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BACKGROUND: Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered. METHODS/DESIGN: The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50-56 Gy) followed by surgery and IORT (10-12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population. DISCUSSION: The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity. TRIAL REGISTRATION: NCT01566123.
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Neoplasias Retroperitoneales/radioterapia , Neoplasias Retroperitoneales/cirugía , Sarcoma/radioterapia , Sarcoma/cirugía , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/métodos , Humanos , Cuidados Intraoperatorios/métodos , Terapia Neoadyuvante , Estudios Prospectivos , Dosificación Radioterapéutica , Radioterapia Adyuvante/métodos , Radioterapia de Intensidad Modulada/métodosRESUMEN
Bottom-up approaches in solutions enable the low-temperature preparation of hybrid thin films suitable for printable transparent and flexible electronic devices. We report the obtainment of new transparent PMMA/ZrO2 nanostructured -building blocks (nBBs) hybrid thin films (61-75 nm) by a modified sol-gel method using zirconium ethoxide, Zr(OEt)4, and 3-methacryloxypropyl trimethoxysilane (MPS) as a coupling agent and methylmethacrylate monomer (MMA). The effect of low-temperature and UV irradiation on the nBBs gel films is discussed. The thermal behaviors of the hybrid sols and as-deposed gel films were investigated by modulated thermogravimetric (mTG) and differential scanning calorimetry (DSC) analysis. The chemical structure of the resulted films was elucidated by X-ray photoelectron (XPS), infrared (IR) and Raman spectroscopies. Their morphology and crystalline structure were observed by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), and grazing incidence X-ray diffraction. The cured films show zirconia nanocrystallites of 2-4 nm in the hybrid matrix and different self-assembled structures for 160 °C or UV treatment; excellent dielectric behavior, with dielectric constant values within 6.7-17.9, depending on the Zr(OEt)4:MMA molar ratio, were obtained.
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BACKGROUND: To investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. METHODS: Between August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. RESULTS: The median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. CONCLUSION: CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.
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Neoplasias Óseas , Osteosarcoma , Adulto , Neoplasias Óseas/radioterapia , Carbono , Terapia Combinada , Humanos , Iones , Osteosarcoma/radioterapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Protones , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To retrospectively analyze patient characteristics, treatment, and treatment outcome of pediatric patients with hematologic diseases treated with total body irradiation (TBI) between 1978 and 2006. PATIENTS AND METHODS: 32 pediatric patients were referred to the Department of Radiation-Oncology at the University of Zurich for TBI. Records of regular follow-up of 28 patients were available for review. Patient characteristics as well as treatment outcome regarding local control and overall survival were assessed. A total of 18 patients suffered from acute lymphoblastic leukemia (ALL), 5 from acute and 2 from chronic myelogenous leukemia, 1 from non-Hodgkin lymphoma, and 2 from anaplastic anemia. The cohort consisted of 15 patients referred after first remission and 13 patients with relapsed leukemia. Mean follow-up was 34 months (2-196 months) with 15 patients alive at the time of last follow-up. Eight patients died of recurrent disease, 1 of graft vs. host reaction, 2 of sepsis, and 2 patients died of a secondary malignancy. RESULTS: The 5-year overall survival rate (OS) was 60%. Overall survival was significantly inferior in patients treated after relapse compared to those treated for newly diagnosed leukemia (24% versus 74%; p=0.004). At the time of last follow-up, 11 patients survived for more than 36 months following TBI. Late effects (RTOG ≥ 3) were pneumonitis in 1 patient, chronic bronchitis in 1 patient, cardiomyopathy in 2 patients, severe cataractogenesis in 1 patient (48 months after TBI with 10 Gy in a single dose) and secondary malignancies in 2 patients (36 and 190 months after TBI). Growth disturbances were observed in all patients treated prepubertally. In 2 patients with identical twins treated at ages 2 and 7, a loss of 8% in final height of the treated twin was observed. CONCLUSION: As severe late sequelae after TBI, we observed 2 secondary malignancies in 11 patients who survived in excess of 36 months. However, long-term morbidity is moderate following treatment with the fractionated TBI at the low-dose rate that was generally used here. Conditioning for bone marrow transplantation without radiation is an attractive option, but is not sufficiently effective to completely replace TBI for the most common pediatric indications.
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Anemia Aplásica/radioterapia , Leucemia Mielógena Crónica BCR-ABL Positiva/radioterapia , Leucemia Mieloide Aguda/radioterapia , Linfoma no Hodgkin/radioterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Irradiación Corporal Total , Adolescente , Anemia Aplásica/mortalidad , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide Aguda/mortalidad , Linfoma no Hodgkin/mortalidad , Masculino , Neoplasias Inducidas por Radiación/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Traumatismos por Radiación/etiología , Dosificación Radioterapéutica , Recurrencia , Inducción de Remisión , Retratamiento , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are <10% and might effectively approach zero if a complete surgical resection of the tumor is not possible. Up to date there is no curative treatment protocol for patients with non-resectable osteosarcomas, who are excluded from current osteosarcoma trials, e.g. EURAMOS1. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases particle Radiotherapy (proton therapy (PT)/heavy ion therapy (HIT) may offer a promising new alternative. Moreover, compared with photons, heavy ion beams provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results. METHODS/DESIGN: This is a monocenter, single-arm study for patients > or = 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (Gy E) with 45 Gy PT (proton therapy) and a carbon ion boost of 15-21 GyE. Weekly fractionation of 5-6 x 3 Gy E is used. PT/HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after PT/HIT will be investigated prospectively. Systemic disease before and after PT/HIT is targeted by standard chemotherapy protocols and is not part of this trial. DISCUSSION: The primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary objectives are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma. TRIAL REGISTRATION: Registration number (ClinicalTrials.gov): NCT01005043.
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Neoplasias Óseas/radioterapia , Oncología Médica/métodos , Osteosarcoma/radioterapia , Radioterapia/métodos , Adolescente , Adulto , Niño , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Iones Pesados , Humanos , Iones , Protones , Proyectos de Investigación , Seguridad , Factores de Tiempo , Resultado del TratamientoRESUMEN
UNLABELLED: The Heidelberg Ion Therapy Center (HIT) started clinical operation in November 2009. In this report we present the first 80 patients treated with proton and carbon ion radiotherapy and describe patient selection, treatment planning and daily treatment for different indications. PATIENTS AND METHODS: Between November 15, 2009 and April 15, 2010, 80 patients were treated at the Heidelberg Ion Therapy Center (HIT) with carbon ion and proton radiotherapy. Main treated indications consisted of skull base chordoma (n = 9) and chondrosarcoma (n = 18), malignant salivary gland tumors (n=29), chordomas of the sacrum (n = 5), low grade glioma (n=3), primary and recurrent malignant astrocytoma and glioblastoma (n=7) and well as osteosarcoma (n = 3). Of these patients, four pediatric patients aged under 18 years were treated. RESULTS: All patients were treated using the intensity-modulated rasterscanning technique. Seventy six patients were treated with carbon ions (95%), and four patients were treated with protons. In all patients x-ray imaging was performed prior to each fraction. Treatment concepts were based on the initial experiences with carbon ion therapy at the Gesellschaft für Schwerionenforschung (GSI) including carbon-only treatments and carbon-boost treatments with photon-IMRT. The average time per fraction in the treatment room per patient was 29 minutes; for irradiation only, the mean time including all patients was 16 minutes. Position verification was performed prior to every treatment fraction with orthogonal x-ray imaging. CONCLUSION: Particle therapy could be included successfully into the clinical routine at the Department of Radiation Oncology in Heidelberg. Numerous clinical trials will subsequently be initiated to precisely define the role of proton and carbon ion radiotherapy in radiation oncology.
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Centros Médicos Académicos , Iones/uso terapéutico , Neoplasias/radioterapia , Radioterapia/métodos , Adolescente , Adulto , Anciano , Carbono/uso terapéutico , Niño , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Terapia de Protones , Radiografía , Planificación de la Radioterapia Asistida por Computador/métodos , Restricción Física/métodos , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: To analyze our experiences concerning radiation treatment in patients with osteosarcoma. MATERIALS AND METHODS: Since 1981, 40 patients with osteosarcoma have undergone radiotherapy in Heidelberg; 3 of them were immediately lost to follow-up. Twenty patients with metastases were treated palliatively and 17 patients were treated with a curative intent. RESULTS: Interestingly, 14 of the 17 patients treated with a curative intent were referred to our clinic during the last 8 years, whereas the number of patients referred for palliation decreased. The mean dose applied for palliation was 47 Gy (range, 26 Gy to > 70 GyE), for cure was 59 Gy (range, 45 Gy to > 70 GyE). Local control until death could be achieved in 15 of the 20 palliatively treated patients, with a mean survival of 7 months after radiation. Five patients experienced local failure with symptom recurrence, and 3 of them had received doses > 60 Gy. At last follow-up, 3 of the 17 curatively treated patients had experienced local recurrence. Median follow-up was 32 months (range, 3-144). Estimated 5-year overall survival and local control rates were 38% and 68%, respectively. Local disease-free survival was shorter in patients treated for recurrent, inoperable or incompletely resected tumors and doses below 60 Gy. CONCLUSIONS: With adequate doses, long-term local control is possible even in inoperable or incompletely resected tumors. Improvements of systemic therapy and modern radiation techniques have begun to bring the possibly curative role of radiation treatment back to the fore. However, in disseminated tumors, even doses beyond 60 Gy do not guarantee local control, suggesting an extremely low radiosensitivity of certain kinds of osteosarcoma.
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Neoplasias Óseas/radioterapia , Osteosarcoma/radioterapia , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Neoplasias Óseas/cirugía , Niño , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteosarcoma/cirugía , Adulto JovenRESUMEN
Analysis of sweat chloride levels in cystic fibrosis (CF) patients is essential not only for diagnosis but also for the monitoring of therapeutic responses to new drugs, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and potentiators. Using iontophoresis as the gold standard can cause complications like burns, is uncomfortable, and requires repetitive hospital visits, which can be particularly problematic during a pandemic, where distancing and hygiene requirements are increased; therefore, it is necessary to develop fast and simple measures for the diagnosis and monitoring of CF. A screen-printed, low-cost chloride sensor was developed to remotely monitor CF patients. Using potentiometric measurements, the performance of the sensor was tested. It showed good sensitivity and a detection limit of 2.7 × 10-5 mol/L, which covered more than the complete concentration range of interest for CF diagnosis. Due to its fast response of 30 s, it competes well with standard sensor systems. It also offers significantly reduced costs and can be used as a portable device. The analysis of real sweat samples from healthy subjects, as well as CF patients, demonstrates a proper distinction using the screen-printed sensor. This approach presents an attractive remote measurement alternative for fast, simple, and low-cost CF diagnosis and monitoring.
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Técnicas Biosensibles , Cloruros/análisis , Sudor/química , Fibrosis Quística/diagnóstico , Regulador de Conductancia de Transmembrana de Fibrosis Quística , HumanosRESUMEN
BACKGROUND: Clostridium septicum infections are rare but often fatal. They are known to be associated with a compromised immune system, e.g. with hematologic malignancies. CASE REPORT: We report on a spontaneous, non-traumatic C. septicum infection in a patient with non-Hodgkin's lymphoma undergoing irradiation due to abdominal bulk. Irradiation was delivered in daily fractions of 1.8 Gy. After 7 fractions, the patient suddenly developed severe pain in the lower leg. Clinical examination showed no pathological findings. However, a rapid progression of symptoms with motoric and sensoric deficits progressed rapidly within hours. Sizzling noise and gas entrainment were detectable about 9 h after the first symptoms. Despite immediate surgical treatment, and in the end amputation, the patient died 14 h later of septic shock. Histopathology showed gas gangrene in the leg tissue, with hemorrhagic muscular necrosis and enclosed gas vesicles. C. septicum was identified as causative organism. CONCLUSIONS: Irradiation as well as chemotherapy may have enhanced the risk by immunosuppression and induction of mucosal damage. Earlier antibiotic treatment might have slowed down the clinical course and thus given more time for correct diagnosis and treatment.
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Infecciones por Clostridium/etiología , Clostridium septicum/aislamiento & purificación , Gangrena Gaseosa/etiología , Linfoma no Hodgkin/radioterapia , Traumatismos por Radiación/etiología , Radioterapia Conformacional/efectos adversos , Anciano , Infecciones por Clostridium/diagnóstico , Resultado Fatal , Gangrena Gaseosa/diagnóstico , Humanos , Traumatismos por Radiación/diagnósticoRESUMEN
PURPOSE: The optimal technique for postoperative radiotherapy (RT) after extrapleural pleuropneumonectomy (EPP) of malignant pleural mesothelioma (MPM) remains debated. METHODS AND MATERIALS: The data from 8 right-sided and 9 left-sided consecutive cases of MPM treated with RT after radical EPP were reviewed. Of the 17 patients, 8 had been treated with three-dimensional (3D) conformal RT (3D-CRT) and 9 with intensity-modulated RT (IMRT) with 6-MV photons. The clinical outcome and adverse events were assessed. For comparative planning, each case was replanned with 3D-CRT using photons and electrons or with IMRT. Homogeneity, doses to the organs at risk, and target volume coverage were analyzed. RESULTS: Both techniques yielded acceptable plans. The dose coverage and homogeneity of IMRT increased by 7.7% for the first planning target volume and 9.7% for the second planning target volume, ensuring >or=95% of the prescribed dose compared with 3D-CRT (p < 0.01). Compared with 3D-CRT, IMRT increased the dose to the contralateral lung, with an increase in the mean lung dose of 7.8 Gy and an increase in the volume receiving 13 Gy and 20 Gy by 20.5% and 7.2%, respectively (p < 0.01). A negligible dose increase to the contralateral kidney and liver was observed. No differences were seen for the spinal cord and ipsilateral kidney. Two adverse events of clinical relevant lung toxicity were observed with IMRT. CONCLUSION: Intensity-modulated RT and 3D-CRT are both suitable for adjuvant RT. IMRT improves the planning target volume coverage but delivered greater doses to the organs at risk. Rigid dose constraints for the lung should be respected.
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Mesotelioma/radioterapia , Neoplasias Pleurales/radioterapia , Radioterapia Conformacional/métodos , Radioterapia de Intensidad Modulada/métodos , Anciano , Femenino , Corazón , Humanos , Riñón , Pulmón , Masculino , Mesotelioma/cirugía , Persona de Mediana Edad , Pleura/cirugía , Neoplasias Pleurales/cirugía , Neumonectomía/métodos , Neumonitis por Radiación/complicaciones , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Adyuvante/métodos , Estudios RetrospectivosRESUMEN
PURPOSE: To evaluate local control and patterns of failure in patients treated with intraoperative electron beam radiotherapy (IOERT) after total mesorectal excision (TME), to appraise the effectiveness of intraoperative target definition. METHODS AND MATERIALS: We analyzed the outcome of 243 patients with rectal cancer treated with IOERT (median dose, 10 Gy) after TME. Eighty-eight patients received neoadjuvant and 122 patients adjuvant external beam radiotherapy (EBRT) (median dose, 41.4 Gy), and in 88% simultaneous chemotherapy was applied. Median follow-up was 59 months. RESULTS: Local failure was observed in 17 patients (7%), resulting in a 5-year local control rate of 92%. Only complete resection and absence of nodal involvement correlated positively with local control. Considering IOERT fields, seven infield recurrences were seen in the presacral space, resulting in a 5-year local control rate of 97%. The remaining local relapses were located as follows: retrovesical/retroprostatic (5), anastomotic site (2), promontorium (1), ileocecal (1), and perineal (1). CONCLUSION: Intraoperative electron beam radiotherapy as part of a multimodal treatment approach including TME is a highly effective regimen to prevent local failure. The presacral space remains the site of highest risk for local failure, but IOERT can decrease the percentage of relapses in this area.
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Electrones/uso terapéutico , Recurrencia Local de Neoplasia/prevención & control , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Periodo Intraoperatorio , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Radioterapia Adyuvante/métodos , Insuficiencia del TratamientoRESUMEN
PURPOSE: To evaluate the impact of endorectal balloon (ERB) on anorectal dose during postoperative VMAT of prostate cancer. METHODS: In ten patients referred for salvage radiotherapy CTs were obtained without ERB and with air-filled ERB of 50ml and 100ml. CTs were repeated weekly (4-6 control CTs) and registered to the respective planning CT. For each planning CT, a VMAT plan was made with defined anorectal dose constraints and propagated on the respective control CTs. The dose volumes V40Gy, V60Gy and V65Gy of the rectal and anal wall (Rwall and Awall, respectively) and the ERB position were obtained from each plan. RESULTS: In plans with ERB, the mean Rwall dose volumes V40Gy, V60Gy and V65Gy were higher by 8%, 5% and 2% (ERB 50ml) and 2%, 3% and 3% (ERB 100ml) in comparison to plans without ERB. The respective Awall dose volume differences were 2%, 0%, -1% (ERB 50ml), and -3%, -2%, -2% (ERB 100ml). The dose volume variability of the Rwall was comparable with and without ERB, but was slightly reduced by ERB for the Awall. The mean ERB position variability was >2mm in anterior-posterior and inferior-superior directions. CONCLUSION: The use of ERB during post-operative VMAT has no advantages for anorectal dose.
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Neoplasias de la Próstata/radioterapia , Radioterapia de Intensidad Modulada/métodos , Canal Anal/efectos de la radiación , Humanos , Masculino , Estudios Prospectivos , Neoplasias de la Próstata/cirugía , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , RectoRESUMEN
PURPOSE: This study assesses the long-term outcome of patients with retroperitoneal soft-tissue sarcomas treated by maximal resection in combination with intraoperative electron-beam therapy (IOERT) and postoperative external-beam radiotherapy. METHODS AND MATERIALS: From 1991 to 2004, 67 patients were treated with curative intent for primary (n = 26) or recurrent (n = 41) retroperitoneal soft-tissue sarcoma. All patients underwent maximal resection in combination with IOERT (mean dose, 15 Gy), 45 patients underwent additional postoperative EBRT, and 20 patients were previously irradiated. RESULTS: The 5-year actuarial overall survival (OS), disease-free survival, local control (LC), and freedom from metastatic disease of all patients was 64%, 28%, 40%, and 50%, respectively. The 5-year LC inside the IOERT field was 72%. For patients who completed IOERT and EBRT after R0-resection 5-year and 10-year OS was 80%, and 5-year and 10-year LC was 100%. Only 1 of the 21 patients after R0-resection and only 8 of 34 patients after R1-resection compared with 9 of 12 patients after R2-resection experienced inside IOERT-field relapse. Grade II or higher late complications were seen in 21% of the patients, but only 2 patients required surgical intervention because of late complications. CONCLUSION: In selected patients, IOERT results in excellent local control and survival, with acceptable morbidity.
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Recurrencia Local de Neoplasia/radioterapia , Neoplasias Retroperitoneales/radioterapia , Sarcoma/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Femenino , Humanos , Periodo Intraoperatorio , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/cirugía , Dosificación Radioterapéutica , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/cirugía , Estudios Retrospectivos , Sarcoma/mortalidad , Sarcoma/cirugía , Estadísticas no ParamétricasRESUMEN
PURPOSE: Intraoperative electron-beam radiotherapy (IOERT) has been applied for local dose escalation in over 1,400 patients in Heidelberg since 1991. Among these were 30 children, in 18 of whom IOERT was employed in radiation treatment with external-beam radiotherapy (EBRT) on account of incomplete resection. We address the question whether IOERT is able to compensate for microscopic or macroscopic tumor residue if employed in the overall radiation regimen. METHODS AND MATERIALS: The data of the aforementioned 18 children were analyzed with regard to local recurrence, overall survival, and complication rates. All children suffered from either sarcomas or neuroblastomas. In all children, IOERT was employed for local dose escalation after or before EBRT. RESULTS: After a median follow-up of 60.5 months, 15 of the treated children are alive. One local failure has been observed. Six children show clinically significant late morbidity, including the loss of a treated limb (Radiation Therapy Oncology Group Grade 4 [RTOG 4]), a severe nerve lesion (RTOG 3), an orthopedic complication (RTOG 2), a ureteral stenosis (not clinically significant), and a kidney hypotrophy (not clinically significant). In 1 child a fracture due to radionecrosis (RTOG 4) was diagnosed; however, in the follow-up, local tumor relapse was diagnosed as another possible reason for the fracture. CONCLUSIONS: Regarding the low incidence of local failure, IOERT seems to be able to compensate incomplete tumor resection in childhood sarcoma and neuroblastoma patients. The incidence of late morbidity is low enough to justify the employment of IOERT as part of the radiation treatment regimen for pediatric patients.
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Neoplasias Óseas/radioterapia , Neuroblastoma/radioterapia , Neoplasias Retroperitoneales/radioterapia , Sarcoma/radioterapia , Adolescente , Niño , Preescolar , Terapia Combinada/métodos , Femenino , Estudios de Seguimiento , Humanos , Lactante , Periodo Intraoperatorio , Masculino , Neoplasia Residual , Neuroblastoma/cirugía , Neoplasias Retroperitoneales/cirugía , Espacio Retroperitoneal , Sarcoma/cirugíaRESUMEN
PURPOSE: To analyze long-term prognosis and morbidity after limb-sparing treatment of patients with extremity soft-tissue sarcoma, with intraoperative electron boost radiotherapy (IOERT) followed by a moderate dose of external beam radiotherapy (EBRT). METHODS AND MATERIALS: A total of 153 patients who were treated in a single center from 1991 to 2004 were evaluated. Median IOERT dose was 15 Gy, mean EBRT dose 43 Gy (range, 40-50.4 Gy) in conventional fractionation (1.8-2 Gy). Median duration of follow-up was 33 months. Acute toxicity was assessed with Common Toxicity Criteria; late toxic effects were scored according to European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group criteria. RESULTS: Five-year overall survival and 5-year local control rates were 77% and 78%, respectively. Whereas tumor size, patient age, and EBRT dose did not significantly affect outcome, resection status and grading were significant for survival; resection status and IOERT dose were significant for local control. Extremity salvage until death or time of follow-up was achieved in 90% of our patients, 86% of whom showed excellent limb function without impairment in activities of daily life. Acute toxicity Grade 2-4 was observed in 23% and late toxicity Grade 2-4 in 17% of patients. CONCLUSIONS: Treatment with IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity soft-tissue sarcoma.
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Extremidades , Recuperación del Miembro/métodos , Sarcoma/radioterapia , Sarcoma/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Electrones/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Radioterapia/métodos , Sarcoma/mortalidad , Tasa de SupervivenciaRESUMEN
BACKGROUND: Minimal improvements in treatment or survival of patients with osteosarcoma have been achieved during the last three decades. Especially in the case of incomplete tumor resection, prognosis remains poor. Heavy ion radiotherapy (HIT) and modern anticancer drugs like histone deacetylase inhibitors (HDACi) have shown promising effects in osteosarcoma in vitro. In this study, we tested the effect of HIT and the combination of HIT and the HDACi suberoylanilide hydroxamic acid (SAHA) in a xenograft mouse model. METHODS: Osteosarcoma xenografts were established by subcutaneous injection of KHOS-24OS cells and treated with either vehicle (DMSO), SAHA, HIT or HIT and SAHA. Tumor growth was determined and tumor necrosis, proliferation rate, apoptotic rate as well as vessel density were evaluated. RESULTS: Here, we show that the combination of HIT and SAHA induced a significant delay of tumor growth through increased rate of apoptosis, increased expression of p53 and p21(Waf1/Cip1), inhibition of proliferation and angiogenesis compared to tumors treated with HIT only. CONCLUSION: HIT and in particular the combination of HIT and histone deacetylase inhibition is a promising treatment strategy in OS and may be tested in clinical trials.
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Radioterapia de Iones Pesados , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Osteosarcoma/radioterapia , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Neoplasias Óseas/patología , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Genes p53 , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ácidos Hidroxámicos/uso terapéutico , Ratones , Ratones SCID , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/radioterapia , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/patología , Tolerancia a Radiación/efectos de los fármacos , Tejido Subcutáneo , Proteína p53 Supresora de Tumor/biosíntesis , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: To report on establishment of workflow and clinical results of particle therapy at the Heidelberg Ion Therapy Center. MATERIALS AND METHODS: We treated 36 pediatric patients (aged 21 or younger) with particle therapy at HIT. Median age was 12 years (range 2-21 years), five patients (14%) were younger than 5 years of age. Indications included pilocytic astrocytoma, parameningeal and orbital rhabdomyosarcoma, skull base and cervical chordoma, osteosarcoma and adenoid-cystic carcinoma (ACC), as well as one patient with an angiofibroma of the nasopharynx. For the treatment of small children, an anesthesia unit at HIT was established in cooperation with the Department of Anesthesiology. RESULTS: Treatment concepts depended on tumor type, staging, age of the patient, as well as availability of specific study protocols. In all patients, particle radiotherapy was well tolerated and no interruptions due to toxicity had to be undertaken. During follow-up, only mild toxicites were observed. Only one patient died of tumor progression: Carbon ion radiotherapy was performed as an individual treatment approach in a child with a skull base recurrence of the previously irradiated rhabdomyosarcoma. Besides this patient, tumor recurrence was observed in two additional patients. CONCLUSION: Clinical protocols have been generated to evaluate the real potential of particle therapy, also with respect to carbon ions in distinct pediatric patient populations. The strong cooperation between the pediatric department and the department of radiation oncology enable an interdisciplinary treatment and stream-lined workflow and acceptance of the treatment for the patients and their parents.
Asunto(s)
Astrocitoma/radioterapia , Neoplasias Encefálicas/radioterapia , Condrosarcoma/radioterapia , Pediatría/métodos , Neoplasias de la Base del Cráneo/radioterapia , Adolescente , Adulto , Anestesia/estadística & datos numéricos , Carbono/efectos adversos , Carbono/uso terapéutico , Niño , Preescolar , Femenino , Alemania , Humanos , Iones/efectos adversos , Iones/uso terapéutico , Masculino , Posicionamiento del Paciente , Proyectos Piloto , Terapia de Protones , Protones/efectos adversos , Flujo de Trabajo , Adulto JovenRESUMEN
PURPOSE: Histone deacetylase inhibitors are promising new substances in cancer therapy and have also been shown to sensitize different tumor cells to irradiation (XRT). We explored the effect as well as the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) in vivo in a malignant rhabdoid tumor (MRT) mouse model. METHODS AND MATERIAL: Potential radiosensitization by SAHA was assessed in MRT xenografts by analysis of tumor growth delay, necrosis (HE), apoptosis (TUNEL), proliferation (ki-67) and γH2AX expression as well as dynamic 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG -PET) after treatment with either SAHA alone, single-dose (10 Gy) or fractionated XRT (3 × 3Gy) solely as well as in combination with SAHA compared to controls. RESULTS: SAHA only had no significant effect on tumor growth. Combination of SAHA for 8 days with single-dose XRT resulted in a higher number of complete remissions, but failed to prove a significant growth delay compared to XRT only. In contrast fractionated XRT plus SAHA for 3 weeks did induce significant tumor growth delay in MRT-xenografts. The histological examination showed a significant effect of XRT in tumor necrosis, expression of Ki-67, γH2AX and apoptosis. SAHA only had no significant effect in the histological examination. Comparison of xenografts treated with XRT and XRT plus SAHA revealed a significantly increased γH2AX expression and apoptosis induction in the mice tumors after combination treatment with single-dose as well as fractionated XRT. The combination of SAHA with XRT showed a tendency to increased necrosis and decrease of proliferation compared to XRT only, which, however, was not significant. The 18F-FDG-PET results showed no significant differences in the standard uptake value or glucose transport kinetics after either treatment. CONCLUSION: SAHA did not have a significant effect alone, but proved to enhance the effect of XRT in our MRT in vivo model.
Asunto(s)
Quimioradioterapia/métodos , Ácidos Hidroxámicos/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Tumor Rabdoide/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones , Radioterapia , Tumor Rabdoide/diagnóstico por imagen , Tumor Rabdoide/radioterapia , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: The pan-HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) has previously shown to be a radio-sensitizer to conventional photon radiotherapy (XRT) in pediatric sarcoma cell lines. Here, we investigate its effect on the response of two sarcoma cell lines and a normal tissue cell line to heavy ion irradiation (HIT). MATERIALS AND METHODS: Clonogenic assays after different doses of heavy ions were performed. DNA damage and repair were evaluated by measuring γH2AX via flow-cytometry. Apoptosis and cell cycle analysis were also measured via flow cytometry. Protein expression of repair proteins, p53 and p21 were measured using immunoblot analysis. Changes of nuclear architecture after treatment with SAHA and HIT were observed in one of the sarcoma cell lines via light microscopy after staining towards chromatin and γH2AX. RESULTS: Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines. In contrast, in the osteoblast cell line (hFOB 1.19), the combination of SAHA and HIT showed a significant radio-protective effect. Laser scanning microscopy revealed no significant morphologic changes after HIT compared to the combined treatment with SAHA. Immunoblot analysis revealed no significant up or down regulation of p53. However, p21 was significantly increased by SAHA and combination treatment as compared to HIT only in the two sarcoma cell lines--again in contrast to the osteoblast cell line. Changes in the repair kinetics of DSB p53-independent apoptosis with p21 involvement may be part of the underlying mechanisms for radio-sensitization by SAHA. CONCLUSION: Our in vitro data suggest an increase of the therapeutic ratio by the combination of SAHA with HIT in infantile sarcoma cell lines.
Asunto(s)
Terapia Combinada/métodos , Iones Pesados , Ácidos Hidroxámicos/uso terapéutico , Radioterapia/métodos , Sarcoma/terapia , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Separación Celular , Cromatina/química , Cromatina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Citometría de Flujo/métodos , Histonas/química , Humanos , Recién Nacido , Microscopía Confocal/métodos , Osteoblastos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , VorinostatRESUMEN
BACKGROUND: To evaluate the effectivity of fractionated radiotherapy in adolescent and adult patients with pineal parenchymal tumors (PPT). METHODS: Between 1982 and 2003, 14 patients with PPTs were treated with fractionated radiotherapy. 4 patients had a pineocytoma (PC), one a PPT with intermediate differentiation (PPTID) and 9 patients a pineoblastoma (PB), 2 of which were recurrences. All patients underwent radiotherapy on the primary tumor site with a median total dose of 54 Gy. In 9 patients with primary PB treatment included whole brain irradiation (3 patients) or irradiation of the craniospinal axis (6 patients) with a median total dose of 35 Gy. RESULTS: Median follow-up was 123 months in the PC patients and 109 months in the patients with primary PB. 7 patients were free from relapse at the end of follow-up. One PC patient died from spinal seeding. Among 5 PB patients treated with radiotherapy without chemotherapy, 3 developed local or spinal tumor recurrence. Both patients treated for PB recurrences died. The patient with PPTID is free of disease 7 years after radiotherapy. CONCLUSION: Local radiotherapy seems to be effective in patients with PC and some PPTIDs. Diagnosis and treatment of patients with more aggressive variants of PPTIDs as well as treatment of PB needs to be further improved, since local and spinal failure even despite craniospinal irradiation (CSI) is common. As PPT are very rare tumors, treatment within multi-institutional trials remains necessary.