RESUMEN
BACKGROUND AND PURPOSE: Renal cell carcinoma (RCC) has traditionally been considered radioresistant with a limited role for conventional fractionation as a local approach. Nevertheless, since the appearance of stereotactic body radiation therapy (SBRT), radiotherapy (RT) has been increasingly employed in the management of metastatic RCC (mRCC). The aim of this study was to evaluate the role of SBRT for synchronous and metachronous oligo metastatic RCC patients in terms of local control, delay of systemic treatment, overall survival and toxicity. PATIENTS AND METHODS: A Monocentric single institution retrospective data collection was performed. Inclusion criteria were: (1) oligo-recurrent or oligo-progressive disease (less than 5 metastases) in mRCC patients after radical/partial nephrectomy or during systemic therapy, (2) metastasectomy or other metastasis-directed, rather than SBRT not feasible, (3) any contraindication to receive systemic therapy (such as comorbidities), (4) all the histologies were included, (5) available signed informed consent form for treatment. Tumor response and toxicity were evaluated using the response evaluation criteria in solid tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. Progression-free survival in-field and out-field (in-field and out-field PFS) and overall survival (OS) were calculated via the Kaplan-Meier method. The drug treatment-free interval was calculated from the start of SBRT to the beginning of any systemic therapy. RESULTS: From 2010 to December 2018, 61 patients with extracranial and intracranial metastatic RCC underwent SBRT on 83 lesions. Intracranial and extracranial lesions were included. Forty-five (74%) patients were treated for a solitary metastatic lesion. Median RT dose was 25 Gy (range 10-52) in 5-10 fractions. With a median follow-up of 2.3 years (range 0-7.15), 1-year in-field PFS was 70%, 2-year in-field PFS was 55%. One year out-field PFS was 39% and 1-year OS was 78%. Concomitant systemic therapy was employed for only 11 (18%) patients, for the others 50 (82%) the drug treatment-free rate was 70% and 50% at 1 and 2 years, respectively. No > G1 acute and late toxicities were reported. CONCLUSION: The pattern of failure was pre-dominantly out-of-field, even if the population was negatively selected and the used RT dose could be considered palliative. Therefore, SBRT appears to be a well-tolerated, feasible and safe approach in oligo metastatic RCC patients with an excellent in-field PFS. SBRT might play a role in the management of selected RCC patients allowing for a delay systemic therapy begin (one out of two patients were free from new systemic therapy at 2 years after SBRT). Further research on SBRT dose escalation is warranted.
Asunto(s)
Carcinoma de Células Renales/radioterapia , Neoplasias Renales/radioterapia , Radiocirugia/métodos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/radioterapia , Nefrectomía , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 (SDF1), adenylate cyclase 7 (ADCY7), and p21 protein-activated kinase 1 (PAK1). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, ß, γ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1ß had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.
Asunto(s)
Caquexia/etiología , Caquexia/patología , Quimiocina CXCL12/metabolismo , Atrofia Muscular , Neoplasias/complicaciones , Neoplasias/metabolismo , Receptores CXCR4/metabolismo , Transducción de Señal , Animales , Bencilaminas , Biomarcadores , Ciclamas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Indoles/farmacología , Masculino , Ratones , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neoplasias/genética , Pirroles/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , SunitinibRESUMEN
Mathematical modeling of tumor response to radiotherapy has the potential of enhancing the quality of the treatment plan, which can be even tailored on an individual basis. Lack of extensive in vivo validation has prevented, however, reliable clinical translation of modeling outcomes. Image-guided radiotherapy is a consolidated treatment modality based on computed tomographic (CT) imaging for tumor delineation and volumetric cone beam CT data for periodic checks during treatment. In this study, a macroscopic model of tumor growth and radiation response is proposed, being able to adapt along the treatment course as volumetric tumor data become available. Model parameter learning was based on cone beam CT images in 13 uterine cervical cancer patients, subdivided into three groups (G1, G2, G3) according to tumor type and treatment. Three group-specific parameter sets (PS1, PS2, and PS3) on one general parameter set (PSa) were applied. The corresponding average model fitting errors were 14%, 18%, 13%, and 21%, respectively. The model adaptation testing was performed using volume data of three patients, other than the ones involved in the parameter learning. The extrapolation performance of the general model was improved, while comparable prediction errors were found for the group-specific approach. This suggests that an online parameter tuning can overcome the limitations of a suboptimal patient stratification, which appeared otherwise a critical issue.
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Tomografía Computarizada de Haz Cónico/métodos , Modelos Biológicos , Radioterapia Guiada por Imagen , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/radioterapia , Progresión de la Enfermedad , Femenino , Humanos , Modelos Estadísticos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To retrospectively evaluate external beam reirradiation (re-EBRT) delivered to the prostate/prostatic bed for local recurrence, after radical or adjuvant/salvage radiotherapy (RT). METHODS: 32 patients received re-EBRT between February 2008 and October 2013. All patients had clinical/radiological local relapse in the prostate or prostatic bed and no distant metastasis. re-EBRT was delivered with selective RT technologies [stereotactic RT including CyberKnife(TM) (Accuray, Sunnyvale, CA); image-guidance and intensity-modulated RT etc.]. Toxicity was evaluated using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Biochemical control was assessed according to the Phoenix definition (NADIR + 2 ng ml(-1)). RESULTS: Acute urinary toxicity: G0, 24 patients; G1, 6 patients; G2, 2 patients. Acute rectal toxicity: G0, 28 patients; G1, 2 patients; and G2, 1 patient. Late urinary toxicity (evaluated in 30 cases): G0, 23 patients; G1, 6 patients; G2, 1 patient. Late renal toxicity: G0, 25 patients; G1, 5 patients. A mean follow-up of 21.3 months after re-EBRT showed that 13 patients were free of cancer, 3 were alive with biochemical relapse and 12 patients were alive with clinically evident disease. Four patients had died: two of disease progression and two of other causes. CONCLUSION: re-EBRT using modern technology is a feasible approach for local prostate cancer recurrence offering 2-year tumour control in about half of the patients. Toxicity of re-EBRT is low. Future studies are needed to identify the patients who would benefit most from this treatment. ADVANCES IN KNOWLEDGE: Our series, based on experience in one hospital alone, shows that re-EBRT for local relapse of prostate cancer is feasible and offers a 2-year cure in about half of the patients.
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Recurrencia Local de Neoplasia/cirugía , Neoplasias de la Próstata/cirugía , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones/métodos , Radiocirugia/métodos , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/métodos , Reoperación , Estudios Retrospectivos , Terapia Recuperativa/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
We report a direct DNA sequencing analysis of the MECP2 gene undertaken on a further 64 Italian patients with Rett syndrome by using a LICOR 4200 Automated Sequencer. All of the girls entering the study had a consistent clinical diagnosis for this disorder. All coding regions and the flanking intronic splice site sequences were amplified as three non-overlapping fragments by using both forward and reverse primers. The results were then compared to the MECP2 reference sequences published in GenBank. Mutations of the MECP2 gene were identified in 64 of 75 (85.33%) unrelated sporadic Rett syndrome girls. Genotype/phenotype correlation studies, in particular in groups of patients with the same mutation, did not offer definitive and interesting data.
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Proteínas Cromosómicas no Histona , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Pruebas Genéticas , Mutación/genética , Proteínas Represoras , Síndrome de Rett/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , Codón sin Sentido/genética , ADN/genética , Femenino , Mutación del Sistema de Lectura/genética , Genotipo , Humanos , Italia , Proteína 2 de Unión a Metil-CpG , Mutación Missense/genética , Fenotipo , Síndrome de Rett/fisiopatologíaAsunto(s)
Diabetes Mellitus/mortalidad , Neoplasias/mortalidad , Factores de Edad , Anciano , Complicaciones de la Diabetes , Diabetes Mellitus/patología , Femenino , Humanos , Italia/epidemiología , Masculino , Microcirculación , Persona de Mediana Edad , Neoplasias/irrigación sanguínea , Neoplasias/complicaciones , Tasa de Supervivencia/tendenciasRESUMEN
Early menopause in the fragile X carriers has been well documented in several reports. All surveys demonstrated that 13-25% of fragile X carriers experienced premature ovarian failure (POF), defined as menopause before the age of 40 years. In 1995 we started screening two groups of subjects as a part of a Fragile X Research Program: 1) women previously diagnosed as fragile X carriers from the register of our center and 2) women with POF and without a family history of fragile X or other forms of mental retardation. In this study we report the preliminary data collected from 75 fragile X families; in 30 of them, POF was present in one or several subjects, all of whom had a fragile X premutation. None of the women with a full mutation experienced POF in our series of patients. We also identified 89 families without a family history of fragile X or mental retardation, and there were 108 subjects who experienced POF, of which 6.5% had a fragile X premutation. This is 70-fold higher than the background prevalence of fragile X premutation in the Italian population and suggests an association with POF. These data confirm the results of other surveys.
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Síndrome del Cromosoma X Frágil/genética , Mutación/genética , Insuficiencia Ovárica Primaria/genética , Adolescente , Adulto , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad , LinajeAsunto(s)
Síndrome de Angelman/genética , Síndrome de Prader-Willi/genética , Femenino , Genotipo , Humanos , Cariotipificación , Masculino , FenotipoRESUMEN
Partial trisomy 7p has been observed associated with particular anatomo-pathological findings. A newborn female with several congenital anomalies, whose chromosome constitution was: 46,XX,-14, + der (7;14) (7pter----7p11::14p11----14qter), is reported. The patient died at the age of 10 months, because of cardiac failure and autopsy was performed: the microscopic study showed spongy degeneration in the brain.