Ondas de choque. Evidencias y recomendaciones SETOC (Sociedad Española de Tratamientos con Ondas de Choque) / Current evidences in shockwave treatment. SETOC (Spanish Society of Shockwave Treatment) recommendations

El documento consenso SETOC muestra la evidencia científica de la tecnología en ondas de choque extracorpóreas (OCE) y ondas de presión radial (OPR) en diversidad de patologías musculoesqueléticas, cutáneas, espasticidad, urológicas, etc. Las OCE y las OPR son un tratamiento eficaz, seguro, no invasivo, coste-efectivo, bien tolerado por el paciente, sin necesidad de anestesia, que reduce la necesidad de cirugía, con menor riesgo de complicaciones y menor tiempo de recuperación que una cirugía. Por todo ello, las OCE y las OPR deberían ser la primera opción terapéutica de las patologías crónicas mencionadas, cuando las alternativas conservadoras hayan fallado, teniendo en cuenta las recomendaciones de este artículo, de las sociedades científicas y de la evidencia para cada tecnología (AU)

This SETOC consensus document shows the scientific evidence of the technology in shockwaves (SW) and radial pressure waves (RPW) in a variety of spasticity disorders, musculoskeletal, skin, urological diseases, etc. SW and RPW, without anesthesia, are an effective, safe, non-invasive, cost-effective treatment, which reduces the need for surgery, lower risk of complications, faster recovery and greater acceptability to patients than surgery. Consequently, SW and RPW should be the first therapeutic option in the aforementioned chronic pathologies, when conservative alternatives have failed. SETOC advises to follow the recommendations given in this article, including the ones given by SW scientific societies and best evidence for each technology as well (AU)

[Current evidences in shockwave treatment. SETOC (Spanish Society of Shockwave Treatment) recommendations]. / Ondas de choque. Evidencias y recomendaciones SETOC (Sociedad Española de Tratamientos con Ondas de Choque).

This SETOC consensus document shows the scientific evidence of the technology in shockwaves (SW) and radial pressure waves (RPW) in a variety of spasticity disorders, musculoskeletal, skin, urological diseases, etc. SW and RPW, without anesthesia, are an effective, safe, non-invasive, cost-effective treatment, which reduces the need for surgery, lower risk of complications, faster recovery and greater acceptability to patients than surgery. Consequently, SW and RPW should be the first therapeutic option in the aforementioned chronic pathologies, when conservative alternatives have failed. SETOC advises to follow the recommendations given in this article, including the ones given by SW scientific societies and best evidence for each technology as well.

MHC class II tetramer guided detection of Mycobacterium tuberculosis-specific CD4+ T cells in peripheral blood from patients with pulmonary tuberculosis.

Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma-based assays have recently been developed in addition to the more than 100-year-old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen-specific T cells. We identified novel MHC class II-restricted MTB epitopes and used HLA-DR4 tetrameric complexes to visualize ex vivo CD4(+) T cells directed against the antigens Ag85B and the 19-kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4(+) T cells which recognize the MTB-associated ESAT-6 antigen. MTB-reactive CD4(+) T cells reside predominantly in the CD45RA(+) CD28(+) and CD45(-) CD28(+) T-cell subset and recognize naturally processed and presented MTB epitopes. HLA-DR4-restricted, Ag85B or ESAT-6-specific CD4(+) T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8(+) T cells directed against the corresponding HLA-A2-presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T-cell responses directed against the 19-kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4(+) T cells directed against MTB.

Definition of the HLA-A2 restricted peptides recognized by human CD8+ effector T cells by flow-assisted sorting of the CD8+ CD45RA+ CD28- T cell subpopulation.

In response to antigenic stimulation, naive MHC-class I restricted and antigen-specific CD8+ CD45RA+ CD28+ T cells undergo clonal expansion, differentiate into CD8+ CD45RO+ memory T cells and convert to CD8+ CD45RA+ CD28- T cells displaying potent immune effector functions upon re-encounter with the nominal antigen. We show that the effector CD8+ CD45RA+ CD28- T cell subset is expanded in peripheral blood lymphocytes (PBL) from patients with human papilloma virus (HPV)+ cervical lesions as well as in PBL from patients with pulmonary tuberculosis. Flow-cytometric cell sorted CD8+ CD45RA+ CD28- and CD8+ CD45RA+ CD28- T cells were tested for recognition of HLA-A2 restricted peptides derived either from the human papillomavirus (HPV)16-E7 gene product, or from M. tuberculosis antigens. Mostly CD8+ CD45+ CD28- T cells define antigen/peptide-specific and MHC-restricted responses. These data were confirmed in PBL from patients with tuberculosis using HLA-A2 tetramer-complexes loaded with a peptide from the M. tuberculosis Ag85b antigen by flow cytometry. The sorting of this T cell subset enables to determine the fine specificity of CD8+ effector T cells without the need for in vitro manipulation.

Longitudinal analysis of the T-cell receptor (TCR)-VA and -VB repertoire in CD8+ T cells from individuals immunized with recombinant hepatitis B surface antigen.

Recent studies have suggested that vaccination induces alterations in the T cell receptor (TCR) repertoire. We investigate the diversity of the TCR repertoire after immunization with a recombinant hepatitis B surface vaccine in seven healthy subjects in CD8+ T cells in peripheral blood lymphocytes. Cellular immune responses were monitored over time by sorting CD8 T cells followed by TCR-VA and -VB complementarity determining region 3 (CDR3) analysis. Frequency of individual VB families was determined by flow cytometry. TCR-VA/VB repertoires obtained from CD8+ T cells drawn after vaccination were compared to the TCR repertoire determined prior to vaccination. Monoclonal TCR transcripts could be detected exclusively in CD8+, but not in CD4+ T cells. Such monoclonal TCR transcripts were either stable in some individuals, or could only be detected at certain time points after vaccination. Sorting of monoclonal TCR-VB3+ T cells, which constituted up to 5% of the CD8+ T cell population from one individual, revealed that this T cell clone recognizes an epitope provided by the recombinant hepatitis B vaccine presented by MHC-class I on autologous antigen-presenting cells. Examination of the structural anatomy, defined by the TCR, and the frequency of T cells responding to the immunizing antigen may be helpful to provide surrogate markers to monitor cellular immune responses induced by protein antigens utilized for vaccination.

Improved assessment of T-cell receptor (TCR) VB repertoire in clinical specimens: combination of TCR-CDR3 spectratyping with flow cytometry-based TCR VB frequency analysis.

Antigen-specific T-cell responses may be described by combining three categories: (i) the specificity and effector functions of a T-cell population, (ii) the quantity of T-cell responses (i.e., the number of responding T cells within the CD4/CD8 population), and (iii) the "quality" of T cells (defined by the T-cell receptor [TCR] structure). Several methods to measure T-cell responses are now available including evaluation of T-cell precursors using limiting dilution, the enzyme-linked immunospot assay, ex vivo TCR variable (v)-segment analysis determined by flow cytometry, and TCR-CDR3 length analysis (spectratyping), as well as identification of peptide-specific T cells using major histocompatibility complex (MHC) class I tetramers containing appropriate peptides. Until now, only a limited set of MHC-peptide complexes have been available as tetramer complexes. We demonstrate that CD8(+) or CD4(+) T cells in patients with cancer can be molecularly defined using a combination of spectratyping (TCR structure and "molecular composition") plus the implementation of an antibody panel directed against 21 individual VB TCR chains ("quantity" of T-cell families). This approach is instrumental in defining and comparing the magnitudes of CD4(+) or CD8(+) T-cell responses over time in individual patients, in comparing the TCR VA and VB repertoire in different anatomic compartments, and in comparing the TCR VA-VB diversity with that in normal healthy controls. This method provides the means of objectively defining and comparing the TCR repertoire in patients undergoing vaccination protocols and underlines the necessity to calibrate the TCR-CDR3 analysis with a qualitative assessment of individual TCR VB families.

Antigen-driven T-cell selection in patients with cervical cancer as evidenced by T-cell receptor analysis and recognition of autologous tumor.

We characterized the T-cell receptor (TCR) repertoire in freshly harvested tumor lesions, in short-term-expanded CD4(+) tumor infiltrating lymphocytes (TIL) as well as in CD4(+) and CD8(+) peripheral blood lymphocytes (PBL) from three patients with cervical cancer. Skewing of the T-cell repertoire as defined by measuring the length of the complementarity-determining region 3 (CDR3) of the TCR VA and VB chains was observed in CD8(+) PBL, in freshly harvested tumor tissue, as well as in CD4(+) TIL. Comparative analysis of the TCR repertoire revealed unique monoclonal TCR transcripts within the tumor lesion which were not present in PBL, suggesting selection of TCR clonotypes due to antigenic stimulation. TCR repertoire analysis of the short-term (7-day) CD4(+) TIL lines revealed that the TCR composition is markedly different from that in CD4(+) PBL or in the freshly harvested tumor tissue. Only one-third of CD4(+) TIL lines showed HLA-DR-restricted recognition of autologous tumor cells as defined by cytolysis. These data provide support for the antigen-driven selection of T cells within cervical cancer lesions and suggest that analysis of the TCR repertoire may aid in obtaining an objective description of the immune response in patients with cervical cancer who are undergoing epitope-based immunotherapy.

Human leucocyte antigen-A2 restricted and Mycobacterium tuberculosis 19-kDa antigen-specific CD8+ T-cell responses are oligoclonal and exhibit a T-cell cytotoxic type 2 response cytokine-secretion pattern.

CD8+ T cells can be grouped into two different types of secretory T lymphocytes, based on the cytokine-secretion pattern upon antigen exposure: those with a T-cell cytotoxic type 1 response (Tc1), which secrete interferon-gamma (IFN-gamma), or those with a T-cell cytotoxic type 2 response, which secrete interleukin (IL)-4 and IL-10. We examined the CD8+ T-cell response directed against an immunodominant human leucocyte antigen (HLA)-A2-presented peptide derived from a 19-kDa Mycobacterium tuberculosis-associated antigen. T cells were examined by functional analysis and by T-cell receptor (TCR) complementarity-determining region 3 (CDR3)-spectratyping, which defines the complexity of a T-cell response. T-cell stimulation with the immunodominant VLTDGNPPEV epitope yielded a Tc2 (IL-4) cytokine-secretion pattern and resulted in oligoclonal expansion of TCR-variable beta chain (VB) families, which differed from patient to patient. Generation of T-cell clones corroborated the notion that the CD8+ T-cell response directed against the HLA-A2-presented VLTDGNPPEV epitope leads to a Tc2 cytokine-secretion pattern in CD8+ T cells, as defined by IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Characterization of the cytokine-secretion profile in HLA-A2/VLTDGNPPEV-tetramer sorted T cells from patients with active tuberculosis supported this observation: peptide-specific T cells from three of three patients secreted IL-4 and only one of three patients produced IFN-gamma in response to the nominal target epitope. Permutation of this T-cell epitope may aid to elicit a qualitatively different CD8+ T-cell response in patients with M. tuberculosis infection.

Rhodium/iridium-titanium azaheterometallocubanes.

Treatment of [[Ti(eta5-C5Me5)(mu-NH)]3(mu3-N)] (1) with the diolefin complexes [[MCl(cod)]2] (M = Rh, Ir; cod = 1,5-cyclooctadiene) in toluene afforded the ionic complexes [M-(cod)(mu3-NH)3Ti3(eta5-C5Me5)3(mu3-N)]Cl [M = Rh (2), Ir (3)]. Reaction of complexes 2 and 3 with [Ag(BPh4)] in dichloromethane leads to anion metathesis and formation of the analogous ionic derivatives [M(cod)(mu3-NH)3Ti3-(eta5-C5Me5)3(mu3-N)][BPh4] [M = Rh (4), Ir (5)]. An X-ray crystal structure determination for 5 reveals a cube-type core [IrTi3N4] for the cationic fragment, in which 1 coordinates in a tripodal fashion to the iridium atom. Reaction of the diolefin complexes [[MCl(cod))2] (M = Rh, Ir) and [[RhCl(C2H4)2]2] with the lithium derivative [[Li(mu3-NH)2(mu3-N)-Ti3(eta5-C5Me5)3(mu3-N)]2] x C7H8 (6 C7H8) in toluene gave the neutral cube-type complexes [M(cod)(mu-NH)2(mu3-N)Ti3-(eta5-C5Me5)3(mu3-N)] [M = Rh (7), Ir (8)] and [Rh(C2H4)2(mu3-NH)2(mu3-N)Ti3(eta5-C5Me5)3(mu3-N)] (9), respectively. Density functional theory calculations have been carried out on the ionic and neutral azaheterometallocubane complexes to understand their electronic structures.

Randomized trial of cefotiam prophylaxis in the prevention of postoperative infectious morbidity after elective cesarean section.

A prospective, randomized study was performed in order to evaluate the effect of cefotiam in the prevention of postoperative infectious morbidity in patients undergoing low-risk elective cesarean section. A total of 146 patients were randomly assigned to receive either intraoperative single-shot prophylaxis with 2 g cefotiam (study group, n =76) or no prophylaxis (control group, n=70). Due to a higher rate of urinary tract infections, the incidence of infectious morbidity after cefotiam prophylaxis was higher in the study group than in the control group (16% vs. 9%, P=0.1). Postoperative infectious morbidity following low-risk elective cesarean section cannot be reduced by intraoperative cefotiam prophylaxis.

Acute starvation and subsequent refeeding affect lymphocyte subsets and proliferation in cats.

Although the early identification of patients with suboptimal nutritional status can allow the implementation of nutritional intervention to enhance the ability of the body to fight infection and disease, currently no definitive test of nutritional status exists. Therefore, this study was conducted to identify possible functional indicators of acute nutritional deprivation. The effects of total nutritional deprivation and subsequent refeeding on lymphocyte functions and subpopulations were examined in 23 healthy cats. Peripheral blood samples were analyzed at various times during food deprivation and refeeding periods. During the food deprivation period, decreases were observed in leukocyte number (P: < 0.05), lymphocyte number (P: < 0.05), percentage of CD4(+) cells [before stimulation with concanavalin-A (Con-A); P: < 0.05] and the CD4/CD8 ratio (before stimulation with Con-A; P: < 0.01) compared with d 0. Increases were observed in the percentage of CD8(+) cells [before (P: < 0.05) and after (P: < 0.01) stimulation with Con-A] and in intracellular calcium (P: < 0.01) during acute starvation. During the refeeding period, increases were observed in the percentage of CD4(+) cells (before and after stimulation with Con-A; P: < 0.01), the percentage of CD8(+) cells (before stimulation with Con-A; P: < 0.05) and lymphocyte number (P: < 0.05) compared with d 7. Lymphocyte proliferative capacity tended to decrease (P: = 0.07) during starvation and increased (P: < 0.01) during the refeeding period. These findings suggest that a 7-d starvation period had immunosuppressive effects on cats and that these effects were not completely normalized during 7 d of refeeding. CD4(+)/CD8(+) subset alterations and CD4/CD8 ratio in conjunction with lymphocyte proliferation may be useful as indices of nutritional status.

Human papillomavirus type 33 E7 peptides presented by HLA-DR*0402 to tumor-infiltrating T cells in cervical cancer.

Several characteristics make human papillomavirus (HPV) amenable to vaccination. Anti-HPV-directed vaccines are based on the observation that HPV E6 and E7 oncoproteins are constitutively expressed in HPV-positive cervical cancer and may serve as tumor rejection antigens. Five HPV types (16, 18, 31, 33, and 45) account for 80% of cervical cancer. Until now, the type of immune response capable of mediating an effective antitumor response has not been defined. In order to define the anticancer-directed immune response in situ, we characterized CD4(+) and CD8(+) sorted T cells from peripheral blood lymphocytes, freshly harvested tumor tissue, and tumor-infiltrating lymphocytes (TIL) from a patient with cervical cancer. The HLA-DR-restricted CD4(+) T-cell receptor VB16-, VA10-, VA21-, and VA22-positive CD4(+) T-cell line derived from TIL recognizes autologous HLA-DR*0402(+) (HPV33(+)) cervical cancer cells, as determined by gamma interferon secretion. Testing of different peptides spanning the E7 gene revealed that the HPV33(73-87) peptide ASDLRTIQQLLMGTV represents the immunodominant epitope which can also be presented by the DR*0401 allele to TIL. Such major histocompatibility complex class II-presented peptides represent attractive candidates to augment T-cell responses directed against autologous tumor cells.

Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice.

Both antigen-presenting cells and immune effector cells are required to effectively eradicate or contain Mycobacterium tuberculosis-infected cells. A variety of cytokines are involved to ensure productive "cross talk" between macrophages and T lymphocytes. For instance, infection of macrophages with mycobacteria leads to effective interleukin-7 (IL-7) and IL-15 secretion, and both cytokines are able to maintain strong cellular immune responses of alpha/beta and gamma/delta T cells. Here we show that either cytokine is able to enhance survival of M. tuberculosis-infected BALB/c mice significantly compared to application of IL-2, IL-4, or phosphate-buffered saline (as a control). Enhanced survival could be achieved only when IL-7 or IL-15 was delivered as a treatment (i.e., 3 weeks postinfection), not when it was administered at the time of infection. Increased survival of M. tuberculosis-infected animals was observed following passive transfer of spleen cells harvested from M. tuberculosis-infected, IL-7- or IL-15-treated animals, but not after transfer of spleen cells obtained from mice which received either cytokine alone. Histological examination revealed that IL-7 and IL-15 failed to significantly impact on the number and composition of granulomas formed or the bacterial load. Our data indicated that administration of IL-7 or IL-15 to M. tuberculosis-treated animals resulted in a qualitatively different cellular immune response in spleen cells as reflected by increased tumor necrosis factor alpha and decreased gamma interferon secretion in response to M. tuberculosis-infected antigen-presenting cells.

FDG PET evaluation of granular cell tumor of the breast.

Granular cell tumor is a rare, usually benign neoplasm of neural origin that may arise in virtually any site and, when situated in the breast, can mimic breast carcinoma. We describe a case of granular cell tumor of the breast in a 57-yr-old woman. Clinical evaluation, mammography, sonography and MRI suggested a carcinoma with infiltration of skin and muscle. However, the tumor did not display increased glucose metabolism on PET. Clinical findings, imaging results, histological characteristics and surgical management are discussed.

-Intravenous or oral etoposide therapy of platinum refractory ovarian cancer with early recurrence. Results of a prospective randomized study-. / Die intravenöse oder orale Etoposid-Therapie des Platin-refraktären Ovarialkarzinom-Frührezidivs. Ergebnisse einer prospektiven randomisierlen Studie.

121 patients with advanced ovarian cancer resistant to or relapsing following platinum-based chemotherapy participated in this prospective randomised multicenter study. The second-line treatment was indicated according to the relapse-free interval. 36 assessable patients were resistant to platinum-based chemotherapy or relapsed within 12 months following primary surgery. This group of patients with early relapse was randomized to oral or parenteral etoposide. 82 patients relapsed within an interval longer then 12 months following primary surgery; these patients with delayed relapse underwent a secondary tumour-debulking surgery. The data of this group of patients with delayed relapse will be published as soon as the time of observation allows adequate results. In this paper the efficiency of etoposide in the patients with early relapse is analysed according to the application form of the drug (oral vs. parenteral). No statistically significant difference in response rate, toxicity, and median survival time was found between the oral (n = 18) and parenteral (n = 18) treatment. In both application groups the response rate was 22%, the median survival time 14 and 13 months respectively. Alopecia and leucopenia were the most frequent toxicities. As a result etoposide is efficient in unfavorable ovarian cancer patients with early relapse. Because of better compliance etoposide should be administered parenterally. In respect of response rate and median survival time, etoposide is comparable with paclitaxel.