Biomarkers of resistance to radiation therapy: a prospective study in cervical carcinoma.

BACKGROUND: Clinical parameters and proteins have recently been suggested as possible causes of radiotherapy (RT) resistance in cervical carcinoma (CC). The objective of the present study was to validate prognostic biomarkers of radiation resistance. METHODS: The present prospective study included patients undergoing RT with curative intent for histologically proven locally advanced squamous cell CC. Tissues and blood samples were systematically collected before RT initiation. Immuno-histochemistry was performed (IGF-IR α and ß, GAPDH, HIF-1 alpha, Survivin, GLUT1, CAIX, hTERT and HKII). Response to radiation was assessed through tumour response 3 months after RT completion, through overall survival (OS) and through progression-free survival (PFS). RESULTS: One hundred forty nine patients with a mean age of 46 years were included, with FIGO IIB (n = 53) and FIGO IIIB (n = 96) CCs. 61 patients were treated with exclusive RT + brachytherapy and 88 underwent chemo-radiotherapy + brachytherapy. Our findings suggest an association between hemoglobin level (Hb) (>11 g/dL) and 3 months complete response (p = 0.02). Hb level < 11 g/dL was associated with decreased PFS (p = 0.05) and OS (p = 0.08). Overexpression of IGF-1R ß was correlated with a decreased OS (p = 0.007). Overexpression of GLUT1 was marginally correlated with reduced OS (p = 0.05). PFS and OS were significantly improved in patients undergoing chemoradiation versus exclusive radiotherapy (PFS: p = 0.04; OS: p = 0.01). CONCLUSIONS: IGF-1R ß overexpression and Hb level (≤11 g/dl) were associated with poor prognosis, and thus appear to be possible interesting biomarkers of radiation resistance. Our results corroborate previous pre-clinical studies suggesting IGF-1R and hypoxia to be part of the biological pathways leading to radio-resistance.

HPV-16 variants' impact on uterine cervical cancer response to radiotherapy: A descriptive pilot study.

PURPOSE: Although the large impact of Human papilloma virus (HPV) in cervical cancer is established, its place as a therapeutic target is new and according to the growing literature, could be promising. In the present study, radiosensitivity's difference based on HPV-16 variants is assessed. PATIENTS AND METHODS: Variants of Human papilloma virus were identified before the exclusive radiotherapy in patients with cervical cancer. Data were prospectively collected. Fifty-nine patients were screened. RESULTS: Among the 59 screened patients, 34 (57.6%) were identified to be HPV-16 (+), with 13 European and two non-European variants. Of the 34 patients, 15 experienced exclusive radiotherapy. Among them, eight had complete response (seven with European and one with non-European variants), four with European variant had partial response, three with European variant had tumour persistence and one with non-European variant progressed at 3 months. CONCLUSION: No radiosensitivity difference was established, probably because of the limited population. Non-European variant aggressiveness might be suggested in accordance with the literature, as it was associated with the only tumour progression. Exclusive radiotherapy provides a unique and "pure" model of radioresistance in cervical cancer and could be the missing link between in vitro studies and state of the art chemoradiotherapy studies that probably feature too many parameters to identify radioresistance causes. The present study was a first step, with the future prospects of building a larger cohort study in order to better understand HPV-induced radioresistance and then to be able to propose new made-to-measure treatments.

[Malignant peripheric nerve sheath tumor of the orbit: first description of orbital location in a patient with NF1]. / Tumor maligno de la vaina del nervio periférico (MPNST) glandular de la órbita: primera descripción de la literatura de localización orbitaria en un paciente con neurofibromatosis tipo 1.

INTRODUCTION: The malignant peripheric nerve sheath tumor (MPNST), is a malignant neoplastic lesion originated in Schwann cells of the lining sheath of peripheral nerves. This neoplasia may appear with benign or malignant heterologous components, with divergent differentiation, as the glandular one. AIM: To describe for the first time in the literature, a case of a glandular MPNST, located at the orbit and to revise the literature on this tumoral lesion. CLINICAL CASE: Nine year old male, with a base diagnosis of NF1, who had exophthalmos, retro-ocular pain, headache, facial asymmetry and descent of the right eyeball, that started 1 year earlier. This patient showed in the Computed Tomography an Magnetic Resonance, a well delimited, lobulated, solid mass at the eyeball, which extended to the fontal and temporal brain parenchyma. A right Fronto-temporal craniotomy was made with fronto -orbital- zygomatic resection of the tumoral lesion. Later, a dural plasty and reconstruction with titanium mesh was made at the skull base. At present, the patient is asymptomatic after 4 months of follow up. A malignant biphasic neoplastic lesion was observed, reactive in the mesenchymal elements S100, PGP 9.5, neurofilaments and vimentin. The glandular component was positive for AE1/AE3, EMA, CEA and focally for CD57. There was also reactivity to cromogranin, synaptophysin, serotonin and somatostatin. The diagnosis of Glandular MPNST was made. CONCLUSION: For the first time in the literature a case of Glandular MPNST located at the orbit, which occurred in child with NF1, is described. This extremely uncommon neoplasia must be taken into account, in the study of biphasic malignant lesions, as its diagnosis is of great importance because of the bad prognosis of the affected patients.

Tumor maligno de la vaina del nervio periférico (MPNST) glandular de la órbita: primera descripción de la literatura de localización orbitaria en un paciente conneurofibromatosis tipo 1 / Malignant peripheric nerve sheath tumor of the orbit: First description of orbital location in a patient with NF1

Introducción. El tumor maligno de la vaina delnervio periférico (MPNST, por sus siglas en inglesMalignant Peripheral Sheath Tumor), es una neoplasiamaligna originada en las células de Schwann de la vainade revestimiento de los nervios periféricos. Esta neoplasiapuede presentar componentes heterólogos benignoso malignos, con diferenciación divergente, como la diferenciaciónglandular.Objetivo. Describir el primer caso en la literatura deMPNST glandular maligno localizado a nivel orbitarioy realizar una revisión sobre esta neoplasia.Caso clínico. Niño de 9 años de edad, con diagnosticode NF1, quien presentó exoftalmos ocular, dolorretro-ocular, cefalea, asimetría facial y descenso delglobo ocular derecho de 1 año de evolución; a quien sedocumento masa sólida orbitaria, delimitada, lobulada,que se proyecta al parénquima cerebral frontal y temporalen los estudios de tomografía computarizada yresonancia magnética. La lesión se abordó en formafronto-orbito-cigomática con resección completa de lamisma. Posteriormente, se hizo una plastia dural enbase de cráneo y reconstrucción con malla de titanio.Actualmente el paciente se encuentra asintomáticodespués de 6 meses de tratamiento. En el estudioanatomopatológico se observó una neoplasia malignabifásica, reactiva en los elementos mesenquimales paraS100, PGP 9.5, neurofilamentos y vimentina. El componenteglandular fue positivo para AE1/AE3, EMA, CEAy focalmente para CD57. Se observó además reactividadpara cromogranina, sinaptofisina, serotonina y somatostatina.Se realizo el diagnostico de MPNST glandularde la órbita (AU)

Introduction. The malignant peripheric nerve sheathtumor (MPNST), is a malignant neoplastic lesion originatedin Schwann cells of the lining sheath of peripheralnerves. This neoplasia may appear with benignor malignant heterologous components, with divergentdifferentiation, as the glandular one.Aim. To describe for the first time in the literature, acase of a glandular MPNST, located at the orbit and torevise the literature on this tumoral lesion.Clinical case. Nine year old male, with a base diagnosisof NF1, who had exophthalmos, retro-ocular pain,headache, facial asymmetry and descent of the righteyeball, that started 1 year earlier. This patient showedin the Computed Tomography an Magnetic Resonance,a well delimited, lobulated, solid mass at the eyeball,which extended to the fontal and temporal brain parenchyma.A right Fronto-temporal craniotomy was madewith fronto -orbital- zygomatic resection of the tumorallesion. Later, a dural plasty and reconstruction withtitanium mesh was made at the skull base. At present,the patient is asymptomatic after 4 months of follow up.A malignant biphasic neoplastic lesion was observed,reactive in the mesenchymal elements S100, PGP 9.5,neurofilaments and vimentin. The glandular componentwas positive for AE1/AE3, EMA, CEA and focallyfor CD57. There was also reactivity to cromogranin,synaptophysin, serotonin and somatostatin. The diagnosisof Glandular MPNST was made (AU)

Immunomodulatory properties of Mycoplasma pulmonis. I. Characterization of the immunomodulatory activity.

For many years, it has been recognized that Mycoplasma infection affects the host's immune system in different ways. In this work, experiments were performed to characterize the influence of Mycoplasma pulmonis infection on various immunological parameters and to follow the kinetics of their variations. A Balb/c mouse model was used to assess hematological evaluations, changes in spleen weight, antibody responses against sheep erythrocytes, neutrophil phagocytosis, colloidal carbon clearance, and anti-Mycoplasma antibody responses. At the hematological level, infected animals were found to have significantly increased total lymphocyte and polymorphonuclear leukocyte counts and an augmentation in spleen weight. Seven days after Mycoplasma infection, antibody responses against sheep erythrocytes were considerably diminished, and at days 7 and 14 after infection, phagocytic activity was also reduced. After 1 week of infection, the colloidal carbon clearance pattern was decreased, and during the whole infectious process, anti-Mycoplasma antibody titers were found to be low. Results from this part of research show a persistent infection that does not resolve in a short period, which is associated with a general dysfunction in the immune system and poor immune responses against several different antigens.

Immunomodulatory properties of Mycoplasma pulmonis. II. Studies on the mechanisms of immunomodulation.

Mycoplasma infection affects the host's immune system in different ways. In this work, a kinetic approach was used to try to determine the mechanisms by which Mycoplasma cause these effects. Experiments were performed using Balb/c mice infected with Mycoplasma pulmonis and several immunological parameters were determined. It was found that at days 10 and 15 post-infection, there were significant changes in the percentages of CD4+ and CD8 + cells, in both peripheral blood and the thymus. Significant sequential increases in concentrations of both IFN-gamma and IL-4 were detected in sera, such that at day 15, there was a peak in IFN-gamma, concentration and at day 38, IL-4 concentration also peaked. By day 46, both IFN-gamma and IL-4 fell to control levels despite continued infection. Delayed hypersensitivity (DTH) was reduced in infected animals compared to non-infected controls. A small recovery in DTH was observed at day 30, which was reduced again by day 40. Altogether, the results show features of a transitional shift from Th1 to Th2 in animals that are ultimately immunologically incompetent (in both cellular and humoral immunity). It appears to be this state of incompetence that allows the microorganism to survive and thus provides an explanation for the chronic state of the disease, which is a characteristic of Mycoplasma infection.

Immunomodulatory properties of Mycoplasma pulmonis. III. Lymphocyte stimulation and cytokine production by Mycoplasma pulmonis products.

Experiments are presented that were performed in order to understand the mechanisms causing these effects on the immune system. Mitogenic effects of Mycoplasma membranes on mouse spleen cells were shown using M. capricolum. The observed mitogenic activity is proportional to the amount of membranes used, as measured by protein content. Separation of T and B cells was performed by two techniques, the anti-Thyl.2 plus complement method and the Dynabead technique. Using the former technique, it was shown that removal of T cells markedly reduced effects of stimulation by mycoplasma membranes, but did not abolish it. The separated cells were still stimulated by PHA, indicating that the preparation still contained T cells. Furthermore, removal of T cells preferentially reduced the PHA response over that of mycoplasma membranes, indicating that mycoplasma membranes stimulate both B and T lymphocytes. The Dynabead system was found to be the more efficient separation technique, and by using it we were able to make the following observations. Inactivated Mp, membranes and culture supernatant stimulated B cells, whereas T cells were only slightly stimulated by inactivated Mp and membranes. There was an increase in proliferation when T cells were incubated with adherent cells from peripheral blood. Finally, we showed that spleen cells from infected animals produce more IL-4 and less IFN-gamma than cells from non-infected animals when stimulated with membranes, inactivated Mp, culture supernatant or phytohemagglutinin. Altogether, these results show that lymphocytes from Mycoplasma-infected animals are directly affected and this effect is probably due to superantigen-like molecules from M. pulmonis.