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PURPOSE OF REVIEW: This report highlights several of the recent therapeutic advancements in the treatment of BRAF-mutant tumors, discusses the most common adverse events observed with BRAF-targeted agents, and suggests strategies to manage and mitigate treatment-related toxicities. RECENT FINDINGS: BRAF and MEK inhibitors represent a significant advancement in the treatment of BRAF-mutated malignancies with data across tumor types demonstrating the anti-tumor efficacy of dual MAPK inhibition. Although these agents have a reasonable toxicity profile, variable side effects across organ systems can develop. The discovery of activating BRAF mutations and subsequent development of BRAF and MEK inhibitors has transformed the treatment algorithms of BRAF-mutant malignancies. With increased application of these targeted regimens, identification and prompt management of their unique adverse events are crucial.
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Neoplasias , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Humanos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias/tratamento farmacológico , Mutação , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular/efeitos adversosRESUMO
Immune checkpoint inhibitors (ICI) have improved metastatic melanoma outcomes; however, toxicities, such as hepatitis, can be dose-limiting or even fatal.1 Systemic glucocorticoids and antimetabolite immunosuppressive medications remain the mainstay of treatment for ICI-hepatitis, but options for patients refractory to these therapies are limited.2 Herein we present 3 cases of glucocorticoid-refractory ICI-hepatitis treated with tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3. These patients represent consecutive patients referred to the Massachusetts General Hospital Severe Immunotherapy Complications service who were determined by our experts to have treatment failure with systemic glucocorticoid and antimetabolite combination therapy between August 2022 and September 2023.3 These were the only 3 patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis during that time.
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Inibidores de Checkpoint Imunológico , Piperidinas , Pirimidinas , Humanos , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Solid organ transplant recipients (SOTRs) are at â¼100-fold increased risk for developing skin cancers compared with the general population, with increased morbidity and mortality. These patients are closely followed by dermatology; however, it is unclear how referral reasons from nondermatologic providers affect care in these patients. OBJECTIVE: This study examines the reason SOTRs are referred to dermatologic care by nondermatologic providers as a potential predictor of nonmelanoma skin cancer (NMSC) outcomes. MATERIALS AND METHODS: A retrospective case-control study was conducted with the records of 353 adult SOTRs referred to a specialized transplant dermatology clinic within an academic tertiary care center between 2007 and mid-2012. RESULTS: Eighty-one patients were diagnosed with 491 total premalignant and malignant skin lesions. A considerable proportion of patients diagnosed with NMSC were referred for benign skin conditions such as rash or acne. CONCLUSION: These results indicate that some SOTRs referred to dermatology for benign skin disorders are incidentally diagnosed with cutaneous malignancies; this is concerning given that referrals for benign skin conditions may delay appropriate care for cutaneous malignancies and preventative care. Better risk stratification, improved interdisciplinary collaboration, and prompt referrals for dermatologic care are needed in the care of SOTRs.
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Complicações Pós-Operatórias/epidemiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Transplantes , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Estudos Retrospectivos , Dermatopatias/diagnósticoRESUMO
Cutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.
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Antineoplásicos/administração & dosagem , Arginase/antagonistas & inibidores , Arginina/análogos & derivados , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Cutânea , Animais , Antineoplásicos/farmacologia , Arginina/administração & dosagem , Arginina/farmacologia , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologiaRESUMO
PURPOSE: Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor-negative/low (AR-/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response and tumor progression. EXPERIMENTAL DESIGN: Unique prostate cancer cell models that capture AR-/Low stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human prostate cancer xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-κB pathway activity in Sox9 overexpression was explored. RESULTS: Prostate cancer stem cell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of prostate cancer cells. Sox9 was transiently upregulated in castration-induced progression of prostate cancer xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT)-treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-κB dimer activation in prostate cancer cells. CONCLUSIONS: Developmentally reprogrammed prostate cancer cell models recapitulate features of clinically advanced prostate tumors, including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies prostate cancer cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-κB pathway.
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Antagonistas de Receptores de Andrógenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Células Neuroendócrinas/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOX9/metabolismo , Células-Tronco/patologia , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , NF-kappa B/metabolismo , Células Neuroendócrinas/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Abatacepte/uso terapêutico , Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores de Calcineurina/uso terapêutico , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/prevenção & controle , Estudos de Casos e Controles , Intervalo Livre de Doença , Substituição de Medicamentos/estatística & dados numéricos , Feminino , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle , Transplantados/estatística & dados numéricos , Resultado do TratamentoRESUMO
Patients with AIDS have increased risk of developing lymphomas, such as anaplastic large cell lymphoma (ALCL), which generally carry a poor prognosis. The DUSP-IRF4 genetic rearrangement in ALCL confers a favourable prognosis in HIV-negative patients; it is unknown how this interacts clinically with HIV/AIDS. A man aged 53 years presented with subcutaneous nodules on the scalp and axillae, and diffuse lymphadenopathy. Biopsy of subcutaneous nodule and lymph node showed large atypical anaplastic lymphocytes which were CD30+ and anaplastic lymphoma kinase-negative, consistent with primary systemic ALCL. In addition, he was found to be HIV-positive and diagnosed with AIDS. Genetic testing of the tissue revealed a DUSP22-IRF4 rearrangement. Complete remission was achieved with HyperCVAD and subsequent brentuximab vedotin monotherapy. We report a case of AIDS-associated primary systemic ALCL with a DUSP22-IRF4 rearrangement. AIDS-associated ALCL is an aggressive lymphoma, with a poor prognosis. However, the presence of the genetic rearrangement, previously unseen in this disease, drastically altered the disease course. This case highlights the value of genetic testing and identifies DUSP22-IRF4-associated ALCL in the setting of HIV-associated lymphoproliferative disorders.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Fosfatases de Especificidade Dupla/genética , Linfoma Relacionado a AIDS/patologia , Linfoma Anaplásico de Células Grandes/patologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Neoplasias Cutâneas/patologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/imunologia , Rearranjo Gênico/genética , Humanos , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/genética , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Resultado do TratamentoRESUMO
Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) have different clinical behaviors, despite both being keratinocyte carcinomas mainly caused by ultraviolet radiation. Whether these distinct features are associated with tumor-associated macrophages (TAMs) is largely unknown. The main goal of this study was to conduct a comprehensive analysis of density and polarization states of TAMs in SCCs versus BCCs. The role of lactic acid in TAM polarization in SCC versus BCC was examined. We found that SCCs have a higher density of CD68 + TAMs compared to BCCs. TAMs in SCCs express higher levels of TAM-associated markers (arginase-1, MMP9, CD40 and CD127) than those in BCCs. Interestingly, differential expression of TAM-associated markers between SCCs and BCCs was reproduced in human monocytic THP-1 cells stimulated with SCC- or BCC-conditioned media. Analysis of soluble factor(s) in these tumors further revealed that SCCs have a significantly higher concentration of lactic acid than BCCs, and lactic acid was sufficient to upregulate TAM markers. Our results demonstrate that TAMs in SCCs versus BCCs differ in density and polarization states, which can be determined by soluble factors including tumor-derived lactic acid. These differences in TAMs may contribute to the distinct clinical behaviors of SCCs versus BCCs. This work was supported by grants from the National Institutes of Health and the Doris Duke Charitable Foundation. RESEARCH IN CONTEXT: Few studies have studied tumor-associated macrophages in the context of SCC versus BCC. It has been demonstrated that macrophages mobilize to the epidermis after being exposed to ultraviolet-B radiation and produce interleukin-10 (IL-10). It has also been shown that the production of IL-10 results in the evasion of T cell-mediated immunity in BCCs and SCCs. However, the relationship between TAMs and the clinical behaviors of SCCs and BCCs remains largely unclear. Our study shows that despite their similar origins, human cutaneous SCCs and BCCs are considerably different in their TAMs. To our knowledge, these results provide the first evidence of differential TAM density and polarization in SCCs versus BCCs, which may contribute to their characteristic clinical behaviors. Future studies are necessary to elucidate the mechanisms by which TAMs influence these cancers with the goal of developing therapies tailored to each type of malignancy.
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STUDY DESIGN: A prospective multicenter cohort study. OBJECTIVE: To assess the clinical accuracy of six commonly cited prognostic scoring systems for patients with spinal metastases. SUMMARY OF BACKGROUND DATA: There are presently several available methods for the estimation of prognosis in metastatic spinal disease, but none are universally accepted by surgeons for clinical use. These scoring systems have not been rigorously tested and validated in large datasets to see if they are reliable enough to inform day-to-day patient management decisions. We tested these scoring systems in a large cohort of patients. A total of 1469 patients were recruited into a secure internet database, and prospectively collected data were analyzed to assess the accuracy of published prognostic scoring systems. METHODS: We assessed six prognostic scoring systems, described by the first authors Tomita, Tokuhashi, Bauer, van der Linden, Rades, and Bollen. Kaplan-Meier survival estimates were created for different patient subgroups as described in the original publications. Harrell's C-statistic was calculated for the survival estimates, to assess the concordance between estimated and actual survival. RESULTS: All the prognostic scoring systems tested were able to categorize patients into separate prognostic groups with different overall survivals. However none of the scores were able to achieve "good concordance" as assessed by Harrell's C-statistic. The score of Bollen and colleagues was found to be the most accurate, with a Harrell's C-statistic of 0.66. CONCLUSION: No prognostic scoring system was found to have a good predictive value. The scores of Bollen and Tomita were the most effective with Harrell's C-statistic of 0.66 and 0.65, respectively. Prognostic scoring systems are calculated using data from previous years, and are subject to inaccuracies as treatments advance in the interim. We suggest that other methods of assessing prognosis should be explored, such as prognostic risk calculation. LEVEL OF EVIDENCE: 3.
Assuntos
Neoplasias da Coluna Vertebral/secundário , Idoso , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias da Coluna Vertebral/mortalidade , Taxa de SobrevidaRESUMO
The purpose of this study is to assess the effect of insurance type (Medicaid, Medicare, private insurance) on the ability for patients with operative ankle fractures to access orthopedic traumatologists. The research team called 245 board-certified orthopedic surgeons specializing in orthopedic trauma within 8 representative states. The caller requested an appointment for their fictitious mother in order to be evaluated for an ankle fracture which was previously evaluated by her primary care physician and believed to require surgery. Each office was called 3 times to assess the response for each insurance type. For each call, information was documented regarding whether the patient was able to receive an appointment and the barriers the patient confronted to receive an appointment. Overall, 35.7% of offices scheduled an appointment for a patient with Medicaid, in comparison to 81.4%and 88.6% for Medicare and BlueCross, respectively (P < .0001). Medicaid patients confronted more barriers for receiving appointments. There was no statistically significant difference in access for Medicaid patients in states that had expanded Medicaid eligibility vs states that had not expanded Medicaid. Medicaid reimbursement for open reduction and internal fixation of an ankle fracture did not significantly correlate with appointment success rates or wait times. Despite the passage of the Affordable Care Act, patients with Medicaid have reduced access to orthopedic surgeons and more complex barriers to receiving appointments. A more robust strategy for increasing care-access for patients with Medicaid would be more equitable.
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Fraturas do Tornozelo/cirurgia , Acessibilidade aos Serviços de Saúde/economia , Cobertura do Seguro , Seguro Saúde , Patient Protection and Affordable Care Act/economia , Fraturas do Tornozelo/diagnóstico , Fraturas do Tornozelo/economia , Humanos , Medicaid , Medicare , Estados UnidosRESUMO
BACKGROUND: Indications for surgery for symptomatic spinal metastases have become better defined in recent years, and suitable outcome measures have been established against a changing backdrop of patient characteristics, tumor behavior, and oncologic treatments. Nonetheless, variations still exist in the local management of patients with spinal metastases. In this study, we aimed to review global trends and habits in the surgical treatment of symptomatic spinal metastases, and to examine how these have changed over the last 25 years. METHODS: In this cohort study of consecutive patients undergoing surgery for symptomatic spinal metastases, data were collected using a secure Internet database from 22 centers across 3 continents. All patients were invited to participate in the study, except those unable or unwilling to give consent. RESULTS: There was a higher incidence of colonic, liver, and lung carcinoma metastases in Asian countries, and more frequent presentation of breast, prostate, melanoma metastases in the West. Trends in surgical technique were broadly similar across the centers. Overall survival rates after surgery were 53% at 1 year, 31% at 2 years, and 10% at 5 years after surgery (standard error 0.013 for all). Survival improved over successive time periods, with longer survival in patients who underwent surgery in 2011-2016 compared with those who underwent surgery in earlier time periods. CONCLUSIONS: Surgical habits have been fairly consistent among countries worldwide and over time. However, patient survival has improved in later years, perhaps due to medical advances in the treatment of cancer, improved patient selection, and operating earlier in the course of disease.
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Neoplasias da Coluna Vertebral/epidemiologia , Neoplasias da Coluna Vertebral/cirurgia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/secundário , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
Soft tissue coverage and tension-free closure can often be challenging in patients with ankle arthropathy being considered for total ankle arthroplasty. We present 2 patients with severe posttraumatic ankle arthropathy who underwent placement of a soft tissue expander to assist with soft tissue coverage prior to total ankle arthroplasty. LEVELS OF EVIDENCE: Level IV.
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Artroplastia de Substituição do Tornozelo/efeitos adversos , Osteoartrite/cirurgia , Complicações Pós-Operatórias/cirurgia , Terapia de Tecidos Moles/métodos , Dispositivos para Expansão de Tecidos/estatística & dados numéricos , Adulto , Artroplastia de Substituição do Tornozelo/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico por imagem , Osteoartrite/etiologia , Complicações Pós-Operatórias/diagnóstico , Cuidados Pré-Operatórios/métodos , Amplitude de Movimento Articular/fisiologia , Procedimentos de Cirurgia Plástica/métodos , Recuperação de Função Fisiológica , Reoperação/métodos , Estudos Retrospectivos , Medição de Risco , Estudos de Amostragem , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Perioperative clotting factor replacement is administered to reverse the inherent haemostatic defect in persons with haemophilia (PWH), potentially increasing their risk for developing venous thromboembolism (VTE) postoperatively. It was our objective to determine the prevalence of VTE in PWH undergoing total hip or knee arthroplasty (THA, TKA). Patients with haemophilia A or B who underwent THA or TKA were enrolled in this prospective, multicentre observational cohort study. Lower extremity venous duplex ultrasound was performed prior to surgery and 4-6 weeks after surgery. Eleven centres enrolled 51 subjects, 46 of whom completed the study. Six subjects (13.0 %) were treated with bypass agents perioperatively; the remaining 40 subjects received factor VIII or IX replacement. Intermittent pneumatic compression devices were utilised postoperatively in 23 subjects (50 %), and four subjects (8.7 %) also received low-molecular-weight heparin prophylaxis. One subject (2.2 %) with moderate haemophilia A was diagnosed with symptomatic distal deep-vein thrombosis (DVT) on day 6 following TKA. One subject (2.2 %) with severe haemophilia A was diagnosed with pulmonary embolism on day 9 following bilateral TKA. No subjects had asymptomatic DVT. Eighteen subjects (39.1 %) had major bleeding, and three subjects (6.5 %) experienced minor bleeding. The observed prevalence of ultrasound-detectable, asymptomatic DVT in PWH following TKA or THA in this study was low, but the incidence of symptomatic VTE (4.3 %, 95 % CI, 0.5-14.8 %) appeared similar to the estimated incidence in the general population without thromboprophylaxis.
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Hemofilia A/complicações , Hemofilia A/cirurgia , Hemofilia B/complicações , Hemofilia B/cirurgia , Complicações Pós-Operatórias/etiologia , Trombose Venosa/etiologia , Adulto , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Estudos de Coortes , Hemofilia A/terapia , Hemofilia B/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle , Estudos Prospectivos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/prevenção & controleRESUMO
The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 × 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart. Over 90% of these pairs are replicated (FDR<5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (P<0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.
Assuntos
Neoplasias do Colo/genética , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Locos de Características Quantitativas , Doenças Autoimunes/genética , Estudos de Casos e Controles , Genótipo , Humanos , Linfócitos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways.
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Colo/metabolismo , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Sistema Imunitário/metabolismo , Polimorfismo de Nucleotídeo Único , Sequência de Aminoácidos , Western Blotting , Células CACO-2 , Linhagem Celular Tumoral , Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Predisposição Genética para Doença/classificação , Células HCT116 , Células HEK293 , Células HL-60 , Células HT29 , Células HeLa , Humanos , Sistema Imunitário/patologia , Imuno-Histoquímica , Células Jurkat , Células K562 , Células MCF-7 , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Filogenia , RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Células U937RESUMO
CONTEXT: When laxative regimens have failed, methylnaltrexone may be indicated for the relief of opioid-induced constipation (OIC) in patients with advanced illness receiving palliative care. OBJECTIVES: A cost-benefit analysis (CBA), based on a willingness-to-pay (WTP) approach, was performed to determine if methylnaltrexone should be added to the formulary list of drugs being reimbursed by third-party payers in Canada for the treatment of cancer patients in palliative care suffering from OIC. METHODS: The WTP study had two components: a decision board explaining treatment options (Component A) and a questionnaire to measure individual WTP using a bidding game approach (Component B). Component A had two options: Option 1 (laxatives only) and Option 2 (laxatives+methylnaltrexone injection). Only participants choosing Option 2 were invited to complete Component B. The results of the WTP survey were then incorporated into a CBA. Within a hypothetical cohort, additional monthly premiums that individuals were willing to pay for methylnaltrexone were compared with the monthly costs to the insurer for providing methylnaltrexone to all patients who would potentially be using it. RESULTS: Four hundred one Canadians, of age 18 years and older, were surveyed and yielded a WTP in additional monthly insurance premiums of Canadian dollar (CAD) $8.65 (95% confidence interval: CAD$6.17-CAD$11.13). The CBA resulted in additional CAD$89,307 with a cost of CAD$139,840 and benefits of CAD$229,147. A set of 10,000 Monte Carlo simulations resulted in average CBA savings of CAD$145,011 with a 99.86% probability of dominance. CONCLUSION: The present CBA provides pharmacoeconomic evidence for the adoption of methylnaltrexone for treating OIC in terminally ill cancer patients.
Assuntos
Analgésicos Opioides/economia , Constipação Intestinal/economia , Comportamento do Consumidor/economia , Naltrexona/análogos & derivados , Neoplasias/economia , Dor/economia , Cuidados Paliativos/economia , Adolescente , Adulto , Distribuição por Idade , Analgésicos Opioides/uso terapêutico , Constipação Intestinal/epidemiologia , Constipação Intestinal/prevenção & controle , Comportamento do Consumidor/estatística & dados numéricos , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/economia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Ontário/epidemiologia , Dor/tratamento farmacológico , Cuidados Paliativos/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Compostos de Amônio Quaternário/economia , Compostos de Amônio Quaternário/uso terapêutico , Distribuição por Sexo , Fatores Socioeconômicos , Resultado do Tratamento , Adulto JovemRESUMO
MOTIVATION: Mass spectrometry (MS), such as the surface-enhanced laser desorption and ionization time-of-flight (SELDI-TOF) MS, provides a potentially promising proteomic technology for biomarker discovery. An important matter for such a technology to be used routinely is its reproducibility. It is of significant interest to develop quantitative measures to evaluate the quality and reliability of different experimental methods. RESULTS: We compare the quality of SELDI-TOF MS data using unfractionated, fractionated plasma samples and abundant protein depletion methods in terms of the numbers of detected peaks and reliability. Several statistical quality-control and quality-assessment techniques are proposed, including the Graeco-Latin square design for the sample allocation on a Protein chip, the use of the pairwise Pearson correlation coefficient as the similarity measure between the spectra in conjunction with multi-dimensional scaling (MDS) for graphically evaluating similarity of replicates and assessing outlier samples; and the use of the reliability ratio for evaluating reproducibility. Our results show that the number of peaks detected is similar among the three sample preparation technologies, and the use of the Sigma multi-removal kit does not improve peak detection. Fractionation of plasma samples introduces more experimental variability. The peaks detected using the unfractionated plasma samples have the highest reproducibility as determined by the reliability ratio. AVAILABILITY: Our algorithm for assessment of SELDI-TOF experiment quality is available at http://www.biostat.harvard.edu/~xlin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.