Ultrastaging methods of sentinel lymph nodes in endometrial cancer - a systematic review.

OBJECTIVE: Sentinel lymph node mapping has emerged as an alternative to lymphadenectomy in evaluating the lymph node status in endometrial cancer. Several pathological methods to examine the sentinel lymph node are applied internationally. The aim of this study was to determine the value of ultrastaging and to assess the ultrastaging method with the highest detection rate of metastases. METHODS: A systematic review was conducted. Inclusion criteria were: pathologically-confirmed endometrial cancer with sentinel lymph node mapping, report of the histological outcomes, metastases found by hematoxylin and eosin staining and metastases found by ultrastaging were separately mentioned, and description of the ultrastaging method. The primary outcome was the detection of metastases found by ultrastaging that were not detected by routine hematoxylin and eosin staining. The secondary outcome was the difference in detection rate of metastases between several ultrastaging methods. Random effects meta-analyses were conducted. RESULTS: Fifteen studies were selected, including 2259 patients. Sentinel lymph nodes were examined by routine hematoxylin and eosin staining. Subsequently, multiple ultrastaging methods were used, with differences in macroscopic slicing (bread-loaf/longitudinal), number of microscopic slides, and distance between slides, but all used immunohistochemistry. A positive sentinel lymph node was found in 14% of patients. In 37% of these, this was detected only by ultrastaging. Using more ultrastaging slides did not result in a higher detection rate. Bread-loaf slicing led to a higher detection rate compared with longitudinal slicing (mean detection rates 53% and 33%, respectively). CONCLUSION: Pathological ultrastaging after routine hematoxylin and eosin staining in endometrial cancer patients has led to an increased detection rate of sentinel lymph node metastases. Different ultrastaging methods are used, with a preference for bread-loaf slicing. However, due to the large heterogeneity of the studies, assessing which ultrastaging method has the highest detection rate of sentinel lymph node metastases was not possible.

Tetraspanin microdomains control localized protein kinase C signaling in B cells.

Activation of B cells by the binding of antigens to the B cell receptor (BCR) requires the protein kinase C (PKC) family member PKCß. Because PKCs must translocate to the plasma membrane to become activated, we investigated the mechanisms regulating their spatial distribution in mouse and human B cells. Through live-cell imaging, we showed that BCR-stimulated production of the second messenger diacylglycerol (DAG) resulted in the translocation of PKCß from the cytosol to plasma membrane regions containing the tetraspanin protein CD53. CD53 was specifically enriched at sites of BCR signaling, suggesting that BCR-dependent PKC signaling was initiated at these tetraspanin microdomains. Fluorescence lifetime imaging microscopy studies confirmed the molecular recruitment of PKC to CD53-containing microdomains, which required the amino terminus of CD53. Furthermore, we showed that Cd53-deficient B cells were defective in the phosphorylation of PKC substrates. Consistent with this finding, PKC recruitment to the plasma membrane was impaired in both mouse and human CD53-deficient B cells compared to that in their wild-type counterparts. These data suggest that CD53 promotes BCR-dependent PKC signaling by recruiting PKC to the plasma membrane so that it can phosphorylate its substrates and that tetraspanin-containing microdomains can act as signaling hotspots in the plasma membrane.

The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

OBJECTIVE: Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. METHODS: A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). RESULTS: Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. CONCLUSION: The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial.

BACKGROUND: Autoantigen-specific immunotherapy by mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Human cartilage glycoprotein-39 (HC gp-39) has been identified as a potential key autoantigen in RA. Based on animal studies, intranasal administration of the autoantigen is hypothesised to induce immunological tolerance in patients with RA and to ameliorate disease activity. In a phase I/IIA clinical trial in patients with RA, intranasal application of HC gp-39 was safe and well tolerated. OBJECTIVE: To investigate the efficacy of intranasally administered fully human, recombinant HC gp-39 (Org 39141) by a large clinical study. METHODS: In a 13-week multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding, proof-of-concept trial, patients with RA (disease-modifying antirheumatic drug (DMARD) naive or after washout of DMARD treatment) were randomised to receive either intranasal applications of placebo or HC gp-39 in doses of 30, 150, 300 or 600 microg, once a week. The primary efficacy variable was the 28 joint count Disease Activity Score (DAS28). RESULTS: During the treatment period the DAS28 decreased similarly for all treatment groups-including placebo-indicating lack of efficacy of intranasal HC gp-39 treatment in the current setting. Safety variables were similar for all study groups. CONCLUSION: It was concluded that with the treatment protocol used (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in more clinical improvement than in placebo-treated patients.