RESUMEN
BACKGROUND: Rectal cancer constitutes nearly one-third of all colorectal cancer diagnoses, and certain clinical and molecular markers have been studied as potential prognosticators of patient survival. The main objective of our study was to investigate the relationship between the expression intensities of certain proteins, including growth-hormone-releasing hormone receptor (GHRH-R), Hsp90, Hsp16.2, p-Akt and SOUL, in specimens of locally advanced rectal cancer patients, as well as the time to metastasis and 10-year overall survival (OS) rates. We also investigated whether these outcome measures were associated with the presence of other clinical parameters. METHODS: In total, 109 patients were investigated retrospectively. Samples of pretreatment tumors were stained for the proteins GHRH-R, Hsp90, Hsp16.2, p-Akt and SOUL using immunhistochemistry methods. Kaplan-Meier curves were used to show the relationships between the intensity of expression of biomarkers, clinical parameters, the time to metastasis and the 10-year OS rate. RESULTS: High levels of p-Akt, GHRH-R and Hsp90 were associated with a significantly decreased 10-year OS rate (p = 0.001, p = 0.000, p = 0.004, respectively) and high expression levels of p-Akt and GHRH-R were correlated with a significantly shorter time to metastasis. Tumors localized in the lower third of the rectum were linked to both a significantly longer time to metastasis and an improved 10-year OS rate. CONCLUSIONS: Hsp 90, pAkt and GHRH-R as well as the lower-third localization of the tumor were predictive of the 10-year OS rate in locally advanced rectal cancer patients. The GHRH-R and Hsp90 expression levels were independent prognosticators of OS. Our results imply that GHRH-R could play a particularly important role both as a molecular biomarker and as a target for the anticancer treatment of advanced rectal cancer.
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Non-invasive procedures completing traditional surgical treatment play an increasing role in the management of central nervous system malignancies. Conformal stereotactic irradiation (radiosurgery) has become a routine method in intracranial malignancies. However, application of this modality in tumours of the spinal cord and spinal column is much more difficult to perform. It is because extracranial organs can be only inaccurately fixed, and radio-sensitivity of the spinal cord and risks of radionecrosis with ensuing paraplegia are high. A recurrent sacrum chordoma treated by means of this modality - first reported in Hungary - has been chosen for case presentation as the criteria for radiotherapy such as high dose to target volume, minimal dose to neighbouring structures highly sensitive to radiation are best met in these tumours by means of conformal stereotactic radiotherapy. On the basis of further 13 extracranial cases treated with this method one can conclude that high precision stereotactic conformal radiotherapy offers up-grade to traditional radiotherapy despite the fact that it is a time-consuming procedure. The oncological efficiency, the reduced risks of side effects and the improved quality of life due to this treatment modality compensate duly for the increased labour input.
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Recurrencia Local de Neoplasia/radioterapia , Radiocirugia/métodos , Radioterapia Conformacional/métodos , Sacro , Neoplasias de la Médula Espinal/radioterapia , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Hungría , Imagen por Resonancia Magnética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Planificación de la Radioterapia Asistida por Computador , Neoplasias de la Médula Espinal/patología , Neoplasias de la Médula Espinal/cirugía , Resultado del TratamientoRESUMEN
A comparative analysis of human and experimental animal (canine) tissues was performed to characterize and describe cellular and histological responses during the processes of newly forming intravascular tissues after stent implantation. Routine histological and immunohistochemical evaluation of 20 human samples and 9 samples from animal models were used one day, one week and one month after the stent implantation. After one day of implantation, there was no difference between the human and canine peripheral arteries, suggesting a similar cellular and histological response in the early phase. In contrast, after one week of implantation, during the proliferative phase the repairing human tissue showed less intensive production of inflammatory cells and more intensive increase in number of vascular cells than did the canine model. In addition, cellular changes normally restituted by the end of one month in canine peripheral arteries, but vascular cells persisted in human atherosclerotic arteries. In conclusion, results of this study suggest differences in both phases of vascular repair in the post-stented period, because both proliferative and regressive phases showed histological differences in canine and human samples. In canine, the restitution of vascular wall was completed by the end of first month but persistent vascular cell proliferation was visible in the human peripheral arteries. It can be suggested that delayed cellular response might indicate restenosis but also can be considered considered as a progression of the original arterial disease.
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Vasos Sanguíneos/patología , Modelos Animales , Stents/efectos adversos , Anciano , Anciano de 80 o más Años , Animales , Perros , Femenino , Humanos , Masculino , Persona de Mediana Edad , Túnica Íntima/patología , Procedimientos Quirúrgicos VascularesRESUMEN
BACKGROUND: Gliomas are the most common neoplasm of the brain. High-grade gliomas often resist treatment even with aggressive surgical resection and adjuvant radiation and chemotherapy. Despite the combined treatment, they frequently recur with the same or higher-grade histology. Genetic instability is commonly associated with inactivation of the normal DNA repair function and tumour suppressor genes as well as activation of oncogenes resulting from alterations of promoter hypermethylation, but the molecular mechanisms of the histological and clinical progression of gliomas are still poorly understood. METHODS: This study involved longitudinal analysis samples of primary and recurrent gliomas to determine whether the progression of low- and high-grade gliomas is associated with the promoter methylation of the DNMT1, MGMT and EGFR genes by PCR-based restriction enzyme assay. Epigenetic inactivation of these three important glioma-associated genes was analyzed in paired biopsy samples from 18 patients with tumour recurrence. RESULTS: The methylation analysis of the CpG sites in the DNA methyltransferase (DNMT1) promoter revealed a total of 6 hypermethylations (6/18), the methylguanine-DNA methyltransferase (MGMT) promoter revealed a total of 10 hypermethylations (10/18) and the epithelial grow factor receptor (EGFR) promoter revealed a total of 12 (12/18) hypermethylations respectively in recurrent gliomas. The results demonstrated that DNMT1 promoter hypermethylation does not occur in low-grade gliomas, it was mainly observed in secondary glioblastomas. Additionally, the MGMT and EGFR promoter was hypermethylated in both low-and high-grade GLs and their corresponding histological transformed GLs. CONCLUSION: This study has provided further evidence that the histological transformation and progression of gliomas may be associated with the inactivation of the EGFR and MGMT genes. It seems that EGFR and MGMT promoter hypermethylations are early events in the clonal evolution of gliomas and this gene inactivation has proved to be stable even in tumour recurrence. However, the DNMT hypermethylation is a late part of glioma progression. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460.
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Neoplasias Encefálicas/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Receptores ErbB/genética , Silenciador del Gen , Glioma/genética , Recurrencia Local de Neoplasia/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Biopsia , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Islas de CpG , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/análisis , Metilasas de Modificación del ADN/análisis , Enzimas Reparadoras del ADN/análisis , Progresión de la Enfermedad , Receptores ErbB/análisis , Femenino , Predisposición Genética a la Enfermedad , Glioma/enzimología , Glioma/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/patología , Fenotipo , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor/análisis , Adulto JovenRESUMEN
PURPOSE: The response to neoadjuvant chemoradiotherapy (CRT) varies greatly in patients suffering from locally advanced rectal cancer. Our aim was to correlate the response to CRT with the pre-treatment expression of heat shock protein 90 (Hsp90), small heat shock protein 16.2 (sHsp 16.2), phospho-Akt (p-Akt), growth hormone-releasing hormone receptor (GHRH-R) and heme-binding protein 2 (SOUL) in order to try to identify one or more as a predictive marker. MATERIALS AND METHODS: Sixty-nine patients receiving combined CRT for locally advanced rectal cancer were examined retrospectively. Surgical resection was carried out 6-9 weeks following CRT. The histopathological response to neoadjuvant treatment was determined according to the modified Mandard score. Using immunohistochemistry, we investigated the relationship between the expression of the five cited proteins in the pre-operative samples as well as various clinical parameters and the histopathological regression of the tumors. RESULTS: Thirty-one patients (48%) were good responders, and 33 patients (52%) were found to respond poorly to neoadjuvant therapy. Among patients undergoing surgery 7 weeks following CRT, there were significantly more good responders than among patients who underwent surgery sooner (63% vs. 37%). High levels of expression of GHRH-R and Hsp90 were shown to be significantly correlated with minor or absent histological regression. CONCLUSIONS: GHRH-R and Hsp90 were found to be independent predictive factors of histopathological response to neoadjuvant RCT. Since GHRH-R antagonists and Hsp90 inhibitors are currently being tested as potential anticancer agents, our study implies the possible elaboration of an effective and individualized treatment of poor responders.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Proteínas HSP90 de Choque Térmico/análisis , Terapia Neoadyuvante/métodos , Receptores de Neuropéptido/análisis , Receptores de Hormona Reguladora de Hormona Hipofisaria/análisis , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Adulto , Anciano , Quimioradioterapia Adyuvante , Femenino , Proteínas de Choque Térmico Pequeñas/análisis , Proteínas de Unión al Hemo , Hemoproteínas/análisis , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteínas Gestacionales/análisis , Proteínas Proto-Oncogénicas c-akt/análisis , Neoplasias del Recto/química , Resultado del TratamientoRESUMEN
Myelination is considered as one of the last steps of neuronal development and is essential to the physiologically matured function of afferent and efferent pathways. In the present study, myelin formation was examined in the human fetal, postnatal and adult hippocampal formation in Down syndrome and in age-matched controls with immunohistochemistry detecting a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelination is mainly a postnatal event in the hippocampal formation of both healthy controls and in patients with Down syndrome. In patients with Down syndrome the sequence of myelination of the hippocampal formation followed a similar developmental pattern to that in controls. However, myelin formation was generally delayed in Down syndrome compared to age-matched controls. In addition, in the hilus of the dentate gyrus a decreased density of myelinated axons was detected from the start of myelination until adulthood. The majority of local axons (mossy fibers) are not myelinated in the hilar region and myelinated fibers arriving in the hilus come mainly from the subcortical septal nuclei. Since intact septo-hippocampal connections are necessary for memory formation, we hypothesize that decreased myelination in the hilus may contribute to the mental retardation of Down syndrome patients.
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Síndrome de Down/patología , Síndrome de Down/fisiopatología , Hipocampo/crecimiento & desarrollo , Hipocampo/patología , Vaina de Mielina/genética , Fibras Nerviosas Mielínicas/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Síndrome de Down/genética , Femenino , Hipocampo/anomalías , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Vaina de Mielina/patología , Adulto JovenRESUMEN
Here, we present a male infant with clinical signs of typical Leigh syndrome. The first symptom, myoclonus was presented already on the 5th day of life; at 7 months of age limb convulsions and cerebral paresis with hypotonia were developed. At the age of 11 months, MRI verified increased signal intensity in the entire mesencephalon and medulla oblongata; while gray matter proton spectroscopy revealed presence of lactate increase in the brain. At age of 17 months, the child died in cardiorespiratory arrest. After autopsy, the diagnosis of Leigh syndrome was established; using DNA isolated from skeletal muscle and liver, heteroplasmic (>50%) mitochondrial 11777C>A was detected in the fourth subunit of NADH dehydrogenase enzyme (MTND4) encoding gene, which causes Arg --> Ser replacement. The mutation was also detected in low copy number in blood of mother. Albeit this mutation type is well recognized as a typical mtDNA mutation, according the reports available on the PubMed, this mutation was described only in four patients with wide phenotypic variations; here, we reviewed the characteristic clinical features of them. Taken together, the earliest onset of symptoms, the nature of the first presentation signs, the most rapid progression, the character of minor additional symptoms, and the early fatal outcome differentiate the phenotypic variant of the proband presented here from cases reported so far by others.
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ADN Mitocondrial/genética , Enfermedad de Leigh/genética , Mutación Puntual , Encéfalo/metabolismo , Encéfalo/patología , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Haplotipos , Humanos , Lactante , Enfermedad de Leigh/fisiopatología , Masculino , Linaje , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Myelination, one of the last steps of neuronal development, was examined in the human fetal and postnatal hippocampal formation using immunohistochemistry to detect a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelin basic protein-immunoreactive oligodendroglial cells were first seen at the 20th gestational week in the fimbria fornicis and in the alveus. Between the 21st and 35th weeks, myelinated axons also appeared in the fimbria fornicis. At the age of 39 gestational weeks, short and thin myelinated fibers were present in the fimbria, in the alveus, and less so in the stratum oriens of the hippocampus, while the first oligodendroglial cells appeared in the stratum lacunosum-moleculare and in the hilus. By the 2nd postnatal week myelinated fibers appeared in the stratum lacunosum-moleculare of Ammon's horn. At the 3rd month, myelination was strong in the alveus, moderate in the strata oriens, lacunosum-moleculare and radiatum of Ammon's horn, while only a small number of myelinated fibers were detected in the hilus. By the 5th month, the first oligodendroglial cells were detected in the molecular layer of the dentate gyrus. Myelination continued in the following years, particularly in the dentate gyrus, where even at the age of 11 years the density of myelinated fibers did not reach the adult level. It appears that the first myelinated axons belong to the long-projecting large hippocampal pyramidal cells and/or to their subcortical and cortical afferents. The sequence of myelination follows the known developmental pattern of hippocampal afferent and efferent pathways, and the prolonged myelination might be a factor in the prolonged functional maturation of hippocampal circuitry.
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Edad Gestacional , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Proteína Básica de Mielina/metabolismo , Fibras Nerviosas Mielínicas/fisiología , Adulto , Niño , Preescolar , Giro Dentado/citología , Giro Dentado/embriología , Giro Dentado/crecimiento & desarrollo , Femenino , Hipocampo/citología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Vaina de Mielina/fisiología , Vaina de Mielina/ultraestructura , Fibras Nerviosas Mielínicas/ultraestructura , Neurogénesis/fisiologíaRESUMEN
OBJECTIVES: Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. Its etiology is still unclear. Neurogenic components might contribute to the inflammatory process. The oral mucosa is richly innervated by sensory fibers. Mediators secreted by inflammatory cells activate sensory nerves via transient receptor potential vanilloid receptor 1 (TRPV1) and lead to the release of neuropeptides. So far, TRPV1 receptor expression was detected on neurons. Only recently, TRPV1 receptors were identified in nonneuronal tissues. The aim of the present study was to detect the presence of TRPV1 receptors and peripheral expression of receptor mRNA in normal oral mucosa and mucous membranes from OLP patients. METHODS: Presence of TRPV1 receptor proteins in the mucosal tissue was assessed by immunohistochemistry. Expression of TRPV1 receptor mRNA was determined by quantitative RT-PCR. RESULTS: We provided qualitative and quantitative immunohistochemical evidence that TRPV1 receptors are present in normal human oral mucosa and that their expression is increased in OLP. The number of immunopositive cells was elevated in the epithelium, and vascular endothelial cells, lymphocytes and fibroblasts of the subepithelium were also labeled in samples obtained from OLP patients. The local expression of nonneuronal TRPV1 receptors was proven at mRNA level using quantitative real-time RT-PCR. CONCLUSIONS: Since the number of TRPV1 receptor-positive nonneural cells is increased in inflammatory conditions, we hypothesize that TRPV1-receptor-mediated processes might play role in the pathogenesis of OLP.
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Inflamación/metabolismo , Liquen Plano Oral/metabolismo , Mucosa Bucal/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica/fisiología , Humanos , Inmunohistoquímica , Inflamación/genética , Inflamación/fisiopatología , Liquen Plano Oral/genética , Liquen Plano Oral/fisiopatología , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Bucal/patología , Mucosa Bucal/fisiopatología , Nociceptores/metabolismo , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Receptoras Sensoriales/metabolismo , Canales Catiónicos TRPV/genética , Regulación hacia Arriba/fisiologíaRESUMEN
CASE REPORT: pLMS in the wall of the inferior vena cava is an extremely rare form of retroperitoneal malignancies. A case in a young female patient is presented; clinical symptoms, pre- and postoperative diagnosis and surgical treatment are discussed. A retroperitoneal mass detected by imaging was found to be a large tumor mass located at the middle segment of the IVC on exploration. The tumour was successfully excised and the IVC was reconstructed with a synthetic graft. Eight years later, this patient needed a repeat surgery due to local recurrence. This time tumour was attached to the left renal vein. A re-resection of the IVC was performed with subsequent synthetic graft reconstruction and the distal end of the left renal vein was reimplanted into a lower segment of IVC. DISCUSSION: Primary leiomyosarcoma of the inferior vena cava (pLMS-IVC) is an extremely rare form of retroperitoneal malignancies. The tumour arises from the medial layer of the venous wall and can grow either intraluminally, or extraluminally or in both directions, as well. It can be localized in the first segment of IVC (above the hepatic veins), in the second segment between hepatic and renal veins and finally in the third segment between the right common iliac vein and renal veins. Therefore, the tumour can infiltrate both hepatic and/or renal vessels. Upper segment tumours can cause Budd-Chiari syndrome (hepatomegaly, abdominal pain, jaundice and ascites) with a bad prognosis. Middle segment tumours usually present with right upper quadrant pain, or may mimic biliary tract disease with a much better prognosis. Accumulating experience suggests that radio-chemotherapy alone seems to be less effective than "en bloc" resection with clear margins including loco-regional lymph nodes. Therefore, our choice of treatment was the latter. Although radical resection can be carried out in most of cases, 50% of patients develop a late recurrence yet.
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Leiomiosarcoma/diagnóstico , Leiomiosarcoma/terapia , Recurrencia Local de Neoplasia/cirugía , Neoplasias Retroperitoneales/diagnóstico , Neoplasias Retroperitoneales/terapia , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/terapia , Vena Cava Inferior , Adulto , Femenino , Humanos , Leiomiosarcoma/patología , Leiomiosarcoma/cirugía , Escisión del Ganglio Linfático , Pronóstico , Reoperación , Neoplasias Retroperitoneales/patología , Neoplasias Retroperitoneales/cirugía , Neoplasias Vasculares/patología , Neoplasias Vasculares/cirugía , Vena Cava Inferior/patología , Vena Cava Inferior/cirugíaRESUMEN
Calbindin (CB) is a calcium-binding protein that is present in principal cells as well as in interneurons of the hippocampal formation of various species including humans. Studies with transgenic mice revealed that CB is essential for long-term potentiation and synaptic plasticity which are the cellular basis of learning and memory. In a previous study we have shown that CB expression in granule cells of the dentate gyrus correlates with the functional maturation of the hippocampal formation in the rat. In the present study we examined the ontogeny of CB using immunohistochemistry in the human hippocampal formation paying special attention to the granule cells of the dentate gyrus. As early as the 14(th) week of gestation (GW), CB was being expressed by pyramidal cells of CA1-3 regions in the deepest cell rows of the pyramidal layer towards the ventricular zone. Later, CB sequentially appears in more superficial cell rows. After midgestation, CB disappears from CA3 pyramidal neurons. Expression of CB by granule cells starts at the 22(nd)-23(rd) GW, first by the most superficial neurons of the ectal end of the dorsal blade. At the 24(th) GW, CB is expressed by granule cells of the crest and medial portion of the ventral blade whereas later the entire ventral blade revealed CB immunoreactivity. At term, and in the first few postnatal months, CB-immunoreaction is detected in granule cells of both blades except for those neurons in the deepest cell rows at the hilar border. At around 2-3 years of age, all granule cells of the entire cell layer are CB-immunoreactive. Axons of granule cells, the mossy fibers, start to express CB around the 30(th) GW in stratum lucidum of CA3a. With further development, CB is expressed in CA3b and c, as well as in the hilus. An adult-like pattern of CB-immunoreactivity could be observed at 11 years of age. Our results indicate that (i) CB is expressed by hippocampal pyramidal cells a few weeks before midgestation; (ii) similarly to rodents, migration of postmitotic human hippocampal pyramidal cells follows the inside-out gradient; (iii) CB was expressed transiently in pyramidal cells of the CA3 area of the human hippocampus; (iv) granule cells of the dentate gyrus start to express CB as early as midgestation; (v) maturation and migration of human granule cells follow the outside-in migrational gradient described in rodents and non-human primates; (vi) CB-immunoreactivity in the axon terminals of granule cells could be observed a few weeks before birth with a long-lasting increase in staining intensity postnatally; (vii) the maturation pattern of the CB-positive mossy fiber system suggests that the development of connectivity and the mature topographical termination pattern between dentate gyrus and the CA3 area of Ammon's horn in humans resembles that previously described for rodents; (viii) the dorsal-ventral delay in development may explain the topography of neuropathologic alterations of the granule cell layer found in temporal lobe epilepsy related to febrile seizures.
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Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Axones/metabolismo , Calbindinas , Movimiento Celular , Niño , Preescolar , Giro Dentado/citología , Giro Dentado/embriología , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , Femenino , Hipocampo/embriología , Humanos , Inmunohistoquímica , Lactante , Recién Nacido , Masculino , Neuronas/metabolismo , Fotomicrografía , Células Piramidales/metabolismo , Sinaptofisina/metabolismoRESUMEN
We investigated the response rate and side effects of simultaneous, neoadjuvant radiochemotherapy (RCT) in locally advanced rectal cancer. Between 2005 and 2007, we treated 112 patients in stage II-III rectal carcinoma at the Institute of Oncotherapy, University of Pécs. For staging abdomino-pelvic CT (112) and transrectal US (49) or pelvic MR (10), or PET-CT (1) was performed. Radiation therapy was delivered with 3D CRT-based technique using belly-board with 18 MV photon energy, while patients in prone position. A total dose of 45 Gy (single dose 1.8 Gy) was delivered to the tumor and the pelvic lymph nodes. 5-FU and Ca-folinate was administered concomitantly in the 1st and 5th week of radiotherapy. Four weeks after delivering neoadjuvant RCT the patients' control CT was evaluated according to RECIST criteria. RCT was followed by surgery in 6-9 weeks. We graded the histology using the Mandard regression score system. Side effects were registered using CTCAE v 3.0. Grade 1, 2 or 3 acute gastrointestinal toxicity occurred in 12%, grade 3 hematological toxicity in 9.5% of the patients. The response rate determined by using control CT was 64.85%. According to the Mandard regression score, TRG1 occurred in 15%, TRG2 in 30.4%, TRG3 in 28%, TRG4 in 24% and TRG5 in 2.6% of the cases. Radical surgery was performed in 89 cases, 72 with R0 resection. By assessing the histological samples we found downstaging in 46% of the T and 34.5% of the N stage. We have no information on increased postoperative complications. We followed 86 patients after neoadjuvant therapy. Until March 2009 there was no progression in 48 of our patients. In 13 cases local relapse occurred, and in 25 cases the disease progressed because of distant metastasis, although local control was maintained. 10 patients had local relapse and distant metastases. 17 patients passed away. As a conclusion, neoadjuvant RCT of Stage II-III patients is an effective and well tolerated treatment, allowing for high R0 resection rate and bearing no higher risk for postoperative morbidity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante/métodos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante/efectos adversos , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Radioterapia Adyuvante/efectos adversos , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
The anti-tumor response of human invariant NKT (NKT) cells is well established. A novel T cell subset, mucosal-associated invariant T (MAIT) cells, possesses similar regulatory properties to NKT cells in autoimmune models and disease. Here, we examined the clonality of four T cell subsets expressing invariant alphaTCR, including Valpha7.2-Jalpha33 of MAIT cells, in 19 kidney and brain tumors. The MAIT clonotype was identified and co-expressed with NKT clonotype in half of the tumors. In contrast, two other invariant T cell clonotypes (Valpha4 and Valpha19) were not present in tumors. Such tumors also expressed Vbeta2 and Vbeta13, the restricted TCRbeta chain of MAIT cells and the antigen-presenting molecule MR1. A high percentage of infiltrating T cells was CD8+ and expressed HLA-DR suggesting activation. Although the MAIT alphaTCR was identified in both peripheral CD56+ and CD56- subsets, infiltrating lymphocytes were CD56 negative. The clonal presence of MAIT cells in tumors correlated with the expression of pro-inflammatory cytokines but no IL-4, IL-5 and IL-10, suggesting that a pro-inflammatory subset of human MAIT cells may exist. Our data imply that a CD56- subset of MAIT cells may participate in tumor immune responses similarly to NKT cells.
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Neoplasias Encefálicas/metabolismo , Carcinoma de Células Renales/metabolismo , Glioblastoma/metabolismo , Neoplasias Renales/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Células T Asesinas Naturales/metabolismo , Subgrupos de Linfocitos T/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Antígeno CD56/biosíntesis , Antígeno CD56/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Separación Celular , Citocinas/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T/inmunología , Glioblastoma/genética , Glioblastoma/patología , Antígenos HLA-DR/biosíntesis , Antígenos HLA-DR/genética , Humanos , Inmunidad Mucosa , Inmunohistoquímica , Neoplasias Renales/genética , Neoplasias Renales/patología , Activación de Linfocitos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patología , Meningioma/genética , Meningioma/patología , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
BACKGROUND: Small heat shock proteins are molecular chaperones that protect proteins against stress-induced aggregation. They have also been found to have anti-apoptotic activity and to play a part in the development of tumors. Recently, we identified a new small heat shock protein, Hsp16.2 which displayed increased expression in neuroectodermal tumors. Our aim was to investigate the expression of Hsp16.2 in different types of brain tumors and to correlate its expression with the histological grade of the tumor. METHODS: Immunohistochemistry with a polyclonal antibody to Hsp16.2 was carried out on formalin-fixed, paraffin-wax-embedded sections using the streptavidin-biotin method. 91 samples were examined and their histological grade was defined. According to the intensity of Hsp16.2 immunoreactivity, low (+), moderate (++), high (+++) or none (-) scores were given. Immunoblotting was carried out on 30 samples of brain tumors using SDS-polyacrylamide gel electrophoresis and Western-blotting. RESULTS: Low grade (grades 1-2) brain tumors displayed low cytoplasmic Hsp16.2 immunoreactivity, grade 3 tumors showed moderate cytoplasmic staining, while high grade (grade 4) tumors exhibited intensive cytoplasmic Hsp16.2 staining. Immunoblotting supported the above mentioned results. Normal brain tissue acted as a negative control for the experiment, since the cytoplasm did not stain for Hsp16.2. There was a positive correlation between the level of Hsp16.2 expression and the level of anaplasia in different malignant tissue samples. CONCLUSION: Hsp16.2 expression was directly correlated with the histological grade of brain tumors, therefore Hsp16.2 may have relevance as becoming a possible tumor marker.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Citoplasma/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Proteínas de Choque Térmico Pequeñas/biosíntesis , Proteínas de Choque Térmico Pequeñas/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Citoplasma/genética , Proteínas de Choque Térmico Pequeñas/fisiología , Humanos , Péptidos y Proteínas de Señalización IntracelularRESUMEN
The development of cerebral cortex includes highly organized, elaborate and long-lasting series of events, which do not come to an end by the time of birth. Indeed, many developmental events continue after the 40th postconceptual week resulting in a long morphological, behavioral and cognitive development of children. Premature birth causes an untimely dramatic change in the environment of the human fetus and often results in serious threats for life. Cognitive abilities of prematurely born children vary, but a correlation between cognitive impairment and the time of birth is evident. In this study we review the morphological evidence of cortical maturation in preterm and full-term infants. Various aspects of postnatal cortical development including cell proliferation and maturation of neurons in the temporal archi- and neocortex are discussed and compared in preterm infants and age-matched full-term controls. Our results suggest that cell proliferation and maturation are not influenced by the preterm delivery. In contrast, the perinatal decrease of the number of Cajal-Retzius cells might be regulated by a mechanism that is affected by preterm birth. We demonstrate that cognitive deficiencies of the prematurely born infants cannot be explained with light microscopically observed alteration of proliferation and maturation of neurons.
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Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Diferenciación Celular/fisiología , Proliferación Celular , Neuronas/fisiología , Nacimiento Prematuro/patología , Ácido Aminosalicílico/metabolismo , Bromodesoxiuridina/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Antígeno Ki-67/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Cambios Post MortemRESUMEN
Progressive multifocal leukoencephalopathy is a rare disease caused by the reactivation of an opportunistic agent, JC virus almost in every cases in immunodeficient conditions. The disease is characterized by multifocal demyelinating lesions of the central nervous system and causes death within a few months. The authors report two patients: a 67 year-old male treated because of chronic lymphoid leukemia, and a 19 year-old male having a hereditary immunodeficiency, X-linked hyper IgM syndrome. In both cases continuously progressive right, later both hemispheric signs were detected. Cerebrospinal fluid was not helpful. Brain MRI showed bilateral large, white matter lesion. The progression was not influenced by the treatment, finally both patient died ten and six weeks after the appearance of first complaints. The diagnosis was confirmed by brain biopsy and autopsy in both cases. Our cases demonstrate that progressive multifocal leukoencephalopathy can develop in various immunodeficiencies.
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Encéfalo/patología , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Leucoencefalopatía Multifocal Progresiva/etiología , Adulto , Anciano , Antivirales/uso terapéutico , Encéfalo/virología , Quimioterapia Combinada , Resultado Fatal , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Leucoencefalopatía Multifocal Progresiva/inmunología , Leucoencefalopatía Multifocal Progresiva/patología , Leucoencefalopatía Multifocal Progresiva/virología , Masculino , Infecciones por Polyomavirus/complicaciones , Infecciones Tumorales por Virus/complicacionesRESUMEN
Gliomas (GLs) are characterized by highly variable biologic behavior. After surgical resection and postoperative therapy, they frequently recur with the same or higher-grade histology. Although a number of genetic aberrations have been described in different histologic types of GLs, the molecular mechanisms of histologic and clinical progression are poorly understood. In this study, we have performed longitudinal mismatch repair gene polymerase chain reaction-single strand conformation polymorphism and methylation analysis in paired samples of primary and recurrent GLs to reveal whether the inactivation of the normal DNA repair mechanism is associated with tumor progression. Polymerase chain reaction-single strand conformation polymorphism analysis of the hMLH1 gene was performed in 24 cases, in each case the samples of the first and second biopsies being evaluated simultaneously, but no alterations in the hMLH1 gene were found. Methylation analysis of the CpG sites in the hMLH1 promoter revealed a total of 4 (16.6%) hypermethylations in recurrent GLs. These results suggest that hMLH1 promoter hypermethylation may occur in low-grade GLs, associated with the development and progression of moderate malignant GL, but not with structural alterations in the hMLH1 gene. It seems that hMLH1 promoter hypermethylation is an early event in the development and progression or the clonal evolution of GLs, this gene inactivation proving stable even on tumor recurrence.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Encefálicas/genética , Epigénesis Genética , Silenciador del Gen , Glioma/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Niño , Terapia Combinada , Metilación de ADN , ADN de Neoplasias/análisis , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Glioma/mortalidad , Glioma/patología , Glioma/terapia , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Recurrencia Local de Neoplasia , Proteínas Nucleares/metabolismo , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Tasa de SupervivenciaRESUMEN
NCBI database analysis indicated that the human C1orf41 protein (small heat shock-like protein-Hsp16.2) has sequence similarity with small heat shock proteins (sHsps). Since sHsps have chaperone function, and so prevent aggregation of denatured proteins, we determined whether Hsp16.2 could prevent the heat-induced aggregation of denatured proteins. Under our experimental conditions, recombinant Hsp16.2 prevented aggregation of aldolase and glyceraldehyde-3-phosphate dehydrogenase, and protected Escherichia coli cells from heat stress indicating its chaperone function. Hsp16.2 also formed oligomeric complexes in aqueous solution. Hsp16.2 was found to be expressed at different levels in cell lines and tissues, and was mainly localized to the nucleus and the cytosol, but to a smaller extent, it could be also found in mitochondria. Hsp16.2 could be modified covalently by poly(ADP ribosylation) and acetylation. Hsp16.2 over-expression prevented etoposide-induced cell death as well as the release of mitochondrial cytochrome c and caspase activation. These data suggest that Hsp16.2 can prevent the destabilization of mitochondrial membrane systems and could represent a suitable target for modulating cell death pathways.
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Apoptosis , Proteínas de Choque Térmico Pequeñas/metabolismo , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Citocromos c/metabolismo , Activación Enzimática/efectos de los fármacos , Etopósido/farmacología , Expresión Génica/efectos de los fármacos , Genoma Humano/efectos de los fármacos , Genoma Humano/genética , Células HeLa , Proteínas de Choque Térmico Pequeñas/química , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Estructura Cuaternaria de Proteína/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Alineación de Secuencia , Homología de Secuencia , TemperaturaRESUMEN
OBJECTIVE: To report an exceptional association between X-linked hyper-IgM syndrome and progressive multifocal leukoencephalopathy. DESIGN: Clinical, immunological, and histological analysis. Patient A 19-year-old male patient with X-linked hyper-IgM syndrome developed typical signs and symptoms of progressive multifocal leukoencephalopathy. RESULTS: The serum level of IgA was decreased; the serum level of IgM was slightly increased; and the serum level of IgG was normal as a result of monthly infusions of immunoglobulin. The expression of CD40 ligand on T cells was markedly reduced in the patient. Magnetic resonance imaging indicated confluent lesions involving the majority of the right hemisphere with a mass effect. The patient died after 6 weeks despite combined antiviral treatment. CONCLUSION: Progressive multifocal leukoencephalopathy may follow a rapid course in patients with X-linked hyper-IgM syndrome because of global defects of cellular and B cell responses.
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Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/complicaciones , Leucoencefalopatía Multifocal Progresiva/complicaciones , Adulto , Antígenos CD40/metabolismo , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/inmunología , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/patología , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/terapia , Inmunoglobulinas/administración & dosificación , Leucoencefalopatía Multifocal Progresiva/inmunología , Leucoencefalopatía Multifocal Progresiva/patología , Leucoencefalopatía Multifocal Progresiva/terapia , Imagen por Resonancia Magnética , MasculinoRESUMEN
AlphaB-crystallin homology, heat stress induction and chaperone activity suggested that a previously encloned gene product is a novel small heat shock protein (Hsp16.2). Suppression of Hsp16.2 by siRNA sensitized cells to hydrogen peroxide or taxol induced cell-death. Over-expressing of Hsp16.2 protected cells against stress stimuli by inhibiting cytochrome c release from the mitochondria, nuclear translocation of AIF and endonuclease G, and caspase 3 activation. Recombinant Hsp16.2 protected mitochondrial membrane potential against calcium induced collapse in vitro indicating that Hsp16.2 stabilizes mitochondrial membrane systems. Hsp16.2 formed self-aggregates and bound to Hsp90. Inhibition of Hsp90 by geldanamycin diminished the cytoprotective effect of Hsp16.2 indicating that this effect was Hsp90-mediated. Hsp16.2 over-expression increased lipid rafts formation as demonstrated by increased cell surface labeling with fluorescent cholera toxin B, and increased Akt phosphorylation. The inhibition of PI-3-kinase-Akt pathway by LY-294002 or wortmannin significantly decreased the protective effect of the Hsp16.2. These data indicate that the over-expression of Hsp16.2 inhibits cell death via the stabilization of mitochondrial membrane system, activation of Hsp90, stabilization of lipid rafts and by the activation of PI-3-kinase-Akt cytoprotective pathway.