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1.
Clin Lung Cancer ; 21(2): 127-135.e3, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31932216

RESUMO

INTRODUCTION: Understanding temporal and anatomic patterns of lung cancer recurrence could guide disease management and monitoring. However, these data are not available in population-based datasets and are not routinely recorded in clinical trials. MATERIALS AND METHODS: We identified cases of stage 1 to 3 lung cancer diagnosed January 1, 2000, to December 31, 2017, in the tumor registry of a National Cancer Institute-designated comprehensive cancer center. For cases with documented disease recurrence, we recorded anatomic site(s) and timing. We estimated time to recurrence using Kaplan-Meier methods. Associations between case characteristics and recurrence features were assessed using univariable and multivariable logistic regression models and Cox regression models. RESULTS: A total of 1619 cases of stage 1 to 3 lung cancer from 1549 patients were included in the analysis. Of these, 466 (30%) patients developed recurrent lung cancer. The most common type of first recurrence was distant disease, most commonly central nervous system (CNS) (37%). In multivariable analyses, race (P = .02) and primary treatment modality (P < .001) correlated with recurrent disease, whereas tumor histology (P = .004) and primary treatment modality (P < .001) were associated specifically with distant recurrence. Patient age (P = .05) and initial TNM stage (P = .001) correlated with timing of recurrence. CONCLUSION: In this single-center series of stage 1 to 3 lung cancer, recurrent disease was associated with race, histology, and treatment modality, and most commonly occurred in the CNS. Modulation of clinical and radiographic disease monitoring according to recurrence risk, timing, and site may offer a means to identify future lung cancer when it remains asymptomatic and highly treatable.

2.
Urol Oncol ; 37(10): 758-764, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31378586

RESUMO

PURPOSE: To identify preoperative risk factors for disease recurrence, following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), and to create a predictive nomogram. MATERIALS AND METHODS: Based on a multicenter database, we identified patients who underwent RNU due to high grade UTUC. Urothelial carcinoma of the bladder or contralateral UTUC was not considered as recurrence. Cox regression model was used to determine the effect of different preoperative variables as predictors of recurrence. RESULTS: Two hundred and forty-five patients were included in the analysis. The 2 and 5 years recurrence rates were 16.3% and 19.2%, respectively. Factors associated with recurrence on univariable analysis were sessile architecture hazard ratio (HR) 3.16 (95% CI, 1.38-7.26, P = 0.006), ≥cT3 disease HR 2.30 (95% CI, 1.12-4.72, P= 0.023), age >65 HR 2.02 (95% CI, 1.00-4.05, P= 0.048), Eastern Cooperative Group > 0 HR 1.98 (95% CI, 1.09-3.57, P= 0.023), hydronephrosis HR 1.93 (95% CI, 1.04-3.57, P= 0.035). Higher hemoglobin levels HR 0.81 (95% CI, 0.69-0.96, P= 0.013) and preoperative estimated glomerular filtration rate ≥ 50 HR 0.48 (95% CI, 0.25-0.92, P = 0.028) were associated with lower probability for recurrence. Multivariable analysis identified sessile architecture as the only independent predictor of recurrence HR 2.52 (95% CI, 1.09-5.86, P= 0.0308). C-index of 0.71 was calculated for a predictive model including all variables in the multivariable analysis, indicating good predictive accuracy. A nomogram predicting 2 and 5 year recurrence free probability was developed accordingly. CONCLUSIONS: Based on a multicenter database, we developed a nomogram with good predictive accuracy for recurrence following RNU. This may serve as an aid in decision-making regarding the use of neoadjuvant chemotherapy.

3.
J Surg Res ; 241: 119-127, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31022677

RESUMO

BACKGROUND: The robotic approach to an inguinal hernia has not been compared head to head with the open and laparoscopic techniques in randomized controlled trials. Furthermore, long-term outcomes for robotic inguinal hernia repair (RHR) are lacking. In this study, we compared laparoscopic inguinal hernia repair (LHR) and RHR with open inguinal hernia repair (OHR) in veteran patients performed by surgeons most familiar with each approach. METHODS: A retrospective single-institution analysis of 1299 inguinal hernia repairs performed at the VA North Texas Health Care System between 2005 and 2017 was undertaken. Three surgeons performed the operations, each an expert in one approach, and there was no crossover in techniques. A total of 1100 OHRs, 128 LHRs, and 71 RHRs were performed. Univariable analysis was undertaken to determine associations between techniques and outcomes (OHR versus LHR; OHR versus RHR; LHR versus RHR). Setting complications as a dependent variable, multivariable analyses were undertaken to determine an association with complications as well as independent predictors of complications. RESULTS: Patient demographics were similar among groups except for age that was higher in the OHR cohort. The average follow-up was 5.2 ± 3.4 y. In the present report, recurrence was associated with a higher rate in the RHR versus OHR (5.6% versus 1.7%; P < 0.02), but not in the LHR versus OHR (3.9% versus 1.9%; P = 0.09). Inguinodynia was more likely to occur in both the LHR and RHR compared with the OHR (9.4% and 14.1 versus 1.5%; both P's < 0.001). Urinary retention was also more common in the LHR and RHR than in the OHR (5.5% and 5.6% versus 1.8%, both P's < 0.05) as was the rate of overall complications (34.4% and 38.0% versus 11.2%, both P's < 0.001). Multivariable regression analysis showed femoral hernias, ASA, serum albumin, operative room time, a recurrent hernia, and the minimally invasive approaches were independent predictors of overall complications. CONCLUSIONS: Outcomes in the OHR cohort were, in general, superior compared with both the LHR and RHR. However, these strategies should be viewed as complementary. The best approach to an inguinal hernia repair rests on the specific expertise of the surgeon.


Assuntos
Hérnia Inguinal/cirurgia , Herniorrafia/efeitos adversos , Laparoscopia/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Idoso , Feminino , Hérnia Inguinal/sangue , Herniorrafia/métodos , Humanos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Prognóstico , Recidiva , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Albumina Sérica Humana/análise , Resultado do Tratamento
4.
Oral Oncol ; 88: 18-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30616791

RESUMO

OBJECTIVES: To determine the comparative effectiveness of primary radiotherapy (RT) and primary surgery (PS) for locally advanced oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: Eligible individuals were patients in the SEER-Medicare registry diagnosed with locally advanced OPSCC between 2000 and 2011. Patients were categorized as receiving either primary RT ±â€¯chemotherapy, or PS ±â€¯adjuvant RT or chemoradiotherapy (CRT). Overall survival (OS) was analyzed using Cox multivariable analysis (MVA). Risks of gastrostomy dependence (GD), esophageal stricture (ES), and osteoradionecrosis (ORN) were analyzed using logistic regression. RESULTS: A total of 2754 patients (69% RT, 31% PS) were included in this cohort, with a median age of 72 years. Patients treated with RT, CRT and PS experienced 3-year OS outcomes of 36.1%, 52.8%, and 54.9%, respectively (p < 0.001). Increasing age, unmarried status, increasing comorbidity, lower income, base of tongue (BOT) site, higher stage, no prior PET, and RT alone (but not CRT) were associated with inferior OS. Independent predictors of GD at 6 months included black race, BOT site, advanced stage, and CRT. The risks of ORN and stricture were not associated with treatment modality. Concurrent chemotherapy improved OS with definitive RT but had no impact in adjuvant RT. Only cisplatin- and taxane-containing regimens improved OS, but all concurrent agents, including cetuximab, significantly worsened GD. CONCLUSION: Local therapy decisions for locally advanced OPSCC must be individualized, with CRT increasing acute and chronic GD. The differential survival impact of concurrent chemotherapy in the definitive and adjuvant setting may be a consideration in decision-making.

5.
Cancer Res ; 78(21): 6196-6208, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30185546

RESUMO

Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non-small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to γ-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth in vivo These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA-damaging agents or as an immunotherapeutic target in patients.Significance: This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC. Cancer Res; 78(21); 6196-208. ©2018 AACR.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Animais , Antígenos de Neoplasias/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Dano ao DNA , Reparo do DNA , Feminino , Radicais Livres , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Mutagênicos , Transplante de Neoplasias , Estresse Oxidativo , Prognóstico , Recombinação Genética
6.
J Oncol Pract ; 13(12): e982-e991, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29019706

RESUMO

PURPOSE: The National Cancer Institute (NCI) requirement that clinical trials at NCI-designated cancer centers undergo institutional scientific review in addition to institutional review board evaluation is unique among medical specialties. We sought to evaluate the effect of this process on protocol activation timelines. METHODS: We analyzed oncology clinical trials that underwent full board review by the Harold C. Simmons Comprehensive Cancer Center Protocol Review and Monitoring Committee (PRMC) from January 1, 2009, through June 30, 2013. We analyzed associations between trial characteristics, PRMC decisions, protocol modifications, and process timelines using the χ2 test, Fisher's exact test, Wilcoxon rank sum test, Kruskal-Wallis test, and logistic regression. RESULTS: A total of 226 trials were analyzed. Of these, 77% were industry sponsored and 23% were investigator initiated. The median time from submission to PRMC approval was 55 days. The length of review was associated with trial phase, timing of approval, and number of committee changes/clarifications requested. The median process time was 35 days for those approved at first decision, 68 days for second decision, and 116 days for third decision ( P < .001). The median process time was 39 days if no changes/clarifications were requested, 64 days for one to three changes/clarifications, and 73 days for four or more changes/clarifications ( P < .001). Requested changes/clarifications had a greater effect on industry-sponsored trials than on investigator-initiated trials. CONCLUSION: NCI-mandated institutional scientific review of oncology clinical trials contributes substantially to protocol activation timelines. Further evaluation of this process and the value added to research quality is warranted.


Assuntos
Neoplasias/tratamento farmacológico , Comitês Consultivos/estatística & dados numéricos , Protocolos Clínicos , Comitês de Ética em Pesquisa/estatística & dados numéricos , Humanos , National Cancer Institute (U.S.)/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Estados Unidos
7.
J Thorac Oncol ; 12(10): 1489-1495, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28802905

RESUMO

INTRODUCTION: Eligibility criteria and screening procedures are designed to optimize the scientific yield and maximize the safety of clinical trials. However, they may also heighten trial complexity, hinder enrollment, decrease generalizability, and increase costs. We analyzed the types and number of eligibility criteria and screening procedures among thoracic oncology clinical trials sponsored or endorsed by the Eastern Cooperative Oncology Group. METHODS: We identified trials and obtained protocols from the Eastern Cooperative Oncology Group website. Eligibility criteria were grouped and categorized as comorbidity (classified by organ system), administrative requirements, prior treatment, and measurable disease requirements. Associations between trial characteristics and eligibility criteria were analyzed by using the Kruskal-Wallis and Wilcoxon tests. RESULTS: A total of 74 lung cancer trials activated in 1986-2016 were identified. The total number of eligibility criteria was associated with trial principal therapy (a median of nine for surgical, 18 for radiation, and 20 for medical therapy [p = 0.02]), trial primary end point (a median of 20 for overall survival, 28 for progression-free survival, and 17 for other [p = 0.001]), number of therapies (p = 0.05), and year of activation (a median of 16 for 1986-1995, 19 for 1996-2005, and 27 for 2006-2016 [P < 0.001]). The increase in trial eligibility requirements over time was limited to medical therapy trials. Over time, there was also an increase in blood test screening procedures (p = 0.05) but not in imaging, cardiac assessment, or pulmonary function screening procedures. CONCLUSIONS: The number of eligibility criteria and screening procedures in medical therapy lung cancer clinical trials continues to rise. Continued efforts to simplify protocol eligibility and procedures are warranted to promote trial adherence, enrollment, completion, and generalizability.


Assuntos
Ensaios Clínicos como Assunto/métodos , Definição da Elegibilidade/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Torácicas/diagnóstico , Humanos , Neoplasias Pulmonares/patologia , Projetos de Pesquisa , Neoplasias Torácicas/patologia
8.
Clin Lung Cancer ; 18(6): 626-630, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28576594

RESUMO

BACKGROUND: Increasingly, analysis of tumor tissue samples for predictive and pharmacodynamic biomarkers is incorporated into lung cancer clinical trials. We determined the time and effort required for tissue acquisition and submission. PATIENTS AND METHODS: We analyzed data from patients enrolled from 2009 to 2016 at UT Southwestern onto lung cancer trials with mandatory or optional submission of tumor tissue. We collected dates of treatment-related events and staff communications; nature of tissue requirement and biomarker analysis; and location of archival tissue. Associations between case characteristics, clinical intervals, and number of staff communications were analyzed by Fisher's exact test, Wilcoxon 2-sample test, and Kruskal-Wallis test. RESULTS: We identified 129 patients enrolled onto 19 clinical trials, of whom 108 (84%) ultimately received study therapy. For cases in which tissue submission was required if available or optional, 16% and 0%, respectively, had tissue sent. The median interval between consent and treatment was 28 (interquartile range, 11-43) days if tissue was requested and 7 (interquartile range, 6-13) days if tissue was not requested (P < .001). Among cases with requested tissue, the median number of related research staff communications was 3 (range, 0-10). Over time, the number of staff communications increased (P < .001). Location of archival tissue was not associated with number of staff communications or treatment intervals. CONCLUSION: Lung cancer clinical trial requirements for tissue acquisition and submission affect the time to treatment initiation and require increasing staff effort. Improved systems to expedite these processes, as well as use of blood- or imaging-based biomarkers, may help address these issues.


Assuntos
Biomarcadores/análise , Ensaios Clínicos como Assunto/métodos , Neoplasias Pulmonares/patologia , Manejo de Espécimes/métodos , Comunicação , Humanos , Estatísticas não Paramétricas , Fatores de Tempo
9.
Am J Clin Oncol ; 40(6): 612-620, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26165416

RESUMO

OBJECTIVES: Salvage radiation therapy (SRT) is an effective treatment for recurrent prostate cancer (PCa) after radical prostatectomy. We report the long-term outcome of men who developed biochemical recurrence (BCR) after SRT and were treated >14 years ago. METHODS: In total, 61 patients treated with SRT from 1992 to 2000 at our institution were identified. Survival was calculated by Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters. RESULTS: The median follow-up was 126 months (interquartile range, 66-167 mo). Thirty-four (56%) had prostate-specific antigen (PSA) failure after SRT. At 10 years, overall survival (OS) was 67%, freedom from PSA failure (FFPF) was 33%, prostate cancer-specific survival (PCSS) was 84%, and distant metastases-free survival (DMFS) was 84%. Pathologic T-stage, Gleason score, seminal vesicle involvement, and pre-SRT PSA were associated with FFPF. For patients who failed SRT, the median time to BCR after SRT was 30 mo. A total of 19 (68%) received androgen deprivation therapy. The median OS was 13.6 years. At 10 years from time of BCR, OS was 59%, PCSS was 73%, DMFS was 75%, and castration-resistant-free survival was 70%. Early SRT failure correlated with significantly decreased DMFS and PCSS. Ten-year DMFS from SRT was 43% (BCR≤1 y) versus 91% (BCR>1 y). CONCLUSIONS: Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.


Assuntos
Recidiva Local de Neoplasia/radioterapia , Prostatectomia , Neoplasias da Próstata/radioterapia , Radioterapia , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Humanos , Calicreínas/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/sangue , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos
10.
Pract Radiat Oncol ; 7(1): e43-e49, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27637137

RESUMO

PURPOSE: We hypothesized that high-dose stereotactic body radiation therapy (SBRT) would lead to faster time to nadir and lower nadir values compared with conventional radiation therapy experiences. We now report prostate-specific antigen (PSA) kinetics following high-dose SBRT in patients treated with radiation alone. METHODS AND MATERIALS: Ninety-one patients were enrolled on the phase 1/2 dose escalation study of SBRT for localized prostate cancer. All patients with at least 36 months of follow-up and without hormone therapy were included in this analysis (n = 47). Treatment response parameters evaluated include time to nadir, nadir value, occurrence of PSA bounces (rise of ≥0.2 ng/mL followed by a subsequent fall), magnitude of bounces, duration of bounces, and correlation of bounces with clinical outcomes. RESULTS: Median follow-up was 42 months (range, 36-78 months). Treatment dose levels were 45 Gy (n = 10), 47.5 Gy (n = 8), and 50 Gy (n = 29) in 5 fractions. Biochemical control rate was 98%. Median PSA at follow-up was 0.10 ± 0.20 ng/mL. Median time to nadir was 36 ± 11 months. A total of 24/47 (51.1%) patients had ≥1 PSA bounce. Median magnitude of PSA rise during bounce was 0.50 ± 1.2 ng/mL. Median time to first bounce was 9 ± 7.0 months. Median bounce duration was 3 ± 2.3 months for the first bounce and 6 ± 5.2 months for subsequent bounces. Prostate volumes <30 mL were associated with a decreased likelihood of bounce (P = .0202), and increasing prostate volume correlated with increasingly likelihood of having ≥2 bounces (P = .027). Patients reaching PSA nadir of ≤0.1 ng/mL were less likely to experience any bounce (P = .0044). CONCLUSIONS: Compared with other SBRT experiences, our study demonstrated a higher PSA bounce rate, a similar or shorter median time to bounce, and a very low nadir. Prostate volume appears correlated with bounce.


Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/radioterapia , Radiocirurgia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Dosagem Radioterapêutica , Resultado do Tratamento
11.
Breast Cancer Res Treat ; 161(3): 463-471, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28005245

RESUMO

PURPOSE: The objective is to define the therapeutic role of antiplatelet agents in a triple-negative breast cancer (TNBC) population. METHODS: We performed retrospective analysis using the UTSW TNBC registry containing data from 222 Stage II-III TNBC patients treated between 1998 and 2016. Univariate analysis and multivariable logistic regression models were constructed to identify factors associated with disease-free survival (DFS), distant metastases rate (DMR), and overall survival outcomes. Antiplatelet drug use was determined by review of electronic medical records. RESULTS: A total of 65 patients used antiplatelet (AP) agents, and 157 patients did not use AP agents. Median follow-up for AP and non-AP groups was 41.3 and 40.9 months, respectively. There was an improvement in the AP group compared with the control group in 5-year DFS (80.4% at 5 years compared with 62.3% in the control group, p = 0.04) and 5-year DMR (8.8 vs. 31.9%, p = 0.007). In multivariate analysis, AP use was found to be significantly associated with improvements in DFS and DMR. CONCLUSIONS: We illustrate that antiplatelet agent use improves DMR and DFS among a stage II and III TNBC population despite our short follow-up evaluation. Longer follow-up evaluation will be required to determine additional outcome advantage for antiplatelet agent use. Our findings support consideration of investigation of antiplatelet therapy as an adjunctive therapy for TNBC at high risk for disease recurrence.


Assuntos
Aspirina/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aspirina/administração & dosagem , Neoplasias da Mama , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores da Agregação de Plaquetas/administração & dosagem , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/diagnóstico
12.
Cancer Cell ; 30(6): 940-952, 2016 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-27960087

RESUMO

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and ß-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with ß-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and ß-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , NAD(P)H Desidrogenase (Quinona)/genética , Naftoquinonas/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Camundongos , Naftoquinonas/farmacologia , Neoplasias Pancreáticas/genética , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Radiother Oncol ; 119(3): 501-4, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27156652

RESUMO

PURPOSE/OBJECTIVE: The aim of this study is to predict early distant failure in early stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) using clinical parameters by machine learning algorithms. MATERIALS/METHODS: The dataset used in this work includes 81 early stage NSCLC patients with at least 6months of follow-up who underwent SBRT between 2006 and 2012 at a single institution. The clinical parameters (n=18) for each patient include demographic parameters, tumor characteristics, treatment fraction schemes, and pretreatment medications. Three predictive models were constructed based on different machine learning algorithms: (1) artificial neural network (ANN), (2) logistic regression (LR) and (3) support vector machine (SVM). Furthermore, to select an optimal clinical parameter set for the model construction, three strategies were adopted: (1) clonal selection algorithm (CSA) based selection strategy; (2) sequential forward selection (SFS) method; and (3) statistical analysis (SA) based strategy. 5-cross-validation is used to validate the performance of each predictive model. The accuracy was assessed by area under the receiver operating characteristic (ROC) curve (AUC), sensitivity and specificity of the system was also evaluated. RESULTS: The AUCs for ANN, LR and SVM were 0.75, 0.73, and 0.80, respectively. The sensitivity values for ANN, LR and SVM were 71.2%, 72.9% and 83.1%, while the specificity values for ANN, LR and SVM were 59.1%, 63.6% and 63.6%, respectively. Meanwhile, the CSA based strategy outperformed SFS and SA in terms of AUC, sensitivity and specificity. CONCLUSIONS: Based on clinical parameters, the SVM with the CSA optimal parameter set selection strategy achieves better performance than other strategies for predicting distant failure in lung SBRT patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Radiocirurgia , Idoso , Algoritmos , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Falha de Tratamento
14.
Mol Cancer Ther ; 15(7): 1757-67, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27196777

RESUMO

UNLABELLED: Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H: quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and ß-lapachone (ß-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. ß-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by ß-lap using long-term survival assays. The combination of nontoxic ß-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD(+), and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating ß-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to ß-lap-induced radiosensitization. Mol Cancer Ther; 15(7); 1757-67. ©2016 AACR.


Assuntos
Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , NAD(P)H Desidrogenase (Quinona)/genética , Tolerância a Radiação/genética , Radiação Ionizante , Trifosfato de Adenosina/metabolismo , Animais , Catalase/genética , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Modelos Animais de Doenças , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nat Commun ; 6: 8840, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26567849

RESUMO

Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer-testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFß signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFß signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology.


Assuntos
Antígenos de Neoplasias/genética , Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Animais , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Imunofluorescência , Células HCT116 , Células HEK293 , Humanos , Immunoblotting , Técnicas In Vitro , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Proteínas de Membrana/genética , Camundongos Endogâmicos NOD , Proteínas Mitocondriais , Transplante de Neoplasias , Neoplasias/imunologia , Neoplasias/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Proteína Smad7/genética , Fator de Crescimento Transformador beta/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Ubiquitina-Proteína Ligases/genética , Via de Sinalização Wnt
16.
Cancer Med ; 4(12): 1844-52, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26471467

RESUMO

Decreased expression of tumor suppressor DAB2IP is linked to aggressive cancer and radiation resistance in several malignancies, but clinical survival data is largely unknown. We hypothesized that pretreatment DAB2IP reduction would predict worse prostate cancer-specific survival (PCSS). Immunohistochemistry of pretreatment biopsies was scored by an expert genitourinary pathologist. Other endpoints analyzed include freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Seventy-nine patients with NCCN-defined high-risk prostate cancer treated with radiotherapy from 2005 to 2012 at our institution were evaluated. Twenty-eight percent (22/79) of pretreatment biopsies revealed DAB2IP-reduction. The median follow up times were 4.8 years and 5.3 years for patients in the DAB2IP-reduced group and DAB2IP-retained group, respectively. Patients with reduced DAB2IP demonstrated worse outcome compared to patients retaining DAB2IP, including FFBF (4-year: 34 vs. 92%; P < 0.0001), CRFS (4-year: 58 vs. 96%; P = 0.0039), DMFS (4-year: 58 vs. 100%; P = 0.0006), and PCSS (5-year: 83 vs. 100%; P = 0.0102). Univariate analysis showed T stage, N stage, and Gleason score were statistically significant variables. Pretreatment tumor DAB2IP status remained significant in multivariable analyses. This study suggests that about one-fourth of men with high-risk prostate cancer have decreased tumor expression of DAB2IP. This subpopulation with reduced DAB2IP has a suboptimal response and worse malignancy-specific survival following radiation therapy and androgen deprivation. DAB2IP loss may be a genetic explanation for the observed differences in aggressive tumor characteristics and radiation resistance. Further study into improving treatment response and survival in this subpopulation is warranted.


Assuntos
Biomarcadores Tumorais , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Proteínas Ativadoras de ras GTPase/metabolismo , Idoso , Biópsia , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/radioterapia , Radioterapia
17.
Oncologist ; 20(6): 674-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26018661

RESUMO

BACKGROUND: Lack of access to available cancer clinical trials has been cited as a key factor limiting trial accrual, particularly among medically underserved populations. We examined the trends and factors in clinical trial availability within a major U.S. safety-net hospital system. MATERIALS AND METHODS: We identified cancer clinical trials activated at the Harold C. Simmons Cancer from 1991 to 2014 and recorded the characteristics of the trials that were and were not activated at the Parkland Health and Hospital System satellite site. We used univariate and multivariate logistic regression to determine the association between trial characteristics and nonactivation status, and chi-square analysis to determine the association between the trial characteristics and the reasons for nonactivation. RESULTS: A total of 773 trials were identified, of which 152 (20%) were not activated at Parkland. In multivariable analysis, nonactivation at Parkland was associated with trial year, sponsor, and phase. Compared with the 1991-2006 period, clinical trials in the 2007-2014 period were almost eightfold more likely not to be activated at Parkland. The most common reasons for nonactivation at Parkland were an inability to perform the study procedures (27%) and the startup costs (15%). CONCLUSION: Over time, in this single-center setting, a decreasing proportion of cancer clinical trials were available to underserved populations. Trial complexity and costs appeared to account for much of this trend. Efforts to overcome these barriers will be key to equitable access to clinical trials, efficient accrual, and the generalizability of the results. IMPLICATIONS FOR PRACTICE: Despite numerous calls to increase and diversify cancer clinical trial accrual, the present study found that cancer clinical trial activation rates in a safety-net setting for medically underserved populations have decreased substantially in recent years. The principal reasons for study nonactivation were expenses and an inability to perform the study-related procedures, reflecting the increasing costs and complexity of cancer clinical trials. Future efforts need to focus on strategies to mitigate the increasing disparity in access to clinical research and cutting-edge therapies, which also threatens to hinder study accrual, completion rates, and generalizability.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias/epidemiologia , Populações Vulneráveis , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estados Unidos
18.
BMC Urol ; 15: 24, 2015 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-25885592

RESUMO

BACKGROUND: To assess pathological correlations and temporal trends of Angiopoietin-2 (ANGPT2), vascular endothelial growth factor (VEGF) and M2 Pyruvate kinase (TuM2PK), markers of tumor vascular development and metabolism, in patients with renal cell carcinoma (RCC). METHODS: We prospectively collected plasma samples from 89 patients who underwent surgical/ablative therapy for RCC and 38 patients with benign disease (nephrolithiasis, hematuria without apparent neoplastic origin, or renal cysts). In RCC patients, marker levels were compared between at least 1 preoperative and 1 postoperative time point generally 3 weeks after surgery. Marker temporal trends were assessed using the Wilcoxon sign-rank test. Plasma VEGF, ANGPT2, and TuM2PK levels were determined by ELISA and tested for association with pathological variables. RESULTS: Median age was comparable between groups. 83/89 (93%) of the cohort underwent surgical extirpation. 82% of the tumors were organ confined (T ≤ 2, N0). Only ANGPT2 exhibited significantly elevated preoperative levels in patients with RCC compared to benign disease (p = 0.046). Elevated preoperative levels of ANGPT2 and TuM2PK significantly correlated with increased tumor size and advanced grade (p < 0.05). Chromophobe RCC exhibited higher levels of ANGPT2 compared to other histologies (p < 0.05). A decline in marker level after surgery was not observed, likely due to the timing of the analyses. CONCLUSION: Our results suggest that ANGPT2 is a marker of RCC. Additionally, ANGPT2 and TuM2PK significantly correlated with several adverse pathological features. Further studies are needed to determine clinical applicability.


Assuntos
Angiopoietina-2/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Neoplasias Renais/sangue , Piruvato Quinase/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto Jovem
19.
J Natl Compr Canc Netw ; 13(4): 409-16, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25870377

RESUMO

PURPOSE: The NCI requirement that clinical trials at NCI-designated cancer centers undergo scientific review in addition to Institutional Review Board review is unique among medical specialties. We evaluated the impact of this process on protocol development and content. METHODS: We analyzed cancer clinical trials that underwent full board review by the Harold C. Simmons Cancer Center Protocol Review and Monitoring Committee (PRMC) from January 1, 2009, through June 30, 2013. We analyzed associations between trial characteristics, PRMC decisions, and protocol modifications using Chi-square testing, Fishers exact testing, and logistic regression. RESULTS: A total of 226 trials were analyzed. Of these, 77% were industry-sponsored and 23% were investigator-initiated. Initial PRMC decisions were: approval (40%), provisional approval (52%), deferral (7%), and disapproval (1%). These decisions were associated with study sponsor (P<.001) and phase (P<.001). Ultimately, 97% of industry-sponsored and 90% of investigator-initiated trials were approved (P=.05). Changes were requested for 27% of industry-sponsored trials compared with 54% of investigator-initiated trials (P<.001). Total changes requested (mean, 5.6 vs 2.4; P<.001) and implemented (mean, 4.6 vs 2.1; P=.008) per protocol were significantly greater for investigator-initiated trials. Changes related to study design were more commonly requested (35% vs 13% of trials) and implemented (40% vs 5% of trials) for investigator-initiated trials compared with industry-sponsored trials (P=.03). CONCLUSIONS: NCI-mandated scientific protocol review seems to have a substantial impact on investigator-initiated trials but less effect on industry-sponsored trials. These findings may provide guidance on development and prioritization of institutional protocol review policies.


Assuntos
Comitês Consultivos , Pesquisa Biomédica/normas , Protocolos Clínicos/normas , Ensaios Clínicos como Assunto/normas , Neoplasias/terapia , Pesquisa Biomédica/economia , Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Regulamentação Governamental , Humanos , Indústrias/economia , National Cancer Institute (U.S.)/legislação & jurisprudência , Projetos de Pesquisa/normas , Apoio à Pesquisa como Assunto , Estados Unidos
20.
EBioMedicine ; 2(11): 1827-33, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26870808

RESUMO

BACKGROUND: The US Preventative Service Task Force recommends that physicians perform a genetic risk assessment to identify women at risk for BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) syndrome. However, outcomes data after a diagnosis of HBOC syndrome especially in diverse populations, are minimal. Here we asked if genetic screening of high-risk underserved women identified in the mammogram population reduces cancer incidence. METHODS: We evaluated 61,924 underserved women at screening mammography for family histories suggestive of HBOC syndrome over the course of 21 months. Data were collected retrospectively from patients at two safety net hospitals through chart review. A computer model was used to calculate the long-term effect of this screening on cancer incidence by assessing both the mutation detection rate and the completion of prophylactic surgeries in BRCA1/2 mutation carriers. FINDINGS: We identified 20 of the 85 (23.5%) expected BRCA1/2 mutation carriers in the underserved population. The frequencies of prophylactic mastectomies and oophorectomies in the mutation carriers were 25% and 40%, respectively. Using these data, our model predicted only an 8.8% reduction in both breast and ovarian cancer in the underserved patients. This contrasts with a 57% reduction in breast cancer and 51% reduction in ovarian cancer in an insured reference population. Our data indicate that underserved patients with HBOC syndrome are difficult to identify and when identified are limited in their ability to adhere to NCCN guidelines for cancer prevention. INTERPRETATION: Screening for women at risk for HBOC syndrome in mammogram populations will only prevent cancers if we can increase compliance with management guidelines. This study provides prototypic baseline data for step-wise analysis of the efficacy of the use of family history analysis in the mammography setting for detection and management of HBOC syndrome.


Assuntos
Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/prevenção & controle , Simulação por Computador , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/cirurgia , Heterozigoto , Humanos , Mamografia , Programas de Rastreamento , Modelos Biológicos , Mutação , Taxa de Mutação , Vigilância da População , Texas/epidemiologia
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