Surveillance for stage I non-seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined

Forty-six patients with clinical stage I testicular non-seminomatous germ cell tumours were followed up according to a protocol of active surveillance between 1979 and 1987. The median follow-up time was 40+ months. Thirteen patients (28%) relapsed, predominantly in retroperitoneum and/or lung. Ten of these relapses (76%) occurred within 8 months of orchiectomy. Relapses occurred in 7/35 T1 tumours and 5/10 T2 to T4 tumours. No correlation was detected between the histological type and relapse rate. Three late relapses were diagnosed at 23, 29 and 36 months. Eleven of the relapsed patients remain in prolonged complete remission after PVB chemotherapy +/- surgery; one patient, who initially refused treatment at the time of relapse, has died. Another relapsed with predominant elements of rhabdomyosarcoma intermingled with malignant teratoma in a bone metastasis. He had a partial response to PVB chemotherapy but subsequently died. Thirty-four patients (74%) did not undergo lymphography (LG) and had a higher relapse rate (11/34) than those who had LG (2/12); this was not a statistically significant difference in this small series. The policy of active surveillance is not yet the "state of the art" and should be under constant scrutiny with respect to safety and practice.     

Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells

Summary: Emerging evidence indicates that the Achilles' heel of cancer immunotherapies is often the complex interplay of tumor-derived factors and deviant host properties, which involve a wide range of immune elements in the lymphoid and myeloid compartments. Regulatory lymphocytes, tumor-conditioned myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and dysfunctional and immature dendritic cells take part in a complex immunoregulatory network. Despite the fact that some mechanisms governing tumor-induced immune tolerance and suppression are starting to be better understood and their complexity dissected, little is known about the diachronic picture of immune tolerance. Based on observations of MDSCs, we present a time-structured and topologically consistent idea of tumor-dependent tolerance progression in tumor-bearing hosts.     

Genetic vaccination for the active immunotherapy of cancer

Molecular biology techniques have given novel impetus to the immunotherapy of cancer because they have catalyzed the identification of several potential tumor antigens, and permitted the generation of vectors for the delivery of genetic material encoding these antigens. Vaccines can be defined "genetic" when the antigen they enclose is present as DNA or RNA. Microrganisms used as vectors can deliver the genetic information, but naked nucleic acids have also been shown to be effective immunogens thanks to built-in adjuvants that activate professional antigen presenting cells. Although gene-based cancer vaccines have been tested in mouse models and selected for pilot clinical trials, enthusiasm has somewhat waned due to an apparently major drawback of cancer vaccination: tumor antigens are weak, and therefore fail to stimulate a sterilizing immune response in tumor-bearing patients. Mouse studies, however, have shown that cancer vaccines are extremely efficacious in establishing a state of active immunosurvellance against tumor growth. This review reconsiders the findings emerging from preclinical studies in the context of our current knowledge of the cellular and molecular bases of the immune responses to vaccines, in an attempt to approach critically the use of genetic vaccination for the treatment of cancer.     

Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease

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Tailoring a commercial radioimmunoassay to the range of levels of progesterone occurring in human serum during controlled ovarian hyperstimulation and following embryo/gamete transfer

Summary While the Pantex direct P radioimmunoassay is used widely in programs of assisted conception, its sensitivity and range do not encompass the wide range of levels of P in serum of many patients during COH and through the first trimester of pregnancy. The present communication details minor modifications to the proprietary Pantex assay which accommodate these requirements. The nature of the changes does not compromise the performance characteristics or simplicity of the original assay and facilitates precise, accurate, and rapid measurement of serum P between 0.05 and 1280 ng/ml.     

Luteotropic activity in serum of women following embryo or gamete transfer in a program of assisted conception

In an attempt to track the proliferation/demise of trophoblastic tissues in women following gamete transfer (GT) or in vitro fertilization/embryo transfer (IVF/ET), we have measured levels of human chorionic gonadotropin (hCG) in serum of 180 patients on days 7 and 14 following oocyte pickup (OPU). Serum hCG levels were measured by immunoassay and by a bioassay based on the capacity of the sample to stimulate testosterone secretion by cultured mouse Leydig cells. Based on determinations of bioactive and immunoactive hCG in serum from 18 of 180 patients who subsequently delivered (12 of 73 GT, 6 of 107 IVF/ET;P<0.05) and classification of patients in accord with their compliance or noncompliance with these ranges of values, about 70% of all patients in the present study were classified as pregnant 7 days following OPU. Based on these same criteria, about 23% were pregnant 7 days later. Biochemical pregnancy rates on days 7 and 14 following GT (near 73 and 27%, respectively) were not different from the respective values following IVF/ET (near 68 and 20%, respectively:P>0.05). The luteotropin bioassay described is highly sensitive to hCG (to 0.02 mIU/ml serum) and appears appropriate to the characterization of proliferation/demise of embryonic tissues during the 14 days after gamete/embryo transfer. In addition, through its representation of the cumulative luteotropic properties of human serum and its insensitivity to biologically inactive hCG subunits; this bioassay appears more appropriate than hCG immunoassay in the monitoring of early embryonic signalling following assisted (or spontaneous) conception in the woman.     

High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells

Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1+/CD11b+ myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, l-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines.     

Quantitative lateralized measures of bradykinesia at different stages of Parkinson's disease: The role of the less affected side

The onset of motor abnormalities in Parkinson's disease (PD) is usually unilateral. However, current therapeutic trials do not analyze separately the performance of the more affected (MA) and less affected (LA) limbs. From a cohort of 85 subjects at different stages of PD, we asked whether the relationship between bradykinesia and disease severity was similar on both limbs and if the MA side remained more bradykinetic than the LA side in advanced PD. MA and LA limb determination was made from the history of the side first affected. Twenty‐one age‐matched subjects were used as controls. The velocities of finger and arm movements on both sides were inversely correlated with disease severity (P < 0.03). The slope of the decline in wrist movement velocity was steeper on the LA side (P = 0.029). When the regression lines were extrapolated to the y‐axis (UPDRS III = 0) the performance of the LA side was not different from that of controls (P = 0.954 and P = 0.829 for finger and arm movements, respectively), whereas that of the MA side was slower (P = 0.019 and P = 0.016), suggesting that at the theoretical state of no disease the LA side would reflect less or no contralateral nigral pathology. With increasing disease severity, there was less difference between MA and LA sides in both finger and arm bradykinesia (P < 0.004). These findings highlight the value of analyzing separately the MA and LA sides in subjects with PD, especially for clinical trials of potential disease modifying agents in early stages of disease. © 2009 Movement Disorder Society     

Differential expression of constitutive and inducible proteasome subunits in human monocyte‐derived DC differentiated in the presence of IFN‐α or IL‐4

Several studies strongly suggest that DC differentiated in vitro in the presence of type I IFN acquire more potent immune stimulatory properties, compared with DC differentiated in vitro with IL‐4. However, little is known about the molecular mechanisms underlying this phenomenon. To address this question, we compared the Ag‐processing machinery (APM) profile in human DC grown in the presence of IFN‐α (_IFNDC) or IL‐4 (_IL‐4DC). Using a panel of APM component‐specific mAb in Western blot experiments, we found that _IFNDC preferentially express inducible proteasome subunits (LMP2, LMP7, and MECL1) both at immature and mature stages. In contrast, immature _IL‐4DC co‐express both constitutive (β1, β2, and β5) and inducible subunits, as shown by Western blotting analysis. In addition, immature _IFNDC express higher levels of TAP1, TAP2, calnexin, calreticulin, tapasin, and HLA class I molecules than _IL‐4DC. The different proteasome profiles of _IFNDC and _IL‐4DC were associated with a greater ability of _IFNDC to present an immunodominant epitope that requires LMP7 expression for its processing. In general, these data show the impact of cytokines on APM component expression and hence the Ag‐processing ability of DC.