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Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.
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Solid-state batteries (SSBs) have received attention as a next-generation energy storage technology due to their potential to superior deliver energy density and safety compared to commercial Li-ion batteries. One of the main challenges limiting their practical implementation is the rapid capacity decay caused by the loss of contact between the cathode active material and the solid electrolyte upon cycling. Here, we use the promising high-voltage, low-cost LiNi0.5Mn1.5O4 (LNMO) as a model system to demonstrate the importance of the cathode microstructure in SSBs. We design Al2O3-coated LNMO particles with a hollow microstructure aimed at suppressing electrolyte decomposition, minimizing volume change during cycling, and shortening the Li diffusion pathway to achieve maximum cathode utilization. When cycled with a Li6PS5Cl solid electrolyte, we demonstrate a capacity retention above 70% after 100 cycles, with an active material loading of 27 mg cm-2 (2.2 mAh cm-2) at a current density of 0.8 mA cm-2.
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OBJECTIVE: End of life communication (EOLC) is generally regarded as a challenging aspect of the medical profession, with high influences of culture, the physician's experience and awareness. The aim of the current study was to assess the awareness of Austrian oncologists towards EOLC practices in their daily clinical routine and to identify limiting and supporting factors of these conversations. METHODS: Overall, 45 oncologists participated in the assessment in this cross-sectional, mixed-method design using semi-structured interviews and questionnaire. RESULTS: Themes that occurred during the interviews included the initiation of EOLC, EOLC in practice, strategies for EOLC, limiting and supporting factors and consequences of EOLC. There were several variations in the EOLC approach, that is, the use of time frames, timing, initiation and the amount of details given to the patient. CONCLUSION: Oncologists agreed that EOLC is important in their daily clinical routine and for their patients. Nevertheless, there seems to be an underlying variation in approaches chosen by Austrian oncologists. This variation might be reduced by asking patients about their information preferences in advance and by routine implementation of communication guidelines, nomograms and prognostic calculators to reduce uncertainty.
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Coraje , Oncólogos , Cuidado Terminal , Humanos , Cuidado Terminal/métodos , Estudios Transversales , Actitud del Personal de Salud , Comunicación , MuerteRESUMEN
BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.
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Braquiterapia/métodos , Imagen por Resonancia Magnética/métodos , Radioterapia Guiada por Imagen/métodos , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Quimioradioterapia/métodos , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Calidad de Vida , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patologíaRESUMEN
PURPOSE: Predicting morbidity for patients with locally advanced cervix cancer after external beam radiotherapy (EBRT) based on dose-volume parameters remains an unresolved issue in definitive radiochemotherapy. The aim of this prospective study was to correlate patient characteristics and dose-volume parameters to various early morbidity endpoints for different EBRT techniques, including volumetric modulated arc therapy (VMAT) and adaptive radiotherapy (ART). METHODS AND MATERIALS: The study population consisted of 48 patients diagnosed with locally advanced cervix cancer, treated with definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). Multiple questionnaires (CTCAE 4.03, QLQ-C30 and EORTC QLQ-CX24) were assessed prospectively for patients treated with different EBRT techniques, including online adaptive VMAT. Contouring and treatment planning was based on the EMBRACE protocols. Acute toxicity, classified as general, gastrointestinal (GI) or genitourinary (GU) and their corresponding dose-volume histograms (DVHs) were first correlated by applying least absolute shrinkage and selection operator (LASSO) and subsequently evaluated by multiple logistic binomial regression. RESULTS: The treated EBRT volumes varied for the different techniques with ~2500â¯cm3 for 3D conformal radiotherapy (3D-CRT), ~2000â¯cm3 for EMBRACEI VMAT, and ~1800â¯cm3 for EMBRACE-II VMAT and ART. In general, a worsening of symptoms during the first 5 treatment weeks and recovery afterwards was observed. Dose-volume parameters significantly correlating with stool urgency, rectal and urinary incontinence were as follows: bowel V40Gyâ¯< 250â¯cm3, rectum V40Gyâ¯< 80% and bladder V40Gyâ¯< 80-90%. CONCLUSION: This prospective study demonstrated the impact of EBRT treatment techniques in combination with chemotherapy on early morbidity. Dose-volume effects for dysuria, urinary incontinence, stool urgency, diarrhea, rectal bleeding, rectal incontinence and weight loss were found.
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Braquiterapia/efectos adversos , Quimioradioterapia/efectos adversos , Tracto Gastrointestinal/efectos de la radiación , Traumatismos por Radiación/radioterapia , Radioterapia Conformacional/efectos adversos , Sistema Urogenital/efectos de la radiación , Neoplasias del Cuello Uterino/terapia , Adolescente , Adulto , Anciano , Braquiterapia/métodos , Quimioradioterapia/métodos , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Irradiación Linfática/efectos adversos , Persona de Mediana Edad , Estudios Prospectivos , Traumatismos por Radiación/patología , Dosificación Radioterapéutica , Radioterapia Conformacional/métodos , Radioterapia Guiada por Imagen/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Carga Tumoral , Sistema Urogenital/lesiones , Pérdida de Peso , Adulto JovenRESUMEN
OBJECTIVE: To prospectively compare the interobserver variability of combined transrectal ultrasound (TRUS)/computed tomography (CT)- vs. CT only- vs. magnetic resonance imaging (MRI) only-based contouring of the high-risk clinical target volume (CTVHR) in image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). METHODS: Five patients with LACC (FIGO stages IIb-IVa) treated with radiochemotherapy and IGABT were included. CT, TRUS, and T2-weighted MRI images were performed after brachytherapy applicator insertion. 3D-TRUS image acquisition was performed with a customized ultrasound stepper device and software. Automatic applicator reconstruction using optical tracking was performed in the TRUS dataset and TRUS and CT images were fused with rigid image registration with the applicator as reference structure. The CTVHR (based on the GEC-ESTRO recommendations) was contoured by five investigators on the three modalities (CTVHR_CT, CTVHR_TRUS-CT, and CTVHR_MRI). A consensus reference CTVHR_MRI (MRIref) was defined for each patient. Descriptive statistics and overlap measures were calculated using RTslicer (SlicerRT Community and Percutaneous Surgery Laboratory, Queen's University, Canada), comparing contours of every observer with one another and with the MRIref. RESULTS: The interobserver coefficient of variation was 0.18⯱ 0.05 for CT, 0.10⯱ 0.04 for TRUS-CT, and 0.07⯱ 0.03 for MRI. Interobserver concordance in relation to the MRIref expressed by the generalized conformity index was 0.75⯱ 0.04 for MRI, 0.51⯱ 0.10 for TRUS-CT, and 0.48⯱ 0.06 for CT. The mean CTVHR_CT volume of all observers was 71% larger than the MRIref volume, whereas the mean CTVHR_TRUS-CT volume was 15% larger. CONCLUSION: Hybrid TRUS-CT as an imaging modality for contouring the CTVHR in IGABT for LACC is feasible and reproducible among multiple observers. TRUS-CT substantially reduces overestimation of the CTVHR volume of CT alone while maintaining similar interobserver variability.
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Braquiterapia/métodos , Carcinoma de Células Escamosas/radioterapia , Imagen Multimodal/métodos , Radioterapia Guiada por Imagen/métodos , Tomografía Computarizada por Rayos X/métodos , Ultrasonido Enfocado Transrectal de Alta Intensidad/métodos , Neoplasias del Cuello Uterino/radioterapia , Antineoplásicos Alquilantes/uso terapéutico , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/tratamiento farmacológico , Quimioterapia Adyuvante , Cisplatino/uso terapéutico , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Variaciones Dependientes del Observador , Estudios Prospectivos , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
BACKGROUND: Deficiency in butyrylcholinesterase (BChE), a condition commonly noticed in liver damage, inflammation, and malnutrition, has previously been associated with impaired prognosis in different malignancies. The aim of the present study was to investigate the value of pretreatment serum BChE levels as a prognostic biomarker in patients with cervical cancer treated with primary (chemotherapy-[chemo-])radiation therapy. METHODS: We retrospectively evaluated data of a consecutive series of patients with cervical cancer treated with primary (chemo-)radiation therapy between 1998 and 2015. Pretreatment serum BChE levels were correlated with clinico-pathological parameters and response to treatment. Uni- and multivariate survival analyses were performed to assess the association between decreased serum BChE levels and progression-free (PFS), cancer-specific (CSS), and overall survival (OS). RESULTS: A total of 356 patients were eligible for inclusion into the present study. The median (IQR) pretreatment serum BChE level was 6180 (4990-7710)â¯IU/l. Lower serum BChE levels were associated with lower BMI (pâ¯< 0.001), advanced tumor stage (pâ¯= 0.04), poor treatment response (pâ¯= 0.002), the occurrence of disease recurrence (pâ¯= 0.003), and the risk of death (pâ¯< 0.001). In uni- and multivariate analyses, low pretreatment serum BChE levels were independently associated with shorter PFS (HR 1.8 [1.2-2.6]; pâ¯= 0.002), CSS (HR 2.2 [1.4-3.5], pâ¯< 0.001), and OS (HR 2.0 [1.4-2.9]; pâ¯< 0.001). CONCLUSIONS: Low pretreatment serum BChE levels are associated with advanced tumor stage and poor response to treatment, and serve as an independent prognostic biomarker for shorter PFS, CSS, and OS in patients with cervical cancer treated with primary (chemo-)radiation therapy.
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Biomarcadores/sangre , Butirilcolinesterasa/sangre , Quimioradioterapia , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/terapia , Adulto , Anciano , Índice de Masa Corporal , Correlación de Datos , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patologíaRESUMEN
Medical students have to acquire theoretical knowledge, practical skills, and a personal attitude to meet the emerging needs of palliative care. The present study aimed to assess the personal attitude of Austrian medical students towards end of life communication (EOLC), as key part of palliative care. This cross-sectional, mono-institutional assessment invited all medical students at the Medical University of Vienna in 2015. The assessment was conducted web-based via questionnaire about attitudes towards EOLC. Additional socio-demographic and medical education-related parameters were collected. Overall, 743 medical students participated in the present report. Differences regarding the agreement or disagreement to several statements concerning the satisfaction of working with chronically ill patients, palliative care, and health care costs, as well as the extent of information about palliative disease, were found for age, gender, and academic years. The overall attitude towards EOLC in the present sample can be regarded as quite balanced. Nevertheless, a considerable number of medical students are still reluctant to inform patients about their incurable disease. Reservations towards palliative care as part of the health care system seem to exist. The influence of the curriculum as well as practical experiences seems to be important but needs further investigation.
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Actitud del Personal de Salud , Curriculum/normas , Comunicación en Salud , Estudiantes de Medicina/psicología , Cuidado Terminal/organización & administración , Adolescente , Adulto , Austria , Estudios Transversales , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Cuidado Terminal/psicología , Adulto JovenRESUMEN
PURPOSE: The aim of this work was to characterise actuarial incidence and prevalence of early and late side effects of local versus pelvic three-dimensional conformal postoperative radiotherapy for prostate cancer. MATERIALS AND METHODS: Based on a risk-adapted protocol, 575 patients received either local (n = 447) or local-plus-pelvic (n = 128) radiotherapy. Gastrointestinal (GI) and genitourinary (GU) side effects (≥grade 2 RTOG/EORTC criteria) were prospectively assessed. Maximum morbidity, actuarial incidence rate, and prevalence rates were compared between the two groups. RESULTS: For local radiotherapy, median follow-up was 68 months, and the mean dose was 66.7 Gy. In pelvic radiotherapy, the median follow-up was 49 months, and the mean local and pelvic doses were 66.9 and 48.3 Gy respectively. Early GI side effects ≥ G2 were detected in 26% and 42% of patients respectively (p < 0.001). Late GI adverse events were detected in 14% in both groups (p = 0.77). The 5year actuarial incidence rates were 14% and 14%, while the prevalence rates were 2% and 0% respectively. Early GU ≥ G2 side effects were detected in 15% and 16% (p = 0.96), while late GU morbidity was detected in 18% and 24% (p = 0.001). The 5year actuarial incidence rates were 16% and 35% (p = 0.001), while the respective prevalence rates were 6% and 8%. CONCLUSIONS: Despite the low prevalence of side effects, postoperative pelvic radiotherapy results in significant increases in the actuarial incidence of early GI and late GU morbidity using a conventional 4field box radiotherapy technique. Advanced treatment techniques like intensity-modulated radiotherapy (IMRT) or volumetric modulated arc radiotherapy (VMAT) should therefore be considered in pelvic radiotherapy to potentially reduce these side effects.
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Terapia Combinada/estadística & datos numéricos , Tracto Gastrointestinal/efectos de la radiación , Prostatectomía , Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/epidemiología , Radioterapia Adyuvante/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Incidencia , Escisión del Ganglio Linfático , Irradiación Linfática/efectos adversos , Masculino , Persona de Mediana Edad , Pelvis/efectos de la radiación , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Traumatismos por Radiación/etiología , Radioterapia Conformacional/efectos adversos , Tasa de SupervivenciaRESUMEN
BACKGROUND: A comprehensive evaluation of the current national and regional radiotherapy capacity in Austria with an estimation of demands for 2020 and 2030 was performed by the Austrian Society for Radiation Oncology, Radiobiology and Medical Radiophysics (ÖGRO). MATERIALS AND METHODS: All Austrian centers provided data on the number of megavoltage (MV) units, treatment series, fractions, percentage of retreatments and complex treatment techniques as well as the daily operating hours for the year 2014. In addition, waiting times until the beginning of radiotherapy were prospectively recorded over the first quarter of 2015. National and international epidemiological prediction data were used to estimate future demands. RESULTS: For a population of 8.51 million, 43 MV units were at disposal. In 14 radiooncological centers, a total of 19,940 series with a mean number of 464 patients per MV unit/year and a mean fraction number of 20 (range 16-24) per case were recorded. The average re-irradiation ratio was 14%. The survey on waiting times until start of treatment showed provision shortages in 40% of centers with a mean waiting time of 13.6 days (range 0.5-29.3 days) and a mean maximum waiting time of 98.2 days. Of all centers, 21% had no or only a limited ability to deliver complex treatment techniques. Predictions for 2020 and 2030 indicate an increased need in the overall number of MV units to a total of 63 and 71, respectively. CONCLUSION: This ÖGRO survey revealed major regional differences in radiooncological capacity. Considering epidemiological developments, an aggravation of the situation can be expected shortly. This analysis serves as a basis for improved public regional health care planning.
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Accesibilidad a los Servicios de Salud/tendencias , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Necesidades y Demandas de Servicios de Salud/tendencias , Radioterapia/estadística & datos numéricos , Radioterapia/tendencias , Sociedades Médicas , Austria , Fraccionamiento de la Dosis de Radiación , Predicción , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Radioterapia/instrumentación , Radioterapia de Alta Energía/instrumentación , Radioterapia de Alta Energía/estadística & datos numéricos , Radioterapia de Alta Energía/tendencias , Retratamiento/instrumentación , Retratamiento/tendencias , Listas de EsperaRESUMEN
Immobilization of a Mn polypyridyl CO2 reduction electrocatalyst on nanocrystalline TiO2 electrodes yields an active heterogeneous system and also significantly triggers a change in voltammetric and catalytic behaviour, relative to in solution. A combination of spectroelectrochemical techniques are presented here to elucidate the mechanism of the immobilized catalyst in situ.
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BACKGROUND: Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. OBJECTIVE: The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. METHODS: The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. RESULTS: The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.
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Neoplasias del Cuello Uterino/terapia , Cuidados Posteriores , Cuello del Útero/patología , Femenino , Preservación de la Fertilidad , Humanos , Estadificación de Neoplasias , Tratamientos Conservadores del Órgano , Embarazo , Complicaciones Neoplásicas del Embarazo/terapia , Radioterapia , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. METHODS: We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0·16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0·10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27·0% (95% CI 23·0-30·9) in the whole-breast irradiation group versus 23·3% (19·9-26·8) in the APBI group (p=0·12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10·7% (95% CI 8·0-13·4) in the whole-breast irradiation group versus 6·9% (4·8-9·0) in the APBI group (difference -3·8%, 95% CI -7·2 to 0·4; p=0·020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9·7% (95% CI 7·1-12·3) in the whole-breast irradiation group versus 12·0% (9·4-14·7) in the APBI group (difference 2·4%; 95% CI -1·4 to 6·1; p=0·28). The cumulative incidence of grade 2-3 breast pain was 11·9% (95% CI 9·0-14·7) after whole-breast irradiation versus 8·4% (6·1-10·6) after APBI (difference -3·5%; 95% CI -7·1 to 0·1; p=0·074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0·62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0·12). No treatment-related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated. INTERPRETATION: 5-year toxicity profiles and cosmetic results were similar in patients treated with breast-conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation. FUNDING: German Cancer Aid.
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Braquiterapia/efectos adversos , Neoplasias de la Mama/radioterapia , Cosméticos , Necrosis Grasa/etiología , Mastectomía Segmentaria/efectos adversos , Mastectomía/efectos adversos , Radiodermatitis/etiología , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/radioterapia , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Lobular/patología , Carcinoma Lobular/radioterapia , Carcinoma Lobular/cirugía , Terapia Combinada , Necrosis Grasa/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Radiodermatitis/diagnóstico , Dosificación Radioterapéutica , Factores de TiempoRESUMEN
BACKGROUND: In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS: We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole-breast irradiation and 0% with APBI (p=0.46). INTERPRETATION: The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING: German Cancer Aid.
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Braquiterapia/métodos , Neoplasias de la Mama/radioterapia , Carcinoma in Situ/radioterapia , Carcinoma Ductal de Mama/radioterapia , Adulto , Anciano , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/terapia , Carcinoma in Situ/cirugía , Carcinoma in Situ/terapia , Carcinoma Ductal de Mama/cirugía , Carcinoma Ductal de Mama/terapia , Catéteres de Permanencia , Terapia Combinada , Femenino , Humanos , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Dosificación Radioterapéutica , Resultado del TratamientoRESUMEN
OBJECTIVE: Ischemia-reperfusion (IR) is a limb- and life-threatening complication of acute limb ischemia and musculoskeletal trauma. Carbon monoxide-releasing molecules (CORMs) have recently been shown to protect microvascular perfusion and to reduce inflammation and injury in various ischemic animal models. The purpose of this study was to examine the effects of water-soluble CORM-3 on the extent of IR-induced muscle injury. METHODS: Wistar rats were randomized into three groups: sham (no ischemia), IR + CORM-3 (10 mg/kg intraperitoneally), and IR + inactive CORM-3 (iCORM-3; 10 mg/kg intraperitoneally). No-flow ischemia was induced by the application of a tourniquet to the hind limb for 2 hours; tourniquet release commenced the reperfusion phase. Both CORM-3 and iCORM-3 were injected immediately after tourniquet release. Temporal changes in microvascular perfusion, cellular tissue injury (ethidium bromide and bisbenzimide staining), and inflammatory response (leukocyte recruitment) within the extensor digitorum longus muscle were assessed using intravital video microscopy every 15 minutes for a total of 90 minutes after initiation of reperfusion. Systemic levels of tumor necrosis factor-α were also measured. RESULTS: Hind limb IR resulted in (1) a significant no-reflow phenomenon followed by progressive increase in microvascular perfusion deficit (21% ± 2% continuously perfused capillaries in IR vs 76% ± 4% in sham [P < .001]; 52% ± 8% nonperfused capillaries in IR vs 13% ± 2% in sham at 90 minutes of reperfusion [P < .001]), (2) tissue injury (ethidium bromide and bisbenzimide staining of 0.52 ± 0.07 in IR vs 0.05 ± 0.03 in sham at 90 minutes of reperfusion [P < .001]), (3) leukocyte recruitment (13.7 ± 0.9 adherent leukocytes/30 seconds/1000 µm2 in IR vs 1.8 ± 0.5 adherent leukocytes/30 seconds/1000 µm2 in sham at 90 minutes of reperfusion [P < .001]), and (4) an increase in circulating tumor necrosis factor-α levels. Systemic administration of CORM-3 (but not of iCORM-3) effectively reduced the IR-associated skeletal muscle perfusion deficits, tissue injury, and inflammatory activation. CONCLUSIONS: CORM-3 displays potent protective and anti-inflammatory effects in an experimental model of hind limb IR, suggesting a potential therapeutic application of CORMs in treatment of ischemic conditions.
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Antiinflamatorios/administración & dosificación , Monóxido de Carbono/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Compuestos Organometálicos/administración & dosificación , Daño por Reperfusión/prevención & control , Animales , Antiinflamatorios/metabolismo , Velocidad del Flujo Sanguíneo , Adhesión Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Miembro Posterior , Mediadores de Inflamación/sangre , Inyecciones Intraperitoneales , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Microcirculación , Músculo Esquelético/patología , Compuestos Organometálicos/metabolismo , Ratas Wistar , Flujo Sanguíneo Regional , Daño por Reperfusión/sangre , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND PURPOSE: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients. MATERIALS AND METHODS: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV. RESULTS: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified. CONCLUSION: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting.
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Bevacizumab/uso terapéutico , Quimioradioterapia/estadística & datos numéricos , Fístula del Sistema Digestivo/epidemiología , Recurrencia Local de Neoplasia/terapia , Fístula Urinaria/epidemiología , Neoplasias del Cuello Uterino/terapia , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Austria/epidemiología , Braquiterapia/estadística & datos numéricos , Terapia Combinada/estadística & datos numéricos , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Radioterapia Guiada por Imagen/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Neoplasias del Cuello Uterino/epidemiologíaRESUMEN
BACKGROUND: Clinical decision making in oncology is based on both inter- and multidisciplinary approach. Hence teaching future doctors involved in oncology or general health practice is crucial. The aim of the Vienna Summer School on Oncology (VSSO) as an international, integrated, undergraduate oncology course is to teach medical students interdisciplinary team communication and application of treatment concepts/algorithms in a multidisciplinary setting. METHOD: The teaching is based on an inter- and multidisciplinary faculty and a multimodal education approach to address different learning styles. The participants rated their satisfaction of the program voluntarily after finishing the course according to a grading scale from one (not good) to five (very good). The learning success was assessed by a compulsory pre-VSSO and post-VSSO single choice questionnaire. RESULTS: Program organisation was rated with a mean score of 4.47 out of 5.0 (SD 0.51), composition of the program and range of topics with a mean score of 4.68 (SD 0.58) and all teachers with a mean score of 4.36 (SD 0.40) points. Student evaluation at the beginning and end of the program indicated significant knowledge acquisition -i.e., general aspects of cancer: median 8.75 points (IQR 7.5-9.4) vs.10.0 points (IQR 9.4-10.0) p = 0.005; specific aspects of cancer: median 4.87 points (IQR 3.33-5.71) vs. 8.72 points (IQR 6.78-9.49) p ≤ 0.001, respectively. CONCLUSION: Even though the participants represent a selection of students with special interest in cancer, the results of the VSSO indicate the benefit of an inter- and multidisciplinary teaching approach within an oncology module.
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Toma de Decisiones Clínicas/métodos , Educación de Pregrado en Medicina , Comunicación Interdisciplinaria , Estudios Interdisciplinarios , Oncología Médica/educación , Estaciones del Año , Estudiantes de Medicina , Austria , Educación de Pregrado en Medicina/normas , Investigación sobre Servicios de Salud , Humanos , Evaluación de Programas y Proyectos de SaludRESUMEN
Recent studies have shown that diffusion on the surface of organic glasses can be many orders of magnitude faster than bulk diffusion. Developing new probes that can readily measure surface diffusion can help study the effect of parameters such as chemical structure, intermolecular interaction, molecules' shape and size on the enhanced surface diffusion. In this study, we develop a novel probe that significantly simplifies these types of studies. Tobacco mosaic virus (TMV) is used as probe particle to measure surface diffusion coefficient of molecular glass N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine (TPD). The evolution of the meniscus formed around TMV is probed as a function of time at various temperatures. TMV has a well-defined, mono-dispersed, cylindrical shape, with a large aspect-ratio (average diameter of 16.6 nm, length of 300 nm). As such, the shape of the meniscus around the center of TMV is semi-two dimensional, which compared to using a nanosphere as probe, increases the driving force for meniscus formation and simplifies the analysis of surface diffusion. We show that under these conditions, after a short transient time the shape of the meniscus is self-similar, allowing accurate determination of the surface diffusion coefficient. Measurements at various temperatures are then performed to investigate the temperature dependence of the surface diffusion coefficient. It is found that surface diffusion is greatly enhanced in TPD and has a lower activation barrier compared to the bulk counterpart. These observations are consistent with previous studies of surface diffusion on molecular glasses, demonstrating the accuracy of this method.
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Difusión , Vidrio/química , Virus del Mosaico del Tabaco , TemperaturaRESUMEN
Charged particle therapy is generally regarded as cutting-edge technology in oncology. Many proton therapy centres are active in the USA, Europe, and Asia, but only a few centres use heavy ions, even though these ions are much more effective than x-rays owing to the special radiobiological properties of densely ionising radiation. The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. So far, more than 8000 patients have had this treatment at NIRS, and the centre thus has by far the greatest experience in carbon ion treatment worldwide. A panel of radiation oncologists, radiobiologists, and medical physicists from the USA and Europe recently completed peer review of the carbon ion therapy at NIRS. The review panel had access to the latest developments in treatment planning and beam delivery and to all updated clinical data produced at NIRS. A detailed comparison with the most advanced results obtained with x-rays or protons in Europe and the USA was then possible. In addition to those tumours for which carbon ions are known to produce excellent results, such as bone and soft-tissue sarcoma of the skull base, head and neck, and pelvis, promising data were obtained for other tumours, such as locally recurrent rectal cancer and pancreatic cancer. The most serious impediment to the worldwide spread of heavy ion therapy centres is the high initial capital cost. The 20 years of clinical experience at NIRS can help guide strategic decisions on the design and construction of new heavy ion therapy centres.
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Carbono/uso terapéutico , Radioterapia de Iones Pesados , Neoplasias/radioterapia , Humanos , Japón , Factores de TiempoRESUMEN
OBJECTIVE: Exogenously administered CO interferes with PMN recruitment to the inflamed organs. The mechanisms of CO-dependent modulation of vascular proadhesive phenotype, a key step in PMN recruitment, are unclear. METHODS: We assessed the effects/mechanisms of CO liberated from a water-soluble CORM-3 on modulation of the proadhesive phenotype in hCMEC/D3 in an in vitro model of endotoxemia. To this end, hCMEC/D3 were stimulated with LPS (1 µg/mL) for six hours. In some experiments hCMEC/D3 were pretreated with CORM-3 (200 µmol/L) before LPS-stimulation. PMN rolling/adhesion to hCMEC/D3 were assessed under conditions of laminar shear stress (0.7 dyn/cm(2) ). In parallel, expression of adhesion molecules E-selectin, ICAM-1, and VCAM-1 (qPCR), activation of transcription factors, NF-κB and AP-1 (ELISA), and MAPK-signaling (expression/phosphorylation of p38, ERK1/2, and JNK1/2; western blot) were assessed. RESULTS: The obtained results indicate that CORM-3 pretreatment reduces PMN rolling/adhesion to LPS-stimulated hCMEC/D3 (p < 0.05). Decreased PMN rolling/adhesion to hCMEC/D3 was associated with CORM-3-dependent inhibition of MAPK JNK1/2 activation (Tyr-phosphorylation), inhibition of transcription factor, AP-1 (c-Jun phosphorylation), and subsequent suppression of VCAM-1 expression (p < 0.05). CONCLUSIONS: These findings indicate that CORM-3 pretreatment interferes with JNK/AP-1 signaling and suppresses LPS-induced upregulation of the proadhesive phenotype in hCMEC/D3.