RESUMO
BACKGROUND: To report our experience of postoperative haemorrhage in patients following transoral robotic surgery (TORS). METHODS: Data were collected on patients having TORS. Postoperative haemorrhage within 30 days was graded using the Mayo Clinic grading system. RESULTS: Transoral robotic surgery operations were performed on 122 patients. There were 23 bleeding events classified as minor to severe following 19 operations (16%). Haemorrhage requiring a return to the operating room occurred after 7 operations (6%). The odds of an emergent haemorrhage were 5.19 times greater in patients who had a staged neck dissection after TORS (P = .05). The odds of a postoperative bleeding event were 2.6 times greater in patients receiving a larger resection (P = .107). There were no haemorrhage events in the 36 patients who received a synchronous neck dissection with transcervical ligation of the external carotid artery. CONCLUSIONS: Surgical intervention for TORS haemorrhage occurred in 6% patients. No haemorrhage occurred in patients who had ligation of the external carotid artery.
Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias Bucais/cirurgia , Esvaziamento Cervical/efeitos adversos , Neoplasias Otorrinolaringológicas/cirurgia , Hemorragia Pós-Operatória/epidemiologia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Idoso , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Neoplasias Otorrinolaringológicas/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: The complex lymphatic drainage in the head and neck makes sentinel lymph node biopsy (SLNB) for melanomas in this region challenging. This study describes the incidence, and location of additional positive nonsentinel lymph nodes (NSLN) in patients with cutaneous head and neck melanoma following a positive SLNB. METHODS: A retrospective review was performed using a single institution prospective database. Patients with a primary melanoma in the head or neck with a positive cervical SLNB were identified. The lymphadenectomy specimen was divided intraoperatively into lymph node levels I-V, and NSLN status determined for each level. RESULTS: Of 387 patients with melanoma of the head and neck who underwent cervical SLNB, 54 had a positive SLN identified (14%). Thirty six patients (67%) underwent immediate completion lymph node dissection (CLND) of whom eight patients (22%) had a positive NSLN. The remaining 18 patients (33%) did not undergo CLND and were observed. Half of positive NSLNs (50%) were in the same lymph node level as the SLN and 33% were in an immediately adjacent level; only two patients were found to have NSLNs in non-adjacent levels. The only factor predictive of NSLN involvement was the size of the tumor deposit in the SLN>0.2 mm (p = 0.05). Superficial parotidectomy at CLND revealed metastatic melanoma only in patients with a positive parotid SLN. CONCLUSIONS: A positive NLSN was identified in 22% of patients undergoing CLND after a positive SLNB. The majority of positive NSLNs are found within or immediately adjacent to the nodal level containing the SLN.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Linfonodos/patologia , Melanoma/secundário , Biópsia de Linfonodo Sentinela/métodos , Neoplasias Cutâneas/patologia , Adulto , Idoso , Distribuição de Qui-Quadrado , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Incidência , Estimativa de Kaplan-Meier , Excisão de Linfonodo/métodos , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/cirurgia , Masculino , Melanoma/mortalidade , Melanoma/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Estatísticas não Paramétricas , Análise de SobrevidaRESUMO
Retinoids have been investigated for their effects in the prevention and treatment of cancer. Scores of synthetic and natural ligands suppress growth and normalize differentiation of cells in vitro and in vivo. The molecular mechanisms of these activities are being elucidated with the goal of improving the therapeutic index. Here we summarize recent advances in the understanding of retinoid signaling via nuclear receptors, corepressors, and coactivators and review the effects of retinoid treatment on cell-cycle control elements and cyclin proteins.
Assuntos
Ciclinas/metabolismo , Neoplasias/prevenção & controle , Retinoides/farmacologia , Ciclo Celular , Humanos , Neoplasias/metabolismo , Transdução de SinaisRESUMO
Loss of heterozygosity (LOH) involving chromosomes 3p, 5q, 9p, or 17p and aberrant expression or mutation of p53 are reported previously in selected bronchial dysplasias and squamous cell cancers (SCCs). Yet, comprehensive analyses of LOH patterns at these chromosomal sites and of p53 alterations are not reported for histologically normal bronchial epithelium, high-grade bronchial dysplasia, and SCC present in the same pulmonary resections. Whether concordant or discordant genetic changes are detected in these bronchial tissues, especially when multiple high-grade dysplastic bronchial lesions are present, was studied. Genomic DNA was microdissected from eight pulmonary SCCs and high-grade dysplastic lesions that were associated with SCC. In four cases, two independent high-grade dysplastic bronchial lesions were identified. When available, histologically normal bronchial epithelium was microdissected. Germ-line genomic DNA was isolated from normal lymph nodes. LOH was assessed for 15 microsatellite markers on chromosomes 3p, 5q, 9p, or 17p, sites frequently deleted in lung cancers. Immunohistochemical p53 expression was studied and correlated with p53 DNA sequence analyses. Progressive LOH for these markers was found when SCCs were compared with high-grade dysplasia and histologically normal bronchial epithelium present in the same resections. Histologically normal bronchial specimens had LOH in up to 27% of informative markers. High-grade dysplastic lesions exhibited LOH for 18-45% and SCC had LOH for 18-73% of the markers. Common regions of LOH were found in some dysplasias compared with SCCs. In other dysplasias, discordance was found relative to SCCs, especially for p53 mutations. In cases with a single or second high-grade dysplasia associated with SCC, heterogeneity in LOH markers was detected. These concordant and discordant changes were consistent with convergent and divergent clonal selection pathways in pulmonary squamous cell carcinogenesis. Some histologically normal bronchial epithelial tissues had genetic changes more similar to those in the SCCs than in dysplastic lesions. DNA loss or mutations accumulate in SCC, but discordant genetic changes can exist in the same carcinogen-exposed bronchial tissues. These findings have implications for lung cancer prevention trials.
Assuntos
Broncopatias/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutação , Broncopatias/patologia , Carcinoma de Células Escamosas/patologia , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , Primers do DNA/genética , DNA de Neoplasias/análise , Genes p53 , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/patologia , Repetições de Microssatélites/genética , Proteínas de Neoplasias/genéticaRESUMO
Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2), an inducible form of COX, represents a potential pharmacologic target to prevent cancer. Key data suggesting a causal relationship between increased COX-2 activity and carcinogenesis and possible mechanisms of action of COX-2 in this context will be discussed. The possibility that COX-2 represents a pharmacological target for preventing upper aerodigestive cancers (head and neck, lung) will be emphasized. Importantly, clinical trials have been initiated to assess the chemopreventive properties of selective COX-2 inhibitors.
Assuntos
Anticarcinógenos/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Neoplasias Esofágicas/prevenção & controle , Isoenzimas/antagonistas & inibidores , Neoplasias do Sistema Respiratório/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Esôfago de Barrett/tratamento farmacológico , Transformação Celular Neoplásica/efeitos dos fármacos , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Progressão da Doença , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Esofágicas/enzimologia , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/prevenção & controle , Isoenzimas/fisiologia , Leucoplasia Oral/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/prevenção & controle , Camundongos , Camundongos Knockout , Neoplasias Experimentais/prevenção & controle , Lesões Pré-Cancerosas/tratamento farmacológico , Prostaglandina-Endoperóxido Sintases/fisiologia , Neoplasias do Sistema Respiratório/enzimologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Understanding the mechanisms underlying carcinogenesis provides insights that are necessary for the development of therapeutic strategies to prevent cancer. Chemoprevention--the use of drugs or natural substances to inhibit carcinogenesis - is an important and rapidly evolving aspect of cancer research. We discuss evidence that cyclooxygenase 2 (COX 2), an inducible form of the enzyme, is a potential pharmacological target to prevent cancer. Key data implicating a causal relation between increased activity of COX 2 and carcinogenesis and possible mechanisms of action of COX 2 in this context are covered. Importantly, selective COX 2 inhibitors appear to be safe enough in human beings to allow large-scale clinical testing in healthy people. Several chemoprevention trials using selective COX 2 inhibitors are underway.
Assuntos
Antineoplásicos/uso terapêutico , Isoenzimas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Apoptose , Ciclo-Oxigenase 2 , Humanos , Terapia de Imunossupressão , Inflamação , Isoenzimas/fisiologia , Proteínas de Membrana , Invasividade Neoplásica , Neoplasias/enzimologia , Neoplasias/etiologia , Neoplasias/patologia , Neovascularização Patológica , Prostaglandina-Endoperóxido Sintases/fisiologia , Prostaglandinas/biossíntese , XenobióticosRESUMO
BACKGROUND: Unknown primary head and neck squamous cell carcinoma (HNSCC) presents as a cervical lymph node metastasis without identification of the primary tumor, despite thorough diagnostic work-up that includes physical examination, computed tomography, esophagoscopy, laryngoscopy, bronchoscopy, and multiple surveillance biopsies. We investigated whether the site of origin of the primary tumor could be localized in the upper aerodigestive tract mucosa by detection of genetic alterations identical to those found in metastatic lesions. METHODS: Microsatellite analysis was performed on metastatic tumors obtained from 18 patients with unknown primary HNSCC. Histologically benign surveillance biopsy specimens were also analyzed. Patients were followed up to 13 years with continuing surveillance for primary mucosal tumors. Most patients were treated with neck dissection followed by radiation therapy to the affected neck and ipsilateral Waldeyer's ring. RESULTS: In 10 (55%) of the 18 patients, at least one histopathologically benign mucosal biopsy specimen from defined anatomic sites (i.e., most likely sites for an occult primary tumor) demonstrated a pattern of genetic alterations identical to that present in cervical lymph node metastases. One patient harboring genetic alterations in the base of the tongue and two patients harboring genetic alterations in a tonsillar fossa subsequently developed HNSCC in the identical or adjacent mucosal region; all three of the primary head and neck mucosal tumors that eventually appeared between 1 and 13 years later in these patients had genetic changes identical to those in the benign mucosal biopsy specimens and in the metastatic lymph nodes. CONCLUSIONS: These data support the hypothesis that histopathologically benign mucosa of the upper aerodigestive tract may harbor foci of clonal, preneoplastic cells that are genetically related to metastatic HNSCC and that such mucosal sites are the sites of origin of unknown primary HNSCC. Microsatellite analysis may represent a clinically useful tool for determining such sites.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , DNA de Neoplasias/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Repetições de Microssatélites , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Linfática , Neoplasias Primárias Desconhecidas/patologia , Reação em Cadeia da PolimeraseRESUMO
The purpose of this study was to determine whether cyclooxygenase-2 (COX-2) was overexpressed in squamous cell carcinoma of the head and neck (HNSCC). Quantitative reverse transcription-PCR, immunoblotting, and immunohistochemistry were used to assess the expression of COX-2 in head and neck tissue. Mean levels of COX-2 mRNA were increased by nearly 150-fold in HNSCC (n = 24) compared with normal oral mucosa from healthy volunteers (n = 17). Additionally, there was about a 50-fold increase in amounts of COX-2 mRNA in normal-appearing epithelium adjacent to HNSCC (n = 10) compared with normal oral mucosa from healthy volunteers. Immunoblotting demonstrated that COX-2 protein was present in six of six cases of HNSCC but was undetectable in normal oral mucosa from healthy subjects. Immunohistochemical analysis showed that COX-2 was expressed in both HNSCC and adjacent normal-appearing epithelium. Taken together, these results suggest that COX-2 may be a target for the prevention or treatment of HNSCC.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/enzimologia , Isoenzimas/genética , Prostaglandina-Endoperóxido Sintases/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Ciclo-Oxigenase 2 , Primers do DNA , Regulação Enzimológica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Isoenzimas/biossíntese , Proteínas de Membrana , Mucosa Bucal/enzimologia , Prostaglandina-Endoperóxido Sintases/biossíntese , RNA Mensageiro/biossíntese , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição GênicaRESUMO
BACKGROUND: Retinoids (derivatives of vitamin A) are reported to reduce the occurrence of some second primary cancers, including aerodigestive tract tumors. In contrast, beta-carotene does not reduce the occurrence of primary aerodigestive tract cancers. Mechanisms explaining these effective retinoid and ineffective carotenoid chemoprevention results are poorly defined. Recently, the all-trans-retinoic acid (RA)-induced proteolysis of cyclin D1 that leads to the arrest of cells in G1 phase of the cell cycle was described in human bronchial epithelial cells and is a promising candidate for such a mechanism. In this study, we have investigated this proteolysis as a common signal used by carotenoids or receptor-selective and receptor-nonselective retinoids. METHODS: We treated cultured normal human bronchial epithelial cells, immortalized human bronchial epithelial cells (BEAS-2B), and transformed human bronchial epithelial cells (BEAS-2BNNK) with receptor-selective or receptor-nonselective retinoids or with carotenoids and studied the effects on cell proliferation by means of tritiated thymidine incorporation and on cyclin D1 expression by means of immunoblot analysis. We also examined whether calpain inhibitor I, an inhibitor of the 26S proteasome degradation pathway, affected the decline (i.e., proteolysis) of cyclin D1. RESULTS: Receptor-nonselective retinoids were superior to the carotenoids studied in mediating the decline in cyclin D1 expression and in suppressing the growth of bronchial epithelial cells. Retinoids that activated retinoic acid receptor beta or retinoid X receptor pathways preferentially led to a decrease in the amount of cyclin D1 protein and a corresponding decline in growth. The retinoid-mediated degradation of cyclin D1 was blocked by cotreatment with calpain inhibitor I. CONCLUSIONS: Retinoid-dependent cyclin D1 proteolysis is a common chemoprevention signal in normal and neoplastic human bronchial epithelial cells. In contrast, carotenoids did not affect cyclin D1 expression. Thus, the degradation of cyclin D1 is a candidate intermediate marker for effective retinoid-mediated cancer chemoprevention in the aerodigestive tract.
Assuntos
Anticarcinógenos/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Carotenoides/farmacologia , Ciclina D1/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Retinoides/farmacologia , Neoplasias Brônquicas/metabolismo , Neoplasias Brônquicas/prevenção & controle , Calpaína/antagonistas & inibidores , Células Cultivadas , HumanosRESUMO
Cyclooxygenase (COX) catalyzes the formation of prostaglandins (PG) from arachidonic acid. A large body of evidence has accumulated to suggest that COX-2, the inducible form of COX, is important in carcinogenesis. In this study, we determined whether (1) COX-2 was overexpressed in squamous cell carcinoma of the head and neck (HNSCC) and whether (2) retinoids, a class of chemopreventive agents, blocked epidermal growth factor (EGF)-mediated activation of COX-2 expression. Levels of COX-2 mRNA were determined in 15 cases of HNSCC and 10 cases of normal oral mucosa. Nearly a 100-fold increase in amounts of COX-2 mRNA was detected in HNSCC. By immunoblot analysis, COX-2 protein was detected in 6 of 6 cases of HNSCC but was undetectable in normal mucosa. Because retinoids protect against oral cavity cancer, we investigated whether retinoids could suppress EGF-mediated induction of COX-2 in cultured oral squamous carcinoma cells. Treatment with EGF led to increased levels of COX-2 mRNA, COX-2 protein, and synthesis of PG. These effects were suppressed by a variety of retinoids. Based on the results of this study, it will be important to establish whether newly developed selective COX-2 inhibitors are useful in preventing or treating HNSCC. Moreover, the anticancer properties of retinoids may be due, in part, to inhibition of COX-2 expression. Combining a retinoid with a selective COX-2 inhibitor may be more effective than either agent alone in preventing cancer of the upper aerodigestive tract.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/prevenção & controle , Inibidores Enzimáticos/farmacologia , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/prevenção & controle , Isoenzimas/biossíntese , Isoenzimas/farmacologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/farmacologia , Retinoides/farmacologia , Ciclo-Oxigenase 2 , Inibidores Enzimáticos/uso terapêutico , Humanos , Proteínas de Membrana , Retinoides/uso terapêuticoRESUMO
Advances in combined transcranial and transfacial (craniofacial) approaches for malignant tumors involving the anterior skull base have demonstrated improved survival. The technique allows adequate assessment of the intracranial extent of the tumor through an appropriate craniotomy. Vital structures, such as the dura, brain, and blood vessels, can be protected or resected and reconstructed safely. An en bloc excision can be accomplished. Dural defects and/or tears are satisfactorily repaired under direct vision, ensuring a watertight closure. Finally, adequate closure of the soft tissue defect is obtained, thus segregating the cranial cavity from the potentially infected nasal cavity and the nasopharynx with a resultant decrease in morbidity. Operative mortality is low, although complication rates are high. The technique is safe and continues to be improved to reduce morbidity. To evaluate the true impact of this surgical procedure on improvement in survival as well as quality of life, a multiinstitutional registry with uniform indications is indicated. With increasing experience and well-defined indications, improvement in survival (from 50% to 60%) and reduction in morbidity (from 30% to 40%) can be demonstrated through multiinstitutional, cooperative efforts.
Assuntos
Craniotomia/métodos , Ossos Faciais/cirurgia , Neoplasias da Base do Crânio/cirurgia , Humanos , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Procedimentos de Cirurgia Plástica/métodos , Base do Crânio/anatomia & histologia , Neoplasias da Base do Crânio/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: While squamous cell carcinoma of the head and neck (HNSCC) most commonly affects individuals in the fifth to seventh decades of life, it occasionally arises in older patients. Biologic and epidemiologic factors of HNSCC in elderly patients have been investigated to shed light on the process of neoplastic transformation in that population. DESIGN: The medical records of patients with new onset of HNSCC presenting between 1988 and 1993 were reviewed retrospectively. SETTING: Tertiary-care hospital-based clinic. PATIENTS: Eighty-one individuals who developed HNSCC of the upper aerodigestive tract after their 75th birthday constituted the study group. A control group consisting of 102 patients who developed HNSCC between the ages of 40 and 70 years was also analyzed. MAIN OUTCOME MEASURE: Information about each individual's tobacco and ethanol exposure, family history of cancer, history of second primary cancer, treatment provided, and current disease status were derived from the medical record. The presence or absence of p53 gene mutation was tabulated for a subset of individuals in both the elderly and the middle-aged groups. RESULTS: The elderly patients had a significantly lower degree of alcohol and tobacco exposure, but a significantly higher rate of second primary cancers, especially in sites outside the upper aerodigestive tract. There was no difference in the incidence of cancer in first-degree relatives in the two groups. These findings were interpreted in light of results from our laboratory examining the incidence of p53 gene mutation in a large number of patients with HNSCC. A significantly higher percentage of tumors from the younger group contained a p53 gene mutation. Major surgery was an integral part of the treatment plan for most of the older patient group despite their advanced age. CONCLUSIONS: These findings suggest that HNSCC arising after the seventh decade of life less frequently involves a genetic change commonly found in younger patients. Heavy carcinogen exposure and p53 gene mutations are present less often in elderly individuals, whereas this group appears to be more susceptible to multiple cancers. The precise biologic factors involved in neoplastic transformation in this older population await discovery. Since aggressive therapy can be successfully tolerated by many elderly patients, an individualized approach to treatment is advocated.
Assuntos
Carcinoma de Células Escamosas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/epidemiologia , Baltimore/epidemiologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Transformação Celular Neoplásica/patologia , Feminino , Seguimentos , Genes p53/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação/genética , Segunda Neoplasia Primária/patologia , Estudos Retrospectivos , Fumar/epidemiologia , Taxa de SobrevidaRESUMO
BACKGROUND: Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. METHODS: Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. RESULTS: We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001). CONCLUSIONS: In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.
Assuntos
Carcinoma de Células Escamosas/genética , Genes p53 , Neoplasias de Cabeça e Pescoço/genética , Mutação , Fumar/efeitos adversos , Composição de Bases , Carcinoma de Células Escamosas/etiologia , Intervalos de Confiança , Sequência Conservada , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SequênciaRESUMO
BACKGROUND: Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes. METHODS: We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck. RESULTS: We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinoma has recurred locally, as compared with none of 12 patients with negative margins (P = 0.02 by the log-rank test). Furthermore, molecular analysis identified neoplastic cells in 6 of 28 lymph nodes (21 percent) that were initially negative by histopathological assessment. CONCLUSIONS: Among specimens initially believed to be negative by light microscopy, a substantial percentage of the surgical margins and lymph nodes from patients with squamous-cell carcinoma of the head and neck contained p53 mutations specific for the primary tumor. Patients with these positive margins appear to have a substantially increased risk of local recurrence. Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Genes p53 , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Mutação , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/cirurgia , DNA de Neoplasias/análise , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Cirurgia de Mohs , Recidiva Local de Neoplasia/diagnóstico , Estadiamento de Neoplasias , Probabilidade , Resultado do TratamentoRESUMO
BACKGROUND: Cancer is caused by the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes. The result is a clonal expansion of genetically identical daughter cells that eventually become clinical malignancies. The specific mutations acquired by the progenitor cell are like a fingerprint carried by each cell of the tumor. These mutations can serve as very specific markers for the presence of tumor cells in a background of normal cells. METHODS: Mutations in the p53 gene recovered from head and neck squamous cell carcinomas were sequenced, and these altered DNA sequences were used retrospectively as tumor-specific genetic markers for cancer cells in the patient's saliva. Cloned p53 sequences amplified by the polymerase chain reaction from DNA extracted from banked preoperative saliva specimens were screened for the presence of tumor-specific mutations using radiolabeled oligonucleotide probes. RESULTS: We identified tumor-specific mutations in preoperative saliva samples of 5 of the 7 patients evaluated (71%). CONCLUSIONS: These results suggest a potential for clinical applications of this novel approach to cancer detection using gene mutations as molecular markers for carcinomas.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Genes p53/genética , Neoplasias de Cabeça e Pescoço/genética , Mutação Puntual , Saliva , Análise Mutacional de DNA , Marcadores Genéticos , Humanos , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase , Saliva/metabolismoRESUMO
OBJECTIVE: To demonstrate how genetic mutations may be used as specific markers for the study and management of head and neck squamous cell carcinomas. DESIGN: Mutations in the p53 gene were identified by DNA sequencing in synchronous primary head and neck squamous cell carcinomas from one patient. The polymerase chain reaction and mutant-specific oligomer probes were used to detect rare tumor cells in surgical margins, lymph nodes, and swabs of the oral cavity. PATIENTS: Selected from a consecutive series of individuals with head and neck squamous cell carcinomas at a tertiary referral center. RESULTS: Two synchronous primary invasive cancers displayed different missense mutations in the p53 gene. The mutated sequence from one primary tumor was detected in metastases from both sides of the neck. Infiltrating cells from this biologically aggressive tumor were also detected by a polymerase chain reaction-based assay in a histologically normal surgical margin, accurately predicting tumor recurrence. CONCLUSIONS: p53 gene mutations were useful as molecular markers to distinguish between tumors in this case. The potential utility of detection of tumor cells in surgical margins and saliva by molecular techniques merits further investigation.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Genes p53/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Mutação PuntualRESUMO
The Johns Hopkins Lung Project developed an archive of sputum specimens during a randomized trial of lung cancer screening (1974-1982). We identified 15 patients from that trial who later developed adenocarcinoma of the lung. The primary lung carcinomas from 10 of these 15 patients contained either a ras or a p53 gene mutation. Using a polymerase chain reaction-based assay, stored sputum samples obtained prior to clinical diagnosis were examined for the presence of these same oncogene mutations. In 8 of 10 patients, the identical mutation identified in the primary tumor was also detected in at least one sputum sample. The earliest detection of a clonal population of cancer cells in sputum was in a sample obtained more than 1 year prior to clinical diagnosis. These results provide the basis of a novel approach for detection of lung cancer based on the evolving molecular genetics of this disease.
Assuntos
Genes p53 , Genes ras , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutação Puntual , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/genética , Escarro/citologia , Idoso , Sequência de Aminoácidos , Sequência de Bases , DNA/isolamento & purificação , Primers do DNA , Desoxirribonuclease EcoRI , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas/patologiaRESUMO
To establish a genetic model of the progression of head and neck squamous carcinoma we have defined the incidence and timing of p53 mutations in this type of cancer. We sequenced the conserved regions of the p53 gene in 102 head and neck squamous carcinoma lesions. These included 65 primary invasive carcinomas and 37 noninvasive archival specimens consisting of 13 severe dysplasias and 24 carcinoma in situ lesions. The incidence of p53 mutations in noninvasive lesions was 19% (7/37) and increased to 43% (28/65) in invasive carcinomas. These data suggest that p53 mutations can precede invasion in primary head and neck cancer. Furthermore, the spectrum of codon hotspots is similar to that seen in squamous carcinoma of the lung and 64% of mutations are at G nucleotides, implicating carcinogens from tobacco smoke in the etiology of head and neck squamous carcinoma.
Assuntos
Carcinoma/genética , Carcinoma/patologia , Genes p53 , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Clonagem Molecular , Primers do DNA , DNA de Neoplasias/isolamento & purificação , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Invasividade Neoplásica , Reação em Cadeia da Polimerase , FumarRESUMO
Difluoromethylornithine (DFMO) is an investigational chemopreventive agent that inhibits ornithine decarboxylase (ODC) activity, lowers cellular polyamine concentrations, and decreases cell proliferation in vivo and in vitro. In five subjects we have compared the polyamine concentrations in rectal mucosal biopsies and in exfoliated buccal mucosal cells (EBM) before and after DFMO treatment to assess the suitability of EBM as an easily accessible marker tissue for DFMO suppression of polyamine synthesis in the rectal mucosa. One month of 3 g/m2/day of DFMO treatment caused a statistically significant decrease in putrescine and spermidine concentrations in rectal mucosa biopsy specimens but not in EBM samples. ODC activity in EBM was high (approximately 1 mumol/min/mg protein), resistant to DFMO inhibition (Ki = 4200 microM), dependent on GTP concentration (maximal at 0.1 mM), and was reduced concomitantly with bacterial concentration by antiseptic mouthwashing. Bacteria adherent to EBM were visible by electron microscopy. Forty bacterial colonies/ng protein were culturable from washed EBM samples. Oral bacteria preclude the use of EBM samples as a marker tissue of DFMO effect in the rectal mucosa, but oral DFMO therapy is effective in depleting polyamines in rectal mucosa.
Assuntos
Eflornitina/farmacologia , Mucosa Intestinal/química , Mucosa Bucal/química , Putrescina/análise , Espermidina/análise , Espermina/análise , Administração Oral , Anti-Infecciosos Locais/uso terapêutico , Aderência Bacteriana , Biópsia , Divisão Celular/efeitos dos fármacos , Bochecha , Contagem de Colônia Microbiana , Avaliação de Medicamentos , Resistência a Medicamentos , Eflornitina/administração & dosagem , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Microscopia Eletrônica , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/microbiologia , Antissépticos Bucais/uso terapêutico , Ornitina Descarboxilase/química , Ornitina Descarboxilase/efeitos dos fármacos , RetoRESUMO
Coccidioidomycosis is a pulmonary fungal infection endemic to the desert southwest of the United States and northern Mexico. Rarely (0.5% of cases), the fungus disseminates widely, causing life-threatening complications. Seven percent of these cases will involve the head and neck. We report a case of disseminated coccidioidomycosis that involved the larynx and cervical lymph nodes in a 40-year-old white woman who presented with hoarseness and unsuspected airway compromise. Review of the 12 reported cases of laryngeal coccidioidomycosis showed a predominance of male and dark-skinned patients; seven were children, and nine presented with airway compromise. Other reported sites of head and neck involvement include the skin, mucosa, bones of the skull, and meninges, and there have been reports of abscesses of the soft tissues and fascial spaces of the neck.