Integrated strategies for chemotherapy cycles in nasopharyngeal carcinoma patients: Real-world data from two epidemic centers guiding decision-making

objective:Two cycles of induction chemotherapy(IC)followed by 2 cycles of platinum-based concurrent chemoradiotherapy(CCRT)(2IC+2CCRT)for locoregionally advanced nasopharyngeal carcinoma(LA-NPC)is widely adopted but not evidence-confirmed.This study aimed to determine the clinical value of 2IC+2CCRT regarding efficacy,toxicity and cost-effectiveness.Methods:This real-world study from two epidemic centers used propensity score matching(PSM)and inverse probability of treatment weighting(IPTW)analyses.The enrolled patients were divided into three groups based on treatment modality:Group A(2IC+2CCRT),Group B(3IC+2CCRT or 2IC+3CCRT)and Group C(3IC+3CCRT).Long-term survival,acute toxicities and cost-effectiveness were compared among the groups.We developed a prognostic model dividing the population into high-and low-risk cohorts,and survivals including overall survival(OS),progression-free survival(PFS),distant metastasis-free survival(DMFS)and locoregional relapse-free survival(LRRFS)were compared among the three groups according to certain risk stratifications.Results:Of 4,042 patients,1,175 were enrolled,with 660,419,and 96 included in Groups A,B and C,respectively.Five-year survivals were similar among the three groups after PSM and confirmed by IPTW.Grade 3-4 neutropenia and leukocytopenia were significantly higher in Groups C and B than in Group A(52.1%vs.41.5%vs.25.2%;41.7%vs.32.7%vs.25.0%)as were grade 3-4 nausea/vomiting and oral mucositis(29.2%vs.15.0%vs.6.1%;32.3%vs.25.3%vs.18.0%).Cost-effective analysis suggested that 2IC+2CCRT was the least expensive,while the health benefits were similar to those of the other groups.Further exploration showed that 2IC+2CCRT tended to be associated with a shorter PFS in high-risk patients,while 3IC+3CCRT potentially contributed to poor PFS in low-risk individuals,mainly reflected by LRRFS.Conclusions:In LA-NPC patients,2IC+2CCRT was the optimal choice regarding efficacy,toxicity and costeffectiveness;however,2IC+2CCRT and 3IC+3CCRT probably shortened LRRFS in high-and low-risk populations,respectively.

Transforming cancer cells for long-term living with cancer: An inspiring new approach

Cancer is the leading cause of human death and imposes a huge health burden. Currently, no matter what advanced therapeutic modalities or technologies are applied, it is still peculiarly rare for most cancers to be radically cured whereas therapy resistance and tumor recurrence are ever so common. The long-standing cytotoxic therapy is hard to achieve long-term tumor control, and produces side-effects or even promotes cancer progression. With growing understandings of tumor biology, we came to realize that it is possible to transform but not kill cancer cells to achieve long-term living with cancer, and directly altering cancer cells is a promising way. Remarkably, tissue microenvironment is involved in the fate determination of cancer cells. Of note, leveraging cell competition to combat malignant or therapy-resistant cells shows some therapeutic potentials. Furthermore, modulating tumor microenvironment to restore a normal state might help to transform cancer cells. Especially, reprogramming cancer-associated fibroblasts, and tumor-associated macrophages, or normalization of tumor vessel, tumor immune microenvironment, and tumor extracellular matrix or their combinations, et al., revealed some long-term therapeutic benefits. Despite the massive challenges ahead, it would be possible to transform cancer cells for long-term cancer control and living with cancer longevously. The related basic researches and corresponding therapeutic strategies are also ongoing.

Genetic variants in C1GALT1 are associated with gastric cancer risk by influencing immune infiltration

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1(C1GALT1)is known to play a critical role in the development of gastric cancer,but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk.By using the genome-wide association study data from the database of Genotype and Phenotype(dbGAP),we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk(odds ratio,0.83;95% confidence interval[CI],0.75-0.92;P=3.95×10^(-4)).C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues,and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates(hazards ratio,1.33;95%CI,1.05-1.68;P_(log-rank)=1.90×10^(-2)).Furthermore,we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4^(+)T cells and macrophages.These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

Forty-six cases of nasopharyngeal carcinoma treated with 50 Gy radiotherapy plus hematoporphyrin derivative:20 years of follow-up and outcomes from the Sun Yat-sen University Cancer Center

Background:With the improved overall survival(OS) of nasopharyngeal carcinoma(NPC) patients,the importance of quality of life(Qo L) is increasingly being recognized.For some radiosensitive NPC patients,whether low?dose radio?therapy can improve the Qo L without affecting clinical efficacy is unknown.This study aimed to assess the survival rates and Qo L of NPC patients treated with 50 Gy radiotherapy plus hematoporphyrin derivative(HPD).Methods:Forty?six newly diagnosed NPC patients treated with 50 Gy radiotherapy plus HPD between June 1988 and July 1992 were analyzed.All patients were restaged according to the 7th edition of the American Joint Commit?tee on Cancer staging system.The radiotherapy plan was designed on the basis of pretreatment computed tomog?raphy.The OS,local recurrence?free survival(LRFS),distant metastasis?free survival(DMFS),and disease?free survival(DFS) rates were estimated using the Kaplan–Meier method.Qo L was assessed using the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group.Results:The 5?year OS,LRFS,DMFS,and DFS rates were 74.3%,72.6%,82.1%,and 61.2%,respectively.The corre?sponding 10?year rates were 38.4%,62.9%,78.5%,and 49.8%,respectively,and the 20?year rates were 27.7%,51.4%,78.5%,and 40.7%,respectively.None of the patients developed severe radiation?related complications,such as radiation?induced temporal lobe necrosis,hearing loss,trismus,and dysphagia.Conclusion:Some NPC patients were sensitive to 50 Gy radiotherapy plus HPD,and this sensitivity was characterized by long?term survival without significant late treatment morbidities.

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

Modeling human gastric cancers in immunocompetent mice

Gastric cancer(GC)is a major cause of cancer-related mortality worldwide.GC is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high heterogeneity,with different cellular origins and diverse histological and molecular features.This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics.In the past decade,great progress has been made in the study of GC,particularly in molecular subtyping,investigation of the immune microenvironment,and defining the evolutionary path and dynamics.Preclinical mouse models,particularly immunocompetent models that mimic the cellular and molecular features of human GC,in combination with organoid culture and clinical studies,have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion,and the development of novel therapeutic strategies.Herein,we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models,emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression

Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

Nursing Care and Causative Analysis of Grade IV Capsular Contracture Following Breast Cancer Expander Implantation

Objective: By observing the treatment and nursing care of a patient with Grade IV capsular contracture following breast cancer expander implantation and subsequent Stage II reconstruction, we aim to analyze the reasons for the formation of capsular contracture after Stage I expander implantation and prevent its recurrence following Stage II reconstruction. Methods: In May 2020, the patient noticed an increase in the size of a breast mass. In August, she underwent AC-THP neoadjuvant chemotherapy, followed by a “right breast-conserving nipple-areolar subglandular excision + right axillary lymph node dissection + expander implantation” surgery in November 2020. Radiation therapy began in January 2021. During radiation therapy, the patient experienced severe breast hardening, distortion, tenderness, and was diagnosed with Grade IV capsular contracture. To relieve the capsular contracture, the patient underwent a “contracted capsule incision and release procedure + removal of the right breast expander + right breast implantation” surgery in July 2021. Postoperatively, measures were taken to prevent incision infection, emphasizing aseptic techniques, ensuring smooth negative pressure drainage, reducing skin flap tension, monitoring skin flap blood supply, actively preventing subcutaneous effusion and hematoma, and applying appropriate compression dressings. Results: The patient was discharged after the removal of the drainage tube. During the postoperative follow-up at 3 and 6 months, there was no recurrence of capsular contracture, and the breast appeared full, upright, and relatively soft. There were no complications such as hematoma, infection, breast implant rupture, breast sagging, or displacement. The patient had a good outcome without additional financial or surgical burdens. Conclusion: The occurrence of Grade IV capsular contracture in the patient is generally related to infection after Stage I expander implantation, improper compression dressing, excessive saline injection causing content infiltration, and radiation therapy. Therefore, it is recommended to enhance the intraoperative and postoperative prophylactic use of antibiotics after Stage I expander implantation. Intermittent saline injection after surgery, with the amount of saline gradually increasing rather than filling all at once, is advisable. This helps the breast tissue gradually adapt to expansion, reducing the risk of capsular contracture. Postoperatively, patients should be instructed to wear pressure garments and breast elastic bandages while intensifying breast monitoring during radiation therapy and increasing postoperative follow-up.

Preoperative neutrophil-to-lymphocyte ratio plus platelet-to-lymphocyte ratioin predicting survival for patients with stage Ⅰ-Ⅱgastric cancer

Background:The preoperative neutrophil-to-lymphocyte ratio(NLR) and the platelet-to-lymphocyte ratio(PLR) are associated with poor prognosis of gastric cancer.We aimed to determine whether the combination of NLR and PLR(NLR-PLR) could better predict survival of patients after curative resection for stage Ⅰ-Ⅱ gastric cancer.Methods:We collected data from the medical records of patients with stage Ⅰ-Ⅱ gastric cancer undergoing curative resection between December 2000 and November 2012 at the Sun Yat-sen Cancer Center.The preoperative NLRPLR was calculated as follows:patients with both elevated NLR(≥2.1) and PLR(≥ 120) were given a score of 2,and patients with only one or neither were given a score of 1 or 0,respectively.Results:Kaplan-Meier analysis and log-rank tests revealed significant differences in overall survival(OS) among patients with NLR-PLR scores of 0,1 and 2(P < 0.001).Multivariate analysis showed that OS was independently associated with the NLR-PLR score[hazard ratio(HR) = 1.51,95%confidence interval(CI) 1.02-2.24,P = 0.039]and TNM stage(HR = 1.36,95%CI 1.01-1.83,P= 0.041).However,other systemic inflammation-based prognostic scores,including the modified Glasgow prognostic score,the prognostic nutritional index,and the combination of platelet count and NLR,were not.In TNM stage-stratified analysis,the prognostic significance of NLR-PLR was maintained in patients with stage Ⅰ(P < 0.001) and stage Ⅱ cancers(P= 0.022).In addition,the area under the receiver operating characteristic curve for the NLR-PLR score was higher than those of other systemic inflammation-based prognostic scores(P = 0.001).Conclusion:The preoperative NLR-PLR score is a useful predictor of postoperative survival in the patients with stage l-ll gastric cancer and may help identify high-risk patients for rational therapy and timely follow-up.

Predictive factors for the local recurrence and distant metastasis of phyllodes tumors of the breast: a retrospective analysis of 192 cases at a single center

The local recurrence rate of phyllodes tumors of the breast varies widely among different subtypes, and distant metastasis is associated with poor survival. This study aimed to identify factors that are predictive of local recurrence-free survival(LRFS), distant metastasis-free survival(DMFS), and overall survival(OS) in patients with phyllodes tumors of the breast. Clinical data of all patients with a phyllodes tumor of the breast(n = 192) treated at Sun Yat-sen University Cancer Center between March 1997 and December 2012 were reviewed. The Pearson χ2 test was used to investigate the relationship between clinical features of patients and histotypes of tumors. Univariate and multivariate Cox regression analyses were performed to identify factors that are predictive of LRFS, DMFS, and OS. In total, 31(16.1%) patients developed local recurrence, and 12(6.3%) developed distant metastasis. For the patients who developed local recurrence, the median age at the diagnosis of primary tumor was 33 years(range, 17-56 years), and the median size of primary tumor was 6.0 cm(range, 0.8-18 cm). For patients who developed distant metastasis, the median age at the diagnosis of primary tumor was 46 years(range, 24-68 years), and the median size of primary tumor was 5.0 cm(range, 0.8-18 cm). In univariate analysis, age, size, hemorrhage, and margin status were found to be predictive factors for LRFS(P = 0.009, 0.024, 0.004, and 0.001, respectively), whereas histotype, epithelial hyperplasia, margin status, and local recurrence were predictors of DMFS(P = 0.001, 0.007, 0.007, and < 0.001, respectively). In multivariate analysis, independent prognostic factors for LRFS included age [hazard ratio(HR) = 3.045, P = 0.005], tumor size(HR = 2.668, P = 0.013), histotype(HR = 1.715, P = 0.017), and margin status(HR = 4.530, P< 0.001). Histotype(DMFS: HR = 4.409, P = 0.002; OS: HR = 4.194, P = 0.003) and margin status(DMFS: HR = 2.581, P = 0.013; OS: HR = 2.507, P = 0.020) were independent predictors of both DMFS and OS. In this cohort, younger age, a larger tumor size, a higher tumor grade, and positive margins were associated with lower rates of LRFS. Histotype and margin status were found to be independent predictors of DMFS and OS.

Prognostic nutritional index is an independent prognostic factor for gastric cancer patients with peritoneal dissemination

Objective： The predictive and prognostic role of prognostic nutritional index（PNI） in gastric cancer patients with peritoneal dissemination remains unclear. This study aims to explore the role of the PNI in predicting outcomes of gastric cancer patients with peritoneal dissemination.Methods： A total of 660 patients diagnosed with gastric adenocarcinoma with peritoneal metastasis between January 2000 and April 2014 at Sun Yat-sen University Cancer Center and the Sixth Affiliated Hospital of Sun Yatsen University were retrospectively analyzed. The clinicopathologic characteristics and clinical outcomes of patients with peritoneal dissemination were analyzed.Results： Compared with PNI-high group, PNI-low group was correlated with advanced age（P=0.036）, worse performance status（P0.001）, higher frequency of ascites（P0.001） and higher frequency of multisite distant metastasis（P0.001）. Kaplan-Meier survival curves showed that PNI-high group had a significantly longer median overall survival than PNI-low group（13.13 vs. 9.03 months, P0.001）. Multivariate survival analysis revealed that Borrmann type IV（P=0.014）, presence of ascites（P=0.017） and lower PNI（P=0.041） were independent poor prognostic factors, and palliative surgery（P0.001） and first-line chemotherapy（P0.001） were good prognostic factors. For patients receiving palliative surgery, the postoperative morbidity rates in the PNI-low group and PNIhigh group were 9.1% and 9.9%, respectively（P=0.797）. The postoperative mortality rate was not significantly different between PNI-low and PNI-high groups（2.3% vs. 0.9%, P=0.362）.Conclusions： PNI is a useful and practical tool for evaluating the nutritional status of gastric cancer patients with peritoneal dissemination, and is an independent prognostic factor for these patients.

Validation of clinical significance of examined lymph node count for accurate prognostic evaluation of gastric cancer for the eighth edition of the American Joint Committee on Cancer(AJCC) TNM staging system

Objective： To validate the necessity of increasing the examined lymph node （ELN） count for enhancing the accuracy of prognostic evaluation of gastric cancer （GC） patients after curative gastrectomy in multiple medical centers of China.Methods： The clinicopathological data of 7,620 patients who underwent the curative resection for GC between 2001 and 2011 were included to demonstrate whether the ELN count is indispensable for enhancing the accuracy of prognostic evaluation of GC patients after surgery. After a meticulous stratification by using the cut-point survival analysis, all included 7,620 patients were allocated into three groups as： less than 16 （〈16）, between 16 and 30 （16-30）, and more than 30 （〉30） ELNs. Survival differences among various subgroups of GC patients were analyzed to assess the impact of the ELN count on the stage migration in accordance with the overall survival （OS） of GC patients.Results： Survival analyses revealed that the ELN count was positively correlated with the OS （P：0.001） and was an independent prognostic predictor （P〈0.01） of 7,620 GC patients. Stratum analysis showed that the accuracy of prognostic evaluation could be enhanced when the ELN count was no less than 16 （≥16） for node-negative patients and 〉30 for node-positive patients. Stage migrations were mainly detected in the various subgroups of patients with specific pN stages as follows： pN0 with 16-30 ELNs （pN016-30） and pN0 with 〉30 ELNs （pN0〉30）, pN0 with 〈16 ELNs （pN0〈16） and pNl〉30, pNl〈l6 and pN216_30, pNl：6_30 and pN2〉30, pN3a〈l6 and pN3b16-30, and pN3a〈16 and pN3 b〉30. These findings indicate that increasing the ELN count is a prerequisite to guarantee precisely prognostic evaluation of GC patients.Conclusions： The ELN count should be proposed to be 〉30 for acquiring the accurate prognostic evaluadort for GC patients, especially for node-positive patients.

At-home cancer screening:a solution for China and other developing countries with a large population and limited number of healthcare practitioners

Five-year survival rate for patients with all cancers combined, in China, is only 30.9%, which is much lower than those in developed countries. The three main reasons for the low cancer curative rates in China include differences in the spectrum of cancer types, in early detection rates, and in the percentage of cancer patients receiving standardized treatment between China and developed countries.The most important mechanism for improving the curative rate is to improve early detection rates of major cancers in China using novel and affordable technologies that can be operated at home by the patients themselves.This attempt could be helpful in setting up a practical example for other developing countries with limited medical resources and a limited number of healthcare practitioners.

Prognostic role of the ABO blood types in Chinese patients with curatively resected non-small cell lung cancer:a retrospective analysis of 1601 cases at a single cancer center

Background:A positive association between the ABO blood types and survival has been suggested in several malignancies.The aim of this study was to assess the role of the ABO blood types in predicting the prognosis of Chinese patients with curatively resected non-small cell lung cancer(NSCLC).Methods:We retrospectively analyzed 1601 consecutive Chinese patients who underwent curative surgery for NSCLC between January 1,2005 and December 31,2009.The relationship between the ABO blood types and survival was investigated.In addition,univariate and multivariate analyses were performed.Results:Group 1(patients with the blood type O or B) had significantly prolonged overall survival(OS) compared with group 2(patients with the blood type A or AB),with a median OS of 74.9 months versus 61.5 months[hazard ratio(HR) 0.83;95%confidence interval(CI) 0.72-0.96;P = 0.015].Additionally,group 1 had significantly longer disease-free survival(DFS;HR 0.86;95%CI 0.76-0.98;P = 0.022) and locoregional relapse-free survival(LRFS;HR 0.79;95%CI 0.64-0.98;P = 0.024) than group 2.The association was not significantly modified by other risk factors for NSCLC,including smoking status,pathologic tumor-node-metastasis stage,pT category,pN category,and chemotherapy.Conclusions:There is an association between the ABO blood types and the survival of Chinese patients with resected NSCLC.Patients with the blood type O or B had significantly prolonged OS,DFS,and LRFS compared with those with the blood type A or AB.

Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data

BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.

The rationale for preventing cancer cachexia：targeting excessive fatty acid oxidation

Cachexia commonly occurs at the terminal stage of cancer and has largely unclear molecular mechanisms.A recent study published in Nature Medicine,entitled "Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia," reveals that cachectic cancer cells can secrete multiple cytokines that induce excessive fatty acid oxidation,which is responsible for muscle loss in cancer cachexia.Inhibition of fatty acid oxidation using etomoxir can increase muscle mass and body weight in cancer cachexia animal models.The usage of stable cachexia animal models is also discussed in this research highlight.

Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial

Introduction: Multimodality therapy, including preoperative chemoradiotherapy(CRT) and total mesorectal excision(TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy(CCRT) involving XELOX regimen(oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma.Methods: We randomly assigned patients to the TME group(TME without preoperative CCRT) or CCRT + TME group(TME with preoperative CCRT). The primary endpoint was disease-free survival(DFS); the secondary endpoints were overall survival(OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months.Results: A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 %(P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 %(P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT +TME groups were 71.3 % and 70.0 %(P = 0.849), respectively. In the TME group, 16(17.0 %) patients were proven to have p TNM stage I disease after surgery. In the CCRT + TME group, 32(35.6 %) patients achieved a pathologic complete response(p CR).Conclusions: Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high p CR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted.

Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase

Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also been observed in a wide spectrum of cancers.This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.Methods:ROS level,NADPH oxidase(NOX) aaivity and expression,and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeaed with K-ras^(G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin,a NOX inhibitor,were also tested in vitro and in vivo.Results:K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase(PI3K) pathway.Importantly,capsaicin preferentially inhibited the enzyme aaivity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells.Furthermore,capsaicin effeaively inhibited cell proliferation,prevented invasiveness of /(-ras-transformed pancreatic cancer cells,and caused minimum toxicity to parental E6E7 cells.In vivo,capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.Conclusions:K-ras oncogenic signaling causes increased ROS stress through NOX,and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors.Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.

Revisiting tumor angiogenesis:vessel co-option,vessel remodeling,and cancer cell-derived vasculature formation

Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen,nutrients,and other essential factors.The well-known vascular endothelial growth factor(VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature,which has become therapeutic targets in clinical practice.However,the survival benefits gained from targeting VEGF signaling have been very limited,with the inevitable development of treatment resistance.In this article,we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy,with a special focus on vessel co-option,vessel remodeling,and tumor cell-derived vasculature establishment.Vessel co-option may occur in tumors independently of sprouting angiogenesis,and sprouting angiogenesis is not always required for tumor growth.The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced.The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.