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1.
J Med Case Rep ; 15(1): 486, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34598716

RESUMO

INTRODUCTION: Metastases to the female genital tract from extragenital primary tumors are unusual. We report a rare case of uterine cervix metastasis from colon adenocarcinoma and discuss diagnostic and therapeutic issues. CASE REPORT: We report a case of a 38-year-old North African Caucasian woman treated for a non-metastatic colon adenocarcinoma. She had a sigmoidectomy and incomplete adjuvant chemotherapy. Six months later, she consulted with vaginal bleeding caused by a cervical tumor, which was confirmed to be metastatic disease, and the patient underwent decompressive and hemostatic radiotherapy. CONCLUSION: Uterine cervix metastasis from primary colon adenocarcinoma is rare. The resection remains the standard protocol for the local treatment of resectable metastatic disease. Otherwise, systemic therapy is the preferable option.


Assuntos
Adenocarcinoma , Carcinoma , Neoplasias do Colo , Neoplasias do Colo do Útero , Adenocarcinoma/terapia , Adulto , Neoplasias do Colo/terapia , Feminino , Humanos , Neoplasias do Colo do Útero/terapia
2.
BMC Cancer ; 21(1): 891, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353300

RESUMO

BACKGROUND: Colon cancer is largely implicated in elderly patients (age ≥ 60 years). The prognosis of patients diagnosed with the M1b stage is vastly poor. Marital and insurance status has been considered important prognostic factors in various cancer types. However, how these factors influence elderly patients with stage M1b colon cancer remains to be explored. This study aims to uncover the role of marital and insurance status in the survival of elderly patients with stage M1b colon cancer. METHODS: We retrieved data for patients diagnosed with stage M1b colon cancer between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis of the clinicopathological features, overall survival (OS), and cancer-specific survival (CSS) was based on the marital and insurance status, respectively. RESULTS: In sum, 5709 stage M1b colon cancer patients with complete information from SEER were enrolled for analysis. The OS and CSS of the Non-married group were poorer compared to that of the Married group. The OS and CSS of the Uninsured group were poorer than both of the Insured group and Medicaid group. However, OS was comparable between Uninsured group and Medicaid groups. The findings allude that marital and insurance status potentially impact the long-term survival of elderly patients with M1b colon cancer. The subgroup survival analyses revealed the lowest risk for death among the Insured Married group based on the comparison of the OS and CSS across all other groups. Moreover, Univariate and multivariate analyses revealed race, marital status, surgery, and chemotherapy as independent predictors for OS, whereas insurance status, surgery,and chemotherapy were independent predictors for CSS in elderly patients with M1b colon cancer. CONCLUSION: The marital and insurance status greatly impact the survival of elderly patients with M1b colon cancer. Therefore, it is imperative to provide more support to this vulnerable patient group who are lonely and uninsured, particularly in the psychological and health insurance aspect.


Assuntos
Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Cobertura do Seguro , Estado Civil , Fatores Etários , Neoplasias do Colo/mortalidade , Neoplasias do Colo/terapia , Terapia Combinada , Bases de Dados Factuais , Feminino , Humanos , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde , Masculino , Estado Civil/estatística & dados numéricos , Estadiamento de Neoplasias , Prognóstico , Programa de SEER , Análise de Sobrevida
3.
Int J Nanomedicine ; 16: 5211-5232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366664

RESUMO

Background: Gene therapy has emerged as a new strategy for cancer therapy. As an alternative nucleic acid material, messenger ribonucleic acid (mRNA) is being increasingly utilized in cancer gene therapy. However, unfulfilled requirements and a lack of ideal mRNA delivery vectors persist. Methods: We developed an advanced mRNA delivery system, DMP-039, by fusing a cell-penetrating peptide, cRGD-R9, and a cationic nano-sized DMP backbone together. The DMP gene vector backbone was synthesized by the self-assembly of DOTAP lipid and mPEG-PCL polymer. Introduction of the cRGD-R9 peptide onto the DMP backbone was performed to elevate the mRNA delivery capacity, which resulted in a peptide-functionalized hybrid delivery system. Results: The average size of the synthesized DMP-039 was 268.9 ± 12.4 nm (PDI = 0.382), with a potential of 17.4 ± 0.5 mV. The synthesized DMP-039 hybrid nanoparticles exhibited high mRNA delivery efficiency through multiple mechanisms during transmembrane transportation. By loading the encoding mRNA from the suicide gene Bim, a locally administered mBim/DMP-039 complex strongly inhibited growth in two colon cancer models. Moreover, intravenous administration of the mBim/DMP-039 complex efficiently suppressed C26 pulmonary metastatic tumor progression with high safety. The in vivo distribution, degradation, and excretion were also investigated in detail. Conclusion: Our results suggest that the DMP-039 peptide-functionalized hybrid nanoparticle is an advanced candidate for mRNA-based suicide gene therapy.


Assuntos
Neoplasias do Colo , Nanopartículas , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/terapia , Ácidos Graxos Monoinsaturados , Terapia Genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Poliésteres , Polietilenoglicóis , Compostos de Amônio Quaternário , RNA Mensageiro/genética
4.
BMJ Open ; 11(8): e048985, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429313

RESUMO

OBJECTIVES: The I CARE study (Improving Care After colon canceR treatment in the Netherlands) aims to compare surgeon-led to general practitioner (GP)-led colon cancer survivorship care. Recruitment to the trial took longer than expected. In this descriptive study, recruitment is critically reviewed. SETTING: Patients were recruited from eight Dutch medical centres. PARTICIPANTS: Patients treated with curative intent for stages I-III colon cancer. Target patient sample size was calculated at 300. INTERVENTIONS: Patients were randomised to surgeon-led (usual) versus GP-led care, with or without access to an eHealth application (Oncokompas). OUTCOME MEASURES: Baseline characteristics of (non-)participants, reasons for non-participation and strategies to improve recruitment were reviewed. RESULTS: Out of 1238 eligible patients, 353 patients were included. Of these, 50 patients dropped out shortly after randomisation and before start of the intervention, resulting in a participation rate of 25%. Participants were on average slightly younger (68.1 years vs 69.3 years) and more often male (67% vs 50%) in comparison to non-participants. A total of 806 patients declined participation for reasons most often relating to research (57%), including the wish to remain in specialist care (31%) and too much effort to participate (12%). Some patients mentioned health (9%) and confrontation with the disease (5%) as a reason. In 43 cases, GPs declined participation, often related to the study objective, need for financial compensation and time restraints. The generally low participation rate led to concerns about reaching the target sample size. Methods to overcome recruitment challenges included changes to the original recruitment procedure and the addition of new study centres. CONCLUSIONS: Challenges were faced in the recruitment to a randomised trial on GP-led colon cancer survivorship care. Research on the transition of care requires sufficient time, funding and support base among patients and healthcare professionals. These findings will help inform researchers and policy-makers on the development of future practices. TRIAL REGISTRATION NUMBER: NTR4860.


Assuntos
Neoplasias do Colo , Clínicos Gerais , Neoplasias do Colo/terapia , Humanos , Masculino , Tamanho da Amostra , Sobrevida , Sobrevivência
5.
Biomater Sci ; 9(16): 5577-5587, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34241605

RESUMO

Colon cancer is one of the most common cancers with high mortality, and can easily spread and metastasize, remaining an urgent disease to be solved. Nanomaterial-associated starvation or photothermal therapy has been considered to be a promising strategy in tumor therapy. However, the therapeutic effect of a single regimen for cancer treatment still needs to be improved due to their respective limitations. Herein, a biomimetic multifunctional nanoreactor is developed by encapsulating glucose oxidase and gold nanorods (AuNRs) in an erythrocyte membrane camouflaged metal-organic framework (MOF) nanoparticle (ZGAM), which was exploited for synergistic treatment of colon cancer by combining glucose oxidase-based starvation with AuNR-based photothermal therapy (PTT). This biomimetic nanoreactor could not only exhaust endogenous glucose to suppress the growth of the tumor by the released glucose oxidase (GOx), but also enhance the effect of photothermal therapy via inhibiting the expression of heat shock protein (HSP). In vitro and in vivo investigations indicate that this biomimetic nanoreactor shows excellent therapeutic effects on tumors, resulting from the synergistic treatment of starvation therapy and PTT. Therefore, the proposed strategy may open a window to develop an intelligent therapeutic system for better therapeutic efficacy against cancer.


Assuntos
Neoplasias do Colo , Estruturas Metalorgânicas , Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Neoplasias do Colo/terapia , Glucose Oxidase , Humanos , Neoplasias/terapia , Terapia Fototérmica
7.
Ugeskr Laeger ; 183(25)2021 06 21.
Artigo em Dinamarquês | MEDLINE | ID: mdl-34169826

RESUMO

An estimated 14% of patients diagnosed with colonic cancer present with acute obstruction. An increasing number of colonic obstructions is observed on the basis of benign causes. The use of a self-expanding metal stent (SEMS) is one of the treatment options, and in this review the background and the recommendations for the application in different settings is described. The use of SEMS has clinical outcomes similar to acute resection and is the first line of choice in palliation. Moreover, recent studies have shown SEMS to be an efficient and safe treatment for benign colonic stenosis.


Assuntos
Doenças do Colo , Neoplasias do Colo , Obstrução Intestinal , Doenças do Colo/terapia , Neoplasias do Colo/complicações , Neoplasias do Colo/terapia , Constrição Patológica/terapia , Humanos , Obstrução Intestinal/cirurgia , Cuidados Paliativos , Estudos Retrospectivos , Stents , Resultado do Tratamento
8.
Methods Mol Biol ; 2323: 267-280, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086287

RESUMO

Spontaneous tumor regression following bacterial infection has been observed for hundreds of years. These observations along with anecdotal medical findings in 1890s led to the development of Coley's "toxins," consisting of killed Streptococcus pyogenes and Serratia marcescens bacteria, as the first cancer immunotherapy. The use of this approach, however, was not widely accepted at the time especially after the introduction of radiation therapy as a treatment for cancer in the early 1900s. Over the last 30-40 years there has been renewed interest in the use of bacteria to treat human solid tumors. This is based on the observation that various nonpathogenic anaerobic bacteria can infiltrate and replicate within solid tumors when given intravenously. Bacteria tested as potential anticancer agents include the Gram-positive obligate anaerobes Bifidobacterium and Clostridium, as well as the gram-negative facultative anaerobe Salmonella. Recent advances in synthetic biology and clinical success in cancer immunotherapy provide renewed momentum for developing bacteria-based cancer immunotherapy for cancer treatment and should allow greater potential for the development of novel therapeutic approaches for this devastating disease.


Assuntos
Terapia Biológica/métodos , Neoplasias/terapia , Interferência de RNA , Biologia Sintética/métodos , Animais , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Neoplasias do Colo/microbiologia , Neoplasias do Colo/terapia , Escherichia coli/genética , Escherichia coli/fisiologia , Feminino , Vetores Genéticos/genética , Vetores Genéticos/uso terapêutico , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias/microbiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Indução de Remissão , Salmonella typhimurium/genética , Salmonella typhimurium/fisiologia , Especificidade da Espécie , Organismos Livres de Patógenos Específicos , Biologia Sintética/tendências , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Theranostics ; 11(14): 6668-6681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093846

RESUMO

Background: Newly emerging cancer immunotherapy has led to significant progress in cancer treatment; however, its efficacy is limited in solid tumors since the majority of them are "cold" tumors. Oncolytic viruses, especially when properly armed, can directly target tumor cells and indirectly modulate the tumor microenvironment (TME), resulting in "hot" tumors. These viruses can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies. Cytokines are good candidates to arm oncolytic viruses. IL-23, an IL-12 cytokine family member, plays many roles in cancer immunity. Here, we used oncolytic vaccinia viruses to deliver IL-23 variants into the tumor bed and explored their activity in cancer treatment on multiple tumor models. Methods: Oncolytic vaccinia viruses expressing IL-23 variants were generated by homologue recombination. The characteristics of these viruses were in vitro evaluated by RT-qPCR, ELISA, flow cytometry and cytotoxicity assay. The antitumor effects of these viruses were evaluated on multiple tumor models in vivo and the mechanisms were investigated by RT-qPCR and flow cytometry. Results: IL-23 prolonged viral persistence, probably mediated by up-regulated IL-10. The sustainable IL-23 expression and viral oncolysis elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, TNF-α, Perforin, IL-2, Granzyme B and activated T cells in the TME, transforming the TME to be more conducive to antitumor immunity. This leads to a systemic antitumor effect which is dependent on CD8+ and CD4+ T cells and IFN-γ. Oncolytic vaccinia viruses could not deliver stable IL-23A to the tumor, attributed to the elevated tristetraprolin which can destabilize the IL-23A mRNA after the viral treatment; whereas vaccinia viruses could deliver membrane-bound IL-23 to elicit a potent antitumor effect which might avoid the possible toxicity normally associated with systemic cytokine exposure. Conclusion: Either secreted or membrane-bound IL-23-armed vaccinia virus can induce potent antitumor effects and IL-23 is a candidate cytokine to arm oncolytic viruses for cancer immunotherapy.


Assuntos
Adenocarcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia/métodos , Interleucina-23/farmacologia , Vírus Oncolíticos/genética , Microambiente Tumoral/imunologia , Vírus Vaccinia/genética , Adenocarcinoma/imunologia , Adenocarcinoma/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vírus Oncolíticos/metabolismo , Perforina/metabolismo , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo , Vírus Vaccinia/metabolismo
10.
Theranostics ; 11(14): 6860-6872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093858

RESUMO

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.


Assuntos
Neoplasias do Colo/terapia , Terapia Combinada/métodos , Hipertermia , Imunoterapia/métodos , Lipossomos/química , Terapia de Campo Magnético/métodos , Nanopartículas de Magnetita/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzotiazóis/farmacocinética , Benzotiazóis/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Feminino , Humanos , Lipossomos/metabolismo , Lipossomos/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacologia , Ratos , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Chem Commun (Camb) ; 57(59): 7240-7243, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34190264

RESUMO

Herin, we report a Cu(ii)-porphyrin-derived nanoscale COF, which can be triggered by endogenous H2S via an intracellular sulfidation reaction to generate a metal-free COF-photosensitizer for PDT against H2S-enriched colon tumors with controllable singlet oxygen release; meanwhile in situ generated CuS can be synchronously used as a photothermal agent for PTT.


Assuntos
Neoplasias do Colo/terapia , Sulfeto de Hidrogênio/química , Estruturas Metalorgânicas/química , Fototerapia/métodos , Animais , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Cobre/química , Células HCT116 , Humanos , Raios Infravermelhos , Camundongos , Microscopia Confocal , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Oxigênio Singlete/metabolismo , Transplante Heterólogo
12.
J Biol Chem ; 296: 100782, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34000297

RESUMO

Hyperactivation of Wnt/ß-catenin (canonical) signaling in colorectal cancers (CRCs) was identified in the 1990s. Most CRC patients have mutations in genes that encode components of the Wnt pathway. Inactivating mutations in the adenomatous polyposis coli (APC) gene, which encodes a protein necessary for ß-catenin degradation, are by far the most prevalent. Other Wnt signaling components are mutated in a smaller proportion of CRCs; these include a FZD-specific ubiquitin E3 ligase known as ring finger protein 43 that removes FZDs from the cell membrane. Our understanding of the genetic and epigenetic landscape of CRC has grown exponentially because of contributions from high-throughput sequencing projects such as The Cancer Genome Atlas. Despite this, no Wnt modulators have been successfully developed for CRC-targeted therapies. In this review, we will focus on the Wnt receptor complex, and speculate on recent discoveries about ring finger protein 43regulating Wnt receptors in CRCs. We then review the current debate on a new APC-Wnt receptor interaction model with therapeutic implications.


Assuntos
Neoplasias do Colo/terapia , Receptores Wnt/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Genes APC , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Mutação , Transdução de Sinais , beta Catenina/metabolismo
14.
Medicine (Baltimore) ; 100(18): e25756, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950962

RESUMO

ABSTRACT: We conducted a population-based cohort study enrolling patients with Stage II and III colon cancer receiving postoperative adjuvant chemotherapy with uracil and tegafur (UFT) or fluorouracil (5-FU) from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the current study were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were calculated by multivariate Cox proportional hazard regression models. We compared our effectiveness results from the literature by meta-analysis, which provided the best evidence. Severe adverse events were compared in meta-analysis of reported clinical trials. In the nationwide cohort study, UFT (14,486 patients) showed DFS similar to postoperative adjuvant chemotherapy (adjusted HR 1.037; 95% confidence interval [CI] 0.954-1.126; P = .397) and OS (adjusted HR 0.964; 95% CI 0.891-1.041; P = .349) compared with the 5-FU (866 patients). Our meta-analysis confirmed the similarity of effectiveness and found the incidence of leucopaenia was statistically significantly reduced in UFT (risk ratio 0.12; 95% CI 0.02-0.67; I2 = 0%). Through our analysis, we have confirmed that UFT is a well-tolerated adjuvant therapy choice, and has similar treatment efficacy as 5-FU in terms of DFS and OS in patients with Stage II and III colon cancer.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias do Colo/terapia , Fluoruracila/administração & dosagem , Recidiva Local de Neoplasia/epidemiologia , Tegafur/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Colectomia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taiwan/epidemiologia , Tegafur/efeitos adversos
15.
Cancer Sci ; 112(7): 2915-2920, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33931919

RESUMO

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.


Assuntos
DNA Tumoral Circulante/sangue , Neoplasias Colorretais/sangue , Recidiva Local de Neoplasia/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Quimioterapia Adjuvante , Neoplasias do Colo/sangue , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Método Duplo-Cego , Humanos , Japão , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Oxaliplatina/administração & dosagem , Estudos Prospectivos , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem
16.
J Surg Res ; 264: 279-286, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33839343

RESUMO

BACKGROUND: Safety-net hospitals serve a vital role in society by providing care for vulnerable populations. Existing data regarding oncologic outcomes of patients with colon cancer treated at safety-net hospitals are limited and variable. The objective of this study was to delineate disparities in treatment and outcomes for patients with colon cancer treated at safety-net hospitals. METHODS: This retrospective cohort study identified 802,304 adult patients with colon adenocarcinoma from the National Cancer Database between 2004-2016. Patients were stratified according to safety-net burden of the treating hospital as previously described. Patient, tumor, facility, and treatment characteristics were compared between groups as were operative and short-term outcomes. Cox proportional hazards regression was utilized to compare overall survival between patients treated at high, medium, and low burden hospitals. RESULTS: Patients treated at safety-net hospitals were demographically distinct and presented with more advanced disease. They were also less likely to receive surgery, adjuvant chemotherapy, negative resection margins, adequate lymphadenectomy, or a minimally invasive operative approach. On multivariate analysis adjusting for patient and tumor characteristics, survival was inferior for patients at safety-net hospitals, even for those with stage 0 (in situ) disease. CONCLUSION: This analysis revealed inferior survival for patients with colon cancer treated at safety-net hospitals, including those without invasive cancer. These findings suggest that unmeasured population differences may confound analyses and affect survival more than provider or treatment disparities.


Assuntos
Adenocarcinoma/mortalidade , Neoplasias do Colo/mortalidade , Disparidades em Assistência à Saúde/estatística & dados numéricos , Provedores de Redes de Segurança/estatística & dados numéricos , Populações Vulneráveis/estatística & dados numéricos , Adenocarcinoma/diagnóstico , Adenocarcinoma/economia , Adenocarcinoma/terapia , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/economia , Quimioterapia Adjuvante/estatística & dados numéricos , Colectomia/economia , Colectomia/estatística & dados numéricos , Colo/patologia , Colo/cirurgia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/economia , Neoplasias do Colo/terapia , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Disparidades em Assistência à Saúde/economia , Humanos , Masculino , Margens de Excisão , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Provedores de Redes de Segurança/economia , Análise de Sobrevida , Estados Unidos/epidemiologia
17.
Int J Radiat Oncol Biol Phys ; 110(5): 1306-1316, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794306

RESUMO

PURPOSE: Harnessing the immune-stimulatory effects of radiation by combining it with immunotherapy is a promising new treatment strategy. However, more studies characterizing immunotherapy and radiation dose scheduling for the optimal therapeutic effect is essential for designing clinical trials. METHODS AND MATERIALS: A new ablative radiation dosing scheme, personalized ultrafractionated stereotactic adaptive radiation therapy (PULSAR), was tested in combination with α-PD-L1 therapy in immune-activated and resistant syngeneic immunocompetent mouse models of cancer. Specifically, tumor growth curves comparing immunotherapy and radiation therapy dose sequencing were evaluated in immunologically cold and hot tumor models. The response relative to cytotoxic killer T cells was evaluated using an α-CD8 depleting antibody, and immunologic memory was tested by tumor rechallenge of cured mice. RESULTS: We report that both radiation and immunotherapy sequencing, as well as radiation therapy fraction spacing, affect the combination treatment response. Better tumor control was achieved by giving α-PD-L1 therapy during or after radiation, and spacing fractions 10 days apart (PULSAR) achieved better tumor control than traditional daily fractions. We showed that CD8+ depleting antibody abrogated tumor control in the PULSAR combination treatment, and certain treatment schedules induced immunologic memory. CONCLUSIONS: These results illustrate that radiation therapy dosing and scheduling affect tumor control, in combination with checkpoint blockade therapies. PULSAR-style radiation dosing is more complementary in combination with single-agent immunotherapy than traditional daily fractions in this preclinical model. Preclinical investigation could prove helpful in designing clinical trials investigating combination therapy.


Assuntos
Carcinoma Pulmonar de Lewis/terapia , Neoplasias do Colo/terapia , Fracionamento da Dose de Radiação , Inibidores de Checkpoint Imunológico/farmacologia , Medicina de Precisão/métodos , Radioimunoterapia/métodos , Radiocirurgia/métodos , Animais , Antígeno B7-H1 , Carcinoma Pulmonar de Lewis/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Feminino , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Dosagem Radioterapêutica , Distribuição Aleatória , Linfócitos T Citotóxicos , Resultado do Tratamento
18.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920230

RESUMO

In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-ß1 (TGF-ß1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-ß1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune-inflammatory responses. In patients with Crohn's disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-ß1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-ß1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.


Assuntos
Neoplasias do Colo/genética , Doenças Inflamatórias Intestinais/genética , Proteína Smad7/genética , Fator de Crescimento Transformador beta1/genética , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos , Oligonucleotídeos Antissenso/uso terapêutico , Transdução de Sinais/imunologia , Proteína Smad7/antagonistas & inibidores
19.
Nutrients ; 13(4)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916690

RESUMO

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Triptofano/metabolismo , Evasão Tumoral/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Terapia Combinada/métodos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis/administração & dosagem , Indóis/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Cinurenina/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/imunologia , Probióticos/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Simbiose/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
20.
Am J Clin Oncol ; 44(7): 315-324, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33899807

RESUMO

OBJECTIVES: Location of the primary tumor has prognostic value and predicts the effect of certain therapeutics in synchronous metastatic colorectal cancer. We investigated whether the association between primary tumor resection (PTR) and overall survival (OS) also depends on tumor location. METHODS: Data on synchronous metastatic colorectal cancer patients from the Netherlands Cancer Registry (n=16,106) and Surveillance, Epidemiology, and End Results (SEER) registry (n=19,584) were extracted. Cox models using time-varying covariates were implemented. Median OS for right-sided colon cancer (RCC), left-sided colon cancer, and rectal cancer was calculated using inverse probability weighting and a landmark point of 6 months after diagnosis as reference. RESULTS: The association between PTR and OS was dependent on tumor location (P<0.05), with a higher median OS of upfront PTR versus upfront systemic therapy in Netherlands Cancer Registry (NCR) of 1.9 (95% confidence interval: 0.9-2.8), 4.3 (3.3-5.6), and 3.4 (0.6-7.6) months in RCC, left-sided colon cancer and rectal cancer, respectively. In SEER data, the difference was 6.0 (4.0-8.0), 8.0 (5.0-10.0), and 10.0 (7.0-13.0) months, respectively. Hazard plots indicate a higher hazard of death 2 to 3 months after PTR in RCC. CONCLUSION: Upfront PTR is associated with improved survival regardless of primary tumor location. Patients with RCC appear to have less benefit because of higher mortality during 2 to 3 months after PTR.


Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Idoso , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Neoplasias do Colo/terapia , Neoplasias Colorretais/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Programa de SEER , Resultado do Tratamento , Estados Unidos/epidemiologia
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