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1.
Artigo em Inglês | MEDLINE | ID: mdl-33548185

RESUMO

BACKGROUND: Colorectal cancer screening programmes worldwide have been disrupted during the COVID-19 pandemic. We aimed to estimate the impact of hypothetical disruptions to organised faecal immunochemical test-based colorectal cancer screening programmes on short-term and long-term colorectal cancer incidence and mortality in three countries using microsimulation modelling. METHODS: In this modelling study, we used four country-specific colorectal cancer microsimulation models-Policy1-Bowel (Australia), OncoSim (Canada), and ASCCA and MISCAN-Colon (the Netherlands)-to estimate the potential impact of COVID-19-related disruptions to screening on colorectal cancer incidence and mortality in Australia, Canada, and the Netherlands annually for the period 2020-24 and cumulatively for the period 2020-50. Modelled scenarios varied by duration of disruption (3, 6, and 12 months), decreases in screening participation after the period of disruption (0%, 25%, or 50% reduction), and catch-up screening strategies (within 6 months after the disruption period or all screening delayed by 6 months). FINDINGS: Without catch-up screening, our analysis predicted that colorectal cancer deaths among individuals aged 50 years and older, a 3-month disruption would result in 414-902 additional new colorectal cancer diagnoses (relative increase 0·1-0·2%) and 324-440 additional deaths (relative increase 0·2-0·3%) in the Netherlands, 1672 additional diagnoses (relative increase 0·3%) and 979 additional deaths (relative increase 0·5%) in Australia, and 1671 additional diagnoses (relative increase 0·2%) and 799 additional deaths (relative increase 0·3%) in Canada between 2020 and 2050, compared with undisrupted screening. A 6-month disruption would result in 803-1803 additional diagnoses (relative increase 0·2-0·4%) and 678-881 additional deaths (relative increase 0·4-0·6%) in the Netherlands, 3552 additional diagnoses (relative increase 0·6%) and 1961 additional deaths (relative increase 1·0%) in Australia, and 2844 additional diagnoses (relative increase 0·3%) and 1319 additional deaths (relative increase 0·4%) in Canada between 2020 and 2050, compared with undisrupted screening. A 12-month disruption would result in 1619-3615 additional diagnoses (relative increase 0·4-0·9%) and 1360-1762 additional deaths (relative increase 0·8-1·2%) in the Netherlands, 7140 additional diagnoses (relative increase 1·2%) and 3968 additional deaths (relative increase 2·0%) in Australia, and 5212 additional diagnoses (relative increase 0·6%) and 2366 additional deaths (relative increase 0·8%) in Canada between 2020 and 2050, compared with undisrupted screening. Providing immediate catch-up screening could minimise the impact of the disruption, restricting the relative increase in colorectal cancer incidence and deaths between 2020 and 2050 to less than 0·1% in all countries. A post-disruption decrease in participation could increase colorectal cancer incidence by 0·2-0·9% and deaths by 0·6-1·6% between 2020 and 2050, compared with undisrupted screening. INTERPRETATION: Although the projected effect of short-term disruption to colorectal cancer screening is modest, such disruption will have a marked impact on colorectal cancer incidence and deaths between 2020 and 2050 attributable to missed screening. Thus, it is crucial that, if disrupted, screening programmes ensure participation rates return to previously observed rates and provide catch-up screening wherever possible, since this could mitigate the impact on colorectal cancer deaths. FUNDING: Cancer Council New South Wales, Health Canada, and Dutch National Institute for Public Health and Environment.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33130189

RESUMO

BACKGROUND & AIMS: The population prevalence of gastrointestinal (GI) disease is unclear and difficult to assess in an asymptomatic population. The aim of this study was to determine prevalence of GI lesions in a largely asymptomatic population undergoing colon capsule endoscopy (CCE). METHODS: Participants aged between 50-75years were retrieved from the Rotterdam Study, a longitudinal epidemiological study, between 2017-2019. Participants received CCE with bowel preparation. Abnormalities defined as clinically relevant were Barrett segment>3cm, severe ulceration, polyp>10 mm or ≥3 polyps in small bowel(SB) or colon, and cancer. RESULTS: Of 2800 invited subjects, 462 (16.5%) participants (mean age 66.8 years, female 53.5%) ingested the colon capsule. A total of 451 videos were analyzed, and in 94.7% the capsule reached the descending colon. At least one abnormal finding was seen in 448 (99.3%) participants. The prevalence of abnormalities per GI segment, and the most common type of abnormality, were as follows: Esophageal 14.8% (Barrett's esophagus <3 cm in 8.3%), gastric 27.9% (fundic gland polyps in 18.1%), SB abnormalities 33.9% (erosions in 23.8%), colon 93.3% (diverticula in 81.2%). A total of 54 participants (12%) had clinically relevant abnormalities, three (0.7%) in esophagus/stomach (reflux esophagitis grade D, Mallory Weiss lesion and severe gastritis), five (1.1%) in SB (polyps > 10 mm n= 4, severe ulcer n= 1,) and 46 (10.2%) in colon (polyp > 10 mm or ≥3 polyps n= 46, colorectal cancer n= 1). CONCLUSIONS: GI lesions are very common in a mostly asymptomatic Western population, and clinically relevant lesions were found in 12% at CCE. These findings provide a frame of reference for the prevalence rates of GI lesions in the general population.

3.
J Natl Cancer Inst ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32761199

RESUMO

BACKGROUND: Colorectal cancer (CRC) screening with colonoscopy and the fecal immunochemical test (FIT) is underutilized. Innovative tests could increase screening acceptance. This study determined which of the available alternatives is most promising from a cost-effectiveness perspective. METHODS: The previously-validated MISCAN-Colon model was used to evaluate the cost-effectiveness of screening with capsule endoscopy every 5 or 10 years, computed tomographic colonography (CTC) every 5 years, the multi-target stool DNA (mtSDNA) test every 1 or 3 years, and the methylated SEPT9 DNA plasma assay (mSEPT9) every 1 or 2 years. We also compared these strategies to annual FIT screening and colonoscopy screening every 10 years. Quality-adjusted life-years gained (QALYG), number of colonoscopies, and incremental cost-effectiveness ratios (ICERs) were projected. We assumed a willingness-to-pay threshold of $100,000 per QALYG. RESULTS: Among the alternative tests, CTC every 5 years, annual mSEPT9 and annual mtSDNA screening had ICERs of $1,092, $63,253 and $214,974 per QALYG, respectively. Other screening strategies were more costly and less effective than (a combination of) these three. Under the assumption of perfect adherence, annual mSEPT9 screening resulted in more QALYG, CRC cases averted and CRC deaths averted than annual FIT screening, but led to a high rate of colonoscopy referral (51% after 3 years, 69% after 5 years). The alternative tests were not cost-effective compared to FIT and colonoscopy. CONCLUSION: This study suggests that for individuals not willing to participate in FIT or colonoscopy screening, mSEPT9 is the test of choice if the high colonoscopy referral rate is acceptable to them.

4.
Clin Gastroenterol Hepatol ; 18(12): 2760-2767.e12, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629885

RESUMO

BACKGROUND & AIMS: The province of Ontario, Canada is considering immunohistochemical followed by cascade analyses of all patients who received a diagnosis of colorectal cancer (CRC) at an age younger than 70 years to identify individuals with Lynch syndrome. We evaluated the costs and benefits of testing for Lynch syndrome and determined the optimal surveillance interval for first-degree relatives (FDRs) found to have Lynch syndrome. METHODS: We developed a patient flow diagram to determine costs and yield of immunohistochemical testing for Lynch syndrome in CRC cases and, for those found to have Lynch syndrome, their FDRs, accounting for realistic uptake. Subsequently, we used the MISCAN-colon model to compare costs and benefits of annual, biennial, and triennial surveillance in FDRs identified with Lynch syndrome vs colonoscopy screening every 10 years (usual care for individuals without a diagnosis of Lynch syndrome). RESULTS: Testing 1000 CRC cases was estimated to identify 20 CRC index cases and 29 FDRs with Lynch syndrome at a cost of $310,274. Despite the high cost of Lynch syndrome tests, offering the FDRs with Lynch syndrome biennial colonoscopy surveillance was cost-effective at $8785 per life-year gained compared with usual care because of a substantial increase in life-years gained (+122%) and cost savings in CRC care. Triennial surveillance was more costly and less effective, and annual surveillance showed limited additional benefit compared with biennial surveillance. CONCLUSIONS: Immunohistochemical testing for Lynch syndrome in persons younger than 70 years who received a diagnosis of CRC and then testing FDRs of those found to have Lynch syndrome provide a good balance between costs and long-term benefits. Colonoscopy surveillance every 2 years is the optimal surveillance interval for patients with Lynch syndrome.

5.
Gastroenterology ; 158(5): 1274-1286.e12, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31866242

RESUMO

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Idade de Início , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Estilo de Vida , Masculino , Anamnese , Pessoa de Meia-Idade , Taxa de Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Sequenciamento Completo do Genoma
6.
Cancer ; 124(14): 2964-2973, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29846933

RESUMO

BACKGROUND: In 2016, the Microsimulation Screening Analysis-Colon (MISCAN-Colon) model was used to inform the US Preventive Services Task Force colorectal cancer (CRC) screening guidelines. In this study, 1 of 2 microsimulation analyses to inform the update of the American Cancer Society CRC screening guideline, the authors re-evaluated the optimal screening strategies in light of the increase in CRC diagnosed in young adults. METHODS: The authors adjusted the MISCAN-Colon model to reflect the higher CRC incidence in young adults, who were assumed to carry forward escalated disease risk as they age. Life-years gained (LYG; benefit), the number of colonoscopies (COL; burden) and the ratios of incremental burden to benefit (efficiency ratio [ER] = ΔCOL/ΔLYG) were projected for different screening strategies. Strategies differed with respect to test modality, ages to start (40 years, 45 years, and 50 years) and ages to stop (75 years, 80 years, and 85 years) screening, and screening intervals (depending on screening modality). The authors then determined the model-recommended strategies in a similar way as was done for the US Preventive Services Task Force, using ER thresholds in accordance with the previously accepted ER of 39. RESULTS: Because of the higher CRC incidence, model-predicted LYG from screening increased compared with the previous analyses. Consequently, the balance of burden to benefit of screening improved and now 10-yearly colonoscopy screening starting at age 45 years resulted in an ER of 32. Other recommended strategies included fecal immunochemical testing annually, flexible sigmoidoscopy screening every 5 years, and computed tomographic colonography every 5 years. CONCLUSIONS: This decision-analysis suggests that in light of the increase in CRC incidence among young adults, screening may be offered earlier than has previously been recommended. Cancer 2018;124:2964-73. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Programas de Rastreamento/normas , Guias de Prática Clínica como Assunto , Adulto , Comitês Consultivos/normas , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , American Cancer Society , Colonografia Tomográfica Computadorizada/normas , Colonoscopia/normas , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Simulação por Computador , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Humanos , Incidência , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Modelos Biológicos , Sangue Oculto , Serviços Preventivos de Saúde/normas , Medição de Risco , Programa de SEER/estatística & dados numéricos , Estados Unidos/epidemiologia
7.
Cancer ; 124(14): 2974-2985, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29846942

RESUMO

BACKGROUND: Colorectal cancer (CRC) risk varies by race and sex. This study, 1 of 2 microsimulation analyses to inform the 2018 American Cancer Society CRC screening guideline, explored the influence of race and sex on optimal CRC screening strategies. METHODS: Two Cancer Intervention and Surveillance Modeling Network microsimulation models, informed by US incidence data, were used to evaluate a variety of screening methods, ages to start and stop, and intervals for 4 demographic subgroups (black and white males and females) under 2 scenarios for the projected lifetime CRC risk for 40-year-olds: 1) assuming that risk had remained stable since the early screening era and 2) assuming that risk had increased proportionally to observed incidence trends under the age of 40 years. Model-based screening recommendations were based on the predicted level of benefit (life-years gained) and burden (required number of colonoscopies), the incremental burden-to-benefit ratio, and the relative efficiency in comparison with strategies with similar burdens. RESULTS: When lifetime CRC risk was assumed to be stable over time, the models differed in the recommended age to start screening for whites (45 vs 50 years) but consistently recommended screening from the age of 45 years for blacks. When CRC risk was assumed to be increased, the models recommended starting at the age of 45 years, regardless of race and sex. Strategies recommended under both scenarios included colonoscopy every 10 or 15 years, annual fecal immunochemical testing, and computed tomographic colonography every 5 years through the age of 75 years. CONCLUSIONS: Microsimulation modeling suggests that CRC screening should be considered from the age of 45 years for blacks and for whites if the lifetime risk has increased proportionally to the incidence for younger adults. Cancer 2018;124:2974-85. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Disparidades nos Níveis de Saúde , Programas de Rastreamento/normas , Guias de Prática Clínica como Assunto , Adulto , Afro-Americanos/estatística & dados numéricos , Fatores Etários , Idoso , American Cancer Society , Causas de Morte , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Simulação por Computador , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Modelos Biológicos , Medição de Risco , Programa de SEER/estatística & dados numéricos , Fatores Sexuais , Taxa de Sobrevida , Estados Unidos/epidemiologia
8.
Br J Cancer ; 118(8): 1074-1083, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29576625

RESUMO

INTRODUCTION: Chondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for chondrosarcoma was evaluated. METHODS: Expression of glutaminase was determined in 120 cartilage tumours by immunohistochemistry. Ten chondrosarcoma cell lines were treated with the metabolic compounds CB-849, metformin, phenformin (lipophilic analogue of metformin) and chloroquine. RESULTS: A difference in glutaminase expression levels between the different tumour grades (p = 0.001, one-way ANOVA) was identified, with the highest expression observed in high-grade chondrosarcomas. Treatment with CB-839, metformin, phenformin or chloroquine revealed that chondrosarcoma cell lines are sensitive to glutaminolysis inhibition. Metformin and phenformin decreased mTOR activity in chondrosarcoma cells, and metformin decreased LC3B-II levels, which is counteracted by chloroquine. CONCLUSION: Targeting glutaminolysis with CB-839, metformin, phenformin or chloroquine is a potential therapeutic strategy for a subset of high-grade chondrosarcomas, irrespective of the presence or absence of an IDH1/2 mutation.


Assuntos
Benzenoacetamidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Cloroquina/uso terapêutico , Condrossarcoma/tratamento farmacológico , Glutaminase/metabolismo , Glutamina/metabolismo , Metformina/uso terapêutico , Tiadiazóis/uso terapêutico , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Condrossarcoma/genética , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Glutaminase/antagonistas & inibidores , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Mutação , Gradação de Tumores , Células Tumorais Cultivadas
9.
Health Aff (Millwood) ; 36(12): 2151-2159, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29200350

RESUMO

Financial barriers to colorectal cancer screening persist despite the Affordable Care Act (ACA). Medicare beneficiaries may face 20 percent coinsurance for a screening colonoscopy when the procedure includes the removal of polyps or follows a positive fecal screening test. Using an established microsimulation model, we estimated that waiving this coinsurance would result in 1.7 fewer colorectal cancer deaths (a decrease of 13 percent) and $17,000 higher colorectal cancer-related costs (an increase of 0.6 percent) for the Centers for Medicare and Medicaid Services per 1,000 sixty-five-year-olds, assuming a 10-percentage-point increase in the rates of first colonoscopy screening, follow-up, and surveillance. If the rates did not change, waiving coinsurance would increase total costs by $51,000 (1.9 percent) per 1,000 sixty-five-year-olds. Estimated screening benefits were comparable when fecal testing was assumed to be the primary screening method. Moreover, waiving coinsurance would be cost-effective if the screening rate increased by 0.6 percentage points, assuming a willingness-to-pay threshold of $50,000 per quality-adjusted life-year gained. Thus, the waiver is likely to have a favorable balance of health and cost impact.


Assuntos
Neoplasias Colorretais/diagnóstico , Dedutíveis e Cosseguros/estatística & dados numéricos , Detecção Precoce de Câncer/economia , Programas de Rastreamento/economia , Medicare/economia , Idoso , Colonoscopia/economia , Colonoscopia/estatística & dados numéricos , Análise Custo-Benefício/economia , Análise Custo-Benefício/métodos , Dedutíveis e Cosseguros/economia , Feminino , Humanos , Masculino , Medicare/estatística & dados numéricos , Medicare/tendências , Sangue Oculto , Estados Unidos
10.
Mol Cancer Res ; 15(12): 1714-1721, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28860121

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2-mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored. Eleven chondrosarcoma cell lines were treated with NAMPT inhibitors, in which the effect on cell viability, colony formation, and 3D collagen invasion was assessed. The expression level of NAMPT and NAPRT transcripts in chondrosarcoma cells was determined by qRT-PCR. Methylation of the NAPRT promoter was evaluated using a previously published dataset of genome-wide methylation. In addition, a methylation dataset was used to determine methylation of the NAPRT promoter in 20 IDH1/2-mutated cartilage tumors. Chondrosarcoma cells showed a dose-dependent decrease in cell viability, 3D collagen invasion, and colony formation upon treatment with NAMPT inhibitors, in which nearly half of the cell lines demonstrated absolute IC50s in the low nanomolar range. Increasing IC50s correlated to increasing NAPRT expression levels and decreasing NAPRT promoter methylation. No correlation between IDH1/2 mutation status and sensitivity for NAMPT inhibitors was observed. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. In conclusion, this study identified NAMPT as a potential target for treatment of chondrosarcoma.Implications: Chondrosarcoma patients, especially those of high histologic grade with lower expression and hypermethylation of NAPRT, may benefit from inhibition of the NAD synthesis pathway. Mol Cancer Res; 15(12); 1714-21. ©2017 AACR.


Assuntos
Condrossarcoma/genética , Citocinas/genética , Isocitrato Desidrogenase/genética , Neoplasias de Tecido Ósseo/genética , Nicotinamida Fosforribosiltransferase/genética , Pentosiltransferases/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Condrossarcoma/tratamento farmacológico , Condrossarcoma/patologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação , NAD/antagonistas & inibidores , NAD/biossíntese , NAD/genética , Invasividade Neoplásica/genética , Neoplasias de Tecido Ósseo/tratamento farmacológico , Neoplasias de Tecido Ósseo/patologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Pentosiltransferases/antagonistas & inibidores , Regiões Promotoras Genéticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
J Bone Oncol ; 7: 29-31, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28443232

RESUMO

Osteosarcoma is a primary malignant bone tumour, for which no improvement in survival rate has been made since the nineteen seventies. We set out to systemically identify the in vitro studies performed in the past two decades describing potential future therapies. Strikingly, we obtained a total of 5282 PubMed hits on this subject. The amount of publications has increased almost exponentially over the past few years. Studies from Chinese institutes are mainly responsible for this huge increase, accounting for 53% of the publications in 2015. Approximately 1/3 of all drugs described in the past three years could be classified as traditional medicine. Furthermore, it struck our attention that even though in such studies multiple cell lines are essential to represent the heterogeneity in patients, many studies were performed with only one or two cell lines, i.e. U-2 OS or MG-63. These cells are fast growing, facilitating rapid experimental application but also boosting drug responsiveness. This probably explains why so many in vitro studies have been published for this relatively rare disease. Furthermore, it illustrates the current publication pressure, especially in China.

12.
BMC Cancer ; 16: 475, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27418340

RESUMO

BACKGROUND: Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. METHODS: Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. RESULTS: Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the same tumour, suggesting that in vitro culturing upregulates IGF1R expression. CONCLUSIONS: The results from this study indicate that the IGF pathway is not essential for chondrosarcoma growth, migration or chemoresistance. Furthermore, IGF1R is only minimally expressed in chondrosarcoma primary tumours. Therefore, the IGF pathway is not expected to be an effective therapeutic target for chondrosarcoma of bone.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Receptores de Somatomedina/antagonistas & inibidores , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Terapia de Alvo Molecular , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1 , Receptores de Somatomedina/metabolismo , Transdução de Sinais
14.
Oncotarget ; 6(34): 36113-25, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26416351

RESUMO

High-grade conventional osteosarcoma is the most common primary bone tumor. Prognosis for osteosarcoma patients is poor and resistance to chemotherapy is common. We performed an siRNA screen targeting members of the Bcl-2 family in human osteosarcoma cell lines to identify critical regulators of osteosarcoma cell survival. Silencing the anti-apoptotic family member Bcl-xL but also the pro-apoptotic member Bak using a SMARTpool of siRNAs as well as 4/4 individual siRNAs caused loss of viability. Loss of Bak impaired cell cycle progression and triggered autophagy. Instead, silencing Bcl-xL induced apoptotic cell death. Bcl-xL was expressed in clinical osteosarcoma samples but mRNA or protein levels did not significantly correlate with therapy response or survival. Nevertheless, pharmacological inhibition of a range of Bcl-2 family members showed that inhibitors targeting Bcl-xL synergistically enhanced the response to the chemotherapeutic agent, doxorubicin. Indeed, in osteosarcoma cells strongly expressing Bcl-xL, the Bcl-xL-selective BH3 mimetic, WEHI-539 potently enhanced apoptosis in the presence of low doses of doxorubicin. Our results identify Bcl-xL as a candidate drug target for sensitization to chemotherapy in patients with osteosarcoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Doxorrubicina/farmacologia , Inibidores Enzimáticos/farmacologia , Osteossarcoma/tratamento farmacológico , Proteína bcl-X/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Benzopiranos/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/secundário , Nitrilos/farmacologia , Nitrofenóis/farmacologia , Osteossarcoma/patologia , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Análise Serial de Tecidos , Transfecção , Proteína bcl-X/biossíntese , Proteína bcl-X/genética
15.
Cell ; 155(2): 410-22, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-24120139

RESUMO

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Elementos de Resposta , Fator de Células-Tronco/genética , Neoplasias Testiculares/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Proliferação de Células , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Seleção Genética , Transcrição Genética
16.
BMC Cancer ; 13: 245, 2013 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-23688189

RESUMO

BACKGROUND: High-grade osteosarcoma is an aggressive tumor most often developing in the long bones of adolescents, with a second peak in the 5th decade of life. Better knowledge on cellular signaling in this tumor may identify new possibilities for targeted treatment. METHODS: We performed gene set analysis on previously published genome-wide gene expression data of osteosarcoma cell lines (n=19) and pretreatment biopsies (n=84). We characterized overexpression of the insulin-like growth factor receptor (IGF1R) signaling pathways in human osteosarcoma as compared with osteoblasts and with the hypothesized progenitor cells of osteosarcoma - mesenchymal stem cells. This pathway plays a key role in the growth and development of bone. Since most profound differences in mRNA expression were found at and upstream of the receptor of this pathway, we set out to inhibit IR/IGF1R using OSI-906, a dual inhibitor for IR/IGF1R, on four osteosarcoma cell lines. Inhibitory effects of this drug were measured by Western blotting and cell proliferation assays. RESULTS: OSI-906 had a strong inhibitory effect on proliferation of 3 of 4 osteosarcoma cell lines, with IC50s below 100 nM at 72 hrs of treatment. Phosphorylation of IRS-1, a direct downstream target of IGF1R signaling, was inhibited in the responsive osteosarcoma cell lines. CONCLUSIONS: This study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma.


Assuntos
Neoplasias Ósseas/metabolismo , Imidazóis/farmacologia , Osteossarcoma/metabolismo , Pirazinas/farmacologia , Receptor IGF Tipo 1/biossíntese , Receptor de Insulina/biossíntese , Transdução de Sinais/fisiologia , Western Blotting , Proliferação de Células/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
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