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1.
Oncologist ; 24(6): 791-797, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30373905

RESUMO

BACKGROUND: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics. METHODS: We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy. RESULTS: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1-mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73-mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity. CONCLUSION: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Neoplasias das Paratireoides/tratamento farmacológico , Medicina de Precisão/métodos , Adulto , Idoso , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Estudos de Coortes , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Taxa de Mutação , Neoplasias das Paratireoides/genética , Seleção de Pacientes
2.
Strahlenther Onkol ; 193(12): 995-1004, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28474090

RESUMO

BACKGROUND: The optimal treatment strategy for stage I-II glottic squamous cell carcinoma (SCC) is not well-defined. This study analyzed treatment results and prognostic factors. PATIENTS AND METHODS: This is a single-institution retrospective analysis of 244 patients with T1-2 glottic SCC who underwent normofractionated radiotherapy (RT) and/or surgery between 1990 and 2013. The primary endpoint was relapse-free survival (RFS). RESULTS: Median age was 65 years (range: 36-92 years), the majority (82%) having stage I disease. Definitive RT was used in 82% (median dose: 68 Gy, 2 Gy per fraction). Median follow-up was 59 months. The 5­year RFS rates were 83 and 75% (p = 0.05) for stage I and 62 and 50% (p = 0.47) for stage II in the RT and surgery groups, respectively. Multivariate analyses indicate T1 vs. T2 and RT vs. surgery as independent prognostic factors for RFS, with hazard ratios of 0.38 (95% confidence interval, CI: 0.21-0.72) and 0.53 (95% CI: 0.30-0.99), respectively (p < 0.05). The 5­year overall and cause-specific survival rates in the whole cohort were 92 and 96%, respectively, with no significant differences between treatment groups. Anterior commissure involvement was neither a prognostic nor a predictive factor. The incidence of secondary malignancies was not significantly different between patients treated with and without RT (22 vs. 9% at 10 years, respectively, p = 0.18). CONCLUSION: Despite a possible selection bias, our series demonstrates improved RFS with RT over surgery in stage I glottic SCC.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Glote/patologia , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/terapia , Laringectomia/mortalidade , Radioterapia Conformacional/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Terapia Combinada/métodos , Terapia Combinada/mortalidade , Intervalo Livre de Doença , Glote/efeitos da radiação , Glote/cirurgia , Humanos , Neoplasias Laríngeas/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Prevalência , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Suíça/epidemiologia , Resultado do Tratamento
3.
J Neurooncol ; 103(2): 343-51, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20857319

RESUMO

Methylation of the MGMT promoter is supposed to be a predictive and prognostic factor in glioblastoma. Whether MGMT promoter methylation correlates with tumor response to temozolomide in low-grade gliomas is less clear. Therefore, we analyzed MGMT promoter methylation by a quantitative methylation-specific PCR in 22 patients with histologically verified low-grade gliomas (WHO grade II) who were treated with temozolomide (TMZ) for tumor progression. Objective tumor response, toxicity, and LOH of microsatellite markers on chromosomes 1p and 19q were analyzed. Histological classification revealed ten oligodendrogliomas, seven oligoastrocytomas, and five astrocytomas. All patients were treated with TMZ 200 mg/m2 on days 1-5 in a 4 week cycle. The median progression-free survival was 32 months. Combined LOH 1p and 19q was found in 14 patients; one patient had LOH 1p alone and one patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. LOH 1p and/or 19q correlated with longer time to progression but not with radiological response to TMZ. MGMT promoter methylation was detectable in 20 patients by conventional PCR and quantitative analysis revealed the methylation status was between 12 and 100%. The volumetric response to chemotherapy analyzed by MRI and time to progression correlated with the level of MGMT promoter methylation. Therefore, our retrospective case series suggests that quantitative methylation-specific PCR of the MGMT promoter predicts radiological response to chemotherapy with TMZ in WHO grade II gliomas.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioma/genética , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Feminino , Glioma/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Temozolomida
4.
Cancer Lett ; 471: 49-60, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31830557

RESUMO

Mutations in mitochondrial DNA (mtDNA) have been linked to risk, progression, and treatment response of head and neck squamous cell carcinoma (HNSCC). Due to their clonal nature and high copy number, mitochondrial mutations could serve as powerful molecular markers for detection of cancer cells in bodily fluids, surgical margins, biopsies and lymph node (LN) metastasis, especially at sites where tumor involvement is not histologically apparent. Despite a pressing need for high-throughput, cost-effective mtDNA mutation profiling system, current methods for library preparation are still imperfect for detection of low prevalence heteroplasmic mutations. To this end, we have designed an ultra-deep amplicon-based sequencing library preparation approach that covers the entire mitochondrial genome. We sequenced mtDNA in 28 HNSCCs, matched LNs, surgical margins and bodily fluids, and applied multiregional sequencing approach on 14 primary tumors. Our results demonstrate that this quick, sensitive and cost-efficient method allows obtaining a snapshot on the mitochondrial heterogeneity, and can be used for detection of low frequency tumor-associated mtDNA mutations in LNs, sputum and serum specimens. These findings provide the foundation for using mitochondrial sequencing for risk assessment, early detection, and tumor surveillance.


Assuntos
DNA Mitocondrial/genética , Genoma Mitocondrial , Neoplasias de Cabeça e Pescoço/genética , Mutação Puntual , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Genéticas , Feminino , Heterogeneidade Genética , Neoplasias de Cabeça e Pescoço/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
5.
Radiat Oncol ; 14(1): 101, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186027

RESUMO

BACKGROUND: The functional outcome after the treatment of laryngeal cancer is tightly related to the quality of life of affected patients. The aim of this study is to describe the long-term morbidity and functional outcomes associated with the different treatment modalities for laryngeal cancer. METHODS: Retrospective chart review of 477 patients undergoing curatively intended treatment for laryngeal cancer at our tertiary referral center from 2001 to 2014: Details on patient and disease characteristics, diagnostics and treatment related functional outcomes were analyzed. RESULTS: With a median follow-up of 51 months, the crude rate of functional larynx preservation was 74.6%. Radiotherapy +/- chemotherapy was the dominant treatment modality (n = 359-75.3%), whereas 24.7% (n = 118) underwent primary surgery, with 58.5% (69) receiving adjuvant treatment. The 5-year laryngectomy-free survival was 57% (95% CI, 48-66%) after surgery vs. 69% (95% CI, 64-75%) after chemoradiotherapy (p < 0.01). In stage III-IVB, these rates were 26% (95% CI, 16-39%) vs. 47% (95% CI, 36-59%), respectively (p < 0.01). Aspiration occurred in 7%, tracheostomy was necessary in 19.8% and feeding tube placement in 25.4%. Feeding tube and tracheostomy necessity was higher in the initially surgically treated group. Primary surgery (HR: 1.67, 95% CI: 1.19-2.32; p < 0.01), stage III-IVB (HR: 4.07, 95% CI: 2.97-5.60; p < 0.01) and tumor recurrence (HR: 3.83, 95% CI: 2.79-5.28; p < 0.01) remained as adverse factors for laryngectomy-free survival. CONCLUSIONS: Preserving the laryngeal function after cancer treatment is challenging. Advanced tumor stages, primary surgery and recurrence are related to a poor functional outcome. Therefore, the criteria for initial decision-making needs to be further refined.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia/mortalidade , Neoplasias Laríngeas/mortalidade , Laringectomia/mortalidade , Recidiva Local de Neoplasia/mortalidade , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Feminino , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Qualidade de Vida , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
6.
Nat Commun ; 8(1): 1772, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29176703

RESUMO

Squamous cell carcinomas of the head and neck (SCCHN) affect anatomical sites including the oral cavity, nasal cavity, pharynx, and larynx. Laryngeal cancers are characterized by high recurrence and poor overall survival, and currently lack robust molecular prognostic biomarkers for treatment stratification. Using an algorithm for integrative clustering that simultaneously assesses gene expression, somatic mutation, copy number variation, and methylation, we for the first time identify laryngeal cancer subtypes with distinct prognostic outcomes, and differing from the non-prognostic laryngeal subclasses reported by The Cancer Genome Atlas (TCGA). Although most common laryngeal gene mutations are found in both subclasses, better prognosis is strongly associated with damaging mutations of the methyltransferases NSD1 and NSD2, with findings confirmed in an independent validation cohort consisting of 63 laryngeal cancer patients. Intriguingly, NSD1/2 mutations are not prognostic for nonlaryngeal SCCHN. These results provide an immediately useful clinical metric for patient stratification and prognostication.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Laríngeas/enzimologia , Mutação , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Prognóstico , Proteínas Repressoras/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
7.
Cell Death Discov ; 3: 17022, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28580171

RESUMO

A subset of patients with oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), harbor dysplastic lesions (often visually identified as leukoplakia) prior to cancer diagnosis. Although evidence suggest that leukoplakia represents an initial step in the progression to cancer, signaling networks driving this progression are poorly understood. Here, we applied in silico Pathway Activation Network Decomposition Analysis (iPANDA), a new bioinformatics software suite for qualitative analysis of intracellular signaling pathway activation using transcriptomic data, to assess a network of molecular signaling in OSCC and pre-neoplastic oral lesions. In tumor samples, our analysis detected major conserved mitogenic and survival signaling pathways strongly associated with HNSCC, suggesting that some of the pathways identified by our algorithm, but not yet validated as HNSCC related, may be attractive targets for future research. While pathways activation landscape in the majority of leukoplakias was different from that seen in OSCC, a subset of pre-neoplastic lesions has demonstrated some degree of similarity to the signaling profile seen in tumors, including dysregulation of the cancer-driving pathways related to survival and apoptosis. These results suggest that dysregulation of these signaling networks may be the driving force behind the early stages of OSCC tumorigenesis. While future studies with larger leukoplakia data sets are warranted to further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers, our platform proposes a promising new approach for detecting cancer-promoting pathways and tailoring the right therapy to prevent tumorigenesis.

8.
Laryngoscope ; 125(4): 863-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25387698

RESUMO

OBJECTIVES/HYPOTHESIS: Study of the clinical evolution of a primary ear, nose, and throat infection complicated by septic thrombophlebitis of the internal jugular vein. STUDY DESIGN: Retrospective case-control study. PATIENTS AND METHODS: From 1998 to 2010, 23 patients at our institution were diagnosed with a septic thrombosis of the internal jugular vein. Diagnostics included microbiologic analysis and imaging such as computed tomography, magnetic resonance imaging, and ultrasound. Therapy included broad-spectrum antibiotics, surgery of the primary infectious lesion, and postoperative anticoagulation. The patients were retrospectively analyzed. RESULTS: The primary infection sites were found in the middle ear (11), oropharynx (8), sinus (3), and oral cavity (1). Fourteen patients needed intensive care unit treatment for a mean duration of 6 days. Seven patients were intubated, and two developed severe acute respiratory distress syndrome. An oropharynx primary infection site was most prone to a prolonged clinical evolution. Anticoagulation therapy was given in 90% of patients. All 23 patients survived the disseminated infection without consecutive systemic morbidity. CONCLUSION: In the pre-antibiotic time, septic internal jugular vein thrombophlebitis was a highly fatal condition with a mortality rate of 90%. Modern imaging techniques allow early and often incidental diagnosis of this clinically hidden complication. Anticoagulation, intensive antibiotic therapy assisted by surgery of the primary infection site, and intensive supportive care can reach remission rates of 100%.


Assuntos
Veias Jugulares , Síndrome de Lemierre/diagnóstico , Sepse/diagnóstico , Trombose Venosa/diagnóstico , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Estudos de Casos e Controles , Criança , Terapia Combinada , Feminino , Seguimentos , Humanos , Recém-Nascido , Síndrome de Lemierre/epidemiologia , Síndrome de Lemierre/terapia , Ligadura/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Sepse/epidemiologia , Sepse/terapia , Índice de Gravidade de Doença , Resultado do Tratamento , Trombose Venosa/epidemiologia , Trombose Venosa/terapia , Adulto Jovem
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