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1.
Transplantation ; 100(6): 1278-83, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27123877

RESUMO

BACKGROUND: Recent literature suggests that living kidney donation may be associated with an excess risk of end-stage kidney disease and death. Efforts to maximize access to transplantation may result in acceptance of donors who do not fit within current guidelines, potentially placing them at risk of adverse long-term outcomes. METHODS: We studied the risk profile of Australian and New Zealand living kidney donors using data from the Australia and New Zealand Dialysis and Transplant Living Kidney Donor Registry over 2004 to 2012. We compared their predonation profile against national guidelines for donor acceptance. RESULTS: The analysis included 2,932 donors (mean age 48.8 ± 11.2 years, range 18-81), 58% female and 87% Caucasian. Forty (1%) had measured glomerular filtration rate less than 80 mL/min; 32 (1%) had proteinuria >300 mg/day; 589 (20%) were hypertensive; 495 (18%) obese; 9 (0.3%) were diabetic while a further 55 (2%) had impaired glucose tolerance; and 218 (7%) were current smokers. Overall 767 donors (26%) had at least one relative contraindication to donation and 268 (9%) had at least one absolute contraindication according to national guidelines. CONCLUSIONS: Divergence of current clinical practice from national guidelines has occurred. In the context of recent evidence demonstrating elevated long-term donor risk, rigorous follow-up and reporting of outcomes are now mandated to ensure safety and document any change in risk associated with such a divergence.


Assuntos
Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Doadores Vivos , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Complicações do Diabetes , Feminino , Taxa de Filtração Glomerular , Teste de Tolerância a Glucose , Humanos , Hipertensão/complicações , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Obesidade/complicações , Proteinúria/metabolismo , Diálise Renal/estatística & dados numéricos , Fatores de Risco , Fumar , Resultado do Tratamento , Adulto Jovem
2.
Cancer ; 121(12): 1977-84, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25782027

RESUMO

BACKGROUND: Human papillomavirus (HPV) tumor status and surgical salvage are associated with improved prognosis for patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC). Current data regarding types of surgery and the impact of surgery for patients with distant metastatic disease are limited. METHODS: A retrospective analysis of patients with recurrent OPSCC from 2 institutions between 2000 and 2012 was performed. p16 immunohistochemistry and/or in situ hybridization, as clinically available, were used to determine HPV tumor status. Clinical characteristics, distribution of recurrence site, and treatment modalities were compared by HPV tumor status. Overall survival (OS) was examined using Kaplan-Meier and Cox proportional hazards methods. RESULTS: The current study included 108 patients with 65 locoregional and 43 distant metastatic first recurrences. The majority of patients were HPV-positive (80 patients). HPV-positive tumor status was associated with longer time to disease recurrence (P<.01). Anatomic site distribution of disease recurrences did not differ by HPV tumor status. HPV-positive tumor status (adjusted HR [aHR], 0.23; 95% confidence interval [95% CI], 0.09-0.58 [P = .002]), longer time to disease recurrence (≥ 1 year; aHR, 0.36; 95% CI, 0.18-0.74 [P = .006]), and surgical salvage (aHR, 0.26; 95% CI, 0.12-0.61 [P = .002]) were found to be independently associated with OS after disease recurrence. Surgical salvage was independently associated with improved OS compared with nonsurgical treatment among patients with both locoregional (aHR, 0.15; 95% CI, 0.04-0.56 [P = .005]) and distant (aHR, 0.19; 95% CI, 0.05-0.75 [P = .018]) metastatic disease recurrences. CONCLUSIONS: Surgical salvage was found to be associated with improved OS for patients with recurrent locoregional and distant metastatic OPSCC, independent of HPV tumor status. Further prospective data are needed to confirm the role of surgical salvage for distant metastases.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/cirurgia , Neoplasias de Cabeça e Pescoço/virologia , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/virologia , Neoplasias Orofaríngeas/cirurgia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Neoplasias Orofaríngeas/patologia , Infecções por Papillomavirus/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Terapia de Salvação/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de Sobrevida
3.
Am J Otolaryngol ; 36(1): 24-31, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25245411

RESUMO

PURPOSE: The purpose of this study was to determine the incidence of and risk factors for pharyngocutaneous fistula in patients undergoing total laryngectomy at a single institution. MATERIALS AND METHODS: The records of 59 patients undergoing primary or salvage total laryngectomy at our institution from 2001 to 2012 were retrospectively reviewed. Data collected included patient, tumor and treatment characteristics, and surgical technique. Risk factors were analyzed for association with pharyngocutaneous fistula formation. RESULTS: Twenty patients (34%) developed fistulas. Preoperative tracheostomy (OR 4.1; 95% CI 1.3-13 [p=0.02]) and low postoperative hemoglobin (OR 9.1; 95% CI 1.1-78 [p=0.04]) were associated with fistula development. Regarding surgical technique, primary sutured closure of the total laryngectomy defect had the lowest fistula rate (11%). In comparison, primary stapled closure and pectoralis onlay flap over primary closure had nonsignificantly increased fistula rates (43%, OR 6.0; 95% CI 1.0-37.3 [p=0.06] and 25%, OR 2.7; 95% CI 0.4-23.9 [p=0.38], respectively). Pectoralis flap incorporated into the suture line had a significantly increased fistula rate (50%, OR 7.1; 95% CI 1.4-46 [p=0.02]). After stratification for salvage status, patient comorbidities were associated with fistula in non-salvage cases whereas disease-related characteristics were associated with fistula in salvage cases. Fistula development was associated with increased length of hospital stay (p<0.001) and increased time before oral diet initiation (p<0.001). CONCLUSIONS: Pharyngocutaneous fistula is a common complication of total laryngectomy. Preoperative tracheostomy, postoperative hemoglobin, and surgical technique are important in determining the risk of fistula.


Assuntos
Fístula Cutânea/etiologia , Fístula/etiologia , Doenças da Laringe/cirurgia , Laringectomia/efeitos adversos , Doenças Faríngeas/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Hemoglobinas/análise , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Retalhos Cirúrgicos , Traqueostomia/efeitos adversos , Resultado do Tratamento
4.
J Laparoendosc Adv Surg Tech A ; 23(11): 900-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24083851

RESUMO

OBJECTIVE: To report a single institution's experience with transoral robotic surgery (TORS) and its clinical outcomes. This was a retrospective study carried out at a university-affiliated teaching hospital. SUBJECTS AND METHODS: Forty-four consecutive TORS patients with benign and malignant diseases were reviewed. Data on demographics, clinical parameters, and diet were collected. Surgical margins, local and regional recurrence, distant metastasis, 2-year disease-free survival rate, and 2-year survival data were reviewed for the malignant cases. RESULTS: Nine benign and 35 proven squamous cell carcinoma (SCCA) cases underwent TORS. The set-up time was 17.12 minutes (range, 10-40 minutes), and operative time was 53 minutes (range, 10-300 minutes). Average length of stay was 2.5 days. There were seven (6.8%) grade 3 surgical complications. Surgical infection rate was 2.3%. Benign cases were on a regular diet after TORS. Of the malignant cases, 94% were taking peroral diet immediately after the TORS procedure. There were no intraoperative complications and no 30-day postoperative mortalities. The mean follow-up time was 25.2 months (range, 16-38 months) for malignant disease. The SCCA sites were in the oropharynx (30/35), larynx (2/35), and unknown primary with neck metastasis (3/35). Unknown primary patients were excluded in the surgical margin analyses. Negative margins were achieved in 91% of cases. The local and regional recurrence rates were 6.3% (2/32) and 3.1% (1/32), respectively. Two patients (6.3%) developed distant metastasis. Oropharyngeal SCCA cases were reviewed, of which 23 were human papillomavirus (HPV)/p16 positive and 7 were HPV/p16 negative. The 2-year actual survival for HPV-positive and -negative patients was 96% (22/23) and 86% (6/7), respectively. The 2-year disease-free survival for HPV-positive and -negative cases was 91% (21/23) and 71.4% (5/7), respectively. All malignant cases that underwent TORS received postoperative adjuvant therapy. CONCLUSIONS: TORS is a safe procedure with minimal complications and acceptable clinical and functional outcomes.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias de Cabeça e Pescoço/cirurgia , Neoplasias Primárias Desconhecidas/cirurgia , Procedimentos Cirúrgicos Bucais , Robótica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/mortalidade , Neoplasias Primárias Desconhecidas/patologia , Duração da Cirurgia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
6.
Cancer Immunol Immunother ; 62(1): 171-82, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23011589

RESUMO

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells.


Assuntos
Antineoplásicos/administração & dosagem , Vacinas Anticâncer/imunologia , Ciclofosfamida/administração & dosagem , Neoplasias Experimentais/terapia , Vacinas contra Papillomavirus/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Terapia Combinada , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia
7.
Int J Otolaryngol ; 2012: 628578, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23118755

RESUMO

Purpose. To analyze the patterns and associations of adjunctive service visits by head and neck cancer patients receiving primary, concurrent chemoradiation therapy. Methods. Retrospective chart review of patients receiving adjunctive support during a uniform chemoradiation regimen for stages III-IV head and neck squamous cell carcinoma. Univariate and multivariate models for each outcome were obtained from simple and multivariate linear regression analyses. Results. Fifty-two consecutive patients were assessed. Female gender, single marital status, and nonprivate insurance were factors associated with an increased number of social work visits. In a multivariate analysis, female gender and marital status were related to increased social work services. Female gender and stage IV disease were significant for increased nursing visits. In a multivariate analysis for nursing visits, living greater than 20 miles between home and hospital was a negative predictive factor. Conclusion. Treatment of advanced stage head and neck cancer with concurrent chemoradiation warrants a multidisciplinary approach. Female gender, single marital status, and stage IV disease were correlated with increased utilization of social work and nursing services. Distance over 20 miles from the center was a negative factor. This information may help guide the treatment team to allocate resources for the comprehensive care of patients.

8.
Int J Otolaryngol ; 2012: 754191, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22778748

RESUMO

Objective. We reviewed a cohort of patients with previously untreated locoregional advanced head and neck squamous cell carcinoma (HNSCC) who received a uniform chemoradiotherapy regimen. Methods. Retrospective review was performed of 105 patients with stage III or IV HNSCC treated at Greater Baltimore Medical Center from 2000 to 2007. Radiation included 125 cGy twice daily for a total 70 Gy to the primary site. Chemotherapy consisted of cisplatin (12 mg/m(2)/h) daily for five days and 5-fluorouracil (600 mg/m(2)/20 h) daily for five days, given with weeks one and six of radiation. All but seven patients with N2 or greater disease received planned neck dissection after chemoradiotherapy. Primary outcomes were overall survival (OS), locoregional control (LRC), and disease-free survival (DFS). Results. Median followup of surviving patients was 57.6 months. Five-year OS was 60%, LRC was 68%, and DFS was 56%. Predictors of increased mortality included age ≥55, female gender, hypopharyngeal primary, and T3/T4 stage. Twelve patients developed locoregional recurrences, and 16 patients developed distant metastases. Eighteen second primary malignancies were diagnosed in 17 patients. Conclusions. The CRT regimen resulted in favorable outcomes. However, locoregional and distant recurrences cause significant mortality and highlight the need for more effective therapies to prevent and manage these events.

9.
Int J Otolaryngol ; 2012: 508279, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22844290

RESUMO

Background. The purpose of this study was to assess the effects of amifostine on submandibular gland histology in patients receiving chemoradiation therapy. Methods. We conducted a retrospective submandibular gland histologic slide review of HNSCC patients receiving chemoradiation for head and neck squamous cell carcinoma with three different levels of amifostine exposure. We used six scoring parameters: fatty replacement, lobular architecture degeneration, interstitial fibrosis, ductal degeneration, acinar degeneration, and inflammatory component presence. Results. Differences in gender, tumor stage, amifostine dose, age, number of days after neck dissection, and smoking history (pack years) exposure were not significant between the three groups, although there was a difference between groups in the primary subsite (P = 0.006). The nonparametric Cuzick's test for histologic parameters with varied amifostine treatment showed no significance among the three groups. Conclusions. Although patients did not receive a full dose of amifostine due to side effects, varying doses of amifostine had no apparent evident cytoprotective effects in three groups of cancer patients treated with primary chemoradiation.

10.
Ann Surg Oncol ; 19(6): 1980-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22290566

RESUMO

PURPOSE: The optimal dosage and frequency of platinum-based chemoradiotherapy (CRT) regimen for treating advanced head and neck squamous cell carcinoma remains unresolved. This study aims to compare the toxicity and efficacy of weekly versus more dose-intensive cisplatin-based CRTs. METHODS: We reviewed 155 stage III/IV head and neck squamous cell carcinoma patients with no evidence of distant metastasis treated with one of two CRT regimens from 2000 to 2010 at Greater Baltimore Medical Center. Twice-daily radiation was provided as a split course over a 45-day period. Regimen A consisted of concomitant cisplatin (30 mg/m2/1 h) weekly for 6 cycles; regimen B consisted of concomitant cisplatin (12 mg/m2/1 h) and 5-fluorouracil (600 mg/m2/20 h) on days 1 through 5 and days 29 through 33. Main outcome measures included acute toxicities (myelosuppression, neurotoxicity, nephrotoxicity, gastrointestinal dysfunction), unplanned hospitalizations, and disease control at 12 months. RESULTS: Patients on regimen A were much less likely to experience ototoxicity due to their treatment (0% vs. 9.8%, P = 0.04). They were more likely to experience thrombocytopenia acutely (46% vs. 26%, P = 0.02), but the toxicity was not limiting (grade 1­2). No significant differences exist in the incidence of other toxicities or unplanned hospitalizations. At 1 year, 97% of patients on A vs. 86% of patients on regimen B were free of disease (P = 0.11). CONCLUSIONS: With concurrent radiotherapy, low-dose, single-agent, weekly cisplatin is less likely than higher-dose daily cisplatin plus 5-fluorouracil provided at the beginning and end of treatment to be associated with ototoxicity. The preliminary data suggest at least equivalent efficacy, but longer follow-up is required.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Lesões por Radiação/etiologia , Doença Aguda , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Cisplatino/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
11.
Cancer Prev Res (Phila) ; 4(2): 207-17, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21292634

RESUMO

Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16-associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers.


Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA , DNA Viral/genética , Neoplasias de Cabeça e Pescoço/genética , Papillomavirus Humano 16/genética , Neoplasias do Colo do Útero/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Epigenômica , Feminino , Genoma Viral , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , RNA Viral/genética , Proteínas Repressoras/genética , Saliva , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Carga Viral , Integração Viral
12.
Head Neck ; 33(12): 1727-34, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21246640

RESUMO

BACKGROUND: The purpose of this study was to elucidate factors associated with pharyngoesophageal strictures after treatment for head and neck squamous cell carcinoma (SCC). METHODS: We conducted a retrospective review of patients receiving cisplatin and 5-fluorouracil chemotherapy combined with concurrent hyperfractionated radiation therapy for oropharyngeal squamous cell carcinoma. RESULTS: Strictures developed in 13 of 67 patients (19%). Strictures were associated with tumor location (tonsil vs base of tongue; p = .03), neck dissection after completion of therapy (p = .03), and the duration of treatment-induced mucositis (weeks with mucositis grade ≥2; National Cancer Institute (NCI) Common Toxicity Criteria; p < .001). Age, sex, race, tumor stage, nodal stage, American Joint Committee on Cancer (AJCC) stage, human papillomavirus (HPV) status, smoking, radiation dose, maximum severity of mucositis, amifostine use, and pretreatment swallow dysfunction were not significantly associated with stricture. In multivariate analysis, only duration of mucositis, after controlling for age, sex, and tumor location, remained highly significant (p < .01). CONCLUSION: The duration of treatment-related mucositis is an independent risk factor for stricture formation in patients with oropharyngeal SCC treated with concurrent chemotherapy and radiation therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/radioterapia , Estenose Esofágica/etiologia , Neoplasias Orofaríngeas/radioterapia , Doenças Faríngeas/etiologia , Lesões por Radiação , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Terapia Combinada , Constrição Patológica , Fracionamento da Dose de Radiação , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/tratamento farmacológico , Estomatite/etiologia
15.
Ear Nose Throat J ; 89(1): 34-7, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20155698

RESUMO

Lipomas are benign mesenchymal tumors that are often found in the head and neck. Intrinsic lipomas of the larynx and supraglottic area are rare, as fewer than 115 cases have been reported in the literature; almost all of these occurred in isolation. We report a case of a laryngeal lipoma that was associated with diffuse systemic lipomatosis. The tumor was successfully removed via an endoscopic laser resection. To the best of our knowledge, this is only the second case of laryngeal lipoma associated with lipomatosis to be reported in the English-language literature. We also review the literature on head and neck lipomas.


Assuntos
Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/patologia , Lipoma/patologia , Lipomatose/epidemiologia , Humanos , Neoplasias Laríngeas/cirurgia , Lipoma/cirurgia , Masculino , Pessoa de Meia-Idade
16.
Laryngoscope ; 120(3): 504-10, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20025042

RESUMO

OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV) types 6 and 11 are associated with recurrent respiratory papillomatosis (RRP). Although a prophylactic vaccine has been developed that protects against HPV infection, a therapeutic vaccine is still needed for those patients infected with and/or suffering from persistent disease. Therefore, we developed a novel, therapeutic DNA vaccine targeting HPV-11 and characterized the in vivo immunologic responses generated against HPV-11 E6 and E7 after DNA vaccination in a preclinical model. METHODS: We generated a DNA vaccine that encodes the HPV-11 E6 and E7 genes in a pcDNA3 backbone plasmid. We then vaccinated C57BL/6 mice with the pcDNA3-HPV11-E6E7 DNA plasmid. Splenocytes were harvested from these vaccinated animals and were incubated with overlapping peptides spanning either the HPV-11 E6 or E7 protein. The frequency of interferon-gamma-releasing CD8(+) T cell responses was then analyzed by flow cytometry. RESULTS: Vaccinated mice with the HPV11-E6E7 DNA generated strong CD8(+) T cell responses against the E6(aa44-51) peptide. We determined that the epitope is presented by the MHC class I H2-K(b) molecule. No significant E7 peptide-specific T cell responses were observed. CONCLUSIONS: We developed a novel DNA vaccine that targets the E6 gene of HPV-11. Characterization of the immunologic responses elicited by this DNA vaccine reveals that the E6(aa44-51) peptide contains the most immunogenic region for the HPV-11 viral type. Knowledge of this specific T cell epitope and generation of a RRP preclinical model will allow for the development and evaluation of novel vaccine strategies targeting the RRP patient population.


Assuntos
Papillomavirus Humano 11/imunologia , Infecções por Papillomavirus/imunologia , Vacinas de DNA/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos C57BL
17.
Otolaryngol Head Neck Surg ; 141(6): 737-42, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19932847

RESUMO

OBJECTIVE: To determine whether a comprehensive neck dissection (CND) or a selective neck dissection (SND) is indicated as planned post-primary chemoradiation treatment (CRT) for patients with advanced oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Case series with chart review. SETTING: A community teaching hospital. SUBJECTS: Patients with advanced OPSCC who received a uniform CRT protocol at Greater Baltimore Medical Center (GBMC). METHODS: Medical records of patients treated with primary CRT for locoregionally advanced OPSCC at GBMC between 2001 and 2007 were reviewed. All patients received 7000 to 7500, 6000, and 5000 cGy to primary disease sites, involved cervical lymphatics, and uninvolved cervical and supraclavicular lymphatics, respectively, with concomitant cisplatin (12 mg/m(2)/1 h) and 5-fluorouracil (600 mg/m(2)/20 h) given on days one through five and 29 through 33. RESULTS: Seventy-six patients received CRT, and 41 met the criteria for neck dissection. Forty-eight neck dissections were performed (34 unilateral and 7 bilateral), of which 23 (48%) were CNDs and 25 (52%) were SNDs. Residual carcinoma was found in six (26%) of the CND and five (20%) of the SND heminecks. The CND group had six (26%) complications, whereas the SND group had two (8%). CONCLUSION: The high rate of residual disease demonstrated in this study supports the need for post-CRT neck dissection. Although complication rates were not significantly different between the two groups, the trend in this study indicates that SND results in less morbidity. The presumed reduced morbidity and equivalent regional control rate suggest that SND is an appropriate surgical option for OPSCC patients after primary CRT.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Esvaziamento Cervical/métodos , Neoplasias Orofaríngeas/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Distribuição de Qui-Quadrado , Cisplatino/administração & dosagem , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/radioterapia , Complicações Pós-Operatórias , Dosagem Radioterapêutica , Taxa de Sobrevida , Resultado do Tratamento
18.
Artigo em Inglês | MEDLINE | ID: mdl-19776658

RESUMO

OBJECTIVE: The purpose of our study was to evaluate PET/CT in predicting residual nodal disease after primary chemoradiation (CRT) for head and neck cancer (HNSCC) with N2 disease or greater. DESIGN: A retrospective cohort analysis was conducted. Thirty-eight patients received primary CRT for HNSCC with N2 or greater disease, PET/CT after treatment and neck dissection from January 2003 to December 2006. PET/CT results were correlated with pathology results from neck dissection specimens for each respective side. RESULTS: Forty-six neck regions were analyzed. Nine were determined to have either PET/CT result reports (n = 5) or pathology reports (n = 4) that were indeterminate. PET/CT demonstrated a sensitivity and specificity of 57.1 and 73.9%, respectively, an accuracy of 67.5%, a positive predictive value of 57.1% and a negative predictive value of 73.9% when compared to the final pathology. CONCLUSION: PET/CT is neither highly sensitive nor highly specific for identifying residual nodal metastases after CRT for advanced-stage HNSCC. Physicians should not rely solely on PET/CT to determine interventions on the neck after CRT. A standardization of language for reporting findings and risk of residual disease is needed.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirurgia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/cirurgia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Idoso , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Neoplasia Residual/radioterapia , Neoplasia Residual/cirurgia , Neoplasias Faríngeas/diagnóstico , Neoplasias Faríngeas/radioterapia , Neoplasias Faríngeas/cirurgia , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/radioterapia , Neoplasias da Língua/cirurgia , Neoplasias Tonsilares/diagnóstico , Neoplasias Tonsilares/radioterapia , Neoplasias Tonsilares/cirurgia , Resultado do Tratamento
19.
Vaccine ; 27(40): 5450-9, 2009 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-19622402

RESUMO

DNA vaccines are an attractive approach to eliciting antigen-specific immunity. Intracellular targeting of tumor antigens through its linkage to immunostimulatory molecules such as calreticulin (CRT) can improve antigen processing and presentation through the MHC class I pathway and increase cytotoxic CD8+ T cell production. However, even with these enhancements, the efficacy of such immunotherapeutic strategies is dependent on the identification of an effective route and method of DNA administration. Electroporation and gene gun-mediated particle delivery are leading methods of DNA vaccine delivery that can generate protective and therapeutic levels of immune responses in experimental models. In this study, we perform a head-to-head comparison of three methods of vaccination--conventional intramuscular injection, electroporation-mediated intramuscular delivery, and epidermal gene gun-mediated particle delivery--in the ability to generate antigen-specific cytotoxic CD8+ T cell responses as well as anti-tumor immune responses against an HPV-16 E7 expressing tumor cell line using the pNGVL4a-CRT/E7(detox) DNA vaccine. Vaccination via electroporation generated the highest number of E7-specific cytotoxic CD8+ T cells, which correlated to improved outcomes in the treatment of growing tumors. In addition, we demonstrate that electroporation results in significantly higher levels of circulating protein compared to gene gun or intramuscular vaccination, which likely enhances calreticulin's role as a local tumor anti-angiogenesis agent. We conclude that electroporation is a promising method for delivery of HPV DNA vaccines and should be considered for DNA vaccine delivery in human clinical trials.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas de DNA/administração & dosagem , Animais , Anticorpos Antivirais/sangue , Linhagem Celular Tumoral , Eletroporação , Feminino , Injeções Intradérmicas , Injeções Intramusculares , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus , Vacinas contra Papillomavirus/imunologia , Vacinação/métodos , Vacinas de DNA/imunologia
20.
Laryngoscope ; 119(8): 1542-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19522004

RESUMO

OBJECTIVES/HYPOTHESIS: The human papillomavirus (HPV) has been identified as a causative factor in 20% to 25% of all head and neck squamous cell carcinomas (HNSCC). Ongoing research suggests that the presence of HPV DNA in HNSCC predicts a positive prognosis with respect to disease-free and overall survival. However, most studies have been limited by the heterogeneity in treatment regimens and/or anatomic subsites of tumor origin. In this study, we correlate clinical outcomes with HPV status for patients with oropharyngeal carcinomas who were uniformly treated with a concurrent chemoradiation treatment protocol. STUDY DESIGN: Retrospective study. METHODS: Demographic and clinicopathologic parameters, including age at diagnosis, gender, race, smoking and alcohol history, tumor stage and grade, locoregional recurrence, metastatic spread, recurrence-free survival, overall survival and disease-specific death, were obtained from medical charts and established databases. These parameters were correlated with HPV status of the tumors established by in situ hybridization analysis. RESULTS: HPV positivity correlated with improved clinical outcomes regarding locoregional control (P = .042), recurrence-free survival (P = .009), overall survival (P = .017), and disease-specific death (P = .09). Advanced T stage was a significant risk factor for recurrence and death independent of HPV status. CONCLUSIONS: In patients with oropharyngeal carcinoma uniformly treated with chemoradiation, the presence of HPV is a favorable prognostic indicator with respect to recurrence and overall survival. However, advanced T stage was an independent risk factor for recurrence and death that can to some degree offset this benefit.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Adulto , Idoso , Análise de Variância , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Terapia Combinada , Intervalos de Confiança , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/virologia , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/terapia , Infecções por Papillomavirus/terapia , Valor Preditivo dos Testes , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
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