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BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is â¼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carbamatos , Cetuximab , Neoplasias Colorrectales , Mutación , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Cetuximab/uso terapéutico , Cetuximab/farmacología , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Carbamatos/uso terapéutico , Carbamatos/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Progresión de la Enfermedad , Supervivencia sin Progresión , Adulto , Anciano de 80 o más Años , Metástasis de la Neoplasia , ItaliaRESUMEN
BACKGROUND: Advances in surgical techniques and systemic treatments have increased the likelihood of achieving radical surgery and long-term survival in metastatic colorectal cancer (mCRC) patients with initially unresectable colorectal liver metastases (CRLMs). Nonetheless, roughly half of the patients resected after an upfront systemic therapy experience disease relapse within 6 months from surgery, thus leading to the question whether surgery is actually beneficial for these patients. MATERIALS AND METHODS: A real-world dataset of mCRC patients with initially unresectable liver-limited disease treated with conversion chemotherapy followed by radical resection of CRLMs at three high-volume Italian institutions was retrospectively assessed with the aim of investigating the association of baseline and pre-surgical clinical, radiological and molecular factors with the risk of relapse within 6 or 12 months from surgery. RESULTS: Overall, 268 patients were included in the analysis and 207 (77%) experienced recurrence. Ninety-six (46%) of them had disease relapse within 6 months after CRLM resection and in spite of several variables associated with early recurrence at univariate analyses, only primary tumour resection at diagnosis [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.32-0.89, P = 0.02] remained significant in the multivariable model. Among patients with resected primary tumours, pN+ stage was associated with higher risk of disease relapse within 6 months (OR 3.02, 95% CI 1.23-7.41, P = 0.02). One hundred and forty-nine patients (72%) had disease relapse within 12 months after CRLMs resection but none of the analysed variables was independently associated with outcome. CONCLUSIONS: Clinical, radiological and molecular factors assessed before and after conversion chemotherapy do not reliably predict early recurrence after secondary resection of initially unresectable CRLMs. While novel markers are needed to optimize the cost/efficacy balance of surgical procedures, CRLM resection should be offered as soon as metastases become resectable during first-line chemotherapy to all patients eligible for surgery.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Recurrencia Local de Neoplasia , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Hepatectomía/métodosRESUMEN
No disponible
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Humanos , Femenino , Niño , Bezoares/complicaciones , Obstrucción Intestinal/etiología , Tricotilomanía/complicaciones , Factores de RiesgoRESUMEN
One important issue in the preclinical development of an anticancer drug is the assessment of the compound under investigation when administered in combination with other drugs. Several experiments are routinely conducted in xenograft mice to evaluate if drugs interact or not. Experimental data are generally qualitatively analyzed on empirical basis. The ability of deriving from single drug experiments a reference response to the joint administrations, assuming no interaction, and comparing it to real responses would be key to recognize synergic and antagonist compounds. Therefore, in this paper, the minimal model of tumor growth inhibition (TGI), previously developed for a single drug, is reformulated to account for the effects of noninteracting drugs and simulate, under this hypothesis, combination regimens. The model is derived from a minimal set of basic assumptions that include and extend those formulated at cellular level for the single drug administration. The tumor growth dynamics is well approximated by the deterministic evolution of its expected value that is obtained through the solution of an ordinary and several partial differential equations. Under suitable assumptions on the cell death process, the model reduces to a lumped parameter model that represents the extension of the very popular Simeoni TGI model to the combined administration of noninteracting drugs.
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Antineoplásicos/farmacología , Descubrimiento de Drogas/métodos , Modelos Biológicos , Neoplasias Experimentales/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Línea Celular Tumoral , Interacciones Farmacológicas , Humanos , Ratones , Neoplasias Experimentales/patologíaRESUMEN
AIM: To describe central nervous system malformations in the surgically induced model of Myelomeningocele (MMC) and their prevention using different prenatal treatments. METHODS: MMC was surgically created in 33 fetal lambs. Fifteen did not undergo fetal repair (group A). Of the lambs that did undergo repair, 10 were repaired with open two layer surgical closure (group B), 5 with fetoscopic coverage using bioglue (group C) and 3 fetoscopically using a patch (group D). All procedures were recorded and lamb brains and spinal cords were examined grossly and microscopically in coronal sections for structural organization anomalies. Histopathological changes were assessed using HE and S-100 neural marker. RESULTS: Hydrocephalus, Arnold-Chiari type II (AC-II) malformation and some neuronal migration disorders were observed in group A. Brains from group B and D were not hydrocephalic and had neither cell migration disorders nor hindbrain herniation. Group C presents mild degrees of hydrocephalus and AC-II. In group C lumbar lesion was covered by fibrous tissue. CONCLUSIONS: Some of the central nervous system abnormalities observed in human disease are present in the surgically induced model of MMC. In this model avoidance of fluid drainage using open fetal surgery limits malformation severity.
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Sistema Nervioso Central/anomalías , Meningomielocele/prevención & control , Animales , Anomalías Congénitas/prevención & control , Modelos Animales de Enfermedad , Feto , OvinosRESUMEN
Objetivo. Describir si el modelo de mielomeningocele (MMC) en oveja presenta alteraciones en el desarrollo vesical semejantes a las del humano y si la cobertura prenatal del defecto puede prevenirlas. Métodos. Realizamos un MMC fetal en veinte ovejas preñadas entre los días 60 y 80 de gestación. Diez casos no fueron corregidos(grupo A), 5 fueron corregidos mediante cirugía fetal abierta (grupo B)y 5 mediante aplicación fetoscópica percutánea de un pegamento biológico (grupo C). Los corderos fueron observados y sus vejigas estudiadas mediante H&E y Masson. Tres corderos sanos sirvieron como controles. Resultados. Cinco animales en el grupo A (50%), 2 en el grupo B (40%) y 3 en el C (60%) nacieron a término. Los corderos del grupo B y C eran continentes y macroscópicamente sus vejigas normales. Microscópicamente, las vejigas del grupo C presentaban un ligero adelgazamiento muscular y urotelial manteniendo su estructura histológica conservada, mientras que las del grupo B no presentaban alteración histológica alguna. En el grupo A, los animales eran incontinentes y sus (..) (AU)
Purpose. To describe the presence of bladder malformations in asurgically induced model of myelomeningocele (MMC).Methods. A MMC like defect was created in the mid gestationusing the previously described model in sheep. Bladders were examined macroscopically and histopathological changes were assessed usingH-E. Results. Non prenatally corrected animals presented dilated bladders and separation between muscle bundles. Those malformations were (..) (AU)
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Animales , Meningomielocele/fisiopatología , Vejiga Urinaria/crecimiento & desarrollo , Vejiga Urinaria Neurogénica/fisiopatología , Modelos Animales de Enfermedad , Anomalías Urogenitales/etiología , OvinosRESUMEN
Objetivo. Describir malformaciones cerebrales en el modelo demielomeningocele (MMC) en oveja que pudieran asociarse a las alteraciones cognitivas observadas en humanos y determinar si algún tipo de abordaje prenatal es capaz de prevenirlas. Métodos. Realizamos un MMC fetal en 33 ovejas preñadas entre los días 60 y 80. En 15 casos el defecto no fue corregido (grupo A); en10 fue corregido mediante cirugía fetal abierta (grupo B); en 5 mediante cobertura fetoscópica con pegamento biológico (grupo C); y en 3mediante la aplicación fetoscópica de un parche de sustituto de dura. Los cráneos y cerebros fueron examinados externamente y en cortes coronales. Buscamos hidrocefalia, alteraciones en la migración neuronal y malformación de Arnold-Chiari tipo II (AC-II) mediante H&E, Masson y el (..) (AU)
Aim. To describe central nervous system malformations in the surgically induced model of Myelomeningocele (MMC) and their prevention using different prenatal treatments. Methods. MMC was surgically created in 33 fetal lambs. Fifteen did not undergo fetal repair (group A). Of the lambs that did undergo repair, 10 were repaired with open two layer surgical closure (group B),5 with fetoscopic coverage using bioglue (group C) and 3 fetoscopically using a patch (group D). All procedures were recorded and lambbrains and spinal cords were examined grossly and microscopically incoronal sections for structural organization anomalies. Histopathological changes were assessed using HE and S-100 neural marker. Results. Hydrocephalus, Arnold-Chiari type II (AC-II) malformation and some neuronal migration disorders were observed in group A. Brains from group B and D were not hydrocephalic and had neither cell (..) (AU)
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Animales , Meningomielocele/cirugía , Fetoscopía/métodos , Procedimientos Neuroquirúrgicos/métodos , Encéfalo/crecimiento & desarrollo , Modelos Animales de Enfermedad , OvinosRESUMEN
PURPOSE: To describe the presence of bladder malformations in a surgically induced model of myelomeningocele (MMC). METHODS: A MMC like defect was created in the mid gestation using the previously described model in sheep. Bladders were examined macroscopically and histopathological changes were assessed using H-E. RESULTS: Non prenatally corrected animals presented dilated bladders and separation between muscle bundles. Those malformations were not found in corrected animals or controls. CONCLUSIONS: Some bladder changes can be described in a surgically-induced model of MMC. These changes could be prevented using open fetal surgery.
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Meningomielocele , Vejiga Urinaria/anomalías , Animales , Anomalías Congénitas/prevención & control , Modelos Animales de Enfermedad , Terapias Fetales , Meningomielocele/complicaciones , Meningomielocele/cirugía , OvinosRESUMEN
In clinical oncology, combination regimens may result in a synergistic, additive or antagonistic interaction (i.e. the effect of the combination is greater, similar or smaller than the sum of the effects of the individual compounds). For this reason, during the drug development process, in vivo pre-clinical studies are performed to assess the interaction of anticancer agents given in combination. Starting from a widely used single compound PK/PD model, a new additivity model able to predict the tumour growth inhibition in xenografted mice after the administration of compounds in combination was developed, under the assumption of a pharmacodynamic null interaction. By comparing the predicted curves with actual tumour weight data, possible departures from additivity can be immediately ascertained by visual inspection; a statistical procedure based on a chi(2) test has also been developed for this aim. The advantages of the proposed approach in comparison to other modelling methodologies are discussed and its application to four combination studies is presented.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Interacciones Farmacológicas , Ratones , Modelos Biológicos , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Obesity in Prader-Willi Syndrome (PWS) is progressive, severe, and resistant to dietary, pharmacological, and behavioral treatment. A body weight reduction is mandatory to reduce the risk of cardio-respiratory and metabolic complications. The aim of the study was to assess risks and benefits of BioEnterics Intragastric Balloon (BIB) for treatment of morbid obesity in PWS patients. METHODS: Twenty-one BIB were positioned in 12 PWS patients (4 M, 8 F), aged from 8.1 to 30.1 years, and removed after 8 +/- 1.4 months (range: 5-10 months). Auxological, clinical, and nutritional evaluations were performed every 2 months. Variations in body composition were analysed by dual energy X-ray absorbiometry (DXA). RESULTS: One patient (28.5 years, BMI: 59.3 kg/m(2)) died 22 days after BIB positioning because of gastric perforation. In another case (26.2 years, BMI: 57.6 kg/m(2)), BIB was surgically removed after 25 days because of symptoms suggesting gastric perforation (not confirmed). The remaining ten patients showed a significant decrease of BMI (p = 0.005) and of fat tissue as measured by DXA (p = 0.012). No significant modifications in bone mineral density (BMD) occurred, but a slight loss in lean body mass (p = 0.036) was documented. In five patients, BIB treatment was repeated more than once. CONCLUSION: This study shows that when noninvasive pharmacological therapies fail, BIB may be effective to control body weight in PWS patients with morbid obesity, particularly when treatment is started in early childhood. However, careful clinical follow-up and close collaboration with parents are crucial to avoid severe complications, which can be caused by persisting unrestrained food intake.
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Balón Gástrico , Obesidad Mórbida/epidemiología , Obesidad Mórbida/terapia , Síndrome de Prader-Willi/epidemiología , Adolescente , Adulto , Niño , Comorbilidad , Endoscopía Gastrointestinal , Femenino , Balón Gástrico/efectos adversos , Humanos , Masculino , Cuidados Posoperatorios , Implantación de Prótesis/métodos , Medición de Riesgo , Pérdida de Peso , Adulto JovenRESUMEN
The authors tackle the complex question of the physiopathogenesis of migraine by examining the various theories which have been proposed, underlining that only through an open and constructive comparison it is possible to reach a real understanding of such a complex pathology such as migraine.
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Trastornos Migrañosos/etiología , Trastornos Migrañosos/fisiopatología , Trastornos de las Plaquetas Sanguíneas/complicaciones , Volumen Sanguíneo , Humanos , Enfermedades del Sistema Nervioso/complicaciones , Núcleos del Trigémino/fisiopatología , Enfermedades Vasculares/complicacionesRESUMEN
Most recent epidemiological data on headaches are here discussed. These data clearly show the great social-economic importance of this problem, giving at the same time many hints of discussion on the different aspects of this complex syndrome. It is here also analyzed the latest international classification of the headache.
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Cefalea/clasificación , Cefalea/epidemiología , HumanosRESUMEN
Erythrocytes from a patient with hypokalemic periodic paralysis (HPP) have been studied, in order to investigate the presence of alterations of membrane cation active transport systems. An original 23Na-NMR method has been used, capable of evaluating quantitatively the Na+ efflux due to the Na+/K+/Cl- cotransport. This method uses a loading system to increase internal cellular Na+ concentration: in the patient with HPP both the internal Na+ concentration after loading and the Na+/K+/Cl- cotransport activity were decreased in comparison to the controls. Our data seem to confirm that the fall of K+ serum levels during attacks in HPP must be ascribed to a shift of K+ from extra- to intracellular compartment (with consequent changes in the fibrocellular membrane polarity), due to an alteration of membrane cation transport system: which does not only consist in a hyperactivity of Na+/K+ ATPase (already described by other AA.), but also in a "secondary" decreased K+ efflux driven by the cotransport. The decrease of cotransport activity may be considered as "compensatory" (in fact, the intracellular Na+ content is normal), since this transport system can work as a kind of "emergency" system that can "help" the ATPase-dependent pump in extruding any excess of cell Na+ content, or can be depressed by any decrease of this value, caused by an hyperactivity of the Na+/K+ ATPase. The decreased cotransport activity results in a powerful contribution to the increase of intracellular potassium due to the hyperactivity of the Na+/K+ pump. This method could supply a useful diagnostic marker in all uncertain cases.
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Hipopotasemia/diagnóstico , Parálisis/diagnóstico , Periodicidad , Potasio/sangre , Sodio/sangre , Adulto , Transporte Biológico Activo , Eritrocitos/metabolismo , Humanos , Hipopotasemia/sangre , Espectroscopía de Resonancia Magnética/métodos , Masculino , Hipotonía Muscular/sangre , Hipotonía Muscular/diagnóstico , Parálisis/sangre , Radioisótopos de Sodio , ATPasa Intercambiadora de Sodio-Potasio/sangreRESUMEN
Aphasic subjects' auditory comprehension of reversible passive sentences is facilitated by preceding predictive and nonpredictive narratives (Hough, Pierce, & Cannito, 1989, Brain and Language, 36, 325-334). The present study found that aphasic subjects also comprehended written reversible passive sentences significantly more accurately when they were preceded by either predictive or nonpredictive five-sentence narratives than when they were presented in isolation. Also tested was the contention that predictive narratives do not improve aphasic subjects' ability to process target sentences but simply allow these sentences to be ignored. This contention was not supported. The aphasic subjects did not comprehend predictive narratives presented without the subsequent target sentences more accurately than they comprehended the target sentences presented in isolation. For comprehension to be enhanced, both the contextual narratives and the target sentences must be present.
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Afasia , Lectura , Anciano , Atención , Femenino , Humanos , Masculino , Persona de Mediana Edad , SemánticaRESUMEN
The authors compare the methacholine (Mch) and the nebulized ultrasonic distilled water (NUDW) bronchial challenge as regard sensitivity and time required to perform them. For military service fitness, were studied 24 asthmatic patients. Each subject performed random a bronchial challenge by Mch (Yan method) and by NUDW (Allegra method) in two different days; for each bronchial challenge has been measured the time required to perform it. The atopic status has been evaluated by skin-prick test. All the subjects have shown a positive response to Mch test (PD 20 FEV1 mean: 352 mcg, range 80-850) whereas 13 subjects (54%) have shown a positive response to NUDW. The time required to evaluate all the subjects by Mch test has been 199.5 minutes whereas the total time required to evaluate all the subjects by NUDW test (127 minutes) and to evaluate by Mch test the non responders to NUDW (100 minutes) has been 227 minutes. The most of subjects were skin reactors. No difference was found as regard onset of disease, basal lung function and atopic status between responders and non responders to NUDW test. We conclude that NUDW test has shown a lack of sensitivity in this sample (50% of asthmatic patients could be misdiagnosed) and that the Mch test is preferable to determine a rapid method for measurement of bronchial responsiveness.
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Pruebas de Provocación Bronquial/métodos , Cloruro de Metacolina , Personal Militar , Agua , Adolescente , Asma/diagnóstico , Asma/fisiopatología , Hiperreactividad Bronquial/diagnóstico , Pruebas de Provocación Bronquial/estadística & datos numéricos , Estudios de Evaluación como Asunto , Humanos , Italia , Pruebas CutáneasRESUMEN
The Authors shortly present some statistical and epidemiological data on RTI and stress that these infections are nowadays the main infectious diseases. After an excursus of the most frequent infectious aetiologies, they show their experience in RTI treatment, mainly acute LRTI, with a new fluorquinolone, ciprofloxacin, at the posology of 250 mg p.o. b.i.d. or t.i.d., with good clinical results (90% of recovery) and excellent tolerability (absence of ADR in 100% of the treated patients).
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Ciprofloxacina/uso terapéutico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/etiología , Índice de Severidad de la EnfermedadRESUMEN
The clinical meaning of high values of blood lipid peroxides, assessed as thiobarbituric acid reactive substances (TBA-RS), was investigated in 19 selected high risk patients with transient ischemic attacks (TIA). Patients were checked every 3-6 months and followed-up for 3 years. 8 patients experienced further vascular episodes, 4 having minor stroke and 4 TIA; one of the latter died from myocardial infarction. Unlike blood cholesterol and glucose. TBA-RS values discriminated patients with vascular episodes: they, indeed, showed significant higher values of TBA-RS. Discriminant analysis further indicated that TBA-RS levels differentiate patients with and without vascular accidents, suggesting that high blood values of lipid peroxides could represent a predictive sign of vascular ischemia.
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Infarto Cerebral/diagnóstico , Arteriosclerosis Intracraneal/diagnóstico , Ataque Isquémico Transitorio/diagnóstico , Peróxidos Lipídicos/sangre , Tiobarbitúricos/farmacocinética , Anciano , Glucemia/metabolismo , Infarto Cerebral/sangre , Colesterol/sangre , Femenino , Estudios de Seguimiento , Humanos , Arteriosclerosis Intracraneal/sangre , Ataque Isquémico Transitorio/sangre , Masculino , Persona de Mediana Edad , Recurrencia , Factores de Riesgo , Triglicéridos/sangreRESUMEN
The effect of active changes in posture, from recumbency to up-right position (60 min) on the circulating levels of atrial natriuretic peptide (ANP) were studied in 52 hypertensive patients, in 30 healthy human subjects and in 24 normotensive subjects with hypertensive parents. At the end of the orthostatic challenge, plasma ANP levels were reduced by about 40% (p less than 0.01) in all subjects without significant differences between the three groups. This indicates that the active postural inhibition of ANP release is substantially similar in the different subjects here studied.
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Factor Natriurético Atrial/sangre , Presión Sanguínea , Hipertensión/sangre , Postura , Adulto , Humanos , Hipertensión/genética , Factores de TiempoRESUMEN
Patients with transient ischemic attacks (TIA) were previously shown to have high plasma values of thiobarbituric acid-reactive substances (TBA-RS). To study whether these changes could be related to platelet activability, TBA-RS was investigated in 24 TIA patients before and 24 h after 1 g aspirin, an inhibitor of platelet cyclooxygenase pathway. Baseline TBA-RS values were significantly higher in TIA than in controls. Conversely, TIA patients had TBA-RS values after aspirin similar to controls, suggesting that the increase of plasma TBA-RS was not attributable to platelet hyperfunction. The evaluation of metabolic profile showed that patients with highest TBA-RS had hypercholesterolemia, hypertriglyceridemia, and/or diabetes mellitus. This study suggests that the increase of plasma TBA-RS in TIA could be an epiphenomenon of altered metabolic pathway.