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1.
Artigo em Inglês | MEDLINE | ID: mdl-33203692

RESUMO

BACKGROUND: Cetuximab, an epidermal growth factor receptor inhibitor used to treat multiple cancer types including colon cancer, causes severe skin toxicity in 5-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. METHODS: Our study included 1,209 stage III colon cancer patients randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating ~10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade >3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as p<5x10-8. RESULTS: Participants were predominantly middle-aged white men; 20% (n=243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity (OR = 3.93, 95% CI 2.47-6.25; p<7.8x10-9). Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. CONCLUSIONS: Identified variants could represent a potential target for risk stratification of colon cancer patients receiving cetuximab. IMPACT: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

2.
J Vet Intern Med ; 34(6): 2622-2635, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33058280

RESUMO

BACKGROUND: English bulldogs disproportionally develop an expansion of small B-cells, which has been interpreted as B-cell chronic lymphocytic leukemia (BCLL). However, clonality testing in these cases has often not been supportive of neoplasia. HYPOTHESIS: English bulldogs have a syndrome of nonneoplastic B-cell expansion. ANIMALS: Eighty-four English bulldogs with small-sized CD21+ B-cell lymphocytosis in the blood as determined by flow cytometry. METHODS: This is a retrospective study. We characterized this syndrome by assessing B-cell clonality, clinical presentation, flow cytometric features, and immunoglobulin gammopathy patterns. We identified 84 cases with CD21+ lymphocytosis among 195 English bulldogs with blood samples submitted to the Colorado State University-Clinical Immunology laboratory for immunophenotyping between 2010 and 2019. Flow cytometry features were compared to normal B-cells and BCLL cases. PCR for antigen receptor rearrangements (PARR) by multiple immunoglobulin primers was performed to assess B-cell clonality. A subset of cases with gammopathy were examined by protein electrophoresis, immunofixation, and immunoglobulin subclass ELISA quantification. RESULTS: Seventy percent (58/83) of cases had polyclonal or restricted polyclonal immunoglobulin gene rearrangements, suggesting nonmalignant B-cell expansion. The median age of all dogs in the study was 6.8 years and 74% were male. The median (range) lymphocyte count was 22 400/µL (2000-384 400/µL) and B-cells had low expression of class II MHC and CD25. Splenomegaly or splenic masses were detected in 57% (26/46) of cases and lymphadenopathy in 11% (7/61). Seventy-one percent (52/73) of cases had hyperglobulinemia and 77% (23/30) with globulin characterization had IgA ± IgM polyclonal or restricted polyclonal gammopathy patterns. CONCLUSIONS AND CLINICAL IMPORTANCE: Polyclonal B-cell lymphocytosis in English bulldogs is characterized by low B-cell class II MHC and CD25 expression, splenomegaly and hyperglobulinemia consisting of increased IgA ± IgM. We hypothesize that this syndrome has a genetic basis.

3.
JNCI Cancer Spectr ; 4(5): pkaa042, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32923935

RESUMO

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het =.01) tumors. Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

4.
BMC Genomics ; 21(1): 464, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631225

RESUMO

BACKGROUND: T zone lymphoma (TZL), a histologic variant of peripheral T cell lymphoma, represents about 12% of all canine lymphomas. Golden Retrievers appear predisposed, representing over 40% of TZL cases. Prior research found that asymptomatic aged Golden Retrievers frequently have populations of T zone-like cells (phenotypically identical to TZL) of undetermined significance (TZUS), potentially representing a pre-clinical state. These findings suggest a genetic risk factor for this disease and caused us to investigate potential genes of interest using a genome-wide association study of privately-owned U.S. Golden Retrievers. RESULTS: Dogs were categorized as TZL (n = 95), TZUS (n = 142), or control (n = 101) using flow cytometry and genotyped using the Illumina CanineHD BeadChip. Using a mixed linear model adjusting for population stratification, we found association with genome-wide significance in regions on chromosomes 8 and 14. The chromosome 14 peak included four SNPs (Odds Ratio = 1.18-1.19, p = .3 × 10- 5-5.1 × 10- 5) near three hyaluronidase genes (SPAM1, HYAL4, and HYALP1). Targeted resequencing of this region using a custom sequence capture array identified missense mutations in all three genes; the variant in SPAM1 was predicted to be damaging. These mutations were also associated with risk for mast cell tumors among Golden Retrievers in an unrelated study. The chromosome 8 peak contained 7 SNPs (Odds Ratio = 1.24-1.42, p = 2.7 × 10- 7-7.5 × 10- 5) near genes involved in thyroid hormone regulation (DIO2 and TSHR). A prior study from our laboratory found hypothyroidism is inversely associated with TZL risk. No coding mutations were found with targeted resequencing but identified variants may play a regulatory role for all or some of the genes. CONCLUSIONS: The pathogenesis of canine TZL may be related to hyaluronan breakdown and subsequent production of pro-inflammatory and pro-oncogenic byproducts. The association on chromosome 8 may indicate thyroid hormone is involved in TZL development, consistent with findings from a previous study evaluating epidemiologic risk factors for TZL. Future work is needed to elucidate these mechanisms.

5.
Vet Comp Oncol ; 18(3): 416-427, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31951040

RESUMO

Canine T-cell lymphoma (TCL) encompasses a heterogeneous group of diseases with variable clinical presentation, cytomorphology, immunophenotype, and biologic behaviour. The most common types of TCL in dogs involving peripheral lymph nodes include indolent T-zone lymphoma (TZL) and biologically aggressive peripheral T-cell lymphoma (PTCL). TCL phenotypes can be categorized by expression of the surface antigen molecules CD4 and CD8. The majority of TCL cases are CD4+ , with far fewer cases being CD8+ or CD4- CD8- . The clinical features of CD4+ TCLs have been previously described. The less common TCL phenotypes, however, are poorly characterized with little to no information about prognosis. In this retrospective study, we describe and correlate the presenting clinical signs, flow cytometry, and outcomes of 119 dogs diagnosed with nodal, non-TZL, CD8+ or CD4- CD8- TCL by flow cytometry. Skin lesions present at the time of diagnosis were more commonly observed in the CD8+ TCL group. Mediastinal enlargement and/or hypercalcemia were more commonly seen in the CD4- CD8- TCL group. Dogs with either CD8+ or CD4- CD8- TCLs had aggressive clinical disease with median overall survival (OS) times of 198 days and 145 days, respectively. In both groups, neoplastic cell size determined by flow cytometry ranged from small to large, and large cell size was associated with shorter OS times (median OS = 61 days). Cases classified as small cell had a median OS of 257 days. Expression levels of major histocompatibility complex (MHC) class II and CD5 were highly variable among cases but were not prognostically significant in this group of patients.

6.
J Vet Intern Med ; 34(1): 105-116, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31693230

RESUMO

BACKGROUND: Lymphocytosis is relatively common in cats, but few studies describe lymphocyte populations or the clinical course associated with different immunophenotypic expansions. HYPOTHESIS/OBJECTIVES: We hypothesized that cats frequently develop non-neoplastic lymphocytosis and that different neoplastic immunophenotypes have variable prognoses. We aimed to characterize the lymphocyte expansions in a large population of cats with lymphocytosis and to assess clinical presentation and outcome in a subset. ANIMALS: Three cohorts of cats older than 1 year with lymphocytosis (>6000/µL) were examined to define immunophenotypic categories (n = 146), evaluate outcome (n = 94), and determine prevalence of immunophenotypes (n = 350). METHODS: Retrospective study of cats with blood submitted for flow cytometry. Medical records (n = 94) were reviewed for clinical data, treatment, and survival information. RESULTS: Five major immunophenotypic categories were identified: B cell, heterogeneous (≥2 lineages expanded), CD4+ T cell, CD4-CD8- (double negative [DN]) T cell, and CD5-low-expressing T cell. B-cell and heterogeneous phenotypes were more consistent with a non-neoplastic process, having polyclonal antigen receptor gene rearrangements, younger age at presentation, lower lymphocyte counts, and prolonged survival. The neoplastic phenotypes, CD4+ T cell, DN T cell, and CD5 low T cell, had different median survival times (752 days [n = 37], 271 days [n = 7], 27.5 days [n = 12], respectively). Among CD4+ T-cell cases, cats with abdominal lymphadenopathy, intestinal involvement, or both and females had shorter survival. Among 350 cats with lymphocytosis, CD4+ T-cell lymphocytosis was most common, followed by heterogeneous and B-cell phenotypes. CONCLUSIONS AND CLINICAL IMPORTANCE: Neoplastic CD4+ T-cell lymphocytosis is common in cats and has a prolonged clinical course compared to aberrant T-cell phenotypes. Cats with heterogeneous and B-cell lymphocyte expansions commonly have non-neoplastic disease.


Assuntos
Subpopulações de Linfócitos B , Doenças do Gato/imunologia , Linfocitose/veterinária , Subpopulações de Linfócitos T , Animais , Doenças do Gato/patologia , Gatos , Feminino , Citometria de Fluxo , Linfocitose/imunologia , Linfocitose/patologia , Masculino , Estudos Retrospectivos
7.
Vet Pathol ; 56(5): 725-731, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31113293

RESUMO

Digital microscopy (DM) has been employed for primary diagnosis in human medicine and for research and teaching applications in veterinary medicine, but there are few veterinary DM validation studies. Region of interest (ROI) digital cytology is a subset of DM that uses image-stitching software to create a low-magnification image of a slide, then selected ROI at higher magnification, and stitches the images into a relatively small file of the embedded magnifications. This study evaluated the concordance of ROI-DM compared to traditional light microscopy (LM) between 2 blinded clinical pathologists. Sixty canine and feline cytology samples from a variety of anatomic sites, including 31 cases of malignant neoplasia, 15 cases of hyperplastic or benign neoplastic lesions, and 14 infectious/inflammatory lesions, were evaluated. Two separate nonblinded adjudicating clinical pathologists evaluated the reports and diagnoses and scored each paired case as fully concordant, partially concordant, or discordant. The average overall concordance (full and partial concordance) for both pathologists was 92%. Full concordance was significantly higher for malignant lesions than benign. For the 40 neoplastic lesions, ROI-DM and LM agreed on general category of tumor type in 78 of 80 cases (98%). ROI-DM cytology showed robust concordance with the current gold standard of LM cytology and is potentially a viable alternative to current LM cytology techniques.


Assuntos
Doenças do Gato/patologia , Técnicas Citológicas/métodos , Doenças do Cão/patologia , Processamento de Imagem Assistida por Computador , Microscopia/métodos , Animais , Doenças do Gato/diagnóstico por imagem , Gatos , Doenças Transmissíveis/diagnóstico por imagem , Doenças Transmissíveis/patologia , Doenças Transmissíveis/veterinária , Doenças do Cão/diagnóstico por imagem , Cães , Inflamação/diagnóstico por imagem , Inflamação/patologia , Inflamação/veterinária , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Neoplasias/veterinária , Software
8.
J Vet Intern Med ; 33(2): 764-775, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30666722

RESUMO

BACKGROUND: T-zone lymphoma (TZL), an indolent disease in older dogs, comprises approximately 12% of lymphomas in dogs. TZL cells exhibit an activated phenotype, indicating the disease may be antigen-driven. Prior research found that asymptomatic aged Golden Retrievers (GLDRs) commonly have populations of T-zone-like cells (phenotypically identical to TZL) of undetermined significance (TZUS). OBJECTIVE: To evaluate associations of inflammatory conditions, TZL and TZUS, using a case-control study of GLDRs. ANIMALS: TZL cases (n = 140), flow cytometrically diagnosed, were identified through Colorado State University's Clinical Immunology Laboratory. Non-TZL dogs, recruited through either a database of owners interested in research participation or the submitting clinics of TZL cases, were subsequently flow cytometrically classified as TZUS (n = 221) or control (n = 147). METHODS: Health history, signalment, environmental, and lifestyle factors were obtained from owner-completed questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using multivariable logistic regression, obtaining separate estimates for TZL and TZUS (versus controls). RESULTS: Hypothyroidism (OR, 0.3; 95% CI, 0.1-0.7), omega-3 supplementation (OR, 0.3; 95% CI, 0.1-0.6), and mange (OR, 5.5; 95% CI, 1.4-21.1) were significantly associated with TZL. Gastrointestinal disease (OR, 2.4; 95% CI, 0.98-5.8) had nonsignificantly increased TZL odds. Two shared associations for TZL and TZUS were identified: bladder infection or calculi (TZL OR, 3.5; 95% CI, 0.96-12.7; TZUS OR, 5.1; 95% CI, 1.9-13.7) and eye disease (TZL OR, 2.3; 95% CI, 0.97-5.2; TZUS OR, 1.9; 95% CI, 0.99-3.8). CONCLUSIONS AND CLINICAL IMPORTANCE: These findings may elucidate pathways involved in TZUS risk and progression from TZUS to TZL. Further investigation into the protective association of omega-3 supplements is warranted.


Assuntos
Doenças do Cão/imunologia , Linfoma de Células T/veterinária , Fatores Etários , Animais , Estudos de Casos e Controles , Suplementos Nutricionais , Doenças do Cão/epidemiologia , Cães , Ácidos Graxos Ômega-3 , Feminino , Citometria de Fluxo/veterinária , Hipotireoidismo/veterinária , Linfoma de Células T/epidemiologia , Linfoma de Células T/imunologia , Masculino , Infestações por Ácaros/veterinária , Linfócitos T , Cálculos da Bexiga Urinária/veterinária , Infecções Urinárias/veterinária
9.
Vet Comp Oncol ; 17(3): 253-264, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30684308

RESUMO

T-cell lymphomas (TCL) are a diverse group of neoplasms with variable diagnostic features, pathophysiologies, therapeutic responses and clinical outcomes. In dogs, TCL includes indolent and aggressive tumours such as T-zone lymphoma (TZL) and peripheral T-cell lymphoma (PTCL), respectively. Delineation of molecular subtypes and investigation into underlying pathophysiologies of aggressive TCLs remains inadequate. We investigate the correlations between flow cytometry and histopathology of 73 cases of nodal TCL. The majority of cases (82.2%) were characterized as CD4+ TCL by flow cytometry. Fewer cases were classified as CD8+ TCL (6.8%) or CD4- CD8- TCL (11.0%). All cases, regardless of immunophenotype, exhibited conserved histologic features consistent with the WHO classification of PTCL. Histologic subsets of PTCL corresponding to immunophenotypic features were not identified. Neoplastic cell size determined by flow cytometry correlated significantly with mitotic rate. RNA-seq was performed on a subset of CD4+ PTCL cases (n = 6) and compared with sorted control CD4+ T-cells. The gene expression pattern of CD4+ PTCL was similar between all cases regardless of breed. PTCL was enriched in pathways representing G-coupled protein receptor signalling, extracellular matrix remodelling and vascular development, immune signalling and mitotic activity. Furthermore, global gene expression changes were consistent with downregulation of PTEN signalling and upregulation of the MTOR-PI3K-ATK axis. In this study, we evaluated the correlations between flow cytometry, histopathology and gene expression within a large cohort of nodal TCLs. We further demonstrate the ability of flow cytometry to identify a subtype of T-cell lymphoma, CD4+ PTCL, with a uniform histomorphology and gene expression profile.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Doenças do Cão/patologia , Citometria de Fluxo/veterinária , Linfoma de Células T/veterinária , Animais , Cães , Feminino , Regulação Neoplásica da Expressão Gênica , Imuno-Histoquímica , Linfoma de Células T/classificação , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo
10.
PLoS One ; 13(1): e0191205, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29385200

RESUMO

Human chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease, and immunoglobulin heavy variable region (IGHV) gene mutational status is an important prognostic marker. IGHV mutational status has not been previously examined in canine CLL. We sequenced the IGHV-D-J rearrangements from 55 canine patients with CLL, including 36 non-Boxer and 19 Boxer dogs. The majority of non-Boxers (75%) had mutated IGHV genes, whereas the majority of Boxers (79%) had unmutated IGHV genes. IGHV3-41 and IGHV3-67 gene usage was significantly higher in Boxers with CLL compared to non-Boxers. Additionally, 11 Boxers with large B-cell lymphoma and the normal IGHV repertoire of six control dogs (three Boxers and three non-Boxers) were sequenced. IGHV3-41 was preferentially used in Boxers with other forms of lymphoma and without lymphoproliferative disease. However, preferential use of unmutated IGHV genes was unique to Boxers with CLL, suggesting Boxers may be a valuable model to investigate unmutated CLL.


Assuntos
Doenças do Cão/genética , Doenças do Cão/imunologia , Genes de Cadeia Pesada de Imunoglobulina , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/veterinária , Animais , Sequência de Bases , Estudos de Casos e Controles , Análise Mutacional de DNA , DNA de Neoplasias/genética , Cães , Feminino , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Mutação , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Éxons VDJ
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