariate Cox regression analyses were used to screen out prognostic immune genes. The immune risk score model was established in light of the regression coefficient between survival and hub immune-related genes. We eventually set up a nomogram for the prediction of the overall survival for ccRCC. Kaplan-Meier (K-M) and ROC curve was used in evaluating the value of the predictive risk model. A P value of < 0.05 indicated statistically significant differences throughout data analysis. RESULTS: Via differential analysis, we found that 556 immune-related genes were expressed differentially between tumor and normal tissues (p < 0. 05). The analysis of univariate Cox regression exhibited that there was a statistical correlation between 43 immune genes and survival risk in patients with ccRCC (p < 0.05). Through Lasso-Cox regression analysis, we established an immune genetic risk scoring model based on 18 immune-related genes. The high-risk group showed a bad prognosis in K-M analysis. (p < 0.001). ROC curve showed that it was reliable of the immune risk score model to predict survival risk (5 year over survival, AUC = 0.802). The model indicated satisfactory AUC and survival correlation in the validation data set (5 year OS, Area Under Curve = 0.705, p < 0.05). From Multivariate regression analysis, the immune-risk score model plays an isolated role in the prediction of the prognosis of ccRCC. Under multivariate-Cox regression analysis, we set up a nomogram for comprehensive prediction of ccRCC patients' survival rate. At last, it was identified that 18 immune-related genes and risk scores were not only tremendously related to clinical prognosis but also contained in a variety of carcinogenic pathways. CONCLUSION: In general, tumor immune-related genes play essential roles in ccRCC development and progression. Our research established an unequal 18-immune gene risk index to predict the prognosis of ccRCC visually. This index was found to be an independent predictive factor for ccRCC.

BACKGROUND: Tumor microenvironment (TME) critically contributed to the malignant progression of transformed cells and the chemical responses to chemotherapy reagents. Osteopontin (OPN) is a secretory onco-protein with several splicing isoforms, all of which were known to regulate tumor growth and able to alter cell-cell or cell-TME communication, however, the exact role and regulation of the OPN splicing isoforms was not well understood. METHODS: In this study, the effects of conditioned medium from the culture of OPN splicing isoforms overexpressing cells on cell functions were evaluated. The methods of nuclear calcium reporter assays and subcellular distribution of nuclear factor of activated T cells c2 (NFATc2) assays were used to investigate the molecular mechanism underlining the roles of OPN splicing isoforms. RESULTS: We found that the survival of NSCLC cells treated with cisplatin was increased by secretory OPNc in the condition medium, where reduction of apoptosis by OPNc was associated with the activation of cellular calcium signals and subsequent nuclear translocation of NFATc2. CONCLUSIONS: The results revealed a mechanism of OPN and downstream signal for tumor cells to survive in chemo-stressed TME, which emphasized the importance of secretory proteins in alternative splicing isoforms. Our study not only demonstrated the importance of OPN neutralization for anti-tumor effects, but also implied that modulation in calcium/NFATc2/ROS axis could be a novel approach for improving the long-term outcome of NSCLC treatment.

BACKGROUND: Almost all Koreans are covered by mandatory national health insurance and are required to undergo health screening at least once every 2 years. We aimed to develop a machine learning model to predict the risk of developing hepatocellular carcinoma (HCC) based on the screening results and insurance claim data. METHODS: The National Health Insurance Service-National Health Screening database was used for this study (NHIS-2020-2-146). Our study cohort consisted of 417,346 health screening examinees between 2004 and 2007 without cancer history, which was split into training and test cohorts by the examination date, before or after 2005. Robust predictors were selected using Cox proportional hazard regression with 1000 different bootstrapped datasets. Random forest and extreme gradient boosting algorithms were used to develop a prediction model for the 9-year risk of HCC development after screening. After optimizing a prediction model via cross validation in the training cohort, the model was validated in the test cohort. RESULTS: Of the total examinees, 0.5% (1799/331,694) and 0.4% (390/85,652) in the training cohort and the test cohort were diagnosed with HCC, respectively. Of the selected predictors, older age, male sex, obesity, abnormal liver function tests, the family history of chronic liver disease, and underlying chronic liver disease, chronic hepatitis virus or human immunodeficiency virus infection, and diabetes mellitus were associated with increased risk, whereas higher income, elevated total cholesterol, and underlying dyslipidemia or schizophrenic/delusional disorders were associated with decreased risk of HCC development (p < 0.001). In the test, our model showed good discrimination and calibration. The C-index, AUC, and Brier skill score were 0.857, 0.873, and 0.078, respectively. CONCLUSIONS: Machine learning-based model could be used to predict the risk of HCC development based on the health screening examination results and claim data.

BACKGROUND: As a marker of differentiation, Killer cell lectin like receptor G1 (KLRG1) plays an inhibitory role in human NK cells and T cells. However, its clinical role remains inexplicit. This work intended to investigate the predictive ability of KLRG1 on the efficacy of immune-checkpoint inhibitor in the treatment of lung adenocarcinoma (LUAD), as well as contribute to the possible molecular mechanisms of KLRG1 on LUAD development. METHODS: Using data from the Gene Expression Omnibus, the Cancer Genome Atlas and the Genotype-Tissue Expression, we compared the expression of KLRG1 and its related genes Bruton tyrosine kinase (BTK), C-C motif chemokine receptor 2 (CCR2), Scm polycomb group protein like 4 (SCML4) in LUAD and normal lung tissues. We also established stable LUAD cell lines with KLRG1 gene knockdown and investigated the effect of KLRG1 knockdown on tumor cell proliferation. We further studied the prognostic value of the four factors in terms of overall survival (OS) in LUAD. Using data from the Gene Expression Omnibus, we further investigated the expression of KLRG1 in the patients with different responses after immunotherapy. RESULTS: The expression of KLRG1, BTK, CCR2 and SCML4 was significantly downregulated in LUAD tissues compared to normal controls. Knockdown of KLRG1 promoted the proliferation of A549 and H1299 tumor cells. And low expression of these four factors was associated with unfavorable overall survival in patients with LUAD. Furthermore, low expression of KLRG1 also correlated with poor responses to immunotherapy in LUAD patients. CONCLUSION: Based on these findings, we inferred that KLRG1 had significant correlation with immunotherapy response. Meanwhile, KLRG1, BTK, CCR2 and SCML4 might serve as valuable prognostic biomarkers in LUAD.

BACKGROUND: The molecular pathogenesis of endometrial cancer is not completely understood. CypB upregulated in many cancers, however, its role in endometrial carcinoma has not been studied. Here, we determine the effect of CypB on the growth of endometrial cancer. METHODS: In this study, we examined the expression of CypB in endometrial cancer tissues using immunohistochemistry. CypB silenced in HEC-1-B cell line by shRNA. CCK-8, colony formation assays, wound healing assays, and transwell analysis were performed to assess its effect on tumor cell proliferation and metastasis. Furthermore, microarray analysis was carried out to compare the global mRNA expression profile between the HEC-1-B and CypB-silenced HEC-1-B cells. Gene ontology and KEGG pathway enrichment analysis were performed to determine the potential function of differentially expressed genes related to CypB. RESULTS: We found that CypB was upregulated in endometrial cancer, inhibit CypB expression could significantly suppress cell proliferation, metastasis, and migration. We identified 1536 differentially expressed genes related to CypB (onefold change, p < 0.05), among which 652 genes were upregulated and 884 genes were downregulated. The genes with significant difference in top were mainly enriched in the cell cycle, glycosphingolipid biosynthesis, adherens junctions, and metabolism pathways. CONCLUSION: The results of our study suggest that CypB may serve as a novel regulator of endometrial cell proliferation and metastasis, thus representing a novel target for gene-targeted endometrial therapy. TRIAL REGISTRATION: YLYLLS [2018] 008. Registered 27 November 2017.

BACKGROUND: Increased bone turnover is frequently observed in advanced cancer and predominantly related to bone metastases or therapy. Cachexia represents an important cause of morbidity and mortality in cancer patients. Key features are weight loss, muscle wasting and chronic inflammation, which induce profound metabolic changes in several organs, including the bone. However, whether cachexia contributes to abnormal bone metabolism in cancer patients is unknown. Aim of the present study was to determine the potential correlation of bone turnover markers with body composition and laboratory parameters in treatment-naïve cancer patients. METHODS: In this cross-sectional study we measured the levels of carboxy terminal telopeptide of collagen (CTX), an indicator of bone resorption, as well as osteocalcin (Ocn) and procollagen type I N-terminal propeptide (PINP), indicators of bone formation, in 52 cancer patients and correlated with body composition and laboratory parameters. Univariate and multivariate logistic analysis were performed to identify determinants of negative bone remodeling balance, estimated by CTX/Ocn and CTX/PINP ratio. RESULTS: Based on weight loss, body mass index and muscle mass, patients were divided into a cachectic (59.6%) and a control (40.4%) group. After correcting for the presence of bone metastases, our results showed a significant upregulation of CTX in cachectic patients compared to non-cachectic cancer patients (median 0.38 vs 0.27 ng/mL, p < 0.05), with no difference in Ocn and PINP levels (mean 14 vs. 16 ng/ml, p = 0.2 and median 32 vs. 26 μg/L, p = 0.5, respectively). In addition, the CTX/Ocn and the CTX/PINP ratio were indicative of bone resorption in 68% and 60% of cachexia patients, respectively (vs. 20% and 31% in the control group, p = 0.002 and p = 0.06). The main determinants of the unbalanced bone turnover were hypoalbuminemia for the CTX/Ocn ratio (OR 19.8, p < 0.01) and high CRP for the CTX/PINP ratio (OR 5.3, p < 0.01) in the multivariate regression analysis. CONCLUSIONS: CTX is substantially higher in cachectic patients compared to non-cachectic oncological patients and hypoalbuminemia as well as elevated CRP concentrations are independent predictors of a negative bone remodeling balance in cancer patients. These results strongly indicate that cachexia correlates with exacerbated bone turnover in cancer.

BACKGROUND: BRE-AS1 is a recently identified tumor suppressor in non-small cell lung cancer. It role in other human diseases remains elusive. METHODS: Differential expression of BRE-AS1 in with triple-negative breast cancer (TNBC) patients (n = 74, patient group) and healthy volunteers (n = 58, control group) was studied with RT-qPCR. The direct interaction between BRE-AS1 and premature microRNA-21 (miR-21) was assessed by RNA pull-down assay. The interactions among BRE-AS1, miR-21 and PTEN were evaluated by overexpression assays. CCK-8 assay and Transwell assay were used to evaluate cell behaviors. RESULTS: BRE-AS1 was downregulated in TNBC, while miR-21 was highly expressed in TNBC. Low expression levels of lncRNA BRE-AS1 and high expression levels of miR-21 were significantly correlated with unfavorable survival outcomes. BRE-AS1 and miRNA-21 were inversely correlated across TNBC samples, not control samples. BRE-AS1 decreased miR-21 expression and increased PTEN expression while miR-21showed no role in BRE-AS1 expression. RNA pull-down assay illustrated that BRE-AS1 may sponge premature miR-21 to suppress it maturation. Overexpression of BRE-AS1 decreased cell behaviors, while overexpression of miR-21 promoted cell behaviors. MiR-21 suppressed the role of BRE-AS1 in cancer cell behaviors. CONCLUSION: Therefore, BRE-AS1 may inhibit TNBC by downregulating miR-21.

BACKGROUND: Carnitine is related to malaise, and cisplatin is associated with decreased carnitine. The purpose of this study was to elucidate the effects of one course of induction chemotherapy (IC) for head and neck cancer on blood carnitine levels, focusing on free carnitine (FC). METHODS: This single-center prospective study investigated 20 patients diagnosed with primary head and neck cancer who underwent IC with cisplatin, docetaxel, and 5-fluorouracil. FC, acylcarnitine (AC), and total carnitine (TC) levels were measured before starting therapy and on Days 7 and 21 after starting IC. In addition, malaise was evaluated before and after therapy using a visual analog scale (VAS). RESULTS: All subjects were men and the most common primary cancer site was the hypopharynx (9 patients). FC levels before starting therapy and on Days 7 and 21 were 47.7 ± 2.2 μM/mL, 56.7 ± 2.2 μM/mL, and 41.1 ± 1.9 μM/mL, respectively. Compared with the baseline before starting therapy, FC had significantly decreased on Day 21 (p = 0.007). AC levels before starting therapy and on Days 7 and 21 were 12.5 ± 1.2 μM/mL, 13.6 ± 1.4 μM/mL, and 10.7 ± 0.7 μM/mL, respectively. TC levels before starting therapy and on Days 7 and 21 were 60.2 ± 2.5 μM/mL, 70.2 ± 3.3 μM/mL, and 51.7 ± 2.3 μM/mL, respectively. No significant differences in AC, TC or VAS were seen before the start of therapy and on Day 21. CONCLUSIONS: After IC, a latent decrease in FC occurred without any absolute deficiency or subjective malaise.

BACKGROUND: Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. METHODS/DESIGN: In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. DISCUSSION: Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a "chronic disease" will be distinguished from "high-risk" cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019-001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36.

BACKGROUND: To investigate the efficacy and safety of interval debulking surgery (IDS) combined with dense hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin in Chinese patients with FIGO stage III serous epithelial ovarian cancer (EOC). METHODS: This retrospective single-center study reviewed the demographic and clinical data of 197 patients with primary FIGO stage III serous EOC who were treated with IDS with (n = 121) or without (n = 76, control group) dense HIPEC between January 2012 and April 2017. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was the occurrence of adverse events. RESULTS: The median PFS was 24 months in the IDS plus dense HIPEC group, whereas it was 19 months in the IDS alone group (hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.33-0.65, p = 0.000). The median OS in patients treated with IDS plus dense HIPEC (51 months) was significantly longer than that in patients treated with IDS alone (40 months, HR 0.52, 95% CI: 0.35-0.78, p = 0.001). The demographic and preoperative clinical characteristics of these two groups were comparable (p > 0.05). In the IDS alone group, no adverse events were recorded in 42 (55.3%) of the 76 patients, and 14 (18.4%) patients were reported to have grade III/IV adverse events. In the IDS plus dense HIPEC group, no adverse events were recorded in 55 (45.5%) of the 121 patients, and 23 (19.0%) patients were reported to have grade III/IV adverse events. No postoperative deaths occurred within 30 days in either group and neither did severe fatal complications in the IDS plus dense HIPEC group. CONCLUSIONS: IDS plus dense HIPEC with cisplatin in Chinese patients with FIGO stage III serous EOC is associated with improved survival and is reasonably well tolerated by patients.

BACKGROUND: NUT carcinoma (NC), previously known as NUT midline carcinoma, is a rare and very aggressive cancer that occurs in both children and adults. NC is largely chemoresistant, with an overall survival of less than 7 months. Because the carcinoma is not restricted to a particular organ, diagnosis is often a challenge. In the absence of a clearly determined incidence for NC, we sought to study the diagnosis of patients in a well-defined population. METHODS: We systematically reviewed records of all patients that presented to the Oncology Department of the Princess Margaret Hospital for Children from 1989 to 2014. This institution in the geographically isolated state of Western Australia has a catchment population of around 2 million. We then identified all high grade undifferentiated sarcomas or carcinomas in the 0-16 year age group. RESULTS: Over 26 years, we found 14 patients of 16 years or younger with undifferentiated malignant tumors. Of these, five tumors were positive by immunohistochemistry for the NUT/NUTM1 (Nuclear Protein in Testis) protein and/or the translocation t(15;19). Three patients presented with thoracic tumors, one with a para-spinal tumor, and one had an upper airway nasopharyngeal carcinoma. In all five cases, there was an initial response to therapy and then progression. This 26-year survey was conducted in a geographically isolated state with a well-defined population, and we determined an estimated incidence of NC of around 0.41 per million child years (0-16 yrs. of age) at risk. From three patients it was feasible to derive cell lines for further genetic analyses and drug screening. CONCLUSIONS: For the first time, the incidence of NC could be determined in a well-defined geographic area. The calculated rate of NC incidence is consistent with a history of under-recognition for this malignancy. These findings indicate that improved diagnostic detection of NC would enable better management and counselling of patients. Our findings emphasize the heterogeneity of NC, and they highlight the need to develop personalised therapy options, and to consider a diagnosis of NC in undifferentiated malignant tumors.

BACKGROUND: From patient-reported surveys and individual interviews by health care providers, we attempted to identify the significant factors related to the improvement of distress and fatigue for cancer survivors by text analysis with machine learning techniques, as the secondary analysis using the single institute data from the Korean Cancer Survivorship Center Pilot Project. METHODS: Surveys and in-depth interviews from 322 cancer survivors were analyzed to identify their needs and concerns. Among the keywords in the surveys, including EQ-VAS, distress, fatigue, pain, insomnia, anxiety, and depression, distress and fatigue were focused. The interview transcripts were analyzed via Korean-based text analysis with machine learning techniques, based on the keywords used in the survey. Words were generated as vectors and similarity scores were calculated by the distance related to the text's keywords and frequency. The keywords and selected high-ranked ten words for each keyword based on the similarity were then taken to draw a network map. RESULTS: Most participants were otherwise healthy females younger than 50 years suffering breast cancer who completed treatment less than 6 months ago. As the 1-month follow-up survey's results, the improved patients were 56.5 and 58.4% in distress and fatigue scores, respectively. For the improvement of distress, dyspepsia (p = 0.006) and initial scores of distress, fatigue, anxiety, and depression (p < 0.001, < 0.001, 0.043, and 0.013, respectively) were significantly related. For the improvement of fatigue, economic state (p = 0.021), needs for rehabilitation (p = 0.035), initial score of fatigue (p < 0.001), any intervention (p = 0.017), and participation in family care program (p = 0.022) were significant. For the text analysis, Stress and Fatigue were placed at the center of the keyword network map, and words were intricately connected. From the regression anlysis combined survey scores and the quantitative variables from the text analysis, participation in family care programs and mention of family-related words were associated with the fatigue improvement (p = 0.033). CONCLUSION: Common symptoms and practical issues were related to distress and fatigue in the survey. Through text analysis, however, we realized that the specific issues and their relationship such as family problem were more complicated. Although further research needs to explore the hidden problem in cancer patients, this study was meaningful to use personalized approach such as interviews.

BACKGROUND: The health burden of breast cancer is rising in China. The effect of informed diagnosis on long-term survival is not fully understood. This retrospective cohort study aims to explore the association between early informed diagnosis and survival time in breast cancer patients. METHODS: A total of 12,327 breast cancer patients were enrolled between October 2002 and December 2016. Potential factors, including knowing the cancer diagnosis status, sex, age, clinical stage, surgery history, grade of reporting hospital and diagnostic year were, analyzed. We followed up all participants every 6 months until June 2017. Propensity score matching (PSM) was used to balance the clinicopathologic characteristics between patients who knew their diagnosis and those who did not. RESULTS: By June 2017, 18.04% of the participants died of breast cancer. Before PSM, both the 3-year and 5-year survival rates of patients who knew their cancer diagnosis were longer (P < 0.001). After PSM, the above conclusion was still established. By stratified analysis, except for the subgroups of male patients and stage III patients, patients who knew their diagnosis showed a better prognosis in all the other subgroups (P < 0.05). Cox regression analysis showed that knowing a cancer diagnosis was an independent risk factor for survival in breast cancer patients (P < 0.001). CONCLUSIONS: Being aware of their cancer diagnosis plays a protective role in extending the survival time of breast cancer patients, which suggests that medical staff and patients' families should disclose the cancer diagnosis to patients in a timely manner. Further prospective studies need to be made to validate our findings.

BACKGROUND: Tracheobronchial adenoid cystic carcinoma (TACC) is a rare tumour. About one-third of patients miss their chance of surgery or complete resection as it is mostly detected in the advanced stage; hence, photon radiotherapy (RT) is used. However, the outcomes of photon RT remain unsatisfactory. Carbon ion radiotherapy (CIRT) is thought to improve the therapeutic gain ratio; however, the outcomes of CIRT in TACC are unclear. Therefore, we aimed to assess the effects and toxicities of CIRT in patients with TACC. METHODS: The inclusion criteria were as follows: 1) age 18-80 years; 2) Eastern Cooperative Oncology Group Performance Status 0-2; 3) histologically confirmed TACC; 4) stage III-IV disease; 5) visible primary tumour; and 6) no previous RT history. The planned prescription doses of CIRT were 66-72.6 GyE/22-23 fractions. The rates of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Treatment-induced toxicities and tumour response were scored according to the Common Terminology Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors, respectively. RESULTS: Eighteen patients with a median age of 48 (range 30-73) years were enrolled. The median follow-up time was 20.7 (range 5.8-44.1) months. The overall response rate was 88.2%. Five patients developed lung metastasis after 12.2-41.0 months and one of them experienced local recurrence at 31.9 months after CIRT. The rates of 2-year OS, LC, and PFS were 100, 100, and 61.4%, respectively. Except for one patient who experienced grade 4 tracheal stenosis, which was relieved after stent implantation, no other ≥3 grade toxicities were observed. CONCLUSIONS: CIRT might be safe and effective in the management of TACC based on a short observation period. Further studies with more cases and longer observation are warranted.

BACKGROUND: A primary pulmonary invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive adenocarcinoma of the lung. The prognosis of advanced IMA depending on chemotherapy regimen has not been fully investigated. Here, we compared the clinical outcomes of patients with advanced IMA treated with different palliative chemotherapies that included novel therapeutics. METHODS: This single-center retrospective study included a total of 79 patients diagnosed with IMA and treated with palliative chemotherapy. The primary outcome was the comparison of overall survival according to palliative chemotherapy type. Risk factors associated with death were evaluated as a secondary outcome. RESULTS: The study cohort of 79 patients comprised 27 progressive or recurrent cases and 52 initial metastatic patients. Thirteen patients (16.5%) received targeted therapy and 18 cases (22.8%) received immunotherapy. When we compared the survival outcomes of the different treatment regimens, patients with IMA treated by immunotherapy (undefined vs. non-immunotherapy 17.0 months, p < 0.001) had better overall survival rates. However, there was no difference in the prognosis between the cases treated with a targeted therapy (35.6 vs. non-targeted therapy 17.0 months, p = 0.211). None of the conventional regimens produced a better outcome. By multivariable analysis, immunotherapy (HR 0.28; 95% CI 0.11-0.74; P = 0.008) was found to be an independent prognostic factor for death. CONCLUSIONS: This study suggests that immunotherapy for patients with advanced IMA may provide favorable outcomes than other chemotherapy options.

BACKGROUND: Ductal carcinoma in situ (DCIS) patients are usually diagnosed through cancer screening programs, suggesting a healthy user effect. In this population-based cohort, we assessed the risk of cardiovascular events and mortality in DCIS patients. METHODS: Using the Korean National Health Insurance Service database, 13,740 women, who were initially diagnosed with DCIS between 2007 and 2013, were analyzed. A control group was matched according to age and the year of diagnosis at a 3:1 ratio (n = 41,220). Follow-up was performed until 2016. Subgroup analysis was performed according to the subsequent diagnosis of invasive breast cancer within 1 year: pure DCIS and DCIS+Invasive group. RESULTS: DCIS patients were more likely to have underlying diseases, higher incomes, and to live in urban districts compared to the control group. Women diagnosed of DCIS had lower myocardial infarct risk (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.46-0.90) and lower stroke risk (HR 0.77; 95% CI 0.60-0.98) compared to the control group. This trend of lower risk was sustained after adjusting for age, income, residence and comorbidities. The mortality rate was similar between the control group and pure DCIS patients but was higher in the DCIS+Invasive group (HR 1.63; 95% CI 1.34-1.98). However, after adjusting for age, income, residence and comorbidities, mortality did not differ between the control group and DCIS+Invasive group (HR 0.99; 95% CI 0.78-1.24). CONCLUSIONS: DCIS patients were at lower risk for MI and stroke compared to a control group despite a higher rate of comorbidities, which may reflect changes in health behaviour. The importance of managing pre-existing comorbidities along with DCIS treatment should be emphasized.

BACKGROUND: The Oncotype DX 21-gene Recurrence Score is predictive of adjuvant chemotherapy benefit for women with early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. In premenopausal women, fluctuations in estrogen and progesterone during the menstrual cycle impact gene expression in hormone-responsive cancers. However, the extent to which menstrual cycling affects the Oncotype DX 21-gene signature remains unclear. Here, we investigate the impact of ovarian cycle stage on the 21-gene signature using a naturally cycling mouse model of breast cancer. METHODS: ER-positive mammary tumours were dissected from naturally cycling Mmtv-Pymt mice at either the estrus or diestrus phase of the ovarian cycle. The Oncotype DX 21-gene signature was assessed through quantitative real time-PCR, and a 21-gene experimental recurrence score analogous to the Oncotype DX Recurrence Score was calculated. RESULTS: Tumours collected at diestrus exhibited significant differences in expression of 6 Oncotype DX signature genes (Ki67, Ccnb1, Esr1, Erbb2, Grb7, Bag1; p ≤ 0.05) and a significant increase in 21-gene recurrence score (21.8 ± 2.4; mean ± SEM) compared to tumours dissected at estrus (15.5 ± 1.9; p = 0.03). Clustering analysis revealed a subgroup of tumours collected at diestrus characterised by increased expression of proliferation- (p < 0.001) and invasion-group (p = 0.01) genes, and increased 21-gene recurrence score (p = 0.01). No correlation between ER, PR, HER2, and KI67 protein abundance measured by Western blot and abundance of mRNA for the corresponding gene was observed, suggesting that gene expression is more susceptible to hormone-induced fluctuation compared to protein expression. CONCLUSIONS: Ovarian cycle stage at the time of tissue collection critically affects the 21-gene signature in Mmtv-Pymt murine mammary tumours. Further studies are required to determine whether Oncotype DX Recurrence Scores in women are similarly affected by menstrual cycle stage.

BACKGROUND: This study aimed to explore and identify key genes and signaling pathways that contribute to the progression of cervical cancer to improve prognosis. METHODS: Three gene expression profiles (GSE63514, GSE64217 and GSE138080) were screened and downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) were screened using the GEO2R and Venn diagram tools. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Gene set enrichment analysis (GSEA) was performed to analyze the three gene expression profiles. Moreover, a protein-protein interaction (PPI) network of the DEGs was constructed, and functional enrichment analysis was performed. On this basis, hub genes from critical PPI subnetworks were explored with Cytoscape software. The expression of these genes in tumors was verified, and survival analysis of potential prognostic genes from critical subnetworks was conducted. Functional annotation, multiple gene comparison and dimensionality reduction in candidate genes indicated the clinical significance of potential targets. RESULTS: A total of 476 DEGs were screened: 253 upregulated genes and 223 downregulated genes. DEGs were enriched in 22 biological processes, 16 cellular components and 9 molecular functions in precancerous lesions and cervical cancer. DEGs were mainly enriched in 10 KEGG pathways. Through intersection analysis and data mining, 3 key KEGG pathways and related core genes were revealed by GSEA. Moreover, a PPI network of 476 DEGs was constructed, hub genes from 12 critical subnetworks were explored, and a total of 14 potential molecular targets were obtained. CONCLUSIONS: These findings promote the understanding of the molecular mechanism of and clinically related molecular targets for cervical cancer.

BACKGROUND: The more selective second-generation BTK inhibitors (BTKi) Acalabrutinib and Zanubrutinib and the first-generation BTKi Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKi with distinct binding selectivity against BTK remain largely unknown. METHODS: AlamarBlue assays were performed to define cytotoxicity of BTKi against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKi on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis. RESULTS: Acalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A, and ATM, in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKi similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences. CONCLUSION: BTKi demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

BACKGROUND: Tryptophan 2,3-dioxygenase (TDO2) is the primary enzyme catabolizing tryptophan. Several lines of evidence revealed that overexpression of TDO2 is involved in anoikis resistance, spheroid formation, proliferation, and invasion and correlates with poor prognosis in some cancers. The aim of this research was to uncover the expression and biofunction of TDO2 in renal cell carcinoma (RCC). METHODS: To show the expression of TDO2 in RCC, we performed qRT-PCR and immunohistochemistry in integration with TCGA data analysis. The interaction of TDO2 with PD-L1, CD44, PTEN, and TDO2 expression was evaluated. We explored proliferation, colony formation, and invasion in RCC cells line affected by knockdown of TDO2. RESULTS: RNA-Seq and immunohistochemical analysis showed that TDO2 expression was upregulated in RCC tissues and was associated with advanced disease and poor survival of RCC patients. Furthermore, TDO2 was co-expressed with PD-L1 and CD44. In silico analysis and in vitro knockout of PTEN in RCC cell lines revealed the ability of PTEN to regulate the expression of TDO2. Knockdown of TDO2 suppressed the proliferation and invasion of RCC cells. CONCLUSION: Our results suggest that TDO2 might have an important role in disease progression and could be a promising marker for targeted therapy in RCC. (199 words).

BACKGROUND: Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments. METHODS: We performed a systematic review to evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs). RESULTS: The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection. CONCLUSIONS: This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population.

BACKGROUND: The tumour-stroma ratio (TSR) is recognized as a practical prognostic factor in colorectal cancer. However, TSR assessment generally utilizes surgical specimens. This study aims to investigate whether the TSR evaluated from preoperative biopsy specimens by a semi-automatic quantification method can predict the response after neoadjuvant chemoradiotherapy (nCRT) of patients with locally advanced rectal cancer (LARC). METHODS: A total of 248 consecutive patients diagnosed with LARC and treated with nCRT followed by resection were included. Haematoxylin and eosin (HE)-stained sections of biopsy specimens were collected, and the TSR was evaluated by a semi-automatic quantification method and was divided into three categories, using the cut-offs determined in the whole cohort to balance the proportion of patients in each category. The response to nCRT was evaluated on the primary tumour resection specimen by an expert pathologist using the four-tier tumour regression grade (TRG) system. RESULTS: The TSR can discriminate patients that are major-responders (TRG 0-1) from patients that are non-responders (TRG 2-3). Patients were divided into stroma-low (33.5%), stroma-intermediate (33.9%), and stroma-high (32.7%) groups using 56.3 and 72.8% as the cutoffs. In the stroma-low group, 58 (69.9%) patients were major-responders, and only 39 (48.1%) patients were considered major-responders in the stroma-high group (P = 0.018). Multivariate analysis showed that the TSR was the only pre-treatment predictor of response to nCRT (adjusted odds ratio 0.40, 95% confidence interval 0.21-0.76, P = 0.002). CONCLUSION: An elevated TSR in preoperative biopsy specimens is an independent predictor of nCRT response in LARC. This semi-automatic quantified TSR could be easily translated into routine pathologic assessment due to its reproducibility and reliability.

BACKGROUND: It has been demonstrated that postmastectomy radiation therapy (PMRT) was beneficial for breast cancer patients who are axillary lymph node-positive. However, the effectiveness of radiotherapy in pathological negative nodes (ypN0) after neoadjuvant chemotherapy (NAC) remains open to considerable debate. Here, we aim to evaluate whether PMRT improves loco-regional control and survival for such patients. METHODS: The literature from January 2004 to June 2019 was searched. The effects of PMRT on local-regional recurrence (LRR) and survival was evaluated in a meta-analysis. Pooled relative risk (RR) values with 95% confidence intervals (CIs) were computed using random and fixed-effect model. Subgroup and heterogeneity analyses were also conducted. RESULTS: Twelve studies that included 17,747 patients met the inclusion criteria. Pooled results showed that PMRT was associated with reduced LRR (RR, 0.38; 95% CI, 0.19-0.77, P = 0.007), particularly in patients with stage III breast cancer (RR, 0.16; 95% CI, 0.07-0.37, P < 0.001). However, no significant difference in disease-free survival were observed with the addition of PMRT for ypN0 patients (RR, 0.70; 95% CI, 0.21-2.27, P = 0.55). Also, there was no statistically significant association between radiotherapy with overall survival (RR, 0.81; 95% CI, 0.64-1.04, P = 0.10). CONCLUSIONS: Our meta-analysis indicated that PMRT might reduce local-regional recurrence for ypN0 patients after NAC, but lack of benefit for survival outcomes. Prospective randomized clinical trial data will be needed to confirm our results.

BACKGROUND: There is evidence that long non-coding RNA (lncRNA) is related to genetic stability. However, the complex biological functions of these lncRNAs are unclear. METHOD: TCGA - KIRC lncRNAs expression matrix and somatic mutation information data were obtained from TCGA database. "GSVA" package was applied to evaluate the genomic related pathway in each samples. GO and KEGG analysis were performed to show the biological function of lncRNAs-mRNAs. "Survival" package was applied to determine the prognostic significance of lncRNAs. Multivariate Cox proportional hazard regression analysis was applied to conduct lncRNA prognosis model. RESULTS: In the present study, we applied computational biology to identify genome-related long noncoding RNA and identified 26 novel genomic instability-associated lncRNAs in clear cell renal cell carcinoma. We identified a genome instability-derived six lncRNA-based gene signature that significantly divided clear renal cell samples into high- and low-risk groups. We validated it in test cohorts. To further elucidate the role of the six lncRNAs in the model's genome stability, we performed a gene set variation analysis (GSVA) on the matrix. We performed Pearson correlation analysis between the GSVA scores of genomic stability-related pathways and lncRNA. It was determined that LINC00460 and LINC01234 could be used as critical factors in this study. They may influence the genome stability of clear cell carcinoma by participating in mediating critical targets in the base excision repair pathway, the DNA replication pathway, homologous recombination, mismatch repair pathway, and the P53 signaling pathway. CONCLUSION SUBSECTIONS: These data suggest that LINC00460 and LINC01234 are crucial for the stability of the clear cell renal cell carcinoma genome.

Author information: (1)Registre général des cancers de Poitou-Charentes, Pôle Biologie, Pharmacie et Santé Publique, CHU de Poitiers, Poitiers, France. gautier.defossez@univ-poitiers.fr. (2)Université de Poitiers, Bâtiment D1, 6 rue de la Milétrie, 86073, Poitiers, France. gautier.defossez@univ-poitiers.fr. (3)INSERM Centre d'Investigation Clinique CIC1402, Poitiers, France. gautier.defossez@univ-poitiers.fr. (4)Réseau français des registres des cancers, Francim, Toulouse, France. gautier.defossez@univ-poitiers.fr. (5)Direction des Maladies Non Transmissibles et des Traumatismes, Santé publique France, Saint-Maurice, France. (6)Service de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France. (7)Université de Lyon, Lyon, France. (8)Université Lyon 1, Villeurbanne, France. (9)Équipe Biostatistique-Santé, Laboratoire de Biométrie et Biologie Évolutive, CNRS, UMR 5558, Villeurbanne, France. (10)Réseau français des registres des cancers, Francim, Toulouse, France. (11)Registre des cancers de l'Isère, CHU de Grenoble Alpes, Grenoble, France. (12)Registre des cancers de la Haute-Vienne, CHU de Limoges, Limoges, France. (13)Registre général des cancers de Lille et de sa région, Centre de Référence Régional en Cancérologie (C2RC), Lille, France. (14)Registre Bourguignon des cancers digestifs, Université de Dijon, Dijon, France. (15)Registre des tumeurs de Loire-Atlantique et Vendée, CHU de Nantes, Nantes, France. (16)Registre des tumeurs du Doubs, CHU de Besançon, Besançon, France. (17)EA 3181, Université de Bourgogne Franche-Comté, Besançon, France. (18)Registre des cancers du Tarn, Institut Claudius Regaud, Toulouse, France. (19)Institut Universitaire du Cancer de Toulouse Oncopole (IUCTO), Toulouse, France. (20)Registre des hémopathies malignes de Gironde, Institut Bergonié, Bordeaux, France. (21)INSERM U219 (équipe EPICENE), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université de Bordeaux, Bordeaux, France.

BACKGROUND: Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). METHODS: The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. RESULTS: Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. CONCLUSION: TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

BACKGROUND: Surgery is still the mainstay of radical treatment for resectable esophageal cancer (EC). It is apparent that the presence or spread of lymph node metastasis (LNM) is a powerful prognostic factor in patients with EC who are eligible for curative treatment. Although the importance and efficacy of lymph node dissection in radical esophagectomy have been reported, the clinical or prognostic relevance of specific metastatic patterns within the mediastinal cavity and abdomen remains unclear. METHODS: We retrospectively analyzed the association of postoperative survival with clinical mediastinal LNM (cMLNM) and abdominal LNM (cALNM) in 157 patients who underwent radical EC surgery at our hospital between May 2012 and March 2018. RESULTS: A significant difference in cause-specific survival (CSS) was observed between patients with and without cALNM (log-rank p = 0.000). A multivariate Cox regression analysis revealed that cALNM and thoracic surgery (mediastinal lymphadenectomy via conventional open right thoracotomy or video-assisted thoracoscopic surgery) independently predicted CSS (p = 0.0007 and 0.021, respectively). Moreover, a significant difference in systemic recurrence-free survival was observed between those with and without cALNM (log-rank p = 0.000). Multivariate Cox regression analysis revealed that cALNM and sex independently predicted systemic recurrence-free survival (p = 0.000 and 0.015, respectively). CONCLUSION: cALNM was an independent poor prognostic factor for CSS after EC surgery. It may also be an independent prognostic factor for postoperative systemic recurrence, which can shorten the CSS. For patients with cALNM-positive EC who have a high potential risk of systemic metastases, more extensive treatment besides the conventional perioperative systemic chemotherapy may be necessary.

BACKGROUND: Cancer registries usually assess data of conventional treatments and/or patient survival. Beyond that, little is known about the influence of other predictors of treatment response related to the use of complementary therapies (CM) and lifestyle factors affecting patients' quality and quantity of life. METHODS: INTREST is a prospective cohort study collecting register data at multiple German certified cancer centers, which provide individualized, integrative, in- and outpatient breast cancer care. Patient-reported outcomes and clinical cancer data of anticipated N = 715 women with pTNM stage I-III breast cancer are collected using standardized case report forms at the time of diagnosis, after completing neo-/adjuvant chemotherapy, after completing adjuvant therapy (with the exception of endocrine therapy) as well as 1, 2, 5, and 10 years after baseline. Endpoints for multivariable prediction models are quality of life, fatigue, treatment adherence, and progression-based outcomes/survival. Predictors include the study center, sociodemographic characteristics, histologic cancer and comorbidity data, performance status, stress perception, depression, anxiety, sleep quality, spirituality, social support, physical activity, diet behavior, type of conventional treatments, use of and belief in CM treatments, and participation in a clinical trial. Safety is recorded following the Common Terminology Criteria for Adverse Events. DISCUSSION: This trial is currently recruiting participants. Future analyses will allow to identify predictors of short- and long-term response to integrative breast cancer treatment in women, which, in turn, may improve cancer care as well as quality and quantity of life with cancer. TRIAL REGISTRATION: German Clinical Trial Register DRKS00014852 . Retrospectively registered at July 4th, 2018.

BACKGROUND: Most NSCLCs metastasised out of the lungs at the time of diagnosis and cannot be surgically removed . Cytotoxic chemotherapy drugs have become the main treatment in recent decades, especially in patients with NSCLC without EGFR, ALK, and ROS gene mutations. The prognosis of lung cancer is poor, and the overall 5-year survival rate is only 9-13%. Therefore the treatment of advanced NSCLC remains a significant medical need. Recent studies have shown a significant relationship between the gut-lung axis microecology and malignant tumors. Intestinal probiotics are likely to play a role in inhibiting tumorigenesis through "intestinal-pulmonary axis microecological regulation". This study will seek to investigate the efficacy of "Microbiota modulation of the Gut-Lung Axis" combined with chemotherapy in patients with advanced NSCLC. METHODS: The research is a multicenter, prospective, double blind, placebo controlled, randomized trial. Based on the theoretical basis of "intestinal and lung axis microecological adjustment", combined with traditional platinum-containing two-drug chemotherapy, the efficacy of the new therapy on patients with advanced NSCLC was observed. Collect the basic information of the patient, and study the effect of platinum-based combined chemotherapy on the diversity of intestinal flora in patients with lung cancer after receiving chemotherapy treatment, feces before and after chemotherapy, and the status and extent of adverse reactions during chemotherapy . A total of 180 subjects were included, divided into a control group (platinum-containing dual-drug chemotherapy) and an intervention group (platinum-containing dual-drug chemotherapy combined with Bifico), and were randomly assigned to the group 1:1. DISCUSSION: As a result, intestinal-pulmonary microecological balance could become a new target for the treatment of lung cancer. This study explores the combination of intestinal microecological regulation and chemotherapy to provide new treatment strategies and basis for lung cancer patients. It can help prolong the survival time of lung cancer patients and improve the quality of life, thereby generating huge economic and social benefits. The results can be promoted and applied to units engaged in the treatment of lung cancer. TRIAL REGISTRATION NUMBER: NCT03642548, date: August 22, 2018, the first version protocol. The URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03642548?term=NCT03642548&draw=2&rank=1 .

BACKGROUND: The optimal treatment volume for Glioblastoma multiforme (GBM) is still a subject of debate worldwide. The current study was aimed to determine the distances between recurring tumors and the edge of primary lesions, and thereby provide evidence for accurate target area delineation. METHODS: Between October 2007 and March 2019, 68 recurrent patients with GBM were included in our study. We measured the distance from the initial tumor to the recurrent lesion of GBM patients by expanding the initial gross tumor volume (GTV) to overlap the center of recurrent lesion, with the help of the Pinnacle Treatment Planning System. RESULTS: Recurrences were local in 47(69.1%) patients, distant in 12(17.7%) patients, and both in 9(13.2%) patients. Factors significantly influencing local recurrence were age (P = 0.049), sex (P = 0.049), and the size of peritumoral edema (P = 0.00). A total number of 91 recurrent tumors were analyzed. All local recurrences occurred within 2 cm and 94.8% (55/58) occurred within 1 cm of the original GTV based on T1 enhanced imaging. All local recurrences occurred within 1.5 cm and 98.3%(57/58) occurred within 0.5 cm of the original GTV based on T2-FLAIR imaging. 90.9% (30/33) and 81.8% (27/33) distant recurrences occurred >3 cm of T1 enhanced and T2-Flair primary tumor margins, respectively. CONCLUSIONS: The 1 cm margin from T1 enhanced lesions and 0.5 cm margin from T2-Flair abnormal lesions could cover 94.8 and 98.3% local recurrences respectively, which deserves further prospective study as a limited but effective target area.

BACKGROUND: Pyruvate carboxylase (PC) is an important anaplerotic enzyme in the tricarboxylic acid cycle (TCA) in cancer cells. Although PC overexpression has been observed in thyroid cancer (TC), the mechanisms involved in the carcinogenic effects of PC are still unclear. METHODS: Bioinformatics analysis and clinical specimens were used to analyze the relationship of PC expression with clinicopathological variables in TC. Fatty acid synthesis was monitored by LC/MS, Nile red staining, and triglyceride analysis. Mitochondrial oxygen consumption was evaluated by the Seahorse XF Mito Cell Stress Test. The correlation of PC with FASN and SREBP1c was assessed by qRT-PCR and IHC in 38 human TC tissues. Western blotting was used to evaluate the protein expression of PC, FASN, and SREBP1c and members of the AKT/mTOR and EMT pathways in TC cell lines. Wound-healing, CCK-8, and Transwell assays and a nude mouse xenograft model were used to verify the regulatory effects of PC and SREBP1c on thyroid tumor cell proliferation, migration and invasion. RESULTS: We demonstrated that PC increased fatty acid synthesis, which then promoted TC progression and metastasis. Analysis of GEO data showed that the overexpression of PC in papillary thyroid cancer (PTC) was associated with PTC invasion and the fatty acid synthesis pathway. Analysis of clinical tissue specimens from PTC patients revealed that PC was more highly expressed in specimens from PTC patients with lymph node metastasis than in those from patients without metastasis. Multiple genes in the fatty acid synthesis signaling pathway, including FASN and SREBP1c, were downregulated in PC-knockdown TC cells compared to control cells. Lipid levels were also decreased in the PC-knockdown TC cells. Moreover, the ability of cells to grow, invade, and metastasize was also suppressed upon PC knockdown, suggesting that PC-mediated lipogenesis activation increases the aggressiveness of TC cells. In addition, PC was found to activate the AKT/mTOR pathway, thus improving FASN-mediated de novo lipogenesis in TC cells by upregulating SREBP1c expression. Studies in a nude mouse xenograft model showed that PC knockdown decreased tumor weight, but this effect was attenuated by forced expression of SREBP1c. CONCLUSIONS: Our results demonstrate that PC is strongly involved in the tumor aggressiveness of TC via its stimulation of fatty acid synthesis.

BACKGROUND: The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. METHODS: We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. RESULTS: Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95-5.92] L h- 1 and central volume of distribution of 4.29 [1.81-7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7-25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. CONCLUSION: A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

PURPOSE: To evaluate the effectiveness and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during chemoradiotherapy in patients with cervical cancer. METHODS: From August 2018 to April 2020, 60 patients who were pathologically confirmed as cervical cancer were randomly divided into two groups at a ratio of 2:1: PEG-modified-rhG-CSF experimental group and control group. The primary endpoints were the incidence of grade 3-4 neutropenia. Secondary endpoints included the duration of grade 3-4 neutropenia, the incidence of grade 4 neutropenia, the incidence of febrile neutropenia (FN), delay rate of chemotherapy, prolonged time of chemotherapy, time to complete radiotherapy and safety. RESULTS: The incidence of grade 3-4 neutropenia in the experimental group was significantly lower than the control group (10% vs. 77.78%, P < 0.001). However, there was no statistical significance between the two groups in the duration of grade 3-4 neutropenia (3.75 days vs. 5.07 days, P = 0.871). The experimental group was better than the control group in the incidence of grade 4 neutropenia, the incidence of FN and delay rate of chemotherapy, and the difference was statistically significant (P < 0.05). Besides, the prolonged time of chemotherapy and the time to complete radiotherapy in the experimental group were less than those in the control group, but the difference was not statistically significant (P > 0.05). The incidence of adverse events in the experimental group and control group were 55.00 and 94.44%, respectively, and the difference was statistically significant (P = 0.003). CONCLUSION: PEG-rhG-CSF preventive treatment used in the course of chemoradiotherapy for patients with cervical cancer can reduce the incidence of neutropenia and improve the incidence of delayed chemotherapy cycles. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04542356 . Registered 9 September 2020 - Retrospectively registered.

BACKGROUND: Head and Neck Cancer (HNC) survivors are at increased risk of developing a second primary cancer (SPC). Along with the environmental risk factors, genetic factors have been associated with a potential increased susceptibility to SPC development. We aim to identify the Single Nucleotide Polymorphisms (SNPs) that contribute to SPC development among HNC survivors through a systematic review and meta-analysis. METHODS: We searched PubMed, Scopus and ISI Web of Science for eligible studies published in English until January 31st, 2020. We included studies reporting primary data that evaluated the association between SNPs and SPC risk in HNC patients. Data were pooled in a random-effect meta-analyses, when at least two studies on the same SNP evaluated the same genotype model. Heterogeneity was assessed using the χ2-based Q-statistics and the I2 statistics. Quality of the included studies was assessed using the Q-Genie tool. RESULTS: Twenty-one studies, of moderate to good quality, were included in the systematic review. Fifty-one genes were reported across the included studies to have significant associations with an increased SPC risk. Overall, 81 out of 122 investigated SNPs were significantly associated with the SPC risk. Seven studies were included in the meta-analysis, which showed five SNPs associated with an increased risk of SPC: p21C70T, CT + TT (HR = 1.76; 95% CI: 1.28-2.43); FASLG -844C > T, CT + TT (HR = 1.82; 95% CI: 1.35-2.46), P21 C98A, CA + AA (HR = 1.75; 95% CI: 1.28-2.38); FAS -670A > G (HR = 1.84; 95% CI: 1.28-2.66) and GST-M1, Null genotype (HR = 1.54; 95% CI: 1.13-2.10). CONCLUSIONS: The identified SNPs in our systematic review and meta-analysis might serve as potential markers for identification of patients at high risk of developing SPC after primary HNC. PROSPERO REGISTRATION NUMBER: CRD42019135612 .

BACKGROUND: In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. METHODS: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. RESULTS: Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. CONCLUSIONS: Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02195479 , registered September 21, 2014.

BACKGROUND: Melanoma is a malignant cancer that affects melanocytes and is considered the most aggressive skin-type cancer. The prevalence for melanoma cancer for the last five year is about one million cases. The impact caused of this and other types of cancer, revel the importance of research into potential active compounds. The natural products are an important source of compounds with biological activity and research with natural products may enable the discovery of compounds with potential activity in tumor cells. METHODS: The Sulforhodamine B was used to determine cell density after treatment with lawsone derivatives. Apoptosis and necrosis were analyzed by flow cytometer. Morphological changes were observed by fluorescence using the Phalloidin/FITC and DAPI stains. The clonogenic and wound healing assays were used to analyze reduction of colonies formation and migratory capacity of melanoma cells, respectability. RESULTS: In pharmacological screening, seven compounds derived from lawsone were considered to have high cytotoxic activity (GI > 75%). Three compounds were selected to assess the inhibitory concentration for 50% of cells (IC50), and the compound 9, that has IC50 5.3 μM in melanoma cells, was selected for further analyses in this cell line. The clonogenic assay showed that the compound is capable of reducing the formation of melanoma colonies at 10.6 μM concentration. The compound induced apoptotic morphological changes in melanoma cells and increased by 50% the cells dying from apoptosis. Also, this compound reduced the migratory capacity of melanoma cells. CONCLUSIONS: The results of this study showed that the evaluated lawsone derivatives have potential activity on tumor cells. The compound 9 is capable of inducing cell death by apoptosis in melanoma cells (B16F10).

BACKGROUND: Long non-coding RNAs exert vital roles in several types of cancer. The objective of this study was to explore the role of LINC_00355 in gastric cancer (GC) progression and its potential mechanism. METHODS: The expression levels of LINC_00355 in GC tissues and cells were detected by quantitative real-time PCR, followed by assessing the effects of LINC_00355 knockdown or overexpression on cell properties. Dual-luciferase reporter assay was utilized to identify the relationship between LINC_00355 and microRNA (miR)-15a-5p and miR-15a-5p and PHD finger protein 19 (PHF19), followed by the rescue experiments. RESULTS: The results showed that LINC_00355 was highly expressed in GC tissues and cells compared with the corresponding control. LINC_00355 knockdown decreased the viability, migration, and invasion and increased the accumulation of GC cells in G1 phase and apoptosis. Meanwhile, LINC_00355 downregulation markedly increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase protein levels, whereas decreased cyclin D1, cyclin E, matrix metalloproteinase (MMP) 9, MMP2, and N-cadherin protein levels in GC cells. However, LINC_00355 overexpression had the opposite effects. It was verified that LINC_00355 upregulated the expression of PHF19 through sponging miR-15a-5p. Furthermore, PHF19 overexpression reversed the effect of LINC_00355 knockdown on GC cell properties, including cell viability, migration, invasion, and apoptosis. CONCLUSIONS: Collectively, these results suggest that LINC_00355 promotes GC progression by up-regulating PHF19 through sponging miR-15a-5p. Our findings may provide an important clinical basis for reversing the malignant phenotype of GC.

BACKGROUND: Nutritional complications in patients with locally advanced head and neck cancer (LA-HNC) treated by concurrent chemoradiotherapy (CCRT) often lead to placement of a prophylactic gastrostomy (PG) tube, while indication lacks harmonization. Our aim was to explore the current PG tube utilization among Belgian radiation oncology centers. METHODS: A survey was distributed to all 24 Belgian Radiation oncology departments, with questions about the number of patient treated per year, whether the PG indication is discussed at the multidisciplinary board, placement technique, time of starting nutrition and removal, its impact on swallowing function and importance of clinical factors. For the latter Relative Importance and Discordance Indexes were calculated to describe the ranking and agreement. RESULTS: All 24 centers submitted the questionnaire. Twenty three treat more than 20 head and neck (HNC) patients per year, while four (1 in 21-50; 3 in 51-100) are not discussing the gastrostomy tube indication at the multidisciplinary board. For the latter, endoscopic placement (68%) is the dominant technique, followed by the radiologic (16%) and laparoscopic (16%) methods. Seventy-five percent start the enteral nutrition when clinically indicated, 17% immediately and 8% from the start of radiotherapy. Majority of specialists (19/24) keep the gastrostomy tube until the patient assume an adequate oral feeding. Fifteen centres are considering PG decrease swallowing function. Regarding factors and their importance in the decision for the PG, foreseen irradiated volume reached highest importance, followed by 'anatomical site', 'patients' choice' and 'postoperative versus definitive' and 'local expertise', with decreasing importance respectively. Disagreement indexes showed moderate variation. CONCLUSIONS: The use of a PG tube for LAHNC patients treated by CCRT shows disparity at national level. Prospective studies are needed to ensure proper indication of this supportive measure.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and circulating tumor cells (CTCs) have been associated with survival in castration-resistant prostate cancer (CRPC). However, no study has examined the prognostic value of NLR and PLR in the context of CTCs. METHODS: Baseline CTCs from mCRPC patients were enumerated using the CellSearch System. Baseline NLR and PLR values were calculated using the data from routine complete blood counts. The associations of CTC, NLR, and PLR values, individually and jointly, with progression-free survival (PFS) and overall survival (OS), were evaluated using Kaplan-Meier analysis, as well as univariate and multivariate Cox models. RESULTS: CTCs were detected in 37 (58.7%) of 63 mCRPC patients, and among them, 16 (25.4%) had ≥5 CTCs. The presence of CTCs was significantly associated with a 4.02-fold increased risk for progression and a 3.72-fold increased risk of death during a median follow-up of 17.6 months. OS was shorter among patients with high levels of NLR or PLR than those with low levels (log-rank P = 0.023 and 0.077). Neither NLR nor PLR was individually associated with PFS. Among the 37 patients with detectable CTCs, those with a high NLR had significantly shorter OS (log-rank P = 0.024); however, among the 26 patients without CTCs, the OS difference between high- and low-NLR groups was not statistically significant. Compared to the patients with CTCs and low NLR, those with CTCs and high levels of NLR had a 3.79-fold risk of death (P = 0.036). This association remained significant after adjusting for covariates (P = 0.031). Combination analyses of CTC and PLR did not yield significant results. CONCLUSION: Among patients with detectable CTCs, the use of NLR could further classify patients into different risk groups, suggesting a complementary role for NLR in CTC-based prognostic stratification in mCRPC.

BACKGROUND: The aim of this study was to analyze overall survival in endometrial cancer patients' FIGO stages I-III in relation to surgical approach; minimally invasive (MIS) or open surgery (laparotomy). METHODS: A population-based retrospective study of 7275 endometrial cancer patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed from 2010 to 2018. Cox proportional hazard models were used in univariable and multivariable survival analyses. RESULTS: In univariable analysis open surgery was associated with worse overall survival compared with MIS hazard ratio, HR, 1.39 (95% CI 1.18-1.63) while in the multivariable analysis, surgical approach (MIS vs open surgery) was not associated with overall survival after adjustment for known risk factors (HR 1.12, 95% CI 0.95-1.32). Higher FIGO stage, non-endometrioid histology, non-diploid tumors, lymphovascular space invasion and increasing age were independent risk factors for overall survival. CONCLUSION: The minimal invasive or open surgical approach did not show any impact on survival for patients with endometrial cancer stages I-III when known prognostic risk factors were included in the multivariable analyses.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in Africa. In Africa, the major causes of HCC include chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Knowledge of the changes in the incidence of viral hepatitis-associated HCC over time and the factors responsible for such changes is key in informing policies for the prevention of viral hepatitis-associated HCC in Africa. AIM: The study aimed to systematically summarize the changes in the prevalence of viral hepatitis among HCC patients and the overall effect of the prevalence of viral hepatitis on the incidence of HCC over the past four decades in Africa (1980-2019). METHODS: A literature search was conducted in MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Web of Science, and African wide web for articles published on viral hepatitis-associated HCC in Africa from 1980 to 2019. The abstracts of the articles were screened for eligibility and those meeting the inclusion criteria were retrieved and reviewed. RESULTS: A total of 272 studies were included in the analysis. Viral hepatitis-related HCC incidence changed by 1.17% (95% confidence interval (CI): 0.63-1.71, p < 0.001), 0.82% (95% CI: 0.45-1.18, p < 0.001), and 3.34% (95% CI: 2.44-4.25, p < 0.001) for every 1% change in the prevalence of HBV, HCV, and hepatitis D virus (HDV) respectively, per decade. The incidence of HBV-related HCC decreased by - 0.50% (95% CI: - 0.74 - - 0.25, p < 0.001) over the last 40 years, while HCV-related HCC increased. CONCLUSION: Overall, the incidence of viral hepatitis-associated HCC has not declined, mainly due to no decline in the prevalence of HCV, HDV, and the high number of chronic hepatitis B carriers on the African continent. There is an urgent need for the allocation of resources for the implementation of treatment and preventive programs for HBV, HCV, HDV, and HCC in Africa. This systematic review is registered with PROSPERO®, number CRD42020169723.

BACKGROUND: Cumulative evidences have been implicated cancer stem cells in the tumor environment of hepatocellular carcinoma (HCC) cells, whereas the biological functions and prognostic significance of stemness related genes (SRGs) in HCC is still unclear. METHODS: Molecular subtypes were identified by cumulative distribution function (CDF) clustering on 207 prognostic SRGs. The overall survival (OS) predictive gene signature was developed, internally and externally validated based on HCC datasets including The Cancer Genome Atlas (TCGA), GEO and ICGC datasets. Hub genes were identified in molecular subtypes by protein-protein interaction (PPI) network analysis, and then enrolled for determination of prognostic genes. Univariate, LASSO and multivariate Cox regression analyses were performed to assess prognostic genes and construct the prognostic gene signature. Time-dependent receiver operating characteristic (ROC) curve, Kaplan-Meier curve and nomogram were used to assess the performance of the gene signature. RESULTS: We identified four molecular subtypes, among which the C2 subtype showed the highest SRGs expression levels and proportions of immune cells, whereas the worst OS; the C1 subtype showed the lowest SRGs expression levels and was associated with most favorable OS. Next, we identified 11 prognostic genes (CDX2, PON1, ADH4, RBP2, LCAT, GAL, LPA, CYP19A1, GAST, SST and UGT1A8) and then constructed a prognostic 11-gene module and validated its robustness in all three datasets. Moreover, by univariate and multivariate Cox regression, we confirmed the independent prognostic ability of the 11-gene module for patients with HCC. In addition, calibration analysis plots indicated the excellent predictive performance of the prognostic nomogram constructed based on the 11-gene signature. CONCLUSIONS: Findings in the present study shed new light on the role of stemness related genes within HCC, and the established 11-SRG signature can be utilized as a novel prognostic marker for survival prognostication in patients with HCC.

BACKGROUND: Liver metastasis is the most common cause of death in patients with colorectal cancer (CRC). Phosphatase of regenerating liver-3 induces CRC metastasis by epithelial-to-mesenchymal transition, which promotes CRC cell liver metastasis. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. METHODS: Using Immunohistochemistry, western blotting, invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, human miRNA arrays, and xenograft mouse model, we determined the role of hepatocyte exosome-derived miR-203a-3p in CRC MET. RESULTS: In our study, we found that miR-203a-3p derived from hepatocyte exosomes increased colorectal cancer cells E-cadherin expression, inhibited Src expression, and reduced activity. In this way miR-203a-3p induced the decreased invasion rate of CRC cells. COCLUSION: MiR-203a-3p derived from hepatocyte exosomes plays an important role of CRC cells to colonize in liver.

BACKGROUND: Because there is no exact therapeutic target, the systemic treatment of triple-negative breast cancer (TNBC) still relies on chemotherapy. In terms of local treatment, based on the highly malignant characteristics of TNBC, it is still uncertain whether patients should be given more aggressive local treatment. METHODS: This study was based on the SEER database. 13,262 TNBC patients undergoing chemotherapy were included. According to local treatment methods, patients were divided into breast-conserving surgery with radiotherapy (BCS + RT), total mastectomy alone and total mastectomy with radiotherapy (Mastectomy+RT). Kaplan-Meier survival analysis drew the survival curves of Overall Survival (OS) and Breast Cancer Specific Survival (BCSS), and Cox proportional risk regression models were used to analyze the impact of different local treatments on OS and BCSS. RESULTS: After adjusting confounding factors, Mastectomy alone group (HR = 1.57; 95%CI: 1.40-1.77) and Mastectomy+RT group (HR = 1.28; 95%CI: 1.12-1.46) were worse in OS than BCS + RT group, and Mastectomy+RT group (HR = 0.81; 95%CI: 0.73-0.91) was better in OS than Mastectomy alone group. The effect of local treatment for BCSS was similar to that of OS. After stratification according to age, tumor size and lymph node status, when the age was less than 55 years old, at T4, N2 or N3 category, there was no statistical significance between the BCS + RT group and the Mastectomy+RT group in OS or BCSS (all P > 0.05). When the age was less than 65 years old, at T1, T2 or N0 category, there was no statistical significance between the Mastectomy alone group and the Mastectomy+RT group in OS or BCSS (all P > 0.05). The results of other stratified analyses were basically consistent with the results of total population analysis. CONCLUSION: The survival benefit of breast-conserving surgery with radiotherapy was higher than or similar to that of total mastectomy TNBC patients.

BACKGROUND: Enhancer of zesta homologue 2 (EZH2) is an essential component of polycomb repressive complex 2 (PRC2) that contributes to tumor progression and chemo-resistance. The aim of this study was to comprehensively assess the prognostic value of EZH2 across the morphologic and molecular spectra of high-grade serous ovarian carcinoma (HGSOC) by utilizing both immunohistochemistry (IHC) and proteogenomic technologies. METHODS: IHC of EZH2 was performed using a tissue microarray of 79 HGSOC scored (+/-) for lymphovascular invasion (LVI), tumor-infiltrating lymphocytic aggregates ≥1 mm (TIL) and architectural growth patterns. The association of EZH2 H-score with response to therapy and overall survival was evaluated by tumor features. We also evaluated EZH2 transcriptional (RNA sequencing) and protein (mass spectrometry) expression from bulk tumor samples from 336 HGSOC from The Cancer Genome Atlas (TCGA). EZH2 expression and co-expression networks were compared by clinical outcomes. RESULTS: For HGSOC without TIL (58%), EZH2 expression was almost 2-fold higher in platinum resistant tumors (P = 0.01). Conversely, EZH2 was not associated with platinum resistance among TIL+ HGSOC (P = 0.41). EZH2 expression was associated with reduced survival for tumors with LVI (P = 0.04). Analysis of TCGA found higher EZH2 expression in immunoreactive and proliferative tumors (P = 6.7 × 10- 5) although protein levels were similar across molecular subtypes (P = 0.52). Both mRNA and protein levels of EZH2 were lower in platinum resistant tumors although they were not associated with survival. Co-expression analysis revealed EZH2 networks totaling 1049 mRNA and 448 proteins that were exclusive to platinum sensitive or resistant tumors. The EZH2 network in resistant HGSOC included CARM1 which was positively correlated with EZH2 at both mRNA (r = 0.33, p = 0.003) and protein (r = 0.14, P = 0.01) levels. Further, EZH2 co-expression with CARM1 corresponded to a decreased prognostic significance of EZH2 expression in resistant tumors. CONCLUSIONS: Our findings demonstrate that EZH2 expression varies based on its interactions with immunologic pathways and tumor microenvironment, impacting the prognostic interpretation. The association between high EZH2 expression and platinum resistance in TIL- HGSOC warrants further study of the implications for therapeutic strategies.

BACKGROUND: Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. Most APL patients treated with ATRA and/or ATO are now anticipated to have a nearly normal life expectancy. Unfortunately, relapse and resistance to the current treatment occur in APL patients and the outcome remains dismal in these refractory patients. AXL receptor tyrosine kinase (AXL-RTK) has been shown to increase tumour burden, provide resistance to therapy and is critical to maintain cancer stem cells (CSCs) in chronic myeloid leukemia (CML) by stabilizing β-catenin in the Wnt/β-catenin signalling pathway. However, the role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL. METHODS AND RESULTS: By using biochemical and pharmacological approaches, here we report that targeting of AXL-RTK is related to the down-regulation of β-catenin target genes including c-myc (p < 0.001), AXIN2 (p < 0.001), and HIF1α (p < 0.01) and induction of apoptosis in PML/RARα-positive APL cell line. Resistance to all-trans retinoic acid (ATRA) was also overcomed by targeting AXL-RTK with R428 in APL (p < 0.05). CONCLUSION: Our results provide clear evidence of the involvement of AXL-RTK in leukemogenic potential of PML/RARα-positive APL and suggest targeting of AXL-RTK in the treatment of therapy resistant APL patients.

BACKGROUND: This study aims to provide new insights on the role of smoking patterns and cigarette dependence in female lung cancer, and to examine differences by histological subtype. METHODS: We conducted a population-based case-control study in the great Paris area among women including 716 incident cases diagnosed between 2014 and 2017 and 757 age-matched controls. Detailed data on smoking history was collected during in-person interviews to assess intensity and duration of tobacco smoking, time since cessation, smoking habits (depth of smoke inhalation, use of filter, type of tobacco, and type of cigarettes) and Fagerström test for cigarette dependence. The comprehensive smoking index (CSI), a score modelling the combined effects of intensity, duration and time since quitting smoking was determined for each subject. Multivariable logistic regression models were fitted to calculate odds ratios (ORs) and their confidence intervals (95%CI) of lung cancer associated with smoking variables. RESULTS: Lung cancer risk increased linearly with intensity and duration of tobacco smoking while it decreased with time since cessation, to reach the risk in never-smokers after 20 years of abstinence. The combined effect of intensity and duration of tobacco smoking was more than multiplicative (p-interaction 0.012). The OR in the highest vs the lowest quartile of CSI was 12.64 (95%CI 8.50; 18.80) (p-trend < 0.001). The risk of small cell or squamous cell carcinomas increased with the CSI more sharply than the risk of adenocarcinomas. Deep smoke inhalation, dark vs blond tobacco, conventional vs light cigarettes, and unfiltered vs filtered cigarettes, as well as having mixed smoking habits, were found to be independent risk factors. Having high cigarette addiction behaviours also increased the risk after adjusting for CSI. CONCLUSION: This study provides additional insights on the effects of tobacco smoking patterns on lung cancer risk among women.

BACKGROUND: Though sepsis is common in patients with cancer, there are limited studies that evaluated sepsis and septic shock in this patient population. The objective of this study was to evaluate the outcomes and to identify predictors of mortality in cancer patients admitted to the intensive care unit (ICU) with septic shock. METHODS: This was a retrospective study conducted at a medical-surgical oncologic ICU of a comprehensive cancer center. Adult cancer patients admitted with septic shock between January 1, 2008 and December 31, 2019 were enrolled. Septic shock was defined as an ICU admission diagnosis of sepsis that required initiating vasopressors within 24 h of admission. Patient baseline characteristics, ICU length of stay and ICU and hospital mortality were recorded. Univariate analysis and logistic regression were performed to identify predictors associated with ICU and hospital mortality. RESULTS: During the study period, 1408 patients met the inclusion criteria. The mean age was 56.8 ± 16.1 (SD) years and mean Acute Physiology and Chronic Health Evaluation (APACHE) II was 23.0 ± 7.91 (SD). Among the enrolled patients, 67.8% had solid tumors while the remaining had hematological malignancies. Neutropenia and thrombocytopenia were reported in 19.3 and 39.5% of the patients, respectively, and mechanical ventilation was required for 42% of the patients. Positive cultures were reported in 836 (59.4%) patients, most commonly blood (33%) and respiratory (26.6%). Upon admission, about half the patients had acute kidney injury, while elevated total bilirubin and lactic acid levels were reported in 13.8 and 65.2% of the patients, respectively. The median ICU length of stay was 4 days (IQR 3-8), and ICU and hospital mortality were reported in 688 (48.9%) and 914 (64.9%) patients, respectively. Mechanical ventilation, APACHE II, thrombocytopenia, positive cultures, elevated bilirubin and lactic acid levels were significantly associated with both ICU and hospital mortality. CONCLUSIONS: In a relatively large cohort of patients with solid and hematological malignancies admitted to the ICU with septic shock, hospital mortality was reported in about two-third of the patients. Mechanical ventilation, APACHE II, thrombocytopenia, positive cultures, elevated bilirubin and lactic acid levels were significant predictors of mortality.

BACKGROUND: Esophageal and gastric cancers are a significant public health problem worldwide, with most patients presenting with advanced-stage disease and, consequently, poor prognosis. Systemic oncological treatments (SOT) have been widely used over more conservative approaches, such as supportive care. Nevertheless, its effectiveness in this scenario is not sufficiently clear. This paper provides an overview of systematic reviews that assessed the effectiveness of SOT compared with the best supportive care (BSC) or placebo in patients with advanced esophageal or gastric cancers in an end-of-life context. METHODS: We searched MEDLINE, EMBASE, The Cochrane Library, Epistemonikos, and PROSPERO for eligible systematic reviews (SRs) published from 2008 onwards. The primary outcomes were overall survival (OS), progression-free survival (PFS), functional status, and toxicity. Two authors assessed eligibility and extracted data independently. We evaluated the methodological quality of included SRs using the AMSTAR-2 tool and the overlap of primary studies (corrected covered area, CCA). Also, we performed a de novo meta-analysis with data reported for each primary study when it was possible. We assessed the certainty of evidence using the GRADE approach. RESULTS: We identified 16 SRs (19 included trials) for inclusion within this overview. Most reviews had a critically low methodological quality, and there was a very high overlap of primary studies. It is uncertain whether SOT improves OS and PFS over more conservative approaches due to the very low certainty of evidence. CONCLUSIONS: The evidence is very uncertain about the effectiveness of SOT for advanced esophageal or gastric cancers. High-quality SRs and further randomized clinical trials that include a thorough assessment of patient-centered outcomes are needed. TRIAL REGISTRATION: Open Science Framework, https://doi.org/10.17605/OSF.IO/7CHX6 .

BACKGROUND: There is no evidence whether it is best to stop drinking alcohol at all or whether it is okay to drink a little in that light-to-moderate alcohol use was associated with low cardiovascular disease (CVD) compared to non-drinker among colorectal cancer (CRC) survivors, who are regarded as vulnerable to CVD. Therefore, we evaluated the association between alcohol consumption and incident CVD among long-term survivors of CRC. METHODS: This population-based, retrospective cohort study utilized data from the Korean National Insurance Service of 20,653 long-term survivors of CRC diagnosed between 2006 and 2012. Participants were followed up to the date of CVD, death, or December 31, 2018. All patients were categorized according to their daily alcohol consumption (g/day). The outcomes were incident CVD, including ischemic heart disease (IHD) and ischemic and hemorrhagic stroke, analyzed using the Cox proportional hazards regression after adjusting for cardiovascular risk factors and history of chemotherapy and radiotherapy. RESULTS: There was no association between alcohol consumption and incident CVD among long-term survivors of CRC. Additionally, hazardous alcohol consumption (≥ 40 g/day in male patients and ≥ 20 g/day in female patients) was associated with increased CVD, ischemic stroke, and hemorrhagic stroke (adjusted hazard ratio [95% confidence interval]: 1.51 [1.15-1.97], 1.60 [1.03-2.48], and 2.65 [1.25-5.62], respectively) compared with non-drinkers. CONCLUSION: No discernable protective association was found between alcohol consumption and incident CVD for even light-to-moderate drinking among long-term survivors of CRC. Alcohol consumption ≥40 g/day in male patients and ≥ 20 g/day in female patients was associated with an increased risk of stroke compared with non-drinkers. These novel results provide useful evidence when advising survivors of CRC regarding alcohol use.

BACKGROUND: In the surgical treatment of intrahepatic cholangiocarcinoma (ICC), postoperative complications may be predictive of long-term survival. This study aimed to identify an immune-nutritional index (INI) that can be used for preoperative prediction of complications. PATIENTS AND METHODS: Multi-institutional data from 316 patients with ICC who had undergone surgical resection were retrospectively analysed, with a focus on various preoperative INIs. RESULTS: Severe complications (Clavien-Dindo grade III-V) were identified in 66 patients (20.8%), including Grade V complications in 7 patients (2.2%). Comparison of areas under the receiver operating characteristic curve (AUCs) among various INIs identified the prognostic nutritional index (PNI) as offering the highest predictive value for severe complications (AUC = 0.609, cut-off = 50, P = 0.008). Multivariate analysis revealed PNI <  50 (odds ratio [OR] = 2.22, P = 0.013), hilar lesion (OR = 2.46, P = 0.026), and long operation time (OR = 1.003, P = 0.029) as independent risk factors for severe complications. In comparing a high-PNI group (PNI ≥ 50, n = 142) and a low-PNI group (PNI <  50, n = 174), the low-PNI group showed higher rates of both major complications (27% vs. 13.4%; P = 0.003) and infectious complications (14.9% vs. 3.5%; P = 0.0021). Furthermore, median survival time and 1- and 5-year overall survival rates were 34.2 months and 77.4 and 33.8% in the low-PNI group, respectively, and 52.4 months and 89.3 and 47.5% in the high-PNI group, respectively (P = 0.0017). CONCLUSION: Preoperative PNI appears useful as an INI correlating with postoperative severe complications and as a prognostic indicator for ICC.

BACKGROUD: Cancer stemness is associated with metastases in kidney renal clear cell carcinoma (KIRC) and negatively correlates with immune infiltrates. Recent stemness evaluation methods based on the absolute expression have been proposed to reveal the relationship between stemness and cancer. However, we found that existing methods do not perform well in assessing the stemness of KIRC patients, and they overlooked the impact of alternative splicing. Alternative splicing not only progresses during the differentiation of stem cells, but also changes during the acquisition of the stemness features of cancer stem cells. There is an urgent need for a new method to predict KIRC-specific stemness more accurately, so as to provide help in selecting treatment options. METHODS: The corresponding RNA-Seq data were obtained from the The Cancer Genome Atlas (TCGA) data portal. We also downloaded stem cell RNA sequence data from the Progenitor Cell Biology Consortium (PCBC) Synapse Portal. Independent validation sets with large sample size and common clinic pathological characteristics were obtained from the Gene Expression Omnibus (GEO) database. we constructed a KIRC-specific stemness prediction model using an algorithm called one-class logistic regression based on the expression and alternative splicing data to predict stemness indices of KIRC patients, and the model was externally validated. We identify stemness-associated alternative splicing events (SASEs) by analyzing different alternative splicing event between high- and low- stemness groups. Univariate Cox and multivariable logistic regression analysisw as carried out to detect the prognosis-related SASEs respectively. The area under curve (AUC) of receiver operating characteristic (ROC) was performed to evaluate the predictive values of our model. RESULTS: Here, we constructed a KIRC-specific stemness prediction model with an AUC of 0.968,and to provide a user-friendly interface of our model for KIRC stemness analysis, we have developed KIRC Stemness Calculator and Visualization (KSCV), hosted on the Shiny server, can most easily be accessed via web browser and the url https://jiang-lab.shinyapps.io/kscv/ . When applied to 605 KIRC patients, our stemness indices had a higher correlation with the gender, smoking history and metastasis of the patients than the previous stemness indices, and revealed intratumor heterogeneity at the stemness level. We identified 77 novel SASEs by dividing patients into high- and low- stemness groups with significantly different outcome and they had significant correlations with expression of 17 experimentally validated splicing factors. Both univariate and multivariate survival analysis demonstrated that SASEs closely correlated with the overall survival of patients. CONCLUSIONS: Basing on the stemness indices, we found that not only immune infiltration but also alternative splicing events showed significant different at the stemness level. More importantly, we highlight the critical role of these differential alternative splicing events in poor prognosis, and we believe in the potential for their further translation into targets for immunotherapy.

BACKGROUND: The 21-gene recurrence score (RS) can predict chemotherapy benefit in estrogen receptor-positive, human epidermal growth factor receptor-2-negative (ER+/HER2-) early breast cancer patients. Age would influence the interaction between RS and chemotherapy effect. The current study aimed to determine RS thresholds which were predictive of chemotherapy benefit in young and old women, respectively. METHODS: Patients diagnosed with pN0-1, ER+/HER2- breast cancer between 2009 and 2016 were retrospectively reviewed. Propensity score matching was performed according to chemotherapy usage. After stratifying patients with different cutoffs of age, the RS threshold indicating chemotherapy benefit in each age strata were determined by cox proportional hazard models. RESULTS: A total of 1227 patients were included. The median age was 58 years and the median RS was 24. After matching, the RS thresholds suggesting chemotherapy benefit varied with age. For patients ≤55 years, chemotherapy benefit was observed in those having RS > 25 (P = 0.03), with 4-year invasive disease-free survival (IDFS) of 97.0 and 89.3% in patients receiving chemotherapy or not. While patients derived no benefit from chemotherapy if they had RS ≤25 (P = 0.66, 4-year IDFS: 95.3% vs. 94.6%). For patients > 55 years, adjuvant chemotherapy was associated with better prognosis in those with RS > 36 (P = 0.014, 4-year IDFS: 94.7% vs. 76.2%), but not in those having RS ≤36 (P = 0.13, 4-year IDFS: 92.3% vs. 95.8%). CONCLUSIONS: Old patients need higher RS thresholds to demonstrate the chemotherapy benefit. Further efforts are warranted to investigate the association between age and predictive RS thresholds.

PURPOSE: Growing evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role as competing endogenous RNAs (ceRNAs) in tumor occurrence. The lncRNAs' functions and clinical significance in laryngeal squamous cell carcinoma (LSCC) remain unclear. The study aims to reveal the lncRNA-associated ceRNA regulatory network of LSCC and clarify its clinical relevance. METHODS: Here, we obtained LSCC transcriptome data from The Cancer Genome Atlas (TCGA) database and identified the differential expression profile of lncRNAs, miRNAs, and mRNAs by the EdgeR R package. The function enrichment analysis of mRNAs was performed using clusterProfiler R package and GSEA3.0. Then, we constructed a ceRNA network and prognosis model based on lncRNAs through bioinformatic methods. Moreover, we explored the functions of prognosis-related lncRNA in LSCC by CCK-8 and transwell assay. RESULTS: 1961 lncRNAs, 69 miRNAs, and 2224 mRNAs were identified as differentially expressed genes in LSCC tissues. According to the transcriptome differential expression profile, a ceRNA network containing 61 lncRNAs, 21 miRNAs, and 77 mRNAs was established. Then, four lncRNAs (AC011933.2, FAM30A, LINC02086, LINC02575) were identified from the ceRNA network to build a prognosis model for LSCC patients. And we found that LINC02086 and LINC02575 promoted the proliferation, migration, and invasion of LSCC cells while AC011933.2 and FAM30A inhibited these biological functions in vitro. Furthermore, we validated that LINc02086/miR-770-5p/SLC26A2 axis promoted migration in LSCC. CONCLUSION: Four lncRNAs of the ceRNA network were abnormally expressed and related to patient prognosis in LSCC. They played a significant role in the progress of LSCC via affecting the proliferation and metastasis of tumor cells.

BACKGROUND: Epidemiological evidence suggests that synchronous or metachronous presentation of breast and thyroid cancers exceeds that predicted by chance alone. The following potential explanations have been hypothesized: common environmental or hormonal factors, oncogenic effect of the treatment for the first cancer, closer follow-up of cancer survivors, shared underlying genetic risk factors. While some cases were found to be related to monogenic disorders with autosomal inheritance, the genetic background of most cases of co-occurring breast and thyroid cancer is thought to be polygenic. METHODS: In this retrospective case-control study we compared the genetic profile of patients with a history of breast cancer (n = 15) to patients with co-occurring breast and thyroid cancer (n = 19) using next generation sequencing of 112 hereditary cancer risk genes. Identified variants were categorized based on their known association with breast cancer and oncogenesis in general. RESULTS: No difference between patients with breast and double cancers was observed in clinical and pathological characteristics or the number of neutral SNPs. The unweighted and weighted number of SNPs with an established or potential association with breast cancer was significantly lower in the group with breast cancer only (mean difference - 0.58, BCa 95% CI [- 1.09, - 0.06], p = 0.029, and mean difference - 0.36, BCa 95% CI [- 0.70, - 0.02], p = 0.039, respectively). The difference was also significant when we compared the number of SNPs with potential or known association with any malignancy (mean difference - 1.19, BCa 95% CI [- 2.27, - 0.11], p = 0.032 for unweighted, and mean difference - 0.73, BCa 95% CI [- 1.32, - 0.14], p = 0.017 for weighted scores). CONCLUSION: Our findings are compatible with the hypothesis of genetic predisposition in the co-occurrence of breast and thyroid cancer. Further exploration of the underlying genetic mechanisms may help in the identification of patients with an elevated risk for a second cancer at the diagnosis of the first cancer.

BACKGROUND: We evaluated the treatment response and predictive factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT), who underwent stereotactic body radiotherapy (SBRT). Additionally, we developed and validated a personalised prediction model for patient survival. METHODS: Clinical information was retrospectively collected for 80 patients with HCC and PVTT, who were treated with SBRT at the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) between December 2015 and June 2019. A multivariate Cox proportional hazard regression model was used to identify the independent predictive factors for survival. Clinical factors were subsequently presented in a nomogram. The area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to evaluate the accuracy of the model and the net clinical benefit. RESULTS: All patients completed the planned radiotherapy treatment, and the median follow-up duration was 10 months (range, 1-35.3 months). The median survival duration was 11.5 months, with 3-, 6-, and 12-month survival rates of 92.5, 74.5, and 47.5%, respectively. The multivariable Cox regression model indicated that the following were significant independent predictors of OS: clinical T stage (p = 0.001, hazard ratio [HR] = 3.085, 95% confidence interval [CI]: 1.514-6.286), cirrhosis (p = 0.014, HR = 2.988, 95% CI: 1.246-7.168), age (p = 0.005, HR = 1.043, 95% CI: 1.013-1.075), alpha-fetoprotein level (p = 0.022, HR = 1.000, 95% CI: 1.000-1.000), and haemoglobin level (p = 0.008, HR = 0.979, 95% CI: 0.963-0.994). A nomogram based on five independent risk factors and DCA demonstrated a favourable predictive accuracy of patient survival (AUC = 0.74, 95% CI: 0.63-0.85) and the clinical usefulness of the model. CONCLUSIONS: SBRT is an effective treatment for patients with HCC with PVTT. Notably, clinical T stage, presence of cirrhosis, age, alpha-fetoprotein levels, and haemoglobin levels are independent prognostic factors for survival. The presented nomogram can be used to predict the survival of patients with HCC and PVTT, who underwent SBRT.

BACKGROUND: Our previous studies have reported the down-regulation of EGFL8 correlates to the development and prognosis of colorectal and gastric cancer. The present study is carried out to explore the expression pattern and role of EGFL8 in hepatocellular carcinoma (HCC). METHODS AND MATERIALS: EGFL8 expression in 102 cases of HCC tissues matched with adjacent non-tumorous liver tissues, a normal liver cell line and three liver cancer cell lines with different metastatic capacity was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Moreover, the clinicopathological features and prognosis of HCC patients were correlated with expression of EGFL8. Subsequently, the gain-and loss-of-function experiments were carried out to investigate the biological function of EGFL8 in HCC. We also used N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-(S)- phenylglycine t-butyl ester (DAPT), an inhibitor for Notch signaling pathway, in these experiments to verify the involvement of Notch signaling pathway in the effects of EGFL8. Additionally, a mouse model was established to investigate the effect of EGFL8 on metastasis of HCC cells. The expression of Notch signaling pathway in HCC cells and xenograft mouse tumors were detected by Western blot and immunohistochemistory. RESULTS: The expression of EGFL8 was significantly decreased in HCC tissues and cell lines and EGFL8 down-regulation correlated to multiple nodules, vein invasion, high TNM stage and poor prognosis of HCC. Interestingly, the expression levels of EGFL8 in three liver cancer cell lines were negatively associated with their metastatic capacity. In vitro and in vivo experiments indicated that EGFL8 obviously suppressed metastasis and invasion of HCC cells but slightly promoted apoptosis. Meanwhile, the expression of Notch signaling pathway was obviously suppressed in EGFL8 overexpressed HCCLM3 cells and xenograft mouse tumors generated from these cells but markedly elevated in EGFL8 depleted Hep3B cells. Furthermore, the up-regulated expression of Notch signaling pathway and effects induced by EGFL8 knockdown in Hep3B cells could be counteracted by DAPT treatment. CONCLUSION: The down-regulation of EGFL8 was correlated to progression and poor prognosis of HCC and regulates HCC cell migration, invasion and apoptosis through activating the Notch signaling pathway, suggesting EGFL8 as a novel therapeutic target and a potential prognostic marker for HCC.

BACKGROUND: We conducted a single-arm phase II trial to investigate the short-term efficacy and safety of apatinib combined with oxaliplatin and S-1 in the treatment of unresectable gastric cancer. PATIENTS AND METHODS: Previously untreated patients with unresectable HER-2-negative advanced gastric cancer were selected. All the patients received six cycles of S-1 and oxaliplatin and five cycles of apatinib, which were administered at intervals of three weeks. The surgery was performed after six cycles of drug treatment. The primary endpoints were radical resection (R0) rate and safety. This study was registered with the China Trial Register, number ChiCTR-ONC-17010430  (01/12/2016-01/12/2022). RESULTS: A total of 39 patients were enrolled. Efficacy evaluation was feasible for 37 patients. One patient achieved complete response (CR, 2.7%), 26 patients achieved partial response (PR, 70.3%), three patients had stable disease (SD, 8.1%) and seven patients had progressive disease (PD, 18.9%). The objective response rate (ORR) was 73.0% and the disease control rate (DCR) was 81.1%. 22 patients underwent surgery, among which 14 patients underwent radical resection (R0), with a R0 resection rate of 63.6%. The 1-year survival rate of the surgical group (22 patients) was 71.1% and the 2-year survival rate was 41.1%. The median survival time was 21 months. The incidence of adverse events (AEs) was 100%. Leucopenia (65.3%) and granulocytopenia (69.2%) were the most common hematological AEs. The most common non-hematological AEs were fatigue (51.3%) and oral mucositis (35.9%). CONCLUSION: Apatinib combined with oxaliplatin and S-1 showed good short-term survival and acceptable safety in the conversion therapy of unresectable gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy. METHODS: Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytohubba plugin. Their prognostic values were assessed by Kaplan-Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. RESULTS: Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients. CONCLUSIONS: We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment.

BACKGROUND: The number of colorectal cancer patients increases with age. The decision to go through major surgery can be challenging for the aged patient and the surgeon because of the heterogeneity within the older population. Differences in preoperative physical and cognitive status can affect postoperative outcomes and functional recovery, and impact on patients' quality of life. METHODS / DESIGN: A prospective, observational, multicentre study including nine hospitals to analyse the impact of colon cancer surgery on functional ability, short-term outcomes (complications and mortality), and their predictors in patients aged ≥80 years. The catchment area of the study hospitals is 3.88 million people, representing 70% of the population of Finland. The data will be gathered from patient baseline characteristics, surgical interventional data, and pre- and postoperative patient-questionnaires, to an electronic database (REDCap) especially dedicated to the study. DISCUSSION: This multicentre study provides information about colon cancer surgery's operative and functional outcomes on older patients. A further aim is to find prognostic factors which could help to predict adverse outcomes of surgery. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03904121 ). Registered on 1 April 2019.

BACKGROUND: An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. METHODS: Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as 'early recurrence', and recurrence more than 1 year after as 'late recurrence'. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. RESULTS: Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026-1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. CONCLUSION: Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

BACKGROUND: Inflammation plays an important role in tumor proliferation, metastasis, and resistance to chemotherapy. The systemic inflammation response index (SIRI), has been reported to be closely related to prognosis in many tumors, such as breast and gastric cancers. However, the predictive value of pretreatment SIRI on pathological complete response (pCR) rates in patients with breast cancer treated with neoadjuvant chemotherapy (NAC) is unknown. This study examined the correlation between SIRI and pCR in patients with breast cancer receiving NAC and identified convenient and accurate predictive indicators for pCR. METHODS: We retrospectively analyzed the clinicopathological parameters and pretreatment peripheral blood characteristics of the 241 patients with breast cancer who received NAC between June 2015 and June 2020. Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff of SIRI. ROC curves were also plotted to verify the accuracy of inflammatory markers for pCR prediction. The chi-squared test was used to explore the relationships of SIRI with pCR and other clinicopathological parameters. Multivariate analyses were performed using a logistic regression model. RESULTS: Among the 241 patients, 48 (19.92%) achieved pCR. pCR was significantly related to SIRI, the neutrophil-lymphocyte ratio (NLR), the lymphocyte-monocyte ratio (LMR), molecular subtypes and other clinicopathological parameters, such as BMI, clinical T and N staging, and histological grade. Multivariate analyses indicated that the clinical T and N staging, SIRI, and NLR were independent prognostic factors for pCR in patients with breast cancer. The area under the ROC curve for SIRI was larger than that for NLR. Compared to patients with SIRI ≥0.72, patients with SIRI < 0.72 had a nearly 5-fold higher chance of obtaining pCR (odds ratio = 4.999, 95% confidence interval = 1.510-16.551, p = 0.000). CONCLUSIONS: Pretreatment SIRI is predictive of pCR in patients with breast cancer receiving NAC, and the index can assist physicians in formulating personalized treatment strategies.

BACKGROUND: Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). METHODS: The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). RESULTS: Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. CONCLUSIONS: SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.

BACKGROUND: Phase 3 oncologic randomized clinical trials (RCTs) can lead to Food and Drug Administration (FDA) approvals. In this study, we aim to identify trial-related factors associated with trials leading to subsequent FDA drug approvals. METHODS: We performed a database query through the ClinicalTrials.gov registry to search for oncologic phase 3 RCTs on February 2020. We screened all trials for therapeutic, cancer-specific, phase 3, randomized, multi-arm trials. We then identified whether a trial was used for subsequent FDA drug approval through screening of FDA approval announcements. RESULTS: In total, 790 trials were included in our study, with 225 trials (28.4%) generating data that were subsequently used for FDA approvals. Of the 225 FDA approvals identified, 65 (28.9%) were based on trials assessing overall survival (OS) as a primary endpoint (PEP), two (0.9%) were based on trials with a quality of life (QoL) PEP, and 158 approvals (70.2%) were based on trials with other PEP (P = 0.01). FDA approvals were more common among industry funded-trials (219, 97.3%; P < 0.001), and less common among trials sponsored by national cooperative groups (21, 9.3%; P < 0.001). Finally, increased pre-hoc power and meeting patients' accrual target were associated with FDA approvals (P < 0.001). CONCLUSIONS: The majority of FDA approvals are based on data generated from trials analyzing surrogate primary endpoints and trials receiving industry funding. Additional studies are required to understand the complexity of FDA approvals.

BACKGROUNDS: Liver hepatocellular carcinoma (HCC) is one of the most malignant tumors, of which prognosis is unsatisfactory in most cases and metastatic of HCC often results in poor prognosis. In this study, we aimed to construct a metastasis- related mRNAs prognostic model to increase the accuracy of prediction of HCC prognosis. METHODS: Three hundred seventy-four HCC samples and 50 normal samples were downloaded from The Cancer Genome Atlas (TCGA) database, involving transcriptomic and clinical data. Metastatic-related genes were acquired from HCMBD website at the same time. Two hundred thirty-three samples were randomly divided into train dataset and test dataset with a proportion of 1:1 by using caret package in R. Kaplan-Meier method and univariate Cox regression analysis and lasso regression analysis were performed to obtain metastasis-related mRNAs which played significant roles in prognosis. Then, using multivariate Cox regression analysis, a prognostic prediction model was established. Transcriptome and clinical data were combined to construct a prognostic model and a nomogram for OS evaluation. Functional enrichment in high- and low-risk groups were also analyzed by GSEA. An entire set based on The International Cancer Genome Consortium(ICGC) database was also applied to verify the model. The expression levels of SLC2A1, CDCA8, ATG10 and HOXD9 are higher in tumor samples and lower in normal tissue samples. The expression of TPM1 in clinical sample tissues is just the opposite. RESULTS: One thousand eight hundred ninety-five metastasis-related mRNAs were screened and 6 mRNAs were associated with prognosis. The overall survival (OS)-related prognostic model based on 5 MRGs (TPM1,SLC2A1, CDCA8, ATG10 and HOXD9) was significantly stratified HCC patients into high- and low-risk groups. The AUC values of the 5-gene prognostic signature at 1 year, 2 years, and 3 years were 0.786,0.786 and 0.777. A risk score based on the signature was a significantly independent prognostic factor (HR = 1.434; 95%CI = 1.275-1.612; P < 0.001) for HCC patients. A nomogram which incorporated the 5-gene signature and clinical features was also built for prognostic prediction. GSEA results that low- and high-risk group had an obviously difference in part of pathways. The value of this model was validated in test dataset and ICGC database. CONCLUSION: Metastasis-related mRNAs prognostic model was verified that it had a predictable value on the prognosis of HCC, which could be helpful for gene targeted therapy.

BACKGROUND: Cervical cancer (CC) is the primary cause of death in women. This study sought to investigate the potential mechanism and prognostic genes of CC. METHODS: We downloaded four gene expression profiles from GEO. The RRA method was used to integrate and screen differentially expressed genes (DEGs) between CC and normal samples. Functional analysis was performed by clusterprofiler. We built PPI network by Search Tool for the Retrieval of Interacting Genes Database (STRING) and selected hub modules via Molecular COmplex Detection (MCODE). CMap database was used to find molecules with therapeutic potential for CC. The hub genes were validated in GEO datasets, Gene Expession Profiling Interactive Analysis (GEPIA), immunohistochemistry, Cox regression analysis, TCGA methylation analysis and ONCOMINE were carried out. ROC curve analysis and GSEA were also performed to describe the prognostic significance of hub genes. RESULTS: Functional analysis revealed that 147 DEGs were significantly enriched in binding, cell proliferation, transcriptional activity and cell cycle regulation. PPI network screened 30 hub genes, with CDK1 having the strongest connectivity with CC. Cmap showed that apigenin, thioguanine and trichostatin A might be used to treat CC(P < 0.05). Eight genes (APOD, CXCL8, MMP1, MMP3, PLOD2, PTGDS, SNX10 and SPP1) were screened out through GEPIA. Of them, only PTGDS and SNX10 had not appeared in previous studies about CC. The validation in GEO showed that PTGDS showed low expression while SNX10 presented high expression in tumor tissues. Their expression profiles were consistent with the results in immunohistochemistry. ROC curve analysis indicated that the model had a good diagnostic efficiency (AUC = 0.738). GSEA analysis demonstrated that the two genes were correlated with the chemokine signaling pathway (P < 0.05). TCGA methylation analysis showed that patients with lowly-expressed and highly-methylated PTGDS had a worse prognosis than those with highly-expressed and lowly-methylated PTGDS (p = 0.037). Cox regression analysis showed that SNX10 and PTGDS were independent prognostic indicators for OS among CC patients (P = 0.007 and 0.003). CONCLUSIONS: PTGDS and SNX10 showed abnormal expression and methylation in CC. Both genes might have high prognostic value of CC patients.

BACKGROUND: Testicular Self-Examination (TSE) causes earlier diagnosis of Testicular cancer (TC). Hence, all men aged between15 to 35 years should perform TSE every month. This study aims to survey the effect of educational intervention based on health belief model and social support on testicular self-examination in men aged between 15 to 35 years of Fasa City, Fars province, Iran. METHODS: In this quasi-experimental study, 200 men (100 in the experimental group and 100 in the control group) in Fasa City, Fars, Iran, were conducted from June 2018 to August 2019. The educational intervention for the experimental group consisted of six training sessions (testicular cancer, its prevalence and types, its risk factors, symptoms, infected areas, diagnosis, side-effects and its severity, understanding about testicular self-examination and its importance, benefits, and barriers of self-examination and correct way of doing TSE were discussed, role of social support). A questionnaire consisting of demographic information, knowledge, HBM construct, and social support was used to measure testicular self-examination before, 3 months after the intervention, and 6 months later. Data were analyzed using SPSS-22 via chi-squared, independent samples t-test, Mann-Whitney, and repeated measures ANOVA at a significance level of 0.5. RESULTS: The mean age of the men was 27.26 ± 3.16 years in the experimental group and 27.39 ± 3.12 years in the control group. Three months after the intervention and 6 months after the intervention, the experimental group showed a significant increase in knowledge, perceived susceptibility, perceived severity, perceived benefits, self-efficacy, cues to action, social support, and testicular self-examination performance compared to the control group. CONCLUSION: This study showed the effectiveness of the intervention based on the HBM constructs and social support in the adoption of testicular self-examination in 3 and 6 months post-intervention in men aged between 15 to 35 years. Hence, these models can act as a framework for designing and implementing educational interventions for testicular self-examination.

BACKGROUND: Published findings suggest sex differences in lung cancer risk and a potential role for sex steroid hormones. Our aim was to perform a meta-analysis to investigate the effects of sex steroid hormone exposure specifically on the risk of lung cancer in women. METHODS: The PubMed, MEDLINE, Web of Science, and EMBASE databases were searched. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for female lung cancer risk associated with sex steroid hormones were calculated overall and by study design, publication year, population, and smoking status. Sensitivity analysis, publication bias, and subgroup analysis were performed. RESULTS: Forty-eight studies published between 1987 and 2019 were included in the study with a total of 31,592 female lung cancer cases and 1,416,320 subjects without lung cancer. Overall, higher levels of sex steroid hormones, both endogenous (OR: 0.92, 95% CI: 0.87-0.98) and exogenous (OR: 0.86, 95% CI: 0.80-0.93), significantly decreased the risk of female lung cancer by 10% (OR: 0.90, 95% CI: 0.86-0.95). The risk of lung cancer decreased more significantly with a higher level of sex steroid hormones in non-smoking women (OR: 0.88, 95% CI: 0.78-0.99) than in smoking women (OR: 0.98, 95% CI: 0.77-1.03), especially in Asia women (OR: 0.84, 95% CI: 0.74-0.96). CONCLUSIONS: Our meta-analysis reveals an association between higher levels of sex steroid hormone exposure and the decreased risk of female lung cancer. Surveillance of sex steroid hormones might be used for identifying populations at high risk for lung cancer, especially among non-smoking women.

BACKGROUND: The baculoviral IAP repeat containing 5 (BIRC5) related to epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). However, it remains unclear whether BIRC5-related genes can be used as prognostic markers of HCC. METHODS: Kaplan-Meier (K-M) survival curve was used to assess the Overall Survival (OS) of high- and low-expression group divided by the median of BIRC5 expression. The differentially expressed genes (DEGs) between the two groups were screened using the limma package, and performed the functional enrichment analysis by the clusterProfiler package. WGCNA was used to analyze the relationship of the module and the clinical traits. The risk signature was constructed by univariate and multivariate Cox regression analyses and the enrichment analysis of genes in the risk signature was performed by the Intelligent pathway analysis (IPA). The immunophenoscore (IPS) and the tumor immune dysfunction and exclusion (TIDE) were used to estimate the clinical significance of the risk groups. RESULTS: BIRC5 was high-expressed in HCC samples and associated with a poor prognosis (p-value < 0.0001). WGCNA screened 180 module genes which were overlapped with the 241 DEGs, ultimately getting 33 candidate genes. After the Cox regression analyses, CENPA, CDCA8, EZH2, KIF20A, KPNA2, CCNB1, KIF18B and MCM4 were preserved and used to construct risk signature, followed by calculating the risk score. The patients in high-risk groups stratified by median of the risk score were associated with a poor prognosis. The risk score had high accuracy [the area under the curve (AUC) > 0.72] and was closely associated with clinicopathological characteristics of HCC patients. IPA suggested that the 8 genes were enriched in Cancer and Immunological disease related pathways. IPS and TIDE score indicated that the genes in low-risk group could cause an immune response, and patients in the low-risk group may be more sensitive to the immune checkpoint blockade (ICB) therapy. CONCLUSION: The risk score constructed by the 8 genes could not only predict the clinical outcome but also distinguish the cohort of ICB therapy in HCC, which exerted a vital value in treatment and prognosis of HCC.

INTRODUCTION: Access to childhood cancer medicines is a critical global health challenge. There is a lack of sufficient context-specific data in Ghana on access to essential medicines for treating childhood cancers. Here, we present an analysis of essential cancer medicine availability, pricing, and affordability using the pediatric oncology unit of a tertiary hospital as the reference point. METHOD: Data on prices and availability of 20 strength-specific essential cancer medicines and eight non-cancer medicines were evaluated using the modified World Health Organization (WHO)/Health Action International method. Two pharmacies in the hospital and four private pharmacies around the hospital were surveyed. We assessed their median price ratio using the WHO international reference price guide. The number of days wages per the government daily wage salary was used to calculate the affordability of medicines. RESULTS: The mean availability of essential cancer medicines and non-cancer medicines at the hospital pharmacies were 27 and 38% respectively, and 75 and 84% respectively for private pharmacies. The median price ratio of cancer medicines was 1.85, and non-cancer medicines was 3.75. The estimated cost of medicines for treating a 30 kg child with Acute lymphoblastic leukaemia was GHȻ 4928.04 (US$907.56) and GHȻ 4878.00 (US$902.62) for Retinoblastoma, requiring 417 and 413-days wages respectively for the lowest-paid unskilled worker in Ghana. CONCLUSION: The mean availability of cancer medicines at the public and private pharmacies were less than the WHO target of 80%. The median price ratio for cancer and non-cancer medicines was less than 4, yet the cost of medicines appears unaffordable in the local setting. A review of policies and the establishment of price control could improve availability and reduce medicines prices for the low-income population.

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.

Erratum in BMC Cancer. 2021 Jul 15;21(1):811.

BACKGROUND: Currently biomarkers play an essential role in diagnosis, treatment, and management of cancer. In non-small cell lung cancer (NSCLC) determination of biomarkers such as ALK, EGFR, ROS1 or PD-L1 is mandatory for an adequate treatment decision. The aim of this study is to determine the clinical and economic impact of current anaplastic lymphoma kinase testing scenario in Spain. METHODS: A joint model, composed by decision-tree and Markov models, was developed to estimate the long-term health outcomes and costs of NSCLC patients, by comparing the current testing scenario for ALK in Spain vs a hypothetical no-testing. The current distribution of testing strategies for ALK determination and their sensitivity and specificity data were obtained from the literature. Treatment allocation based on the molecular testing result were defined by a panel of Spanish experts. To assess long-term effects of each treatment, 3-states Markov models were developed, where progression-free survival and overall survival curves were extrapolated using exponential models. Medical direct costs (expressed in €, 2019) were included. A lifetime horizon was used and a discount rate of 3% was applied for both costs and health effects. Several sensitivity analyses, both deterministic and probabilistic, were performed in order test the robustness of the analysis. RESULTS: We estimated a target population of 7628 NSCLC patients, including those with non-squamous histology and those with squamous carcinomas who were never smokers. Over the lifetime horizon, the current ALK testing scenario produced additional 5060 and 3906 life-years and quality-adjusted life-years (QALY), respectively, compared with the no-testing scenario. Total direct costs were increased up to € 51,319,053 for testing scenario. The incremental cost-effectiveness ratio was 10,142 €/QALY. The sensitivity analyses carried out confirmed the robustness of the base-case results, being the treatment allocation and the test accuracy (sensitivity and specificity data) the key drivers of the model. CONCLUSIONS: ALK testing in advanced NSCLC patients, non-squamous and never-smoker squamous, provides more than 3000 QALYs in Spain over a lifetime horizon. Comparing this gain in health outcomes with the incremental costs, the resulting incremental cost-effectiveness ratio reinforces that testing non-squamous and never-smoker squamous NSCLC is a cost-effective strategy in Spain.

BACKGROUND: Accumulating evidences demonstrated tumor microenvironment (TME) of bladder cancer (BLCA) may play a pivotal role in modulating tumorigenesis, progression, and alteration of biological features. Currently we aimed to establish a prognostic model based on TME-related gene expression for guiding clinical management of BLCA. METHODS: We employed ESTIMATE algorithm to evaluate TME cell infiltration in BLCA. The RNA-Seq data from The Cancer Genome Atlas (TCGA) database was used to screen out differentially expressed genes (DEGs). Underlying relationship between co-expression modules and TME was investigated via Weighted gene co-expression network analysis (WGCNA). COX regression and the least absolute shrinkage and selection operator (LASSO) analysis were applied for screening prognostic hub gene and establishing a risk predictive model. BLCA specimens and adjacent tissues from patients were obtained from patients. Bladder cancer (T24, EJ-m3) and bladder uroepithelial cell line (SVHUC1) were used for genes validation. qRT-PCR was employed to validate genes mRNA level in tissues and cell lines. RESULTS: 365 BLCA samples and 19 adjacent normal samples were selected for identifying DEGs. 2141 DEGs were identified and used to construct co-expression network. Four modules (magenta, brown, yellow, purple) were regarded as TME regulatory modules through WGCNA and GO analysis. Furthermore, seven hub genes (ACAP1, ADAMTS9, TAP1, IFIT3, FBN1, FSTL1, COL6A2) were screened out to establish a risk predictive model via COX and LASSO regression. Survival analysis and ROC curve analysis indicated our predictive model had good performance on evaluating patients prognosis in different subgroup of BLCA. qRT-PCR result showed upregulation of ACAP1, IFIT3, TAP1 and downregulation of ADAMTS9, COL6A2, FSTL1,FBN1 in BLCA specimens and cell lines. CONCLUSIONS: Our study firstly integrated multiple TME-related genes to set up a risk predictive model. This model could accurately predict BLCA progression and prognosis, which offers clinical implication for risk stratification, immunotherapy drug screen and therapeutic decision.

BACKGROUND: Gastric cancer (GC) is a primary reason for cancer death in the world. At present, GC has become a public health issue urgently to be solved to. Prediction of prognosis is critical to the development of clinical treatment regimens. This work aimed to construct the stable gene set for guiding GC diagnosis and treatment in clinic. METHODS: A public microarray dataset of TCGA providing clinical information was obtained. Dimensionality reduction was carried out by selection operator regression on the stable prognostic genes discovered through the bootstrap approach as well as survival analysis. FINDINGS: A total of 2 prognostic models were built, respectively designated as stable gene risk scores of OS (SGRS-OS) and stable gene risk scores of PFI (SGRS-PFI) consisting of 18 and 21 genes. The SGRS set potently predicted the overall survival (OS) along with progression-free interval (PFI) by means of univariate as well as multivariate analysis, using the specific risk scores formula. Relative to the TNM classification system, the SGRS set exhibited apparently higher predicting ability. Moreover, it was suggested that, patients who had increased SGRS were associated with poor chemotherapeutic outcomes. INTERPRETATION: The SGRS set constructed in this study potentially serves as the efficient approach for predicting GC patient survival and guiding their treatment.

BACKGROUND: Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. METHODS: The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. RESULT: ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo. CONCLUSIONS: HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

BACKGROUND: Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients' opinions on smoking. METHODS: A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form. RESULTS: Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis. CONCLUSION: The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.

OBJECTIVE: Plasma Epstein-Barr virus (EBV) DNA is considered a biomarker for nasopharyngeal carcinoma (NPC). However, its long-term role in NPC development is unclear. MATERIALS AND METHODS: A total of 1363 participants seropositive for EBV VCA-IgA and EBNA1-IgA in a community-based NPC screening program in southern China were tested for plasma EBV DNA levels by real-time qPCR between 2008 and 2015. New NPC cases were confirmed by active follow-up approach and linkage to local cancer registry through the end of 2016. Cox proportional hazards regression analysis was performed to calculate the hazard ratios (HRs) for NPC risk with plasma EBV DNA. RESULTS: Thirty patients were newly diagnosed during a median 7.5 years follow-up. NPC incidence increased with the plasma EBV DNA load ranging from 281.46 to 10,074.47 per 100,000 person-years in participants with undetectable and ≥ 1000 copies/ml levels; the corresponding cumulative incidence rates were 1.73 and 50%. Furthermore, plasma EBV DNA loads conferred an independent risk for NPC development after adjustment for other risk factors, with HRs of 7.63 for > 3-999 copies/ml and 39.79 for ≥1000 copies/ml. However, the HRs decreased gradually after excluding NPC cases detected in the first 2 to 3 years and became statistically nonsignificant by excluding cases detected during the first 4 years. CONCLUSION: Elevated plasma EBV DNA can predict NPC risk over 3 years. Monitoring plasma EBV DNA can be used as a complementary approach to EBV serological antibody-based screening for NPC.

BACKGROUND: Updated response assessment in neuro-oncology (RANO) does not consider peritumoral non-enhancing lesion (NEL) and baseline (residual) contrast enhancement (CE) volume. The objective of this study is to explore helpful imaging characteristics to refine RANO for assessing early treatment response (pseudoprogression and time-to-progression [TTP]) in patients with IDH wild-type glioblastoma. METHODS: This retrospective study enrolled 86 patients with IDH wild-type glioblastoma who underwent consecutive MRI examinations before and after concurrent chemoradiotherapy (CCRT). NEL was classified as edema- or tumor-dominant type on pre-CCRT MRI. CE evolution was categorized into 4 patterns based on post-operative residual CE (measurable vs. non-measurable) and CE volume change (same criteria with RANO) during CCRT. Multivariable logistic regression, including clinical parameters, NEL type, and CE evolution pattern, was used to analyze pseudoprogression rate. TTP and OS according to NEL type and CE evolution pattern was analyzed by the Kaplan-Meier method. RESULTS: Pseudoprogression rate was significantly lower (chi-square test, P = .047) and TTP was significantly shorter (hazard ratio [HR] = 2.03, P = .005) for tumor-dominant type than edema-dominant type of NEL. NEL type was the only predictive marker of pseudoprogression on multivariate analysis (odds ratio = 0.26, P = .046). Among CE evolution patterns, TTP and OS was shortest in patients with residual CE compared with those exhibiting new CE (HR = 4.33, P < 0.001 and HR = 3.71, P = .009, respectively). In edema-dominant NEL type, both TTP and OS was stratified by CE evolution pattern (log-rank, P = .001), whereas it was not in tumor-dominant NEL. CONCLUSIONS: NEL type improves prediction of pseudoprogression and, together with CE evolution pattern, further stratifies TTP and OS in patients with IDH wild-type glioblastoma and may become a helpful biomarker for refining RANO.

BACKGROUND: Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. METHODS: To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. RESULTS: Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells. CONCLUSIONS: Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.