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The challenge of molecular selection in liver-limited metastatic colorectal cancer for surgical resection: a systematic review and meta-analysis in the context of current and future approaches

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Oncology Research 2024年第9期32卷 1407-1422页

作者： ROSSANA RONCATO JERRY POLESEL FEDERICA TOSI ELENA PERUZZI ERIKA BRUGUGNOLI CLAUdiA LAURIA PANTANO MARIA FURFARO FILIPPO di GIROLAMO ALESSANDRO NANI ARIANNA PANI NOEMI MILAN ELENA DE MATTIA ANDREA SARTORE-BIANCHI ERIKA CECCHIN Experimental and Clinical Pharmacology Unit Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano33081Italy Department of Medicine(DMED) University of UdineUdine33100Italy Unit of Cancer Epidemiology Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano33081Italy Department of Oncology and Hemato-Oncology Universitàdegli Studi di MilanoMilan20122Italy Department of Hematology Oncologyand Molecular MedicineGrande Ospedale Metropolitano NiguardaMilan20122Italy Oncology Pharmacy Unit IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino AmadoriMeldola47014Italy Pharmacy Unit Fondazione IRCCS Istituto Tumori di MilanoMilan20122Italy Department of Pharmacy Ca’Foncello Treviso Regional HospitalPiazzale Ospedale 1Treviso31100Italy Department of Medical Surgical and Health Sciences University of TriesteTrieste34127Italy Hospital Pharmacy Cattinara HospitalAzienda Sanitaria Universitaria Giuliano IsontinaTrieste34148Italy Department of Oncology and Onco-Hematology Postgraduate School of Clinical Pharmacology and ToxicologyUniversity of MilanMilan20122Italy

Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this *** meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC(i.e.,RAS,BRAF,SMAD4,PIK3CA)as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM ***:A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM,stratified according to RAS,BRAF,PIK3CA,and SMAD4 mutational *** ratios(HRs)from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were *** search was conducted in numerous databases,including MEDLINE(PubMed),Embase,Cumulative Index to Nursing and Allied Health Literature(CINAHL)(EBSCO host),and WHO Global Index Medicus,through March 18th,***-analyses,editorials,letters to the editor,case reports,studies on other primary cancers,studies with primary metastatic sites other than the liver,studies lacking specific oncological outcome variables or genetic data,non-English language studies,and studies omitting residual disease data from liver metastasectomy were *** remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically ***:RAS mutation status was negatively associated with overall survival(OS)(HR,1.68;95%CI,1.54–1.84)and recurrence free survival(RFS)(HR,1.46;95%CI,1.33–1.61).A negative association was also found for BRAF regarding OS(HR,2.64;95%CI,2.15–3.24)and RFS(HR,1.89;95%CI,1.32–2.73)and SMAD4 regarding OS(HR,1.93;95%CI,1.56–2.38)and RFS(HR,1.95;95%CI,1.31–2.91).For PIK3CA only three studies were eligible and no significant associati

关键词： Metastasectomy Liver metastases RAS BRAF SMAD4 PIK3CA Colorectal

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Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1132-1146页

作者： Gian Luca Rampioni Vinciguerra Marina Capece Luca Reggiani Bonetti Giovanni Nigita Federica Calore Sydney Rentsch Paolo Magistri Roberto Ballarin Fabrizio di Benedetto Rosario distefano Roberto Cirombella Andrea Vecchione Barbara Belletti Gustavo Baldassarre Francesca Lovat Carlo M.Croce Department of Cancer Biology and Genetics and Comprehensive Cancer Center The Ohio State UniversityColumbus 43210 OHUSA Department of Clinical and Molecular Medicine Faculty of Medicine and PsychologySant’Andrea HospitalUniversity of Rome“Sapienza”Rome 00189Italy Department of diagnostic Clinic and Public Health MedicineUniversity of Modena and Reggio EmiliaModena 41100Italy Hepato-pancreato-biliary Surgery and Liver Transplantation Unit University of Modena and Reggio EmiliaModena 41100Italy division of Molecular Oncology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano 33081Italy

Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient *** aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor *** of the onco-suppressor miR-15a has been extensively documented in ***,we identified the transcription factor Fos-related antigen-2(Fra-2)as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient *** report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC ***,we discovered that miR-15a repressed IGF1R expression via Fra-2 *** miR-15a-low context,IGF1R hyperactivated mTOR,modulated the autophagic flux and sustained PDAC growth in nutrient *** a genetic mouse model,Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet ***,nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent ***,our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.

关键词： IGF1R Fra miR

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Unravelling the ion transport and the interphase properties of a mixed olivine cathode for Na-ion battery

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Journal of Energy Chemistry 2024年第9期96卷 300-317页

作者： Luca Minnetti Leonardo Sbrascini Antunes Staffolani Vittorio Marangon Francesco Nobili Jusef Hassoun School of Sciences and Technologies–Chemistry division University of CamerinoVia Madonna delle Carceri ChIP62032 CamerinoItaly Current affiliation:University of Bologna Department of Chemistry“Giacomo Ciamician”Via Francesco Selmi 240126 BolognaItaly Graphene Labs Istituto Italiano di Tecnologiavia Morego 30Genoa 16163Italy Department of Chemical Pharmaceutical and Agricultural SciencesUniversity of FerraraVia Fossato di Mortara 1744121 FerraraItaly GISEL−centro di riferimento Nazionale per i Sistemi di Accumulo Elettrochimico di Energia INSTMFirenze 50121Italy National Interuniversity Consortium of Materials Science and Technology(INSTM)University of Ferrara Research Unit University of FerraraVia Fossato di Mortara1744121 FerraraItaly

The replacement of Li by Na in an analogue battery to the commercial Li-ion one appears a sustainable strategy to overcome the several concerns triggered by the increased demand for the electrochemical energy ***,the apparently simple change of the alkali metal represents a challenging step which requires notable and dedicated ***,we investigate herein the features of a NaFe_(0.6)Mn_(0.4)PO_(4)(NFMP)cathode with triphylite structure achieved from the conversion of a LiFe_(0.6)Mn_(0.4)PO_(4)(LFMP)olivine for application in Na-ion *** work initially characterizes the structure,morphology and performances in sodium cell of NFMP,achieving a maximum capacity exceeding 100 mAh g^(−1)at a temperature of 55℃,adequate rate capability,and suitable retention confirmed by ex-situ ***,the study compares in parallel key parameters of the NFMP and LFMP such as Na^(+)/Li^(+)ions diffusion,interfacial characteristics,and reaction mechanism in Na/Li cells using various electrochemical *** data reveal that relatively limited modifications of NFMP chemistry,structure and morphology compared to LFMP greatly impact the reaction mechanism,kinetics and electrochemical *** changes are ascribed to the different physical and chemical features of the two compounds,the slower mobility of Na^(+)with respect to Li^(+),and a more resistive electrode/electrolyte interphase of sodium compared with ***,the study reveals analogue trends of the charge transfer resistance and the ion diffusion coefficient in NFMP and LFMP during the electrochemical process in ***,the NFMP achieved herein is suggested as a possible candidate for application in a low-cost,efficient,and environmentally friendly Na-ion battery.

关键词： NaFe_(0.6)Mn_(0.4)PO_(4)NFMP Olivine Na-ion lon transport Interphase

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Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications

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World Journal of Stem Cells 2022年第1期14卷 54-75页

作者： Carla Vicinanza Elisabetta Lombardi Francesco Da Ros Miriam Marangon Cristina Durante Mario Mazzucato Francesco Agostini Stem Cell Unit Centro di Riferimento Oncologico di AvianoIRCCSAviano 33081Italy

Mesenchymal stem stromal cells(MSC)are characterized by the intriguing capacity to home toward cancer cells after systemic ***,MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against *** cancer patients,MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was ***,the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor ***,induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic *** vivo cell modifications are,thus,required to improve anti-cancer properties of *** based cellular therapy products must be handled in compliance with good manufacturing practice(GMP)*** the present review we include MSCimproving manipulation approaches that,even though actually tested at preclinical level,could be compatible with GMP *** particular,we describe possible approaches to improve MSC homing on cancer,including genetic engineering,membrane modification and cytokine ***,we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic *** conclusion,we suggest that,to configure MSC as a powerful weapon against cancer,combinations of clinical grade compatible modification protocols that are currently selected,should be introduced in the final *** standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.

关键词： Cancer Mesenchymal stem stromal cells Good manufacturing practice Homing Targeted therapy Ex vivo cell modification

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The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines

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Cancer Drug Resistance 2019年第1期2卷 116-130页

作者： Elena De Mattia Rossana Roncato Chiara Dalle Fratte Fabrizio Ecca Giuseppe Toffoli Erika Cecchin Experimental and Clinical Pharmacology Unit Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano 33081Italy

Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and neck and gastric *** present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening *** the high number of patients receiving FP-based therapies,and the significant effects of toxicities on their quality of life,the prevention of FP-related adverse events is of major clinical *** genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase(DPYD)gene are related to the occurrence of extremely severe,early onset toxicity in FP treated *** pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic *** prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical *** pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways,TYMS and MTHFR,but no additional clinically validated genetic markers of toxicity are available to *** development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic ***,the investigation of the genetic variation in the patients immunological system,a pivotal target in cancer treatment,could bring notable advances in the *** review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.

关键词： Fluoropyrimidines pharmacogenetics colorectal cancer toxicity DPYD TYMS MTHFR

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Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

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World Journal of Gastroenterology 2019年第29期25卷 3870-3896页

作者： Elena De Mattia Erika Cecchin Michela Guardascione Luisa Foltran Tania di Raimo Francesco Angelini Mario D’Andrea Giuseppe Toffoli Clinical and Experimental Pharmacology Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Aviano (PN) 33081 Italy Department of Medical Oncology Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Aviano (PN) 33081 Italy Medical Oncology and Anatomic Pathology Unit “San Filippo Neri Hospital” Rome 00135 Italy Department of Oncology “San Filippo Neri Hospital” Rome 00135 Italy

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and

关键词： Hepatocellular carcinoma Pharmacogenetics Genetic markers Sorafenib Regorafenib Immune checkpoint inhibitors Cytochromes UDP glucuronosyltransferase 1A

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Loss of CDKN1B induces an age-related clonal hematopoietic disorder via Notch2 activity dysregulation

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Cancer Communications 2023年第7期43卷 844-849页

作者： Ilenia Segatto Gian Luca Rampioni Vinciguerra Ilenia Pellarin Alessandra Dall’Acqua Stefania Berton Francesca Citron Sara D’Andrea Giorgia Mungo Davide Viotto Lorena Musco Arianna di Napoli Maria Antonietta Aloe Spiriti Vincenzo Canzonieri Valter Gattei Andrea Vecchione Barbara Belletti Gustavo Baldassarre division of Molecular Oncology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano(PN)Italy Department of Clinical and Molecular Medicine University of Rome“La Sapienza”Santo Andrea HospitalRomeItaly division of Pathology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano(PN)Italy division of Clinical and Experimental Onco-Hematology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano(PN)Italy

Dear Editor,The tumor suppressor gene CDKN1B,encoding for the p27^(Kip1)(p27)protein,defines the smallest region of deletion on chromosome 12p13 described in clonal hematopoietic disorders(CHDs)[1].Among them,myelodysplastic syndromes(MDSs)display typical onset in the elderly and an indolent behavior that may evolve in acute myeloid leukemia(AML)[2].Recent evidences support a model of parallel clonal evolution at the stem or progenitor cell level and implicate the need of more preclinical,translational and clinical research to identify better ways to timely target clones that may evolve toward malignancy[3,4].

关键词： hematopoietic clinical acute

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Genetic biomarkers for hepatocellular cancer risk in a caucasian population

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World Journal of Gastroenterology 2017年第36期23卷 6674-6684页

作者： Elena De Mattia Erika Cecchin Jerry Polesel Alessia Bignucolo Rossana Roncato Francesco Lupo Marina Crovatto Angela Buonadonna Claudio Tiribelli Giuseppe Toffoli Clinical and Experimental Phar-macology “Centro di Riferimento Oncologico”-National Cancer Institute Unit of Cancer Epidemiology “Centro di Riferimento Oncologico”-National Cancer Institute General Surgery 2U and Liver Transplantation Center A.O.U.Cittàdella Salute e della Scienza di TorinoUniversity of Torino Cytogenetics and Molecular Biology Unit Santa Maria degli Angeli Hospital Pordenone Medical Oncology Unit “Centro di Riferimento Oncologico”-National Cancer Institute Fondazione Italiana Fegato AREA Science Park

AIM To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma(HCC)susceptibility in Caucasians. METHODS The present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two,independent,HCC-free,age/sex-matched control *** HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver *** first control group comprised167 patients that were matched to the HCC cohort for the percentage of hepatitis B(HBV)and/or hepatitis C(HCV)infections.A second control group included192 virus-free,healthy individuals that were used to evaluate the generalizability of the identified predictive *** cases and controls were *** three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related *** study end-point was to assess the association between genetic variants and HCC onset. RESULTS Five genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/*** to a dominant model,reduced HCC risk was associated with three polymorphisms:ERCC1rs3212986(OR=0.46,95%CI:0.30-0.71,P=0.0005),GST-P1 rs1138272(OR=0.41,95%CI:0.21-0.81,P=0.0097),and CYP17A1 rs743572(OR=0.50,95%CI:0.31-0.79,P=0.0032).Conversely,according to a recessive model,increased HCC risk was associated with two polymorphisms:XRCC3 rs1799794(OR=3.70,95%CI:1.02-13.39,P=0.0461)and ABCB1 rs1128503(OR=2.06,95%CI:1.18-3.61,P=0.0111).These associations remained significant in a subgroup analysis,where patients were stratified according to viral status(HBV-or HCV-positive serology).Two variants exhibited a serology-specific effect:ABCB1 rs1128503(OR=4.18,95%CI:1.55-11.29,P=0.0048)showed an effect in the HBV-positive subgroup;and ERCC1 rs3212986(OR=0.33,95%CI:0.18-0.60,P=0.0003)showed an effect in the HCV-positive *** the five markers identified,E

关键词： ERCC1 XRCC3 GST-P1 CYP17A1 MDR-1 Polymorphisms Hepatocellular carcinoma risk Early diagnosis Antiviral therapy Hepatitis B viral/hepatitis C viral

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Reactive pathways toward parasitic release of singlet oxygen in metal-air batteries

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npj Computational Materials 2021年第1期7卷 1135-1142页

作者： Adriano Pierini Sergio Brutti Enrico Bodo Department of Chemistry University of Rome“La Sapienza”RomeItaly GISEL—centro di riferimento Nazionale per i Sistemi di Accumulo Elettrochimico di Energia FirenzeItaly

The superoxide disproportionation reaction is a key step in the chemistry of aprotic metal oxygen batteries that controls the peroxide formation upon discharge and opens the way for singlet oxygen *** we clarify the energy landscape of the disproportionation of superoxide in aprotic media catalyzed by group 1A *** analysis is based on ab initio multireference computational methods and unveils the competition between the expected reactive path leading to peroxide and an unexpected reaction channel that involves the reduction of the alkaline *** channels lead to the release of triplet and singlet O_(2).The existence of this reduction channel not only facilitates singlet oxygen release but leads to a reactive neutral solvated species that can onset parasitic chemistries due to their well-known reducing ***,we show that the application of moderate overpotentials makes both these channels accessible in aprotic batteries.

关键词： properties release singlet

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Surveillance strategies following curative resection and nonoperative approach of rectal cancer:How and how long?Review of current recommendations

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World Journal of Gastrointestinal Surgery 2023年第2期15卷 177-192页

作者： Andrea Lauretta Giulia Montori Gian Piero Guerrini Department of Surgical Oncology Centro di Riferimento Oncologico di Aviano IRCCSAviano 33081Italy Department of General Surgery Vittorio Veneto HospitalULSS 2 Marca TrevigianaVittorio Veneto 31029Italy Hepato-Pancreato-Biliary Surgical Oncology and Liver Transplantation Unit Policlinico-AUO ModenaModena 41124Italy

different follow-up strategies are available for patients with rectal cancer following curative treatment.A combination of biochemical testing and imaging investigation,associated with physical examination are commonly ***,there is currently no consensus about the types of tests to perform,the timing of the testing,and even the need for follow-up at all has been *** aim of this study was to review the evidence of the impact of different followup tests and programs in patients with non-metastatic disease after definitive treatment of the primary.A literature review was performed of studies published on MEDLINE,EMBASE,the Cochrane Library and Web of Science up to November *** published guidelines from the most authoritative specialty societies were also *** to the follow-up strategies available,the office visit is not efficient but represents the only way to maintain direct contact with the patient and is recommended by all authoritative specialty *** colorectal cancer surveillance,carcinoembryonic antigen represents the only established tumor *** and chest computed tomography scan is recommended considering that the liver and lungs are the most common sites of *** local relapse in rectal cancer is higher than in colon cancer,endoscopic surveillance is *** follow-up regimens have been published but randomized comparisons and meta-analyses do not allow to determine whether intensive or less intensive follow-up had any significant influence on survival and recurrence detection *** available data do not allow the drawing of final conclusions on the ideal surveillance methods and the frequency with which they should be *** is very useful and urgent for clinicians to identify a cost-effective strategy that allows early identification of recurrence with a special focus for highrisk patients and patients undergoing a“watch and wait”approach.

关键词： Rectal cancer Follow-up Surveillance Recurrence Carcinoembryonic antigen Computed tomography

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