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Centrosome amplification results into genetic instability and predisposes cells to neoplastic transformation. Supernumerary centrosomes trigger p53 stabilization dependent on the PIDDosome (a multiprotein complex composed by PIDD1, RAIDD and Caspase-2), whose activation results in cleavage of p53's key inhibitor, MDM2. Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar distal appendage protein ANKRD26. PIDDosome-dependent Caspase-2 activation requires not only PIDD1 centrosomal localization, but also its autoproteolysis. Following cytokinesis failure, supernumerary centrosomes form clusters, which appear to be necessary for PIDDosome activation. In addition, in the context of DNA damage, activation of the complex results from a p53-dependent elevation of PIDD1 levels independently of centrosome amplification. We propose that PIDDosome activation can in both cases be promoted by an ANKRD26-dependent local increase in PIDD1 concentration close to the centrosome. Collectively, these findings provide a paradigm for how centrosomes can contribute to cell fate determination by igniting a signalling cascade.
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Proteína Adaptadora de Señalización CRADD/metabolismo , Caspasa 2/metabolismo , Centrosoma/metabolismo , Cisteína Endopeptidasas/metabolismo , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Células A549 , Proteína Adaptadora de Señalización CRADD/genética , Caspasa 2/genética , Diferenciación Celular , Cisteína Endopeptidasas/genética , Daño del ADN , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Transducción de Señal , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use. METHODS: Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined. RESULTS: Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC. CONCLUSIONS: Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.
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Neoplasias de Cabeza y Cuello , Nimorazol , Humanos , Xenoinjertos , Nimorazol/farmacología , Nimorazol/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Pronóstico , Quimioradioterapia , Hipoxia/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapiaRESUMEN
Public health messages disseminated by trusted government authorities are likely to have more influence over individuals' intentions and behaviors. However, individuals worldwide have different levels of trust in government authorities, which leads to varying levels of compliance intentions. Additionally, these trust levels may vary during major public crises, such as pandemics. Based on a COVID-19 pandemic communication survey (N = 3,065) disseminated throughout six countries (Australia, Finland, Italy, South Korea, Sweden, and the United States), this study examined the association among trust in distinct government sources, cultural orientations, and health behavioral intentions. Findings indicated that trust in official health communication sources at four governmental levels (i.e. national government, the head of the national government, the national health authority, and the chief representative of the national health authority) was related to vaccination intentions and other behavioral compliance intentions (i.e. willingness to prevent COVID-19 infection in other ways). Meanwhile, these direct associations were mediated by the cultural orientations of power distance and uncertainty avoidance. Findings also revealed that the direct association of trust in government sources and the indirect relationship through the above cultural orientations varied by country. This study offers insight into the important role of credible sources and individuals' cultural orientations in the domain of health communication aimed at influencing behavioral intentions.
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BACKGROUND: To evaluate the impact of radiation dose on overall survival (OS) in patients treated with adjuvant chemoradiation (CRT) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A multicenter retrospective analysis on 514 patients with PDAC (T1-4; N0-1; M0) treated with surgical resection with macroscopically negative margins (R0-1) followed by adjuvant CRT was performed. Patients were stratified into 4 groups based on radiotherapy doses (group 1: < 45 Gy, group 2: ≥ 45 and < 50 Gy, group 3: ≥ 50 and < 55 Gy, group 4: ≥ 55 Gy). Adjuvant chemotherapy was prescribed to 141 patients. Survival functions were plotted using the Kaplan-Meier method and compared through the log-rank test. RESULTS: Median follow-up was 35 months (range: 3-120 months). At univariate analysis, a worse OS was recorded in patients with higher preoperative Ca 19.9 levels (≥ 90 U/ml; p < 0.001), higher tumor grade (G3-4, p = 0.004), R1 resection (p = 0.004), higher pT stage (pT3-4, p = 0.002) and positive nodes (p < 0.001). Furthermore, patients receiving increasing doses of CRT showed a significantly improved OS. In groups 1, 2, 3, and 4, median OS was 13.0 months, 21.0 months, 22.0 months, and 28.0 months, respectively (p = 0.004). The significant impact of higher dose was confirmed by multivariate analysis. CONCLUSIONS: Increasing doses of CRT seems to favorably impact on OS in adjuvant setting. The conflicting results of randomized trials on adjuvant CRT in PDAC could be due to < 45 Gy dose generally used.
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Carcinoma Ductal Pancreático/terapia , Quimioradioterapia Adyuvante/mortalidad , Neoplasias Pancreáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antígeno CA-19-9/sangre , Relación Dosis-Respuesta en la Radiación , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Dosificación Radioterapéutica , Estudios Retrospectivos , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays. SUMMARY: This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors. KEY MESSAGES: VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.
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Enfermedades Cardiovasculares/mortalidad , Trasplante de Riñón/mortalidad , Calcificación Vascular/epidemiología , Aorta , Calcifediol/sangre , Proteínas de Unión al Calcio/metabolismo , Vasos Coronarios , Diabetes Mellitus/epidemiología , Progresión de la Enfermedad , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Hiperparatiroidismo Secundario/epidemiología , Inmunosupresores , Osteoprotegerina/metabolismo , Diálisis Renal , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/terapia , Factores de Riesgo , Calcificación Vascular/metabolismo , alfa-2-Glicoproteína-HS/metabolismo , Proteína Gla de la MatrizRESUMEN
BACKGROUND/AIMS: The shortage in organ supply has required the use of expanded criteria donors (ECD) for kidney transplantation. Current pre-transplant evaluations of ECD organs are based on histological, clinical or mixed criteria. This monocentric study investigates the predictivity of Karpinski's histological score on 3-year graft function in renal transplant. Ex-post classification using Nyberg's score was carried out to assess the reliability of a purely clinical score and its applicability for organ allocation. METHODS: We evaluated 407 deceased donors (251 optimal and 156 ECD) for renal transplants performed between 2001 and 2006. The differences in creatinine levels and MDRD-GFR at transplant and 1, 2 and 3 years post-transplant between optimal donors and ECD were recorded. Amongst ECD organs, the effect of different Karpinski score classes (0-1, 2, 3, 4, double transplants) on 3-year graft outcomes was analyzed. We then compared renal function over time across the Nyberg grades (A, B, C, and D). RESULTS: Karpinski scores 0-1 and 2 and double transplants were associated with improved graft function compared to scores 3 and 4. Nyberg's clinical score shows a good fit with medium-term outcome and Karpinski's score, but among the donors with a high Nyberg grade (C and D), it fails to differentiate between allocable or non-allocable organs (due to Karpinski's score ≥7). CONCLUSIONS: Our data demonstrate a correlation of histological damage at the time of transplant with 3-year graft function, but at present we are unable to provide any supposition on the possible outcome of the discarded kidneys.
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Supervivencia de Injerto , Trasplante de Riñón , Riñón/patología , Riñón/fisiología , Obtención de Tejidos y Órganos/normas , Adulto , Anciano , Análisis de Varianza , Creatinina/sangre , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Estimación de Kaplan-Meier , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate in two different settings - clinical practice and education/training - the reliability, time efficiency and the ideal sequence of an atlas-based auto-segmentation system in pelvic delineation of locally advanced rectal cancer. METHODS: Fourteen consecutive patients were selected between October and December 2011. The images of four were used as an atlas and 10 used for validation. Two independent operators participated: a Delineator to contour and a Reviewer to perform an independent check (IC). The CTV, pelvic subsites and organs at risk were contoured in four different sequences. These included A: manual; B: auto-segmentation; C: auto-segmentation + manual revision; and D: manual + auto-segmentation + manual revision. Contouring was performed by the Delineator using the same planning CT. All of them underwent an IC by a Reviewer. The time required for all the contours were recorded and overlapping evaluation was assessed using a Dice coefficient. RESULTS: In the clinical practice setting there have been 13 minutes time saved between sequences A versus sequences B (from 38 to 25 minutes, p = 0.002), a mean Dice coefficient in favor of sequences A for CTV and all subsites (p = 0.0195). In the educational/training setting there have been 35.2 minutes time saved between sequences C and D 8 (from 73.1 min to 37.9 min, p = 0.002). CONCLUSION: The preliminary data suggest that the use of an atlas-based auto-contouring system may help improve efficiencies in contouring in the clinical practice setting and could have a tutorial role in the educational/training setting.
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Atlas como Asunto , Ganglios Linfáticos/diagnóstico por imagen , Reconocimiento de Normas Patrones Automatizadas , Pelvis/diagnóstico por imagen , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias del Recto/diagnóstico por imagen , Recto/diagnóstico por imagen , Algoritmos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Ilustración Médica , Pronóstico , Interpretación de Imagen Radiográfica Asistida por Computador , Neoplasias del Recto/radioterapia , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Carga TumoralRESUMEN
PURPOSE: To perform a preclinical trial comparing the efficacy of fractionated radiotherapy versus radiochemotherapy with cisplatin in HPV-positive and negative human head and neck squamous cell carcinoma (HNSCC) xenografts. MATERIAL AND METHODS: Three HPV-negative and three HPV-positive HNSCC xenografts in nude mice were randomized to radiotherapy (RT) alone or to radiochemotherapy (RCT) with weekly cisplatin. To evaluate tumour growth time, 20 Gy radiotherapy (±cisplatin) were administered in 10 fractions over 2 weeks. Dose-response curves for local tumour control were generated for RT with 30 fractions over 6 weeks to different dose levels given alone or combined with cisplatin (RCT). RESULTS: One of three investigated HPV-negative and two out of three HPV-positive tumour models showed a significant increase in local tumour control after RCT compared to RT alone. Pooled analysis of the HPV-positive tumour models showed a statistically significant and substantial benefit of RCT versus RT alone, with an enhancement ratio of 1.34. Although heterogeneity in response to both RT and RCT was also observed between the different HPV-positive HNSCC, these overall were more RT and RCT sensitive than HPV-negative models. CONCLUSION: The impact of adding chemotherapy to fractionated radiotherapy on local control was heterogenous, both in HPV-negative and in HPV-positive tumours, calling for predictive biomarkers. RCT substantially increased local tumour control in the pooled group of all HPV-positive tumours whereas this was not found in HPV-negative tumours. Omission of chemotherapy in HPV-positive HNSCC as part of a treatment de-escalation strategy is not supported by this preclinical trial.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Animales , Ratones , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Cisplatino/uso terapéutico , Virus del Papiloma Humano , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Xenoinjertos , Carcinoma de Células Escamosas/patología , QuimioradioterapiaRESUMEN
Background and purpose: Motion mitigation is of crucial importance in particle therapy (PT) of patients with abdominal tumors to ensure high-precision irradiation. Magnetic resonance imaging (MRI) is an excellent modality for target volume delineation and motion estimation of mobile soft-tissue tumors. Thus, the aims of this study were to develop an MRI- and PT-compatible abdominal compression device, to investigate its effect on pancreas motion reduction, and to evaluate patient tolerability and acceptance. Materials and methods: In a prospective clinical study, 16 patients with abdominal tumors received an individualized polyethylene-based abdominal corset. Pancreas motion was analyzed using time- and phase resolved MRI scans (orthogonal 2D-cine and 4D MRI) with and without compression by the corset. The pancreas was manually segmented in each MRI data set and the population-averaged center-of-mass motion in inferior-superior (IS), anterior-posterior (AP) and left-right (LR) directions was determined. A questionnaire was developed to investigate the level of patient acceptance of the corset, which the patients completed after acquisition of the planning computed tomography (CT) and MRI scans. Results: The corset was found to reduce pancreas motion predominantly in IS direction by on average 47 % - 51 % as found in the 2D-cine and 4D MRI data, respectively, while motion in the AP and LR direction was not significantly reduced. Most patients reported no discomfort when wearing the corset. Conclusion: An MRI- and PT-compatible individualized abdominal corset was presented, which substantially reduced breathing-induced pancreas motion and can be safely applied with no additional discomfort for the patients. The corset has been successfully integrated into our in-house clinical workflow for PT of tumors of the upper abdomen.
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LAPC is associated with a poor prognosis and requires a multimodal treatment approach. However, the role of radiation therapy in LAPC treatment remains controversial. This systematic review aimed to explore the role of proton and photon therapy, with varying radiation techniques and fractionation, in treatment outcomes and their respective toxicity profiles. METHODS: Clinical studies published from 2012 to 2022 were systematically reviewed using PubMed, MEDLINE (via PubMed) and Cochrane databases. Different radiotherapy-related data were extracted and analyzed. RESULTS: A total of 31 studies matched the inclusion criteria. Acute toxicity was less remarkable in stereotactic body radiotherapy (SBRT) compared to conventionally fractionated radiotherapy (CFRT), while in proton beam therapy (PBT) grade 3 or higher acute toxicity was observed more commonly with doses of 67.5 Gy (RBE) or higher. Late toxicity was not reported in most studies; therefore, comparison between groups was not possible. The range of median overall survival (OS) for the CFRT and SBRT groups was 9.3-22.9 months and 8.5-20 months, respectively. For the PBT group, the range of median OS was 18.4-22.3 months. CONCLUSION: CFRT and SBRT showed comparable survival outcomes with a more favorable acute toxicity profile for SBRT. PBT is a promising new treatment modality; however, additional clinical studies are needed to support its efficacy and safety.
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Background: Proton beam therapy (PBT) is being increas16ingly used to treat residual craniopharyngioma (CP) after hypothalamus-sparing surgery. Compared to photon-based radiation therapy (XRT) with PBT, less irradiation in the penumbra reduces the scattered dose to critical organs neighboring but outside the area of treatment, minimizing the risk of sequelae. Patients and methods: Between 2007 and 2019, 99 of 290 (34%) childhood-onset CP patients recruited in KRANIOPHARYNGEOM 2007 received external radiation therapy (RT) (65% PBT, 35% XRT). Outcome was analyzed in terms of survival, endocrinological and anthropometric parameters (BMI and height SDS), quality of life (QoL using PEDQOL), and functional capacity (FMH) with special regard to irradiation technique. Results: PBT became predominant (used in 43% and 72% of all irradiated patients registered within the first and second halves of the recruitment period, between 2008 and 2013 and 2013 and 2018, respectively). Five-year event-free survival rates after PBT or XRT were comparable (92% ± 4% vs. 91% ± 4%, p = 0.42) and higher than for the whole cohort since diagnosis, including non-RT patients (37% ± 4%). Radiation doses to the hypothalamus and pituitary did not differ between PBT and XRT. Endocrine deficits due to disturbances of the hypothalamic-pituitary axis (HPA) were already common before irradiation. During the first 5 years after CP diagnosis/RT, no differences between PBT, XRT, and non-RT CP patients concerning functional capacity and anthropometric parameters have been obtained. Only for the PEDQOL domain "physical function", parental-assessed QoL was lower 12 months after PBT versus XRT or non-RT patients. Conclusion: QoL, functional capacity, degree of obesity, and endocrinopathy varied over time from diagnosis, but by 5 years, there was no significant difference between PBT and XRT upfront or delayed, nor was there any compromise in historic survival rates, which remained high >90%. RT of any type is extremely effective at stabilizing disease after hypothalamic-sparing surgery. The purported specific benefits of PBT-reducing sequelae are not proven in this study where the organ of critical interest is itself diseased, increasing an urgent need to better address and treat the tumor-induced endocrine harm from diagnosis in dedicated pituitary services. Other hypothesized benefits of PBT versus XRT on vascular events and secondary cancers await longer comparison. Clinical trial registration number: https://clinicaltrials.gov/study/, identifier NCT01272622.
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Despite technological advances, normal tissue sparing in photon beam irradiation is still challenging. Since in esophageal cancer this may inflict damage on the lungs, heart and bone marrow, possibly impacting on outcome, the aim of this study was to investigate the association of normal tissue dose and blood parameters on the survival of patients having undergone neoadjuvant radiochemotherapy (RCTx) followed by surgery. This retrospective study included 125 patients irradiated to 40−41.4 Gy with photons or protons combined with concurrent chemotherapy. On initial and restaging 18F-FDG-PET/CT, the lungs and heart were contoured as organs at risk for which standardized uptake values (SUV) were evaluated. The mean radiation dose (Dmean) to the lungs and heart, the volume of the lungs receiving at least 20 Gy (V20Gy_lung) and various pre- and per-treatment blood parameters were included in the Cox regression analyses. Results: The median follow-up time was 19.8 months and median overall survival 37 months (95% confidence interval: 16−58.9 months). In multivariate analysis, higher radiation doses to the lungs and heart were statistically significantly associated with decreased overall survival (Dmean_lung: p < 0.001; V20Gy_lung: p < 0.002; Dmean_heart: p = 0.005). Neither the 18F-FDG-PET nor blood parameters were predictive for overall survival. In patients with locally advanced esophageal cancer treated with RCTx, the radiation dose to the heart and lungs was significantly associated with overall survival.
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Design: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC).Several studies have shown a correlation between a longer interval between the end of nCRT and surgery (surgical interval - SI) and an increased pathological complete response (pCR) rate, with a maximum obtained between 10 and 13 weeks.The primary endpoint of this multicenter, 2-arm randomised trial is to investigate SI lengthening, evaluating the difference in terms of complete response (CR) and Tumor Regression Grade (TRG)1 rate in the two arms. Secondly, the impact of SI lengthening on survival outcomes and quality of life (QoL) will be investigated. Methods: Intermediate-risk LARC patients undergoing nCRT will be prospectively included in the study. nCRT will be administered with a total dose of 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum of 45 Gy in 25 fractions on the whole pelvis. Chemotherapy with oral capecitabine will be administered continuously.The patients achieving a clinical major or complete response assessed at clinical-instrumental re-evaluation at 7-8 weeks after treatment completion, will be randomized into two groups, to undergo surgery or local excision at 9-11 weeks (control arm) or at 13-16 weeks (experimental arm). Pathological response will be assessed on the surgical specimen using the AJCC TNM v.7 and the TRG according to Mandard. Patients will be followed up to evaluate toxicity and QoL.The promoter center of the trial will conduct the randomization process through an automated procedure to prevent any possible bias.For sample size calculation, using CR difference of 20% as endpoint, 74 patients per arm will be enrolled. Conclusions: The results of this study may prospectively provide a new time frame for the clinical re-evaluation for complete/major responders patients in order to increase the CR rate to nCRT.Trial registration:ClinicalTrials.gov Identifier: NCT03581344.
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Red cell distribution width (RDW) is a quantitative measurement of anisocytosis. This hematological parameter is an important prognostic biomarker for different cardiovascular disorders in humans but its influence on survival has been poorly investigated in dogs with cardiovascular disease. The RDW and various clinical, complete blood count, serum biochemical and echocardiographic variables were retrospectively investigated in 146 client-owned dogs with myxomatous mitral valve disease (MMVD) at various disease stages, with or without concurrent diseases and treatment. Laboratory variables, including RDW, urea, and white blood cell (WBC), in addition to the echocardiographic variable left atrium to aorta ratio were found to be independent predictors of all-cause mortality at six months in a multivariable Cox proportional hazards regression model. In particular, the hazard ratio of RDW was 1.203 (95% confidence interval = 1.045-1.384; p = 0.010). The negative effect of increased RDW on outcome was confirmed using Kaplan-Meier curve analysis. The results of this study indicate that RDW acted as an independent predictor of negative outcome in dogs with MMVD.
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BACKGROUND: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as the model-based approach. In this study, we assessed the dosimetric benefit of PBT compared to photon therapy (XRT), analysed the corresponding changes in normal tissue complication probability (NTCP) on a variety of available models, and illustrated model-based patient selection in an in-silico study for patients with brain tumours. METHODS: For 92 patients treated at two PBT centres, volumetric modulated arc therapy treatment plans were retrospectively created for comparison with the clinically applied PBT plans. Several dosimetric parameters for the brain excluding tumour and margins, cerebellum, brain stem, frontal and temporal lobes, hippocampi, cochleae, chiasm, optic nerves, lacrimal glands, lenses, pituitary gland, and skin were compared between both modalities using Wilcoxon signed-rank tests. NTCP differences (ΔNTCP) were calculated for 11 models predicting brain necrosis, delayed recall, temporal lobe injury, hearing loss, tinnitus, blindness, ocular toxicity, cataract, endocrine dysfunction, alopecia, and erythema. A patient was assumed to be selected for PBT if ΔNTCP exceeded a threshold of 10 percentage points for at least one of the side-effects. RESULTS: PBT substantially reduced the dose in almost all investigated OARs, especially in the low and intermediate dose ranges and for contralateral organs. In general, NTCP predictions were significantly lower for PBT compared to XRT, in particular in ipsilateral organs. Considering ΔNTCP of all models, 80 patients (87.0%) would have been selected for PBT in this in-silico study, mainly due to predictions of a model on delayed recall (51 patients). CONCLUSION: In this study, substantial dose reductions for PBT were observed, mainly in contralateral organs. However, due to the sigmoidal dose response, NTCP was particularly reduced in ipsilateral organs. This underlines that physical dose-volume parameters alone may not be sufficient to describe the clinical relevance between different treatment techniques and highlights potential benefits of NTCP models. Further NTCP models for different modern treatment techniques are mandatory and existing models have to be externally validated in order to implement the model-based approach in clinical practice for cranial radiotherapy.
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Neoplasias Encefálicas , Terapia de Protones , Radioterapia de Intensidad Modulada , Neoplasias Encefálicas/radioterapia , Humanos , Órganos en Riesgo , Probabilidad , Terapia de Protones/efectos adversos , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients' quality of life. METHODS: Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed. RESULTS: In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose-response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland. CONCLUSION: We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.
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Neoplasias Encefálicas , Terapia de Protones , Estudios de Cohortes , Humanos , Probabilidad , Terapia de Protones/efectos adversos , Calidad de VidaRESUMEN
BACKGROUND: Neurocognitive function of adult patients with brain tumours may deteriorate after radiotherapy. Proton beam therapy (PBT) reduces the volume of irradiated healthy brain tissue and could potentially preserve neurocognition and quality of life (QoL). As present data are still limited, the impact of clinical factors and dosimetric parameters on neurocognitive function and QoL during recurrence-free follow-up after PBT is investigated. METHODS: The current study includes 62 brain tumour patients treated with PBT between 2015 and 2017. Neurocognition and QoL were assessed at baseline and every 3 months after PBT using the Montreal Cognitive Assessment (MoCA) test together with EORTC-QLQ-C30 and BN20 questionnaires, respectively. Objective and self-reported measures of neurocognitive functions were correlated. During two years of follow-up, the impact of clinical co-factors as well as dosimetric parameters of several brain structures were analysed using a mixed-model approach. RESULTS: At baseline, mean MoCA total score was 24.8/30 and self-reported cognitive function was 68.9/100. Both remained stable over time. Patients with impaired neurocognition on the MoCA test reported significantly lower global health status, cognitive, physical and role function as well as more fatigue, pain, headache and communication deficits compared to normal performing patients. For most follow-up time points, the majority of MoCA subitems correlated significantly to QoL items regarding neurocognition. Slight deterioration of the MoCA score was associated with tumours located in the left hemisphere and with an increase in relative volume of the anterior cerebellum that received doses of 30-40 Gy(RBE). CONCLUSION: Self-reported and objectively measured neurocognition and most other QoL domains remained largely stable over time during recurrence-free follow-up for brain tumour patients treated with PBT. The association between reduced cognitive function and irradiated volume of the anterior cerebellum requires validation in larger studies and comparison to patients treated with photon therapy.
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Neoplasias Encefálicas , Terapia de Protones , Adulto , Neoplasias Encefálicas/radioterapia , Humanos , Recurrencia Local de Neoplasia , Terapia de Protones/efectos adversos , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Patients on chronic dialysis have an increased risk for SARS CoV-2 virus disease and its complications because of multiple comorbidities and alterations in the immune response caused by renal disease. In this retrospective observational study we describe the clinical features and the evolution of SARS CoV-2-related disease in 19 patients of our Pesaro and Fano facilities, where incidence and mortality of the epidemic were among the highest in Italy. A total of 176 patients were undergoing chronic treatment, 153 hemodialysis and 23 peritoneal dialysis. The incidence of infection was 10,8%, with 84% needing hospitalization and mortality amounting to 53%. The most frequent onset symptom was fever (84,2%) and the most used therapy was an association of low molecular weight heparin and hydroxychloroquine (57,9%). Comparing the deceased and survivor populations we noticed significant differences in age and presence of cardiopathy for what concerns anamnestic data and in fatigue and dyspnea in terms of clinical presentation. LDH and CPK resulted highest among deceased patients, while the use of enoxaparin was more frequent in survivors. By observing contagions over time, we also noticed that most of the cases, and the ones with worse clinical condition and outcome, all occurred in the early stage of the epidemic and in particular within the first 20 days from the implementation and codification of the measures to prevent its spread, the only modifiable factor that had an unmistakable effect on the evolution of events.
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COVID-19/epidemiología , Fallo Renal Crónico/epidemiología , Pandemias , Diálisis Renal , SARS-CoV-2 , Anciano , Anciano de 80 o más Años , COVID-19/diagnóstico por imagen , COVID-19/prevención & control , COVID-19/terapia , Prueba de COVID-19 , Terapia Combinada , Comorbilidad , Humanos , Control de Infecciones , Italia/epidemiología , Estimación de Kaplan-Meier , Fallo Renal Crónico/terapia , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Evaluación de Síntomas , Tomografía Computarizada por Rayos X , Tratamiento Farmacológico de COVID-19RESUMEN
PURPOSE: Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection. METHODS/DESIGN: RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; or T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV_N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV_Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5-6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m2, day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m2 days 1-4 and 29-32). In the experimental arm, Durvalmab (1500 mg absolute dose, intravenously) will be combined with the same RCT as in the control arm. Immunotherapy with Durvalumab will start 14 days before initiation of standard RCT, administered every four weeks (q4w) thereafter for a total of twelve doses. The primary endpoint is disease-free survival (DFS) after 3 years. DISCUSSION: As ASCC is considered an immunogenically "hot" tumor due to its association with HPV infection, the combination of RCT with Durvalumab may improve tumor control and long-term clinical outcome in this patient collective compared to RCT alone.
RESUMEN
BACKGROUND AND PURPOSE: Oesophageal mobility relative to bony anatomy is a major source of geometrical uncertainty in proton radiotherapy of oesophageal carcinoma. To mitigate this uncertainty we investigated the use of implanted fiducial markers for direct target verification in terms of safety, visibility, and stability. MATERIALS AND METHODS: A total of 19 helical gold markers were endoscopically implanted in ten patients. Their placement at the proximal and distal tumour borders was compared to tumour demarcations derived from [18F]Fluorodeoxyglucose positron emission tomography, their visibility quantified via the contrast-to-noise ratio on daily orthogonal X-ray imaging, and their mobility relative to bony anatomy analysed by means of retrospective triangulation. RESULTS: Marker implantation proceeded without complications, but the distal tumour border could not be reached in two patients. Marker locations corresponded reasonably well with metabolic tumour edges (mean: 5.4â¯mm more distally). Marker visibility was limited but mostly sufficient (mean contrast-to-noise ratio: 1.5), and sixteen markers (84%) remained in situ until the end of treatment. Overall, marker excursions from their planned position were larger than 5(10) mm in 59(17)% of all analysed fractions. On one occasion severe target displacement was only identified via markers and was corrected before treatment delivery. CONCLUSION: Implanted helical gold fiducial markers are a safe and reliable method of providing target-centric positioning verification in proton beam therapy of oesophageal carcinoma.