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1.
Br J Dermatol ; 189(5): 588-602, 2023 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-37470440

RESUMO

BACKGROUND: Cutaneous squamous cell carcinomas (cSCCs) are the second most diagnosed skin cancer worldwide; however, little is known about the pathobiological factors that contribute to the diverse clinical outcomes seen. OBJECTIVES: To profile cSCCs comprehensively and identify the pathological processes that contribute to the disparities seen in their clinical behaviour. METHODS: We characterized the genomic, transcriptomic and immunohistochemical profiles of 211 cSCC tumours, including 37 cSCCs from immunocompromised patients. RESULTS: cSCCs from immunocompromised patients were characterized by a lack of B cells in the peritumoral stroma compared with immunocompetent patients. Further, an abundance of a memory B-cell-like population in the peritumoral stroma was associated with a better prognosis in all patients (immunocompetent and immunocompromised), as well as only immunocompetent patients. No differences in genetic -variants, tumour mutational burden or mutational signatures were observed between cSCCs from immunocompetent and immunocompromised patients. Thus, differences in survival between cSCCs from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but may be associated with differential host immune response. cSCC not from a primary head and neck site had lower tumour mutational burden and exhibited upregulation of the epithelial-mesenchymal transition programme compared with head and neck cSCC. Both factors were implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. CONCLUSIONS: We identified tumour and host immune factors that contribute to the disparate clinical behaviour of cSCC, with broad translational application, including prognostication, treatment prediction to current therapies and the identification of novel anticancer therapy approaches in cSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/patologia , Prognóstico , Pescoço/patologia
2.
Nucleic Acids Res ; 46(D1): D465-D470, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29140456

RESUMO

Minimotif Miner (MnM) is a database and web system for analyzing short functional peptide motifs, termed minimotifs. We present an update to MnM growing the database from ∼300 000 to >1 000 000 minimotif consensus sequences and instances. This growth comes largely from updating data from existing databases and annotation of articles with high-throughput approaches analyzing different types of post-translational modifications. Another update is mapping human proteins and their minimotifs to know human variants from the dbSNP, build 150. Now MnM 4 can be used to generate mechanistic hypotheses about how human genetic variation affect minimotifs and outcomes. One example of the utility of the combined minimotif/SNP tool identifies a loss of function missense SNP in a ubiquitylation minimotif encoded in the excision repair cross-complementing 2 (ERCC2) nucleotide excision repair gene. This SNP reaches genome wide significance for many types of cancer and the variant identified with MnM 4 reveals a more detailed mechanistic hypothesis concerning the role of ERCC2 in cancer. Other updates to the web system include a new architecture with migration of the web system and database to Docker containers for better performance and management. Weblinks:minimotifminer.org and mnm.engr.uconn.edu.


Assuntos
Bases de Dados de Proteínas , Peptídeos/química , Processamento de Proteína Pós-Traducional , Receptores Acoplados a Proteínas G/química , Software , Proteína Grupo D do Xeroderma Pigmentoso/química , Sequência de Aminoácidos , Sítios de Ligação , Sequência Consenso , Ontologia Genética , Genoma Humano , Humanos , Internet , Modelos Moleculares , Anotação de Sequência Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/genética , Peptídeos/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Alinhamento de Sequência , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
3.
Semin Cancer Biol ; 52(Pt 2): 228-240, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29355614

RESUMO

Head and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous group of tumors that arise from the squamous epithelium of the oral cavity, oropharynx, larynx and hypopharynx. While many HNSCCs are related to classical etiologic factors of smoking and alcohol, a clinically, genomically, and immunologically distinct subgroup of tumors arise from the epithelium of the tonsil and the base of tongue as a result of infection with Human Papilloma Virus (HPV). In this review we describe the genomic and immunologic landscape of HNSCC, highlighting differences between HPV-positive and HPV-negative HNSCC. While HPV-negative tumors are characterized by tobacco-associated mutations in genes including TP53 and CDKN2A, in HPV-positive HNSCC integration of viral genome from HPV into the host cellular genome results in expression of the E6 and E7 viral oncoproteins, with consequent degradation of p53 and functional inactivation of Rb. The immune microenvironment of HNSCC is characterized by changes in immune cell populations, immune checkpoints, as well as tumor or microenvironmental factors that alter the balance of the immune milieu in favor of immunosuppression, allowing tumor evasion and escape from immune surveillance. Immune therapies, in particular those targeting the PD1 receptor or its ligand PD-L1, including nivolumab, pembrolizumab, durvalumab, and atezolizumab have shown significant efficacy in subsets of patients with HNSCC. Current trials are evaluating the efficacy of these agents in combination with chemotherapy, radiotherapy and other immune therapies including CTLA-4 and IDO-1 inhibitors. While biomarkers including PD-L1 expression, PD-L2 expression and the interferon-gamma gene signature show potential to predict benefit from checkpoint inhibitor therapy - it is hoped that improved understanding of the genomic and immune landscape will lead to ways to improved strategies to stratify patients and to select which HNSCC are most likely to benefit from these therapies.


Assuntos
Biomarcadores Tumorais/genética , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Biomarcadores Tumorais/imunologia , Genômica/métodos , Humanos , Imunoterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia
4.
Int J Cancer ; 142(10): 2139-2152, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29243224

RESUMO

Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridinas/farmacologia , Animais , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Melanoma/enzimologia , Camundongos , Camundongos SCID , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Oral Pathol Med ; 47(1): 18-24, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29024035

RESUMO

BACKGROUND: The aim of this study was to identify the presence and frequency of human papillomavirus (HPV) nucleic acid in p16-positive oral squamous cell carcinomas (OSCCs), to assess whether the virus was transcriptionally active and to assess the utility of p16 overexpression as a surrogate marker for HPV in OSCC. METHODS: Forty-six OSCC patients treated between 2007 and 2011 with available formalin-fixed paraffin-embedded (FFPE) specimens were included. Twenty-three patients were positive for p16 by immunohistochemistry (IHC) and these were matched with 23 patients with p16-negative tumours. Laser capture microdissection of the FFPE OSCC tissues was undertaken to isolate invasive tumour tissue. DNA was extracted and tested for high-risk HPV types using a PCR-ELISA method based on the L1 SPF10 consensus primers, and a real-time PCR method targeting HPV-16 and HPV-18 E6 region. Genotyping of HPV-positive cases was performed using a reverse line blot hybridization assay (Inno-LiPA). RNAScope® (a chromogenic RNA in situ hybridization assay) was utilized to detect E6/E7 mRNA of known high-risk HPV types for detection of transcriptionally active virus. RESULTS: HPV DNA was found in 3 OSCC cases, all of which were p16 IHC-positive. Two cases were genotyped as HPV-16 and one as HPV-33. Only one of the HPV-16 cases was confirmed to harbour transcriptionally active virus via HPV RNA ISH. CONCLUSION: We have shown that the presence of transcriptionally active HPV rarely occurs in OSCC and that p16 is not an appropriate surrogate marker for HPV in OSCC cases. We propose that non-viral mechanisms are responsible for the majority of IHC p16 overexpression in OSCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Idoso , Carcinoma de Células Escamosas/química , DNA Viral/análise , DNA Viral/isolamento & purificação , Feminino , Genótipo , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Imuno-Histoquímica , Hibridização In Situ , Microdissecção e Captura a Laser , Masculino , Neoplasias Bucais , Sondas de Ácido Nucleico , Papillomaviridae/classificação , Papillomaviridae/genética , RNA Mensageiro/análise , RNA Viral/análise , Fatores de Risco , Transcrição Gênica
6.
Nucleic Acids Res ; 43(13): 6399-412, 2015 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-26068475

RESUMO

Since the function of a short contiguous peptide minimotif can be introduced or eliminated by a single point mutation, these functional elements may be a source of human variation and a target of selection. We analyzed the variability of ∼300 000 minimotifs in 1092 human genomes from the 1000 Genomes Project. Most minimotifs have been purified by selection, with a 94% invariance, which supports important functional roles for minimotifs. Minimotifs are generally under negative selection, possessing high genomic evolutionary rate profiling (GERP) and sitewise likelihood-ratio (SLR) scores. Some are subject to neutral drift or positive selection, similar to coding regions. Most SNPs in minimotif were common variants, but with minor allele frequencies generally <10%. This was supported by low substation rates and few newly derived minimotifs. Several minimotif alleles showed different intercontinental and regional geographic distributions, strongly suggesting a role for minimotifs in adaptive evolution. We also note that 4% of PTM minimotif sites in histone tails were common variants, which has the potential to differentially affect DNA packaging among individuals. In conclusion, minimotifs are a source of functional genetic variation in the human population; thus, they are likely to be an important target of selection and evolution.


Assuntos
Motivos de Aminoácidos/genética , Evolução Molecular , Animais , Genoma Humano , Histonas/química , Humanos , Polimorfismo Genético
7.
Cancer ; 122(8): 1201-8, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26881928

RESUMO

BACKGROUND: The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. METHODS: One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. RESULTS: The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. CONCLUSIONS: p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.


Assuntos
Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/virologia , Proteínas de Neoplasias/genética , Neoplasias Primárias Desconhecidas/patologia , Infecções por Papillomavirus/patologia , Neoplasias Cutâneas/virologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Estudos de Coortes , Inibidor p16 de Quinase Dependente de Ciclina , Bases de Dados Factuais , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/secundário , Papillomavirus Humano 16/genética , Humanos , Estimativa de Kaplan-Meier , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/mortalidade , Infecções por Papillomavirus/virologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário , Estatísticas não Paramétricas , Análise de Sobrevida , Fatores de Tempo
8.
Eur J Nucl Med Mol Imaging ; 43(4): 617-25, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26577940

RESUMO

PURPOSE: While methods for imaging tumor hypoxia with positron emission tomography (PET) have been developed, optimal methods for interpreting and utilizing these datasets in the clinic remain unclear. In this study, we analyzed hypoxia PET images of head and neck cancer patients and compared imaging metrics with human papilloma virus (HPV) status and clinical outcome. METHODS: Forty-one patients treated as part of a phase III trial of the hypoxic cytotoxin tirapazamine (TROG 02.02) were imaged with PET using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA). FDG and FAZA PET images were interpreted qualitatively and quantitatively, and compared with tumor T stage, HPV status, and treatment outcome using multivariate statistics. RESULTS: PET signals in the tumor and lymph nodes exhibited significant intra- and inter-patient variability. The FAZA hypoxic volume demonstrated a significant correlation with tumor T stage. PET-hypoxic tumors treated with cisplatin exhibited significantly worse treatment outcomes relative to PET-oxic tumors or PET-hypoxic tumors treated with tirapazamine. CONCLUSION: Quantitative analysis of FAZA PET yielded metrics that correlated with clinical T stage and were capable of stratifying patient outcome. These results encourage further development of this technology, with particular emphasis on establishment of robust quantitative methods.


Assuntos
Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Nitroimidazóis , Infecções por Papillomavirus/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto , Idoso , Interpretação Estatística de Dados , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico
9.
Eur J Nucl Med Mol Imaging ; 42(12): 1825-32, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26173619

RESUMO

PURPOSE: To report 5-year outcomes of a prospective registry study investigating posttherapy FDG PET/CT in women with locally advanced cervical cancer. A secondary analysis assessing the prognostic significance of HPV infection was performed. METHODS: Patients underwent definitive chemoradiation followed by a single FDG PET/CT scan for response assessment. A complete metabolic response (CMR) was defined as no evidence of FDG-avid disease. Patients were dichotomized according to HPV infection status into a 'higher-risk' group and a 'lower-risk' group, with the higher-risk group comprising those with alpha-7 strain HPV (subtypes 18, 39 and 45) and those who were HPV-negative and the lower-risk group comprising those with alpha-9 strain HPV (subtypes 16, 31, 33, 52 and 58) and those with mixed strains. Survival outcomes, patterns of failure and salvage therapy outcomes were investigated for their association with metabolic response and HPV status. RESULTS: In 105 patients the median prospective follow-up was 5.2 years. The 5-year cancer-specific, overall and progression-free survival rates in patients with a CMR were 97 %, 93 % and 86 %, respectively. In patients without a CMR, the corresponding 5-year survival rates were 36 %, 22 % and 0 % respectively (p < 0.01). PET response was associated with patterns of failure (p < 0.01), with the 5-year freedom from local, nodal and distant failure in patients with a CMR being 94 %, 90 % and 94 %, respectively. Of 16 patients who underwent salvage therapy, 12 had disease detected on the surveillance PET scan, and 8 achieved a post-salvage CMR of whom all were alive at a median of 4.9 years. DNA adequate for HPV analysis was extracted in 68 patients. The likelihood of a PET metabolic response was not influenced by HPV infection status, with 71 % and 75 % of higher-risk and lower-risk patients, respectively, achieving CMR (p = 0.83). Higher-risk patients had a poorer OS (HR 2.6, range 1.0 - 6.6, p = 0.05) in univariable analysis but not multivariable analysis (p = 0.11). CONCLUSION: At 5 years CMR remains a powerful factor predicting survival after initial and salvage therapy. Metabolic response was not associated with HPV infection risk. Further studies are required to establish the association with HPV infection risk and survival after chemoradiation.


Assuntos
Quimiorradioterapia , Fluordesoxiglucose F18 , Papillomaviridae/fisiologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapia , Intervalo Livre de Doença , Feminino , Humanos , Imagem Multimodal , Estudos Prospectivos , Terapia de Salvação , Resultado do Tratamento , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
10.
Int J Cancer ; 135(4): 887-95, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24436120

RESUMO

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes p16 , Neoplasias da Língua/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Metilação de DNA , DNA de Neoplasias/genética , Feminino , Homozigoto , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Resultado do Tratamento , Adulto Jovem
11.
Mod Pathol ; 27(12): 1621-31, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24762544

RESUMO

The aim of this study was to investigate the prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification by fluorescence in situ hybridization (FISH) in a lung cancer patient cohort and to correlate results with morphology, silver in situ hybridization (SISH), and patient outcome. FGFR1 FISH and SISH were performed in 406 and 385 lung cancer cases, respectively, and the results were compared. High-level FGFR1 amplification was defined as the ratio of FGFR1/centromere 8 ≥2, or tumor cell percentage with ≥15 signals ≥10%, or average number of signals/tumor cell nucleus ≥6. Low-level amplification was defined as tumor cell percentage with ≥5 signals ≥50%. Of 406 tumors tested, there were 191 squamous cell carcinomas, 28 carcinomas with focal squamous morphology, 24 large cell carcinomas with squamous immunoprofile, 115 adenocarcinomas, 17 neuroendocrine tumors, and 31 carcinomas without squamous morphology or immunoprofile. FGFR1 FISH was assessable in 368 tumors, with FGFR1 amplification identified in 50, including 48 tumors with either squamous morphology or immunoprofile (48 of 225, 21.3%), and two 'marker-null' tumors without squamous or glandular morphology or immunoprofile (2 of 143, 1.4%; P<0.0001). FGFR1 SISH was assessable in 347 tumors. All 46 FGFR1 FISH-amplified tumors with tumor available for testing showed amplification with SISH, while all other tumors were negative. There was no relationship between FGFR1 amplification status and disease-free (P=0.88, HR=1.04, 95% confidence interval (CI)=0.67-1.60) or overall survival (P=0.97, HR=1.01, 95% CI=0.65-1.58) in surgically radically treated patients with tumors with any squamous morphology or immunoprofile. FGFR1 amplification is a common abnormality in tumors with any squamous morphology or immunoprofile, but it is also present in 'marker-null' tumors. The results of FGFR1 SISH showed 1:1 correlation with the results of FGFR1 FISH, indicating that SISH may be an alternative method to detect FGFR1 amplification. No relationship was detected between patient outcome and FGFR1 amplification.


Assuntos
Carcinoma de Células Escamosas/genética , Hibridização In Situ/métodos , Neoplasias Pulmonares/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise Serial de Tecidos , Adulto Jovem
12.
Brain Sci ; 14(7)2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-39061434

RESUMO

Transcranial direct current stimulation (tDCS) increases primary motor cortex (M1) excitability and improves motor performance when applied unilaterally to the dominant hemisphere. However, the influence of tDCS on contralateral M1 excitability both during and after application has not been quantified. The purpose was to determine the influence of tDCS applied to the dominant M1 on the excitability of the contralateral non-dominant M1. This study employed a double-blind, randomized, SHAM-controlled, within-subject crossover experimental design. Eighteen young adults performed two experimental sessions (tDCS, SHAM) in counterbalanced order separated by a one-week washout. Transcranial magnetic stimulation (TMS) was used to quantify the excitability of the contralateral M1 to which anodal tDCS was applied for 20 min with a current strength of 1 mA. Motor evoked potential (MEP) amplitudes were assessed in 5 TMS test blocks (Pre, D5, D10, D15, and Post). The Pre and Post TMS test blocks were performed immediately before and after tDCS application, whereas the TMS test blocks performed during tDCS were completed at the 5, 10, and 15 min stimulation timepoints. MEPs were analyzed with a 2 condition (tDCS, SHAM) × 5 test (Pre, D5, D10, D15, Post) within-subject ANOVA. The main effect for condition (p = 0.213), the main effect for test (p = 0.502), and the condition × test interaction (p = 0.860) were all not statistically significant. These results indicate that tDCS does not modulate contralateral M1 excitability during or immediately after application, at least under the current set of common tDCS parameters of stimulation.

13.
Cancers (Basel) ; 16(8)2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38672534

RESUMO

Non-melanomatous cutaneous spindle cell neoplasms are a rare group of malignancies that present a diagnostic challenge, and for which there is a lack of consensus on how to best manage patients with advanced disease and only limited reports of immune-checkpoint inhibitor (ICI) responses. In this study, we performed a single-center retrospective review of treatment outcomes for all advanced non-melanomatous cutaneous spindle cell neoplasms treated with ICIs. Blinded histopathology reviews occurred to confirm each diagnosis. Comprehensive tumour profiling included whole exome sequencing for tumour mutational burden (TMB) and ultraviolet(UV) signatures, and immunohistochemistry for immune-cell infiltration (CD4/CD3/CD8/CD103/CD20) and immune-checkpoint expression (PD-L1/LAG3/TIGIT). Seven patients were identified. The objective response rate was 86% (6/7) with five complete responses (CR). Responses were durable with two patients in CR > 30 months after ICI commencement. All patients had high TMB and UV signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression. In advanced non-melanomatous cutaneous spindle cell neoplasms, excellent responses to ICIs with durable disease control were observed. ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment.

14.
Oral Oncol ; 150: 106687, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38262249

RESUMO

OBJECTIVES: The incidence of human papillomavirus positive oropharyngeal cancer (HPV+OPC) is increasing, and new biomarkers are required to better define prognostic groups and guide treatment. Infiltrating T cells have been well studied in head and neck cancer, however the presence and role of B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment has not, even though the interplay between T and B cells is increasingly being recognised. MATERIALS AND METHODS: Using CD20 immunohistochemistry (IHC) to identify B cells and TLS in a cohort of 159 HPV + OPC patients, we semi-quantitatively scored abundance and location (intra-tumoral or stromal) and correlated findings with patient survival. RESULTS: 32% (51/157) of patients had high intra-tumoral (IT) abundance of CD20+ B cells (≥5%) and this was prognostic for improved overall survival (OS) with an adjusted hazard ratio (HR) of 0.2 (95 % CI 0.0-0.7, p = 0.014). We validated our results in an independent cohort comprising 171 HPV + OPC where 14% (23/171) were IT CD20+ high, again showing improved survival with an adjusted HR for OS of 0.2 (95 % CI 0.0-1.4, p = 0.003). Neither stromal abundance nor the presence of TLS were prognostic in either cohort. B cells were subtyped by multispectral IHC, identifying CD20+CD27+ cells, consistent with memory B cells, as the predominant subtype. Combined with validated biomarker CD103, a marker of tissue-resident memory T cells, IT CD20+ B cells abundance was able to prognostically stratify patients further. CONCLUSIONS: CD20+ B cell abundance has the potential to be used as a biomarker to identify good and poor prognosis HPV + OPC patients.


Assuntos
Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Prognóstico , Biomarcadores , Papillomavirus Humano , Microambiente Tumoral
15.
Brain Sci ; 13(8)2023 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-37626581

RESUMO

Previous research has shown that some forms of non-invasive brain stimulation can increase fatigue resistance. The purpose of this study is to determine the influence of transcranial alternating current stimulation (tACS) on the time to task failure (TTF) of a precision grip task. The study utilized a randomized, double-blind, SHAM-controlled, within-subjects design. Twenty-six young adults completed two experimental sessions (tACS and SHAM) with a 7-day washout period between sessions. Each session involved a fatiguing isometric contraction of the right hand with a precision grip with either a tACS or SHAM stimulation applied to the primary motor cortex (M1) simultaneously. For the fatiguing contraction, the participants matched an isometric target force of 20% of the maximum voluntary contraction (MVC) force until task failure. Pre- and post-MVCs were performed to quantify the force decline due to fatigue. Accordingly, the dependent variables were the TTF and MVC force decline as well as the average EMG activity, force error, and standard deviation (SD) of force during the fatiguing contractions. The results indicate that there were no significant differences in any of the dependent variables between the tACS and SHAM conditions (p value range: 0.256-0.820). These findings suggest that tACS does not increase the TTF during fatiguing contractions in young adults.

16.
Differentiation ; 79(4-5): 272-84, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20163909

RESUMO

Many members of the transforming growth factor-beta (TGF-beta) superfamily have been shown to be important regulators of metanephric development. In this study, we characterized the effect of TGF-beta2 on metanephric development. Rat and mouse metanephroi cultured in the presence of exogenous TGF-beta2 for up to 15 days were small, and contained rudimentary ureteric branches and few glomeruli. These metanephroi were mostly comprised of mesenchymal cells, with two cell populations (designated Type 1 and Type 2 cells) evident. Type 1 cells were only observed when TGF-beta2 was added from the commencement of culture, they resembled chondroblasts and were Alcian Blue and Col IIB positive. Type 2 cells were observed whenever TGF-beta2 was added to the media, formed a band at the periphery of the explants consisting of 5-10 layers of spindle-shaped cells, and were alpha-smooth muscle actin positive. Molecular and RNA in situ hybridization analysis of metanephroi cultured in the presence of TGF-beta2 for 6 days demonstrated that Type 1 and 2 cells were negative for Pax2, WT1, GDNF and FoxD1. Gene expression profiling demonstrated an upregulation of chondrocyte, myogenic and stromal genes, some of which were identified as markers of Type 1 and Type 2 cells. In addition, TGF-beta2 was capable of maintaining the survival of mouse isolated metanephric mesenchyme (iMM) in the absence of serum or inductive signals from the ureteric epithelium. TGF-beta2 also induced the differentiation of iMM into Type 1 and 2 cells. The presence of chondrocytes and muscle in these cultures is reminiscent of the cell types found in some Wilms' tumors. These studies demonstrate that TGF-beta2 is capable of differentiating metanephric mesenchyme away from a renal cell fate.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Condrócitos/fisiologia , Rim , Mesoderma , Células Estromais/fisiologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologia , Actinas/metabolismo , Animais , Proteína Morfogenética Óssea 4/metabolismo , Diferenciação Celular/fisiologia , Linhagem da Célula , Células Cultivadas , Condrócitos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Rim/fisiologia , Mesoderma/citologia , Mesoderma/efeitos dos fármacos , Mesoderma/fisiologia , Camundongos , Dados de Sequência Molecular , Ratos , Ratos Sprague-Dawley , Células Estromais/citologia
17.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34625515

RESUMO

BACKGROUND: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. METHODS: Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAFV600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. RESULTS: Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). CONCLUSIONS: Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.


Assuntos
Neoplasias Encefálicas/etiologia , Ipilimumab/uso terapêutico , Melanoma/complicações , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Feminino , Humanos , Ipilimumab/farmacologia , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Adulto Jovem
18.
Nat Commun ; 12(1): 1434, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664264

RESUMO

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.


Assuntos
Aneuploidia , Variações do Número de Cópias de DNA/genética , Genoma Humano/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Progressão da Doença , Exoma/genética , Humanos , Mutação INDEL/genética , Melanócitos/patologia , Mutação Puntual/genética , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento do Exoma , Sequenciamento Completo do Genoma , Melanoma Maligno Cutâneo
19.
Oral Oncol ; 101: 104516, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31838340

RESUMO

We previously showed in human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV+OPSCC) that the presence of intratumoral (IT) PD-L1+ immune cells (ICs) or CD8+ infiltrating ICs are of prognostic value. Here we report the prognostic significance of these immune biomarkers in an independent validation cohort of 177 HPV+OPSCC patients. IT and stromal (S) localisation of PD-L1+ and CD8+ ICs were scored. High abundance (≥5%) of PD-L1+ IT ICs was found in 51/167 patients (30.5%) and was associated with improved overall survival (OS) (HR, 0.21; 95% CI, 0.05-0.91; P = 0. 012) validating our previous results. High abundance (≥30%) of CD8+ IT or S ICs, found in 77/167 patients (46.1%) provided a HR of 0.45 for OS however the confidence interval was wide (95% CI 0.16-1.25, p = 0.105). Multiplex immunohistochemistry revealed CD68+ macrophages and CD3+CD8+ T cells to be the most common ICs expressing PD-L1. Gene expression analysis showed tumors with high abundance of PD-L1+ IT ICs exhibit gene signatures associated with responses to PD1 or PD-L1 inhibitors pembrolizumab and atezolizumab. These data support the role of immune biomarkers such as PD-L1+ ICs to identify subgroups of HPV+OPSCC patients with an excellent outcome that may be suitable for trials evaluating de-intensification of therapy.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/mortalidade , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/mortalidade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/diagnóstico , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/diagnóstico , Prognóstico , Adulto Jovem
20.
Oral Oncol ; 110: 104988, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32889172

RESUMO

OBJECTIVE: Accurate determination of human papilloma virus (HPV) status is critical when identifying patients with oropharyngeal squamous cell carcinoma (OPSCC) who may be candidates for de-escalation trials. In this study we investigated whether local p16 screening, by immunohistochemistry (IHC), has high positive predictive value (PPV) for HPV status in a good prognosis HPV positive OPSCC (HPVOPSCC) population treated on a clinical trial. METHODS AND MATERIALS: Patients enrolled on the TROG 12.01 randomised trial for good prognosis HPVOPSCC were randomised based on local p16 IHC testing but subsequently had central p16 IHC and HPV RNA in situ hybridisation (HPV RNA ISH) testing. Correlations between the local and central p16 and central HPV RNA ISH were studied. The main outcome was the positive predictive value (PPV) of local pathology laboratory testing of p16. RESULTS: 176/182 patients had samples available for central testing. 172/176 were evaluable for central testing of p16, and all were confirmed to be p16 positive (172/172, 100%, 95% CI = [97.9%, 100%]). Similarly, 100% of those evaluable for HPV RNA ISH (155/155, 100%, 95% CI = [97.6%, 100%]) were confirmed HPV positive, indicating p16 overexpression driven by transcriptionally active HPV and a PPV of 100% for local p16 testing. CONCLUSIONS: Our results validate the suitability of local pathology laboratory p16 testing alone, in populations with a high attributable fraction of OPSCC due to HPV, to screen and enrol low risk HPVOPSCC patients onto de-intensification trials. This obviates the need for upfront more complex and expensive HPV assays and/or central laboratory testing.


Assuntos
Alphapapillomavirus , Proteínas Oncogênicas Virais/metabolismo , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/etiologia , Infecções por Papillomavirus/complicações , Alphapapillomavirus/genética , Biomarcadores Tumorais , Detecção Precoce de Câncer , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Estadiamento de Neoplasias , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/virologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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