RESUMEN
BACKGROUND: In 2015, cancer patient pathways (CPP) were implemented in Norway to reduce unnecessary non-medical delay in the diagnostic process and start of treatment. The main aim of this study was to investigate the equality in access to CPPs for patients with either lung, colorectal, breast or prostate cancer in Norway. METHODS: National population-based data on individual level from 2015 to 2017 were used to study two proportions; i) patients in CPPs without the cancer diagnosis, and ii) cancer patients included in CPPs. Logistic regression was applied to examine the associations between these proportions and place of residence (hospital referral area), age, education, income, comorbidity and travel time to hospital. RESULTS: Age and place of residence were the two most important factors for describing the variation in proportions. For the CPP patients, inconsistent differences were found for income and education, while for the cancer patients the probability of being included in a CPP increased with income. CONCLUSIONS: The age effect can be related to both the increasing risk of cancer and increasing number of GP and hospital contacts with age. The non-systematic results for CPP patients according to income and education can be interpreted as equitable access, as opposed to the systematic differences found among cancer patients in different income groups. The inequalities between income groups among cancer patients and the inequalities based on the patients' place of residence, for both CPP and cancer patients, are unwarranted and need to be addressed.
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Renta , Neoplasias de la Próstata , Humanos , Masculino , Noruega/epidemiología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/terapia , Derivación y Consulta , Sistema de RegistrosRESUMEN
Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III)+(II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III)+(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III)+(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR = 1.30, 1.14-1.48, p = 0.0001) and overall survival (OS) (HR = 1.75, 1.52-2.02, p < 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III)+(II-III) was an independent biomarker of short OS (HR = 1.45, 1.20-1.75, p = 0.0001). There were no significant interactions between plasma uPAR(I-III)+(II-III) levels, KRAS mutational status and treatment either PFS (p = 0.43) or OS (p = 0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX + cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set.
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Antineoplásicos/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Compuestos Organoplatinos/administración & dosificación , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/sangre , Cetuximab/uso terapéutico , Neoplasias Colorrectales/sangre , Femenino , Humanos , Masculino , Metástasis de la Neoplasia , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: The primary objective was to compare overall survival (OS) in patients with colorectal cancer (CRC) with nonresectable liver-only metastases treated by liver transplantation or chemotherapy. BACKGROUND: CRC is the third most common cancer worldwide. About 50% of patients will develop metastatic disease primarily to the liver and the lung. The majority of patients with liver metastases receive palliative chemotherapy, with a median OS of trial patients of about 2 years, and less than 10% are alive at 5 years. METHODS: Patients with nonresectable liver-only CRC metastases underwent liver transplantation in the SECA study (n = 21). Disease-free survival (DFS) and OS of patients included in the SECA study were compared with progression-free survival (PFS) and OS in a similar cohort of CRC patients with liver-only disease included in a first-line chemotherapy study, the NORDIC VII study (n = 47). PFS/DFS and OS were estimated by the Kaplan-Meier method. RESULTS: DFS/PFS in both groups were 8 to 10 months. However, a dramatic difference in OS was observed. The 5-year OS rate was 56% in patients undergoing liver transplantation compared with 9% in patients starting first-line chemotherapy. The reason for the large difference in OS despite similar DFS/PFS is likely different metastatic patterns at relapse/progression. Relapse in the liver transplantation group was often detected as small, slowly growing lung metastases, whereas progression of nonresectable liver metastases was observed in the chemotherapy group. CONCLUSIONS: Compared with chemotherapy, liver transplantation resulted in a marked increased OS in CRC patients with nonresectable liver-only metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Antígeno Carcinoembrionario/sangre , Neoplasias Colorrectales/sangre , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/secundario , Proyectos Piloto , Estudios ProspectivosRESUMEN
BACKGROUND: Polymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314). METHODS: 504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991). RESULTS: The response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival. CONCLUSION: Patients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Polimorfismo de Nucleótido Simple , Receptores de IgG/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Cetuximab , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Mutación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven , Proteínas ras/genéticaRESUMEN
BACKGROUND: Intraoperative radiotherapy (IORT) has been given for primary and locally recurrent rectal cancer for 30 years. Still, its effect is not clear. MATERIAL AND METHODS: PubMed and EMBASE search for papers after 1989 on surgical treatment and external beam radiotherapy (EBRT) for primary advanced and locally recurrent rectal cancer, with and without IORT. From each center the most recent paper was generally selected. Survival and local recurrence at five years was tabulated for the total groups and separate R-stages. Also, the technique for IORT, use of EBRT and chemotherapy as well as surgical approach was registered. RESULTS: In primary cancer 18 papers from 14 centers were tabulated, including one randomized and five internally comparing studies, as well as seven studies without IORT. In locally recurrent cancer 18 papers from 13 centers were tabulated, including four internally comparing studies and also five without IORT. Overall survival (OS) and local recurrence rate (LRR) were higher for primary cancer compared to recurrent cancer. Patients with R0 resections had better outcome than patients with R1 or R2 resections. For primary cancer OS and LR rate of the total groups and R0 stages was not influenced by IORT. An effect on R1/R2 stages cannot be excluded. The only randomized study (primary cancer) did not show any effect of IORT. CONCLUSION: IORT does not convincingly improve OS and LR rate for primary and locally recurrent rectal cancer. If there is an effect of IORT, it is small and cannot be shown outside randomized studies analyzing the separate R stages.
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Neoplasias del Recto/mortalidad , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Humanos , Cuidados Intraoperatorios/métodos , Recurrencia Local de Neoplasia , Neoplasias del Recto/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: To investigate long-term development of sickness absence and disability pension among colorectal cancer (CRC) survivors compared to matched cancer-free controls, and to assess to what degree socio-demographic and disease characteristics influence these outcomes. PATIENTS AND METHODS: In a register-based cohort study with data from the Cancer Registry of Norway and longitudinal data from other national registries, 740 patients with CRC diagnosed 1992-1996 at the age 45-54 years were observed up to 14 years post-diagnosis. Also 740 matched controls were observed over the same time period. RESULTS: During the first year after diagnosis, 85% of the CRC survivors were on sick-leave at some point, compared to 19% of the controls. Among survivors with localized cancer, 21% were on sick-leave 12 months after diagnosis, versus 33% with regional, and 52% with distant cancer. Survivors with rectum cancer were more likely than colon cancer survivors to be on sick-leave the first year after diagnosis (OR 2.53, 95% CI 1.61-3.98). CRC survivors were at higher risk for disability pension (DP) than controls, depending on extent of disease. Hazard ratios for DP were 1.67 (95% CI 1.13-2.46) for survivors with localized cancer, 3.12 (95% CI 2.06-4.72) for regional, and 10.13 (95% CI 4.17-24.62) for distant cancer, respectively. In survivors, distant cancer, low level of education, not having children<18 years in the household, pre-diagnostic sick-leave and not being employed at diagnosis were associated with increased likelihood for DP. CONCLUSION: A considerable proportion of CRC survivors, for years after diagnosis, will experience reduced work ability compared to controls. Rehabilitation and workplace adjustment to reduce sickness absence and improve work ability should be a long-term concern.
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Neoplasias Colorrectales/epidemiología , Pensiones/estadística & datos numéricos , Sistema de Registros , Reinserción al Trabajo/estadística & datos numéricos , Ausencia por Enfermedad/estadística & datos numéricos , Sobrevivientes/estadística & datos numéricos , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Neoplasias Colorrectales/patología , Evaluación de la Discapacidad , Escolaridad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Noruega , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: The study aims to investigate long-term development in annual labor income (ALI) among patients with colorectal cancer (CRC) compared to individually matched cancer-free controls. METHODS: In a register-based cohort study based on data from Norwegian national registries, 752 patients diagnosed with CRC 1992-1996 at the age 45-54 years were observed annually up to 10 years post-diagnosis. Also, 752 individually matched controls were observed correspondingly. The relationship of CRC and ALI development was modeled by linear mixed model statistics. RESULTS: CRC was associated with reduced ALI in females in the year of diagnosis, irrespective of extent of disease. From the year after diagnosis and onwards, ALI decreased in female patients and controls, most strongly in females with distant CRC, and also in males with regional and distant CRC. Five years after diagnosis, mean ALI was reduced by 22 % in females and 6 % in males with localized CRC. Corresponding numbers were 21 % in females and 11 % in males with regional CRC and 6 % reduction in female and less than 1 % reduction in male controls. After adjustment for post-diagnostic disability pension and days of employment, ALI developed similarly in male patients and controls, whereas CRC remained associated with reduced ALI in the year of diagnosis in females and throughout observation in females with distant CRC. CONCLUSION: Except for males with localized cancer, CRC was associated with negative development in ALI in both sexes, varying by extent of disease. The work ability and income status of female CRC patients and males with metastasing disease should be checked during follow-up.
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Neoplasias Colorrectales , Renta/estadística & datos numéricos , Sistema de Registros/estadística & datos numéricos , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Noruega , Factores SexualesRESUMEN
BACKGROUND: Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3'untranslated region (3'UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/- cetuximab. METHODS: The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314). RESULTS: LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16). CONCLUSIONS: The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/- cetuximab.
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Regiones no Traducidas 3' , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Alelos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Sitios de Unión , Cetuximab , Supervivencia sin Enfermedad , Detección Precoz del Cáncer/métodos , Femenino , Fluorouracilo/administración & dosificación , Genotipo , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Polimorfismo Genético , Prevalencia , Proteínas Proto-Oncogénicas p21(ras) , Adulto JovenRESUMEN
BACKGROUND: Patients with right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ clinically and molecularly. The main objective was to investigate stage-stratified survival and recurrence of RCC and LCC across four 10-year periods. METHODS: Patients diagnosed from 1977 to 2016 with colon adenocarcinoma were included from the Cancer Registry of Norway. Primary tumor location (PTL) was defined as RCC if proximal and LCC if distal to the splenic flexure. Multivariable regressions were used to estimate HRs for overall survival (OS), recurrence-free survival (RFS), survival after recurrence (SAR), and excess HRs (eHR) for relative survival (RS). RESULTS: 72,224 patients were eligible for analyses [55.1% (n = 39,769/72,224) had RCC]. In 1977 to 1986, there was no difference between LCC and RCC in OS [HR, 1.01; 95% confidence interval (CI), 0.97-1.06; P = 0.581] or RS (eHR, 0.96; 95% CI, 0.90-1.02; P = 0.179). In 2007 to 2016, LCC had significantly better OS (HR, 0.84; 95% CI, 0.80-0.87; P < 0.001) and RS (eHR, 0.76; 95% CI, 0.72-0.81; P < 0.001) compared with RCC. The gradually diverging and significantly favorable prognosis for LCC was evident for distant disease across all time periods and for regional disease from 2007 onward. There was no difference in RFS between LCC and RCC in patients less than 75 years during 2007 to 2016 (HR, 0.99; 95% CI, 0.91-1.08; P = 0.819); however, SAR was significantly better for LCC (HR, 0.61; 95% CI, 0.53-0.71; P < 0.001). CONCLUSIONS: A gradually diverging and increasingly favorable prognosis was observed for patients with LCC with advanced disease over the past four decades. IMPACT: Current PTL survival disparities stress the need for further exploring targetable molecular subgroups across and within different PTLs to further improve patient outcomes.
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Adenocarcinoma/patología , Neoplasias del Colon/patología , Adenocarcinoma/mortalidad , Anciano , Neoplasias del Colon/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Noruega/epidemiología , Sistema de Registros , Estudios RetrospectivosRESUMEN
BACKGROUND: Compromised epithelial barriers are found in dysplastic tissue of the gastrointestinal tract. Claudins are transmembrane proteins important for tight junctions. Claudins regulate the paracellular transport and are crucial for maintaining a functional epithelial barrier. Down-regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both in vivo and in vitro. We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression. We have previously shown that the matriptase expression level decreases during colorectal carcinogenesis. In the present study we investigated whether claudin-7 expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue. METHODS: The mRNA level of claudin-7 (CLDN7) was determined in samples from 18 healthy individuals, 100 individuals with dysplasia and 121 colorectal cancer patients using quantitative real time RT-PCR. In addition, immunohistochemical stainings were performed on colorectal adenomas and carcinomas, to confirm the mRNA findings. RESULTS: A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001). Reductions in the claudin-7 mRNA levels were also detected in mild/moderate dysplasia (p < 0.001), severe dysplasia (p < 0.01) and carcinomas (p < 0.01), compared to a control sample from the same individual. The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings. CONCLUSIONS: Our results show that the claudin-7 mRNA level is decreased already as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas.
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Adenoma/genética , Carcinoma/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/genética , Proteínas de la Membrana/genética , Adenoma/metabolismo , Anciano , Anciano de 80 o más Años , Carcinoma/metabolismo , Transformación Celular Neoplásica/metabolismo , Claudinas , Neoplasias Colorrectales/metabolismo , Regulación hacia Abajo/genética , Detección Precoz del Cáncer , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/análisis , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Modelos BiológicosRESUMEN
BACKGROUND: Invasive growth of epithelial cancers is a complex multi-step process which involves dissolution of the basement membrane. Type IV collagen is a major component in most basement membranes. Type VII collagen is related to anchoring fibrils and is found primarily in the basement membrane zone of stratified epithelia. Immunohistochemical studies have previously reported changes in steady-state levels of different alpha(IV) chains in several epithelial cancer types. In the present study we aimed to quantitatively determine the mRNA levels of type IV collagen (alpha1/alpha 4/alpha 6) and type VII collagen (alpha1) during colorectal cancer carcinogenesis. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for alpha1(IV), alpha 4(IV), alpha 6(IV), and alpha1(VII) in colorectal cancer tissue (n = 33), adenomas (n = 29) and in normal tissue from the same individuals. In addition, corresponding tissue was examined from healthy volunteers (n = 20). mRNA levels were normalized to beta-actin. Immunohistochemical analysis of the distributions of type IV and type VII collagens were performed on normal and affected tissues from colorectal cancer patients. RESULTS: The alpha1(IV) and alpha1(VII) mRNA levels were statistically significantly higher in colorectal cancer tissue (p < 0.001) as compared to corresponding tissue from healthy controls. This is an early event as tissue from adenomas also displayed a higher level. There were small changes in the levels of alpha 4(IV). The level of alpha 6(IV) was 5-fold lower in colorectal cancer tissue as compared to healthy individuals (p < 0.01). The localisation of type IV and type VII collagen was visualized by immunohistochemical staining. CONCLUSION: Our results suggest that the down-regulation of alpha 6(IV) mRNA coincides with the acquisition of invasive growth properties, whereas alpha1(IV) and alpha1(VII) mRNAs were up-regulated already in dysplastic tissue. There are no differences in collagen expression between tissues from healthy individuals and normal tissues from affected individuals.
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Colágeno Tipo IV/genética , Colágeno Tipo VII/genética , Neoplasias Colorrectales/patología , ARN Mensajero/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Colágeno Tipo IV/metabolismo , Colágeno Tipo VII/metabolismo , Colon/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Clinical trials where cancer patients were treated with protease inhibitors have suggested that the serine protease, prostasin, may act as a tumour suppressor. Prostasin is proteolytically activated by the serine protease, matriptase, which has a very high oncogenic potential. Prostasin is inhibited by protease nexin-1 (PN-1) and the two isoforms encoded by the mRNA splice variants of hepatocyte growth factor activator inhibitor-1 (HAI-1), HAI-1A, and HAI-1B. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for prostasin and PN-1 in colorectal cancer tissue (n = 116), severe dysplasia (n = 13), mild/moderate dysplasia (n = 93), and in normal tissue from the same individuals. In addition, corresponding tissues were examined from healthy volunteers (n = 23). A part of the cohort was further analysed for the mRNA levels of the two variants of HAI-1, here denoted HAI-1A and HAI-1B. mRNA levels were normalised to beta-actin. Immunohistochemical analysis of prostasin and HAI-1 was performed on normal and cancer tissue. RESULTS: The mRNA level of prostasin was slightly but significantly decreased in both mild/moderate dysplasia (p < 0.001) and severe dysplasia (p < 0.01) and in carcinomas (p < 0.05) compared to normal tissue from the same individual. The mRNA level of PN-1 was more that two-fold elevated in colorectal cancer tissue as compared to healthy individuals (p < 0.001) and elevated in both mild/moderate dysplasia (p < 0.01), severe dysplasia (p < 0.05) and in colorectal cancer tissue (p < 0.001) as compared to normal tissue from the same individual. The mRNA levels of HAI-1A and HAI-1B mRNAs showed the same patterns of expression. Immunohistochemistry showed that prostasin is located mainly on the apical plasma membrane in normal colorectal tissue. A large variation was found in the degree of polarization of prostasin in colorectal cancer tissue. CONCLUSION: These results show that the mRNA level of PN-1 is significantly elevated in colorectal cancer tissue. Future studies are required to clarify whether down-regulation of prostasin activity via up regulation of PN-1 is causing the malignant progression or if it is a consequence of it.
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Carcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica , Serina Endopeptidasas/biosíntesis , Anciano , Empalme Alternativo , Precursor de Proteína beta-Amiloide/biosíntesis , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nexinas de Proteasas , Isoformas de Proteínas , Proteínas Inhibidoras de Proteinasas Secretoras/biosíntesis , ARN Mensajero/metabolismo , Receptores de Superficie Celular/biosíntesis , Serpina E2RESUMEN
BACKGROUND: Genetic polymorphisms in metabolizing enzymes may modify the association of environmental exposure on colorectal cancer (CRC) and adenoma risk. MATERIALS AND METHODS: One hundred and ninety-eight CRC cases, 422 adenomas (206 low-risk and 216 high-risk adenomas) and 222 controls were genotyped for the CYP1A2 164 A-->C polymorphism and questionnaires were used to assess environmental exposure. RESULTS: The smoking parameter "current smoking" was significantly associated with CRC risk, and all the smoking parameters related to current smoking, having ever smoked or high numbers of cigarette years were significantly associated with risk of adenomas. No association was detected between red meat consumption or how well red meat was cooked and colorectal carcinogenesis. When stratifying the case groups based on CYP1A2 genotype, all the smoking parameters yielded stronger risk association in carriers of the C allele. CONCLUSION: These findings may indicate that the association between cigarette smoking and colorectal carcinogenesis can be modified by the CYP1A2 genotype.
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Adenoma/etiología , Neoplasias Colorrectales/etiología , Citocromo P-450 CYP1A2/genética , Dieta , Carne , Fumar , Adenoma/enzimología , Adenoma/genética , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Citocromo P-450 CYP1A2/metabolismo , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population. METHODS: We used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1, GSTT1, GSTP1 Ile105Val, EPHX1 Tyr113His and EPHX1 His139Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression. RESULTS: A higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2nd quartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of the EPHX1 codon 113 polymorphism. An association was also observed for the EPHX1 codon 113 polymorphism in the low-risk adenomas, although not as obvious. CONCLUSION: Although, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma.
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Adenoma/etiología , Carcinoma/etiología , Neoplasias Colorrectales/etiología , Ingestión de Alimentos/fisiología , Carne , Polimorfismo Genético , Verduras , Adenoma/genética , Anciano , Carcinoma/genética , Estudios de Casos y Controles , Estudios de Cohortes , Neoplasias Colorrectales/genética , Epóxido Hidrolasas/genética , Femenino , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/fisiología , Factores de RiesgoRESUMEN
BACKGROUND: It has recently been shown that NDRG2 mRNA is down-regulated or undetectable in several human cancers and cancer cell-lines. Although the function of NDRG2 is unknown, high NDRG2 expression correlates with improved prognosis in high-grade gliomas. The aim of this study has been to examine NDRG2 mRNA expression in colon cancer. By examining affected and normal tissue from individuals with colorectal adenomas and carcinomas, as well as in healthy individuals, we aim to determine whether and at which stages NDRG2 down-regulation occurs during colonic carcinogenesis. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for NDRG2 in low-risk (n = 15) and high-risk adenomas (n = 57), colorectal carcinomas (n = 50) and corresponding normal tissue, as well as control tissue from healthy individuals (n = 15). NDRG2 levels were normalised to beta-actin. RESULTS: NDRG2 mRNA levels were lower in colorectal carcinomas compared to normal tissue from the control group (p < 0.001). When comparing adenomas/carcinomas with adjacent normal tissue from the same individual, NDRG2 expression levels were significantly reduced in both high-risk adenoma (p < 0.001) and in colorectal carcinoma (p < 0.001). There was a trend for NDRG2 levels to decrease with increasing Dukes' stage (p < 0.05). CONCLUSION: Our results demonstrate that expression of NDRG2 is down-regulated at a late stage during colorectal carcinogenesis. Future studies are needed to address whether NDRG2 down-regulation is a cause or consequence of the progression of colorectal adenomas to carcinoma.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , Regulación hacia Abajo , Proteínas Supresoras de Tumor/metabolismo , Adenoma/patología , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP- 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy.
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Neoplasias Colorrectales/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Inhibidor Tisular de Metaloproteinasa-1/sangre , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Cetuximab/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Metástasis de la Neoplasia , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Fenotipo , Transducción de Señal , Análisis de Supervivencia , Inhibidor Tisular de Metaloproteinasa-1/genéticaRESUMEN
BACKGROUND: Drugs that target tyrosine kinases belong to a new class of antineoplastic therapeutics, directed at cellular signalling mechanisms. Notes on the use of these agents and some of the clinical data are discussed in this review. METHODS: The article is based on a review of recent literature and the authors' personal experience. RESULTS AND INTERPRETATION: Receptor tyrosine kinases and intracellular tyrosine kinases regulate cellular events that may be involved in tumour development, such as proliferation, survival, and angiogenesis. Some of these agents are established in clinical practice, in particular the small-molecular tyrosine kinase inhibitor imatinib in the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours and the antibody trastuzumab in the treatment of breast cancer. Inhibitors of epidermal growth factor receptor (EGFR) and other tyrosine kinases are either established in clinical practice or under clinical investigation.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Benzamidas , Cetuximab , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Clorhidrato de Erlotinib , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/enzimología , Tumores del Estroma Gastrointestinal/inmunología , Gefitinib , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Neoplasias/enzimología , Neoplasias/inmunología , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/inmunología , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/inmunología , Transducción de Señal/efectos de los fármacos , TrastuzumabRESUMEN
PURPOSE: To estimate actual utilization rates of radiation therapy (RT) in Norway, describe time trends (1997-2010), and compare these estimates with corresponding optimal RT rates. METHODS AND MATERIALS: Data from the population-based Cancer Registry of Norway was used to identify all patients diagnosed with cancer and/or treated by RT for cancer in 1997-2010. Radiation therapy utilization rates (RURs) were calculated as (1) the proportion of incident cancer cases who received RT at least once within 1 year of diagnosis (RUR1Y); and (2) the proportion who received RT within 5 years of diagnosis (RUR5Y). The number of RT treatment courses per incident cancer case (TCI) was also calculated for all cancer sites combined. The actual RURs were compared with corresponding Australian and Canadian epidemiologic- and evidence-based model estimates and criterion-based benchmark estimates of optimal RURs. The TCIs were compared with TCI estimates from the 1997 Norwegian/National Cancer Plan (NCP). Joinpoint regression was used to identify changes in trends and to estimate annual percentage change (APC) in actual RUR1Y and actual TCI. RESULTS: The actual RUR5Y (all sites) increased significantly to 29% in 2005 but still differed markedly from the Australian epidemiologic- and evidence-based model estimate of 48%. With the exception of RUR5Y for breast cancer and RUR1Y for lung cancers, all actual RURs were markedly lower than optimal RUR estimates. The actual TCI increased significantly during the study period, reaching 42.5% in 2010, but was still lower than the 54% recommended in the NCP. The trend for RUR1Y (all sites) and TCI changed significantly, with the annual percentage change being largest during the first part of the study period. CONCLUSIONS: Utilization rates of RT in Norway increased after the NCP was implemented and RT capacity was increased, but they still seem to be lower than optimal levels.
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Implementación de Plan de Salud/estadística & datos numéricos , Neoplasias/radioterapia , Humanos , Incidencia , Neoplasias/epidemiología , Noruega/epidemiología , Radioterapia/estadística & datos numéricos , Radioterapia/tendencias , Retratamiento/estadística & datos numéricosRESUMEN
PURPOSE: According to current recommendations for adjuvant treatment, patients with colon cancer stage II are not routinely offered chemotherapy, unless considered to have a high risk of relapse based on specific clinicopathological parameters. Following these criteria, it is challenging to identify the subgroup of patients that will benefit the most from adjuvant treatment. Contrarily, patients with colon cancer stage III are routinely offered chemotherapy, but due to expected adverse effects and frailty, elderly patients are often excluded from standard protocols. Colon cancer is a disease of the elderly and accordingly, there is a large subgroup of patients for which guidelines for adjuvant treatment remain less clear. In these two clinical settings, improved risk stratification has great potential impact on patient care, anticipating that high-risk patients will benefit from chemotherapy. However, microsatellite instability is the only molecular prognostic marker recommended for clinical use. EXPERIMENTAL DESIGN: In this perspective, we provide an updated view on the status and clinical potential of the many proposed prognostic gene expression-based tests for colon cancer stage II and III. RESULTS: The main limitation for clinical implementation is lack of prospective validation. For patients with stage II, highly promising tests have been identified and clinical trials are ongoing. For elderly patients with stage III, the value of such tests has received less focus, but promising early results have been shown. CONCLUSION: Although awaiting results from prospective trials, improved risk assessment for patients with stage II and III is likely to be achieved in the foreseeable future.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Regulación Neoplásica de la Expresión Génica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Quimioterapia Adyuvante , Neoplasias del Colon/patología , Fluorouracilo/administración & dosificación , Humanos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: A randomised study in non-resectable rectal cancer showed that preoperative chemoradiotherapy (CRT) resulted in better local control and disease-specific survival, but not overall survival than radiotherapy alone. The present paper presents long-term (>4 years) health-related quality of life (HRQoL) and a comparison between the results and reference values from the Norwegian general population. MATERIAL AND METHODS: A total of 207 patients with primarily non-resectable rectal cancer were randomised to preoperative CRT (2Gyx25+5FU/leucovorin) or RT (2Gyx25) before surgery. HRQoL was assessed using EORTC QLQ-C30, completed at baseline and sent to all patients alive in Norway and Sweden (n=105) after a minimum of 4 years post treatment. A difference of ≥5 points on the 0-100 scales was considered clinically significant. RESULTS: Seventy-six (72%) patients answered at follow-up. No statistically significant differences between the CRT and RT groups appeared at follow-up, although clinically significant differences in social functioning, dyspnoea and diarrhoea were found. Over time, a clinically significant reduction in physical functioning was found in both groups. Moreover, reduced social functioning and less diarrhoea in the CRT group and better role functioning and more diarrhoea in the RT group were found. Comparisons between the study group and age and gender matched reference values indicate impaired social functioning and more diarrhoea among the patients. CONCLUSION: There were no statistically significant differences in HRQoL between the randomisation groups. In general, despite having impaired social functioning and more diarrhoea, patients reported HRQoL comparable with the reference population several years after treatment.