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1.
Methods Mol Biol ; 2571: 45-55, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36152149

RESUMO

This methodological work demonstrates the potential of metabolomic approaches based on liquid chromatography coupled to high-resolution mass spectrometry (LC-ESI(+/-)-HRMS) to investigate the antiproliferative capacity of underexplored biomasses (e.g., Passiflora mollissima seeds and Physalys peruviana calyx), by evaluating the molecular changes induced at the metabolite expression levels on HT-29 human colon cancer cells. This protocol describes in detail the optimal conditions to obtain bioactive extracts by pressurized liquid extraction (PLE), the experimental procedure to grow and treat HT-29 human colon cancer cells and CCD-18Co normal human colon fibroblasts with the target extracts, the metabolites extraction from the cytosolic fraction, and subsequent metabolomic fingerprinting. After treatment for 48 and 72 h, the viability of HT-29 colon cancer cells is markedly affected, and metabolites can be extracted for investigation. Following the proposed metabolomic data analysis and interpretation workflow, altered cellular redox homeostasis, as well as inactivation or dysfunction on other metabolic pathways, constitutes valuable biological information to understand the mechanisms underlying the antiproliferative effect.


Assuntos
Neoplasias do Colo , Frutas , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Frutas/metabolismo , Humanos , Metabolômica/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
2.
Int J Cancer ; 152(2): 123-136, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35904874

RESUMO

Data on diet and survival among people with metastatic colorectal cancer are limited. We examined dietary fat in relation to all-cause mortality and cancer progression or death among 1149 people in the Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group (SWOG) 80405 trial who completed a food frequency questionnaire at initiation of treatment for advanced or metastatic colorectal cancer. We examined saturated, monounsaturated, total and specific types (n-3, long-chain n-3 and n-6) of polyunsaturated fat, animal and vegetable fats. We hypothesized higher vegetable fat intake would be associated with lower risk of all-cause mortality and cancer progression. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Over median follow-up of 6.1 years (interquartile range [IQR]: 5.3, 7.2 y), we observed 974 deaths and 1077 events of progression or death. Participants had a median age of 59 y; 41% were female and 86% identified as White. Moderate or higher vegetable fat was associated with lower risk of mortality and cancer progression or death (HRs comparing second, third and fourth to first quartile for all-cause mortality: 0.74 [0.62, 0.90]; 0.75 [0.61, 0.91]; 0.79 [0.63, 1.00]; P trend: .12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88]; P trend: .01). No other fat type was associated with all-cause mortality and cancer progression or death. Moderate or higher vegetable fat intake may be associated with lower risk of cancer progression or death among people with metastatic colorectal cancer.


Assuntos
Doenças Cardiovasculares , Neoplasias do Colo , Neoplasias Retais , Feminino , Animais , Masculino , Gorduras na Dieta , Dieta , Causas de Morte
3.
Reg Anesth Pain Med ; 48(1): 7-13, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36167477

RESUMO

BACKGROUND AND AIMS: An opioid-sparing postoperative analgesic regimen following laparoscopic hemicolectomy is optimal to promote minimal postoperative pain, early mobilization, and improved quality of recovery. Various regional anesthesia techniques have been tested to improve postoperative pain management after laparoscopic hemicolectomy. In this study, we aimed to assess the effect of administering a preoperative bilateral ultrasound-guided anterior quadratus lumborum nerve block on postoperative opioid consumption after laparoscopic colon cancer surgery. METHODS: In this randomized, controlled, double-blinded trial, 69 patients undergoing laparoscopic hemicolectomy due to colon cancer were randomized to receive an anterior quadratus lumborum block with ropivacaine 0.375% 30 mL on each side or isotonic saline (placebo). The primary outcome measure was total opioid consumption during the first 24 hours postsurgery. The secondary outcome measures were pain scores, accumulated opioid consumption in 6-hour intervals, nausea and vomiting, ability of postoperative ambulation, time to first opioid, orthostatic hypotension or intolerance, postoperative Quality of Recovery-15 scores, surgical complications, length of hospital stay, and adverse events. RESULTS: The total opioid consumption in the first 24 hours postsurgery was not significantly reduced in the ropivacaine group compared with the saline group (mean 129 mg (SD 88.4) vs mean 127.2 mg (SD 89.9), p=0.93). In addition, no secondary outcome measures showed any statistically significant intergroup differences. CONCLUSION: The administration of a preoperative bilateral anterior quadratus lumborum nerve block as part of a multimodal analgesic regimen for laparoscopic hemicolectomy did not significantly reduce opioid consumption 24 hours postsurgery. Trial registration number NCT03570541.


Assuntos
Neoplasias do Colo , Laparoscopia , Bloqueio Nervoso , Humanos , Analgésicos Opioides , Ropivacaina/uso terapêutico , Anestésicos Locais , Bloqueio Nervoso/efeitos adversos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Colectomia/efeitos adversos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Método Duplo-Cego , Analgésicos/uso terapêutico , Neoplasias do Colo/cirurgia , Neoplasias do Colo/complicações , Neoplasias do Colo/tratamento farmacológico
4.
Int J Cancer ; 152(2): 195-202, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36054722

RESUMO

Colon cancer is the second most frequently diagnosed cancer in women in Norway, where incidence rates of colon cancer increased 3-fold between 1955 and 2014, for unknown reasons. We aimed to assess the burden of colon cancer attributable to modifiable risk factors in Norwegian women using the data from the Norwegian Women and Cancer (NOWAC) study. Self-reported information from 35 525 women from the NOWAC study were available. These included the following exposures: smoking status, alcohol consumption, body mass index, physical activity, intake of calcium, fibers, and red and processed meat. Colon cancer cases were identified from the Cancer Registry of Norway. A parametric piecewise constant hazards model was used to estimate the strength of exposure-cancer associations. Population attributable fractions with 95% confidence intervals (CIs) were calculated considering competing risk of death. The fraction of incident colon cancer attributable to ever smoking was 18.7% (95% CI 4.7%-30.6%), low physical activity 10.8% (95% CI -0.7% to 21.0%), alcohol consumption 14.5% (95% CI -2.8% to 28.9%), and low intake of calcium 10.0% (95% CI -7.8% to 24.8%). A small proportion of colon cancer cases was attributable to combined intake of red and processed meat over 500 g/week, overweight/obesity, and low intake of fibers. Jointly, these seven risk factors could explain 46.0% (95% CI 23.0%-62.4%) of the colon cancer incidence burden. Between 23% and 62% of the colon cancer burden among women in Norway was attributable to modifiable risk factors, indicating an important preventive potential of a healthy lifestyle.


Assuntos
Neoplasias do Colo , Segunda Neoplasia Primária , Feminino , Humanos , Cálcio , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/etiologia , Fatores de Risco , Cálcio na Dieta
5.
Bioorg Chem ; 130: 106230, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36375352

RESUMO

Colorectal cancer is a type of cancer encountered worldwide and ranks third among all cancer types in terms of incidence. Polyphenols have been shown to have a wide range of biological functions, including a significant impact on cancer start, development, and promotion through regulating many signaling pathways. The aim of this study was to investigate the anticancer effects of isoeugenol based compounds 1, 2 on HT29 colorectal cancer cell line in vitro. MTT test and scratch assay were carried out to determine the effect of these compounds on HT29 cell proliferation and migration respectively. In addition, mRNA expression levels of apoptosis and metastasis-related genes (p53, Bcl2, Bax, Caspase 3, Caspase7, Caspase8, Caspase9, HIF1-α, VEGF, MMP-2, MMP-9) were examined by quantitative real-time PCR. The results indicated that 1 and 2 inhibited HT29 cell proliferation and induced apoptosis by increasing the Bax/Bcl2 ratio and Caspase-9 and Caspase-3 mRNA expression. In conclusion, the results of this study showed that the treatment of these compounds significantly suppressed the mRNA expressions of metastasis-related genes such as Matrix Metalloproteinase-2, Matrix Metalloproteinase-9, Vascular Endothelial Growth Factor and Hypoxia­Inducible Factor 1α.


Assuntos
Neoplasias do Colo , Metaloproteinase 2 da Matriz , Humanos , Metaloproteinase 2 da Matriz/genética , Proteína X Associada a bcl-2/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/farmacologia , Neoplasias do Colo/tratamento farmacológico , Proliferação de Células , Fenóis/farmacologia , RNA Mensageiro
6.
Ann R Coll Surg Engl ; 104(4): 257-260, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34939845

RESUMO

INTRODUCTION: The aim of this study was to assess faecal immunochemical test (FIT) negativity in terms of its effect on cancer risk in the local symptomatic two-week wait (2WW) population. FIT was introduced to the colorectal 2WW pathway at the start of the pandemic. This study analyses the FIT-negative (<10µg Hb/g) cohort and calculates the relative risk and odds ratio associated with a negative FIT test. METHODS: FIT tests were sent to symptomatic 2WW patients without rectal bleeding, iron-deficient anaemia or palpable mass. Where FIT was <10µg Hb/g investigations were moved to a radiology protocol. RESULTS: The test return rate was 91% with a FIT-negative (<10µg Hb/g) rate of 82%. The FIT-negative group in the symptomatic referral pathway in Cornwall have a low (1.4%) risk of colon cancer but a significant risk (6.6%) when all cancer types are considered. The impact of a negative quantitative FIT changes the odds ratio of a patient having a luminal cancer by 0.26. The odds ratio for 'all cancer' risk was affected by 0.83. CONCLUSION: A negative FIT test within the local NG12 symptomatic patient group signifies a low risk of colon cancer and identifies patients who can be initially investigated with cross-sectional imaging. However, when all cancer types are considered, cancer prevalence in this group remains above 6%. In relative risk terms a negative FIT represents a small change in overall risk and this patient group still qualify for investigation through 2WW pathways.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Fezes , Humanos , Sangue Oculto , Reto , Encaminhamento e Consulta
8.
Clin. transl. oncol. (Print) ; 24(11): 2155-2165, noviembre 2022. graf, tab
Artigo em Inglês | IBECS | ID: ibc-210143

RESUMO

Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB).MethodsIn this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38).ResultsBetween February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B.ConclusionsThe BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation. (AU)


Assuntos
Humanos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/uso terapêutico , DNA Tumoral Circulante/genética , Neoplasias do Colo/etiologia , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia
9.
Cell Death Dis ; 13(11): 923, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333284

RESUMO

Metastasis is the dominant cause of cancer-related mortality. Metastasis-associated with colon cancer protein 1 (MACC1) has been proven to play a critical role in cancer metastasis. However, the prometastatic role of MACC1 in regulating the pancreatic cancer (PC) metastatic phenotype remains elusive. Here, we report that MACC1 is highly expressed in The Cancer Genome Atlas (TCGA) and tissue microarray (TMA) and identified as a good indicator for poor prognosis. Overexpression or knockdown of MACC1 in PC cells correspondingly promoted or inhibited pancreatic cancer cell migration and invasion in a MET proto-oncogene receptor tyrosine kinase (MET)-independent manner. Notably, knockdown of MACC1 in PC cells markedly decreased the liver metastatic lesions in a liver metastasis model. Mechanistically, MACC1 binds to the epithelial-mesenchymal transition (EMT) regulator snail family transcriptional repressor 1 (SNAI1) to drive EMT via upregulating the transcriptional activity of SNAI1, leading to the transactivation of fibronectin 1 (FN1) and the trans-repression of cadherin 1 (CDH1). Collectively, our results unveil a new mechanism by which MACC1 drives pancreatic cancer cell metastasis and suggest that the MACC1-SNAI1 complex-mediated mesenchymal transition may be a therapeutic target in pancreatic cancer.


Assuntos
Neoplasias do Colo , Neoplasias Pancreáticas , Humanos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Transativadores/genética , Transativadores/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Movimento Celular/genética , Neoplasias Pancreáticas/genética , Neoplasias do Colo/genética , Metástase Neoplásica , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
10.
Iran J Allergy Asthma Immunol ; 21(5): 549-560, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36341563

RESUMO

It is believed that preformed antibodies are responsible for blood transfusion reactions and transplant rejections. In order to remove a tumor, the tissue must be rejected. On the basis of transfusion reaction and transplantation immunology, we hypothesized that allogeneic serum can inhibit tumor growth when injected intra-tumor. Initially, an in vitro cytotoxicity test was conducted using the C57BL/6 serum (intact or decomplemented) in combination with the BALB/c-originating CT26 cell line.  The CT26 cell line was used to establish a mouse model of colon cancer. When the tumor was palpable, C57BL/6 serum was injected intra-tumor. In addition to tumor size, hypoxia, metastatic capacity, angiogenesis, and metabolic and inflammatory status, we evaluated matrix metalloproteinase-2 (MMP)-2 and 9, vascular endothelial growth factor (VEGF)-A, Cluster of Designation (CD) 31, CD38 and interleukine (IL)-10. An in vitro experiment showed that heat-inactivated C57BL/6 serum had significantly lower cytotoxic effects on BALB/c-derived CT26 cells than intact C57BL/6 serum or BALB/c serum. In vivo experiments revealed that tumor size, HIF-1α, MMP-2, and MMP-9 levels were significantly lower in the experimental group than in the control group. In contrast to control animals, allogeneic serum treatment led to marked reductions in CD31, VEGF-1, CD38, and IL-10 levels. A new approach to serum or plasma therapy and allogeneic vaccines for cancer is intra-tumor injection of allogeneic serum. In light of the ease and availability of allogeneic immunotherapies, allogeneic serum and plasma therapy could potentially be used as an alternative monotherapy or in combination with other therapies.


Assuntos
Neoplasias do Colo , Transplante de Células-Tronco Hematopoéticas , Camundongos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Neoplasias do Colo/terapia , Neovascularização Patológica/terapia , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , Imunoterapia
11.
J Immunother Cancer ; 10(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36323433

RESUMO

BACKGROUND: The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet. METHODS: The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression. RESULTS: Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade. CONCLUSIONS: This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.


Assuntos
Produtos Biológicos , Colite , Neoplasias do Colo , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Camundongos , Azoximetano , Antígeno B7-H1/genética , Colite/induzido quimicamente , Di-Iodotirosina/genética , Interleucina-15/genética , Antígenos de Histocompatibilidade Menor/genética , Acúmulo de Mutações , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral
12.
J Adv Res ; 41: 159-168, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36328745

RESUMO

INTRODUCTION: Photothermal therapy can be synergistically combined with chemotherapy to improve the therapeutic effect for colon cancer. However, conventional therapeutic agents have side effects in normal tissues, limiting their application. OBJECTIVES: To reduce these side effects, a smart agent (Cur@HKUST-1@PVP) whose functionality is triggered by the high content of endogenous hydrogen sulfide in colon tumors was engineered for photoacoustic imaging-guided combination of photothermal therapy and chemotherapy for colon tumors. METHODS: After reacting with hydrogen sulfide, Cur@HKUST-1@PVP simultaneously generates CuS and releases curcumin. The generated CuS serves as an imaging agent for both photothermal therapy and photoacoustic imaging, while the released curcumin is used for chemotherapy. RESULTS: In vivo photoacoustic imaging experiments demonstrated that Cur@HKUST-1@PVP can be used for selectively imaging colon cancer tumors. In vivo experiments in mice for treatment suggested that the endogenous hydrogen sulfide-activated combination of photothermal therapy and chemotherapy has a better treatment effect that photothermal therapy or chemotherapy treatment alone. CONCLUSION: The endogenous hydrogen sulfide-activated Cur@HKUST-1@PVP agent developed herein shows great potential for the accurate diagnosis and effective treatment of colon cancer.


Assuntos
Neoplasias do Colo , Curcumina , Sulfeto de Hidrogênio , Técnicas Fotoacústicas , Camundongos , Animais , Técnicas Fotoacústicas/métodos , Terapia Fototérmica , Curcumina/uso terapêutico , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico
13.
Int J Colorectal Dis ; 37(11): 2291-2301, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36329204

RESUMO

PURPOSE: Accumulating evidence indicate that antibiotic use could induce microbiome dysbiosis, which was a critical driver to the onset and progression of colorectal cancer (CRC). But the relationship between antibiotics use and CRC was still disputed. Hence, we conducted this systematic review and meta-analysis to appraise and synthesize the present available evidence to clarify the association. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for relevant observational studies from inception to June 5, 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to explore the association between antibiotics use and CRC using random-effects model. Subgroup analyses, sensitive analyses, and publication bias were conducted to assess the robust reliability of pooled results. RESULTS: A total of 15 observational studies containing 5,164,138 patients were included in this meta-analysis. The pooled analysis indicated that the total antibiotic use was correlated with increased risk of CRC (OR, 1.11; 95% CI, 1.05-1.18). The subgroup analyses suggested that antibiotic use significantly elevated risk of colon cancer, but not rectal cancer. Furthermore, we found that penicillin, cephalosporin, anti-anaerobic, and anti-aerobic antibiotics increased the risk of CRC, in particular metronidazole but no significant associations were identified in macrolide, tetracycline, sulfonamides, nitrofurans, and quinolone use. The results of sensitive analyses and publication bias indicated the conclusions were robust. CONCLUSION: The findings showed that antibiotics use may be associated with the onset of CRC. Policy-makers and clinicians should adequately assess possible benefits and harms of antibiotics use, especially in some high-risk populations. Also, for high-risk patients with previous antibiotics use, it was suggested to perform early colonoscopy screening to find or even eliminate early-stage CRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Antibacterianos/efeitos adversos , Reprodutibilidade dos Testes , Neoplasias Colorretais/diagnóstico , Colonoscopia/efeitos adversos , Neoplasias do Colo/complicações , Estudos Observacionais como Assunto
14.
Sci Rep ; 12(1): 20075, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36418865

RESUMO

Carcinoembryonic antigen (CEA) levels and imaging are used to guide treatment for metastatic colorectal cancer (mCRC). This study evaluated changes in CEA and imaging findings in mCRC patients following systemic therapy and their clinical significance, especially the ones with inconsistent results of CEA and image findings. We enrolled 330 stage IV CRC patients who systemic therapy. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) and a modification for CEA, patients were stratified into consistent and inconsistent response groups. Clinicopathological features and prognoses were compared between each groups. Different CEA/IMG groups showed no significant differences in terms of tumor location, initial CEA level, mucinous component, tumor differentiation and further surgical treatment rate. Inconsistent responses were observed in half of the patients (n = 165, 50%). The prognosis in the inconsistent groups with either CEA-SD or IMG-SD was dependent on the result of the other evaluation method (PR or PD). Cases with conflicting results between CEA and image groups (CEA-RD/IMG-PD, CEA-PD/IMG-PR) had an OS close to that of CEA-SD/IMG-SD (18.2 m, 16.2 m vs. 18.8 m, P = 0.620). The overall survival (OS) in the consistent (PR/PR ro PD/PD) groups were significantly different (P < 0.001). Combining CEA and imaging provides more information about mCRC patients who have undergone systemic therapy. Approximately half the patients have inconsistent responses, which is still valuable in predicting the prognosis.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Antígeno Carcinoembrionário , Prognóstico , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Critérios de Avaliação de Resposta em Tumores Sólidos
15.
BMC Gastroenterol ; 22(1): 482, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36419007

RESUMO

BACKGROUND: Previous studies have reported that the tumor heterogeneity and complex oncogenic mechanisms of proximal and distal colon cancer (CRC) are divergent. Therefore, we aim to analyze the differences between left-sided CRC (L_cancer) and right-sided CRC (R_cancer), as well as constructing respective nomograms. METHODS: We enrolled 335 colon cancer patients (146 L_cancer patients and 189 R_cancer patients) from The Cancer Genome Atlas (TCGA) data sets, and 102 pairs of color cancer tissue and adjacent normal tissue (51 L_cancer patients and 51 R_cancer patients) from our hospital. Firstly, we analyzed the differences between the L_cancer patients and R_cancer patients, and then established the L_cancer and R_cancer prognostic models using LASSO Cox. RESULTS: R_cancer patients had lower survival than L_cancer patients. R_cancer patients had higher ESTIMATE and immune scores and lower tumor purity. These patterns of expression of immune checkpoint-related genes and TMB level were higher in R_cancer than in L_cancer patients. Finally, we using Lasso Cox regression analyses established a prognostic model for L_cancer patients and a prognostic model for R_cancer patients. The AUC values of the risk score for OS in L_cancer were 0.862 in the training set and 0.914 in the testing set, while those in R_cancer were 0.835 in the training set and 0.857 in the testing set. The AUC values in fivefold cross-validation were between 0.727 and 0.978, proving that the two prognostic models have great stability. The nomogram of L_cancer included prognostic genes, age, pathological M, pathological stage, and gender, the AUC values of which were 0.800 in the training set and 0.905 in the testing set. Meanwhile, the nomogram of R_cancer comprised prognostic genes, pathological N, pathological T, and age, the AUC values of which were 0.836 in the training set and 0.850 in the testing set. In the R_cancer patients, high-risk patients had a lower proportion of 'B cells memory', 'Dendritic cells resting', immune score, ESTIMATE score, immune checkpoint-related genes, and HLA-family genes, and a higher proportion of 'T cells follicular helper', 'Dendritic cells activated', and 'Mast cells activated'. CONCLUSIONS: We found significant differences between L_cancer and R_cancer patients and established a clinical predictive nomogram for L_cancer patients and a nomogram for R_cancer patients. Additionally, R_cancer patients in low-risk groups may be more beneficial from immunotherapy.


Assuntos
Neoplasias do Colo , Imunoterapia , Humanos , Prognóstico , Oncogenes , Nomogramas , Neoplasias do Colo/genética
16.
Front Immunol ; 13: 1034774, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405748

RESUMO

Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (K D) mainly varying in their dissociation rates (k off) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (K D = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (K D = 0.54 or 46 nM) due to the slow k off from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (K D = 130 nM) and a faster k off. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.


Assuntos
Neoplasias do Colo , Interleucina-12 , Camundongos , Animais , Linfócitos T CD8-Positivos , Trastuzumab , Receptor ErbB-2 , Citocinas , Antígenos de Neoplasias , Anticorpos , Microambiente Tumoral
17.
BMJ Open ; 12(11): e063700, 2022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36410812

RESUMO

OBJECTIVE: The BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system. DESIGN: A partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values. OUTCOME MEASURES: The effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted. RESULTS: The ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively. CONCLUSIONS: This analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.


Assuntos
Neoplasias do Colo , Neoplasias Retais , Adulto , Humanos , Cetuximab/uso terapêutico , Análise Custo-Benefício , Proteínas Proto-Oncogênicas B-raf/genética , Irinotecano , Bevacizumab/uso terapêutico , Inibidores de Proteínas Quinases , França
18.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 38(4): 326-331, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-36414556

RESUMO

Objective: To study the effects of resveratrol (Res) on pyroptosis of colorectal cancer cells . Methods: ①The experiment of dextran sodium sulfate (DSS) induced colon cancer (CRC) in mice: 30 C57BL/6 mice were randomly divided into control group, Azoxymethane (AOM) group, AOM/DSS group, AOM/DSS+Res group and Res group, with 6 mice in each group, the modeling cycle was 70 days in total. Mice in AOM group, AOM/DSS group and AOM/DSS+Res group, at the first day of the first week, were intraperitoneally injected with AOM (10 mg/kg) once, and the ordinary chaw was replaced with high iron feed, and sterile water was given, 1% DSS water was given to AOM/DSS group and AOM/DSS+Res group. The mice in AOM/DSS+Res and Res groups were given resveratrol (50 mg/kg) by oral gavage, When the mold was finished, colon tissue of mice was fixed, embedded and sectionalized. The expressions of NLRP3, Caspase-1 and IL-18 in colon tissues of mice were detected by IHC and Western blot. ②In vitro experiment: HCT 116 cells were given Res (2.4 µg/L) and transfected with miR-31. The Res was divided into 4 groups and labeled with 0 h, 12 h, 24 h and 48 h respectively. The transfected cells were divided into 5 groups: Control group, miR-31 mimic group, miR-31 mimic + Res group, miR-31 inhibitor group, miR-31 inhibitor + Res group. The protein expressions of NLRP3, Caspase-1, GSDMD-N, IL-18 and IL-1ß were detected by Western blot. Results: Animal experiments: Compared with control group, the protein expressions of NLRP3, Caspase-1 and IL-18 in AOM/DSS group were increased significantly (P<0.01). The protein expression levels of NLRP3, Caspase-1 and IL-18 in AOM/DSS+Res group were significantly lower than those in AOM/DSS group (P<0.01). Cell experiments: Compared with the control group, the protein expressions of NLRP3 (P<0.01), GSDMD-N (P<0.05) and IL-18 (P< 0.01) in miR-31 mimic group were increased significantly. The protein expressions of NLRP3, GSDMD-N and IL-18 in miR-31 inhibitor group were decreased significantly (P<0.05). Conclusion: Res inhibited the pyroptosis of colorectal cancer cells through pyroptosis.


Assuntos
Neoplasias do Colo , MicroRNAs , Camundongos , Animais , Sulfato de Dextrana , Resveratrol/farmacologia , Interleucina-18 , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos Endogâmicos C57BL , Azoximetano , Água , Caspases
20.
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