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1.
Cancer Treat Rev ; 95: 102174, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33721596

RESUMO

In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Reparo de Erro de Pareamento de DNA/genética , Animais , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/secundário , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunoterapia
2.
JAMA ; 325(7): 669-685, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591350

RESUMO

Importance: Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850 000 deaths annually. Of new colorectal cancer diagnoses, 20% of patients have metastatic disease at presentation and another 25% who present with localized disease will later develop metastases. Observations: Colorectal cancer is the third most common cause of cancer mortality for men and women in the United States, with 53 200 deaths projected in 2020. Among people diagnosed with metastatic colorectal cancer, approximately 70% to 75% of patients survive beyond 1 year, 30% to 35% beyond 3 years, and fewer than 20% beyond 5 years from diagnosis. The primary treatment for unresectable metastatic CRC is systemic therapy (cytotoxic chemotherapy, biologic therapy such as antibodies to cellular growth factors, immunotherapy, and their combinations.) Clinical trials completed in the past 5 years have demonstrated that tailoring treatment to the molecular and pathologic features of the tumor improves overall survival. Genomic profiling to detect somatic variants is important because it identifies the treatments that may be effective. For the 50% of patients with metastatic CRC with KRAS/NRAS/BRAF wild-type tumors, cetuximab and panitumumab (monoclonal antibodies to the epithelial growth factor receptor [EGFR]), in combination with chemotherapy, can extend median survival by 2 to 4 months compared with chemotherapy alone. However, for the 35% to 40% of patients with KRAS or NRAS sequence variations (formerly termed mutations), effective targeted therapies are not yet available. For the 5% to 10% with BRAF V600E sequence variations, targeted combination therapy with BRAF and EGFR inhibitors extended overall survival to 9.3 months, compared to 5.9 months for those receiving standard chemotherapy. For the 5% with microsatellite instability (the presence of numerous insertions or deletions at repetitive DNA units) or mismatch repair deficiency, immunotherapy may be used in the first or subsequent line and has improved treatment outcomes with a median overall survival of 31.4 months in previously treated patients. Conclusions and Relevance: Advances in molecular profiling of metastatic CRC facilitate the ability to direct treatments to the biologic features of the tumor for specific patient subsets. Although cures remain uncommon, more patients can anticipate extended survival. Genomic profiling allows treatment selection so that more patients derive benefit and fewer are exposed to toxicity from ineffective therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/secundário , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Perfil Genético , Humanos , Quimioterapia de Manutenção , Masculino , Técnicas de Diagnóstico Molecular , Prognóstico , Taxa de Sobrevida
3.
BMJ Case Rep ; 13(12)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33370932

RESUMO

A 58-year-old woman presented with a 1-week history of lower limb bruising. She had a medical history of recurrent metastatic colon cancer with a sigmoid colectomy and complete pelvic exenteration leading to colostomy and urostomy formation. She had malignant sacral mass encroaching on the spinal cord. This caused a left-sided foot drop for which she used an ankle-foot orthosis. She was on cetuximab and had received radiotherapy to the sacral mass 1 month ago. On examination, there were macular ecchymoses with petechiae on the lower limbs. There was sparing of areas that had been compressed by the ankle-foot orthosis. Bloods showed mild thrombocytopaenia and anaemia with markedly raised inflammatory markers. Coagulation studies consistent with inflammation rather than disseminated intravascular coagulation. She was found to have Klebsiella bacteraemia secondary to urinary source. Skin biopsy showed dermal haemorrhage without vessel inflammation. Vitamin C levels were low confirming the diagnosis of scurvy.


Assuntos
Ácido Ascórbico , Colectomia/efeitos adversos , Neoplasias Colorretais , Equimose , Desnutrição , Apoio Nutricional/métodos , Escorbuto , Antineoplásicos Imunológicos/uso terapêutico , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/sangue , Bacteriemia/diagnóstico , Bacteriemia/microbiologia , Colectomia/métodos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Neoplasias Colorretais/secundário , Neoplasias Colorretais/terapia , Diagnóstico Diferencial , Equimose/sangue , Equimose/diagnóstico , Equimose/etiologia , Feminino , Humanos , Klebsiella/isolamento & purificação , Extremidade Inferior , Desnutrição/etiologia , Desnutrição/terapia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Exenteração Pélvica/efeitos adversos , Exenteração Pélvica/métodos , Escorbuto/sangue , Escorbuto/etiologia , Escorbuto/fisiopatologia , Escorbuto/terapia , Pele/patologia , Resultado do Tratamento , Vitaminas/administração & dosagem
4.
BMC Bioinformatics ; 21(Suppl 13): 382, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32938394

RESUMO

BACKGROUND: Introducing deep learning approach to medical images has rendered a large amount of un-decoded information into usage in clinical research. But mostly, it has been focusing on the performance of the prediction modeling for disease-related entity, but not on the clinical implication of the feature itself. Here we analyzed liver imaging features of abdominal CT images collected from 2019 patients with stage I - III colorectal cancer (CRC) using convolutional neural network (CNN) to elucidate its clinical implication in oncological perspectives. RESULTS: CNN generated imaging features from the liver parenchyma. Dimension reduction was done for the features by principal component analysis. We designed multiple prediction models for 5-year metachronous liver metastasis (5YLM) using combinations of clinical variables (age, sex, T stage, N stage) and top principal components (PCs), with logistic regression classification. The model using "1st PC (PC1) + clinical information" had the highest performance (mean AUC = 0.747) to predict 5YLM, compared to the model with clinical features alone (mean AUC = 0.709). The PC1 was independently associated with 5YLM in multivariate analysis (beta = - 3.831, P < 0.001). For the 5-year mortality rate, PC1 did not contribute to an improvement to the model with clinical features alone. For the PC1, Kaplan-Meier plots showed a significant difference between PC1 low vs. high group. The 5YLM-free survival of low PC1 was 89.6% and the high PC1 was 95.9%. In addition, PC1 had a significant correlation with sex, body mass index, alcohol consumption, and fatty liver status. CONCLUSION: The imaging features combined with clinical information improved the performance compared to the standardized prediction model using only clinical information. The liver imaging features generated by CNN may have the potential to predict liver metastasis. These results suggest that even though there were no liver metastasis during the primary colectomy, the features of liver imaging can impose characteristics that could be predictive for metachronous liver metastasis.


Assuntos
Abdome/diagnóstico por imagem , Neoplasias Colorretais/secundário , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Redes Neurais de Computação , Tomografia Computadorizada por Raios X/métodos , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pré-Operatório
5.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(7): 701-708, 2020 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-32683833

RESUMO

Objective: To identify the prognostic factors in metastatic colorectal cancer (mCRC) patients treated with cetuximab and establish a prognostic nomogram and validate its accuracy. Methods: A retrospective case-control study was conducted. Patients were selected as following criteria: patients with metastatic colorectal cancer(mCRC), which primary site confirmed by pathology and metastatic lesions confirmed by CT or MRI with at least one measurable and evaluable target lesion; patients' expected survival longer than 3 months; Eastern Cooperative Oncology Group (ECOG) score between 0 to 2; patients have signed informed consent; both KRAS and NRAS genes were wild-type; and at least 2 cycles of cetuximab combined with chemotherapy as the first-line regimen. Patients who met the following criteria were excluded: patients with incomplete clinicopathological and follow-up data; patients with severe diseases of vital organs such as heart, brain, lung, kidney, or other advanced malignant tumors; patients without informed consent. According to the above criteria, clinicopathological data of 95 patients with mCRC admitted in the Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine for first-line treatment with cetuximab from January 2010 to January 2017 were analyzed retrospectively. The Cox proportional hazards model was used to analyze the clinicopathological factors to determine the independent prognostic factors for progression-free survival(PFS). The R software was adopted to establish a prognostic nomogram model. Then, the nomograms of 6-month, 12-month and 18-month progression-free survivals (PFS) were drawn, and compared with the reality. The internal validation and accuracy of the nomogram were determined by the Bootstrap method and also the calculated concordance index (C-index). Results: The median follow-up time was 16.5 (2-43) months and the median PFS was 8.5 months. PFS at 6-,12- and 18-month was 73.7%, 35.8%, and 17.9%, respectively. ECOG score of 1-2 (HR=5.733, 95% CI:2.408-13.649, P<0.001), primary tumor was located in the ileocecal region (HR=5.880, 95% CI:1.645-21.023, P=0.006), Ki-67 index ≥45% (HR=3.574,95% CI:1.403-9.108,P=0.008), baseline D-dimer level ≥345 mg/L (HR=2.536,95% CI:1.531-7.396, P=0.012), NLR≥2.8 (HR=5.573,95% CI:2.107-14.740,P=0.001) and the combined treatment for FOLFOX (HR=0.465, 95% CI: 0.265-0.817, P=0.008) were independent risk factors for PFS of mCRC patients (all P<0.05). These independent risk factors were taken into account to construct a nomogram prediction model. The bootstrap method was used to perform internal validation, and the C-index of the nomogram prediction model in this study was 0.67 (95% CI: 0.64~0.71). The 6-, 12- and 18-month PFS predicted by the nomogram were consistent with the actual values. Conclusion: The nomogram model constructed by ECOG score, primary tumor site, Ki-67 index, baseline D-dimer level, baseline NLR and chemotherapy regimen may predict the prognosis of mCRC patients treated with cetuximab more accurately and individually, which can assist clinicians in making treatment decisions.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Nomogramas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/secundário , Humanos , Prognóstico , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 99(21): e20238, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481300

RESUMO

OBJECTS: The present study aimed to identify the clinicopathological characteristics of colorectal cancer (CRC) with invasive micropapillary components (IMPCs) and the relationship between different amounts of micropapillary components and lymph node metastasis. METHODS: A cohort of 363 patients with CRC who underwent surgical treatment in the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2013 and December 2016 were retrospectively reviewed. We compared the clinicopathological characteristics, including survival outcomes and immunohistochemical profiles (EMA, MUC1, MLH1, MSH2, MSH6, and PMS2), between CRC with IMPCs and those with conventional adenocarcinoma (named non-IMPCs in this study). Logistic regression was used to identify the association between IMPCs and lymph node invasion. A multivariate analysis was performed using the Cox proportional hazard model to evaluate significant survival predictors. RESULTS: Among 363 patients, 76 cases had IMPCs, including 22 cases with a lower proportion of IMPCs (≤5%, IMPCs-L) and 54 cases with a higher proportion (>5%, IMPCs-H). Compared to the non-IMPC group, the IMPC group (including both IMPC-L and IMPC-H) had a lower degree of tumor differentiation (P = .000), a higher N-classification (P = .000), more venous invasion (P = .019), more perineural invasion (P = .025) and a later tumor node metastasis (TNM) stage (P = .000). Only tumor differentiation (P = .031) and tumor size (P = .022) were different between IMPCs-L and IMPCs-H. EMA/MUC1 enhanced the characteristic inside-out staining pattern of IMPCs, whereas non-IMPCs showed luminal staining patterns. The percentage of mismatch repair deficiency (dMMR) in the non-IMPC group was much higher than that in the IMPC group (14.7% vs 4.7%). The overall survival time of patients with IMPCs was significantly less than that of patients with non-IMPCs (P = .002), then that of IMPCs-H was lower than that of IMPCs-L (P = .030). Logistic regression revealed that patients with IMPCs were associated with lymph metastasis, regardless of the proportion of IMPCs. Multivariate analysis demonstrated both IMPCs-L and IMPCs-H as negative prognostic factors. CONCLUSIONS: IMPCs are significantly associated with lymph node metastasis and poor outcome, and even a minor component (≤5%) may render significant information and should therefore be part of the pathology report.


Assuntos
Neoplasias Colorretais/secundário , Neoplasias Colorretais/cirurgia , Linfonodos/patologia , Metástase Linfática/patologia , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/epidemiologia , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias/métodos , Síndromes Neoplásicas Hereditárias/epidemiologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
7.
Sci Rep ; 10(1): 682, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959771

RESUMO

Generation of large amounts of genomic data is now feasible and cost-effective with improvements in next generation sequencing (NGS) technology. Ribonucleic acid sequencing (RNA-Seq) is becoming the preferred method for comprehensively characterising global transcriptome activity. Unique to cytoreductive surgery (CRS), multiple spatially discrete tumour specimens could be systematically harvested for genomic analysis. To facilitate such downstream analyses, laser capture microdissection (LCM) could be utilized to obtain pure cell populations. The aim of this protocol study was to develop a methodology to obtain high-quality expression data from matched primary tumours and metastases by utilizing LCM to isolate pure cellular populations. We demonstrate an optimized LCM protocol which reproducibly delivered intact RNA used for RNA sequencing and quantitative polymerase chain reaction (qPCR). After pathologic annotation of normal epithelial, tumour and stromal components, LCM coupled with cDNA library generation provided for successful RNA sequencing. To illustrate our framework's potential to identify targets that would otherwise be missed with conventional bulk tumour sequencing, we performed qPCR and immunohistochemical technical validation to show that the genes identified were truly expressed only in certain sub-components. This study suggests that the combination of matched tissue specimens with tissue microdissection and NGS provides a viable platform to unmask hidden biomarkers and provides insight into tumour biology at a higher resolution.


Assuntos
Neoplasias Colorretais/cirurgia , Perfilação da Expressão Gênica/métodos , Tumor de Krukenberg/cirurgia , Microdissecção e Captura a Laser/métodos , Neoplasias Ovarianas/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/secundário , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Tumor de Krukenberg/genética , Neoplasias Ovarianas/genética , Análise de Sequência de RNA , Manejo de Espécimes , Fluxo de Trabalho
8.
In Vivo ; 34(1): 441-445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882511

RESUMO

A 59-year-old woman, undergoing treatment with encorafenib for metastatic BRAF mutated colorectal cancer, developed during the first two months of therapy multiple eruptive nevi and changes in pre-existing nevi. Development of eruptive nevi has increasingly been reported in association with medications, most frequently conventional immunosuppressants and biologics. Some drugs are associated with eruptive nevi through an indirect effect of their mechanism of action, whereas other drugs are directly implicated in melanocyte proliferation. In this regard, BRAF inhibitors have been demonstrated to activate the MAPK pathway, and to promote cellular proliferation and survival, therefore leading to the development of new melanocytic nevi and to an increase in the size and hyperpigmentation of pre-existing nevi. A dermatological assessment and follow-up should be recommended in all patients presenting with eruptive nevi, regardless of the pathogenesis, because a high number of acquired melanocytic nevi may represent an adjunctive risk factor for melanoma.


Assuntos
Carbamatos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Melanoma/induzido quimicamente , Nevo Pigmentado/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/induzido quimicamente , Sulfonamidas/efeitos adversos , Neoplasias Colorretais/secundário , Feminino , Humanos , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Nevo Pigmentado/patologia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/patologia
9.
Surgeon ; 18(1): 31-36, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31324447

RESUMO

BACKGROUND: The number of harvested lymph nodes (LNs) in colorectal cancer surgery relates to oncologic radicality and accuracy of staging. In addition, it affects the choice of adjuvant therapy, as well as prognosis. The American Joint Committee on Cancer defines at least 12 LNs harvested as adequate in colorectal cancer resections. Despite the importance of the topic, even in high-volume colorectal centres the rate of adequacy never reaches 100%. The aim of this study was to identify factors that affect the number of harvested LNs in oncologic colorectal surgery. MATERIALS AND METHODS: We prospectively collected all consecutive patients who underwent colorectal cancer resection from January 1st 2013 to December 31st 2017 at Emergency Surgery Unit St Orsola University Hospital of Bologna. RESULTS: Six hundred and forty-three consecutive patients (382 elective, 261 emergency) met the study inclusion criteria. Emergency surgery and laparoscopic approach did not have a significant influence on the number of harvested LNs. The adequacy of lymphadenectomy was negatively affected by age >80 (OR 3.47, p < 0.001), ASA score ≥3 (OR 3.48, p < 0.001), Hartmann's or rectal resection (OR 3.6, p < 0.001) and R1-R2 resection margins (OR 3.9, p = 0.006), while it was positively affected by T-status ≥3 (OR 0.33 p < 0.001). CONCLUSION: Both the surgical technique and procedure regimen did not affect the number of lymphnodes retrieved. Age >80 and ASA score ≥3 and Hartmann's procedure or rectal resection showed to be risk factors related to inadequate lymphadenectomy in colorectal cancer surgery.


Assuntos
Colectomia/métodos , Neoplasias Colorretais/cirurgia , Excisão de Linfonodo/métodos , Linfonodos/patologia , Estadiamento de Neoplasias , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/secundário , Feminino , Humanos , Metástase Linfática , Masculino , Período Pós-Operatório , Prognóstico , Estudos Prospectivos
10.
Medicine (Baltimore) ; 98(50): e18227, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852082

RESUMO

OBJECTIVE: To identify the optimal treatment strategy after first-line induction chemotherapy for metastatic colorectal cancer (mCRC). METHODS: We conducted a meta-analysis of randomized controlled trials comparing bevacizumab-based maintenance therapy, observation, and continuous chemotherapy.We searched the PubMed, Embase, and Cochrane databases for relevant articles published through March 2018. All randomized phase-III trials evaluating bevacizumab-based maintenance treatment after bevacizumab-based induction treatment were eligible for inclusion. The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Hazard ratios (HRs) with 95% confidence intervals (CIs) or data for calculating HRs with 95% CIs were extracted. The RevMan v5.3 (Copenhagen, Denmark) software was used for data analysis. RESULTS: Nine trials (3121 patients) were included in this meta-analysis. Compared with observation alone, bevacizumab-based maintenance therapy significantly improved PFS (HR: 0.62, 95% CI: 0.47-0.82) and showed a trend toward prolonged OS (HR: 0.93, 95% CI: 0.83-1.05). The incidence of grade 3/4 toxicity, including hypertension and fatigue, was higher after maintenance therapy than after observation alone. PFS (HR: 0.91, 95% CI: 0.70-1.18) and OS (HR: 0.88, 95% CI: 0.74-1.04) did not differ between the maintenance treatment and continuous chemotherapy groups. Grade 3/4 toxicity, including diarrhea and sensory neuropathy, was less common after maintenance therapy than after continuous chemotherapy. CONCLUSION: Bevacizumab-based maintenance therapy significantly improved PFS, showed a trend toward prolonged OS, and reduced cumulative grade 3/4 toxicity relative to continuous chemotherapy with comparable efficacy. Although maintenance therapy was beneficial, the optimal strategy should be individualized.


Assuntos
Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/secundário , Humanos , Metástase Neoplásica , Resultado do Tratamento
11.
J Coll Physicians Surg Pak ; 29(12): 1173-1178, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31839090

RESUMO

OBJECTIVE: To evaluate the factors that influence pericolorectal lymph node (LN) retrieval from colectomy specimens in colorectal in cancer staging. STUDY DESIGN: Descriptive study Place and Duration of Study: Ortadogu Private Hospital Adana, Turkey, between January 2012 and March 2018. METHODOLOGY: The inclusion criteria was right hemi-colon, left hemi-colon and rectum carcinoma specimen, respectively. The exclusion criteria was total colectomies due to synchronous colorectal carcinomas and cancers developed on the basis of ulcerative colitis and familial polyposis coli. Age and gender of the patients, the length of the colectomy specimen, the location and size of the tumor-node-metastasis (TNM) stage, and the count of retrieved lymph nodes were evaluated. RESULTS: Among the 145 patients in this study, the mean count of recovered and metastatic lymph nodes was 32.5 and 2.9, respectively. Sufficient lymph node assessment was done in 130 of the 145 patients. The number of lymph node yields was independently associated with depth of invasion, T-classification, tumor size, AJCC/UICC stage as well as right-sided tumor location. The count of harvested lymph nodes significantly decreased in patients who received preoperative therapy. Increased node counts were associated with increased overall survival (OS). CONCLUSION: Tumor site and size, length of the surgical specimen, T-classification, depth of invasion and AJCC/UICC stage are predictors for the lymph node numbers in colorectal cancer surgery. Retrieval of removed nodes and counting helps in staging and number of removed nodes, and affects survival.


Assuntos
Colectomia/métodos , Neoplasias Colorretais/diagnóstico , Excisão de Linfonodo/métodos , Linfonodos/patologia , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/secundário , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Reto , Estudos Retrospectivos , Adulto Jovem
12.
Cytokine Growth Factor Rev ; 49: 1-9, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31679887

RESUMO

Colorectal cancer (CRC) is the fourth most common cancer type and is the second leading cause of cancer deaths annually in the United States. Conventional treatment options include postoperative (adjuvant) and preoperative (neoadjuvant) chemotherapy and radiotherapy. Although these treatment modalities have shown to decrease tumor burden, a major limitation to chemothearpy/radiotherapy is the high recurrence rate in patients. Immune-modulation strategies have emerged as a promising new therapeutic avenue to reduce this recurrence rate while minimizing undesirable systemic side effects. This review will focus specifically on the mechanisms of monoclonal antibodies: immune checkpoint inhibitors and cytokines, as well as current drugs approved by the Food and Drug Administration (FDA) and new clinical/pre-clinical trials. Finally, this review will investigate emerging methods used to monitor tumor response post-treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Citocinas/uso terapêutico , Imunoterapia , Animais , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/secundário , Humanos , Imunomodulação , Camundongos
13.
Int J Colorectal Dis ; 34(11): 1871-1877, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31598748

RESUMO

PURPOSE: Colorectal cancer is the fourth cause of cancer-related death. Drug toxicity and resistance remain concerns of major importance. miR-100 and miR-218 are micro-RNAs that regulate cellular proliferation, differentiation and apoptosis acting as oncogenes and tumour suppressors; their functions and have been linked with toxicity development and drug resistance. METHODS: We investigated the correlation between rs11134527 miR-218 and rs1834306 miR-100 polymorphisms and irinotecan-based regimens with regard to drug efficacy and toxicity. A total of 105 mCRC patients receiving irinotecan-based regimens were included in our study and assessed in terms of toxicity development and response to treatment. Rs11134527 miR-218 and rs1834306 miR-100 polymorphism genotyping in the peripheral blood was performed with PCR-RFLP. RESULTS: Neither rs11134527 miR-218 nor rs1834306 miR-100 are associated with toxicity risk to treatment regimens. GA/AA genotypes of rs11134527 and CT/TT genotypes of rs1834306 were associated with a significantly reduced time-to-progression (TTP) and overall survival (OS). CONCLUSIONS: GA/AA genotypes of rs11134527 miR-218 and CT/TT genotypes of rs1834306 miR-100 polymorphisms could serve as prognostic biomarkers of TTP and OS. Carriers of the A allele of the miR-218 rs11134527 and T allele of the miR-100 rs1834306 polymorphisms are more likely not to respond to irinotecan-based therapies. However, further studies in larger patient populations are required.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Irinotecano/uso terapêutico , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/secundário , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
14.
Indian J Pathol Microbiol ; 62(3): 467-469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31361243

RESUMO

Histiocytic sarcoma is a rare malignant neoplasm that demonstrates mature histiocytic traits as characterized by immunohistochemistry. We report a case of extranodal histiocytic sarcoma (ENHS) of colon in a 56-year-old man presenting with gastrointestinal symptoms. Radiological findings were indicative of lymphoma or diffuse metastatic disease in colon. Histopathology of colectomy specimen was suggestive of ENHS, and immunohistochemical studies confirmed the uncommon diagnosis. The patient refused further therapy and succumbed to systemic complications of metastatic disease within a month of diagnosis. There have only been seven previous reports in world literature of ENHS involving large intestine.


Assuntos
Sarcoma Histiocítico/diagnóstico por imagem , Metástase Neoplásica , Abdome/diagnóstico por imagem , Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/secundário , Evolução Fatal , Sarcoma Histiocítico/complicações , Sarcoma Histiocítico/patologia , Humanos , Imuno-Histoquímica , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Recusa do Paciente ao Tratamento
15.
Cardiovasc Intervent Radiol ; 42(9): 1213-1220, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270570

RESUMO

Substantial improvements have been made in the systemic treatment of colorectal cancer over the last two decades. Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has been constantly increased and the most recent first-line studies exceeded the 30-month median overall survival. The standard first-line regimen for mCRC is a combination of chemotherapy plus a biological agent either targeting the main angiogenic growth factor vascular endothelial growth factor (VEGF) via Bevacizumab or by antibodies targeting the epidermal growth factor receptor (EGRF) via Panitumumab or Cetuximab. Recent improvements have been shown in the efficacy of the biological agent by stratifying these agents according to the primary tumor location. In this context EGFR-inhibitors showed improved OS when used first-line in tumors derived from the left-sided colon or rectum, while tumor sidedness was not predictive for anti-VEGF-antibodies. Furthermore, the biological activity of anti-EGFR antibodies is restricted to tumors with a rat sarcoma virus (RAS)-wild-type genotype but not RAS-mutated tumors. The RAS-mutation status is not predictive for VEGF-inhibitors. Recent developments in the molecular characterisation of tumor cells led to the development of specific so called targeted therapies in colorectal cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/secundário , Adulto , Receptores ErbB/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
16.
Int J Biol Markers ; 34(3): 269-275, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31213130

RESUMO

BACKGROUND: Several prognostic factors were proposed to improve early detection of recurrence after liver resection of metastases of colorectal cancer. Circulating tumor cell-related transcripts were evaluated in colorectal cancer patients with conflicting results. The aim of this study was to investigate usefulness of carcinoembryonic antigen CAM5, epidermal growth factor receptor, and ERCC1 transcripts in the bloodstream as predictive factors of recurrence in patients who underwent liver resection for metastases of colorectal cancer. METHODS: Peripheral blood was collected from 29 patients at the time of the colorectal cancer liver metastasis resection, and from 25 normal controls. Follow-up draws (FUDs) were also performed at 30 days, and 3 and 12 months since surgery. On each sample, carcinoembryonic antigen CAM5, ERCC1, and GAPDH mRNAs were examined by quantitative reverse transcription (qRT). RESULTS: Carcinoembryonic antigen transcript levels were linearly correlated to the number of spiked cells (qRT analytical limit = five cells). Among 29 patients (20 M/9 F; mean age 63 years (range 32-79), highly significant levels of carcinoembryonic antigen, if compared to the baseline, were detected in those relapsing after surgery (P <0.05). The main differences were between the 1st- and 12th-month FUDs. Significantly higher levels of carcinoembryonic antigen were also detected in patients who died from disease progression during the follow-up (as evaluated at 30 days and 90 days FUDs). CONCLUSIONS: Blood carcinoembryonic antigen-mRNA absolute copy number overtime variation can represent a valid early predictor of relapse after liver resection in colorectal liver metastases patients. Prospective studies, in the context of large clinical trials, will provide further data to also qualify ERCC1 as a predictive biomarker for decisions on therapeutic strategies.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/secundário , Neoplasias Hepáticas/sangue , Fígado/cirurgia , Recidiva Local de Neoplasia/sangue , Adulto , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico
17.
BMC Cancer ; 19(1): 640, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253124

RESUMO

BACKGROUND: In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy. METHODS: A total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed. DISCUSSION: Liquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC. TRIAL REGISTRATION: The date of trial registration ( NCT03401957 ) in this study was January 17, 2018.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas ras/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Protocolos Clínicos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/secundário , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Biópsia Líquida , Mutação , Análise de Sobrevida , Resultado do Tratamento , Proteínas ras/sangue
18.
J Transl Med ; 17(1): 137, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036005

RESUMO

BACKGROUND: Over the past few years, next-generation sequencing (NGS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for NGS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously. METHODS: We optimized a 14-amplicon NGS panel to assess, in a consecutive cohort of 219 patients affected by mCRC, the presence and clinico-pathological associations of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes from formalin-fixed, paraffin-embedded specimens collected for diagnostics and research at the time of diagnosis. RESULTS: We observed a statistically significant association of RAS mutations with sex, young age, and tumor site. We demonstrated that concomitant mutations in the RAS/RAF pathway are not infrequent in mCRC, and as anticipated by whole-genome studies, RAS and PIK3CA tend to be concurrently mutated. We corroborated the association of BRAF mutations in right mCRC tumors with microsatellite instability. We established tumor side as prognostic parameter independently of mutational status. CONCLUSIONS: To our knowledge, this is the first monocentric, consecutively accrued clinical mCRC cancer cohort tested by NGS in a real-world context for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF pathway, the presence of multiple mutations in single gene, the co-occurrence of RAS and PIK3CA mutations, the prognostic value of tumor side and possible associations of sex with specific mutations.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/secundário , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais , Proteínas ras/genética , Idoso , Neoplasias Colorretais/patologia , Feminino , Genes Neoplásicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética
19.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(4): 321-328, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31054545

RESUMO

The incidence of colorectal cancer liver metastasis (CRLM) increased gradually in recent years. Surgical resection is the most important treatment for CRLM patients to obtain long-term survival, with a 5-year survival rate of about 50%. However, only 20% of the CRLM patients are initially resectable. The recurrence rate after surgery is more than 70%. Perioperative chemotherapy has been widely used with the development of effective chemotherapy regimens and targeted therapies. For patients with initially resectable liver metastases, perioperative chemotherapy may help reduce recurrence and prolong survival. For patients with unresectable liver metastases, conversion chemotherapy with high efficiency provides opportunity for radical resection. However, CRLM is a disease with high heterogeneity and with many factors influencing prognosis, and there is a lack of large-scale prospective clinical trial evidence in many problems. Hence there are still many controversies in the clinical practice of perioperative chemotherapy, including whether chemotherapy alone is the best preoperative treatment for resectable CRLM, whether preoperative chemotherapy combined with targeted therapy is superior to chemotherapy alone, who can benefit most from preoperative chemotherapy combined with targeted therapy, who are the exact patients suitable for conversion therapy, how to choose the best first-line conversion therapy. Here we discuss the current status of research on perioperative chemotherapy in three aspects: neoadjuvant chemotherapy, conversion therapy and adjuvant chemotherapy. We also emphasized the importance of multidisciplinary team during the treatment process to give patients individualized therapy considering their specific conditions.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/secundário , Terapia Combinada , Hepatectomia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Assistência Perioperatória , Estudos Prospectivos
20.
Expert Rev Gastroenterol Hepatol ; 13(9): 899-905, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31104533

RESUMO

Background: Transarterial radioembolization (TARE) is used to treat unresectable colorectal cancer with liver metastases (CRCLM). This study aimed to assess survival after TARE and to identify potential prognostic factors in this patient population. Methods: Patients with unresectable and chemorefractory CRCLM treated with TARE at our institution between February 2006 and September 2015 were included in the study. Survival rate, hepatic tumor response, and potential prognostic factors were analyzed. Results: In the 43 study patients, the mean follow-up was 15.0 ± 14.2 months, with a median survival of 13.0 months and 1-, 2-, 3-, 4-, and 5-year survival rates of 52.1%, 24.9%, 21.4%, 21.4%, and 7.1%, respectively. The mean activity of yttrium-90 administered was 1.55 ± 0.28 GBq for the disease-controlled group and 1.19 ± 0.27 GBq for the progressive disease group (p= 0.031). Survival was correlated with Child-Pugh class (p< 0.001), hepatic tumor response (p= 0.001), and baseline carcinoembryonic antigen (CEA) level (p= 0.013). Conclusion: Child-Pugh class B, low degree of hepatic tumor response, and normal baseline CEA levels are prognostic factors for poorer survival after TARE in patients with unresectable and chemorefractory CRCLM. Hepatic tumor response is related to radiation activity delivered to the liver.


Assuntos
Braquiterapia/métodos , Neoplasias Colorretais/terapia , Embolização Terapêutica/métodos , Neoplasias Hepáticas/mortalidade , Compostos Radiofarmacêuticos/administração & dosagem , Radioisótopos de Ítrio/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/secundário , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
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