Justification of noninferiority margin: methodology considerations in an exposure-response analysis.

The pivotal clinical trial to support the indication of liver transplantation for everolimus was based on a noninferiority trial design. The unique trial design made it impossible to estimate the noninferiority margin at the design stage. Even though the trial was conducted based on a noninferiority margin of 12% for the primary efficacy endpoint, the lack of consensus on this margin made the efficacy results difficult to interpret. A novel pharmacometric approach was applied to derive a new margin. Even though it was smaller than 12%, the new margin was large enough so that the observed efficacy results became interpretable. This novel analysis was an important contributor to the "totality of evidence" approach that led to the approval of everolimus for the new indication. This approval represents the approval of a new drug in more than 10 years for the indication of liver transplantation.

Summary of FDA workshop on ischemia reperfusion injury in kidney transplantation.

The Food and Drug Administration (FDA) held an open public workshop in September 2011 to discuss the current state of science related to the effects of ischemia reperfusion injury (IRI) on outcomes in kidney transplantation. Topics included the development of IRI and delayed graft function (DGF), histology and biomarkers, donor factors, recipient factors, organ quality and organ preservation by means of cold storage solutions or machine perfusion. Various mechanisms of injury and maladaptive response to IRI were discussed as potential targets of intervention. Animal models evaluating specific pathophysiological pathways were presented, as were the limitations of extrapolating animal results to humans. Clinical trials of various drug products administered in the peri-transplant period were summarized; a few demonstrated early improvements in DGF, but none demonstrated an improvement in late graft function. Clinical trial design for IRI and DGF were also discussed.

Summary of FDA antibody-mediated rejection workshop.

The Food and Drug Administration (FDA) held an open public workshop in June 2010 to discuss the current state of science related to antibody-mediated rejection (AMR) in kidney transplantation. Desensitization, acute AMR and chronic AMR (CAMR) were considered in the context of clinical trial design. Participants discussed experiences with HLA antibody detection and quantitation and the utility of monitoring donor-specific antibodies (DSAs) to inform the management of patients with AMR. The role for animal models was discussed. Diagnostic and prognostic features of histology were presented, followed by discussion of sensitivity and specificity of various criteria. The published literature on treatment of acute AMR was summarized, which consisted of case series and limited data from controlled clinical trials. Considerations for future clinical trials were presented, including endpoints and statistical evaluations of outcome. Although many issues need further consideration, the meeting enabled an important exchange of ideas between experts in the field.

Protocol biopsies in renal transplantation: insights into patient management and pathogenesis.

A 1-day symposium on the application of protocol biopsies in renal transplantation was held in Boston, 21 July 2006. Representatives from centers with extensive experience in the use of protocol biopsies for routine patient care and research reported results on the pathological findings and their value in patient management. The consensus was that protocol biopsies, in experienced hands, are a safe and valuable means of detecting subclinical disease that can benefit from modification of therapy. Furthermore, molecular studies reveal evidence of activity or progression not readily appreciated by histological techniques. Wider application is expected in multicenter clinical trials to predict and validate outcomes. The principal barrier to wider use of protocol biopsies is knowledge of the benefits of intervention.

Loss of receptors for transforming growth factor beta in human T-cell malignancies.

Ki-1 (CD30)+ cutaneous T-cell lymphomas CTCLs) are slowly progressive lymphomas in which initial spontaneous regression is often observed. To better understand the mechanisms of spontaneous regression and eventual tumor progression in Ki-1+ CTCLs, type beta transforming growth factor (TGF-beta)-mediated growth inhibition of clonally related cell lines derived from two time points, before and after tumor progression, was studied. TGF-beta 1 inhibited colony-forming efficiency (CFE) of a cell line (Mac-1) derived from clinically indolent Ki-1+ CTCLs but failed to inhibit CFE of Mac-2A and -2B cell lines from advanced CTCLs. To determine the basis for TGF-beta 1 resistance in advanced CTCL cells, we looked for possible defects in the expression of cell surface TGF-beta receptors. Mac-1 cells were found to express TGF-beta receptors I and II, which mediate growth inhibition, and the TGF-beta-binding proteoglycan betaglycan. In contrast, receptors I and II were not detected in CTCL lines Mac-2A and -2B even though these cell lines did express betaglycan. Various treatments that unmask or induce TGF-beta receptors in other cells failed to show evidence for these receptors in advanced CTCL cells. Loss of TGF-beta receptor expression in these cells correlated with a marked decrease in TGF-beta receptor II mRNA levels. Loss of cell surface TGF-beta receptors was also found in two of five other patients with T-cell lymphomas including the Sezary syndrome and a noncutaneous T-cell lymphoma, suggesting that loss of TGF-beta receptor expression may be a recurrent feature of human T-cell malignancies.

Is there correlation of T cell proliferative functions and surface marker phenotypes in patients with acquired immune deficiency syndrome or lymphadenopathy syndrome?

We have investigated the respective role of quantitative T lymphocyte subset abnormalities, interleukin-2 (IL-2) production and responsiveness to IL-2, in the proliferative deficiency that is observed in acquired immune deficiency syndrome (AIDS) and Lymphadenopathy syndrome (LAS) patients or even in some apparently healthy male homosexuals. 83 subjects were evaluated: 35 symptom free male homosexuals (HC), 24 LAS and 24 AIDS patients. As expected, many HC and most patients presented with T lymphocyte subset imbalance. These quantitative defects were associated with decreased reactivity to PHA and reduced production of IL-2 by PHA stimulated lymphocytes. No correlation however could be found between these two functions and variations in the T lymphocyte subset distribution. On the other hand, PHA responsiveness appeared to closely depend on IL-2 activity. Addition of exogenous IL-2 to lymphocytes from patients with low proliferative responses, stimulated with suboptimal PHA concentration, enhanced proliferation in some but not all the cases. In most instances this increase never reached the levels observed with similarly treated cells from normal individuals. In these patients, the limited number of lymphocytes which express IL-2 receptors upon PHA stimulation may explain both low PHA reactivity and reduced IL-2 responsiveness. These data indicate some possible mechanisms of immunodeficiency in AIDS and LAS.

Lymphadenopathy in patients at risk for acquired immunodeficiency syndrome. Histopathology and histochemistry.

Lymph node biopsies of 12 patients at high risk for acquired immunodeficiency syndrome (AIDS) with generalized lymphadenopathy (AIDS-related complex [ARC]) and seven controls with conventional lymph node hyperplasia were examined by light microscopy and immunohistochemical staining of frozen tissue. The immunohistochemical results were quantified by planimetric means. Our findings show that the T helper/T suppressor-cytotoxic (Th/Tsc) ratio in lymph nodes from ARC patients is significantly decreased with respect to controls and that this decrease precedes the change in the Th/Tsc ratio in peripheral blood. Our findings distinguish between lymphadenopathy from patients with ARC and other forms of hyperplasia; the relation to AIDS is discussed.

[Acquired immunodeficiency syndrome and related syndromes. Critical analysis of biological tests of cell-mediated immunity]. / Syndrome d'immunodéficit acquis et syndromes apparentés. Analyse critique des examens biologiques de l'immunité à médiation cellulaire.

In order to assess the actual value of the in vitro tests of cellular immunity performed to provide diagnostic evidence for acquired immune deficiency syndrome (AIDS) or related syndromes, we have evaluated T-lymphocyte subsets and in vitro proliferative responses. The respective profiles of 44 symptom-free homosexual men, 30 patients with AIDS and 42 patients with lymphadenopathy were compared with each other and with profiles of blood bank volunteers, using stepwise discriminant analysis. At first investigation, control homosexuals, AIDS patients and lymphadenopathy patients displayed varying degrees of the same type of immunological abnormalities. The percentage of OKT4+ cells was the most discriminant variable between blood donors and control homosexuals, AIDS or lymphadenopathy patients. The latter differed from homosexuals by a higher percent of OKT8+ cells and from AIDS patients by a lesser reduction in T-lymphocyte counts. OKT4+ cell counts differentiated AIDS patients from control homosexuals. However, none of these major discriminant variables could classify correctly more than 70% of subjects in the homosexual and in the two patient groups. Thus, a single investigation of T-lymphocyte immune parameters does not provide substantial diagnostic and prognostic evidence.

Critical analysis of T cell subset and function evaluation in patients with persistent generalized lymphadenopathy in groups at risk for AIDS.

In order to determine whether there exists a distinct immunological profile that discriminates between healthy homosexual men and those expressing persistent generalized hyperplastic lympadenopathy GHL and which of the observed abnormalities in GHL would be most indicative of patients who would eventually develop AIDS, we evaluated T lymphocyte subset and in vitro proliferative responses. The respective profiles of 44 symptom free homosexual men (HC), 42 patients with GHL and 30 cases of AIDS were compared to that of blood bank volunteers (BBV) and to each other, using stepwise discrimination analysis. HC, GHL and AIDS patients demonstrated upon their first investigation varying degrees of the same type of abnormal immunological characteristics. The percentage of OKT4+ cells was the most discriminant variable between BBV and HC, GHL or AIDS. GHL was distinguished from HC primarily by a higher percentage of OKT8+ cells and from AIDS by higher T lymphocyte counts, while the OKT4+ cell count discriminated between AIDS and HC. However, none of these major discriminant variables could classify correctly more than 71% within the HC and the two patient groups. Thus, there exists a continuity between GHL and AIDS in the range of observed immunological abnormalities without clearcut boundaries. This, together with the existence of abnormal background values in HC will not permit a single investigation of T lymphocyte immune parameters to provide substantial diagnostic and prognostic evidence.

[Acquired ocular toxoplasmosis and immunosuppression of tumoral thymic origin]. / Toxoplasmose oculaire acquise et immunodépression d'origine thymique tumorale.

A rare case of acute bilateral unifocal chorioretinitis in a 24 years old man is described. The patient had been followed for more than 3 years for a benign thymoma, detected by systematic radiography, that was initially operated on with success. Later, after recurrence of clinical signs a second operation was performed that revealed local invasion of the tumor which was histologically identified as a benign, lymphoid thymoma. Serological data permitted us to attribute the lesions to a sub-acute ganglionary toxoplasmosis, contracted five months before any ocular localization. A treatment including local corticotherapy and oral pyrimethamine and sulfonamide was undertaken. Healing of the retinal lesions occurred slowly. A complete study of the patient's immunity revealed an important deficiency of cell-mediated functions. The problem of diagnosis of opportunistic chorioretinitis is discussed. In patients with impairment of cellular-type immunity, the following are commonly observed: herpes group viral diseases (including cytomegalic inclusion disease), fungus diseases (candida, aspergillus, mucormycosis, cryptococcus), and, rarely, toxoplasmosis. The presence of specific serum antibodies is the most important element in making a diagnosis, considering that the ophthalmoscopic appearance and clinical course may vary.