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Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumors. Ionizing radiation (IR) induces dose-specific variations in transcriptional programs, implicating that they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by effective vs. non-effective IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to effective or non-effective IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. The radiation-activated genes were pre-positioned in active sub-nuclear compartments and were upregulated following the DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of the events, which was linked to their spatial nuclear positioning. Thus, the distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.
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Glioblastoma , Radiación Ionizante , Humanos , Reparación del ADN/genética , Radiación no Ionizante , Transporte Biológico , Glioblastoma/genética , Glioblastoma/radioterapiaRESUMEN
High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.
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Astrocitoma , Neoplasias Encefálicas , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Homocigoto , Eliminación de Secuencia , Astrocitoma/genética , Astrocitoma/patología , Mutación/genética , Metilación de ADN/genéticaRESUMEN
BACKGROUND: Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation's efficacy. We sought to assess the tolerability and feasibility of this approach. METHODS: A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. RESULTS: A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. CONCLUSIONS: The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Glioma/tratamiento farmacológico , Glioma/radioterapia , Humanos , Cetonas , Metformina/uso terapéutico , Persona de Mediana Edad , Recurrencia Local de NeoplasiaRESUMEN
OBJECTIVE Local therapy to spine tumors has been shown to be effective in selected cases. Spinal radiosurgery (SRS) is an evolving radiotherapy regimen allowing for noninvasive, highly efficacious local treatment. The learning curve can compromise the results of any newly employed technology and should be studied to minimize its effects. In this paper the first 100 SRSs performed at several medical centers are presented and analyzed for the effects of the learning curve on outcome. METHODS A retrospective analysis was undertaken to evaluate data from patients treated with SRS at Sheba Medical Center and Assuta Medical Centers in the period from September 2011 to February 2016. Medical history, clinical and neurological findings, pathological diagnoses, SRS variables, complications, and follow-up data were collected and analyzed. Local control rates were calculated, and local treatment failure cases were qualitatively studied. RESULTS One hundred treatment sessions were performed for 118 lesions at 179 spinal levels in 80 patients. The complication rate was low and did not correlate with a learning curve. Mean follow-up time was 302 days, and the overall local control rate was 95%. The local control rate was dose dependent and increased from 87% (among 35 patients receiving a dose of 16 Gy) to 97% (among 65 patients receiving a dose of 18 Gy). The 6 treatment failure cases are discussed in detail. CONCLUSIONS Spinal radiosurgery is a safe and effective treatment. Comprehensive education of the treating team and continuous communication are essential to limit the effects of the learning curve on outcome.
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Radiocirugia/métodos , Neoplasias de la Columna Vertebral/cirugía , Resultado del Tratamiento , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Lymphopenia and high neutrophil-to-lymphocyte ratio are known negative prognostic factors in rectal cancer. Until recently, however, lymphopenia was regarded as a minor sequela following radiation therapy (RT). The immune system's influence on rectal cancer treatment outcomes led us to evaluate the impact of lymphopenia at various time points, before, during, and following radiotherapy. We hypothesized that chronic lymphopenia following radiotherapy might negatively influence the survival of patients, and pre-treatment lymphopenia may be predictive of poor outcomes. METHODS: This retrospective study involved 110 patients treated for rectal cancer between 2015 and 2019. The oncological outcomes are defined as alive without disease (AWOD), alive with disease (AWD), and death. These outcome probabilities tested against variables of lymphopenia before RT, during RT, and at several post-RT follow-up time points. RESULTS: At the end of the study, 69 patients were AWOD (63 %), 13 were AWD (12 %) and 28 had died (25 %). Treatment results were assessed with according level of lymphocytes measured one year following RT: 35 out of 39 patients (89.7 %) with normal values were AWOD. In 65 patients with sustained lymphopenia, 52 % were AWOD, 18.5 % AWD and 29 % died. A similar difference was found at all time-points up to 2 years following RT (p < 0.004). The results of our study shows that pre-existing lymphopenia (prior to RT) is associated with a 3 times greater chance of death compared to patients with normal lymphocyte levels prior to RT. The PFS significantly affected by lymphopenia at all time-points after RT. An NLR of more than 4 was associated with a 3-time higher risk of recurrence than lower NLR scores (p = 0.0054). CONCLUSION: Our results support the relevance of lymphopenia and NLR in the prognosis of rectal cancer. We believe this is the first study showing a negative correlation between sustained lymphopenia and OS following RT.
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PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.
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Terapia de Protones , Traumatismos por Radiación , Neoplasias de la Base del Cráneo , Humanos , Terapia de Protones/efectos adversos , Terapia de Protones/métodos , Neoplasias de la Base del Cráneo/diagnóstico por imagen , Neoplasias de la Base del Cráneo/radioterapia , Calidad de Vida , Traumatismos por Radiación/patología , Dosificación Radioterapéutica , Encéfalo/efectos de la radiaciónRESUMEN
BACKGROUND: Pharmacological treatment of CNS diseases is limited due to the presence of the blood-brain barrier (BBB). Recent years showed significant advancement in the field of CNS drug delivery enablers, with technologies such as MR-guided focused ultrasound reaching clinical trials. This have inspired researchers in the field to invent novel brain barriers opening (BBo) technologies that are required to be simple, fast, safe and efficient. One such technology, recently developed by us, is BDF (Barrier Disrupting Fields), based on low pulsed electric fields (L-PEFs) for opening the BBB in a controlled, safe, reversible and non-invasive manner. Here, we conducted an in vivo study to show that BDF is a feasible technology for delivering Doxorubicin (Doxo) into mice brain. Means for depicting BBBo levels were developed and applied for monitoring the treatment and predicting response. Overall, the goals of the presented study were to demonstrate the feasibility for delivering therapeutic Doxo doses into naïve and tumor-bearing mice brains and applying delayed-contrast MRI (DCM) for monitoring the levels of BBBo. METHODS: L-PEFs were applied using plate electrodes placed on the intact skull of naïve mice. L-PEFs/Sham mice were scanned immediately after the procedure by DCM ("MRI experiment"), or injected with Doxo and Trypan blue followed by delayed (4 h) perfusion and brain extraction ("Doxo experiment"). Doxo concentrations were measured in brain samples using confocal microscopy and compared to IC50 of Doxo in glioma cell lines in vitro. In order to map BBBo extent throughout the brain, pixel by pixel MR image analysis was performed using the DCM data. Finally, the efficacy of L-PEFs in combination with Doxo was tested in nude mice bearing intracranial human glioma tumors. RESULTS: Significant amount of Doxo was found in cortical regions of all L-PEFs-treated mice brains (0.50 ± 0.06 µg Doxo/gr brain) while in Sham brains, Doxo concentrations were below or on the verge of detection limit (0.03 ± 0.02 µg Doxo/gr brain). This concentration was x97 higher than IC50 of Doxo calculated in gl261 mouse glioma cells and x8 higher than IC50 of Doxo calculated in U87 human glioma cells. DCM analysis revealed significant BBBo levels in the cortical regions of L-PEFs-treated mice; the average volume of BBBo in the L-PEFs-treated mice was x29 higher than in the Sham group. The calculated BBBo levels dropped exponentially as a function of BBBo threshold, similarly to the electric fields distribution in the brain. Finally, combining non-invasive L-PEFs with Doxo significantly decreased brain tumors growth rates in nude mice. CONCLUSIONS: Our results demonstrate significant BBBo levels induced by extra-cranial L-PEFs, enabling efficient delivery of therapeutic Doxo doses into the brain and reducing tumor growth. As BBBo was undetectable by standard contrast-enhanced MRI, DCM was applied to generate maps depicting the BBBo levels throughout the brain. These findings suggest that BDF is a promising technology for efficient drug delivery into the brain with important implications for future treatment of brain cancer and additional CNS diseases.
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Neoplasias Encefálicas , Glioma , Humanos , Animales , Ratones , Barrera Hematoencefálica , Ratones Desnudos , Encéfalo/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Doxorrubicina/farmacologíaRESUMEN
There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. METHODS: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009-2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (ß-hydroxybutyrate) were measured in blood and/or urine. RESULTS: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. CONCLUSIONS: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.
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Factores de Edad , Dieta Cetogénica , Cetonas/sangre , Adolescente , Anciano , Neoplasias Encefálicas/dietoterapia , Niño , Preescolar , Dieta Baja en Carbohidratos , Dieta Alta en Grasa , Epilepsia/dietoterapia , Femenino , Glioma/dietoterapia , Humanos , Lactante , Cetonas/orina , Cetosis/sangre , Cetosis/etiología , Masculino , Enfermedades Metabólicas/dietoterapia , Persona de Mediana Edad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Most anterior visual pathway meningiomas (AVPM) are benign and slow-growing, but these tumors may affect visual functions, including visual acuity (VA) and visual field (VF). Due to location, most are treated non-surgically by fractionated stereotactic radiotherapy (FSRT), aiming to prevent tumor progression and visual functions deterioration. Unfortunately, FSRT in itself may affect visual functions. The current preferred treatment regimen (in terms of safety and effectiveness) is undetermined. While most cases are treated with conventional fractionation (cFSRT)-50.4-54 Gy in 28-30 fractions of 1.8-2 Gy, advances in technology have allowed shortening of total treatment length to hypofractionation (hSRT)-25-27 Gy in 3-5 fractions of 5-9 Gy. Our aim was to evaluate the association of radiotherapy regimen for treating AVPM (cFSRT vs. hSRT) with visual function outcomes (VA, VF) at the last neuro-ophthalmologic evaluation. METHODS: We conducted a retrospective cohort study of AVPM cases treated at Sheba Medical Center during 2004-2015. We compared cFSRT and hSRT regimens regarding visual function (VA, VF) outcomes at the last neuro-ophthalmologic evaluation. VA was determined by the logarithm of the minimum angle of resolution (LogMAR). VF was determined by the mean deviation (MD). A clinically relevant change in VA was defined as 0.2 LogMAR. RESULTS: 48 patients (13 receiving hSRT, 35 receiving cFSRT) were included, with a median follow-up of 55 months. No significant difference was evident regarding LogMAR or MD of involved eyes at the last evaluation. Six (17%) patients in the cFSRT group experienced clinically relevant VA deterioration in the involved eye, compared with six (46%) in hSRT (p = 0.06). CONCLUSION: Our findings, using comprehensive and meticulous investigation of visual outcomes, suggest that hSRT may be associated with higher risk for VA and VF deterioration in AVPM especially in ONSM. We recommend the use of cFSRT for ONSM.
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Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Radiocirugia/efectos adversos , Agudeza Visual , Campos Visuales , Vías Visuales , Humanos , Neoplasias Meníngeas/diagnóstico por imagen , Meningioma/diagnóstico por imagen , Hipofraccionamiento de la Dosis de Radiación , Dosificación Radioterapéutica , Estudios RetrospectivosRESUMEN
BACKGROUND: Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. METHODS: Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low (<1.24 µm2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. RESULTS: Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCL identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADCL phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS. CONCLUSION: Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.
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BACKGROUND: Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. METHODS: This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). RESULTS: Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; Pâ =â 0.19) and ORR was 27.3% versus 21.9% (Pâ =â 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. CONCLUSIONS: In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. CLINICAL TRIALS REGISTRATION: NCT02511405.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Encefálicas , Glioblastoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Humanos , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
An external respiratory surrogate that not only highly correlates with but also quantitatively predicts internal tidal volume should be useful in guiding four-dimensional computed tomography (4DCT), as well as 4D radiation therapy (4DRT). A volumetric surrogate should have advantages over external fiducial point(s) for monitoring respiration-induced motion of the torso, which deforms in synchronization with a patient-specific breathing pattern. This study establishes a linear relationship between the external torso volume change (TVC) and lung air volume change (AVC) by validating a proposed volume conservation hypothesis (TVC = AVC) throughout the respiratory cycle using 4DCT and spirometry. Fourteen patients' torso 4DCT images and corresponding spirometric tidal volumes were acquired to examine this hypothesis. The 4DCT images were acquired using dual surrogates in ciné mode and amplitude-based binning in 12 respiratory stages, minimizing residual motion artifacts. Torso and lung volumes were calculated using threshold-based segmentation algorithms and volume changes were calculated relative to the full-exhalation stage. The TVC and AVC, as functions of respiratory stages, were compared, showing a high correlation (r = 0.992 +/- 0.005, p < 0.0001) as well as a linear relationship (slope = 1.027 +/- 0.061, R(2) = 0.980) without phase shift. The AVC was also compared to the spirometric tidal volumes, showing a similar linearity (slope = 1.030 +/- 0.092, R(2) = 0.947). In contrast, the thoracic and abdominal heights measured from 4DCT showed relatively low correlation (0.28 +/- 0.44 and 0.82 +/- 0.30, respectively) and location-dependent phase shifts. This novel approach establishes the foundation for developing an external volumetric respiratory surrogate.
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Tamaño Corporal , Movimiento , Respiración , Tomografía Computarizada por Rayos X/métodos , Abdomen/anatomía & histología , Abdomen/fisiología , Aire , Gases , Tracto Gastrointestinal/diagnóstico por imagen , Tracto Gastrointestinal/metabolismo , Humanos , Modelos Lineales , Pulmón/anatomía & histología , Pulmón/fisiología , Presión , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tórax/anatomía & histología , Tórax/fisiología , Volumen de Ventilación PulmonarRESUMEN
An analytical approach to predict respiratory diaphragm motion should have advantages over a correlation-based method, which cannot adapt to breathing pattern changes without re-calibration for a changing correlation and/or linear coefficient. To quantitatively calculate the diaphragm motion, a new expandable 'piston' respiratory (EPR) model was proposed and tested using 4DCT torso images of 14 patients. The EPR model allows two orthogonal lung motions (with a few volumetric constraints): (1) the lungs expand (DeltaV(EXP)) with the same anterior height variation as the thoracic surface, and (2) the lungs extend (DeltaV(EXT)) with the same inferior distance as the volumetrically equivalent 'piston' diaphragm. A volume conservation rule (VCR) established previously (Li et al 2009 Phys. Med. Biol. 54 1963-78) was applied to link the external torso volume change (TVC) to internal lung volume change (LVC) via lung air volume change (AVC). As the diaphragm moves inferiorly, the vacant space above the diaphragm inside the rib cage should be filled by lung tissue with a volume equal to DeltaV(EXT) (=LVC-DeltaV(EXP)), while the volume of non-lung tissues in the thoracic cavity should conserve. It was found that DeltaV(EXP) accounted for 3-24% of the LVC in these patients. The volumetric shape of the rib cage, characterized by the variation of cavity volume per slice over the piston motion range, deviated from a hollow cylinder by -1.1% to 6.0%, and correction was made iteratively if the variation is >3%. The predictions based on the LVC and TVC (with a conversion factor) were compared with measured diaphragm displacements (averaged from six pivot points), showing excellent agreements (0.2 +/- 0.7 mm and 0.2 +/- 1.2 mm, respectively), which are within clinically acceptable tolerance. Assuming motion synchronization between the piston and points of interest along the diaphragm, point motion was estimated but at higher uncertainty ( approximately 10% +/- 4%). This analytical approach provides a patient-independent technique to calculate the patient-specific diaphragm motion, using the anatomical and respiratory volumetric constraints.
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Diafragma/fisiología , Imagenología Tridimensional/métodos , Modelos Biológicos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Radiografía Torácica/métodos , Mecánica Respiratoria/fisiología , Tórax/fisiología , Algoritmos , Simulación por Computador , Diafragma/diagnóstico por imagen , Humanos , Tamaño de los Órganos/fisiología , Tomografía Computarizada por Rayos X/métodosRESUMEN
AIMS AND OBJECTIVES: To review a series of patients with brain metastases from ovarian cancer at a single institution. To describe treatment modalities, their outcomes and to determine prognostic factors. PATIENTS AND METHODS: Between January 1995 and December 2014, 25 patients with ovarian cancer brain metastases were treated at The Sheba Medical Center. The medical records were retrospectively reviewed to collect demographic, clinical, and imaging data as well as the information on the treatment modalities used and their outcomes. RESULTS: Mean patient age at the time of brain metastasis diagnosis was 62.7 years. The median interval between the diagnosis of primary cancer and brain metastasis was 42.3 months. Neurologic deficits, headache, and seizure were the most common symptoms. The brain was the only site of metastasis in 20% of the patients. Active ovarian cancer at the time of diagnosis of brain metastasis was observed in half of the patients with systemic disease. Multiple brain metastases were observed in 25% of the patients. We treated 11 patients with surgery plus radiation therapy protocols in various orders: surgery followed by complementary whole-brain radiation therapy (WBRT), surgery followed by stereotactic radiosurgery (SRS), and surgery followed by WBRT and then by adjuvant SRS. Five patients underwent surgery alone and nine patients were treated with radiation alone (WBRT, SRS, or both). Univariate analysis for predictors of survival demonstrated that age above 62.7 years at the time of central nervous system involvement was a significant risk factor and leptomeningeal disease was a poor prognostic factor in reference to supra-tentorial lesions. Multivariate analysis for predictors of survival, however, showed that multiple brain lesions (>4) were a poor prognostic factor, and multivariate analysis of the time to progression revealed that combined treatments of surgery and radiation resulted in longer median periods of progression-free survival than each modality alone. CONCLUSION: We conclude that the only significant predictors of survival or progression-free survival in our cohort were the number of brain metastases and the treatment modality.
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Neoplasias Encefálicas/secundario , Irradiación Craneana , Cistadenocarcinoma Seroso/secundario , Procedimientos Neuroquirúrgicos , Neoplasias Ováricas/patología , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Terapia Combinada , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/terapia , Bases de Datos Factuales , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
â¢Of 310 brain tumors patients recruited, histology of 99 lesions was available.â¢Of those, 5 were histologically confirmed as radiation-induced malformations.â¢TRAMs cannot differentiate active tumor from vascular malformation.
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BACKGROUND: Glial brain tumors span a wide range of neoplasms with distinct clinical and histopathological features. This report presents the descriptive epidemiology of glial tumors by histological subtype and tumor behavior. METHODS: The study population included all incident cases of glial tumors diagnosed in Israel during March 2001 to July 2003. Age-standardized incidence rates (ASR) were calculated using the world population as a standard. RESULTS: A total of 548 tumors were diagnosed, of which 520 had histological confirmation. The ASR of all adult (>20 years) glial tumors was 5.82/100,000 (7.11 for males; 4.75 for females, p < 0.001). The majority of tumors (78%) were classified as high grade; astrocytic tumors were the most frequent (85%), with glioblastoma multiforme accounting for 70% of them. A significant positive association was shown between age at diagnosis and grade. The highest ASR was seen for Europe- and-American-born, followed by Israeli, Asian and African-born individuals (6.78, 5.86, 4.94 and 3.84/100,000, respectively). CONCLUSIONS: In general, these results describing data of incident cases of pathologically validated glial tumors are consistent with previous reports. To enhance our understanding of these diseases, epidemiological studies should rely on well-defined histological tumor types, incorporating comprehensive information which will allow comparability between different groups of patients.
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Neoplasias Encefálicas/epidemiología , Glioma/epidemiología , Judíos/estadística & datos numéricos , Adulto , África/epidemiología , Anciano , Anciano de 80 o más Años , Américas/epidemiología , Asia/epidemiología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Etnicidad/estadística & datos numéricos , Europa (Continente)/epidemiología , Femenino , Glioma/patología , Glioma/cirugía , Salud Global , Humanos , Incidencia , Israel/epidemiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Prevalencia , Caracteres SexualesRESUMEN
PURPOSE: Spine stereotactic radiosurgery (SRS) delivers an accurate and efficient high radiation dose to vertebral metastases in 1-5 fractions. We aimed to compare volumetric modulated arc therapy (VMAT) to static beam intensity modulated radiotherapy (IMRT) for spine SRS. METHODS AND MATERIALS: Ten spine lesions of previously treated SRS patients were planned retrospectively using both IMRT and VMAT with a prescribed dose of 16 Gy to 100% of the planning target volume (PTV). The plans were compared for conformity, homogeneity, treatment delivery time, and safety (spinal cord dose). RESULTS: All evaluated parameters favored the VMAT plan over the IMRT plans. D min in the IMRT was significantly lower than in the VMAT plan (7.65 Gy/10.88 Gy, p < 0.001), the Dice Similarity Coefficient (DSC) was found to be significantly better for the VMAT plans compared to the IMRT plans (0.77/0.58, resp., p value < 0.01), and an almost 50% reduction in the net treatment time was calculated for the VMAT compared to the IMRT plans (6.73 min/12.96 min, p < 0.001). CONCLUSIONS: In our report, VMAT provides better conformity, homogeneity, and safety profile. The shorter treatment time is a major advantage and not only provides convenience to the painful patient but also contributes to the precision of this high dose radiation therapy.
Asunto(s)
Radiocirugia , Radioterapia de Intensidad Modulada , Neoplasias de la Columna Vertebral/cirugía , Columna Vertebral/cirugía , Femenino , Humanos , Masculino , Procedimientos Neuroquirúrgicos , Dosificación Radioterapéutica , Neoplasias de la Columna Vertebral/patología , Neoplasias de la Columna Vertebral/secundario , Columna Vertebral/patologíaRESUMEN
Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Sulfonas/uso terapéutico , Adulto , Quinasa de Linfoma Anaplásico , Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/secundario , Irradiación Craneana , Crizotinib , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/genética , Sulfonas/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients. METHODS: One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist. RESULTS: Histological validation confirmed that regions of contrast agent clearance in the TRAMs >1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P < .0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated. CONCLUSIONS: The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.