RESUMEN
PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Imagen por Resonancia Magnética , Temozolomida/uso terapéuticoRESUMEN
Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.
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Hidroxicloroquina , Neoplasias Pulmonares , Masculino , Humanos , Hidroxicloroquina/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Monóxido de Carbono/farmacología , Próstata , Estudios Retrospectivos , AutofagiaRESUMEN
PURPOSE: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy. EXPERIMENTAL DESIGN: Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses. RESULTS: The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months. CONCLUSIONS: The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Leucocitos Mononucleares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Paclitaxel/uso terapéutico , Platino (Metal)/uso terapéuticoRESUMEN
Ketogenic diets (KD) are high in fat and low in carbohydrates, forcing cells to utilize mitochondrial fatty acid oxidation for energy production. Since cancer cells demonstrate increased mitochondrial oxidative stress relative to normal cells, we hypothesized that a KD may selectively enhance metabolic oxidative stress in head and neck cancer cells, sensitizing them to radiation and platinum-based chemotherapy without causing increased toxicity in surrounding normal tissues. This hypothesis was tested in preclinical murine xenografts and in a phase 1 clinical trial (NCT01975766). In this study, mice bearing human head and neck cancer xenografts (FaDu) were fed either standard mouse chow or KetoCal® KD (90% fat, 8% carbohydrate, 2% protein) and exposed to ionizing radiation. Tumors were harvested from mice to test for glutathione, a biomarker of oxidative stress. In parallel, patients with locally advanced head and neck cancer were enrolled in a phase 1 clinical trial where they consumed KD and received radiation with concurrent platinum-based chemotherapy. Subjects consumed KetoCal KD via percutaneous endoscopic gastrostomy (PEG) tube and were also allowed to orally consume water, sugar-free drinks, and foods approved by a dietitian. Oxidative stress markers including protein carbonyls and total glutathione were assessed in patient blood samples both pre-KD and while consuming the KD. Mice bearing FaDu xenografts that received radiation and KD demonstrated a slight improvement in tumor growth rate and survival compared to mice that received radiation alone; however a variation in responses was seen dependent on the fatty acid composition of the diet. In the phase 1 clinical trial, a total of twelve patients were enrolled in the study. Four patients completed five weeks of the KD as per protocol (with variance in compliance). Eight patients did not tolerate the diet with concurrent radiation and platinum-chemotherapy (5 were patient decision and 3 were removed from study due to toxicity). The median number of days consuming a KD in patients who did not complete the study was 5.5 (range: 2-8 days). Reasons for discontinuation included "stress of diet compliance" (1 patient), grade 2 nausea (3 patients), and grade 3 fatigue (1 patient). Three patients were removed from the trial due to dose-limiting toxicities including: grade 4 hyperuricemia (2 patients) and grade 3 acute pancreatitis (1 patient). Median weight loss was 2.95% for the KD-tolerant group and 7.92% for patients who did not tolerate the diet. In conclusion, the ketogenic diet shows promise as a treatment combined with radiation in preclinical mouse head and neck cancer xenografts. A phase 1 clinical trial evaluating the safety and tolerability of KD demonstrated difficulty with diet compliance when combined with standard-of-care radiation therapy and cisplatin chemotherapy.
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Dieta Cetogénica/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/dietoterapia , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , 3-Hidroxiacil-CoA Deshidrogenasas/efectos de los fármacos , 3-Hidroxiacil-CoA Deshidrogenasas/efectos de la radiación , Acetil-CoA C-Aciltransferasa/efectos de los fármacos , Acetil-CoA C-Aciltransferasa/efectos de la radiación , Adulto , Anciano , Animales , Isomerasas de Doble Vínculo Carbono-Carbono/efectos de los fármacos , Isomerasas de Doble Vínculo Carbono-Carbono/efectos de la radiación , Quimioradioterapia/efectos adversos , Dieta Cetogénica/efectos adversos , Enoil-CoA Hidratasa/efectos de los fármacos , Enoil-CoA Hidratasa/efectos de la radiación , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Racemasas y Epimerasas/efectos de los fármacos , Racemasas y Epimerasas/efectos de la radiación , Radiación Ionizante , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/efectos de la radiaciónRESUMEN
Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131I-metaiodobenzylguanidine (131I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90Y-DOTATOC plus 131I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90Y-DOTATOC and 131I-MIBG.
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Tumores Neuroendocrinos , Humanos , Radioisótopos de Yodo , Selección de Paciente , Resultado del TratamientoRESUMEN
Pharmacological ascorbate (P-AscH-) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe3+) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe2+). Because paramagnetic Fe3+ may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH--induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe3+ or Fe2+ were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH- plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH- infusion, post-P-AscH- infusion, and post-radiation (3-4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe3+ and Fe2+ gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe3+ demonstrated detectable changes in T2* and QSM relaxation times relative to Fe2+ phantoms. Compared to pre-P-AscH-, GBM T2* and QSM imaging were significantly changed post-P-AscH- infusion consistent with conversion of Fe3+ to Fe2+. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH- inducing greater changes in tumor labile iron pools compared to the normal tissue. CONCLUSIONS: T2* and QSM MR-imaging responses are consistent with P-AscH- reducing Fe3+ to Fe2+, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH--induced changes in redox-active iron.
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Hierro , Imagen por Resonancia Magnética , Biomarcadores , Encéfalo , Oxidación-ReducciónRESUMEN
Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment of patients with metastatic neuroendocrine tumors, delivering modest objective tumor response rates but notable survival and symptomatic benefits. The first PRRT approved by the US Food and Drug Administration was lutetium 177-DOTATATE and is for use in adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The treatment paradigm typically leads to significant improvement in symptomology coupled with an extended period of progression-free survival. Side effects are limited, with a small fraction of individuals experiencing clinically significant long-term renal or hematologic toxicity.
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Neoplasias Intestinales/radioterapia , Lutecio/uso terapéutico , Tumores Neuroendocrinos/radioterapia , Neoplasias Pancreáticas/radioterapia , Radioisótopos/uso terapéutico , Radiofármacos/uso terapéutico , Receptores de Somatostatina/metabolismo , Neoplasias Gástricas/radioterapia , Animales , Humanos , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH- to standard RT/TMZ therapy. PATIENTS AND METHODS: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH-) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH- phase). Eight P-AscH- dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH- doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). RESULTS: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months. CONCLUSIONS: P-AscH-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.
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Antineoplásicos Alquilantes/uso terapéutico , Glioblastoma/terapia , Radioterapia , Temozolomida/uso terapéutico , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Quimioradioterapia , Terapia Combinada , Femenino , Glioblastoma/diagnóstico , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia/efectos adversos , Radioterapia/métodos , Temozolomida/administración & dosificación , Temozolomida/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: The number of studies that evaluate treatment margins for high grade gliomas (HGG) are limited. We hypothesize that patients with HGG who are treated with a gross tumor volume (GTV) to planning tumor volume (PTV) expansion of ≤1 cm will have progression-free survival (PFS) and overall survival (OS) rates similar to those treated in accordance with standard protocols by the Radiation Therapy Oncology Group or European Organisation for Research and Treatment of Cancer. Furthermore, the PFS and OS of subgroups within the study population will have equivalent survival outcomes with GTV1-to-PTV1 margins of 1.0 cm and 0.4 cm. METHODS AND MATERIALS: Treatment plans and outcomes for patients with pathologically confirmed HGG were analyzed (n = 267). Survival (PFS and OS) was calculated from the time of the first radiation treatment and a χ2 test or Fisher exact test was used to calculate the associations between margin size and patient characteristics. Survival was estimated using Kaplan-Meier and compared using the log-rank test. All analyses were performed on the univariate level. RESULTS: The median PFS and OS times were 10.6 and 19.1 months, respectively. By disease, the median PFS and OS times were 8.6 and 16.1 months for glioblastoma and 26.7 and 52.5 months for anaplastic glioma. The median follow-up time was 18.3 months. The treatment margin had no effect on outcome and the 1.0 cm GTV1-PTV1 margin subgroup (n = 212) showed median PFS and OS times of 10.7 and 19.1 months, respectively, and the 0.4 cm margin subgroup (n = 55) 10.2 and 19.3 months, respectively. In comparison with the standard treatment with 2 cm to 3 cm margins, there was not a significant difference in outcomes. CONCLUSIONS: There is no apparent difference in survival when utilizing smaller versus larger margins as defined by the guidelines of the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer. Although there remains no class I evidence that outcomes after treatment with smaller margins are identical to those after treatment with larger margins, this large series with long-term follow up suggests that a reduction of the margins is safe and further investigation is warranted.
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Neoplasias Encefálicas/mortalidad , Glioma/mortalidad , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Femenino , Estudios de Seguimiento , Glioma/patología , Glioma/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.
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Ácido Ascórbico/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Colágeno/metabolismo , Daño del ADN , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Glutatión/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Estrés Oxidativo , Tolerancia a Radiación , Radioterapia , Proteínas Recombinantes/metabolismo , Resultado del Tratamiento , GemcitabinaRESUMEN
Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.
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Quimioradioterapia/métodos , Dietoterapia/métodos , Dieta Cetogénica/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pancreáticas/terapia , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Femenino , Humanos , Iowa , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Resultado del TratamientoRESUMEN
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2â - and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.
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Ácido Ascórbico/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Hierro/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Línea Celular Tumoral , Quimioradioterapia/métodos , Femenino , Glioblastoma/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/radioterapia , Masculino , Ratones Desnudos , Oxígeno/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS: We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS: 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. CONCLUSIONS: In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted.
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OBJECTIVES: Celecoxib is a cyclooxygenase-2-specific inhibitor indicated to treat acute pain and pain secondary to osteoarthritis and rheumatoid arthritis. Surgical models of acute pain have demonstrated superior pain relief to placebo. The objective of this study was to test the safety and efficacy of celecoxib for pain relief after tonsillectomy compared to placebo. METHODS: Adult subjects were randomized to 200 mg celecoxib versus placebo with a loading dose the night before surgery then twice daily for 10 days. Subjects were instructed to supplement the study drug with hydrocodone/acetaminophen liquid or acetaminophen for pain as needed. Subjects completed a daily diary regarding their pain, nausea, vomiting, diet, and activity. RESULTS: Seventeen subjects enrolled. Intraoperative blood loss was similar between groups, and no subject had postoperative bleeding. Three patients returned to the emergency department for treatment, and 2 patients could not complete the diaries, all in the placebo group. Subjects in the placebo group required statistically significant (P < .05) higher doses of narcotic and acetaminophen to control pain. Pain and diet rating scores were slightly better in the celecoxib group compared to placebo. CONCLUSIONS: In this small cohort, celecoxib reduced postoperative narcotic and acetaminophen requirements compared to placebo without complications.
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Celecoxib/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Tonsilectomía , Tonsilitis/cirugía , Acetaminofén/uso terapéutico , Adulto , Analgésicos no Narcóticos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Enfermedad Crónica , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Hidrocodona/uso terapéutico , Masculino , Manejo del Dolor , Dimensión del Dolor , Estudios Prospectivos , Recurrencia , Adulto JovenRESUMEN
Patient accrual is essential for the success of oncology clinical trials. Recruitment for trials involving the development of quantitative imaging biomarkers may face different challenges than treatment trials. This study surveyed investigators and study personnel for evaluating accrual performance and perceived barriers to accrual and for soliciting solutions to these accrual challenges that are specific to quantitative imaging-based trials. Responses for 25 prospective studies were received from 12 sites. The median percent annual accrual attained was 94.5% (range, 3%-350%). The most commonly selected barrier to recruitment (n = 11/25, 44%) was that "patients decline participation," followed by "too few eligible patients" (n = 10/25, 40%). In a forced choice for the single greatest recruitment challenge, "too few eligible patients" was the most common response (n = 8/25, 32%). Quantitative analysis and qualitative responses suggested that interactions among institutional, physician, and patient factors contributed to accrual success and challenges. Multidisciplinary collaboration in trial design and execution is essential to accrual success, with attention paid to ensuring and communicating potential trial benefits to enrolled and future patients.
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PURPOSE: To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). METHODS AND MATERIALS: Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurements were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. RESULTS: The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant (P=.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. CONCLUSIONS: This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients.
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Neoplasias de la Mama/radioterapia , Mama/patología , Mama/efectos de la radiación , Pentoxifilina/uso terapéutico , Traumatismos por Radiación/prevención & control , Protectores contra Radiación/uso terapéutico , Vitamina E/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Adaptabilidad/fisiología , Adaptabilidad/efectos de la radiación , Quimioterapia Combinada/métodos , Femenino , Fibrosis/diagnóstico , Fibrosis/prevención & control , Humanos , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Response evaluation criteria in solid tumors (RECIST) is the accepted method for determining tumor progression. However, RECIST may not estimate disease burden accurately because the axial plane often does not produce the actual longest diameter. Volumetric measurements may be an alternative to better determine tumor size. Our aim was to compare volumetric measurements with RECIST in pancreatic ductal adenocarcinomas (PDA) and hepatocellular carcinomas (HCC). METHODS: RECIST and volumetric measurements were determined in 9 patients with metastatic PDA and 17 patients with HCC who subsequently underwent liver transplantation. Gross pathologic measurements after hepatectomy also were analyzed for volumes. RESULTS: Three-dimensional diameter in volumetric analysis was 38% and 36% higher than RECIST diameter in PDA and HCC, respectively (P < .01). However, RECIST yielded 78% and 23% larger estimated tumor volumes than volumetric analysis in PDA and HCC, respectively (P < .01). Gross pathologic volume in HCC showed a linear correlation with both volumetric analysis (r = .95; P < .01) and RECIST (r = .96; P < .01) but RECIST significantly overestimated gross pathologic volume by an average of 28% (P < .01) whereas volumetric analysis was similar to gross pathologic volume (P = .56). In categorizing treatment response in PDA, RECIST and volumetric analysis were in moderate agreement (κ = .49). CONCLUSIONS: RECIST significantly may overestimate tumor burden compared with volumetric measurements in both PDA and HCC. Volumetric analysis may be the preferred method to detect tumor progression.
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Carcinoma Hepatocelular/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética , Neoplasias Pancreáticas/patología , Tomografía Computarizada por Rayos X , Carga Tumoral , Carcinoma Hepatocelular/terapia , Carcinoma Ductal Pancreático/terapia , Progresión de la Enfermedad , Humanos , Neoplasias Hepáticas/terapia , Variaciones Dependientes del Observador , Neoplasias Pancreáticas/terapia , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
Upon receipt of the National Institutes of Health Clinical and Translational Science Award, the University of Iowa's Institute for Clinical and Translational Science committed to develop an infrastructure for research professionals. Three goals were established: (1) identification of research professionals within the University of Iowa, (2) development of an educational series, including orientation and continuing education, and (3) development of a mentoring system. The purpose of this paper is to describe the process of development, initiation, and outcomes of a successful networking, educational, and mentoring system crafted for research professionals at the University of Iowa.