RESUMEN

PURPOSE: Linear accelerator-based stereotactic radiosurgery (SRS) has become a mainstay for simultaneous management of multiple intracranial targets. Recent improvements in treatment planning systems (TPS) have enabled treatment of multiple brain metastases using dynamic conformal arcs (DCA) and a single treatment isocenter. However, as the volume of healthy tissue receiving at least 12 Gy (V12) is linked to the probability of developing radionecrosis, balancing target coverage while minimizing V12 is a critical factor affecting SRS plan quality. Current TPS allow users to adjust various parameters influencing plan optimization. The purpose of this work is to quantify the effect of negative margins on V12 for cranial SRS plans managing multiple brain metastases. METHODS: Using the Brainlab Elements v3.0 TPS (Brainlab, Munich, Germany), we calculated V10, V12, V15, monitor units, and conformity index for seventeen SRS plans treating 2-10 metastases on our Elekta Versa HD (Elekta, Stockholm, Sweden) linear accelerator. We compared plans optimized using 70%-90% prescription isodose lines (IDL) in 5% increments. RESULTS: Irrespective of the number of treated metastases, optimization at a lower prescription IDL reduced V10, V12, and V15 and increased MU compared to the 90% IDL (p < 0.01). However, comparing the 70% and 75% IDL optimizations, there was little difference in tissue sparing. The conformity index showed no consistent trends at different IDLs due to a significant spread in case data. CONCLUSION: For our plans treating up to 10 metastases, diminishing returns for tissue sparing at IDLs below 80% paired with increasing treatment MU and dosimetric hot spot made optimization at lower IDLs less favorable. In our clinic, after consulting with a physician, it was determined that optimization at the 80% IDL achieved the best balance of V12, treatment MU, and maximum dose. Clinics implementing LINAC-based SRS programs may consider using similar evaluations to develop their own clinical protocols.

Asunto(s)

Neoplasias Encefálicas , Órganos en Riesgo , Aceleradores de Partículas , Radiocirugia , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada , Humanos , Radiocirugia/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/radioterapia , Órganos en Riesgo/efectos de la radiación , Aceleradores de Partículas/instrumentación , Radioterapia de Intensidad Modulada/métodos , Tratamientos Conservadores del Órgano/métodos , Radioterapia Conformacional/métodos

RESUMEN

BACKGROUND: We present efficacy and toxicity outcomes among patients with chordoma treated on the Proton Collaborative Group prospective registry. METHODS: Consecutive chordoma patients treated between 2010-2018 were evaluated. One hundred fifty patients were identified, 100 had adequate follow-up information. Locations included base of skull (61%), spine (23%), and sacrum (16%). Patients had a performance status of ECOG 0-1 (82%) and median age of 58 years. Eighty-five percent of patients underwent surgical resection. The median proton RT dose was 74 Gy (RBE) (range 21-86 Gy (RBE)) using passive scatter proton RT (PS-PBT) (13%), uniform scanning proton RT (US-PBT) (54%) and pencil beam scanning proton RT (PBS-PBT) (33%). Rates of local control (LC), progression-free survival (PFS), overall survival (OS) and acute and late toxicities were assessed. RESULTS: 2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively. LC did not differ based on surgical resection (p = 0.61), though this is likely limited by most patients having undergone a prior resection. Eight patients experienced acute grade 3 toxicities, most commonly pain (n = 3), radiation dermatitis (n = 2), fatigue (n = 1), insomnia (n = 1) and dizziness (n = 1). No grade ≥ 4 acute toxicities were reported. No grade ≥ 3 late toxicities were reported, and most common grade 2 toxicities were fatigue (n = 5), headache (n = 2), CNS necrosis (n = 1), and pain (n = 1). CONCLUSIONS: In our series, PBT achieved excellent safety and efficacy outcomes with very low rates of treatment failure. CNS necrosis is exceedingly low (<1%) despite the high doses of PBT delivered. Further maturation of data and larger patient numbers are necessary to optimize therapy in chordoma.

Asunto(s)

Cordoma , Terapia de Protones , Humanos , Persona de Mediana Edad , Terapia de Protones/efectos adversos , Protones , Resultado del Tratamiento , Cordoma/radioterapia , Dolor/etiología , Sistema de Registros

RESUMEN

BACKGROUND: Evidence-based guidelines for the management of systemic therapy-naïve oligometastatic renal cell carcinoma (RCC) are lacking. OBJECTIVE: To evaluate the potential of stereotactic ablative radiotherapy (SAbR) to provide longitudinal disease control while preserving quality of life (QOL) in patients with systemic therapy-naïve oligometastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: RCC patients with three or fewer extracranial metastases were eligible. SAbR was administered longitudinally to all upfront and, as applicable, subsequent metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This prospective phase II single-arm trial was powered to achieve a primary objective of freedom from systemic therapy for >1 yr in >60% of patients (using the Clopper and Pearson methodology). Secondary endpoints included progression-free survival (PFS), defined as the time from first SAbR to progression not amenable to SAbR (local failure at SAbR-treated sites, new metastases not amenable to SAbR, more than three new metastases, or brain metastases); patient-reported QOL metrics; local control (LC) rates; toxicity; cancer-specific survival (CSS); and overall survival (OS). RESULTS AND LIMITATIONS: Twenty-three patients received SAbR to 33 initial and 57 total sites. The median follow-up was 21.7 mo (interquartile range 16.3-30.3). Exceeding the prespecified 60% benchmark, freedom from systemic therapy at 1 yr was 91.3% (95% confidence interval [CI]: 69.5, 97.8). One-year PFS was 82.6% (95% CI: 60.1, 93.1). QOL was largely unaffected. LC was 100%. There were no grade 3/4 toxicities, but there was one death due to immune-related colitis 3 mo after SAbR while on subsequent checkpoint inhibitor therapy, where a SAbR contribution could not be excluded. One-year OS was 95.7% (95% CI: 72.9, 99.4); one-year CSS was 100%. CONCLUSIONS: SAbR for oligometastatic RCC was associated with meaningful longitudinal disease control while preserving QOL. These data support further evaluation of SAbR for systemic therapy-naïve oligometastatic RCC. PATIENT SUMMARY: Sequential stereotactic radiation therapy can safely and effectively control metastatic kidney cancer with limited spread for over a year without compromising patients' quality of life.

Asunto(s)

Carcinoma de Células Renales , Neoplasias Renales , Radiocirugia , Humanos , Radiocirugia/métodos , Calidad de Vida , Estudios Prospectivos , Neoplasias Renales/patología

RESUMEN

BACKGROUND: A meta-analysis of patients with sporadic vestibular schwannoma (VS) primarily treated with stereotactic radiosurgery (SRS) or microsurgery (MS) was performed, and hearing preservation outcome (HPO), tumor control (TC), and facial nerve dysfunction (FND) were analyzed. METHODS: A systematic review was conducted (Medline and Scopus database) for the period January 2010-June 2020 with appropriate MeSH. English language articles for small to medium sporadic VS (<3 cm) using SRS or MS as primary treatment modality, with minimum follow-up of 3 years, were included. Studies had to report an acceptable standardized hearing metric. RESULTS: Thirty-two studies met the inclusion criteria: 10 MS; 23 radiosurgery, and 1 comparative study included in both. HPO, at approximately 65 months follow-up, were comparable between MS group (10 studies; 809 patients) and SRS group (23 studies; 1234 patients) (56% vs. 59%; P = 0.1527). TC, at approximately 70 months follow-up, was significantly better in the MS group (9 studies; 1635 patients) versus the SRS group (19 studies; 2260 patients) (98% vs. 92%; P < 0.0001). FND, at approximately 12 months follow-up, was significantly higher in the MS group (8 studies; 1101 patients) versus the SRS group (17 studies; 2285 patients) (10% vs. 2%; P < 0.0001). CONCLUSIONS: MS and SRS are comparable primary treatments for small (<3 cm) sporadic VS with respect to HPO at 5-year follow-up in patients with serviceable hearing at presentation; approximately 50% of patients for both modalities likely lose serviceable hearing by that time point. High TC rates (>90%) were seen with both modalities; MS 98% versus SRS 92%. The posttreatment FND was significantly less with the SRS group (2%) versus the MS group (10%).

Asunto(s)

Neuroma Acústico , Radiocirugia , Estudios de Seguimiento , Audición , Humanos , Microcirugia/métodos , Neuroma Acústico/radioterapia , Neuroma Acústico/cirugía , Radiocirugia/métodos , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

PURPOSE: As a means of limiting normal tissue toxicity, proton-beam therapy (PBT) is an emerging radiation modality for glioblastoma (GBM) reirradiation. However, data for recurrent GBM treated with PBT reirradiation is limited. Therefore, we analyzed treatment patterns, toxicities, and clinical outcomes of patients with recurrent GBM treated with PBT reirradiation using the multi-institutional Proton Collaborative Group registry. METHODS AND MATERIALS: Prospectively collected data for patients with recurrent GBM who underwent PBT while enrolled in Proton Collaborative Group study 01-009 (NCT01255748) were analyzed. We evaluated overall survival (OS), progression-free survival (PFS), and toxicity. Toxicities were scored per the Common Terminology Criteria for Adverse Events, version 4.0. Descriptive statistics were used to report patient, tumor, and treatment characteristics. Multivariable analyses (MVA) for toxicity were conducted using logistic regression. The Kaplan-Meier method was used to calculate OS and PFS. MVA for OS and PFS was conducted using Cox proportional-hazards models. The SAS statistical software was used for the analysis. RESULTS: We identified 45 recurrent patients with GBM who underwent PBT reirradiation between 2012 and 2018. The median time between initial GBM diagnosis and recurrence was 20.2 months. The median follow-up time from PBT reirradiation was 10.7 months. Median PFS was 13.9 months (95% confidence interval [CI], 8.23-20.0 months) and median OS was 14.2 months (95% CI, 9.6-16.9 months) after PBT reirradiation. One patient experienced an acute grade 3 toxicity, 4 patients experienced late grade 3 toxicity (no grade ≥4 toxicities). MVA revealed that prior surgery was associated with a 91.3% decreased hazard of death (hazard ratio: 0.087; 95% CI, 0.02-0.42; P < .01). No explanatory variables were associated with PFS or grade 3 toxicities. CONCLUSIONS: This is the largest series to date reporting outcomes for PBT reirradiation of patients with recurrent GBM. Our analysis indicates that PBT is well tolerated and offers efficacy rates comparable with previously reported photon reirradiation.

RESUMEN

OBJECTIVES: Clinical concerns about hematologic toxicities in human immunodeficiency virus (HIV)+ patients with squamous cell anal cancer (SCAC) may lead to de-escalation of treatment intensity. The objective of this study is to evaluate clinical outcomes including toxicity following standard concurrent curative-intent chemoradiation for HIV+ and HIV- patients with SCAC. MATERIALS AND METHODS: Among 97 evaluable patients treated between 2009 and 2016 (median age 52.2 y), 43 (44.3%) were HIV+ and 54 (55.7%) HIV-. The majority of the radiation was delivered using intensity-modulated radiation therapy and chemotherapy consisting primarily (93%) of 5-fluorouracil and mitomycin C. Clinical outcomes assessed included toxicity, locoregional control (LRC), distant metastasis (DM), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), and cause-specific survival (CSS). RESULTS: With a median follow-up of 45 months, HIV+ patients exhibited a trend toward reduced OS compared with HIV- patients (4 y OS 61.2% vs. 78.3%; HR 2.09; 95% CI, 0.97-4.52; P=0.055) on univariable analysis, but HIV status was not significant after adjusting for additional parameters on multivariable analysis. Toxicity rates, LRC, CFS, PFS, freedom from DM, and CSS were similar between the 2 cohorts. On multivariable analysis, tumor size >5 cm impacted all clinical outcomes (trend for LRC) except CFS. Radiation treatment extension beyond 7 days was found to negatively impact LRC and CSS. Male sex was associated with worse CFS. CONCLUSIONS: Radiation therapy with concurrent 5-fluorouracil and mitomycin C chemotherapy is reasonably well-tolerated as curative treatment for HIV+ patients with SCAC, and no significant difference in outcomes was noted relative to HIV- patients.

Asunto(s)

Neoplasias del Ano/terapia , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/métodos , Infecciones por VIH/complicaciones , Huésped Inmunocomprometido , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Ano/etiología , Neoplasias del Ano/inmunología , Neoplasias del Ano/mortalidad , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/mortalidad , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/uso terapéutico , Radioterapia de Intensidad Modulada/métodos , Resultado del Tratamiento

RESUMEN

PURPOSE: Stereotactic ablative radiotherapy (SAbR) is a promising alternative for selected patients with renal cell carcinoma (RCC) with oligometastasis. The objective of this study was to evaluate the potential of SAbR for longitudinal control in patients with persistently oligometastatic RCC. We report the impact of SAbR on tumor control rates as well as its tolerability in systemic therapy-naïve patients with oligometastatic disease (without brain metastases) and assess the effect of SAbR on subsequent first line systemic therapy by comparison to historical controls. METHODS AND MATERIALS: We reviewed patients with metastatic RCC treated with front-line SAbR with a curative intent from 2007 to 2017 at UT Southwestern Kidney Cancer Program. We analyzed local control rates (LCR), toxicity, freedom from systemic therapy (FST), type and duration of first-line systemic therapy, and overall survival (OS). Cox regression and Kaplan-Meier analyses were used. RESULTS: We identified 47 patients with oligometastatic RCC treated with SAbR to 88 metastases; 11 patients had more than 1 SAbR course. The local control rate was 91.5% at 2 years with no reported grade ≥3 toxicity. With a median follow-up of 30 months (interquartile range, 13.7-40.9), median FST from first SAbR was 15.2 months (95% confidence interval [CI], 8.8-40.1). The most common systemic therapies initiated after SAbR were pazopanib (60.7%) and sunitinib (14.3%). The duration of first line systemic therapy appeared unaffected by SAbR. Improved FST was observed in patients with metachronous disease (hazard ratio, 2.67; P = .02), solitary metastasis (HR, 2.26; P = .05), and non-bone metastasis (HR, 2.21; P = .04). One-year and 2-year OS after SAbR were 93.1% (95% CI, 80.1-97.7) and 84.8% (95% CI, 69.1-92.9), respectively. Median OS was not reached. CONCLUSIONS: SAbR is an effective and safe treatment for selected patients with oligometastatic RCC, can provide longitudinal disease control without systemic therapy for over a year, and does not appear to adversely affect the effectiveness of first-line systemic therapy once initiated. Prospective validation of these findings is being sought through a phase 2 trial.

Asunto(s)

Carcinoma de Células Renales/radioterapia , Neoplasias Renales/radioterapia , Radiocirugia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Intervalos de Confianza , Femenino , Estudios de Seguimiento , Humanos , Indazoles , Estimación de Kaplan-Meier , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Calidad de Vida , Radiocirugia/efectos adversos , Radiocirugia/mortalidad , Análisis de Regresión , Estudios Retrospectivos , Sulfonamidas/uso terapéutico , Sunitinib/uso terapéutico , Tasa de Supervivencia , Tomografía Computarizada por Rayos X

RESUMEN

PURPOSE: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years. MATERIALS & METHODS: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types. RESULTS: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents. CONCLUSION: To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients.

Asunto(s)

Neoplasias/radioterapia , Terapia de Protones/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias/epidemiología , Pediatría/métodos , Pediatría/estadística & datos numéricos , Terapia de Protones/métodos , Dosificación Radioterapéutica , Encuestas y Cuestionarios , Adulto Joven

Asunto(s)

Neoplasias del Sistema Nervioso Central/radioterapia , Pautas de la Práctica en Medicina , Terapia de Protones , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Multicéntricos como Asunto , Resultado del Tratamiento , Adulto Joven

RESUMEN

OBJECTIVE: Locally advanced endometrioid adenocarcinoma (LA-EAC) accounts for the majority of deaths for this cancer, yet there is no consensus on adjuvant treatment after surgery. Past studies suggest that combined modality treatment (CMT) may improve outcomes over treatment with chemotherapy (CT) or radiation therapy (RT, either external beam radiotherapy [EBRT] or vaginal brachytherapy [VBT]) alone. Using a large US-based population-based registry, we evaluated adjuvant CMT in LA-EAC and the relative benefit of regional EBRT compared to focused VBT. METHODS: We studied patients diagnosed with Stage III LA-EAC between 2004 and 2013 from the National Cancer Data Base (NCDB). We used Cox regression and a log-rank test to assess survival based on treatment with CT alone, EBRT alone, VBT alone, or CMT with EBRT and/or VBT. We used a χ² test to compare covariates between patients receiving CMT with EBRT or VBT. RESULTS: Patients who received CMT had better survival than those who received CT or EBRT/VBT alone. Compared to CMT with VBT, patients who received CMT with EBRT were slightly older and had more advanced-stage or positive nodes, and fewer had lymph node surgery. We found no survival difference between CMT with EBRT and CMT with VBT even when categorizing patients as high or low risk according to age, grade, and stage (low-risk p=0.3460; high-risk p=0.2158). CONCLUSION: CMT was associated with superior survival outcomes compared to monotherapy. We observed no survival difference between radiation modalities in CMT, which highlights the effectiveness of a more focused treatment like brachytherapy.

Asunto(s)

Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/radioterapia , Quimioradioterapia Adyuvante/métodos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/radioterapia , Adulto , Anciano , Análisis de Varianza , Braquiterapia/estadística & datos numéricos , Carcinoma Endometrioide/mortalidad , Quimioradioterapia Adyuvante/mortalidad , Quimioradioterapia Adyuvante/estadística & datos numéricos , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos

RESUMEN

PURPOSE: Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. METHODS AND MATERIALS: We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ2, Kaplan-Meier, and log-rank tests. RESULTS: In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. CONCLUSIONS: SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies.

Asunto(s)

Carcinoma de Células Renales/radioterapia , Carcinoma de Células Renales/secundario , Neoplasias Renales/patología , Radiocirugia/métodos , Anciano , Análisis de Varianza , Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Carcinoma de Células Renales/patología , Distribución de Chi-Cuadrado , Fraccionamiento de la Dosis de Radiación , Humanos , Estimación de Kaplan-Meier , Modelos Lineales , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Persona de Mediana Edad , Radiocirugia/efectos adversos , Planificación de la Radioterapia Asistida por Computador , Efectividad Biológica Relativa , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Neoplasias de los Tejidos Blandos/radioterapia , Neoplasias de los Tejidos Blandos/secundario , Neoplasias de la Columna Vertebral/radioterapia , Neoplasias de la Columna Vertebral/secundario , Insuficiencia del Tratamiento

RESUMEN

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.

Asunto(s)

Recurrencia Local de Neoplasia/radioterapia , Prostatectomía , Neoplasias de la Próstata/radioterapia , Radioterapia , Terapia Recuperativa , Anciano , Anciano de 80 o más Años , Humanos , Calicreínas/sangre , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/sangre , Estadificación de Neoplasias , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/cirugía , Estudios Retrospectivos

RESUMEN

Prostate cancer recurrences are usually first detected by increased levels of prostate specific antigen (PSA), and systemic therapy is often initiated if distant metastasis is confirmed. However, low or nearly undetectable levels of PSA in the modern era of ultrasensitive PSA assay may be difficult to interpret in patients with a history of prostate cancer. Deciding whether to initiate additional systemic therapy in limited indolent metastatic disease while balancing the quality of life of the patient and ensuring the oncologic control of the disease may be challenging. In the present study, the case of a biopsy-confirmed solitary spine recurrence of prostate cancer with nearly undetectable but persistent levels of PSA (0.05 ng/ml) is reported. Treatment of the recurrence with local ablative radiotherapy improved the pain experienced by the patient, and reduced his levels of PSA to undetectable limits (<0.05 ng/ml). Repeated imaging analysis, PSA assay and clinical assessment demonstrated durable control of the disease without the requirement for additional systemic treatments. The present case highlighted the importance of initiating appropriate work-up according to the clinical scenario. Local treatment for solitary or oligometastatic recurrence of prostate cancer may enhance the effectiveness of current therapeutic strategies and benefit certain patients.

Asunto(s)

Neoplasias Encefálicas/genética , Glioblastoma/genética , Neoplasias Encefálicas/terapia , Ensayos Clínicos como Asunto , Epigénesis Genética , Glioblastoma/terapia , Humanos

RESUMEN

A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2-/-mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cell-intrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2-/- osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2-/- osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Regulación de la Expresión Génica , Osteoclastos/metabolismo , Osteoporosis/genética , Proteínas Adaptadoras Transductoras de Señales/fisiología , Animales , Médula Ósea/metabolismo , Resorción Ósea , Linaje de la Célula , Integrinas , Masculino , Ratones , Ratones Transgénicos , Modelos Biológicos , Osteoblastos/metabolismo , Proteínas Proto-Oncogénicas c-abl/metabolismo

RESUMEN

INTRODUCTION: Cherubism is a human genetic disorder that causes bilateral symmetrical enlargement of the maxilla and the mandible in children. It is caused by mutations in SH3BP2. The exact pathogenesis of the disorder is an area of active research. Sh3bp2 knock-in mice were developed by introducing a Pro416Arg mutation (Pro418Arg in humans) in the mouse genome. The osteoclast phenotype of this mouse model was recently described. METHODS: We examined the bone phenotype of the cherubism mouse model, the role of Sh3bp2 during bone formation, osteoblast differentiation, and osteoblast function. RESULTS: We observed delays in early postnatal development of homozygous Sh3bp2(KI/KI) mice, which exhibited increased growth plate thickness and significantly decreased trabecular bone thickness and bone mineral density. Histomorphometric and microcomputed tomography analyses showed bone loss in the cranial and appendicular skeletons. Sh3bp2(KI/KI) mice also exhibited a significant decrease in osteoid formation that indicated a defect in osteoblast function. Calvarial osteoblast cell cultures had decreased alkaline phosphatase expression and mineralization, suggesting reduced differentiation potential. Gene expression of osteoblast differentiation markers such as collagen type I, alkaline phosphatase, and osteocalcin were decreased in osteoblast cultures from Sh3bp2(KI/KI) mice. CONCLUSIONS: These data suggest that Sh3bp2 regulates bone homeostasis through not only osteoclast-specific effects, but also through effects on osteoblast differentiation and function.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/metabolismo , Querubismo/genética , Osteoblastos/fisiología , Osteogénesis/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Fosfatasa Alcalina/metabolismo , Sustitución de Aminoácidos , Animales , Densidad Ósea/genética , Densidad Ósea/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Querubismo/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/fisiología , Técnicas de Sustitución del Gen , Masculino , Ratones , Ratones Mutantes , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogénesis/genética

RESUMEN

Cherubism is an autosomal dominant disorder in children characterized by unwarranted symmetrical bone resorption of the jaws with fibrous tissue deposition. Mutations causing cherubism have been identified in the adaptor protein SH3BP2. Knock-in mice with a Pro416Arg mutation in Sh3bp2 exhibit a generalized osteoporotic bone phenotype. In this study, we examined the effects of this "cherubism" mutation on spectroscopic indices of "bone quality" and on osteoblast differentiation. Fourier-transform infrared imaging (FTIRI) analysis of femurs from wild-type and Sh3bp2 knock-in mice showed decreased mineral content, decreased mineral crystallinity/crystal size, and increased collagen maturity in homozygous mutants. To assess osteoblast maturation in vivo, knock-in mice were crossed with transgenic mice over-expressing GFP driven by 3.6-kb or 2.3-kb Col1a1 promoter fragments. Reduced numbers of mature osteoblasts were observed in homozygous mice. Neonatal calvarial cultures, which were enriched for osteoblasts by depletion of hematopoietic cells (negative selection for Ter119- and CD45-positive cells) were investigated for osteoblast-specific gene expression and differentiation, which demonstrated that differentiation and mineralization in homozygous osteoblast cultures was impaired. Co-cultures with calvarial osteoblasts and bone marrow macrophages showed that mutant osteoblasts appear to increase osteoclastogenesis resulting in increased bone resorption on bone chips. In summary, the Sh3bp2 mutation in cherubism mice alters bone quality, reduces osteoblast function, and may contribute to excessive bone resorption by osteoclasts. Our data, together with previous osteoclast studies, demonstrate a critical role of Sh3bp2 in bone remodeling and osteoblast differentiation.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/fisiología , Densidad Ósea/fisiología , Huesos/metabolismo , Querubismo/genética , Osteoblastos/citología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Densidad Ósea/genética , Huesos/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Transgénicos , Mutación/genética , Osteoblastos/metabolismo , Osteogénesis/genética , Osteogénesis/fisiología , Reacción en Cadena de la Polimerasa , Ligando RANK/genética , Ligando RANK/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier

RESUMEN

PURPOSE: This study evaluated the biologic effect in vivo of hydroxyapatite (HA) nanoparticle surface modification on commercially pure titanium or titanium alloy (Ti-6Al-4V) implants. MATERIALS AND METHODS: Miniature cylindric titanium and Ti-6Al-4V implants were pretreated with dual acid etching (DAE), and a subset was further modified with HA nanoparticles using discrete crystalline deposition (DCD). The resultant implant surface topography was characterized by interferometry and scanning electron microscopy. Miniature implants of DAE titanium, DAE Ti-6Al-4V, DCD titanium, and DCD Ti-6Al-4V were surgically placed in the femora of rats. After 4 days, 1 week, and 2 weeks of healing, osseointegration was evaluated by implant push-in tests or microcomputed tomography (microCT). Ti-6Al-4V samples were harvested at week 2 and prepared for nondecalcified histology and subjected to bone-to-implant contact (BIC) measurement. RESULTS: DCD treatment generated a complex surface morphology via the bonded HA nanoparticles. However, the amplitude and spatial, hybrid, and functional surface roughness parameters measured at the micron and submicron levels did not depict topographic differences between the DAE and the DCD-modified implants. DAE titanium and DAE Ti-6Al-4V implants showed a sharp increase in push-in values at week 1, followed by a plateau at week 2. DCD titanium and DCD Ti-6Al-4V implants showed similar sharp increases at week 1, but the push-in values continued to increase at week 2. The surrounding bone architecture evaluated by microCT and the BIC ratio did not correlate with the biomechanical implant osseointegration measurement. CONCLUSIONS: DCD-derived surface modification with HA nanoparticles on titanium and Ti-6Al-4V implants resulted in progressive osseointegration profiles that were distinctively different from those of DAE controls. Surrogate measurements such as surface roughness parameters and BIC did not predict the biologic effect of the DCD treatment. The data indicate that early osseointegration may be more sensitively regulated by nanoscale surface characteristics.

Asunto(s)

Materiales Biocompatibles Revestidos/química , Implantes Dentales , Materiales Dentales/química , Durapatita/química , Nanopartículas/química , Oseointegración/fisiología , Titanio/química , Grabado Ácido Dental/métodos , Aleaciones , Animales , Fenómenos Biomecánicos , Aleaciones Dentales/química , Diseño de Prótesis Dental , Fémur/cirugía , Imagenología Tridimensional/métodos , Interferometría , Masculino , Microscopía Electrónica de Rastreo , Ratas , Ratas Sprague-Dawley , Estrés Mecánico , Propiedades de Superficie , Factores de Tiempo , Microtomografía por Rayos X/métodos

RESUMEN

PURPOSE: The patient population varies in nutritional deficiencies, which may confound the host response to biomaterials. The objective of this study was to evaluate the effect of a common deficiency of vitamin D on implant osseointegration in the rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats were maintained under the cessation of vitamin D intake and UV exposure. The serum levels of 1,25(OH)(2)D(3), 25 OHD(3), Ca, and P were determined. Miniature cylindrical Ti6Al4V implants (2-mm long, 1-mm diameter) were fabricated with double acid-etched (DAE) surface or modified DAE with discrete crystalline deposition (DCD) of hydroxyapatite nanoparticles. DAE and DCD implants were placed in the femurs of vitamin D-insufficient and control rats. After 14 days of healing, the femur-implant samples were subjected to implant push-in test and nondecalcified histology. The surfaces of recovered implant specimens after the push-in test were further evaluated by scanning electron microscopy (SEM). RESULTS: The decreased serum level of 25 OHD(3) demonstrated the establishment of vitamin D insufficiency in this model. The implant push-in test revealed that DAE and DCD implants in the vitamin D-insufficient group (15.94 +/- 8.20 N, n = 7; 15.63 +/- 3.96 N, n = 7, respectively) were significantly lower than those of the control group (24.99 +/- 7.92 N, n = 7, p < 0.05; 37.48 +/- 17.58 N, n = 7, p < 0.01, respectively). The transcortical bone-to-implant contact ratio (BIC) was also significantly decreased in the vitamin D-insufficient group. SEM analyses further suggested that the calcified tissues remaining next to the implant surface after push-in test appeared unusually fragmented. CONCLUSIONS: The effect of vitamin D insufficiency significantly impairing the establishment of Ti6Al4V implant osseointegration in vivo was unexpectedly profound. The outcome of Ti-based endosseous implants may be confounded by the increasing prevalence of vitamin D insufficiency in our patient population.

Asunto(s)

Implantes Dentales , Fémur/ultraestructura , Hidroxicolecalciferoles/sangre , Oseointegración/fisiología , Deficiencia de Vitamina D/fisiopatología , Animales , Implantación Dental Endoósea , Fracaso de la Restauración Dental , Análisis del Estrés Dental , Fémur/fisiología , Fémur/cirugía , Masculino , Estado Nutricional , Ratas , Ratas Sprague-Dawley , Deficiencia de Vitamina D/sangre

RESUMEN

Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH. Previous studies of Ank loss-of-function models, Ank(null/null) and Ank(ank/ank) mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice (Ank(KI/KI)) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club-shaped femurs. In addition, Ank(KI/KI) mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N-terminal propeptide of type I procollagen and type I collagen cross-linked C-terminal telopeptide, are significantly increased in Ank(KI/KI) mice, suggesting increased bone turnover. Interestingly, Ank(KI/KI) bone marrow-derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in Ank(KI/KI) mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.

Asunto(s)

Enfermedades del Desarrollo Óseo/sangre , Enfermedades del Desarrollo Óseo/genética , Modelos Animales de Enfermedad , Proteínas de la Membrana/genética , Eliminación de Secuencia , Fosfatasa Ácida/sangre , Fosfatasa Alcalina/sangre , Animales , Enfermedades del Desarrollo Óseo/patología , Colágeno Tipo I/metabolismo , Humanos , Isoenzimas/sangre , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Transgénicos , Proteínas de Transporte de Fosfato , Cráneo/metabolismo , Cráneo/patología , Fosfatasa Ácida Tartratorresistente