Real-world treatment of German patients with recurrent and advanced endometrial cancer with a post-platinum treatment: a retrospective claims data analysis.

PURPOSE: Endometrial cancer (EC) is the sixth most common malignancy among females worldwide. Due to limited therapeutic options, treatment of advanced or recurrent disease is associated with poor outcomes. The aim of this study was to describe the real-world treatment of patients with advanced or recurrent EC who received a systemic treatment following platinum-based chemotherapy. METHODS: This retrospective cohort study was based on anonymized German claims data covering the period between January 1, 2010, and June 30, 2020. Patients with EC who started an anticancer treatment following platinum-based chemotherapy were observed for a minimum follow-up of 12 months. Available claims data were used to describe patient characteristics, subsequent treatment lines, healthcare resource utilization, and overall survival (OS) of patients. RESULTS: Out of 713 patients with advanced or recurrent EC and who had received a platinum-based treatment, 201 (mean age: 68.9 years) with a post-platinum-based treatment were identified and observed. The median OS in this population was 335.0 days. Of the 201 patients, 79 patients (39.3%) received a second line of treatment (LOT), and 21 patients (10.4%) had 3 or more treatment lines. In the LOTs following platinum-based chemotherapy, more than 70 different treatment regimens were observed. The hospitalization rate was generally high, with 5.2 hospitalizations per patient-year in the follow-up period. CONCLUSION: The wide variety of therapeutic regimens applied in patients in Germany who progressed after platinum-based therapy confirms the lack of therapeutic strategy for these patients, and the poor prognosis highlights the urgent need for new treatment strategies.

Impact of modified-release prednisone on functional ability in patients with rheumatoid arthritis.

This observational study assessed functional ability in patients treated with modified-release prednisone under conditions of normal clinical practice. Patients treated with modified-release prednisone were observed over 9 months. The primary outcome measure was the change from baseline total score using the Questionnaire on Activity Status (QAS); total QAS score ranges from 0 (severely impaired) to 100 (completely unimpaired). Other measures included Visual Analogue Scale (VAS) from 0 to 10 (where 10 = full daily performance) and Health Assessment Questionnaire Disability Index (HAQ-DI). There were no restrictions on dose of modified-release prednisone or use of concomitant therapy. A total of 1,733 patients were included in the study, with valid observations at baseline and study end for 1,185 patients (thereof 74 % female, median age 59 years, median disease duration 5 years). Mean total QAS score improved significantly after 9 months of treatment with modified-release prednisone from 54.3 to 70.2 (p < 0.001). There were also significant (p < 0.001) improvements in all three QAS dimensions (occupational performance: 66.6-78.9; household duties: 55.6-70.9; leisure activities: 51.6-69.4), daily performance (mean VAS 5.1-7.0; p < 0.001) and mean HAQ-DI score (1.35-1.00; p < 0.001). Dose of modified-release prednisone was significantly reduced (from 5.0 to 4.4 mg/day, p < 0.001) and fewer patients required biological rheumatoid arthritis (RA) treatments, analgesia and gastroprotectants. Functional ability in patients with RA improved significantly from baseline after 9 months of treatment with modified-release prednisone. This observational study, conducted under daily-practice conditions, confirms the beneficial effects of modified-release prednisone shown previously in randomised controlled trials.

Characterization of patient-reported outcomes in moderate to severe psoriasis.

BACKGROUND: The Patient Benefit Index (PBI) is a recently developed instrument to assess patient satisfaction with treatment. It has been applied to only a limited number of psoriasis patients. OBJECTIVE: Characterization of patient-reported outcomes (PRO) in patients with moderate to severe psoriasis. METHODS: 1787 patients with plaque psoriasis were documented. Psoriasis Area and Severity Index (PASI), body surface area (BSA), Dermatology Life Quality Index (DLQI) and PBI were determined. Correlations were calculated and the persistence of PBI improvement and strength of treatment effect were evaluated. A regression analysis was performed to characterize predictors of PBI and DLQI improvements. RESULTS: Significant correlations exist between ΔPASI/ΔBSA and ΔDLQI. Also, DLQI and PBI are correlated. Improvement in the skin condition has a positive and sustainable impact on all need dimensions of the PBI. The best early predictor for PBI was PASI 75 at treatment week 8, relevant factors predicting quality of life were PBI/subscale 4, (reducing physical impairment), ΔBSA and ΔPASI. CONCLUSION: Improvement in skin condition correlates with improvements in quality of life in patients with plaque psoriasis. Successful treatment leads to significant and sustainable patient benefit. While PBI subscale 4 is a good predictor for quality of life, more work is necessary to identify potential predictors for patient benefit.

Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment.

Cutaneous malignant melanoma is an aggressive disease of poor prognosis. Clinical and experimental studies have provided major insight into the pathogenesis of the disease, including the functional interaction between melanoma cells and surrounding keratinocytes, fibroblasts, and immune cells. Nevertheless, patients with metastasized melanoma have a very poor prognosis and are largely refractory to clinical therapies. Hence, diagnostic tools to monitor melanoma development, as well as therapeutic targets, are urgently needed. We investigated the expression pattern of the kallikrein-related peptidase 6 (KLK6) in human melanoma tissue sections throughout tumor development. Although KLK6 was not detectable in tumor cells, we found strong KLK6 protein expression in keratinocytes and stromal cells located adjacent to benign nevi, primary melanomas, and cutaneous metastatic lesions, suggesting a paracrine function of extracellular KLK6 during neoplastic transformation and malignant progression. Accordingly, recombinant Klk6 protein significantly induced melanoma cell migration and invasion accompanied by an accelerated intracellular Ca(2+) flux. We could further demonstrate that KLK6-induced intracellular Ca(2+) flux and tumor cell invasion critically depends on the protease-activated receptor 1 (PAR1). Our data provide experimental evidence that specific inhibition of the KLK6-PAR1 axis may interfere with the deleterious effect of tumor-microenvironment interaction and represent a potential option for translational melanoma research.

Inverse regulation of the interferon-gamma receptor and its signaling in human endometrial stromal cells during decidualization.

OBJECTIVE: To investigate whether human endometrial stromal cells (ESCs) express the interferon-gamma-receptor (IFN-gamma R) and whether the process of decidualization or human chorionic gonadotropin (hCG) regulate the IFN-gamma R and its signaling pathway. DESIGN: In vitro experiment. SETTING: Research laboratory at a medical university center. PATIENT(S): Premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): Isolation and incubation of ESCs from hysterectomy specimens with 17beta-estradiol, progesterone, recombinant hCG, and IFN-gamma as well as an IFN-gamma R-blocking antibody. MAIN OUTCOME MEASURE(S): We analyzed IFN-gamma R and the phosphorylation of signal transducer and activator of transcription 1 (STAT-1) by flow cytometry. We measured IFN-gamma R and interferon response factor 1 (IRF-1) mRNA using semiquantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULT(S): The IFN-gamma R is up-regulated in human ESCs during decidualization without affecting the phosphorylation of STAT-1. Stimulation of IRF-1 by IFN-gamma is reduced in decidualized ESCs. We found that hCG neither regulates the IFN-gamma R nor its signaling pathway. CONCLUSION(S): These results show an inverse regulation of the IFN-gamma R and its signaling response via STAT-1 and IRF-1 in human ESCs during decidualization. The early embryonic signal hCG has no effect on this process. This mechanism may finely modulate the reactivity of ESCs to IFN-gamma-mediated signals from immune cells at the implantation site.

Human chorionic gonadotropin stimulates matrix metalloproteinases-2 and -9 in cytotrophoblastic cells and decreases tissue inhibitor of metalloproteinases-1, -2, and -3 in decidualized endometrial stromal cells.

OBJECTIVE: To investigate the influence of hCG on trophoblastic matrix metalloproteinases (MMPs) -2 and -9 as well as endometrial tissue inhibitor of metalloproteinases (TIMPs) -1, -2, and -3. DESIGN: In vitro experiment. SETTING: Research laboratory at a university medical center. PATIENT(S): Women undergoing legal abortions and premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): Human first trimester cytotrophoblasts and decidualized endometrial stromal cells were incubated with recombinant hCG. MAIN OUTCOME MEASURE(S): Trophoblastic MMP-2 and -9 were analyzed by enzyme-linked immunosorbent assay (ELISA) and zymography, and endometrial TIMP-1, -2, and -3 were measured by real time reverse transcriptase-polymerase chain reaction and ELISA. RESULT(S): HCG increases the secretion of MMP-2 and -9 in cytotrophoblasts dose dependently. This effect occurs after 4 hours of incubation and becomes less pronounced after 24 hours. In contrast, TIMP-1, -2, and -3 are significantly reduced by hCG in endometrial stromal cells in a time- and dose-dependent manner. CONCLUSION(S): These results suggest a regulatory role of hCG on the MMP/TIMP system at the implantation site. By increasing trophoblastic MMP secretion and reducing endometrial TIMP expression, hCG may be an important tool for the invading embryo to regulate the depth of its implantation.

Different regulation of tissue inhibitors of metalloproteinases-1, -2 and -3 in human endometrial stromal cells during decidualization in vitro.

Aim: Endometrial tissue inhibitors of metalloproteinases (TIMPs) appear to play an essential role during early implantation by modulating the invasiveness of the trophoblast. The expression of TIMP-1, TIMP-2 and TIMP-3 in human endometrial stromal cells (ESC) was investigated during decidualization in vitro. Methods: Endometrial stromal cells were isolated from hysterectomy specimens from premenopausal women undergoing surgery for benign reasons. Decidualization in vitro was induced by the application of 1 µmol/L progesterone and 30 nmol/L 17ß-estradiol over 9 days. The expression of TIMP-1, TIMP-2 and TIMP-3 in ESC was measured by semiquantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay over intervals of 3 days. Results: Decidualization in vitro was confirmed by a significant increase in prolactin expression. TIMP-1 and TIMP-2 mRNA and secreted protein showed no significant changes over the time-course of decidualization. In contrast, TIMP-3 was upregulated during the first 3 days of decidualization. An eightfold upregulation was observed until day 6, and the effect was less pronounced by day 9. Conclusion: These results suggest a regulatory role of the TIMP system for endometrial differentiation in the second half of the menstrual cycle and in early implantation. The expression pattern of endometrial TIMP-3 might be important for the regulation of trophoblast invasion. (Reprod Med Biol 2008; 7: 169-175).

Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis.

The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas-mediated signaling during early implantation. Here we show that ESCs are primarily resistant to Fas-mediated apoptosis independently of their state of hormonal differentiation. Pre-treatment of ESCs with interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha sensitizes them to become apoptotic upon stimulation of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN-gamma and TNF-alpha was accompanied by a significant upregulation of Fas and FLICE-inhibitory protein (FLIP, CFLAR) expression in ESCs. Additionally, we observed an activation of caspase 3, caspase 8 and caspase 9 upon apoptotic Fas triggering. In summary, we demonstrate that IFN-gamma and TNF-alpha sensitize primarily apoptosis-resistant ESCs to Fas-mediated cell death. This might be due to an upregulation of Fas expression, and apoptosis seems to be mediated by active caspase 3, caspase 8 and caspase 9. The observed pro-apoptotic effect of IFN-gamma and TNF-alpha on ESCs could play an important role in the modulation of early implantation.

Human chorionic gonadotropin inhibits insulin-like growth factor-binding protein-1 and prolactin in decidualized human endometrial stromal cells.

Recent data clearly show that hCG, as one of the first hormonal signals of the embryo, is involved in the modulation of endometrial receptivity in the secretory phase. Here we report a significant dose- and time-dependent inhibition of insulin-like growth factor-binding protein-1 and prolactin by hCG in human endometrial stromal cells after decidualization in vitro-findings that further underline the role of hCG in the endometrial milieu during early implantation.