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Idarubicina , Leucemia Mieloide Aguda , Humanos , Idarubicina/efeitos adversos , Citarabina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Estaurosporina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Indução de RemissãoRESUMO
PURPOSE: Hematology/oncology clinical pharmacists' work activities have been described in previous literature, but time spent on pharmacist tasks has not been well characterized. Random work sampling (WS) is a form of activity assessment to determine the proportion of time spent in various types of work. Based on results from previous WS evaluations at University of Utah and its Huntsman Cancer Hospital, activities were changed to maximize time dedicated to clinical activities and pharmacists' benefit to providers and patients in both inpatient and ambulatory care settings. Therefore, updated random WS evaluations were completed during spring 2019 and fall 2020. METHODS: Personal digital assistant (PDA) devices were used to record hematology/oncology clinical pharmacists' onsite or remote location and work activity data. Data were collected 8 times per hour on weekdays, with a goal of 275 observations per pharmacist. Results were then classified as clinical, professional, or technical activities. RESULTS: In 2019, 9,079 observations were recorded by 31 onsite pharmacists. In 2020, 28 pharmacists recorded 8,803 observations (5,524 during onsite work and 3,279 during remote work). The overall distribution of pharmacists' work activities remained stable between 2019 and 2020, with 89% of activities classified as clinical or professional. Pharmacists spent a smaller proportion of time on in-person communication in 2020, balanced by increases in chart review and text-based communication. Onsite pharmacists reported a larger proportion of clinical activities, while remote pharmacists reported a larger proportion of professional activities. CONCLUSION: Continued WS assessment of work activity patterns will allow identification of opportunities to streamline workflows, maximize pharmacist engagement in clinical activities, and development of remote work policy.
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Hematologia , Farmacêuticos , Humanos , Papel Profissional , Autorrelato , Fluxo de Trabalho , Carga de TrabalhoRESUMO
BACKGROUND: The purpose of this study was to describe the relationship of p16 and epidermal growth factor receptor (EGFR) expression with survival in surgically treated patients who had oropharyngeal or oral cavity squamous cell carcinoma (SCC). METHODS: Tissue from 36 patients with oropharyngeal SCC and 49 patients with oral cavity SCC treated between 1997 and 2001 was imbedded and immunostained using a tissue microarray. RESULTS: The p16 was positive in 57% and 13% of patients with oropharyngeal SCC and oral cavity SCC, respectively. EGFR was positive in 60% and 63% of patients with oropharyngeal SCC and oral cavity SCC, respectively. In patients with oropharyngeal SCC, p16 expression was associated with improved disease-specific survival (DSS), overall survival (OS), and time to recurrence (TTR) (p < .01, < .01, and <.01, respectively). EGFR expression was associated with poorer DSS, OS, and TTR (p < .01, = .01, and < .01, respectively). For oropharyngeal SCC, when examining both p16 and EGFR expression as combined biomarkers, high p16 expression coupled with low EGFR expression was associated with improved DSS (p p16 = .01; p EGFR = .01). Patients with oral cavity SCC showed no association between biomarker and outcome. CONCLUSIONS: For patients with oropharyngeal SCC, high p16 and low EGFR were associated with improved outcome, suggesting a predictive role in surgically treated patients.
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Receptores ErbB/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/cirurgia , Proteínas de Neoplasias/metabolismo , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/cirurgia , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Coortes , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Orofaríngeas/mortalidade , Valor Preditivo dos Testes , Prevalência , Taxa de SobrevidaRESUMO
BACKGROUND: People with cancer are increasingly turning to the Internet for health-related information. OBJECTIVE: To compare the patterns of Internet use of people with skin cancer with previous findings by including people with nonmelanoma skin cancer (NMSC) using a comprehensive survey. To evaluate perceived anxiety levels and overall satisfaction after searching the Internet of people with skin cancer. METHODS & MATERIALS: We conducted a survey study and prospectively collected data from people newly diagnosed with melanoma or NMSC. RESULTS: Four hundred fifteen participants with melanoma and 400 with NMSC completed the questionnaire. Internet use and overall satisfaction with the Internet search increased more than 50% in participants with melanoma from 2005. One-third of participants with melanoma, but many fewer participants with NMSC, reported higher anxiety after Internet use. Participants who were younger, female, more highly educated, and diagnosed with melanoma were most likely to use the Internet to search for information about their diagnosis. CONCLUSION: Internet use is prevalent and increasing sharply in individuals with skin cancer. The majority of individuals describe their use of the Internet as a positive experience. Greater anxiety from searching the Internet is more common in individuals with melanoma than in those with NMSC.
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Ansiedade/psicologia , Comportamento de Busca de Informação , Internet/estatística & dados numéricos , Melanoma/psicologia , Neoplasias Cutâneas/psicologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To demonstrate that the 3 reconstructive advantages of the thoracodorsal artery scapular tip transplant (Tdast), a long pedicle, independently mobile tissue components, and the 3-dimensional nature of the scapular tip, will improve the quality and success of complex reconstructions by avoiding vein grafting, preventing the need for 2 separate transplants, and facilitating bony inset. DESIGN: Prospective case series. SETTING: Tertiary care academic medical center. PATIENTS: Twenty-one patients (male to female ratio, 16:5; mean age, 52 years) underwent reconstruction of the upper, middle, and lower face from 2001 through 2006. Indications for reconstruction were tumor ablation in 11 patients, secondary reconstruction in 4 patients, osteoradionecrosis in 4, and posttraumatic reconstruction in 2. Seventeen patients underwent radiation. INTERVENTIONS: All patients underwent harvest of an autogenous transplant of scapular tip bone and latissimus dorsi soft tissue based on the thoracodorsal artery. The mean bone length was 5.2 cm (range, 2.5-9.0 cm), and the mean cutaneous surface area was 68 cm² (range, 20-250 cm²). MAIN OUTCOME MEASURES: Reduction of vein grafting, avoidance of 2 transplants, use of the triangular shape of the scapular tip in reconstruction, complications, and shoulder function. RESULTS: The success rate of transplantation was 100%. The use of this transplant avoided vein grafting in 16 patients and the need for 2 separate transplants in 11 patients, and the 3-dimensional nature of the scapular tip facilitated inset in 13 patients. In 14 patients, more than 1 of these reconstructive advantages was achieved. In 6 patients, all 3 were accomplished. Eleven patients experienced a complication. The major complication rate was 33%, and the minor complication rate was 33%. The mean Constant-Murley test of shoulder function score was 87 of 100 (range, 74-100). CONCLUSIONS: The Tdast is an excellent choice for reconstruction in the head and neck as an alternative to procedures requiring vein grafting and multiple free tissue transplants, or in which the 3-dimensional contour of the scapular tip aids in reconstruction. The complication rate should be assessed in the context of the risk factors of the patient population and the outcome with respect to stable employment, increasing body mass index, and maintenance of shoulder function.
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Procedimentos de Cirurgia Plástica/métodos , Escápula/transplante , Retalhos Cirúrgicos/irrigação sanguínea , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Traumatismos Faciais/cirurgia , Neoplasias Faciais/cirurgia , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
The purpose of this work was to determine SEPT9_v1 expression levels in head and neck squamous cell carcinoma (HNSCC) and to analyze whether SEPT9_v1 expression is relevant to clinical outcomes. Recently, the SEPT9 isoform SEPT9_v1 has been implicated in oncogenesis, and methylation of the SEPT9 promoter region was reported in HNSCC. These findings led us to hypothesize that SEPT9_v1 could be differently expressed in HNSCC. To determine whether SEPT9_v1 is expressed in HNSCC, tissue microarray immunohistochemical analysis was performed using a SEPT9_v1-specific antibody. Tissue microarrays stained with a polyclonal SEPT9_v1-specific antibody was used to determine protein expression levels in HNSCC tissue samples, some with known clinical outcomes. This analysis showed that SEPT9_v1 is in fact highly expressed in HNSCC compared with normal epithelium, and high expression levels directly correlated with poor clinical outcomes. Specifically, a high SEPT9_v1 expression was associated with decreased disease-specific survival (P = .012), time to indication of surgery at primary site (P = .008), response to induction chemotherapy (P = .0002), and response to chemotherapy (P = .02), as well as advanced tumor stage (P = .012) and N stage (P = .0014). The expression of SEPT9_v1 was also strongly correlated with smoking status (P = .00094). SEPT9_v1 is highly expressed in HNSCC, and a high expression of SEPT9_v1 is associated with poor clinical outcomes. These data indicate that SEPT9_v1 warrants additional investigation as a potential biomarker for HNSCC.
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BACKGROUND: Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. METHODS: Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. RESULTS: From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. CONCLUSIONS: Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.
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Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Carcinoma/radioterapia , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Receptores do Fator de Crescimento Derivado de Plaquetas/análise , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidoresRESUMO
BACKGROUND: Esophagectomy is indicated occasionally for the treatment of patients with refractory gastroesophageal reflux disease (GERD) or recurrent hiatus hernia. The purpose of this study was to evaluate the impact of previous gastroesophageal operations on outcomes after esophagectomy for recurrent GERD or hiatus hernia. METHODS: Using a prospectively accumulated database, a retrospective review was performed to identify patients undergoing esophagectomy for complicated GERD or hiatus hernia. Mortality, perioperative and functional outcomes, and need for reoperation were evaluated, assessing esophagectomy patients who had undergone prior operations for GERD or hiatus hernia. RESULTS: Of 258 patients with GERD or hiatus hernia undergoing esophagectomy, 104 had undergone a previous operation, with a median interval to esophagectomy of 28 months. Transhiatal resection was accomplished in fewer patients undergoing reoperation (87 of 104 versus 151 of 154; p<0.005). A gastric conduit was used as an esophageal replacement in fewer patients with previous operation(s) (89 of 104 versus 150 of 154; p<0.005). Esophagectomy patients with a history of prior gastroesophageal surgery, as compared with those without, sustained more blood loss and were more likely to require reoperation, and fewer reported good to excellent swallowing function (p<0.05). There was no difference in the occurrence of anastomotic leak. CONCLUSIONS: Esophagectomy in patients who have undergone prior operations for either GERD or hiatus hernia can be accomplished without thoracotomy and with satisfactory intermediate-term quality of life. Such patients should be evaluated and prepared for the use of alternative conduits should the remobilized stomach prove to be an unsatisfactory esophageal substitute at the time of esophagectomy.
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Esofagectomia , Refluxo Gastroesofágico/cirurgia , Hérnia Hiatal/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy. EXPERIMENTAL DESIGN: Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival. RESULTS: One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221). CONCLUSIONS: Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users.
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Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/virologia , Neoplasias Orofaríngeas/complicações , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Fumar/efeitos adversos , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias Orofaríngeas/patologia , RiscoRESUMO
BACKGROUND: For patients with advanced laryngeal cancer, a trial was designed to determine if chemotherapy alone, in patients achieving a complete histologic complete response after a single neoadjuvant cycle, was an effective treatment with less morbidity than concurrent chemoradiotherapy. METHODS: Thirty-two patients with advanced laryngeal or hypopharyngeal cancer received 1 cycle of induction chemotherapy, and subsequent treatment was decided based on response. RESULTS: A histologic complete response was achieved in 4 patients and were treated with chemotherapy alone. All 4 patients' cancer relapsed in the neck and required surgery and postoperative radiotherapy (RT). Twenty-five patients were treated with concomitant chemoradiation. Three patients were treated with surgery. Overall survival and disease-specific survival at 3 years were 68% and 78%, respectively. CONCLUSION: Chemotherapy alone is not feasible for long-term control of regional disease in patients with advanced laryngeal cancer even when they achieve a histologic complete response at the primary site.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Laríngeas/tratamento farmacológico , Adulto , Idoso , Carboplatina/uso terapêutico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Cisplatino/uso terapêutico , Terapia Combinada , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Neoplasias Hipofaríngeas/patologia , Neoplasias Hipofaríngeas/cirurgia , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
OBJECTIVES/HYPOTHESIS: High rates of overall survival (OS) and laryngeal preservation were achieved in two sequential phase II clinical trials in patients with stage III/IV laryngeal squamous cell carcinoma (SCC). Patients were treated with chemoradiation after a >50% primary tumor response to one cycle of neoadjuvant chemotherapy (IC). We analyzed outcomes for T4 patients with cartilage invasion from both studies. STUDY DESIGN: Retrospective. METHODS: Records from 36 patients with T4 SCC of the larynx with cartilage invasion alone (n = 16) or cartilage invasion and extralaryngeal spread (n = 20) were retrospectively reviewed. All were treated with one cycle of cisplatin (100 mg/m(2)) [or carboplatin (AUC 6)] and 5-fluorouracil (1,000 mg/m(2)/d for 5 days) (P+5FU). Those achieving >50% response at the primary tumor received chemoradiation (70 Gy; 35 fractions with concurrent cisplatin-100 mg/m(2) [carboplatin (AUC 6)] every 21 days for 3 cycles), followed by adjuvant P+5FU for complete histologic responders (CHR). Patients with <50% response after IC underwent total laryngectomy and postoperative radiation. RESULTS: Twenty-nine of 36 patients (81%) had >50% response following IC. Of these, 27 received definitive chemoradiation, 23 (85%) obtained CHR, with 58% laryngeal preservation rate. The 3-year OS was 78%, and the disease-specific survival was 80% (median follow-up 69 months). Following chemoradiation, 8/11 (73%) patients with an intact larynx had >75% understandable speech, 6/36 (17%) were g-tube dependent and 6/36 (17%) were tracheostomy dependent. CONCLUSIONS: Our results suggest that chemo-selection is a feasible organ preservation alternative to total laryngectomy for patients with T4 laryngeal SCC with cartilage invasion.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/mortalidade , Invasividade Neoplásica/patologia , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Cisplatino/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/diagnóstico por imagem , Neoplasias Laríngeas/patologia , Masculino , Terapia Neoadjuvante , Estadiamento de Neoplasias , Preservação de Órgãos , Probabilidade , Prognóstico , Qualidade de Vida , Radiografia , Radioterapia Adjuvante , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Carga TumoralRESUMO
BACKGROUND: To evaluate the efficacy of fluorine-18-fluorodeoxyglucose emission tomography (FDG-PET) and CT versus endoscopy with biopsy under general anesthesia for estimating tumor volume reduction among patients treated with induction chemotherapy for advanced squamous cell carcinoma (SCC) of the oropharynx. METHODS: Twelve patients with oropharyngeal SCC nested in a phase II, induction chemoradiation, organ preservation trial (University of Michigan Cancer Center 9921) underwent tumor volume reduction estimation as assessed by FDG-PET, CT, and endoscopy with biopsy. RESULTS: In 9 of 12 patients, FDG-PET, CT, and endoscopy demonstrated agreement in estimation of tumor reduction. Two patients had discordant results, whereas 1 patient was inadequately evaluated with FDG-PET. The kappa value for PET versus endoscopy was 0.62, which is categorized as substantial agreement. The kappa value for CT versus endoscopy was 0.40, which is categorized as fair agreement. CONCLUSION: FDG-PET may be as efficacious as endoscopy with biopsy under general anesthesia for estimating tumor volume reduction with induction chemotherapy.
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Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Orofaríngeas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Fluordesoxiglucose F18 , Humanos , Laringoscopia , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/tratamento farmacológico , Compostos RadiofarmacêuticosRESUMO
Although studies differ in their definition of the older patient, increasing age, when considered as a continuum, is associated with greater operative mortality. Complication rates also seem to be significantly higher with advancing age, possibly because of limited physiologic reserve. As the understanding of risk factors for perioperative morbidity and mortality following esophagectomy has improved, investigators have sought to develop models for risk stratification in which patient age is a significant but not the sole determinant of prospective assessment of risk for complication or mortality. Such prognostic indicators, if validated among independent patient cohorts, can serve as useful adjuncts in decision making with appropriate clinical judgment. In addition, reported patient survival differs dramatically between rates reported by single centers and rates observed in population-based studies, with operative mortality rates typically lower in single-center reports. Although such reports usually are issued from groups with higher operative volume that might be a surrogate for surgical experience, it also is possible that the association between operation volume and improved outcomes reflects optimization of institution-specific infrastructure and/or clinical care pathways. As these processes of care evolve, they should be tailored with attention to differences in the care of older patients who have esophageal cancer. Whether widespread application of such processes of care then can lead to less perioperative mortality and fewer complications and to improved long-term survival remains untested.
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Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Humanos , Resultado do TratamentoRESUMO
PURPOSE: To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. PATIENTS AND METHODS: Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. RESULTS: EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). CONCLUSION: Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.
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Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Receptores ErbB/metabolismo , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/radioterapia , Fumar/efeitos adversos , Proteína Supressora de Tumor p53/metabolismo , Proteína bcl-X/metabolismo , Idoso , Biópsia , Análise Mutacional de DNA , DNA Viral/genética , DNA Viral/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/metabolismo , Papillomaviridae/isolamento & purificação , Estudos Prospectivos , Fatores Sexuais , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaRESUMO
PURPOSE: To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome. PATIENTS AND METHODS: Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m(2)) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m(2)/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m(2) or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV. RESULTS: Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008). CONCLUSION: Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Orofaríngeas/tratamento farmacológico , Seleção de Pacientes , Adulto , Idoso , Área Sob a Curva , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/virologia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/cirurgia , Neoplasias Orofaríngeas/virologia , Paclitaxel/administração & dosagem , Papillomaviridae/isolamento & purificação , Modelos de Riscos Proporcionais , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G(1)-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P < 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P < 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P < 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P < 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas Ativadoras de GTPase/fisiologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 9 da Matriz/biossíntese , Neoplasias Orofaríngeas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Proliferação de Células , Proteínas Ativadoras de GTPase/biossíntese , Humanos , Imuno-Histoquímica , Metaloproteinase 2 da Matriz/biossíntese , Modelos Biológicos , Invasividade Neoplásica , Neoplasias Orofaríngeas/mortalidade , Fenótipo , Resultado do TratamentoRESUMO
BACKGROUND: A quasi-experimental retrospective study was undertaken to evaluate a new concept of free tissue volume restoration combined with bridging reconstruction plate (compartment approach) to reduce plate-related complication rates. METHODS: We evaluated 40 patients with large lateral mandible defects and associated complex soft tissue defects reconstructed with a revascularized soft tissue flap and titanium hollow screw reconstruction plates. A case-control comparison was performed based on reconstruction type: restoration of soft tissue defect (conventional approach-group 1) versus over-reconstruction of soft tissue defect (compartment approach-group 2). RESULTS: Plate exposure rate was 6 of 16 (38%) in group 1 versus 2 of 24 (8%) in group 2, and the difference was statistically significant (p = .04). The mean time to exposure was 10 months. Plate fracture rate was 6 of 23 (26.1%) in dentulous patients versus 1 of 17 (5.9%) in edentulous patients. Gastrostomy tube dependence was 6 of 16 (38%) in group 1 versus 6 of 24 (25%) in group 2. CONCLUSION: The "compartment approach" reduces plate exposure rate and gastrostomy tube dependence. Revascularized osseocutaneous reconstruction is still required in dentulous patients.
Assuntos
Placas Ósseas , Neoplasias de Cabeça e Pescoço/cirurgia , Boca/cirurgia , Procedimentos Cirúrgicos Ortognáticos , Procedimentos de Cirurgia Plástica/métodos , Retalhos Cirúrgicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Induction chemotherapy and concurrent chemoradiation for responders or immediate surgery for non-responders is an effective treatment strategy head and neck squamous cell carcinoma (HNSCC) of the larynx and oropharynx. Biomarkers that predict outcome would be valuable in selecting patients for therapy. In this study, the presence and titer of high risk human papilloma virus (HPV) and expression of epidermal growth factor receptor (EGFR) in pre-treatment biopsies, as well as smoking and gender were examined in oropharynx cancer patients enrolled in an organ sparing trial. HPV16 copy number was positively associated with response to therapy and with overall and disease specific survival, whereas EGFR expression, current or former smoking behavior, and female gender (in this cohort) were associated with poor response and poor survival in multivariate analysis. Smoking cessation and strategies to target EGFR may be useful adjuncts for therapy to improve outcome in the cases with the poorest biomarker profile.
Assuntos
Carcinoma de Células Escamosas/terapia , Receptores ErbB/metabolismo , Papillomavirus Humano 16/isolamento & purificação , Neoplasias Orofaríngeas/terapia , Fatores Sexuais , Fumar/efeitos adversos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/virologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Rap1, a growth regulatory protein that is strongly expressed in human squamous cell carcinoma (SCC), is inactivated by rap1GAP. Recent evidence in normal rat cells suggests that rap1GAP regulates proliferation. The objective of the current study was to investigate whether rap1GAP functions as a tumor suppressor in SCC. Using a pull-down assay, active GTP-bound rap1 was up-regulated in SCC compared to normal or immortalized keratinocytes. Because both rap1A and rap1B isoforms of rap1 are expressed in SCC, the rap1GAP inactivation of both rap1 isoforms was verified using cells transfected with EGFP-rap1A or EGFP-rap1B or co-transfected with FLAG-tagged rap1GAP. The results demonstrate that expression of rap1GAP in oropharyngeal SCC down-regulated active rap1, ERK activation, and proliferation. Incubation of stably transfected SCC cells with nocodazole, an inhibitor of mitosis, caused a slower accumulation of rap1GAP-transfected cells in the G2 phase, in comparison to the vector control, indicating that rap1GAP-transfected cells have slower progression through the cell cycle. This was supported by down-regulation of cyclin D1, cdk4, and cdk6 in rap1GAP-transfected SCC cells. Furthermore, SCC cells transfected with rap1GAP produced significantly smaller tumors in nude mice as compared to controls (P < 0.01). These novel findings suggest that rap1GAP acts as a tumor suppressor protein in SCC.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/prevenção & controle , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias Orofaríngeas/enzimologia , Neoplasias Orofaríngeas/prevenção & controle , Animais , Antineoplásicos/farmacologia , Proliferação de Células , Células Cultivadas , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Fase G2/efeitos dos fármacos , Proteínas Ativadoras de GTPase/genética , Proteínas de Fluorescência Verde , Humanos , Queratinócitos/citologia , Queratinócitos/enzimologia , Rim/metabolismo , Camundongos , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mitose/efeitos dos fármacos , Nocodazol/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transfecção , Proteínas rap de Ligação ao GTP/genética , Proteínas rap de Ligação ao GTP/metabolismo , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismoRESUMO
PURPOSE: To evaluate the ability of a well-known normal tissue complication probability (NTCP) model to predict radiation esophagitis by determining updated model parameters and then comparing these results with the predictive value of other dosimetric parameters. MATERIAL AND METHODS: Clinical and dosimetric data regarding esophagitis were analyzed in 101 inoperable/unresectable non-small-cell lung cancer patients treated by external beam irradiation. Grade 2 or higher esophagitis counted as events. Parameters (TD50, n, and m) of the Lyman normal tissue complication probability (NTCP) model were determined using maximum likelihood analysis, and compared to other dose/volume threshold values including: percentage of esophagus receiving > 40 Gy (V40) to > 75 Gy (V75), and maximum esophageal doses. RESULTS: Sixteen patients developed grade 2-3 acute esophagitis (no G4 or 5). The maximum likelihood analysis produced new Lyman model parameters of: TD50 = 51 Gy, n = 0.44 and m = 0.32. The mean NTCP value is significantly lower (P < 0.001) in the group of patients without esophagitis (13.5%) than with esophagitis (27.2%). The rates of esophagitis are 2.5, 7, 9 and 13.4%, respectively, when the NTCP values are <10%, <15%, <20% and <25%. A significant association is found between esophagitis and dose/volume parameters V40 (P = 0.001) to V70 (P = 0.024). CONCLUSIONS: New values of TD50, n and m offer a good description of the esophagitis distribution in our population. Compared to the use of this model with previously published parameters (associated with late toxicity) predictions of the model for acute esophagitis using the new parameters would indicate that, for a population of patients, the distribution of events as a function of uniform dose would occur with a lower mean uniform dose value (smaller TD50), over a wider range of uniform doses (larger m), while also exhibiting a bigger volume effect (larger n). These new parameter values are supported in essence by the correlations found for the dose/volume threshold parameters.