Indeterminate pulmonary nodules in colorectal cancer

AIM:To investigate the clinicopathologic parameters of pulmonary metastasis in colorectal cancer(CRC) patients after lung operation of indeterminate pulmonary nodules(IPNs).METHODS:From a prospective database of CRCpatients,40 cases that underwent lung operation between November 2008 and December 2012 for suspicious metastatic pulmonary nodules on chest computed tomography(CT)were enrolled.The decision to perform a lung operation was made if the patient met the following criteria:(1)completely resected or resectable primary CRC;(2)completely resectable IPNs;(3)controlled or controllable extrapulmonary metastasis;and(4)adequate general condition and pulmonary function to tolerate pulmonary operation.Lung operation was performed by a thoracic surgeon without CT-guided biopsy for pathologic confirmation.RESULTS:A total of 40 cases of lung resection was performed in 29 patients.Five patients underwent repeated lung resection.The final pathology result showed metastasis from the CRC in 30 cases(75%)and benign pathology in 10 cases(25%).The primary tumor site was the rectum in 26/30(86.6%)cases with pulmonary metastasis,but only 3/10(30%)cases in the benign group had a primary rectal cancer(P=0.001).Positron emission tomography(PET)-CT was performed for 22/30(73.4%)patients in the lung metastasis group and for 6/10(60.0%)patients in the benign group.PET-CT revealed hot uptake of18fluorine 2-fluoro-2-deoxy-D-glucose with all IPNs in both groups.The group with pulmonary metastasis had a higher incidence of primary rectal cancer(P=0.001),a more advanced tumor stage(P=0.011),and more frequent lymphatic invasion of tumor cells(P=0.005).Six cases with previous liver metastasectomy were present in the lung metastasis group.Serum carcinoembryonic antigen levels before lung operation were not elevated in any of the patients.CONCLUSION:The stage and location of the primary tumor and tumor cell infiltration of lymphatics provide useful indicators for deciding on lung resection of IPNs in CRC.

Prediction of overall survival following colorectal cancer surgery in elderly patients

BACKGROUND With advanced age and chronic illness,the life expectancy of a patient with colorectal cancer(CRC)becomes less dependent on the malignant disease and more on their pre-morbid condition.Justifying major surgery for these elderly patients can be challenging.An accurate tool demonstrating post-operative survival probability would be useful for surgeons and their patients.AIM To integrate clinically significant prognostic factors relevant to elective colorectal surgery in the elderly into a validated pre-operative scoring system.METHODS In this retrospective cohort study,patients aged 70 and above who underwent surgery for CRC at Singapore General Hospital between 1 January 2005 and 31 December 2012 were identified from a prospectively maintained database.Patients with evidence of metastatic disease,and those who underwent emergency surgery or had surgery for benign colorectal conditions were excluded from the analysis.The primary outcome was overall 3-year overall survival(OS)following surgery.A multivariate model predicting survival was derived and validated against an equivalent external surgical cohort from Kyungpook National University Chilgok Hospital,South Korea.Statistical analyses were performed using Stata/MP Version 15.1.RESULTS A total of 1267 patients were identified for analysis.The median post-operative length of stay was 8[interquartile range(IQR)6-12]d and median follow-up duration was 47(IQR 19-75)mo.Median OS was 78(IQR 65-85)mo.Following multivariate analysis,the factors significant for predicting overall mortality were serum albumin<35 g/dL,serum carcinoembryonic antigen≥20μg/L,T stage 3 or 4,moderate tumor cell differentiation or worse,mucinous histology,rectal tumors,and pre-existing chronic obstructive lung disease.Advanced age alone was not found to be significant.The Korean cohort consisted of 910 patients.The Singapore cohort exhibited a poorer OS,likely due to a higher proportion of advanced cancers.Despite the clinicopathologic differences,there was successful validation of the model following recalibration.An interactive online calculator was designed to facilitate post-operative survival prediction,available at http://bit.ly/sgh_crc.The main limitation of the study was selection bias,as patients who had undergone surgery would have tended to be physiologically fitter.CONCLUSION This novel scoring system generates an individualized survival probability following colorectal resection and can assist in the decision-making process.Validation with an external population strengthens the generalizability of this model.

Prognostic value of YKL-40 in colorectal carcinoma patients:A metaanalysis

BACKGROUND In recent years,the predictive role of YKL-40 for long-term survival in colorectal cancer patients has been gradually investigated.However,whether it is a reliable and valuable prognostic indicator for patients with colorectal carcinoma has not been verified.AIM To identify the prognostic value of serum/plasma concentration of YKL-40 or expression status of YKL-40 in tumor cells in colorectal carcinoma patients.METHODS Several electronic databases including the PubMed,EMBASE,Web of Science,CNKI,VIP and WanFang were searched for relevant studies.The hazard ratios(HR)and 95%confidence intervals(CI)were combined and the primary and secondary outcomes were overall survival(OS)and progression-free survival(PFS),respectively.All statistical analysis were conducted by STATA 15.0 software.RESULTS A total of nine studies involving 2545 patients were included.The pooled results indicated that YKL-40 was significantly associated with poor OS(HR=1.80,95%CI:1.32-2.45,P<0.001)and PFS(HR=1.62,95%CI:1.22-2.16,P=0.001).Subgroup analysis stratified by the treatment,tumor type and source of YKL-40 showed similar results.CONCLUSION Elevated serum/plasma concentration of YKL-40 or positive expression in tumor cells was related with worse prognosis of colorectal carcinoma patients.YKL-40 might serve as a novel and reliable indicator for the evaluation of prognosis in colorectal cancer.

Exercise for Cancer Therapy

The number of new cancer cases in China is increasing rapidly,and China now ranks first in the world for the number of cancer patients.Traditional oncology treatment is based on surgery,radiotherapy and chemotherapy,but all three treatments are often accompanied by a poor quality of life,impaired physical function,and significant anxiety and depression.Exercise therapy can provide both prognostic improvement and a better quality of life for cancer patients,and can be adapted to serve patients at all stages from perioperative recovery to hospice.Although the impact of exercise alone is difficult to assess given the influence of lifestyle and other factors,data suggest that consistent exercise can improve the prognosis of cancer patients.Exercise enhances cardiopulmonary function,induces protein synthesis,improves physiological performance and increases physiological reserves;it also helps to improve the metabolic and immune functions,creating an anti-cancer environment in the body.An appropriate exercise plan can reduce adverse effects associated with cancer treatment,improve patients'physiological function,reduce fatigue and improve quality of life.Of note,exercise may also reduce the risk of cancer recurrence and metastasis.In recent years,exercise oncology has received increasing attention,thus,this article reviews the progress made in the clinical application of exercise therapy in oncology patients.

Colorectal cancer-derived extracellular vesicles induce liver premetastatic immunosuppressive niche formation to promote tumor early liver metastasis

Dear Editor,To date,the effect of colorectal cancer(CRC)-derived extracellular vesicles(EVs)on liver pre-metastatic niche(PMN)remain incompletely understood.1 To investigate the role of CRC-derived EVs in the remodeling of the liver PMN,we isolated EVs from CT26 cell culture supernatant.The characteristics of EVs(the morphology,size,and markers)were identified by transmission electron microscopy(TEM),Nanoparticle Tracking Analysis(NTA),and western blotting(Supplementary Fig.S1a–e).Then,BALB/c mice with an intact liver immune status were pretreated with CRCderived EVs and phosphate-buffered saline(PBS)for one month,and a liver metastasis model was established via spleen injection of tumor cells to determine whether EVs influence liver metastasis(Fig.1a).Two hours after the operation,in vivo imaging indicated that the animal model was successfully established,and the tumor fluorescence intensity in the liver was consistent between the two groups(Supplementary Fig.S2a,b).Amazingly,the liver tumor fluorescence intensity in the EVs group was significantly stronger than that in the PBS group after 24 h(Fig.1b;Supplementary Fig.S2c,d).The number of liver tumor nodules in the EVs group was also significantly higher than that in the PBS group on day 4(Fig.1c;Supplementary Fig.S2e,f).

Yiqi Zhuyu Decoction(益气逐瘀汤)Combined with FOLFOX-4 as First-Line Therapy in Metastatic Colorectal Cancer

Objective：To evaluate the efficacy and safety of Yiqi Zhuyu Decoction（益气逐瘀汤,YZD） combined with oxaliplatin plus 5-flurouracil/leucovorin（FOLFOX-4） in the patients with metastatic colorectal cancer（MCRC）.Methods：A total of 120 patients with MCRC were randomly divided into the experimental group（FOLFOX-4 plus YZD,60 cases） and the control group（FOLFOX-4 plus placebo,60 cases）,according to the sequence of hospitalization from January 2005 to December 2007.The treatment was supposed to be continued until disease progression（PD） or for 48 weeks（i.e.,up to 24 cycles of FOLFOX-4）.Response rate （RR）,progression-free survival（PFS）,overall survival（OS） and adverse events（AEs） were observed.Results： RR was 41.5%in the experimental group and 34.0%in the control group[odds ratio（OR）：1.18,95%CI：0.77 to 1.82,P=0.432].Median PFS were 9.0 months and 8.0 months,respectively[hazard ratio（HR）：0.78,95% CI：0.53 to 1.15,P=0.215].Median OS were 21.0 months and 18.0 months（HR：0.65,95%CI：0.43 to 0.99, P=0.043） and grade 3/4 AEs were 56.6%and 76.7%（OR：0.61,95%CI：0.18 to 0.87,P=0.020）,respectively. Conclusions：YZD combined with FOLFOX-4 chemotherapy significantly improved OS in this first-line trial in the patients with MCRC and significantly decreased grade 3/4 AEs.However,RR was not improved,and PFS did not reach statistical significance by the addition of YZD.The treatment of YZD combined with FOLFOX-4 may be necessary in order to optimize efficacy and safety.

The RNA-binding protein Musashi2 governs osteoblast-adipocyte lineage commitment by suppressing PPARγsignaling

Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.

ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells

Apolipoprotein A-I(Apo A-I),the main protein component of high-density lipoprotein(HDL),plays a pivotal role in reverse cholesterol transport(RCT).Previous studies indicated a reduction of serum Apo A-I levels in various types of cancer,suggesting Apo A-I as a potential cancer biomarker.Herein,ectopically overexpressed Apo A-I in MDA-MB-231 breast cancer cells was observed to have antitumor effects,inhibiting cell proliferation and migration.Subsequent studies on the mechanism of expression regulation revealed that estradiol(E2)/estrogen receptorα(ERα)signaling activates Apo A-I gene transcription in breast cancer cells.Mechanistically,our Ch IP-seq data showed that ERαdirectly binds to the estrogen response element(ERE)site within the Apo A-I gene and establishes an acetylation of histone 3 lysine 27(H3 K27 ac)-enriched chromatin microenvironment.Conversely,Fulvestrant(ICI 182780)treatment blocked ERαbinding to ERE within the Apo A-I gene and downregulated the H3 K27 ac level on the Apo A-I gene.Treatment with p300 inhibitor also significantly decreased the Apo A-I messenger RNA(m RNA)level in MCF7 cells.Furthermore,the analysis of data from The Cancer Genome Atlas(TCGA)revealed a positive correlation between ERαand Apo A-I expression in breast cancer tissues.Taken together,our study not only revealed the antitumor potential of Apo A-I at the cellular level,but also found that ERαpromotes the transcription of Apo A-I gene through direct genomic effects,and p300 may act as a co-activator of ERαin this process.

MicroRNA-126 and epidermal growth factor-like domain 7 predict recurrence in patients with colon cancer treated with neoadjuvant chemotherapy

Aim:Neoadjuvant chemotherapy may represent a shift in the treatment of locally advanced colon cancer.The angiogenic couple has-microRNA-126(miRNA-126)and epidermal growth factor-like domain 7(EGFL7)are transcribed from the same gene and regulates all aspects of angiogenesis and may influence the ability of tumor cells to disseminate.The aim was to analyze the relationship between miRNA-126 and EGFL7 and disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy.Methods:This study included 71 patients from a phase II study all planned for three cycles of capecitabine and oxaliplatin before surgery.Blood was sampled at baseline and right before and after the operation.Circulating miRNA-126 was analysed by RT-qPCR and a quantitative immunoassay was used for the analyses of EGFL7.Results:The rates of 5-year disease-free survival(DFS)and overall survival(OS)were 80%and 85%,respectively.The level of circulating miRNA-126 before the operation predicts recurrence,P=0.035.In patients with values below and above the median the recurrence rate was 31%and 4%,respectively.Similar results applied to EGFL7.A combined estimate identified a subgroup of patients(25 of 71)with no recurrence and a 5-year DFS and OS rate of 100%,respectively.Conclusion:MicroRNA-126 and EGFL7 are predictors for disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy and may assist in selection of adjuvant chemotherapy.

The repertoire of germline variants in patients with early-onset rectal cancer

Dear Editor,The incidence of rectal cancer has increased in patients younger than 50 years old during the last decade.It is well established that young age at cancer onset is a hallmark of hereditary cancer.The prevalence of germline variants among early-onset rectal cancer(EORC)patients is largely unexplored.Here,we aimed to determine the spectrum of germline variants and their clinical impact in EORC patients diagnosed at age 40 or younger.We investigated 71 EORC patients(Supplementary Table S1),one of the largest cohorts to date,using a customized panel with 93 genes(Supplementary Table S2).

Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant

The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation.Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant(but not p5372R)with phosphoserine aminotransferase 1(PSAT1).Interestingly,p53^(72P)-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)that otherwise bound to p53^(72P),leading to subsequent nuclear translocation of PGC-1αand activation of oxidative phosphorylation(OXPHOS)and tricarboxylic acid(TCA)cycle.Depletion of PSAT1 restored p53^(72P)-PGC-1αinteraction and impeded the OXPHOS and TCA function,resulting in mitochondrial dysfunction and metastasis suppression.Notably,pharmacological targeting the PSAT1-p53^(72P)interaction by aminooxyacetic acid(AOA)crippled the growth of liver cancer cells carrying the p53^(72P)variant in both in vitro and patient-derived xenograft models.Moreover,AOA plus regorafenib,an FDA-proved drug for hepatocellular carcinoma and colorectal cancer,achieved a better anti-tumor effect on tumors carrying the p53^(72P)variant.Therefore,our findings identified a gain of function of the p53^(72P)variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53^(72P)-PSAT1 perturbation.

Regulation of muscle stem cell fate

Skeletal muscle plays a critical role in human health.Muscle stem cells(MuSCs)serve as the major cell type contribut-ing to muscle regeneration by directly differentiating to mature muscle cells.MuSCs usually remain quiescent with occasionally self-renewal and are activated to enter cell cycle for proliferation followed by differentiation upon muscle injury or under pathological conditions.The quiescence maintenance,activation,proliferation,and differentiation of MuSCs are tightly regulated.The MuSC cell-intrinsic regulatory network and the microenvironments work coordi-nately to orchestrate the fate transition of MuSCs.The heterogeneity of MuSCs further complicates the regulation of MuSCs.This review briefly summarizes the current progress on the heterogeneity of MuSCs and the microenviron-ments,epigenetic,and transcription regulations of MuSCs.

The landscape of aging

Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.