BACKGROUND: Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility. METHODS: DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results. RESULTS: A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74-18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13-13.86, OR = 3.96). CONCLUSIONS: AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. Comparison of prognosis between LS and sporadic CRC (SCRC) were rare, with conflicting results. This study aimed to compare the long-term outcomes between patients with LS and SCRC. METHODS: Between June 2008 and September 2018, a total of 47 patients were diagnosed with LS by genetic testing at Fudan University Shanghai Cancer Center. A 1:2 propensity score matching was performed to obtain homogeneous cohorts from SCRC group. Thereafter, 94 SCRC patients were enrolled as control group. All of enrolled patients received curative surgeries and standardized postoperative monitoring. The long-term survival rates between the two groups were compared, and the prognostic factors were also analyzed. RESULTS: The 5-year overall survival rate of LS group was 97.6%, which was significantly higher than of 82.6% for SCRC group (χ2 = 4.745, p = 0.029). The 5-year recurrence free survival rate showed no significant differences between the two groups (78.0% for LS group vs. 70.6% for SCRC patients; χ2 = 1.260, p = 0.262). The 5-year tumor free survival rates in LS group was 62.1% for LS patients, which were significantly lower than of 70.6% for SCRC group (χ2 = 4.258, p = 0.039). Subgroup analysis of recurrent patients show that the LS group had longer overall survival than the SCRC group after combined chemotherapy. By multivariate analysis, we found that tumor recurrence of primary CRC [Risk ratio (95% (confidence interval): 48.917(9.866-242.539); p < 0.001] and late TNM staging [Risk ratio (95% (confidence interval): 2.968(1.478-5.964); p = 0.002] were independent risk factors for OS. CONCLUSION: LS patients have better long-term survival prognosis than SCRC patients, even though the two groups have statistically comparable recurrence free survival. Combined chemotherapy is an effective treatment for LS patients who developed primary CRC recurrence. Standardized postoperative monitoring for LS patients may enable detection of metachronous tumors at earlier stages, which was a guarantee of a favorable prognosis despite lower tumor free survival.

BACKGROUND: lncRNAs have important roles in regulating cancer biology. Accumulating evidence has established a link between the dysregulation of lncRNAs and microRNA in cancer progression. In previous studies, miR-7-5p has been found to be significantly down-regulated in mesenchymal-like lung cancer cell lines and directly regulated EGFR. In this work, we investigated the lncRNA partner of miR-7-5p in the progression of lung cancer. METHODS: We investigated the expression of miR-7-5p and the lncRNA after transfection with an miR-7-5p mimics using a microarray. The microarray results were validated using quantitative real time-polymerase Chain Reaction (qRT-PCR). The regulatory effects of lncRNA on miR-7-5p and its target were evaluated by changes in the expression of miR-7-5p after transfection with siRNAs for lncRNA and the synthesis of full-length lncRNA. The effect of miR-7-5p on lncRNA and the miRNA target was evaluated after transfection with miRNA mimic and inhibitor. The role of lncRNA in cancer progression was determined using invasion and migration assays. The level of lncRNA and EGFR in lung cancer and normal lung tissue was analyzed using TCGA data. RESULTS: We found that LINC00240 was downregulated in lung cancer cell line after miR-7-5p transfection with an miR-7-5p mimic. Further investigations revealed that the knockdown of LINC00240 induced the overexpression of miR-7-5p. The overexpression of miR-7-5p diminished cancer invasion and migration. The EGFR expression was down regulated after siRNA treatment for LINC00240. Silencing LINC00240 suppressed the invasion and migration of lung cancer cells, whereas LINC00240 overexpression exerted the opposite effect. The lower expression of LINC00240 in squamous lung cancer was analyzed using TCGA data. CONCLUSIONS: Taken together, LINC00240 acted as a sponge for miR-7-5p and induced the overexpression of EGFR. LINC00240 may represent a potential target for the treatment of lung cancer.

BACKGROUND: Surgical resection remains the only curative treatment for pancreatic cancer and is associated with significant post-operative morbidity and mortality. Patients eligible for surgery, increasingly receive neo-adjuvant therapy before surgery or adjuvant therapy afterward, inherently exposing them to toxicity. As such, optimizing physical function through exercise during treatment remains imperative to optimize quality of life either before surgery or during rehabilitation. However, current exercise efficacy and prescription in pancreatic cancer is unknown. Therefore, this study aims to summarise the published literature on exercise studies conducted in patients with pancreatic cancer undergoing treatment with a focus on determining the current prescription and progression patterns being used in this population. METHODS: A systematic review of four databases identified studies evaluating the effects of exercise on aerobic fitness, muscle strength, physical function, body composition, fatigue and quality of life in participants with pancreatic cancer undergoing treatment, published up to 24 July 2020. Two reviewers independently reviewed and appraised the methodological quality of each study. RESULTS: Twelve studies with a total of 300 participants were included. Heterogeneity of the literature prevented meta-analysis. Exercise was associated with improvements in outcomes; however, study quality was variable with the majority of studies receiving a weak rating. CONCLUSIONS: High quality evidence regarding the efficacy and prescription of exercise in pancreatic cancer is lacking. Well-designed trials, which have received feedback and input from key stakeholders prior to implementation, are required to examine the impact of exercise in pancreatic cancer on key cancer related health outcomes.

BACKGROUND: In contrast to the rapid increase in thyroid cancer incidence, the mortality has remained low and stable over the last decades. In Ecuador, however, thyroid cancer mortality has increased. The objective of this study is to determine possible drivers of high rates of thyroid cancer mortality, through a cross-sectional analysis of all patients attending a thyroid cancer referral center in Ecuador. METHODS: From June 2014 to December 2017, a cross-sectional study was conducted at the Hospital de Especialidades Eugenio Espejo, a regional reference public hospital for endocrine neoplasia in adults in Quito, Ecuador. We identified the mechanism of detection, histopathology and treatment modalities from a patient interview and review of clinical records. RESULTS: Among 452 patients, 74.8% were young adults and 94.2% (426) were female. 13.7% had a family history of thyroid cancer, and patients' median tumor size was 2 cm. The incidental finding was 54.2% whereas 45.8% was non-incidental. Thyroid cancer histology reported that 93.3% had papillary thyroid cancer (PTC), 2.7% follicular, 1.5% Hurtle cells, 1.6% medullary, 0.7% poor differentiated, and 0.2% anaplastic carcinoma. The mean MACIS (metastasis, age, completeness, invasion, and size) score was 4.95 (CI 4.15-5.95) with 76.2% of the thyroid cancer patients having MACIS score less than or equal to 6. The very low and low risk of recurrence was 18.1% (79) and 62% (271) respectively. An analysis of 319 patients with non-metastatic thyroid cancer showed that 10.7% (34) of patients had surgical complications. Moreover, around 62.5% (80 from 128 patients with thyroglobulin laboratory results) of TC patients had a stimulated-thyroglobulin value equal or higher than 2 ng/ml. Overall, a poor surgical outcome was present in 35.1% (112) patients. Out of 436 patients with differentiated thyroid carcinoma, 86% (375) received radioactive iodine. CONCLUSION: Thyroid cancer histological characteristics and method of diagnosis are like those described in other reports without any evidence of the high frequency of aggressive thyroid cancer histology. However, we observed evidence of overtreatment and poor surgical outcomes that demand additional studies to understand their association with thyroid cancer mortality in Ecuador.

BACKGROUND: Our previous studies demonstrated that the administration of crude Polysaccharide from Panax notoginseng (CPPN) can effectively prolong the lifespan of tumor-bearing mice via boosting the host immune system as well as weak cytotoxicity against hepatocellular carcinoma (HCC). In the present study, Neutral Polysaccharide (NPPN) were further purified from crude polysaccharide isolated from panax notoginseng. The effects of NPPN on the immune function and hematopoietic function of mice with low immunity and myelosuppression induced by cyclophosphamide (CTX) were investigated. The effect of NPPN combined with CTX on the tumor inhibition rate of the H22 tumor-bearing mice and the impact of NPPN on the proliferation of H22 liver cancer cells in vitro were investigated. METHODS: CPPN was obtained by water extraction and alcohol precipitation method, and further purified by DEAE Sepharose Fast Flow ion exchange resin column. NPPN was added to the immunosuppressed with myelosuppression mice induced by CTX. Thymus index, spleen index, lymphocyte proliferation stimulation index by adding of concanavalin A, determination of serum hemolysin, NK cell activity assay, mice carbon clearance experiment, blood count tests were detected. The tumor inhibition rate of the H22 tumor-bearing mice treated with NPPN combined with CTX was recorded. RESULTS: NPPN and 4 kinds of acid polysaccharide from Panax notoginseng (APPN) were successfully isolated from the CPPN by DEAE Sepharose Fast Flow ion exchange resin column. NPPN inhibited the growth of H22 cells and significantly increase the tumor inhibition rate of the H22 tumor-bearing mice combined with CTX. The elevation of the cellular and humoral immunity levels as well as a variety of blood count tests indicators of immunosuppressive with myelosuppression mice may contribute to the antitumor activity of NPPN. CONCLUSION: NPPN has a potential antitumor activity for the treatment of liver cancer combined with cyclophosphamide.

BACKGROUND: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. METHODS: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. RESULTS: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. CONCLUSIONS: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses. TRIAL REGISTRATION: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ).

BACKGROUND: Anterior gradient-2 (AGR2) is a proto-oncogene involved in tumorigenesis and cancer progression. AGR2, predominantly localized in the endoplasmic reticulum (ER), is also a secreted protein detected in the extracellular compartment in multiple cancers. However, the biological functions of intracellular and extracellular AGR2 remain to be elucidated. METHODS: Based on the biochemical structure of AGR2 protein, PANC-1 pancreatic cancer cells stably expressing ER-resident or secreted AGR2 were generated by a lentivirus-mediated stable overexpression system. The capacities of cell proliferation, migration, invasion and survival were assessed in PANC-1 stable cells. Moreover, EGFR expression and activation were determined to explore the possible mechanism of AGR2 roles in pancreatic cancer tumorigenesis. RESULTS: It was discovered that secreted AGR2, but not ER-resident AGR2, promotes cell proliferation, migration and invasion of PANC-1 cells. Moreover, the data indicated that both the ER-resident and the secreted AGR2 enhance the survival capacity of PANC-1 cells after tunicamycin-induced ER stress and gemcitabine treatment. However, EGFR expression and activation were not found to be involved in AGR2-dependent oncogenic phenotypes in PANC-1 cells. CONCLUSIONS: Secreted AGR2 is predominantly involved in cell proliferation, migration and invasion in PANC-1 pancreatic cancer cells. Both secreted and ER-resident AGR2 contribute to the survival of PANC-1 cells under the challenging conditions. These findings provide insight into how different localizations of AGR2 have contributed to pancreatic cancer growth, metastasis, and drug sensitivity.

BACKGROUND: The aim of our study was to evaluate the cost-effectiveness of cabazitaxel versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel who had progression within 12 months while receiving an alternative inhibitor (abiraterone or enzalutamide) from a US payer's perspective. METHODS: To conduct the cost-effectiveness analysis, a Markov decision model was established. Three health states (progression-free survival (PFS), progressive disease (PD) and death) were included, and the incremental cost-effectiveness ratio (ICER) was regarded as the primary endpoint. The willingness-to-pay (WTP) threshold was set at $100,000.00/quality-adjusted life year (QALY), and discounted rates were set at 3% annually. Efficacy data were derived from the CARD trial and Weibull distribution curves were modeled to fit the survival curves. The robustness of the analysis was tested with a series of one-way sensitivity analyses and probabilistic sensitivity analyses. RESULTS: Overall, the incremental effectiveness and cost of cabazitaxel versus androgen-signaling-targeted inhibitors (ASTIs) were 0.16 QALYs and $49,487.03, respectively, which yielded an ICER of $309,293.94/QALY. Our model was mostly sensitive to the duration of PFS in the cabazitaxel group, cost of cabazitaxel and utility of the PFS state. At a WTP threshold of $100,000.00/QALY, cabazitaxel was the dominant strategy in 0% of the simulations. CONCLUSIONS: Cabazitaxel is unlikely to be a cost-effective treatment option compared with ASTIs in patients with mCRPC previously treated with docetaxel who had progression within 12 months while receiving ASTIs.

BACKGROUND: This study aimed to evaluate the impact of postoperative complications on long-term survival in patients with peritoneal metastasis (PM) arising from colorectal cancer (CRC) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Patients with PM arising from CRC treated with CRS and HIPEC were systematically reviewed at the China National Cancer Center and Huanxing Cancer Hospital from June 2017 to June 2019. High-grade complications that occurred within 30 days were defined as grade 3 to 4 events according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Univariate and multivariable Cox regression models for overall survival were created. Predictors of high-grade postoperative complications were evaluated with univariate and multivariate logistic regression analyses. RESULTS: In all, 86 consecutive cases were included in this study. Forty-one patients (47.7%) developed postoperative complications, while 22 patients (25.6%) experienced high-grade complications. No mortality occurred during the postoperative period. The median survival of all patients was 25 months, and the estimated 3-year overall survival (OS) rate was 35.0%. In the multivariable Cox regression analysis, a high peritoneal carcinomatosis index (PCI) score (HR, 1.07, 95% CI, 1.01-1.14; P=0.015) and grade 3-4 postoperative complications (HR, 1.86, 95% CI, 1.22-3.51; P=0.044) correlated with worse overall survival. High estimated blood loss (OR, 1.01, 95% CI, 1.01-1.02; P< 0.001) was identified as an independent risk factor for developing high-grade complications. CONCLUSION: Careful patient selection, high levels of technical skill and improved perioperative management are crucial to ensure patient survival benefits after CRS+HIPEC.

BACKGROUND: Immune checkpoint inhibitors-induced myocarditis presents unique clinical challenges. Here, we assessed post-marketing safety of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors by mining the real-world data reported in two international pharmacovigilance databases. METHODS: We analyzed immune checkpoint inhibitors (ICIs)-associated fatal adverse drug events (ADEs) reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collected from July 1, 2014 to December 31, 2019 and data from EudraVigilance (EV) database accessed on February 29, 2020. Three different data mining approaches were used to detect the signal of fatal myocarditis caused by ICIs. RESULTS: Based on 7613 ICIs-related ADEs reported to the EV database and 5786 ICIs-associated ADEs submitted to the FAERS database, the most frequently reported ADE was ipilimumab-related colitis. For myocarditis, nivolumab-associated myocarditis was the most common. Among the five fatal toxic effects associated with ICIs, the lethality rate of myocarditis was the highest. Therefore, we further analyzed ICI-associated myocarditis and found that elderly patients and male patients were more likely to develop ICIs-related myocarditis. The results of signal detection showed that the risk signal of avelumab-related myocarditis detected by reporting odds ratio (ROR) method and proportional reporting ratios (PRR) method was the highest, whereas the signal strength of ipilimumab-related myocarditis detected by Bayesian confidence propagation neural networks (BCPNN) method was the strongest. CONCLUSION: The findings of this study indicated the potential safety issues of developing myocarditis when using ICIs, which were consistent with the results of previous clinical trials and could provide a reference for clinical workers when using ICIs.

BACKGROUND: To improve the efficiency of early diagnosis systems for cervical cancer, the use of cellular and viral markers for identifying precancerous lesions with a greater probability to progress to cancer has been proposed. Several cellular proteins and markers of oxidative DNA damage have been suggested as possible biomarkers of cervical carcinogenesis; however, they have not been evaluated together. In this study, we analyzed the expression of the cellular markers p16INK4a, Ki-67, CyclinE1, TOP2A/MCM2, and telomerase, as well as the DNA oxidative damage markers ROS and 8-OHdG. The analyses were performed in liquid-based cervical cytology samples or biopsies with premalignant lesions or cervical cancer diagnosis, with the purpose of selecting a panel of biomarkers that allow the identification of precursor lesions with greater risk of progression to cervical cancer. METHODS: We analyzed 1485 liquid-based cytology samples, including 239 non-squamous intraepithelial lesions (NSIL), 901 low-grade squamous intraepithelial lesions (LSIL), 54 high-grade squamous intraepithelial lesions (HSIL), and 291 cervical cancers (CC). The biomarkers were analyzed by immunocytochemistry and Human Papilloma Virus (HPV) genotyping with the INNO-LiPA genotyping Extra kit. RESULTS: We found that all tested cellular biomarkers were overexpressed in samples with high risk-HPV infection, and the expression levels increased with the severity of the lesion. TOP2A/MCM2 was the best biomarker for discriminating between LSIL and HSIL, followed by p16INK4a and cyclinE1. Statistical analysis showed that TOP2A/MCM2 provided the largest explanation of HSIL and CC cases (93.8%), followed by p16INK4a (91%), cyclin E1 (91%), Ki-67 (89.3%), and telomerase (88.9%). CONCLUSIONS: We propose that the detection of TOP2A/MCM2, p16INK4a and cyclin E1 expression levels is useful as a panel of biomarkers that allow identification of cervical lesions with a higher risk for progression to CC with high sensitivity and precision; this can be done inexpensively, in a single and non-invasive liquid-based cytology sample.

BACKGROUND: In recent years, the relationship between tumor-associated macrophages (TAMs) and solid tumors has become a research hotspot. This study aims to explore the close relationship of TAMs with metabolic reprogramming genes in hepatocellular carcinoma (HCC) to provide new methods of treatment for HCC. METHODS: The study selected 343 HCC patients with complete survival information (survival time > = 1 month) in the Cancer Genome Atlas (TCGA) as study subjects. Kaplan-Meier survival analysis assisted in determining the relationship between macrophage infiltration and overall survival (OS), and Pearson correlation tests were used to identify metabolic reprogramming genes (MRGs) associated with tumor macrophage abundance. Lasso regression algorithms were used on prognosis-related MRGs identified by Kaplan-Meier survival analysis and univariate Cox regression analysis to construct a risk score; another independent cohort (including 228 HCC patients) from the International Cancer Genome Consortium (ICGC) was used to verify prognostic signature externally. RESULTS: A risk score composed of 8 metabolic genes could accurately predict the OS of a training cohort (TCGA) and a testing cohort (ICGC). The risk score could be widely used for people with different clinical characteristics, and it is a predictor that is independent of other clinical factors that affect prognosis. As expected, compared with the low-risk group, the high-risk group exhibited an obviously higher macrophage abundance, together with a positive correlation between the risk score and the expression levels of three commonly used immune checkpoints (PD1, PDL1, and CTLA4). CONCLUSION: Our study constructed and validated a novel eight-gene signature for predicting HCC patient OS, which may contribute to clinical treatment decisions.

BACKGROUND: Aberrant expression of P-cadherin has been reported in various cancers, and has been attracting attention as a target for cancer treatment. Ovarian cancer, the leading cause of death among gynecologic malignancies, is classified into four histological subtypes: serous, mucinous, endometrioid, and clear cell, and each has distinct biological behavior. Although a negative survival impact in serous ovarian cancer patients and some functional role in peritoneal dissemination have been reported, differences of P-cadherin expression in histological subtypes and the proportion and distribution of positive cells remain to be investigated. The aims of this study were to clarify the histological and distributional profiles of P-cadherin expression in ovarian cancer for development of target-therapy in near future. METHODS: A total of 162 primary, 60 metastatic, and 8 recurrent tumors (all cases from 162 ovarian cancer patients) were enrolled in the study. Immunohistochemistry was performed for P-cadherin expression. Associations with clinicopathological characteristics and survival were analyzed. RESULTS: P-cadherin expression showed a strong correlation with the FIGO stage, histological subtypes, positive peritoneal dissemination (P < 0.01), positive distant metastasis (P < 0.05), and trend toward negative overall survival probability (P = 0.050). P-cadherin was intensely and broadly expressed in mucinous, endometrioid, and serous subtypes (P < 0.01). Disseminated tumors demonstrated similar P-cadherin expression to primary tumors whereas metastatic lymph nodes demonstrated significantly decreased expression (P < 0.01). CONCLUSIONS: Mucinous, endometrioid, and serous ovarian cancer patients accompanied with peritoneal disseminations are the most potent candidates for P-cadherin targeted drug delivery strategies. P-cadherin-targeted therapy may benefit and improve survival of poor-prognosis populations.

BACKGROUND: An upgraded understanding of factors (sex/estrogen) associated with survival benefit in advanced colorectal carcinoma (CRC) could improve personalised management and provide innovative insights into anti-tumour mechanisms. The aim of this study was to assess the efficacy and safety of cetuximab (CET) versus bevacizumab (BEV) following prior 12 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus BEV in postmenopausal women with advanced KRAS and BRAF wild-type (wt) CRC. METHODS: Prospectively maintained databases were reviewed from 2013 to 2017 to assess postmenopausal women with advanced KRAS and BRAF wt CRC who received up to 12 cycles of FOLFOXIRI plus BEV inductive treatment, followed by CET or BEV maintenance treatment. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rate. The secondary endpoint was the rate of adverse events (AEs). RESULTS: At a median follow-up of 27.0 months (IQR 25.1-29.2), significant difference was detected in median OS (17.7 months [95% confidence interval [CI], 16.2-18.6] for CET vs. 11.7 months [95% CI, 10.4-12.8] for BEV; hazard ratio [HR], 0.63; 95% CI, 0.44-0.89; p=0.007); Median PFS was 10.7 months (95% CI, 9.8-11.3) for CET vs. 8.4 months (95% CI, 7.2-9.6) for BEV (HR, 0.67; 95% CI 0.47-0.94; p=0.02). Dose reduction due to intolerable AEs occurred in 29 cases (24 [24.0%] for CET vs. 5 [4.8%] for BEV; p< 0.001). CONCLUSIONS: CET tends to be superior survival benefit when compared with BEV, with tolerated AEs.

BACKGROUND: Isocitrate dehydrogenase (IDH1/2) gene mutations are the most frequently observed mutations in cartilaginous tumors. The mutant IDH causes elevation in the levels of R-enantiomer of 2-hydroxylglutarate (R-2HG). Mesenchymal stromal cells (MSCs) are reasonable precursor cell candidates of cartilaginous tumors. This study aimed to investigate the effect of oncometabolite R-2HG on MSCs. METHODS: Human bone marrow MSCs treated with or without R-2HG at concentrations 0.1 to 1.5 mM were used for experiments. Cell Counting Kit-8 was used to detect the proliferation of MSCs. To determine the effects of R-2HG on MSC differentiation, cells were cultured in osteogenic, chondrogenic and adipogenic medium. Specific staining approaches were performed and differentiation-related genes were quantified. Furthermore, DNA methylation status was explored by Illumina array-based arrays. Real-time PCR was applied to examine the signaling component mRNAs involved in. RESULTS: R-2HG showed no influence on the proliferation of human MSCs. R-2HG blocked osteogenic differentiation, whereas promoted adipogenic differentiation of MSCs in a dose-dependent manner. R-2HG inhibited chondrogenic differentiation of MSCs, but increased the expression of genes related to chondrocyte hypertrophy in a lower concentration (1.0 mM). Moreover, R-2HG induced a pronounced DNA hypermethylation state of MSC. R-2HG also improved promotor methylation of lineage-specific genes during osteogenic and chondrogenic differentiation. In addition, R-2HG induced hypermethylation and decreased the mRNA levels of SHH, GLI1and GLI2, indicating Sonic Hedgehog (Shh) signaling inhibition. CONCLUSIONS: The oncometabolite R-2HG dysregulated the chondrogenic and osteogenic differentiation of MSCs possibly via induction of DNA hypermethylation, improving the role of R-2HG in cartilaginous tumor development.

BACKGROUND: Rho-family GTPases, including Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), are important modulators of cancer-relevant cell functions and are viewed as promising therapeutic targets. Based on high-throughput screening and cheminformatics we identified the R-enantiomer of an FDA-approved drug (ketorolac) as an inhibitor of Rac1 and Cdc42. The corresponding S-enantiomer is a non-steroidal anti-inflammatory drug (NSAID) with selective activity against cyclooxygenases. We reported previously that R-ketorolac, but not the S-enantiomer, inhibited Rac1 and Cdc42-dependent downstream signaling, growth factor stimulated actin cytoskeleton rearrangements, cell adhesion, migration and invasion in ovarian cancer cell lines and patient-derived tumor cells. METHODS: In this study we treated mice with R-ketorolac and measured engraftment of tumor cells to the omentum, tumor burden, and target GTPase activity. In order to gain insights into the actions of R-ketorolac, we also performed global RNA-sequencing (RNA-seq) analysis on tumor samples. RESULTS: Treatment of mice with R-ketorolac decreased omental engraftment of ovarian tumor cells at 18 h post tumor cell injection and tumor burden after 2 weeks of tumor growth. R-ketorolac treatment inhibited tumor Rac1 and Cdc42 activity with little impact on mRNA or protein expression of these GTPase targets. RNA-seq analysis revealed that R-ketorolac decreased expression of genes in the HIF-1 signaling pathway. R-ketorolac treatment also reduced expression of additional genes associated with poor prognosis in ovarian cancer. CONCLUSION: These findings suggest that R-ketorolac may represent a novel therapeutic approach for ovarian cancer based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor. R-ketorolac modulates relevant pathways and genes associated with disease progression and worse outcome.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. However, the molecular mechanisms and the prognostic prediction for EC patients remain unclear. METHODS: In the current study, we performed an in-depth analysis of over 500 patients which were obtained from the Cancer Genome Atlas (TCGA) database. The bioinformatics analysis included gene set enrichment analysis (GSEA) and Cox and lasso regression analyses to ensure overall survival (OS)-related genes, moreover, to construct a prognostic model and a nomogram for EC patients. RESULTS: GSEA identified 4 gene sets significantly associated with EC, which are DNA repair, unfolded protein response, reactive oxygen species pathway and UV response up. Twenty-five OS-related DNA repair genes were screened out, after that, a 9-mRNA signature was constructed to measure the risk scores of patients with different outcomes. In addition, a nomogram contained the 9-mRNA model and clinical parameters was also presented to assess the prognosis. Patients with low risk were more likely to have sensitivity to paclitaxel, vinblastine, rapamycin, metformin, imatinib, Akt inhibitor and lapatinib. CONCLUSIONS: The identified highly enriched gene sets may offer a novel insight into the tumorigenesis and treatment of EC. Additionally, the constructed 9-mRNA model and the nomogram have prominent clinical implications for prognosis evaluation and specific therapy guidance for EC patients.

BACKGROUND: An accurate intraoperative prediction of lymph node metastatic risk can help surgeons in choosing precise surgical procedures. We aimed to develop and validate nomograms to intraoperatively predict patterns of regional lymph node (LN) metastasis in patients with esophageal cancer. METHODS: The prediction model was developed in a training cohort consisting of 487 patients diagnosed with esophageal cancer who underwent esophagectomy with complete LN dissection from January 2016 to December 2016. Univariate and multivariable logistic regression were used to identify independent risk factors that were incorporated into a prediction model and used to construct a nomogram. Contrast-enhanced computed tomography reported LN status and was an important comparative factor of clinical usefulness in a validation cohort. Nomogram performance was assessed in terms of calibration, discrimination, and clinical usefulness. An independent validation cohort comprised 206 consecutive patients from January 2017 to December 2017. RESULTS: Univariate analysis and multivariable logistic regression revealed three independent predictors of metastatic regional LNs, three independent predictors of continuous regional LNs, and two independent predictors of skipping regional LNs. Independent predictors were used to build three individualized prediction nomograms. The models showed good calibration and discrimination, with area under the curve (AUC) values of 0.737, 0.738, and 0.707. Application of the nomogram in the validation cohort yielded good calibration and discrimination, with AUC values of 0.728, 0.668, and 0.657. Decision curve analysis demonstrated that the three nomograms were clinically useful in the validation cohort. CONCLUSION: This study presents three nomograms that incorporate clinicopathologic factors, which can be used to facilitate the intraoperative prediction of metastatic regional LN patterns in patients with esophageal cancer.

BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

BACKGROUND: Young adult cancer patients often face unique challenges and have potential unmet needs. This study aimed (1) to describe unmet supportive care needs among young adults with cancer in Japan, and (2) to identify its associated factors. METHODS: In a cross-sectional web-based survey, 206 young adults with cancer were assessed for supportive care needs. Multiple regression analysis examined whether demographics, clinical variables and social support were associated with unmet supportive care needs. RESULTS: A total of 206 patients (180 female) with a mean age of 33.7 years (SD = 4.3, range: 22-39) participated. One hundred and fifty-eight participants (76.7%) reported at least one unmet supportive care needs. The top 20 unmet needs included 9 of the 10 psychological needs, 3 of the 5 physical and daily living needs, 8 of the 11 health system and information needs and 1 of the 5 sexuality needs. Multiple regression analysis revealed that perceived poorer PS, experience of change in work/school after a cancer diagnosis and poor social support were significantly associated with higher supportive care needs. The total score of supportive care needs was significantly associated with both psychological distress and QOL. CONCLUSIONS: More than 70% of young adult cancer patients reported unmet supportive care needs and most of those were psychological needs. The findings suggest potential opportunities for intervention in addressing psychological needs rather than physical and information needs.

BACKGROUND: Serum tumor markers including AFU, AFP, CEA, CA199, CA125 and CA724, are of great importance in the diagnosis, prognostic prediction and recurrence monitoring of gastrointestinal malignancies. However, their significance in gastric cancer (GC) patients with neoadjuvant therapy (NCT) is still uncertain. The aim of this study was to evaluate the predictive value of these six tumor markers in locally advanced GC patients who underwent NCT and curative surgery. METHODS: In total, 290 locally advanced GC patients who underwent NCT and D2 radical gastrectomy were retrospectively analyzed. Data on their tumor markers before (pre-) and after (post-) NCT and pathological characteristics were extracted from the database of our hospital. The optimal cutoff values of the six tumor markers were calculated by the ROC curve and Youden index. Their predictive significance was analyzed and survival curves for overall survival (OS) were obtained by the Kaplan-Meier method. Associations between categorical variables were explored by the chi-square test or Fisher's exact test. Multivariate analyses were performed by the Cox regression model. RESULTS: Pre- and post-CA199, -CA125 and -CA724 could predict overall survival (all P < 0.05), but only the change (diff-) of CA199 was related to prognosis (P = 0.05). In the multivariable analysis, pre- (P = 0.014) and post-CA724 (P = 0.036) remained significant, though diff-CA724 was not an independent prognostic factor (P = 0.581). In addition, pre- and post-CA199, -CA125 and -CA724 were associated with lymph node metastasis (N- vs N+) and pathological stage (I-II vs III) (all P < 0.05). Moreover, post-CA724 was related to the vascular or lymphatic invasion (P = 0.019), while pre-CA724 was not (P = 0.082). However, AFU, AFP and CEA showed no association with survival (P > 0.05). CONCLUSIONS: CA724 is an independent factor for prognosis and could be used to predict ypN and ypTNM stage in locally advanced GC patients undergoing NCT and curative resection.

BACKGROUND: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). METHODS: A prospective observational cohort in Mexico (2012-2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12-16 weeks. RESULTS: The mean age of the cohort was 59 years (interquartile range [IQR] 50-72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7-10.5) and 40 months (95% CI: 34.5-45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2-83.8). On multivariable analyses, age > 65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31-0.86; p = 0.018). The median PFS in subjects aged > 65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2-18.8] vs. 7.2 months [95% CI: 5.3-9.1]; p = 0.012). Adverse events grade ≥ 3 associated with sorafenib occurred in 38 (29%) patients. CONCLUSION: Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 years old.

BACKGROUND: Hepatocellular carcinoma (HCC) remains the most frequent liver cancer, accounting for approximately 90% of primary liver cancers worldwide. The recurrence-free survival (RFS) of HCC patients is a critical factor in devising a personal treatment plan. Thus, it is necessary to accurately forecast the prognosis of HCC patients in clinical practice. METHODS: Using The Cancer Genome Atlas (TCGA) dataset, we identified genes associated with RFS. A robust likelihood-based survival modeling approach was used to select the best genes for the prognostic model. Then, the GSE76427 dataset was used to evaluate the prognostic model's effectiveness. RESULTS: We identified 1331 differentially expressed genes associated with RFS. Seven of these genes were selected to generate the prognostic model. The validation in both the TCGA cohort and GEO cohort demonstrated that the 7-gene prognostic model can predict the RFS of HCC patients. Meanwhile, the results of the multivariate Cox regression analysis showed that the 7-gene risk score model could function as an independent prognostic factor. In addition, according to the time-dependent ROC curve, the 7-gene risk score model performed better in predicting the RFS of the training set and the external validation dataset than the classical TNM staging and BCLC. Furthermore, these seven genes were found to be related to the occurrence and development of liver cancer by exploring three other databases. CONCLUSION: Our study identified a seven-gene signature for HCC RFS prediction that can be used as a novel and convenient prognostic tool. These seven genes might be potential target genes for metabolic therapy and the treatment of HCC.

BACKGROUND: The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various "true" dose-toxicity relationships. METHODS: One thousand studies were simulated for each "true" dose toxicity relationship considered, four were based on clinical trial data (AZD3514, AZD1208, AZD1480, AZD4877), and four were theoretical. The 3 + 3 method and 2-stage extended CRM with six skeletons were applied to identify the MTD, where the true MTD was considered as the largest dose where the probability of experiencing a dose limiting toxicity (DLT) is ≤33%. RESULTS: For every true dose-toxicity relationship, the CRM selected the MTD that matched the true MTD in a higher proportion of studies compared to the 3 + 3 method. The CRM overestimated the MTD in a higher proportion of simulations compared to the 3 + 3 method. The proportion of studies where the correct MTD was selected varied considerably between skeletons. For some true dose-toxicity relationships, some skeletons identified the true MTD in a higher proportion of scenarios compared to the skeleton that matched the true dose-toxicity relationship. CONCLUSION: Through simulation, the CRM generally outperformed the 3 + 3 method for the clinical and theoretical true dose-toxicity relationships. It was observed that accurate estimates of the true skeleton do not always outperform a generic skeleton, therefore the application of wide confidence intervals may enable a generic skeleton to be used. Further work is needed to determine the optimum skeleton.

BACKGROUND: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. METHODS: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. DISCUSSION: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. TRIAL REGISTRATION: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

BACKGROUND: In people with albinism (PWA), the deficiency of melanin increase the risk of skin cancers. The aim of this study was to determine the prevalence of skin cancers and characteristics of these detected skin cancers (histological types, localization) in PWA in 10 cities in Togo in 2019. METHODS: This is a cross-sectional study of medical records of PWA systematically examined during two mobile skin care clinics in 2019, as part of a programme for the prevention and management of skin cancers in these subjects. RESULTS: During the study period, 280 (95.2%) of the 294 PWA consulted, had developed skin lesions. Of the 280 PWA, the pathological reports from the medical records of 33 patients (11.8%; (95%CI = [8.2-16.2]) had concluded to non-melanoma skin cancers. The mean age of these 33 patients was 38.6 ± 15.2 years and the sex-ratio was 1. Their occupations were mainly resellers (21.2%), traders (15.2%) and farmers (12.2%). In the 33 patients, 54 cases of non-melanoma skin cancers were identified, with some patients having more than one tumor, and some of them having more than one (histologically confirmed) diagnosis. These 54 non-melanoma skin cancers were divided into 21 cases of invasive squamous cell carcinomas, 2 cases of Bowen's disease and 31 cases of basal cell carcinomas. These non-melanoma skin cancers mainly occurred in the head and neck (33 cases; 61.1%), the upper limbs (15 cases; 27, 8%) and the trunk (4 cases; 7.4%). CONCLUSION: The results of this study show a high prevalence of skin cancers among PWAs in Togo in 2019, only non-melanoma skin cancers. In addition, they illustrate the role of ultraviolet rays with regard to the localization of skin cancers and the occupations of patients. Popularization and compliance with photo protection measures, systematic and regular examination of the skin of these PWAs will allow early detection and treatment of these skin cancers.

BACKGROUND: Actuarial survival based on the Kaplan-Meier method can overestimate actual long-term survival, especially among those with factors of poor prognosis. Patients with American Joint Committee on Cancer stage III soft tissue sarcoma (STS) represent a subset with a high risk of STS-specific mortality. Therefore, we aimed to characterize the clinicopathological characteristics associated with actual long-term survival in patients with stage III STS. METHODS: We retrospectively reviewed 116 patients who underwent surgical resection for stage III STS with curative intent between March 2000 and December 2013. Long-term survivors (n = 61), defined as those who survived beyond 5 years, were compared with short-term survivors (n = 36), who died of STS within 5 years. RESULTS: Multivariate logistic regression analyses showed that a tumor size < 10 cm [odds ratio (OR) 3.95, p = 0.047], histological grade of 2 (OR 8.12, p = 0.004), and American Society of Anesthesiologists (ASA) score of 1 (OR 11.25, p = 0.001) were independently associated with actual 5-year survival. However, 66% of the long-term survivors exhibited factors of poor prognosis: 36% had a tumor size > 10 cm and 48% had a histological grade of 3. Leiomyosarcoma (3 of 10) was negatively associated with actual long-term survival. CONCLUSIONS: Actual 5-year survival after resection of stage III STS was associated with tumor size, histological grade, and ASA score. However, majority of the actual 5-year survivors exhibit factors of poor prognosis, suggesting that aggressive treatment should be offered for a chance of long-term survival in these patients.

BACKGROUND: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT. METHODS: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety. RESULTS: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable. CONCLUSION: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases. TRIAL REGISTRATION: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

BACKGROUND: Clear cell renal cell carcinoma is susceptible to ferroptosis, and immunotherapy is recently recommended as a priority for the initial treatment of metastatic clear cell renal carcinoma. Increased ferroptosis and immune activation can synergistically reinforce each other in killing cancer cells. NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis. Here, we aim to identify and validate the association between NCOA4 expression, clinicopathologic characteristics, and overall survival in ccRCC by using The Cancer Genome Atlas and Gene Expression Omnibus databases. We further analyze the interacted proteins of NCOA4 and infiltrated immune cells via TIMER and GEPIA databases. METHODS: NCOA4 expression in clear cell renal carcinoma (ccRCC) tissues and normal adjacent tissues in The Cancer Genome Atlas (TCGA) data were primarily screened, and further validated in another independent cohort from the gene expression omnibus (GEO) database and human protein atlas. The relationships of NCOA4 expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which NCOA4 interacted were also built using the online STRING website. Meanwhile, we use TIMER and GEPIA databases to investigate the relationships between NCOA4 expression and infiltrated immune cells and their corresponding gene marker sets. RESULTS: Contrast to normal tissue, NCOA4 expression was lower in ccRCC tumor tissue(p < 0.05). Lower NCOA4 expression was closely associated with high-grade malignancy and advanced TNM stage. Univariate and multivariate analysis indicated the overall survival of ccRCC cases with low NCOA4 level is shorter than those of patients with high NCOA4 expression (p < 0.05). FTL and FTH1 were the important proteins interacting with NCOA4. ccRCC with NCOA4 deficiency presented the paucity of infiltrated immune cells and their matching marker sets, including CD8+ T cells. CONCLUSION: Deficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.

Author information: (1)Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy. (2)Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padova, Italy. (3)Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy. paolo.delfiore@iov.veneto.it. (4)Division of Melanoma, Sarcoma and Rare Tumors, IRCCS, European Institute of Oncology, Milan, Italy. (5)Department of Melanoma and Cancer Immunotherapy, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. (6)Department of Dermatology, Santa Maria degli Angeli Hospital, Pordenone, Italy. (7)Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy. (8)Division of Plastic and Reconstructive Surgery and Burn Unit, University of Bari, Bari, Italy. (9)Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. (10)Section of Dermatology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. (11)Medical Oncology Unit, Santa Croce and Carle Teaching Hospital, Cuneo, Italy. (12)Pathology, ASST-Lariana, Ospedale Sant'Anna, Como, Italy. (13)DSM-Department of Medical Sciences, University of Trieste, Trieste, Italy. (14)Unit of General Surgery, San Pio X Hospital, Milan, Italy. (15)Department of Dermatology, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy. (16)Department of Cardiological, Thoracic and Vascular Sciences, and Public Health, University of Padova, Padova, Italy. (17)Independent Statistician, Solagna, Italy. (18)National Cancer Institute Fondazione G. Pascale, SC Chirurgia Melanoma e dei Tumori Cutanei, Naples, Italy. (19)Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland. METHODS: Cost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes. RESULTS: For unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained. In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus. CONCLUSIONS: Cost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

BACKGROUND: Cutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45-100% of patients receiving kinase inhibitors. Such adverse reactions may include skin inflammation, infection, pruritus and dryness, symptoms that can significantly affect the patient's quality of life. To prevent severe skin damages dose adjustment or drug discontinuation is often required, interfering with the prescribed oncology treatment protocol. This is particularly the case of Epidermal Growth Factor Receptor inhibitors (EGFRi) targeting carcinomas. Since the EGFR pathway is pivotal for epidermal keratinocytes, it is reasonable to hypothesize that EGFRi also affect these cells and therefore interfere with the epidermal structure formation and skin barrier function. METHODS: To test this hypothesis, the effects of EGFRi and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) at therapeutically relevant concentrations (3, 10, 30, 100 nM) were assessed on proliferation and differentiation markers of human keratinocytes in a novel 3D micro-epidermis tissue culture model. RESULTS: EGFRi directly affect basal keratinocyte growth, leading to tissue size reduction and switching keratinocytes from a proliferative to a differentiative phenotype, as evidenced by decreased Ki67 staining and increased filaggrin, desmoglein-1 and involucrin expression compared to control. These effects lead to skin barrier impairment, which can be observed in a reconstructed human epidermis model showing a decrease in trans-epidermal water loss rates. On the other hand, pan-kinase inhibitors mainly targeting VEGFR barely affect keratinocyte differentiation and rather promote a proliferative phenotype. CONCLUSIONS: This study contributes to the mechanistic understanding of the clinically observed CADR during therapy with EGFRi. These in vitro results suggest a specific mode of action of EGFRi by directly affecting keratinocyte growth and barrier function.

BACKGROUND: Kidney cancer (KC) is associated with cardiovascular regulation disorder and easily leads to cardiovascular and cerebrovascular death (CCD), which is one of the major causes of death in patients with KC, especially those with T1/2 status. However, few studies have treated CCD as an independent outcome for analysis. We aimed to identify and evaluate the key factors associated with CCD in patients with T1/2 KC by competing risk analysis and compared these risk factors with those associated with kidney cancer-specific death (KCD) to offer some information for clinical management. METHODS: A total of 45,117 patients diagnosed with first primary KC in T1/2 status were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were divided into the CCD group (n = 3087), KCD group (n = 3212), other events group (n = 6312) or alive group (n = 32,506). Patients' characteristics were estimated for their association with CCD or KCD by a competing risk model. Pearson's correlation coefficient and variance inflation factor (VIF) were used to detect collinearity between variables. Factors significantly correlated with CCD or KCD were used to create forest plots to compare their differences. RESULTS: The competing risk analysis showed that age at diagnosis, race, AJCC T/N status, radiation therapy, chemotherapy and scope of lymph node represented different relationships to CCD than to KCD. In detail, age at diagnosis (over 74/1-50: HR = 9.525, 95% CI: 8.049-11.273), race (white/black: HR = 1.475, 95% CI: 1.334-1.632), AJCC T status (T2/T1: HR = 0.847, 95% CI: 0.758-0.946) and chemotherapy (received/unreceived: HR = 0.574, 95% CI: 0.347-0.949) were correlated significantly with CCD; age at diagnosis (over 74/1-50: HR = 3.205, 95% CI: 2.814-3.650), AJCC T/N status (T2/T1: HR = 2.259, 95% CI: 2.081-2.451 and N1/N0:HR = 3.347, 95% CI: 2.698-4.152), radiation therapy (received/unreceived: HR = 2.552, 95% CI: 1.946-3.346), chemotherapy (received/unreceived: HR = 2.896, 95% CI: 2.342-3.581) and scope of lymph nodes (1-3 regional lymph nodes removed/none: HR = 1.378, 95% CI: 1.206-1.575) were correlated significantly with KCD. CONCLUSIONS: We found that age at diagnosis, race, AJCC T status and chemotherapy as the independent risk factors associated with CCD were different from those associated with KCD.

BACKGROUND: At intensive care unit (ICU) admission, the issue about prognosis of critically ill cancer patients is of clinical interest, especially after ICU discharge. Our objective was to assess the factors associated with 3- and 6-month survival of ICU cancer survivors. METHODS: Based on the French OutcomeRea™ database, we included solid cancer patients discharged alive, between December 2005 and November 2013, from the medical ICU of the university hospital in Grenoble, France. Patient characteristics and outcome at 3 and 6 months following ICU discharge were extracted from available database. RESULTS: Of the 361 cancer patients with unscheduled admissions, 253 (70%) were discharged alive from ICU. The main primary cancer sites were digestive (31%) and thoracic (26%). The 3- and 6-month mortality rates were 33 and 41%, respectively. Factors independently associated with 6-month mortality included ECOG performance status (ECOG-PS) of 3-4 (OR,3.74; 95%CI: 1.67-8.37), metastatic disease (OR,2.56; 95%CI: 1.34-4.90), admission for cancer progression (OR,2.31; 95%CI: 1.14-4.68), SAPS II of 45 to 58 (OR,4.19; 95%CI: 1.76-9.97), and treatment limitation decision at ICU admission (OR,4.00; 95%CI: 1.64-9.77). Interestingly, previous cancer chemotherapy prior to ICU admission was independently associated with lower 3-month mortality (OR, 0.38; 95%CI: 0.19-0.75). Among patients with an ECOG-PS 0-1 at admission, 70% (n = 66) and 61% (n = 57) displayed an ECOG-PS 0-2 at 3- and 6-months, respectively. At 3 months, 74 (55%) patients received anticancer treatment, 13 (8%) were given exclusive palliative care. CONCLUSIONS: Factors associated with 6-month mortality are almost the same as those known to be associated with ICU mortality. We highlight that most patients recovered an ECOG-PS of 0-2 at 3 and 6 months, in particular those with a good ECOG-PS at ICU admission and could benefit from an anticancer treatment following ICU discharge.

BACKGROUND: Ataxia telangiectasia-mutated (ATM) gene contributes to repair damaged DNA and to regulate cell cycle; therefore, ATM variants seem to increase breast cancer risk; however, the results are controversial. So we conducted a systematic review and meta-analysis to clarify the pooled association between various ATM variants and the risk of breast cancer. METHODS: The relevant studies were searched through Scopus, Web of Science, PubMed and Cochrane. Stratified and subgroup analyses were performed to explore heterogeneity between studies and assess effects of study quality. The pooled estimates logarithm with standard error logarithm of odds ratio and relative risk with confidence interval were calculated. RESULTS: This study revealed that there is association between ATM variants and the risk of breast cancer; according to the seven adjusted case-control studies, OR of this association was estimated as 1.67 (95%CI: 0.73-3.82), according to nine unadjusted case-control studies, the crude OR was 2.27 (95% CI: 1.17-4.40) and according to two cohorts, the RR was estimated as 1.68 (95% CI: 1.17-2.40). CONCLUSIONS: The ATM variants are associated with an increased risk of breast cancer that ATM V2424G mutation is detected as the most predisposing factor while ATM D1853V, L546V, and S707P variants have the least predictive ability.

BACKGROUND: Contradictory and limited data are available about the presentation and outcomes of patients with RET-fusion positive metastatic NSCLC as compared to patients without RET fusions. This observational study utilizing a linked electronic health records (EHR) database to genomics testing results was designed to compare characteristics, tumor response, progression-free (PFS) and overall survival (OS) outcomes by RET fusion status among patients with metastatic NSCLC treated with standard therapies. METHODS: Adult patients with metastatic NSCLC with linked EHR and genomics data were eligible who received systemic anti-cancer therapy on or after January 1, 2011. Adjusted, using all available baseline covariates, and unadjusted analyses were conducted to compare tumor response, PFS and OS between patients with RET-fusion positive and RET-fusion negative disease as detected by next-generation sequencing. Tumor response outcomes were analysed using Fisher's exact test, and time-to-event analyses were conducted using Cox proportional hazards model. RESULTS: There were 5807 eligible patients identified (RET+ cohort, N = 46; RET- cohort, N = 5761). Patients with RET fusions were younger, more likely to have non-squamous disease and be non-smokers and had better performance status (all p < 0.01). In unadjusted analyses, there were no significant differences in tumor response (p = 0.17) or PFS (p = 0.06) but OS was significantly different by RET status (hazard ratio, HR = 1.91, 95% CI:1.22-3.0, p = 0.005). There were no statistically significant differences by RET fusion status in adjusted analyses of either PFS or OS (PFS HR = 1.24, 95% CI:0.86-1.78, p = 0.25; OS HR = 1.52, 95% CI: 0.95-2.43, p = 0.08). CONCLUSIONS: Patients with RET fusions have different baseline characteristics that contribute to favorable OS in unadjusted analysis. However, after adjusting for baseline covariates, there were no significant differences in either OS or PFS by RET status among patients treated with standard therapy prior to the availability of selective RET inhibitors.

BACKGROUND: Autophagy is a highly conserved homeostatic process in the human body that is responsible for the elimination of aggregated proteins and damaged organelles. Several autophagy-related genes (ARGs) contribute to the process of tumorigenesis and metastasis of prostate cancer (PCa). Also, miRNAs have been proven to modulate autophagy by targeting some ARGs. However, their potential role in PCa still remains unclear. METHODS: An univariate Cox proportional regression model was used to identify 17 ARGs associated with the overall survival (OS) of PCa. Then, a multivariate Cox proportional regression model was used to construct a 6 autophagy-related prognostic genes signature. Patients were divided into low-risk group and high-risk group using the median risk score as a cutoff value. High-risk patients had shorter OS than low-risk patients. Furthermore, the signature was validated by ROC curves. Regarding mRNA and miRNA, 12 differentially expressed miRNAs (DEMs) and 1073 differentially expressed genes (DEGs) were detected via the GEO database. We found that miR-205, one of the DEMs, was negatively regulated the expression of ARG (NKX2-3). Based on STRING analysis results, we found that the NKX2-3 was moderately related to the part of genes among the 6 autophagy-related genes prognostic signature. Further, NKX 2-3 was significantly correlated with OS and some clinical parameters of PCa by cBioProtal. By gene set enrichment analysis (GSEA). Lastly, we demonstrated that the association between NKX2-3 and tumor mutation burden (TMB) and PDCD1 (programmed cell death 1) of PCa. RESULTS: We identified that the six ARGs expression patterns are independent predictors of OS in PCa patients. Furthermore, our results suggest that ARGs and miRNAs are inter-related. MiR-205 was negatively regulated the expression of ARG (NKX2-3). Further analysis demonstrated that NKX2-3 may be a potential biomarker for predicting the efficacy of anti-PD-1 therapy in PCa. CONCLUSIONS: The current study may offer a novel autophagy-related prognostic signature and may identify a promising miRNA-ARG pathway for predicting the efficacy of anti-PD-1 therapy in PCa.

BACKGROUND: Anti-apoptotic protein Bcl-2 plays a substantial role in the carcinogenesis, whereas the regulation for Bcl-2 in gastric carcinoma (GC) is poorly understood. Specifically, a role of microRNA (miR)-383 in the control of Bcl-2 has not been shown in GC and thus addressed in the current study. METHODS: We investigated the levels of miR-383 and Bcl-2 in 50 GC specimens, and compared them with patients' clinical characteristics. Bioinformatics analyses and luciferase-reporter assay were applied for analyzing the relationship between Bcl-2 and miR-383. An CCK assay was used to determine the survival of Fluorouracil-treated GC cells, and apoptosis of GC cells was assessed by flow cytometric FITC Annexin V apoptosis detection assay and expression of apoptosis-associated proteins. RESULTS: The levels of miR-383 were lower while the levels of Bcl-2 levels were higher in GC specimens, compared to tissue from the adjacent non-tumor region. Low miR-383 and high Bcl-2 seemed to be associated with high malignancy and metastasis. In GC specimens, the levels of Bcl-2 and miR-383 inversely correlated. The overall survival of miR-383-low cases was poorer. Mechanistically, miR-383 targeted the 3'-UTR of Bcl-2 mRNA to inhibit its protein translation. Overexpression of miR-383 downregulated Bcl-2, resulting in reduced survival of Fluorouracil-treated GC cells. Similar conclusion was drawn through analysis of published database. CONCLUSION: MiR-383 reduces survival of Fluorouracil-treated GC cells through downregulating of Bcl-2.

BACKGROUND: In Mainland China, advance directives (ADs) and end-of-life care for patients with tumours, especially patients with brain tumours who may have lost consciousness or the ability to speak at the early stage of their illness, have been poorly acknowledged. Thus, this study aimed to clarify the knowledge and preferences of ADs and end-of-life care in patients with brain tumours and to investigate predictors of patient preferences. METHODS: This was a population-based cross-sectional survey that was conducted via face-to-face interviews. Information on sociodemographic factors, brain tumour illness, knowledge and preferences of the advanced decisions and end-of-life care of the patients was collected. RESULTS: A total of 88.61% of participants had never heard of ADs, but 65.18% reported that they would like to make ADs. Knowledge of ADs, receiving surgical treatment or radiotherapy, being younger than 70 years old, being male, having educational qualifications of college or beyond, being childless, having medical insurance for nonworking or working urban residents and self-paying medical expenses were predictors of preference for making ADs. A total of 79.43% of participants wanted to discuss end-of-life arrangements with medical staff, and 63.29% of participants were willing to receive end-of-life care, even though it would not delay death. A total of 65.82% of patients with brain tumours wanted resuscitation, and as many as 45.45% of the patients thought that they did not need life support if they were in a persistent vegetative state. Brain primary tumours, being younger than 70 years old, male sex, educational qualification of junior middle school or below, having children, having new rural cooperative medical insurance and having medical expenses paid by children or spouses were predictors of choosing appropriate palliative care. CONCLUSIONS: ADs and end-of-life care have been poorly acknowledged among patients with brain tumours in mainland China. Additional efforts should be encouraged amongst patients with primary brain tumours, those who are undergoing surgery and radiotherapy and those who have low socioeconomic status. A longitudinal and comprehensive study is encouraged to promote disease-specific ADs among Chinese patients with brain tumours.

BACKGROUND: The growth- and plasticity-associated protein-43 (GAP43) is biasedly expressed in indigestive system and nervous system. Recent study has shown that GAP43 is responsible for the development of neuronal growth and axonal regeneration in normal nervous tissue, while serves as a specific biomarker of relapsed or refractory neuroblastoma. However, its expression pattern and function in digestive system cancer remains to be clarified. METHODS: In this study, we examined the GAP43 status with qRT-PCR and bisulfite genomic sequencing in colorectal cancer (CRC). We investigated the effect of overexpressed GAP43 in CRC cells with RNA-seq. The RNA-seq data was analyzed with DAVID and IPA. RESULTS: GAP43 was downregulated in CRC compared to the adjacent tissues. DNA methylase inhibitor 5-Aza-CdR treatment could significantly induce GAP43, indicated that the silencing of GAP43 gene in CRC is closely related to DNA methylation. Bisulfite genomic sequencing confirmed the promoter methylation of GAP43 in CRC. To explore the transcriptional alterations by overexpressed GAP43 in CRC, we performed RNA-seq and found that upregulated genes were significantly enriched in the signaling pathways of ABC transporters and ECM-receptor interaction, while downregulated genes were significantly enriched in Ribosome signaling pathway. Further Ingenuity Pathway Analysis (IPA) showed that EIF2 signaling pathway was significantly repressed by overexpression of GAP43. CONCLUSION: Our findings provide a novel mechanistic insight of GAP43 in CRC. Transcriptome profiling of overexpressed GAP43 in CRC uncovered the functional roles of GAP43 in the development of human CRC.

BACKGROUND: Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA). METHODS: A systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary. RESULTS: Of 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS, the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg, ipilimumab 10 mg/kg, or interferon. Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12 months, however, was lower beyond 12 months (HR [95% credible interval] at 24 months, 0.46 [0.27-0.78]; at 36 months, 0.28 [0.14-0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or interferon and was similar to dabrafenib plus trametinib. CONCLUSION: Adjuvant therapy with nivolumab provides an effective treatment option with a promising risk-benefit profile.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and lung cancer are associated diseases. COPD is underdiagnosed and thus undertreated, but there is limited data on COPD diagnosis in the setting of lung cancer. We assessed the diagnosis of COPD with lung cancer in a large public healthcare system. METHODS: Anonymous administrative data was acquired from ICES, which links demographics, hospital records, physician billing, and cancer registry data in Ontario, Canada. Individuals age 35 or older with COPD were identified through a validated, ICES-derived cohort and spirometry use was derived from physician billings. Statistical comparisons were made using Wilcoxon rank sum, Cochran-Armitage, and chi-square tests. RESULTS: From 2002 to 2014, 756,786 individuals were diagnosed with COPD, with a 2014 prevalence of 9.3%. Of these, 51.9% never underwent spirometry. During the same period, 105,304 individuals were diagnosed with lung cancer, among whom COPD was previously diagnosed in 34.9%. Having COPD prior to lung cancer was associated with lower income, a rural dwelling, a lower Charlson morbidity score, and less frequent stage IV disease (48 vs 54%, p < 0.001). Spirometry was more commonly undertaken in early stage disease (90.6% in stage I-II vs. 54.4% in stage III-IV). CONCLUSION: Over a third of individuals with lung cancer had a prior diagnosis of COPD. Among individuals with advanced lung cancer, greater use of spirometry and diagnosis of COPD may help to mitigate respiratory symptoms.

BACKGROUND: We hypothesized that portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) increases portal pressure and causes esophageal varices and variceal bleedings. We examined the incidence of high-risk varices and variceal bleeding and determined the indications for variceal screening and prophylaxis. METHODS: This study included 1709 asymptomatic patients without any prior history of variceal hemorrhage or endoscopic prophylaxis who underwent upper endoscopy within 30 days before or after initial anti-HCC treatment. Of these patients, 206 had PVTT, and after 1:2 individual matching, 161 of them were matched with 309 patients without PVTT. High-risk varices were defined as large/medium varices or small varices with red-color signs and variceal bleeding. Bleeding rates from the varices were compared between matched pairs. Risk factors for variceal bleeding in the entire set of patients with PVTT were also explored. RESULTS: In the matched-pair analysis, the proportion of high-risk varices at screening (23.0% vs. 13.3%; P = 0.003) and the cumulative rate of variceal bleeding (4.5% vs. 0.4% at 1 year; P = 0.009) were significantly greater in the PVTT group. Prolonged prothrombin time, lower platelet count, presence of extrahepatic metastasis, and Vp4 PVTT were independent risk factors related to high-risk varices in the total set of 206 patients with PVTT (Adjusted odds ratios [95% CIs], 1.662 [1.151-2.401]; 0.985 [0.978-0.993]; 4.240 [1.783-10.084]; and 3.345 [1.457-7.680], respectively; Ps < 0.05). During a median follow-up of 43.2 months, 10 patients with PVTT experienced variceal bleeding episodes, 9 of whom (90%) had high-risk varices. Presence of high-risk varices and sorafenib use for HCC treatment were significant predictors of variceal bleeding in the complete set of patients with PVTT (Adjusted hazard ratios [95% CIs], 26.432 [3.230-216.289]; and 5.676 [1.273-25.300], respectively; Ps < 0.05). CONCLUSIONS: PVTT in HCC appears to increase the likelihood of high-risk varices and variceal bleeding. In HCC patients with PVTT, endoscopic prevention could be considered, at least in high-risk variceal carriers taking sorafenib.

BACKGROUND: MicroRNA (miR)-200c has been widely reported to be involved in colon cancer progress. However, the mechanisms of miR-200c in regulating tumor metastasis and growth remain to be fully elucidated. This study aimed to investigate the mechanism of miR-200c targets fucosyltransferase 4 (FUT4) on the proliferation of colon cancer. METHODS: The miR-200c and FUT4 mRNA levels in LoVo and SW480 cells were measured by real-time quantitative polymerase chain reaction. Further, miR-200c mimic, FUT4 siRNA and FUT4 mimic were transfected into cells, separately. Cell counting kit-8, plate colony formation and transwell assays were used to analyse the cells biological behaviour.. Immunofluorescence was used to analyse the Ki-67 expression Moreover, the Wnt/β-catenin pathway-related proteins were detected by western blots. A double luciferase experiment was performed to confirm the relationship between miR-200c and FUT4. In vivo, tumour growth and Wnt/β-catenin pathway-related proteins were also analysed. RESULTS: In vitro, the expression of miR-200c and FUT4 were negatively correlated in LoVo and SW480 cells (correlation coefficients were - 0.9046 and - 0.9236, respectively). MiR-200c overexpression inhibited the proliferation, migration and invasion of LoVo and SW480 cells by downregulating FUT4. The Ki67-positive cells and Wnt/β-catenin signalling pathway-related proteins were reduced in the miR-200c overexpression and FUT4 silencing groups. A dual luciferase reporting system identified FUT4 as the target of miR-200c. The results in vivo were further confirmed the foundation of cells study. CONCLUSIONS: In summary, miR-200c overexpression inhibits proliferation of colon cancer targeting FUT4 to downregulate the Wnt/β-catenin pathway, which promises molecular targets to inhibit metastasis for colon cancer therapy.

BACKGROUND: This study examined current physical activity levels and preferences for exercise settings and activities among adult survivors of childhood cancers as a strategy to inform the feasibility and design of such programs. METHODS: A mixed-methods design was used to investigate current activity levels as well as barriers to and preferences for physical activity among 20 adult survivors of pediatric cancer. RESULTS: One-half of participants reported engaging in regular physical activity, although the frequency, intensity, and duration varied. Overall, 17 of the 20 participants (85%) stated they would be interested in participating in a structured exercise intervention, and they expressed a strong interest in walking (76%), bicycling (53%), and weight training (53%). Common barriers to participation in a potential structured exercise program were insufficient time, current health issues, and program location/distance. Nearly all participants agreed that information on nutrition and diet should be included as part of an exercise intervention. CONCLUSIONS: These findings will help inform the design and implementation of future exercise programs to enhance physical activity among this high-risk group of cancer survivors.

BACKGROUND: LncRNA WT1-AS inhibits gastric cancer, while its role in other cancers is unknown. We investigated the role of WT1-AS in non-small cell lung cancer (NSCLC). METHODS: Sixty-six NSCLC patients (40 males and 26 females; 36 to 68 years old; mean age 52.7 ± 6.4 years old) were selected from the 178 NSCLC patients operated on for lung cancer between 2010 and 2013. RT-qPCR was used to analyze the expression of lncRNA. Overexpression experiments were performed to assess interactions between lncRNAs. CCK-8 assay was carried to evaluate the roles of WT1-AS and UCA1 in regulating cell proliferation. Cell invasion and migration assays were performed to assess the roles of WT1-AS and UCA1 in regulating cell invasion and migration. Western-blot was performed to illustrate the effect of WT1-AS and UCA1 in EMT. RESULTS: WT1-AS was downregulated in NSCLC and was correlated with poor survival. The expression of WT1-AS in NSCLC was not correlated with clinical stages. LncRNA UCA1 was upregulated in cancer tissues and inversely correlated with WT1-AS. Overexpression of UCA1 did not affect WT1-AS, while overexpression of WT1-AS led to inhibited expression of UCA1. Overexpression of UCA1 resulted in increased proliferation, EMT, migration and invasion of NSCLC cells, while overexpression of WT1-AS showed opposite effects. In addition, overexpression of UCA1 inhibited the role of overexpression of WT1-AS. CONCLUSIONS: Therefore, overexpression of WT1-AS may inhibit the cell proliferation and EMT to decrease cell migration and invasion of NSCLC cells by downregulating UCA1.

BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

BACKGROUND: Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear. METHODS: Utilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/- mouse model was used to detect entero-endocrine cell hyperplasia with IHC. RESULTS: Analyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/- mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease. CONCLUSIONS: Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.

BACKGROUND: Health-related quality of life is mainly impacted by colorectal cancer which justified the major importance addressed to the development and validation of assessment questionnaires. We aimed to assess the validity and reliability of the Moroccan Arabic Dialectal version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) in patients with colorectal cancer. METHODS: We conducted a cross-sectional study using the Moroccan version of the EORTC QLQ-C30 on colorectal cancer patients from the National Oncology Institute of Rabat, in the period from February 2015 to June 2017. The QLQ-C30 was administered to 120 patients. Statistical analysis included reliability, convergent, and discriminant validity as well as known-groups comparisons. RESULTS: In total, 120 patients with colorectal cancer were included in the study with 38 (32%) patients diagnosed with colon cancers. Eighty-two patients (68%) had rectal cancer, among which 29 (24%) patients with a stoma. The mean age of diagnosis was 54 years (+/- 13.3). The reliability and validity of the Arabic dialectal Moroccan version of the EORTC QLQ-C30 were satisfactory. [Cronbach's alpha (α =0.74)]. All items accomplished the criteria for convergent and discriminant validity except for question number 5, which did not complete the minimum required correlation with its own scale (physical functioning). Patients with rectal cancer presented with bad Global health status and quality of life (GHS/QOL), emotional functioning as well as higher fatigue symptoms compared to patients with colon cancer. The difference between patients with and without stoma was significant for diarrhea and financial difficulty. CONCLUSIONS: The Moroccan Arabic Dialectal version of the QLQ-C30 is a valid and reliable measure of health-related quality of life (HRQOL) in patients with colorectal cancer.

BACKGROUND: Long intergenic non-coding RNAs (lincRNAs) are capable of regulating several tumours, while competitive endogenous RNA (ceRNA) networks are of great significance in revealing the biological mechanism of tumours. Here, we aimed to study the ceRNA network of lincRNA in glioblastoma (GBM). METHODS: We obtained GBM and normal brain tissue samples from TCGA, GTEx, and GEO databases, and performed weighted gene co-expression network analysis and differential expression analysis on all lincRNA and mRNA data. Subsequently, we predicted the interaction between lincRNAs, miRNAs, and target mRNAs. Univariate and multivariate Cox regression analyses were performed on the mRNAs using CGGA data, and a Cox proportional hazards regression model was constructed. The ceRNA network was further screened by the DEmiRNA and mRNA of Cox model. RESULTS: A prognostic prediction model was constructed for patients with GBM. We assembled a ceRNA network consisting of 18 lincRNAs, 6 miRNAs, and 8 mRNAs. Gene Set Enrichment Analysis was carried out on four lincRNAs with obvious differential expressions and relatively few studies in GBM. CONCLUSION: We identified four lincRNAs that have research value for GBM and obtained the ceRNA network. Our research is expected to facilitate in-depth understanding and study of the molecular mechanism of GBM, and provide new insights into targeted therapy and prognosis of the tumour.

BACKGROUND: There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. METHODS: We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. RESULTS: There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1-8.4). CONCLUSIONS: This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).

BACKGROUND: Due to tumor heterogeneity, the diagnosis, treatment, and prognosis of patients with lung squamous cell carcinoma (LUSC) are difficult. DNA methylation is an important regulator of gene expression, which may help the diagnosis and therapy of patients with LUSC. METHODS: In this study, we collected the clinical information of LUSC patients in the Cancer Genome Atlas (TCGA) database and the relevant methylated sequences of the University of California Santa Cruz (UCSC) database to construct methylated subtypes and performed prognostic analysis. RESULTS: Nine hundred sixty-five potential independent prognosis methylation sites were finally identified and the genes were identified. Based on consensus clustering analysis, seven subtypes were identified by using 965 CpG sites and corresponding survival curves were plotted. The prognostic analysis model was constructed according to the methylation sites' information of the subtype with the best prognosis. Internal and external verifications were used to evaluate the prediction model. CONCLUSIONS: Models based on differences in DNA methylation levels may help to classify the molecular subtypes of LUSC patients, and provide more individualized treatment recommendations and prognostic assessments for different clinical subtypes. GNAS, FZD2, FZD10 are the core three genes that may be related to the prognosis of LUSC patients.

BACKGROUND: Postoperative complications have been linked to the morbidity and mortality of several cancers. However, predicting whether complications will occur in the early period after surgery or not is challenging. Hence, this study aimed to examine the diagnostic accuracy of serum creatine phosphokinase (CPK) and c-reactive protein (CRP) in predicting the development of postgastrectomy complications. METHODS: We retrospectively analyzed 188 patients with gastric cancer (GC) who underwent gastrectomy. The diagnostic accuracy of serum CPK and CRP was investigated using the areas under the curves (AUC). The CPK ratio was defined as the CPK on postoperative day (POD) 1 to the CPK on a preoperative day. RESULTS: Out of 188 patients, 48 (25.5%) developed postoperative complications. The complications group had a greater operative time (p = 0.037), higher CPK ratio on POD1 (p < 0.0001), and a higher serum CRP level on POD3 (p = 0.001). The AUC for the CPK ratio was 0.772, with an optimal cutoff value of 7.05, whereas that for CRP was 0.659, with an optimal cutoff value of 11.4 mg/L. The CPK ratio on POD1 (p < 0.0001) and the CRP on POD3 (p = 0.007) were independent factors for predicting the development of postgastrectomy complications. The CPK ratio on POD1 and the CRP on POD3 predicted postgastrectomy complications in 41 patients (85.4%). According to combined value of both CPK ratio and CRP level, the positive predictive value and the negative predictive value was 0.70 and 0.829. And sensitivity and specificity were 0.438 and 0.936. CONCLUSION: The CPK ratio on POD1 and the CRP on POD3 after gastrectomy for GC were predictive factors for complication development and may be employed to prevent the development of such complications and improve the prognosis of patients with GC.

BACKGROUND: Recent years, survival rates of human with high-risk acute myeloid leukaemia (AML) have not raised substantially. This research aimed to investigate the role of 4'-O-Methylbroussochalcone B, for the treatment of human AML. METHODS: Firstly, we evaluated the effects of six chalcones on AML cells activity by MTT assay. Immunofluorescence staining, tubulin polymerization assay and N,N'-ethylenebis (iodoacetamide) (EBI) competition assay were performed on ML-2 cells. Transwell and apoptosis assay were also utilized in ML-2 cells and OCI-AML5 cells. The expressions of migration-related proteins, apoptosis-related proteins and Wnt/β-catenin pathway were detected by Western Blot. RESULTS: The results found six chalcones exhibited the anti-proliferative activity against different AML cell lines. Based on the results of immunofluorescence staining, tubulin polymerization assay and EBI competition assay, 4'-O-Methylbroussochalcone B was discovered to be a novel colchicine site tubulin polymerization inhibitor. 4'-O-Methylbroussochalcone B could induce apoptosis, inhibit proliferation and migration of ML-2 cells and OCI-AML5 cells. The cells were arrested in the G2-M phase by the treatment of 4'-O-Methylbroussochalcone B. In addition, 4'-O-Methylbroussochalcone B regulated MAPK and Wnt/β-catenin pathways in AML cells. CONCLUSION: 4'-O-Methylbroussochalcone B might inhibit proliferation and migration of the AML cells by MAPK and Wnt/β-catenin pathways as a tubulin polymerization inhibitor. It is promising for 4'-O-Methylbroussochalcone B to become a new drug to treat AML.

BACKGROUND: Treatment of head and neck cancer (HNC) often leads to visible and severe functional impairments. In addition, patients often suffer from a variety of psychosocial problems, significantly associated with a decreased quality of life. We aimed to compare depression, anxiety, fatigue and quality of life (QoL) between HNC patients and a large sample of the general population in Germany and to examine the impact of sociodemographic, behavioral and clinical factors on these symptoms. METHODS: We assessed data of HNC patients during the aftercare consultation at the Leipzig University Medical Center with a patient reported outcome (PRO) tool named "OncoFunction". Depression, anxiety, fatigue and QoL were assessed using validated outcome measures including the PHQ-9, the GAD-2, and the EORTC QLQ-C30 questionnaire. RESULTS: A total of 817 HNC patients were included in our study and compared to a sample of 5018 individuals of the general German population. HNC patients showed significantly higher levels of impairment in all dimensions assessed. Examination of association between depression, anxiety, fatigue and QoL and clinical as well as sociodemographic variables showed significant relationships between occupational status, ECOG-state, body mass index and time since diagnosis. CONCLUSIONS: HNC patients suffer significantly from psychological distress. The used questionnaires are suitable for the use in daily routine practice and can be helpful to increase the detection of depression, anxiety and fatigue and therefore can improve HNC aftercare.

BACKGROUND: Small soft tissue masses are often falsely assumed to be benign and resected with failure to achieve tumor-free margins. Therefore, this study retrospectively investigated the distribution of histopathologic diagnosis to be encountered in small soft tissue tumors (≤ 5 cm) in a large series of a tertiary referral center. METHODS: Patients with a soft tissue mass (STM) with a maximum diameter of 5 cm presenting at our institution over a period of 10 years, who had undergone preoperative Magnetic resonance imaging and consequent biopsy or/and surgical resection, were included in this study. A final histopathological diagnosis was available in all cases. The maximum tumor diameter was determined on MR images by one radiologist. Moreover, tumor localization (head/neck, trunk, upper extremity, lower extremity, hand, foot) and depth (superficial / deep to fascia) were assessed. RESULTS: In total, histopathologic results and MR images of 1753 patients were reviewed. Eight hundred seventy patients (49.63%) showed a STM ≤ 5 cm and were therefore included in this study (46.79 +/- 18.08 years, 464 women). Mean maximum diameter of the assessed STMs was 2.88 cm. Of 870 analyzed lesions ≤ 5 cm, 170 (19.54%) were classified as superficial and 700 (80.46%) as deep. The malignancy rate of all lesions ≤ 5 cm was at 22.41% (superficial: 23.53% / deep: 22.14%). The malignancy rate dropped to 16.49% (20.79% / 15.32%) when assessing lesions ≤ 3 cm (p = 0.007) and to 15.0% (18.18% / 13.79%) when assessing lesions ≤ 2 cm (p = 0.006). Overall, lipoma was the most common benign lesion of superficial STMs (29.41%) and tenosynovial giant cell tumor was the most common benign lesion of deep STMs (23.29%). Undifferentiated pleomorphic sarcoma was the most common malignant diagnosis among both, superficial (5.29%) and deep (3.57%) STMs. CONCLUSIONS: The rate of malignancy decreased significantly with tumor size in both, superficial and deep STMs. The distribution of entities was different between superficial and deep STMs, yet there was no significant difference found in the malignancy rate.

Author information: (1)Royal Liverpool University Hospital, Liverpool University Hospitals NHS Foundation Trust, Prescot Street, Liverpool, L7 8XP, UK. (2)Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, UK. (3)Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Block A, Royal Victoria Hospital, Belfast, BT12 6BA, UK. (4)University of Cambridge, Cambridge, UK. (5)Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. (6)The Nightingale Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, M23 9LT, UK. (7)Department of Plastic Surgery, Wexham Park Hospital, Frimley Health NHS Foundation Trust, Slough, SL2 4HL, UK. (8)NI Cancer Research Consumer Forum, c/o NI Cancer Trials Network, East Podium, C-Floor, Belfast City Hospital, Belfast, BT9 7AB, UK. (9)Liverpool University Hospitals Foundation Trust, Prescot Street, Liverpool, L7 8XP, UK. (10)Guy's Cancer Centre, Guy's & St Thomas' NHS Trust, Great Maze Pond, London, SE1 9RT, UK. (11)School of Cancer & Pharmaceutical Sciences, King's College London, London, SE1 9RT, UK. (12)The Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester, M20 2BX, UK. (13)School of Medical Sciences Faculty of Biology, Medicine and Health University of Manchester, Manchester, M13 9PL, UK. (14)Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. (15)University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK. (16)The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK. (17)Queen Elizabeth Hospital Birmingham and University of Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2GW, UK. (18)Breast Unit, Level 1 Chancellor wing, St James Hospital, Beckett Street, Leeds, LS97TF, UK. (19)Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Canynge Hall, 39 Whatley Road, Clifton, Bristol, BS8 2PS, UK. (20)Bristol Breast Care Centre, North Bristol NHS Trust, Southmead Hospital, Southmead Road, Bristol, BS10 5NB, UK. (21)Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK. s.mcintosh@qub.ac.uk.

BACKGROUND: Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor. GCTB can rarely undergo malignant transformation. This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab. METHODS: This analysis was conducted on patients with pathologically confirmed GCTB and measurable active disease treated with denosumab 120 mg subcutaneously once every 4 weeks, with loading doses on study days 8 and 15, as part of a phase 2, open-label, multicenter study. We identified potential cases of malignancy related to GCTB through an independent multidisciplinary review or medical history, associated imaging or histopathologic reports, and disease course. The findings were summarized and no statistical analysis was performed. RESULTS: Twenty of five hundred twenty-six patients (3.8%) who received at least one dose of denosumab were misdiagnosed with GCTB that was later discovered to be malignancies: five primary malignant GCTB, five secondary malignant GCTB, four sarcomatous transformations, and six patients with other malignancies (giant cell-rich osteosarcoma, undifferentiated pleomorphic sarcoma, spindle cell sarcoma, osteogenic sarcoma, phosphaturic mesenchymal tumor of mixed connective tissue type, and fibrosarcoma/malignant fibrous histiocytoma). Many malignancies were present before denosumab was initiated (8 definitive cases, 7 likely cases), excluding potential involvement of denosumab in these cases. Signs associated with potential misdiagnoses of GCTB included poor mineralization with denosumab treatment, rapid relapse in pain, or a failure of the typical dramatic improvement in pain normally observed with denosumab. CONCLUSIONS: Although rare, GCTB can undergo malignant transformation, and rates in this study were consistent with previous reports. Signs of poor mineralization or lack of response to denosumab treatment may warrant close monitoring. TRIAL REGISTRATION: clinicaltrials.gov , ( NCT00680992 ). Registered May 20, 2008.

BACKGROUND: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. RESULTS: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. CONCLUSIONS: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

BACKGROUND: Endoscopic submucosal dissection (ESD) is gaining enormous popularity in the treatment of early gastric cancers (EGCs) in many institutions across the world. However, appropriate selection of candidates for endoscopic resection is crucial to sufficiently mitigate non-e-curative (NEC) resection. This study aims at identifying the various clinico-pathologic factors that independently predict the NEC outcome and depth of submucosal invasion following ESD procedure in patients with EGC. METHODS: Multiple logistic regression analysis was applied to investigate factors that independently predict both non-curability phenomenon and the level of submucosal invasion in patients with early gastric neoplasia. Statistical Packages for the Social Sciences version 23 was used for analysis. RESULTS: A total of 153 patients (162 EGC lesions) underwent en-bloc ESD after which the rate of complete resection and non-e-curative outcome were 95% and 22.2%, correspondingly. Multivariate analysis depicted that tumor location in the upper two third of stomach (odds ratio [OR], 5.46; 95% confidence interval [95% CI], 1.65-18.12; p = 0.006), tumor size > 2 cm (OR, 7.63; 95% CI, 2.29-25.42; p = 0.001), histologically undifferentiated tumor (OR, 15.54; 95% CI, 1.65-146.22; p = 0.001), and tumors with 0-IIa/0-IIc or their mixed variants with predominant 0-IIa/0-IIc (OR, 9.77; 95% CI, 1.23-77.65; p = 0.031) were all independent predictors of NEC resection for early gastric tumors. Additionally, location in the upper two third of the stomach (OR, 8.88; 95% CI, 2.90-27.17; p < 0.001), ulcerated lesions (OR, 3.70; 95% CI, 1.15-11.90; p = 0.028), lesions with > 2 cm (OR, 2.94; 95% CI, 1.08-8.02; p = 0.036) and those with poor differentiation (OR, 6.51; 95% CI, 2.23-18.98; p = 0.001) were found to have significant association with submucosal invasion. CONCLUSIONS: Tumors located in the upper two third of the stomach having a larger size (> 2 cm), poor histo-differentiation and a gross type of 0-IIa/0-IIc or their mixed variants with predominant 0-IIa/0-IIc were significantly associated with a risk of NEC after ESD procedure. Thus, early gastric tumors displaying these features need to be handled carefully during endoscopic resection. Our findings may shed light on the pre-procedural detection of clinicopathologic factors that determine non-e-curability in patients with EGC.

BACKGROUND: Immediate breast reconstruction with tissue expander in breast cancer patients who were expected to receive adjuvant therapy, such as chemotherapy or radiotherapy, has been a topic of debate. Postoperative complications from tissue expander procedures can delay the timing of adjuvant treatment and subsequently increase the probability of recurrence. The purpose of this study was to identify the impact of chemotherapy and radiotherapy on postoperative complications in patients who underwent immediate reconstruction (IR) using tissue expander. METHODS: We conducted a retrospective study of 1081 breast cancer patients who underwent mastectomy and IR using tissue expander insertion between 2012 and 2017 in Samsung Medical Center. The patients were divided into two groups based on complications (complication group vs. no complication group). Complication group was regarded to have surgical removal or conservative treatment based on clinical findings such as infection, capsular contracture, seroma, hematoma, rupture, malposition, tissue viability, or cosmetic problem. The complication group had 59 patients (5.5%) and the no complication group had 1022 patients (94.5%). RESULTS: In univariate analysis, adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with postoperative complications. In multivariate analysis, however, only higher pathologic N stage was significantly associated with postoperative complications (p < 0.001). Chemotherapy (p = 0.775) or radiotherapy (p = 0.825) were not risk factors for postoperative complications. CONCLUSIONS: IR with tissue expander after mastectomy may be a treatment option even when the patients are expected to receive adjuvant chemotherapy or radiotherapy. These results will aid patients who are concerned about the complications of IR caused by chemotherapy or radiotherapy determine whether or not to have IR. TRIAL REGISTRATION: Patients were selected and registered retrospectively, and medical records were evaluated.

BACKGROUND: The successful transition of childhood cancer survivors (CCSs) from pediatric to adult long-term follow-up care is a critical phase, and determining the right time point can be challenging. We assessed the feasibility of the use of existing transition readiness tools in the context of the Swiss health care system, assessed partly transition readiness in Swiss CCSs, and compared our findings with Canadian CCSs for which these tools were originally developed. METHODS: We officially translated the Cancer Worry Scale (CWS) and Self-Management Skill Scale (SMSS) into German and integrated them into this cross-sectional study. We included CCSs attending the long-term follow-up (LTFU) clinic in the Division of Oncology-Hematology, Department of Pediatrics, Kantonsspital Aarau. We used descriptive statistics to describe transition readiness. RESULTS: We randomly recruited 50 CCSs aged ≥18 years at participation. The CCSs had a median CWS score of 62 (interquartile range 55-71), indicating a moderate level of cancer-related worry. Despite high self-management skills, some answers showed a dependency of CCSs on their parents. Our experience shows that the CWS and SMSS are easy for Swiss CCSs to use, understand, and complete. The interpretation of the results must take differences in health care systems between countries into account. CONCLUSIONS: The translated CWS and SMSS are appropriate additional measures to assess transition readiness in CCSs. These scales can be used longitudinally to find the individual time point for transition and the completion by CCSs enables the health care team to individualize the transition process and to support the CCSs according to their individual needs.

BACKGROUND: Serum bilirubin and total bile acid (TBA) levels have been reported to be strongly associated with the risk and prognosis of certain cancers. Here, we aimed to investigate the effects of pretreatment levels of serum bilirubin and bile acids on the prognosis of patients with colorectal cancer (CRC). METHODS: A retrospective cohort of 1474 patients with CRC who underwent surgical resection between January 2015 and December 2017 was included in the study. Survival analysis was used to evaluate the predictive value of pretreatment levels of bilirubin and bile acids. X-Tile software was used to identify optimal cut-off values for total bilirubin (TBIL), direct bilirubin (DBIL) and TBA in terms of overall survival (OS) and disease-free survival (DFS). RESULTS: DBIL, TBIL, and TBA were validated as significant prognostic factors by univariate Cox regression analysis for both 3-year OS and DFS. Multivariate Cox regression analyses confirmed that high DBIL, TBIL and TBA levels were independent prognostic factors for both OS (HR: 0.435, 95% CI: 0.299-0.637, P < 0.001; HR: 0.436, 95% CI: 0.329-0.578, P < 0.001; HR: 0.206, 95% CI: 0.124-0.341, P < 0.001, respectively) and DFS (HR: 0.583, 95% CI: 0.391-0.871, P = 0.008; HR:0.437,95% CI: 0.292-0.655, P <0.001; HR: 0.634, 95% CI: 0.465-0.865, P = 0.004, respectively). In addition, nomograms for OS and DFS were established according to all significant factors, and the c-indexes were 0.819 (95% CI: 0.806-0.832) and 0.835 (95% CI: 0.822-0.849), respectively. CONCLUSIONS: TBIL, DBIL and TBA levels are independent prognostic factors in colorectal cancer patients. The nomograms based on OS and DFS can be used as a practical model for evaluating the prognosis of CRC patients.

BACKGROUND: Cancer patients' return to work is a growing aspect of survivorship care, yet limited studies have been conducted in Korea to understand the work-related experience of cancer patients. The purpose of this study was to understand the unmet needs of cancer patients and identify the necessary factors to develop a vocational intervention program based on cancer patients' work-related experience after cancer diagnosis. METHODS: Semi-structured individual in-depth interviews were conducted with 50 cancer patients who were working at the time of diagnosis at a university hospital in Seoul, South Korea from July to September of 2017. Interview data were analyzed using qualitative content analysis. RESULTS: 'The changes patients experienced after cancer diagnosis' were categorized into Personal and socio-environmental changes. 'Personal changes' were changes within the patient that were further divided into 'physical', 'psychological' and 'spiritual' changes while 'socio-environmental changes' were changes in either 'attitude' and 'relationship' of other people cancer patients encountered. In addition to these post-diagnosis changes, the following 4 major factors related to return-to-work were identified to affect patients' experience: 'fear of cancer recurrence', 'financial status', 'informational support', and 'job-related work environment'. CONCLUSION: Cancer patients' working status was determined by personal and socio-environmental changes after the cancer diagnosis which as well as psychological distress and practical issues such as fear of cancer recurrence, financial burden, and work environment. Educational materials and intervention programs informing patients on these changes and factors may facilitate their return-to-work after diagnosis.

BACKGROUND: Non-invasive diagnosis of IDH1 mutation for gliomas has great clinical significance, and PET has natural advantage to detect metabolism, as IDH mutated gliomas share lower glucose consumption. METHODS: Clinical data of patients with gliomas and 18F-FDG PET were retrospectively reviewed. Receiver operating characteristic curve (ROC) analysis was conducted, and standard uptake value (SUV) was estimated in combination with grades or IDH1 mutation. The glucose consumption was investigated with U251 cells expressing wild-type or mutated IDH1 by glucose assay. Quantification of glucose was determined by HPLC in clinical tissues. Meanwhile, bioinformatics and western blot were applied to analyze the expression level of metabolic enzymes (e.g. HK1, PKM2, PC) in gliomas. RESULTS: Seventy-one glioma cases were enrolled, including 30 carrying IDH1 mutation. The sensitivity and specificity dependent on SUVmax (3.85) predicting IDH1 mutation reached 73.2 and 86.7%, respectively. The sensitivity and specificity of differentiating grades by SUVmax (3.1) were 92.3 and 64.4%, respectively. Glucose consumption of U251 IDH1 mutant cells (0.209 ± 0.0472 mg/ml) was obviously lower than IDH1wild-type cells (0.978 ± 0.0773 mg/ml, P = 0.0001) and astrocyte controls (0.335 ± 0.0592 mg/ml, P = 0.0451). Meanwhile, the glucose quantity in IDH1mutant glioma samples were significantly lower than those in IDH1 wild-type tissues (1.033 ± 1.19608 vs 6.361 ± 4.3909 mg/g, P = 0.0051). Silico analysis and western blot confirmed that HK1 and PKM2 in IDH1 wild-type gliomas were significantly higher than in IDH1 mutant group, while PC was significantly higher in IDH1 mutant gliomas. CONCLUSION: SUVmax on PET can predict IDH1 mutation with adequate sensitivity and specificity, as is supported by reduced glucose consumption in IDH1 mutant gliomas.

BACKGROUND: BCOR acts as a corepressor of BCL6, a potent oncogenic protein in cancers of the lymphoid lineage. We have found the recurrent somatic mutation of BCOR occurred in mature T-cell lymphoma (TCL). The role of BCOR mutation in lymphoid malignancies is unknown. METHODS: Lymphoma patient samples were analyzed to identify missense mutations in BCOR using Sanger sequencing. Transfection, RNA interference, immunoprecipitation, western blotting, cell proliferation, cytokine assays and quantitative real-time PCR were employed to determine the functional relevance of the novel K607E mutation in BCOR. The significant transcriptional changes were analyzed by performing DNA microarray profiling in cells expressing BCOR K607E mutant. RESULTS: One hundred thirty-seven lymphoma patient samples were analyzed to identify K607E mutation of the BCOR gene. The BCOR K607E mutation was identified in 15 of 47 NK/T cell lymphoma cases (31.9%), 2 of 18 angioimmunoblastic T-cell lymphoma cases (11.1%), 10 of 30 peripheral T-cell lymphoma, not otherwise specified cases (33.3%), and 13 of 42 diffuse large B-cell lymphoma cases (30.9%). Molecular analysis of BCOR K607E mutation revealed that compared to the wild-type BCOR, the mutant BCOR bound to the BCL6, PCGF1, and RING1B proteins with lesser affinity. Ectopic expression of BCOR K607E mutant significantly enhanced cell proliferation, AKT phosphorylation and the expression of interleukin-2 (IL-2) with up-regulated expression of HOX and S100 protein genes in T cells. BCOR silencing also significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 production. CONCLUSIONS: Functional analyses indicated that K607E mutation of BCOR is oncogenic in nature and can serve as a genetic marker of T-cell lymphoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most frequent malignancies; however, the present prognostic factors was deficient. This study aims to explore whether there is a relationship between tumor volume (TV) and oncological outcomes for localized ccRCC. METHODS: Seven hundred forty-nine localized ccRCC patients underwent surgery in our hospital. TV was outlined and calculated using a three-dimensional conformal radiotherapy planning system. We used receiver operating characteristic (ROC) curves to identified optimal cut-off value. Univariable and multivariable Cox regression models were performed to explore the association between TV and oncological outcomes. Kaplan-Meier method and log-rank test were used to estimate survival probabilities and determine the significance, respectively. Time-dependent ROC curve was utilized to assess the prognostic effect. RESULTS: Log rank test showed that higher Fuhrman grade, advanced pT classification and higher TV were associated with shortened OS, cancer-specific survival (CSS), freedom from metastasis (FFM) and freedom from local recurrence (FFLR). multivariable analysis showed higher Fuhrman grade and higher TV were predictors of adverse OS and CSS. The AUC of TV for FFLR was 0.822. The AUC of TV (0.864) for FFM was higher than that of pT classification (0.818) and Fuhrman grade (0.803). For OS and CSS, the AUC of TV was higher than that of Fuhrman grade (0.832 vs. 0.799; 0.829 vs 0.790). CONCLUSIONS: High TV was an independent predictor of poor CSS, OS, FFLR and FFM of localized ccRCC. Compared with pT classification and Fuhrman grade, TV could be a new and better prognostic factor of oncological outcome of localized ccRCC, which might contribute to tailored follow-up or management strategies.

BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumor with poor survival and prognosis. Randomized trials have demonstrated that chemotherapy improves survival in patients with GBM. This study aims to examine the clinical characteristics that are potentially associated with the efficacy of chemotherapy and the risk factors of GBM. METHODS: A total of 25,698 patients diagnosed with GBM were identified between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER). The clinical and demographic variables between groups were examined by Student's t-test and Pearson's chi-square test. GBM-specific survival (GBMSS) and overall survival (OS) were evaluated using the Kaplan-Meier method with the log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazards model to identify statistically significant prognostic factors. RESULTS: Patients who received chemotherapy had better overall survival (median OS 13 vs. Three months, HR = 1.9224, 95%CI 1.8571-1.9900, p < 0.0001) and better GBMSS (median GBMSS of 12 vs. Three months, HR = 1.9379, 95%CI 1.8632-2.0156, p < 0.0001), compared to patients who did not. Further subgroup analysis revealed that among patients who underwent chemotherapy, those who were younger, with a supratentorial tumor, received surgery, or radiotherapy had both improved OS and GBMSS. Age, race, tumor location, tumor size, and treatments were identified as independent prognostic factors by multivariable analyses for patients with glioblastoma. CONCLUSION: Patients with GBM who were younger (< 65 years), underwent surgery, or radiotherapy can benefit more from chemotherapeutic regimens. Age, race, tumor size, tumor location, surgery, radiotherapy, and chemotherapy were factors associated with the prognosis of patients with GBM.

BACKGROUND: The role of capecitabine in neoadjuvant and adjuvant chemotherapy for early-stage triple-negative breast cancer (TNBC) is highly controversial. Our meta-analysis was designed to further elucidate the effects of capecitabine on survival in early-stage TNBC patients and its safety. METHODS: PubMed, Embase, and papers presented at several main conferences were searched up to December 19, 2019, to investigate capecitabine-based versus capecitabine-free neoadjuvant and adjuvant chemotherapy in TNBC patients. Heterogeneity was assessed using I2 test, combined with hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) computed for disease-free survival (DFS), overall survival (OS), and over grade 3 adverse events (AEs). RESULTS: A total of 9 randomized clinical trials and 3842 TNBC patients were included. Overall, the combined capecitabine regimens in neoadjuvant and adjuvant chemotherapy showed significantly improved DFS (HR = 0.75; 95% CI, 0.65-0.86; P < 0.001) and OS (HR = 0.63; 95% CI, 0.53-0.77; P < 0.001). In subgroup analysis, there were improvements in DFS in the groups with addition of capecitabine (HR = 0.64; 95% CI, 0.53-0.78; P < 0.001), adjuvant chemotherapy (HR = 0.73; 95% CI, 0.63-0.85; P < 0.001), and lymph node positivity (HR = 0.62; 95% CI, 0.44-0.86; P = 0.005). Capecitabine regimens were related to higher risks of diarrhea (OR = 2.88, 95% CI 2.23-3.74, P < 0.001), stomatitis (OR = 2.01, 95% CI 1.53-2.64, P < 0.001) and hand-foot syndrome (OR = 8.67, 95% CI 6.70-11.22, P < 0.001). CONCLUSION: This meta-analysis showed that neoadjuvant and adjuvant chemotherapy combined with capecitabine significantly improved both DFS and OS in early-stage TNBC patients with tolerable AEs. There were benefits to DFS in the groups with the addition of capecitabine, adjuvant chemotherapy, and lymph node positivity.

BACKGROUND: A high incidence of upper urinary tract urothelial carcinoma has been reported in the southwestern area of Taiwan, where arsenic water contamination was considered the main cause. However, there is no definite proof to show a correlation between arsenic water contamination and upper urinary tract urothelial carcinoma. To investigate the clinical and epidemiological features of patients with upper urinary tract urothelial carcinoma between arsenic water endemic and non-endemic areas, we analyzed patients in terms of characteristics, stratified overall survival, disease-free survival, and cancer-specific survival. METHODS: The records of a total of 1194 patients diagnosed with upper urinary tract urothelial carcinoma were retrospectively reviewed. Clinical data and current medical status were collected from the medical records. Statistical analyses were performed to determine the clinical variables and stratified survival curves between endemic and non-endemic groups. RESULTS: Female predominance was revealed in both endemic and non-endemic groups (male:female ratio = 1:1.2-1.4). No statistical differences were found in histological types, staging, and tumor size between the two groups. Nonetheless, patients with characteristics of aging and having end-stage renal disease were outnumbered in the non-endemic group, while a higher prevalence of previous bladder tumors and more ureteral tumors were found in the endemic group. Adjusted stratified cumulative survival curves suggested a poorer prognosis in endemic patients, especially in disease-free survival of early stage disease. CONCLUSIONS: A higher mortality rate with more previous bladder cancer history and ureteral tumors was seen in patients with upper urinary tract urothelial carcinoma residing in the arsenic water contamination area. This may be attributed to the long-term carcinogenic effect of arsenic underground water.

AIM: A serious syndrome for cancer in-patients, delirium risk increases with age and medical acuity. Screening tools exist but detection is frequently delayed or missed. We test the 'Single Question in Delirium' (SQiD), in comparison to psychiatrist clinical interview. METHODS: Inpatients in two comprehensive cancer centres were prospectively screened. Clinical staff asked informants to respond to the SQiD: "Do you feel that [patient's name] has been more confused lately?". The primary endpoint was negative predictive value (NPV) of the SQiD versus psychiatrist diagnosis (Diagnostic and Statistics Manual criteria). Secondary endpoints included: NPV of the Confusion Assessment Method (CAM), sensitivity, specificity and Cohen's Kappa coefficient. RESULTS: Between May 2012 and July 2015, the SQiD plus CAM was applied to 122 patients; 73 had the SQiD and psychiatrist interview. Median age was 65 yrs. (interquartile range 54-74), 46% were female; median length of hospital stay was 12 days (5-18 days). Major cancer types were lung (19%), gastric or other upper GI (15%) and breast (14%). 70% of participants had stage 4 cancer. Diagnostic values were similar between the SQiD (NPV = 74, 95% CI 67-81; kappa = 0.32) and CAM (NPV = 72, 95% CI 67-77, kappa = 0.32), compared with psychiatrist interview. Overall the CAM identified only a small number of delirious cases but all were true positives. The specificity of the SQiD was 87% (74-95) The SQiD had higher sensitivity than CAM (44% [95% CI 41-80] vs 26% [10-48]). CONCLUSION: The SQiD, administered by bedside clinical staff, was feasible and its psychometric properties are now better understood. The SQiD can contribute to delirium detection and clinical care for hospitalised cancer patients.

BACKGROUND: To investigate the clinical impact of sarcopenia and skeletal muscle density (SMD) among patients with metastatic pancreatic adenocarcinoma who underwent palliative first line gemcitabine-based chemotherapy. METHODS: A total of 330 patients treated with first line gemcitabine-based chemotherapy between January 2010 and March 2017 were included. CT scans before chemotherapy and after 8±2 weeks were evaluated. The L3 skeletal muscle index (SMI) was used to detect sarcopenia and calculated as the total area of the L3 skeletal muscle divided by the height-squared (cm2/m2). SMD was quantified as the mean muscle radiation attenuation of the muscle cross-sectional area across the L3 vertebral body level and was assessed between - 29 and + 150 Hounsfield units. RESULTS: A SMI to SMD comparison revealed a positive correlation (R2 = 0.058, P < 0.001). Compared with high SMD, the risks of low SMI were 1.516 (95% confidence interval [CI]: 1.164-1.973) among patients with low SMD. Kaplan-Meier analysis showed that the low SMD was related to poor overall survival (OS, median, 6.1 versus [vs.] 7.9 months, P = 0.010). Multivariate analysis using Cox regression showed that low SMI (hazard ratio [HR]: 1.35, 95% CI: 1.03-1.78, P = 0.032) and low SMD (HR: 1.45, 95% CI: 1.09-1.93, P = 0.011) were poor prognostic factors for OS, respectively. Co-presence of low SMI and low SMD had more powerful prognostic implication for OS (HR: 1.58, 95% CI: 1.12-2.23, P = 0.010). Grade 3 or higher toxicity of chemotherapy was more frequently observed in patients who have a low SMI (43% vs. 59%, P = 0.019) and low SMD (44% vs. 60%, P = 0.023). OS was not related to SMD status among patients who were chemotherapy responders (complete or partial responses). However, among non-responders (stable or progressive disease), low SMD groups had significantly poorer OS in comparison with high SMD groups (median, 5.6 vs 7.4 months, P = 0.006). CONCLUSIONS: Sarcopenia and SMD status can be considered a prognostic factor in patients with metastatic pancreatic adenocarcinoma who received palliative first line gemcitabine-based chemotherapy. Severe chemotherapy toxicity occurred in the sarcopenia and low SMD groups. Our data suggest that a comprehensive assessment of skeletal muscle parameters may be more useful prognostic factors.

BACKGROUND: Breast cancer is the most frequently diagnosed malignancy among women. However, the role of microRNA (miRNA) expression in breast cancer progression is not fully understood. In this study we examined predictive interactions between differentially expressed miRNAs and mRNAs in breast cancer cell lines representative of the common molecular subtypes. Integrative bioinformatics analysis identified miR-193 and miR-210 as potential regulatory biomarkers of mRNA in breast cancer. Several recent studies have investigated these miRNAs in a broad range of tumors, but the mechanism of their involvement in cancer progression has not previously been investigated. METHODS: The miRNA-mRNA interactions in breast cancer cell lines were identified by parallel expression analysis and miRNA target prediction programs. The expression profiles of mRNA and miRNAs from luminal (MCF-7, MCF-7/AZ and T47D), HER2 (BT20 and SK-BR3) and triple negative subtypes (Hs578T e MDA-MB-231) could be clearly separated by unsupervised analysis using HB4A cell line as a control. Breast cancer miRNA data from TCGA patients were grouped according to molecular subtypes and then used to validate these findings. Expression of miR-193 and miR-210 was investigated by miRNA transient silencing assays using the MCF7, BT20 and MDA-MB-231 cell lines. Functional studies included, xCELLigence system, ApoTox-Glo triplex assay, flow cytometry and transwell inserts were performed to determine cell proliferation, cytotoxicity, apoptosis, migration and invasion, respectively. RESULTS: The most evident effects were associated with cell proliferation after miR-210 silencing in triple negative subtype cell line MDA-MB-231. Using in silico prediction algorithms, TNFRSF10 was identified as one of the potential regulated downstream targets for both miRNAs. The TNFRSF10C and TNFRSF10D mRNA expression inversely correlated with the expression levels of miR-193 and miR210 in breast cell lines and breast cancer patients, respectively. Other potential regulated genes whose expression also inversely correlated with both miRNAs were CCND1, a known mediator on invasion and metastasis, and the tumor suppressor gene RUNX3. CONCLUSIONS: In summary, our findings identify miR-193 and miR-210 as potential regulatory miRNA in different molecular subtypes of breast cancer and suggest that miR-210 may have a specific role in MDA-MB-231 proliferation. Our results highlight important new downstream regulated targets that may serve as promising therapeutic pathways for aggressive breast cancers.

BACKGROUND: We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. METHODS: A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. RESULTS: In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. CONCLUSIONS: Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Erratum in BMC Cancer. 2021 Jan 29;21(1):105.

BACKGROUND: Breast cancer is the second most common causes of women's death, worldwide. Data on risk factors associated with female breast cancer in the Afghan population is very limited. The aim of our study was to identifying risk factor associated with female breast cancer in Afghanistan. METHODS: A retrospective case-control study was conducted with inclusion of 201 cases and 201 controls. Patient information was collected by interviewing the patient through a structured questionnaire. Histopathological information was collected from the hospital integrated laboratory management system. The data was analyzed by using logistic regression with univariate and multivariable analyses to determine the association between breast cancer and predictors. RESULTS: The results of the current study showed that factors such as: age (OR = 1.02; 95%CI: 0.99-1.04; p-0.148); age at menarche (OR = 0.83; 95%CI: 0.72-0.92; p-0.008); age at first baby (OR = 1.14; 95%CI: 1.07-1.20; p- < 0.001); illiteracy (OR = 1.93; 95%CI: 1.16-3.22; p-0.011); smoking (OR = 2.01; 95%CI: 1.01-3.99; p-0.04) and family history of cancer (OR = 1.98; 95%CI: 1.18-3.32; p-0.009) were significantly associated with breast cancer. However, our study did not demonstrate any statistically significant correlation between breast cancer and some of the predictors that were previously highlighted in literature, such as: marital status, Body Mass Index (BMI), use of hormonal contraceptive, breastfeeding and exercise. CONCLUSION: Our study demonstrated that age at menarche, and age at first baby birth, illiteracy, smoking and family history of cancer were significant risk factors associated with development of breast cancer among women in Afghanistan. Health education of women regarding aforementioned predisposing factors are therefore, expected to be valuable in decreasing the burden of breast cancer with reduction of its burden on the healthcare system in Afghanistan.

BACKGROUND: Patients with lung cancer who are treated with carboplatin-based chemotherapy regimens often experience chemotherapy-induced nausea and vomiting (CINV). However, knowledge on the effect of regimen and cofactors on the risk of CINV is limited. This study aimed to analyze and compare the incidence of CINV between lung cancer patients undergoing carboplatin plus pemetrexed (CBDCA+PEM) and those undergoing carboplatin plus paclitaxel (CBDCA+PTX) chemotherapy. METHODS: Pooled data of 240 patients from two prospective observational studies were compared using propensity score matching. Separate multivariate logistic regression analyses were used to identify risk factors for nausea and vomiting following chemotherapy. RESULTS: Delayed nausea was significantly more common in patients treated with CBDCA+PEM than in those treated with CBDCA+PTX (51.1% vs. 36.2%, P = 0.04), but the incidence of vomiting did not significantly differ between the two groups (23.4% vs. 14.9%, P = 0.14). The occurrence of CINV peaked on day 4 in the CBDCA+PTX group and on day 5 in the CBDCA+PEM group. Multivariate analysis showed that female sex, younger age, and CBDCA+PEM regimen were independent risk factors for delayed nausea, while female sex was an independent risk factor for delayed vomiting. CONCLUSIONS: The CBDCA + PEM regimen has a higher risk of causing delayed nausea than the CBDCA + PTX regimen, and aggressive antiemetic prophylaxis should be offered to patients treated with CBDCA + PEM.

BACKGROUND: Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC. METHODS: We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. RESULTS: Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p < 0.001), diabetes (HR:1.418; p = 0.001), number of tumors (HR: 1.750; p < 0.001), tumor size (HR: 1.406; p = 0.004) and vascular invasion (HR: 1.659; p < 0.001) were independent risk factors for HCC recurrence, whereas statin use (HR: 0.354; p < 0.001) and antiviral therapy (HR: 0.613; p < 0.001) significantly reduced the risk of HCC recurrence. The statin group still had lower RFS than the non-statin group after one-to-four propensity score matching. CONCLUSION: Statins may exert a chemo-preventive effect on HCC recurrence after curative resection.

BACKGROUND: The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response. METHODS: We first analyzed the differential expression of NNMT among fallopian tube epithelium, primary ovarian cancers, metastatic ovarian cancers, and recurrent ovarian cancers using Gene Expression Ominus (GEO) database (GSE10971, GSE30587, GSE44104 and TCGA datasets). Then, we assessed the association of NNMT expression with clinical and molecular parameters using CSIOVDB database and GSE28739 dataset. Next, we evaluate the association of NNMT expression with the prognosis of ovarian cancer patients in both GSE9891 dataset and TCGA dataset. Finally, GSE140082 dataset was used to explore the association of NNMT expression with bevacizumab response. RESULTS: NNMT expression was significantly elevated in lymphovascular space invasion (LVSI)-positive ovarian cancers compared with that in LVSI-negative ovarian cancers (TCGA dataset, P < 0.05), Moreover, increased expression of NNMT was associated with increased tumor stage, grade, and mesenchymal molecular subtype (CSIOVDB database). Survival analysis indicated that increased expression of NNMT was associated with a reduced OS in both GSE9891 dataset (HR: 2.28, 95%CI: 1.51-3.43, Log-rank P < 0.001) and TCGA dataset (HR: 1.55, 95%CI: 1.02-2.36, Log-rank P = 0.039). Multivariate analysis further confirmed the negative impact of NNMT expression on OS in ovarian cancer patients in those two datasets. Furthermore, the NNMT-related nomogram showed that NNMT shared a larger contribution to OS, compared with debulking status. More interestingly, bevacizumab conferred significant improvements in OS for patients with low NNMT expression (HR: 0.56, 95%CI: 0.31-0.99, Log-rank P = 0.049). In contrast, patients with high NNMT expression didn't benefit from bevacizumab treatment significantly (HR: 0.85, 95%CI: 0.48-1.49, Log-rank P = 0.561). NNMT expression was positively correlated with the expression of genes, LDHA and PGAM1, involved in Warburg effect. CONCLUSIONS: In conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment.

BACKGROUND: Chemoresistance is one of the main problems in treatment of cancer. Periostin (PN) is a stromal protein which is mostly secreted from cancer associated fibroblasts in the tumor microenvironment and can promote cancer progression including cell survival, metastasis, and chemoresistance. The main objective of this study was to develop an anti-PN peptide from the bacteriophage library to overcome PN effects in breast cancer (BCA) cells. METHODS: A twelve amino acids bacteriophage display library was used for biopanning against the PN active site. A selected clone was sequenced and analyzed for peptide primary structure. A peptide was synthesized and tested for the binding affinity to PN. PN effects including a proliferation, migration and a drug sensitivity test were performed using PN overexpression BCA cells or PN treatment and inhibited by an anti-PN peptide. An intracellular signaling mechanism of inhibition was studied by western blot analysis. Lastly, PN expressions in BCA patients were analyzed along with clinical data. RESULTS: The results showed that a candidate anti-PN peptide was synthesized and showed affinity binding to PN. PN could increase proliferation and migration of BCA cells and these effects could be inhibited by an anti-PN peptide. There was significant resistance to doxorubicin in PN-overexpressed BCA cells and this effect could be reversed by an anti-PN peptide in associations with phosphorylation of AKT and expression of survivin. In BCA patients, serum PN showed a correlation with tissue PN expression but there was no significant correlation with clinical data. CONCLUSIONS: This finding supports that anti-PN peptide is expected to be used in the development of peptide therapy to reduce PN-induced chemoresistance in BCA.

BACKGROUND: We evaluated the prognostic potential of tumor 18F-fluorodeoxyglucose (FDG) uptake derived from positron emission tomography (PET) and known inflammatory hematological markers, both individually and in combination, for chemosensitivity and survival in patients with stage IIIB-IV non-small cell lung cancer (NSCLC) receiving first-line chemotherapy. METHODS: A total of 149 patients with stage IIIB and IV NSCLC (based on TNM 7th edition) were retrospectively reviewed. Maximum standardized uptake value (SUVmax) were used to quantitatively assess FDG uptake. The lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were selected as hematological markers. Receiver operating characteristic (ROC) curves were constructed for the determination of optimal cut-off values to predict chemotherapeutic response. RESULTS: Patients with SUVmax > 11.6 or LMR ≤3.73 exhibited a significantly lower objective response rate (ORR) to chemotherapy (p < 0.001 and p < 0.001). Through multivariable logistic regression analysis, both the SUVmax and LMR were identified as independent predictive factors for chemotherapeutic response (p = 0.001 and p < 0.001). Furthermore, a multivariable Cox proportional hazard model identified a high SUVmax (> 11.6) and low LMR (≤3.73) as independent predictors of poor PFS (p < 0.001 and p = 0.025) and OS (p < 0.001 and p = 0.032). A novel score system was constructed based on the SUVmax and LMR (SUV_LMR score), and patients were stratified into three subgroups. The patients with a score of 0 had a significantly higher ORR (88.9%) than did those with a score of 1 (59.6%) and score of 2 (25.0%) (p < 0.001). Moreover, multivariable Cox analysis further identified the SUV_LMR score as an independent prognostic factor for PFS (p < 0.001) and OS (p < 0.001). CONCLUSIONS: Pre-treatment SUVmax and LMR were not only predictive factors for chemotherapeutic response but also independent prognostic factors of survival in stage IIIB-IV NSCLC. Moreover, the SUV_LMR score, which is based on primary tumor metabolic activity and the systemic inflammatory response, might provide a promising tool to predict chemosensitivity, recurrence and survival of advanced NSCLC.

BACKGROUND: Prostate cancer among black men is known to have specific molecular characteristics, especially the androgen receptor or enzymes related to the androgen metabolism. These targets are keys to the action of new hormonal therapies. Nevertheless, literature has a lack of data regarding black men. We aimed to gather the available literature data on new hormonal therapies among black populations. METHODS: We conducted a literature review from the PubMed / MEDLINE database until October 2020. All clinical studies of new hormonal therapies and black populations, regardless of methodology, were included. RESULTS: Four studies provided data on new hormonal therapies in black populations. Three studies reported a PSA decline in black patients treated with Abiraterone, higher in black men than in white men. Overall survival also appears to be higher in black patients treated with Abiraterone only or first. CONCLUSION: Few articles have evaluated the effectiveness and safety of use of these treatments among black populations. The first results seem to show that Abiraterone can provide a benefit in overall survival in black populations. Prospective studies are needed to answer these questions in the future.

BACKGROUND: The superior accuracy and sensitivity of 18F-FDG-PET/CT in comparison to morphological imaging alone leads to an upstaging in up to 30% of lymphoma patients. Novel digital PET/CT scanners might enable to reduce administered tracer activity or scan time duration while maintaining diagnostic performance; this might allow for a higher patient throughput or a reduced radiation exposure, respectively. In particular, the radiation exposure reduction is of interest due to the often young age and high remission rate of lymphoma patients. METHODS: Twenty patients with (suspected) lymphoma (6 for initial staging, 12 after systemic treatment, 2 in suspicion of recurrence) sequentially underwent 18F-FDG-PET/CT examinations on a digital PET/CT (Siemens Biograph Vision) with a total scan time duration of 15 min (reference acquisition protocol) and 5 min (reduced acquisition protocol) using continuous-bed-motion. Both data sets were reconstructed using either standalone time of flight (TOF) or in combination with point spread function (PSF), each with 2 and 4 iterations. Lesion detectability by blinded assessment (separately for supra- and infradiaphragmal nodal lesions and for extranodal lesions), lesion image quantification, and image noise were used as metrics to assess diagnostic performance. Additionally, Deauville Score was compared for all patients after systemic treatment. RESULTS: All defined regions were correctly classified in the images acquired with reduced emission time, and therefore, no changes in staging were observed. Lesion quantification was acceptable, that is, mean absolute percentage deviation of maximum and peak standardized uptake values were 6.8 and 6.4% (derived from 30 lesions). A threefold reduction of scan time duration led to an increase in image noise from 7.1 to 11.0% (images reconstructed with 4 iterations) and from 4.7 to 7.2% (images reconstructed with 2 iterations). No deviations in Deauville Score were observed. CONCLUSION: These results suggest that scan time duration or administered tracer activity can be reduced threefold without compromising diagnostic performance. Especially a reduction of administered activity might allow for a lower radiation exposure and better health economics. Larger trials are warranted to confirm our results.

BACKGROUND: This study was aimed to explore the predictive ability of tumor infiltrating neutrophil (TIN) in patients with breast cancer treated with neoadjuvant chemotherapy (NACT). Furthermore, the significance of TIN's dynamic change before and after NACT was investigated. METHODS: Between January 2004 and December 2017, a total of 133 patients with breast cancer who underwent NACT before surgery were enrolled in this retrospective cohort. Eighty-nine of them were able to get the core needle biopsy (CNB) samples and all the pathological samples after surgery were available. TIN was detected by immunohistochemical staining of CD66b. The optimal cut-off value was determined via receiver operating characteristic (ROC) curve analysis. The association of clinicopathologic characteristics and chemotherapy efficiency was analyzed using X2 test or Fisher's exact test or t-test as appropriate, and the prognostic significances were assessed by univariate and multivariate analyses. RESULTS: Patients with higher TIN after NACT were confirmed to be significantly associated with worse prognosis (P = 0.002). After stratifying patients into two groups, high difference group was prone to have better chemotherapy efficiency (P < 0.001) and clinical outcome in both univariate (P = 0.002) and multivariate analyses (P = 0.003). CONCLUSIONS: In this study, higher TIN after NACT was confirmed to be associated with breast cancer patients' worse chemotherapy efficiency and shorter disease-free survival (DFS). Furthermore, the TIN's dynamic change before and after NACT was firstly proved to be a more accurate predictive marker compared with TIN after NACT.

BACKGROUND: Mounting evidence shows that microRNA-34a (miR-34a) is involved in cancer prognosis. Therefore, we summarize the predictive role of miR-34a for survival in patients with gastrointestinal cancers (GICs). METHODS: All eligible studies were found by searching PubMed, Web of Science and EMBASE, and survival results were extracted. Then, the hazard ratio (HR) with the corresponding 95% confidence interval (CI) was calculated to evaluate the prognostic role of miR-34a in GICs. The association between miR-34a expression and clinicopathological characteristics was estimated by odds ratios (ORs) and 95% CIs. RESULTS: A total of 20 studies were included in this meta-analysis. For overall survival (OS), lower miR-34a expression could probably predict poorer outcome in GICs, with a pooled HR of 1.86 (95% CI: 1.52-2.28, P < 0.01). For disease-free survival (DFS), progression-free survival (PFS), and recurrence-free survival (RFS), lower miR-34a expression was related to worse DFS/PFS/RFS with a pooled HR of 1.86 (95% CI: 1.31-2.63, P  <  0.01). A significant relation of differentiation/TNM stage/lymphatic metastasis and the expression level of miR-34a was identified. CONCLUSION: This meta-analysis revealed that lower miR-34a expression is significantly connected with worse OS and DFS/PFS/RFS in GIC patients. In addition, the miR-34a expression level is relatively lower in patients with lymph node metastasis than in patients without lymph node metastasis, and decreased miR-34a expression levels are linked to poor tumour differentiation and late TNM stage. MiR-34a may become a new factor for the prognosis prediction and progression of GICs.

BACKGROUND: Outcomes are poorer in metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations than those without it, but the effect of these mutations on treatment response is unclear. This real-world study assessed the effects of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF V600-mutated mCRC. METHODS: This real-world, multicenter, retrospective, observational study included patients with BRAF V600-mutated mCRC treated in eight hospitals in Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS); overall response rate (ORR) and disease control rate (DCR) were also assessed. The effect of first- and second-line treatment type on OS, PFS, ORR, and DCR were evaluated, plus the impact of systemic inflammatory markers on these outcomes. A systemic inflammation score (SIS) of 1-3 was assigned based on one point each for platelet-lymphocyte ratio (PLR) ≥200, neutrophil-lymphocyte ratio (NLR) ≥3, and serum albumin < 3.6 g/dL. RESULTS: Of 72 patients, data from 64 were analyzed. After a median of 69.1 months, median OS was 11.9 months and median first-line PFS was 4.4 months. First-line treatment was triplet chemotherapy-antiangiogenic (12.5%), doublet chemotherapy-antiangiogenic (47.2%), doublet chemotherapy-anti-EGFR (11.1%), or doublet chemotherapy (18.1%). Although first-line treatment showed no significant effect on OS, antiangiogenic-based regimens were associated with prolonged median PFS versus non-antiangiogenic regimens. Negative predictors of survival with antiangiogenic-based treatment were NLR, serum albumin, and SIS 1-3, but not PLR. Patients with SIS 1-3 showed significantly prolonged PFS with antiangiogenic-based treatment versus non-antiangiogenic-based treatment, while those with SIS=0 showed no PFS benefit. CONCLUSIONS: Antiangiogenic-based regimens, SIS, NLR, and albumin were predictors of survival in patients with mCRC, while SIS, NLR and serum albumin may predict response to antiangiogenic-based chemotherapy. TRIAL REGISTRATION: GIT-BRAF-2017-01.

BACKGROUND: Classical phase 1 dose-finding designs based on a single toxicity endpoint to assess the maximum tolerated dose were initially developed in the context of cytotoxic drugs. With the emergence of molecular targeted agents and immunotherapies, the concept of optimal biological dose (OBD) was subsequently introduced to account for efficacy in addition to toxicity. The objective was therefore to provide an overview of published phase 1 cancer clinical trials relying on the concept of OBD. METHODS: We performed a systematic review through a computerized search of the MEDLINE database to identify early phase cancer clinical trials that relied on OBD. Relevant publications were selected based on a two-step process by two independent readers. Relevant information (phase, type of therapeutic agents, objectives, endpoints and dose-finding design) were collected. RESULTS: We retrieved 37 articles. OBD was clearly mentioned as a trial objective (primary or secondary) for 22 articles and was traditionally defined as the smallest dose maximizing an efficacy criterion such as biological target: biological response, immune cells count for immunotherapies, or biological cell count for targeted therapies. Most trials considered a binary toxicity endpoint defined in terms of the proportion of patients who experienced a dose-limiting toxicity. Only two articles relied on an adaptive dose escalation design. CONCLUSIONS: In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity.

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. METHODS: The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. RESULTS: The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129). CONCLUSIONS: The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

BACKGROUND: Surgery is the only treatment option for operable gastric cancer. The CLASSIC and ACTS-GC studies showed that the 5-year overall survival (OS) of patients with stage III gastric cancer undergoing D2 gastrectomy is still very low. Whether adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combined chemotherapy is more effective than the XELOX standard adjuvant chemotherapy in patients with stage III gastric cancer has not been confirmed. METHODS: This is a multicenter, open-label, phase III clinical study. In this trial, 616 patients with locally advanced stage III gastric cancer that underwent curative D2 radical surgery and achieved R0 are planned to be included. Patients will be randomized 1:1 to nab-paclitaxel combined with S-1 (AS) vs. oxaliplatin combined with capecitabine (XELOX). XELOX group: Patients assigned to the XELOX group received eight 3-week cycles of oral capecitabine (1000 mg/m2) twice daily on days 1-14 of each cycle plus intravenous oxaliplatin 130 mg/m2 on day 1 of each cycle. AS group: AS group received eight 3-week cycles of oral S-1 (80-120 mg) (< 1.25 m2, 40 mg; 1.25 to < 1.5 m2, 50 mg; and > 1.5 m2, 60 mg) twice daily on days 1-14 plus intravenous nab-paclitaxel 120 mg/m2 on days 1 and 8 of each cycle. The primary endpoint was the 3-year disease-free survival (3-year-DFS) defined as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. The secondary endpoints were the overall survival, (defined as the time from the date of randomisation to date of death from any cause) and safety (any adverse event). DISCUSSION: Compared with previous studies, this study includes nab-paclitaxel based on S-1 adjuvant chemotherapy, which is expected to achieve better efficacy and lower toxicity than the standard treatment. This study is the first clinical study to evaluate the safety and efficacy of nab-paclitaxel combined with S-1 in patients with stage III gastric cancer after D2 radical resection. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov, registration number: NCT04135781 , on October 20th, 2019.

BACKGROUND: Autophagy-related genes (ARGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of ARGs and their clinical significance in sarcoma patients is lacking. METHODS: Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed ARGs (DEARGs) were determined by matching the DEG and HADb gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEARGs was conducted, and associations with tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for disease-free survival (DFS), were established and validated in an independent set. RESULTS: In total, 84 DEARGs and two clusters were identified. TME scores, five immune checkpoints, and several types of immune cells were found to be significantly different between two clusters. Two prognostic signatures incorporating DEARGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.818 and 0.747 for the OS and DFS nomograms, respectively. CONCLUSION: This comprehensive analyses of the ARG landscape in sarcoma showed novel ARGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.

BACKGROUND: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib. METHODS: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E. RESULTS: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161). CONCLUSION: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

BACKGROUND: The incidence of glioblastoma increases significantly with age. With the growing and aging population, there is a lack of comprehensive analysis of recent glioblastoma incidence trend in the United States. This study aims to provide in-depth description of the patterns of incidence trends and to examine the age-period-cohort effects to the trends of glioblastoma specific to elderly patients. METHODS: The incidence rates were age-adjusted and reported per 100,000 population. We calculated the annual percent change (APC) in incidence using the Joinpoint Regression Program and conducted an age-period-cohort analysis of elderly glioblastoma reported between 2000 and 2017 to the Surveillance Epidemiology and End Results (SEER) 18 registry database. RESULTS: The overall incidence rate of elderly patients with glioblastoma was 13.16 per 100,000 (95% CI, 12.99-13.32) from 2000 to 2017. Non-Hispanic whites (20,406, 83.6%) made up the majority. The incidence rate of male was about 1.62 times that of female. The trend of incidence remained stable and there was a non-significant increasing tendency for all elderly patients (APC 0.3, 95% CI, - 0.1 to 0.7, p = 0.111). There was a significantly increasing incidence trend for non-Hispanic white (APC 0.6, 95% CI, 0.2 to 1.1, p = 0.013), supratentorial location (APC 0.7, 95% CI, 0.2 to 1.3, p = 0.016), tumor size < 4 cm (APC 2.5, 95% CI, 1.4 to 3.6, p < 0.001), and a significantly decreasing trend for overlapping/NOS location (APC -0.9, 95% CI, - 1.6 to - 0.2, p = 0.012), and unknown tumor size (APC -4.9, 95% CI, - 6.6 to - 3.3, p < 0.001). The age-period-cohort analysis showed the effect of age on incidence trends (p< 0.001, Wald test), while did not indicate the period and cohort effects of the incidence trends of glioblastoma (p = 0.063 and p =0.536, respectively, Wald test). CONCLUSION: The overall incidence of glioblastoma in the elderly population remained stable between 2000 and 2017. Period and cohort effects were not evident in the trend of glioblastoma incidence. Future population-based studies exploring the difference in the trend of glioblastoma incidence by specific molecular subgroups are warranted to further our understanding of the etiology of glioblastoma.

BACKGROUND: Despite much research published on lung cancer screening, China has had no large-scale study on the missed diagnosis of lung cancer in a health examination population. We therefore did a real-world study using the current lung cancer screening guidelines to a health examination population in China to determine the proportion of lung cancer cases that have been missed. METHODS: A real-world cohort study of screening, with the use of low-dose computed tomography, was conducted among people who took yearly health checkup in health management center of West China Hospital between 2006 and 2017. We respectively used current guidelines including lung cancer screening guidelines of the U.S. Preventive Services Task Force (USPSTF) and expert consensus on low dose spiral CT lung cancer screening in China. RESULTS: In a total of 15,996 participants with health examination who completed the baseline screening, 6779 (42.4%) subjects had at least one positive finding, and 142 (2.1%) cases of lung cancer were screened positive. The false positive rate was 97.9%. Of 142 lung cancer cases detected in our study, only 9.2% met the lung cancer screening guidelines proposed by the USPSTF, and 24.4% met that of China. The rates of missed diagnosis were as high as 90.8 and 75.6% respectively. In addition, we did an in-depth analysis by gender. We found that among male patients with lung cancer, the proportion of smokers was 75%, and the proportion of young people under 50 was 23.2%. Among female patients with lung cancer, the proportion of smokers was only 5.8%, and the proportion of young people under 50 was up to 33.3%. CONCLUSIONS: The rate of missed diagnosis was as high as 90.8% applying the current lung cancer screening guidelines to the health examination population in China. Further study to determine screening guidelines for targeted populations, is warranted.

BACKGROUND: Prognosis for pediatric metastatic Retinoblastoma (Rb) is poor and current therapies are limited by high systemic toxicity rates and insufficient therapeutic efficacy for metastatic Rb. Tumor dissemination to the brain is promoted by the heterogeneous adhesive and invasive properties of Rb cells within the tumor. In this study we evaluate, for the first time, the expression, and roles of the ELTD1 and GPR125 adhesion G protein-coupled receptors (GPCRs) in Rb cell migration, viability and invasion. METHODS: We characterized the RNA expression of adhesion-GPCRs in 64 Rb tumors compared to 11 fetal retinas using the database from the Childhood Solid Tumor Network from St Jude Children's Research Hospital. The role of ELTD1 and GPR125 in Rb were investigated ex vivo by microarray analysis, in vitro by cell viability, Western blot and migration assays, in addition to imaging of the subcellular localization of the GPCRs. To elucidate their role in vivo we utilized siRNA technology in an established Rb orthotopic xenograft murine model. RESULTS: Our investigation demonstrates, for the first time, that ELTD1 but not GPR125, is significantly increased in Rb tumors compared to fetal retinas. We utilized established the Rb cell lines Y79 and Weri-Rb-1, which represent an aggressive, metastatic, and non-metastatic phenotype, respectively, for the in vitro analyses. The studies demonstrated that ELTD1 is enriched in Weri-Rb-1 cells, while GPR125 is enriched in Y79 cells. The measured differences extended to their subcellular localization as ELTD1 labeling displayed punctate clusters in cell-to-cell adhesion sites of Weri-Rb-1 cells, while GPR125 displayed a polarized distribution in Y79 cells. Lastly, we demonstrated the lack of both adhesion receptors does not affect Rb cell viability, yet inhibition of ELTD1 decreases Y79 cell migration in vitro and invasion in vivo. CONCLUSION: Taken together, our data suggest that ELTD1, is a potential target to prevent extraocular Rb. The results within establish ELTD1 as a potential therapeutic target for metastatic Rb.

BACKGROUND: Bladder cancer is the ninth most common type of cancer worldwide. In the past, radical cystectomy via open surgery has been considered the gold-standard treatment for muscle invasive bladder cancer. However, in recent years there has been a progressive increase in the use of robot-assisted laparoscopic radical cystectomy. The aim of the current project is to investigate the surgical, oncological, and functional outcomes of patients with bladder cancer who undergo radical cystectomy comparing three different surgical techniques (robotic-assisted, laparoscopic, and open surgery). Pre-, peri- and post-operative factors will be examined, and participants will be followed for a period of up to 24 months to identify risks of mortality, oncological outcomes, hospital readmission, sexual performance, and continence. METHODS: We describe a protocol for an observational, prospective, multicenter, cohort study to assess patients affected by bladder neoplasms undergoing radical cystectomy and urinary diversion. The Italian Radical Cystectomy Registry is an electronic registry to prospectively collect the data of patients undergoing radical cystectomy conducted with any technique (open, laparoscopic, robotic-assisted). Twenty-eight urology departments across Italy will provide data for the study, with the recruitment phase between 1st January 2017-31st October 2020. Information is collected from the patients at the moment of surgical intervention and during follow-up (3, 6, 12, and 24 months after radical cystectomy). Peri-operative variables include surgery time, type of urinary diversion, conversion to open surgery, bleeding, nerve sparing and lymphadenectomy. Follow-up data collection includes histological information (e.g., post-op staging, grading, and tumor histology), short- and long-term outcomes (e.g., mortality, post-op complications, hospital readmission, sexual potency, continence etc). DISCUSSION: The current protocol aims to contribute additional data to the field concerning the short- and long-term outcomes of three different radical cystectomy surgical techniques for patients with bladder cancer, including open, laparoscopic, and robot-assisted. This is a comparative-effectiveness trial that takes into account a complex range of factors and decision making by both physicians and patients that affect their choice of surgical technique. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04228198 . Registered 14th January 2020- Retrospectively registered.

BACKGROUND: Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19-9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. METHODS: Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19-9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. RESULTS: Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19-9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19-9 levels outperformed either individual marker. cfKRASmut outperformed CA 19-9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. CONCLUSIONS: Integrated analysis of cfKRASmut and CA 19-9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker's specific potential.

BACKGROUND: Cisplatin-based chemotherapy is recommended as the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, the benefits are limited due to the acquisition of drug resistance. The mechanisms of resistance remain unclear. Although there are some reports that some molecules are associated with cisplatin resistance in advanced BC, those reports have not been fully investigated. Therefore, we undertook a new search for cisplatin resistance-related genes targeted by tumor suppressive microRNAs as well as genes that were downregulated in cisplatin-resistant BC cells and clinical BC tissues. METHODS: First, we established cisplatin-resistant BOY and T24 BC cell lines (CDDP-R-BOY, CDDP-R-T24). Then, Next Generation Sequence analysis was performed with parental and cisplatin-resistant cell lines to search for the microRNAs responsible for cisplatin resistance. We conducted gain-of-function analysis of microRNAs and their effects on cisplatin resistance, and we searched target genes comprehensively using Next Generation mRNA sequences. RESULTS: A total of 28 microRNAs were significantly downregulated in both CDDP-R-BOY and CDDP-R-T24. Among them, miR-486-5p, a tumor suppressor miRNA, was negatively correlated with the TNM classification of clinical BC samples in The Cancer Genome Atlas (TCGA) database. Transfection of miRNA-486-5p significantly inhibited cancer cell proliferation, migration, and invasion, and also improved the cells' resistance to cisplatin. Among the genes targeted by miRNA-486-5p, we focused on enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), which is involved in the degradation of fatty acids. EHHADH was directly regulated by miRNA-486-5p as determined by a dual-luciferase reporter assay. Loss-of-function study using EHHADH si-RNA showed significant inhibitions of cell proliferation, migration, invasion and the recovery of cisplatin sensitivity. CONCLUSION: Identification of EHHADH as a target of miRNA-486-5p provides novel insights into the potential mechanisms of cisplatin resistance in BC.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is the prime approach to the management of locally advanced breast cancer (LABC). Influenced by different factors such as pathologic tumor characteristics, hormone receptor status, HER2 and proliferation marker expressions, response to therapy cannot be easily predicted. Pathologic complete response (pCR) has been considered as an endpoint to NACT; however, pCR rates have been unsatisfactory in such patients. In this randomized trial, we studied the efficacy of carboplatin/gemcitabine as second-line NACT while evaluating the impact of different factors affecting response. METHODS: In this randomized controlled trial, 52 clinically non-responsive (confirmed by palpation and/or ultrasonography) LABC patients to 4 cycles of doxorubicin/cyclophosphamide followed by 4 cycles of paclitaxel ± trastuzumab were randomly allocated to two groups. "Control" group underwent breast surgery and were further evaluated for pCR (ypT0/is ypN0). "Intervention" group received 2 cycles of carboplatin/gemcitabine and patients were further evaluated for pCR following surgery. RESULTS: In a total of 52 patients, pCR rate was 30.7%. pCR and response rate in lymph nodes were higher in carboplatin/gemcitabine recipients (32% vs 29.7 and 44% vs 40.7% respectively), however differences were insignificant. In both the "intervention" group and total study population, most pCR cases were of the hormone receptor (HR)+/HER2+ subtype (87.5% and 75% respectively). HER2 positivity, ki67 expression, lower extent of ER positivity, higher tumor grade and tumor-infiltrating lymphocyte (TIL) lead to higher pCR rates. Adverse events following addition of carboplatin/gemcitabine were mostly hematologic and none required hospitalization. Anemia was the most common grade 3 adverse event observed. No grade 4 toxicity was evident. CONCLUSION: Although the proposed carboplatin/gemcitabine combination could not improve pCR rates as expected, probability of immune activation following use of carboplatin in achieving response to NACT may be considered. Accounting for the highest number of pCR cases in the "intervention" group, the HR+/HER2+ subtype with high TILs may be considered as most responsive to the proposed regimen in this study. It is noteworthy that the proposed combination imposed minimal toxicity. TRIAL REGISTRATION: This trial was prospectively registered in IRCT.ir ( IRCT2017100136491N1 ). Date of registration: 19 November 2017.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation types are associated with efficacy of EGFR TKIs. We investigated the clinical outcomes of afatinib, erlotinib, and gefitinib according to EGFR mutation type in patients with lung adenocarcinoma. METHODS: Between May 2010 and December 2018, we investigated 363 patients with advanced lung adenocarcinoma harboring EGFR mutations who received EGFR TKIs. Efficacies of EGFR TKIs such as response rate, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated according to exon 19 deletion (E19del), L858R point mutation (L858R) and uncommon mutations. RESULTS: The frequency of E19del was 48.2%, that of L858R was 42.4%, and that of uncommon mutations was 9.4%. E19del and L858R were associated with superior PFS and OS compared with uncommon mutations. Erlotinib showed significantly inferior OS than other TKIs (30.8 ± 3.3 in erlotinib vs. 39.1 ± 4.3 in afatinib vs. 48.4 ± 6.3 in gefitinib; p = 0.031) in patients with L858R. Gefitinib showed significantly inferior PFS (4.6 ± 1.1 in gefitinib vs. 11.6 ± 2.7 in afatinib vs. 10.6 ± 2.7 in erlotinib; p = 0.049) in patients with uncommon mutations. CONCLUSION: Afatinib was significantly associated with a longer PFS, presenting constant effectiveness in all EGFR mutation types. Caution may be needed on the use of erlotinib for L858R and the use of gefitinib for uncommon EGFR mutations.