Biomodulina T partially restores immunosenescent CD4 and CD8 T cell compartments in the elderly.

The changes that occur in the immune system with aging are commonly termed immunosenescence. Immunosenescence affects almost all components and functions of the immune response. The most commonly described change is a decrease in numbers and proportions of naïve T cells combined with the increase of terminally differentiated T lymphocytes, mainly affecting CD8+ T cells. The changes in the naïve T cell compartment are principally attributed to thymic involution and lifelong chronic antigen stimulation, among other triggers. Several strategies such as hormonal products, thymic peptides, or cytokines have been proposed for the restoration of the immune system. Here we show the effects of Biomodulina T (BT) on several populations of the immune system when administered to elderly patients diagnosed with recurrent respiratory infections. BT is a polypeptide fraction of bovine thymus, a Cuban product that obtained sanitary registration in 1994 for its immunomodulatory effects. We found that CD4+ naïve T, CD8+ stem cell-like memory (SCM) T, CD4+ recent thymic emigrants (RTE) T and CD4+ CD31+ naïve T cells increased with the administration of BT, whereas CD4+ and CD8+ T cells expressing PD1 decreased after the treatment with BT. Additionally, the proliferative capacity of CD4+ T cells measured by Ki67 expression, and the CD4+ T cell ability to produce IFN-γ were also improved by BT. Moreover, BT did not increase CD4+ Tregs. Altogether, these findings suggest that BT administration is a promising strategy for immune restoration in elderly patients and improvement of immunotherapeutic potential in cancer patients.

Interim FDG PET/CT as a prognostic factor in diffuse large B-cell lymphoma.

PURPOSE: Interim (18)F-FDG PET performed early during the course of therapy in diffuse large B-cell lymphoma (DLBCL) is a good predictor of outcome. However, interpretation criteria for interim PET for the evaluation of tumour response are still not clearly defined. The study aim was to assess whether interim PET can predict overall survival (OS) and progression-free survival (PFS) in DLBCL patients following three different sets of parameters, two qualitative (visual) methods and one semiquantitative. METHODS: A total of 50 newly diagnosed DLBCL patients were prospectively enrolled in this study. All patients had a PET/CT scan at diagnosis and an interim PET/CT scan after the second or third cycle of chemotherapy. Three methods of evaluation for the interim PET/CT were used: a qualitative three-point scoring (3-PS) method, a qualitative 5-PS method and a semiquantitative method (ΔSUVmax). The degree of correlation between therapy response seen on FDG PET and PFS and OS was determined. RESULTS: The analysis of the visual 3-PS method showed no statistically significant difference in PFS and OS. The estimated 5-year PFS and OS were 79 % and 92 %, respectively, in patients with an interim PET scan showing uptake not greater than in the liver versus 50 % in patients with uptake greater than in the liver, and this difference was statistically significant. The optimal cut-off value of ΔSUVmax that could predict the PFS and OS difference in patients with DLBCL was 76 % (95 % CI 62.7-89.2 %) and 75 % (95 % CI, 54.6-95.4 %), respectively. CONCLUSION: Our results support the use of liver uptake as an indicator in the qualitative evaluation of interim PET, or a ΔSUVmax greater than 75 % in semiquantitative analysis. Interim PET may predict PFS and OS and could be considered in the prognostic evaluation of DLBCL.

Protease-activated receptor 2 signalling promotes dendritic cell antigen transport and T-cell activation in vivo.

Deficiency of protease-activated receptor-2 (PAR2) modulates inflammation in several models of inflammatory and autoimmune disease, although the underlying mechanism(s) are not understood. PAR2 is expressed on endothelial and immune cells, and is implicated in dendritic cell (DC) differentiation. We investigated in vivo the impact of PAR2 activation on DCs and T cells in PAR2 wild-type (WT) and knockout (KO) mice using a specific PAR2 agonist peptide (AP2). PAR2 activation significantly increased the frequency of mature CD11c(high) DCs in draining lymph nodes 24 hr after AP2 administration. Furthermore, these DCs exhibited increased expression of major histocompatibility complex (MHC) class II and CD86. A significant increase in activated (CD44(+) CD62(-)) CD4(+) and CD8(+) T-cell frequencies was also observed in draining lymph nodes 48 hr after AP2 injection. No detectable change in DC or T-cell activation profiles was observed in the spleen. The influence of PAR2 signalling on antigen transport to draining lymph nodes was assessed in the context of delayed-type hypersensitivity. PAR2 WT mice that were sensitized by skin-painting with fluorescein isothiocyanate (FITC) to induce delayed-type hypersensitivity possessed elevated proportion of FITC(+) DCs in draining lymph nodes 24 hr after FITC painting when compared with PAR2 KO mice (0.95% versus 0.47% of total lymph node cells). Collectively, these results demonstrate that PAR2 signalling promotes DC trafficking to the lymph nodes and subsequent T-cell activation, and thus provides an explanation for the pro-inflammatory effect of PAR2 in animal models of inflammation.

Left ventricular function and visual phase analysis with equilibrium radionuclide angiography in patients with biventricular device.

PURPOSE: Cardiac resynchronisation therapy (CRT) is a technique indicated in patients with moderate to severe heart failure and ventricular dyssynchrony. To evaluate left ventricular ejection fraction (LVEF) and synchronisation changes after CRT with a biventricular pacing implant, we used an equilibrium radionuclide angiography (ERNA). METHODS: Fifty patients were studied. An ERNA was made 72 h and 6 months after the implant. Two acquisitions were performed: with the CRT device connected and after disconnecting it. In the follow-up, responders were defined as those who had improved in accordance with various clinical variables. Quantitative changes in LVEF and visual changes in synchronisation (phase analysis) were studied comparing the two studies and also comparing the connected and disconnected modes. RESULTS: At 6 months, 30 patients were defined as responders. LVEF increased significantly at 6 months compared with the 72-h study only in responders. At 72 h, the number of patients showing a decrease in LVEF (p < 0.05) or a synchronisation worsening after disconnecting the device was higher in responders than in nonresponders. At 6 months, 57% of responders had no synchronisation changes between the connected and disconnected modes, suggesting a resynchronisation process. CONCLUSIONS: ERNA permits the study of resynchronisation patients, showing a statistical LVEF improvement at 6 months. Moreover, visual phase analysis permits the study of the mechanism involved in the response, with an important number of responders with no changes between the two modes at 6 months. In the 72-h study, after disconnection of the device, LVEF and resynchronisation worsening can predict patient improvement at 6 months.

[The value of positron emission tomography/computed tomography (PET/CT) in the staging of diffuse large B-cell lymphoma]. / Utilidad de la tomografía por emisión de positrones/ tomografía computarizada (PET/TC) en el estudio de extensión en pacientes con linfoma B difuso de células grandes.

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the role of positron emission tomography/computed tomography (PET/CT) in improving the staging and changing the management of aggressive lymphoma patients in comparison with the conventional imaging modalities (CT, and 67Ga scintigraphy). PATIENTS AND METHOD: Forty consecutive patients with diffuse large B-cell non Hodgkin lymphoma, were prospectively evaluated. All 40 patients underwent a whole body FDG PET/CT and conventional staging techniques (chest and abdomen CT, 67Ga scintigraphy) were studied before therapy. Sixty minutes after the intravenous administration of 370 MBq FDG, a whole body PET/CT was acquired. We hypothesize that PET/CT improves the diagnostic staging of lymphoma and changes the clinical management of patients. RESULTS: PET/CT and CT were concordant in 28 patients (65%). However, PET/CT detected more lesions than CT in 11 patients (27.5%). Only in one patient, CT revealed more extensive disease than PET/CT. Additional information of PET/CT had lead to a change in staging (upstaging) in 6 patients (15%), in turn leading to a change in treatment strategy in 1 patient. PET/CT and 67Ga scintigraphy were concordant in 23 patients (60.5%). PET/CT detected more lesions than 67Ga scintigraphy in 14 patients (42%). PET/CT results changed staging (upstaging) in 4 patients (15%), leading to a change of treatment strategy in one patient. CONCLUSIONS: The impression is that PET/CT detected more lesions than conventional examination, but this rarely translates into changes of staging and treatment strategy in aggressive lymphoma.

Utilidad de la tomografía por emisión de positrones/ tomografía computarizada (PET/TC) en el estudio de extensión en pacientes con linfoma B difuso de células grandes / The value of positron emission tomography/computed tomography (PET/CT) in the staging of diffuse large B-cell lymphoma

Fundamento y objetivo: El objetivo de este trabajo es comparar el rendimiento diagnóstico y el impacto terapéutico de los equipos integrados de tomografía por emisión de positrones/tomografía computarizada (PET/TC) respecto a las exploraciones convencionales (TC y gammagrafía con galio-67 [67Ga]), en el estudio de extensión de los pacientes con linfoma B difuso de células grandes (LDCG-B). Pacientes y método: Se trata de un estudio prospectivo de 40 pacientes con LDCG-B. En el estudio de extensión se realizaron las exploraciones convencionales y la PET/TC. La adquisición de las imágenes de la PET/TC se efectuó tras la inyección intravenosa de 370 MBq de flúor-18 desoxiglucosa (18F-FDG). Se consideró área afectada la existencia de un único o varios ganglios hipercaptantes en la gammagrafía con 67Ga o en la PET/TC. Se calculó el porcentaje de pacientes en los que la PET/TC cambió el estadio y el manejo terapéutico. Resultados: La PET/TC mostró en 11/40 pacientes un mayor número de áreas afectadas respecto a la TC y en 14/38 pacientes respecto a la gammagrafía con 67Ga. No obstante, cambió la estadificación a un estadio superior respecto a la TC en 6/40 pacientes y en 4/38 respecto a la gammagrafía con 67Ga. Sin embargo, los hallazgos de la PET/TC sólo llevaron a modificar el tratamiento en un paciente. Conclusiones: La PET/TC es una exploración que tiene una eficacia diagnóstica superior a las técnicas de imagen convencionales en el estudio de extensión, pero en nuestro grupo de pacientes con LDCG-B ha tenido un escaso impacto en el tratamiento inicial

Background and objective: The aim of this study was to evaluate the role of positron emission tomography/computed tomography (PET/CT) in improving the staging and changing the management of aggressive lymphoma patients in comparison with the conventional imaging modalities (CT, and 67Ga scintigraphy). Patients and method: Forty consecutive patients with diffuse large B-cell non Hodgkin lymphoma, were prospectively evaluated. All 40 patients underwent a whole body FDG PET/CT and conventional staging techniques (chest and abdomen CT, 67Ga scintigraphy) were studied before therapy. Sixty minutes after the intravenous administration of 370 MBq FDG, a whole body PET/CT was acquired. We hypothesize that PET/CT improves the diagnostic staging of lymphoma and changes the clinical management of patients. Results: PET/CT and CT were concordant in 28 patients (65%). However, PET/CT detected more lesions than CT in 11 patients (27.5%). Only in one patient, CT revealed more extensive disease than PET/CT. Additional information of PET/CT had lead to a change in staging (upstaging) in 6 patients (15%), in turn leading to a change in treatment strategy in 1 patient. PET/CT and 67Ga scintigraphy were concordant in 23 patients (60.5%). PET/CT detected more lesions than 67Ga scintigraphy in 14 patients (42%). PET/CT results changed staging (upstaging) in 4 patients (15%), leading to a change of treatment strategy in one patient. Conclusions: The impression is that PET/CT detected more lesions than conventional examination, but this rarely translates into changes of staging and treatment strategy in aggressive lymphoma

Is the identification of in-transit sentinel lymph nodes in malignant melanoma patients really necessary?

The sentinel lymph node (SLN) is the first node in a nodal basin to receive the direct lymphatic flow from a malignant melanoma. However, in some patients, lymphoscintigraphic study reveals the presence of lymphatic nodes in the area between the primary melanoma and the regional basin. These nodes are called "in-transit nodes" or "interval nodes" and, by definition, are also SLNs. The purpose of this study was to determine the incidence and location of in-transit SLNs in patients with malignant melanoma and to assess whether it is really necessary to harvest them. The evaluation involved 600 consecutive malignant melanoma patients. Lymphoscintigraphy was performed on the day before surgery following intradermal injection of 74-111 MBq of (99m)Tc-nanocolloid in four doses around the primary melanoma or the biopsy scar. Dynamic and static images were obtained and revealed SLNs in 599 out of 600 patients. The SLN was intraoperatively identified with the aid of patent blue dye and a hand-held gamma probe. Lymphoscintigraphy showed in-transit SLNs in 59/599 patients (9.8%). During surgery, all these in-transit SLNs were harvested, with those in the popliteal and epitrochlear regions being the most difficult to identify and excise. Metastatic cell deposits were subsequently identified in ten (16.9%) of these in-transit SLNs. In conclusion, lymphoscintigraphy has a key role in the identification of in-transit SLNs. Although the incidence of these nodes is relatively low in malignant melanoma patients, such SLNs present metastatic deposits in a significant percentage of cases and therefore the identification of in-transit SLNs in these patients is really necessary.