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1.
Cancer ; 120(17): 2713-20, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-24845411

RESUMEN

BACKGROUND: The patterns of lobar involvement, optimal treatment, and disease course among patients with gliomatosis cerebri (GC) have not been fully characterized. The current study evaluates the clinical presentations and outcomes for patients with GC treated with radiation therapy (RT) at our institution. METHODS: A total of 26 patients (25 with follow-up) with GC were diagnosed and treated between January 2004 and June 2012. Inclusion criteria consisted of brain magnetic resonance imaging and neuroradiology confirmation of contiguous involvement of ≥ 3 lobes/lobar equivalents with preservation of neural architecture. Patients were treated with either partial-brain RT to involved tumor (25 patients) or whole-brain RT (1 patient). The median RT dose was 54.0 Gray. The median follow-up was 17.3 months. RESULTS: The median age of the patients at the time of diagnosis was 57 years. Twenty-one patients (81%) and 5 patients (19%) had 3 to 6 and ≥ 7 involved lobes/lobar equivalents, respectively. The median progression-free survival and overall survival were 7.4 months and 14.9 months, respectively. Fifteen patients experienced radiographic disease progression after partial-brain RT, 14 of whom (93%) developed infield disease recurrence. On univariate analysis, higher tumor grade and type II GC (with focal mass) were associated with a poorer progression-free survival. The extent of lobar involvement and chemotherapy were not associated with overall survival. CONCLUSIONS: Even with partial-brain RT, nearly all disease recurrences were infield and clinical outcomes were similar to previous GC series, thereby suggesting that whole-brain RT is not necessary for this patient population. A greater number of involved lobes did not correlate with inferior outcomes. Further studies are necessary to establish more uniform and optimal treatments for this rare disease.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neoplasias Neuroepiteliales/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Quimioradioterapia , Quimioterapia Adyuvante , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Neoplasias Neuroepiteliales/tratamiento farmacológico , Neoplasias Neuroepiteliales/mortalidad , Estudios Retrospectivos , Insuficiencia del Tratamiento
2.
Cancer ; 120(10): 1499-506, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24510454

RESUMEN

BACKGROUND: Lymph node extracapsular extension (ECE) is a known adverse prognostic factor in head and neck cancer and is an indication for adjuvant chemoradiation (CRT). However, the extent of ECE may provide additional prognostic information in the setting of adjuvant CRT. METHODS: This study included 350 patients with oral cavity cancer (72.6%) or bulky/nonfunctional laryngeal cancer (27.4%) who underwent initial surgical resection. Extent of ECE was graded from 0 to 4 based on the scale established by Lewis and colleagues. Multivariable analyses (MVA) were adjusted for primary site, pathologic risk factors, and adjuvant therapy. RESULTS: In univariate failure-free survival (FFS) analysis, there was no significant difference in FFS for patients with lymph node-positive disease and no ECE (grade 0) versus patients with ECE grades 1 through 3. However, patients with ECE grade 4 had significantly worse FFS. In MVA for FFS, differences between ECE grades 0 through 3 and grade 4 did not remain significant. In MVA of overall survival, ECE grade 4 was significantly associated with higher risk of death compared with ECE grade 0 (hazard ratio, 0.46; P = .02) and ECE grades 1 through 3 (HR, 0.41; P = .01). CONCLUSIONS: Dichotomous evaluation of ECE is useful for determining appropriate adjuvant therapy but has limited additional prognostic value in the setting of adjuvant CRT. The detrimental effect of ECE grades 1 through 3 relative to no ECE is effectively mitigated with adjuvant CRT, but ECE grade 4 retains a poorer prognosis despite CRT with regard to overall survival. Patients with ECE grade 4 may be candidates for trials investigating novel methods of adjuvant therapy intensification.


Asunto(s)
Quimioradioterapia Adyuvante , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/terapia , Humanos , Estimación de Kaplan-Meier , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Análisis Multivariante , Disección del Cuello , Clasificación del Tumor , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo
3.
Int J Part Ther ; 13: 100111, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39070664

RESUMEN

Purpose: Rectal toxicity after prostate cancer (PCa) radiation therapy (RT) may be greater with protons compared with photon intensity-modulated RT, perhaps due to lateral penumbra and end-of-range uncertainty. Rectal spacers (RSs) have been shown to mitigate RT-associated acute/late rectal toxicity in men treated with photons. The relative benefit of RS in men treated with protons versus photons is unknown. We hypothesize that RS will confer greater bowel toxicity benefits in PCa treated with protons versus photons. Materials and Methods: We conducted a single institution, retrospective review of men receiving photon intensity-modulated RT or pencil-beam scanning proton RT for localized PCa. Four cohorts were compared: photon with or without RS, and proton with or without RS. Acute (<3 months), late (≥3 months), and most recent toxicity were compared among the 4 cohorts. The cumulative incidence of physician-reported grade 1 to 2 gastrointestinal (GI) toxicity (common terminology criteria for adverse events V5.0) was compared using χ2 or Fisher exact test. Patient-reported toxicity was evaluated using the International Prostate Expanded Prostate Composite Index-Clinical Practice and compared using linear mixed modeling. Results: In total, 164 patients were eligible for analysis: 38 photons without RS, 50 photons with RS, 26 protons without RS, and 50 protons with RS. The median follow-up was 17.6 months. In proton patients, acute (6.12% vs 30.77%, P = .009) and most recent (4.26% vs 26.09%, P = .01) G1-2 GI toxicity was lower with versus without RS. In photon patients, there were no significant differences in toxicity with versus without RS. No significant differences in patient-reported outcomes were observed with versus without RS in photon or proton groups. Conclusion: The rectal spacer was associated with lower G1-2 acute and most recent GI toxicity in men treated with protons; this difference was not observed in men treated with photons. While this study is limited by sample size, a relatively greater benefit of RS with proton versus photon therapy was observed.

4.
Pract Radiat Oncol ; 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-39032598

RESUMEN

PURPOSE: Whole-pelvis (WP) radiation therapy (radiation) improved biochemical relapse-free survival (bRFS) compared with prostate bed (PB)-only radiation in the Radiation Therapy Oncology Group 0534, but was performed in an era prior to positron emission tomography (PET) staging. Separately, 18F-fluciclovine PET/CT-guided postprostatectomy radiation improved 3-year bRFS versus radiation guided by conventional imaging alone. We hypothesized that patients who were changed from WP to PB-only radiation after PET would have bRFS that was: (a) no higher than patients initially planned for PB-only radiation; and (b) lower than patients planned for WP radiation without PET guidance. METHODS AND MATERIALS: We conducted a post hoc analysis of a prospective, randomized trial comparing conventional (arm 1) versus PET-guided (arm 2) postprostatectomy radiation. In arm 2, pre-PET treatment field decisions were recorded and post-PET fields were defined per protocol; pathologic node negative (pN0) without pelvic or extrapelvic PET uptake received PB-only radiation. Three-year bRFS was compared in patients planned for WP with change to PB-only radiation (arm 2 [WP:PB]) vs arm 2 patients planned for PB-only with final radiation to PB-only (arm 2 [PB:PB]) and arm 1 pN0 patients treated with WP radiation (arm 1 [WP]) using the Z test and log-rank test. Demographics were compared using the chi-square test, Fisher exact test, or analysis of variance, as appropriate. RESULTS: We identified 10 arm 2 (WP:PB), 31 arm 2 (PB:PB) and 11 arm 1 (WP) patients. Androgen deprivation was used in 50.0% of arm 2 (WP:PB) and 3.2% of arm 2 (PB:PB) patients, P < .01. Median preradiation prostate-specific antigen was higher in arm 2 (WP:PB) vs arm 2 (PB:PB) patients (0.4 vs 0.2 ng/mL, P = .03); however, there were no significant differences in T stage, Gleason score, or margin positivity. Three-year bRFS was 80% in arm 2 (WP:PB) vs 87.4% in arm 2 (PB:PB), P = .47, respectively. Arm 1(WP) patients had significantly worse 3-year (23%) bRFS vs arm 2 (WP:PB), P < .01. CONCLUSIONS: Patients initially planned for WP radiation with field decision change to PB-only radiation after PET showed (1) no significant difference in 3-year bRFS compared with patients initially planned for PB-only radiation; and (2) improved bRFS compared with patients receiving WP radiation without PET guidance. PET-guided volume de-escalation in selected patients may be 1 approach to mitigating toxicity without compromising outcomes.

5.
Cancer Med ; 12(17): 18258-18268, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37537835

RESUMEN

BACKGROUND: Delayed access to care may contribute to disparities in prostate cancer (PCa). The Affordable Care Act (ACA) aimed at increasing access and reducing healthcare disparities, but its impact on timely treatment initiation for PCa men is unknown. METHODS: Men with intermediate- and high-risk PCa diagnosed 2010-2016 and treated with curative surgery or radiotherapy were identified in the National Cancer Database. Multivariable logistic regression modeled the effect of race and insurance type on treatment delay >180 days after diagnosis. Cochran-Armitage test measured annual trends in delays, and joinpoint regression assessed if 2014, the year the ACA became fully operationalized, was significant for inflection in crude rates of major delays. RESULTS: Of 422,506 eligible men, 18,720 (4.4%) experienced >180-day delay in treatment initiation. Compared to White patients, Black (OR 1.79, 95% CI 1.72-1.87, p < 0.001) and Hispanic (OR 1.37, 95% CI 1.28-1.48, p < 0.001) patients had higher odds of delay. Compared to uninsured, those with Medicaid had no difference in odds of delay (OR 0.94, 95% CI 0.84-1.06, p = 0.31), while those with private insurance (OR 0.57, 95% CI 0.52-0.63, p < 0.001) or Medicare (OR 0.64, 95% CI 0.58-0.70, p < 0.001) had lower odds of delay. Mean time to treatment significantly increased from 2010 to 2016 across all racial/ethnic groups (trend p < 0.001); 2014 was associated with a significant inflection for increase in rates of major delays. CONCLUSIONS: Non-White and Medicaid-insured men with localized PCa are at risk of treatment delays in the United States. Treatment delays have been consistently rising, particularly after implementation of the ACA.


Asunto(s)
Patient Protection and Affordable Care Act , Neoplasias de la Próstata , Anciano , Masculino , Humanos , Estados Unidos/epidemiología , Medicare , Cobertura del Seguro , Medicaid , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/terapia , Disparidades en Atención de Salud
6.
JAMA Netw Open ; 6(8): e2327637, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37552479

RESUMEN

Importance: Very high-risk (VHR) prostate cancer is an aggressive substratum of high-risk prostate cancer, characterized by high prostate-specific antigen levels, high Gleason score, and/or advanced T category. Contemporary management paradigms involve advanced molecular imaging and multimodal treatment with intensified prostate-directed or systemic treatment-resources more readily available at high-volume centers. Objective: To examine radiation facility case volume and overall survival (OS) in men with VHR prostate cancer. Design, Setting, and Participants: A retrospective cohort study was performed from November 11, 2022, to March 4, 2023, analyzing data from US facilities reporting to the National Cancer Database. Patients included men diagnosed with nonmetastatic VHR prostate cancer by National Comprehensive Cancer Network criteria (clinical T3b-T4 category, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high-risk features) and treated with curative-intent radiotherapy and androgen deprivation therapy between January 1, 2004, to December 31, 2016. Exposures: Treatment at high- vs low-average cumulative facility volume (ACFV), defined as the total number of prostate radiotherapy cases at an individual patient's treatment facility from 2004 until the year of their diagnosis. The nonlinear association between a continuous ACFV and OS was examined through a Martingale residual plot; an optimal ACFV cutoff was identified that maximized the separation between high vs low ACFV via a bias-adjusted log rank test. Main Outcomes and Measures: Overall survival was assessed between high vs low ACFV using Kaplan-Meier analysis with and without inverse probability score weighted adjustment and multivariable Cox proportional hazards. Results: A total of 25 219 men (median age, 71 [IQR, 64-76] years; 78.7% White) with VHR prostate cancer were identified, 6438 (25.5%) of whom were treated at high ACFV facilities. Median follow-up was 57.4 (95% CI, 56.7-58.1) months. Median OS for patients treated at high ACFV centers was 123.4 (95% CI, 116.6-127.4) months vs 109.0 (95% CI, 106.5-111.2) months at low ACFV centers (P < .001). On multivariable analysis, treatment at a high ACFV center was associated with lower risk of death (hazard ratio, 0.89; 95% CI, 0.84-0.95; P < .001). These results were also significant after inverse probability score weighted-based adjustment. Conclusions and Relevance: In this cohort study of patients with VHR prostate cancer who underwent definitive radiotherapy and androgen deprivation therapy, facility case volume was independently associated with longer OS. Further studies are needed to identify which factors unique to high-volume centers may be responsible for this benefit.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Anciano , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Estudios de Cohortes , Estudios Retrospectivos , Factores de Riesgo
7.
Gynecol Oncol Rep ; 44: 101086, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36281250

RESUMEN

Purpose/Objective: Given the rarity of vulvar cancer, data on the incidence of acute and late severe toxicity and patients' symptom burden from radiotherapy (RT) are lacking. Materials/Methods: This multi-center, single-institution study included patients with vulvar squamous cell carcinoma treated with curative intent RT between 2009 and 2020. Treatment-related acute and late grade ≥ 3 toxicities and late patient subjective symptoms (PSS) were recorded. Results: Forty-two patients with predominantly stage III/IV disease (n = 25, 59.5 %) were treated with either definitive (n = 25, 59.5 %) or adjuvant (n = 17, 40.5 %) external beam RT to a median dose of 64 Gy and 59.4 Gy, respectively. Five patients received a brachytherapy boost with a median total dose of 84.3 Gy in 2 Gy-equivalent dose (EQD2). Intensity-modulated RT was used in 37 (88.1 %) of patients, and 25 patients (59.5 %) received concurrent chemotherapy. Median follow-up was 27 months. Acute grade ≥ 3 toxicity occurred in 17 patients (40.5 %), including 13 (31.0 %) acute grade 3 skin events. No factors, including total RT dose (p = 0.951), were associated with acute skin toxicity. Eleven (27.5 %) patients developed late grade ≥ 3 toxicity events, including 10 (23.8 %) late grade ≥ 3 skin toxicity events. Patients with late grade ≥ 3 skin toxicity had a higher mean body-mass index (33.0 vs 28.2 kg/m2; p = 0.009). Common late PSS included vaginal pain (n = 15, 35.7 %), skin fibrosis (n = 10, 23.8 %), and requirement of long-term opiates (n = 12, 28.6 %). Conclusion: RT for vulvar cancer is associated with considerable rates of severe acute and late toxicity and PSS burden. Larger studies are needed to identify risk factors, explore toxicity mitigation strategies, and assess patient-reported outcomes.

8.
Adv Radiat Oncol ; 6(6): 100803, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34703954

RESUMEN

PURPOSE: Treatment with long-term androgen deprivation therapy (ADT) and radiation therapy (RT) is the nonsurgical standard-of-care for patients with high- or very high-risk prostate cancer (HR-PC), but the optimal timing between ADT and RT initiation is unknown. We evaluate the influence of timing between ADT and RT on outcomes in patients with HR-PC using a large national cancer database. METHODS AND MATERIALS: Data for patients with clinical T1-T4 N0, M0, National Cancer Comprehensive Network HR-PC who were treated with definitive external RT (≥60 Gy) and ADT starting either before or within 14 days after RT start were extracted from the National Cancer Database (2004-2015). Patients were grouped on the basis of ADT initiation: (1) >11 weeks before RT, (2) 8 to 11weeks before RT, and (3) <8 weeks before RT. Kaplan-Meier, propensity score matching, and multivariable Cox proportional hazards were performed to evaluate overall survival (OS). RESULTS: With a median follow-up of 68.9 months, 37,606 patients with HR-PC were eligible for analysis: 13,346 (35.5%) with >11 weeks of neoadjuvant ADT, 11,456 (30.5%) with 8 to 11 weeks of neoadjuvant ADT; and 12,804 (34%) patients with <8 weeks of neoadjuvant ADT. The unadjusted 10-year OS rates for >11 weeks, 8 to 11 weeks, and <8 weeks neoadjuvant ADT groups were 49.9%, 51.2%, and 46.9%, respectively (P = .002). On multivariable and inverse probability of treatment weighting analyses, there was a significant OS advantage for patients in the 8 to 11 weeks neoadjuvant ADT group (adjusted hazard ratio 0.90; 95% confidence interval, 0.86-0.95; P < .001) but not the >11 weeks group. CONCLUSIONS: Neoadjuvant ADT initiation 8 to 11 weeks before RT is associated with significantly improved OS compared with shorter neoadjuvant ADT duration. Although prospective validation is warranted, this analysis is the largest retrospective study suggesting an influence of timing between ADT and RT initiation in HR-PC.

9.
JAMA Netw Open ; 3(12): e2025143, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33301015

RESUMEN

Importance: Long-term control of node-positive (N1) prostate cancer, the incidence of which is increasing, is obtainable with aggressive treatment, and definitive external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT) is an increasingly preferred option. Caring for these patients is complex and may require resources more readily available at high-volume centers. Objective: To evaluate the association between radiation facility case volume and overall survival (OS) in men with N1 prostate cancer. Design, Setting, and Participants: This cohort study included 1899 men diagnosed with T1N1M0 to T4N1M0 prostate cancer treated with curative-intent EBRT and ADT between January 2004 and December 2016 at US facilities reporting to the National Cancer Database. Data analysis was performed from March to June 2020. Exposures: Treatment at a center with high vs low average cumulative facility volume (ACFV), defined as the total number of prostate radiation cases at an individual patient's treatment facility from 2004 until the year of that patient's diagnosis. Main Outcomes and Measures: OS was assessed between high- vs low-ACFV centers using the Kaplan-Meier method with and without propensity score-based weighted adjustment and multivariable Cox proportional hazards. The nonlinear association between continuous ACFV and OS was examined through a Martingale residual plot, and the optimal ACFV cutoff point that maximized the separation between high vs low ACFV was identified via a bias adjusted log rank test. Results: A total of 1899 men met inclusion criteria. The median (interquartile range) age was 66 (60-72) years, 1491 (78.5%) were White individuals, and 1145 (60.3%) were treated at nonacademic centers. The optimal ACFV cutoff point was 66.4 patients treated per year. The median OS for patients treated at high-ACFV vs low-ACFV centers was 111.1 (95% CI, 101.5-127.9) months and 92.3 (95% CI, 87.7-103.9) months, respectively (P = .01). On multivariable analysis, treatment at a low-ACFV center was associated with increased risk of death (HR, 1.22; 95% CI, 1.02-1.46, P = .03) compared with treatment at a high-ACFV center. These results persisted after propensity score-based adjustment. Conclusions and Relevance: This cohort study found a significant association of facility case volume with long-term outcomes in men with N1 prostate cancer undergoing EBRT with ADT. Specifically, treatment at a facility with high radiation case volume was independently associated with longer OS. Further studies should focus on identifying which factors unique to high-volume centers may be responsible for this benefit.


Asunto(s)
Adenocarcinoma/patología , Antagonistas de Andrógenos/uso terapéutico , Instituciones Oncológicas/estadística & datos numéricos , Neoplasias de la Próstata , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/epidemiología , Adenocarcinoma/radioterapia , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Humanos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Sistema de Registros , Sobrevida , Resultado del Tratamiento
10.
Am J Clin Oncol ; 41(4): 326-331, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-26886946

RESUMEN

OBJECTIVES: We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response. MATERIALS AND METHODS: From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization. RESULTS: Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively. CONCLUSIONS: Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Neuroendocrino/terapia , Quimioembolización Terapéutica , Arteria Hepática , Neoplasias Hepáticas/terapia , Carcinoma Neuroendocrino/patología , Terapia Combinada , Femenino , Floxuridina/administración & dosificación , Estudios de Seguimiento , Humanos , Leucovorina/administración & dosificación , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Pronóstico , Dosificación Radioterapéutica , Estreptozocina/administración & dosificación , Tasa de Supervivencia
11.
Carcinogenesis ; 28(11): 2298-304, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17615256

RESUMEN

It has been suggested that phosphorylation of the histone variant H2AX after ultraviolet light (UV) irradiation is triggered by DNA double-strand breaks induced as replication forks collide with UV-induced bulky lesions. More recently, it has been shown that UV-induced H2AX phosphorylation can also occur outside of S-phase, but the mechanism for this replication-independent induction is not well understood. In this study, we show that H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is induced in all phases of the cell cycle. Accumulation of DNA repair intermediates by inhibition of DNA repair synthesis resulted in a marked increase of H2AX phosphorylation in repair proficient but not repair-deficient xeroderma pigmentosum-A cells. Using chemical inhibitors of the PI(3)-like kinase family of protein kinases as well as ataxia telangiectasia mutated and Rad-3 related (ATR)-deficient Seckel syndrome cells and ataxia telangiectasia mutated-deficient ataxia telangiectasia cells, we show that the H2AX phosphorylation induced by accumulation of repair intermediates is mediated primarily by the ATR kinase. We suggest a model for UV light-induced phosphorylation of H2AX where in addition to replication blockage, DNA repair intermediates trigger H2AX phosphorylation via the ATR kinase.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Reparación del ADN , Histonas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Rayos Ultravioleta , Proteínas de la Ataxia Telangiectasia Mutada , Western Blotting , Ciclo Celular , Relación Dosis-Respuesta en la Radiación , Citometría de Flujo , Humanos , Inmunohistoquímica , Fosforilación
12.
Mol Cancer ; 5: 25, 2006 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-16784539

RESUMEN

BACKGROUND: The evolutionary conserved cyclin-dependent kinase phosphatase hCdc14A has been shown to play potential roles in the regulation of mitotic exit and in the centrosome duplication cycle. We have recently shown that hCdc14A also can interact with the tumor suppressor p53 both in vitro and in vivo and specifically dephosphorylates the ser315 site of p53 in vitro. In this study we developed antibodies against hCdc14A to investigate the expression and regulation of hCdc14A in human tissues and cancer cells. RESULTS: We show that hCdc14A is differentially expressed in human tissues and in 75 cancer cell lines examined. Treatments with the histone deacetylase inhibitor TSA, the demethylating agent 5-aza-2'-deoxycytodine or the proteasome inhibitor MG132 significantly induced expression of hCdc14A in cell lines expressing low or undetectable levels of hCdc14A. There was a strong bias for low expression of hCdc14A in cancer cell lines harboring wild-type p53, suggesting that high Cdc14A expression is not compatible with wild-type p53 expression. We present evidence for a role for hCdc14A in the dephosphorylation of the ser315 site of p53 in vivo and that hCdc14A forms a complex with Cdk1/cyclin B during interphase but not during mitosis. CONCLUSION: Our results that hCdc14A is differentially expressed in human cancer cells and that hCdc14A can interact with both p53 and the Cdk1/cyclin B complex may implicate that dysregulation of hCdc14A expression may play a role in carcinogenesis.


Asunto(s)
Proteína Quinasa CDC2/biosíntesis , Ciclina B/biosíntesis , Regulación Neoplásica de la Expresión Génica , Genes p53 , Monoéster Fosfórico Hidrolasas/genética , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular , Línea Celular Tumoral , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/farmacología , Humanos , Mitosis , Modelos Biológicos , Fosforilación , Inhibidores de Proteasoma , Unión Proteica , Proteínas Tirosina Fosfatasas
13.
Head Neck ; 38(6): 846-51, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-25899391

RESUMEN

BACKGROUND: The benefit of combined chemoradiation in elderly patients with human papillomavirus (HPV)-positive locally advanced oropharyngeal squamous cell carcinoma (SCC) must be balanced with the potential for higher toxicity rates. We performed a retrospective review of our institutional experience. METHODS: Patients 70 years or older with p16-positive oropharyngeal SCC treated with definitive chemoradiation from 2005 to 2013 were evaluated. Overall survival (OS), disease-free survival (DFS), and locoregional failure-free survival were calculated. RESULTS: Twenty-one eligible patients had a follow-up of 22.4 months. Estimated 5-year OS, DFS, and locoregional failure-free survival were 76.0%, 40%, and 95%, respectively. There was 1 death from acute toxicity, and 50% had unplanned hospitalizations. Sixty percent had late toxicity, and 6-month feeding tube dependence was 25%. CONCLUSION: Elderly patients with HPV-positive locally advanced SCC of the oropharynx treated with definitive chemoradiation had good OS but high rates of acute and long-term toxicity. © 2015 Wiley Periodicals, Inc. Head Neck 38: 846-851, 2015.


Asunto(s)
Carcinoma de Células Escamosas/terapia , Quimioradioterapia/efectos adversos , Papillomavirus Humano 16/aislamiento & purificación , Neoplasias Orofaríngeas/terapia , Infecciones por Papillomavirus/complicaciones , Anciano , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/mortalidad , Femenino , Humanos , Masculino , Neoplasias Orofaríngeas/etiología , Neoplasias Orofaríngeas/mortalidad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
14.
Clin Cancer Res ; 10(2): 691-700, 2004 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-14760092

RESUMEN

PURPOSE: Overexpression of the ErbB family of receptor tyrosine kinases has been associated with uncontrolled growth of many tumor types and, therefore, presents a promising molecular target for cancer therapy. CI-1033 is a small molecule tyrosine kinase inhibitor that differs from other 4-anilinoquinazolines by being a pan ErbB (instead of epidermal growth factor receptor-specific) irreversible (instead of reversible) inhibitor. Therefore, we investigated the antitumor effect of CI-1033 alone and in combination with ionizing radiation in vitro and in vivo. EXPERIMENTAL DESIGN: We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo. For in vivo studies LoVo and Caco-2 cells were implanted s.c. in the flank of nude mice. After the tumor reached approximately 100 mm(3), treatment was initiated with 20 mg/kg of CI-1033 (orally once daily x 5 for 3 successive weeks), radiation treatment (a total of 30 Gy given in 2 Gy once daily x 5 for 3 successive weeks), or a combination of both CI-1033 and radiation treatment. RESULTS: We found that exposure of LoVo and Caco-2, but not SW620 cells, to CI-1033 in the range of 1-3 micro M could inhibit constitutive signaling by tyrosine kinases, arrest cell growth, inhibit cells in G(1), stimulate expression of p53, and induce apoptosis. The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells. In contrast, the combination of CI-1033 and radiation produced significant (P < 0.0005 and P = 0.0002, respectively) and prolonged suppression of tumor growth in both the tumor types when compared with either treatment alone. CONCLUSIONS: These findings suggest that CI-1033 can increase the effectiveness of radiation therapy. The extent of suppression of tyrosine kinase activity by CI-1033, rather than the amount of activity in untreated cells, seemed to be more closely associated with the efficacy of combination treatment.


Asunto(s)
Morfolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Bromodesoxiuridina/farmacología , Línea Celular Tumoral , Supervivencia Celular , Colorantes/farmacología , ADN/metabolismo , Relación Dosis-Respuesta en la Radiación , Receptores ErbB/metabolismo , Citometría de Flujo , Fase G1 , Humanos , Inmunohistoquímica , Técnicas In Vitro , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Pruebas de Precipitina , Proteínas Tirosina Quinasas/metabolismo , Quinazolinas/farmacología , ARN/metabolismo , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo
15.
Head Neck ; 37(6): 777-82, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24596123

RESUMEN

BACKGROUND: The purpose of this study was to determine if lymph node ratio is associated with locoregional recurrence for patients with oral cavity or laryngeal cancer treated with initial surgical management. METHODS: The study included 350 patients with oral cavity (73%) or laryngeal cancer (27%) who underwent initial surgery. All analyses were multivariable, adjusting for primary site, pathologic prognostic factors, and adjuvant therapy. RESULTS: Lymph node ratio was significantly associated with locoregional recurrence, in which each 1% increase in lymph node ratio had an adjusted hazard ratio (HR) for locoregional recurrence of 1.02 (95% confidence interval [CI], 1.002-1.042; p = .05). Lymph node ratio was also associated with OS, in which each 1% increase in lymph node ratio had an adjusted HR for death of 1.028 (95% CI, 1.012-1.045; p = .001). CONCLUSION: Adjusting for pathologic factors and adjuvant therapy, lymph node ratio was found to be an independent prognostic factor for locoregional recurrence and overall survival (OS). Patients with lymph node ratio ≥20% are at high risk of locoregional recurrence and death, and may be considered for adjuvant chemoradiation.


Asunto(s)
Quimioradioterapia Adyuvante/métodos , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/cirugía , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/cirugía , Metástasis Linfática , Masculino , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Análisis Multivariante , Disección del Cuello/métodos , Disección del Cuello/mortalidad , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
16.
Int J Radiat Oncol Biol Phys ; 88(1): 122-9, 2014 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-24331658

RESUMEN

PURPOSE: Nodal extracapsular extension (ECE) in patients with head-and-neck cancer increases the loco-regional failure risk and is an indication for adjuvant chemoradiation therapy (CRT). To reduce the risk of requiring trimodality therapy, patients with head-and-neck cancer who are surgical candidates are often treated with definitive CRT when preoperative computed tomographic imaging suggests radiographic ECE. The purpose of this study was to assess the accuracy of preoperative CT imaging for predicting pathologic nodal ECE (pECE). METHODS AND MATERIALS: The study population consisted of 432 consecutive patients with oral cavity or locally advanced/nonfunctional laryngeal cancer who underwent preoperative CT imaging before initial surgical resection and neck dissection. Specimens with pECE had the extent of ECE graded on a scale from 1 to 4. RESULTS: Radiographic ECE was documented in 46 patients (10.6%), and pECE was observed in 87 (20.1%). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 43.7%, 97.7%, 82.6%, and 87.3%, respectively. The sensitivity of radiographic ECE increased from 18.8% for grade 1 to 2 ECE, to 52.9% for grade 3, and 72.2% for grade 4. Radiographic ECE criteria of adjacent structure invasion was a better predictor than irregular borders/fat stranding for pECE. CONCLUSIONS: Radiographic ECE has poor sensitivity, but excellent specificity for pECE in patients who undergo initial surgical resection. PPV and NPV are reasonable for clinical decision making. The performance of preoperative CT imaging increased as pECE grade increased. Patients with resectable head-and-neck cancer with radiographic ECE based on adjacent structure invasion are at high risk for high-grade pECE requiring adjuvant CRT when treated with initial surgery; definitive CRT as an alternative should be considered where appropriate.


Asunto(s)
Neoplasias Laríngeas/diagnóstico por imagen , Neoplasias Laríngeas/cirugía , Ganglios Linfáticos/diagnóstico por imagen , Neoplasias de la Boca/diagnóstico por imagen , Neoplasias de la Boca/cirugía , Disección del Cuello/métodos , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Invasividad Neoplásica , Periodo Preoperatorio , Sensibilidad y Especificidad , Adulto Joven
17.
Proc Natl Acad Sci U S A ; 104(31): 12778-83, 2007 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-17616578

RESUMEN

The mechanisms by which DNA-damaging agents trigger the induction of the stress response protein p53 are poorly understood but may involve alterations of chromatin structure or blockage of either transcription or replication. Here we show that transcription-blocking agents can induce phosphorylation of the Ser-15 site of p53 in a replication-independent manner. Furthermore, microinjection of anti-RNA polymerase II antibodies into the nuclei of cells showed that blockage of transcription is sufficient for p53 accumulation even in the absence of DNA damage. This induction of p53 occurs by two independent mechanisms. First, accumulation of p53 is linked to diminished nuclear export of mRNA; and second, inhibition specifically of elongating RNA polymerase II complexes results in the phosphorylation of the Ser-15 site of p53 in a replication protein A (RPA)- and ATM and Rad3-related (ATR)-dependent manner. We propose that this transcription-based stress response involving RPA, ATR, and p53 has evolved as a DNA damage-sensing mechanism to safeguard cells against DNA damage-induced mutagenesis.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína de Replicación A/metabolismo , Transcripción Genética/genética , Proteína p53 Supresora de Tumor/metabolismo , Transporte Activo de Núcleo Celular , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Línea Celular , Núcleo Celular/metabolismo , Replicación del ADN/genética , Humanos , Fosforilación , Fosfoserina/metabolismo , Proteínas Serina-Treonina Quinasas/genética , ARN Polimerasa II/metabolismo , ARN Mensajero/genética , Proteína de Replicación A/genética
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