Treatment of endometrial cancer from 2000 to 2020 in Germany: a retrospective population based cohort study.

PURPOSE: Endometrial cancer (EC) is one of the most common malignancies among women in western countries. This study aimed to assess data on patient treatment in Germany throughout two decades to evaluate the development and effect of surgery, radiation, and chemotherapy. METHODS: This retrospective registry study included 34,349 EC patients diagnosed between 2000 and 2020. Patients were classified into five risk groups. Overall survival was analyzed by Kaplan-Meier method as well as univariable and multivariable Cox regression to evaluate risk factors and treatment options. RESULTS: Over the study period, minimal invasive surgery was used more often compared to open surgery and was associated with better overall survival. Patients with advanced EC were more likely to receive multimodal therapy. Patients with intermediate risk EC had a good prognosis upon surgery, which further improved when radiotherapy was added. High-risk patients showed poorer prognosis but clearly benefited from additional radiotherapy. Survival of elderly high-risk patients with a non-endometrioid histology was improved when chemotherapy was added to surgery and radiotherapy. CONCLUSION: Our study includes a large analysis of data from German clinical cancer registries on the care of endometrial cancer during two decades. We observed an increase of minimal invasive surgery. There is evidence that minimal invasive surgery is not inferior to open surgery. Adjuvant radio- and chemotherapy further improves survival depending on risk group and age.

Justice perceptions of sanctions for unemployed welfare recipients.

Institutions of the welfare state are supposed to function in accordance with normative principles of redistributive justice, which should guide not only the allocation but also the withdrawal of resources. Our study examines justice assessments of sanctions for unemployed individuals receiving welfare benefits, a much-discussed variant of benefit withdrawal. We present results from a factorial survey that asked German citizens to indicate which sanction they would perceive as just under different scenarios. In particular, we look at different kinds of deviant behavior on the part of the unemployed job seeker, which allows for a broad picture concerning potential sanction-triggering events. The findings show that the extent of sanctions perceived as just varies considerably across scenarios. Respondents would impose more sanctions on men, repeaters, and young people. Moreover, they have a clear picture of the severity of the deviant behavior.

A combination of immunohistochemical markers, MUC1, MUC5AC, PAX8 and growth pattern for characterization of mucinous neoplasm of the ovary.

OBJECTIVE: Because mucinous carcinomas are rare tumors that affect several organ sites and are known to originate from different tissues, leading to frequent misdiagnoses, the objective was to characterize the differences between primary mucinous tumors of the ovary and metastatic mucinous cancer to the ovary by studying the expression pattern of several candidate biomarkers. METHODS: Tissue samples of mucinous histology were obtained between 1985 and 2015. Individual ovary and colon tissue samples were analyzed, including standard (PAX8, CK20, CK7, CDX2, SATB2, estrogen/progesterone) and new (MUC1, MUC5AC) biomarkers, which were then scored for immunoreactivity semi-quantitatively. RESULTS: The study cohort included 98 mucinous tumor samples, including benign mucinous cystadenoma (n=24), mucinous borderline tumors (n=24), mucinous carcinomas (n=40), and metastatic mucinous ovarian carcinomas (n=10). A strong positive correlation was found between PAX8 scoring (p=0.003), CK7 scoring (p=0.0001), and MUC1 scoring (p=0.001) in primary mucinous ovarian cancer. Tumors of increasing invasiveness were analyzed and a significant decrease in the scoring of MUC5AC (p=0.001) was observed, with a stronger expression in adenomas (87%) and borderline tumors (75%), and a lower expression in mucinous cancers (42%). Patients survived significantly longer when their tumors expressed high PAX8 and showed an expansile invasion pattern (p=0.005 and p=0.015, respectively) compared with patients with PAX8-negative tumors and destructive invasion pattern. CONCLUSION: The study data support the diagnostic value of MUC1 as a new biomarker to differentiate between primary and metastatic mucinous ovarian cancer. In addition, the tumor growth pattern along with the PAX8 immunophenotype might represent potential prognostic biomarkers for primary mucinous ovarian carcinomas.

The G-Protein-Coupled Estrogen Receptor (GPER) Regulates Trimethylation of Histone H3 at Lysine 4 and Represses Migration and Proliferation of Ovarian Cancer Cells In Vitro.

Histone H3 lysine 4 trimethylation (H3K4me3) is one of the most recognized epigenetic regulators of transcriptional activity representing, an epigenetic modification of Histone H3. Previous reports have suggested that the broad H3K4me3 domain can be considered as an epigenetic signature for tumor-suppressor genes in human cells. G-protein-coupled estrogen receptor (GPER), a new membrane-bound estrogen receptor, acts as an inhibitor on cell growth via epigenetic regulation in breast and ovarian cancer cells. This study was conducted to evaluate the relationship of GPER and H3K4me3 in ovarian cancer tissue samples as well as in two different cell lines (Caov3 and Caov4). Silencing of GPER by a specific siRNA and two selective regulators with agonistic (G1) and antagonistic (G15) activity were applied for consecutive in vitro studies to investigate their impacts on tumor cell growth and the changes in phosphorylated ERK1/2 (p-ERK1/2) and H3K4me3. We found a positive correlation between GPER and H3K4me3 expression in ovarian cancer patients. Patients overexpressing GPER as well as H3K4me3 had significantly improved overall survival. Increased H3K4me3 and p-ERK1/2 levels and attenuated cell proliferation and migration were observed in Caov3 and Caov4 cells via activation of GPER by G1. Conversely, antagonizing GPER activity by G15 resulted in opposite effects in the Caov4 cell line. In conclusion, interaction of GPER and H3K4me3 appears to be of prognostic significance for ovarian cancer patients. The results of the in vitro analyses confirm the biological rationale for their interplay and identify GPER agonists, such as G1, as a potential therapeutic approach for future investigations.

Primary platinum resistance and its prognostic impact in patients with recurrent ovarian cancer: an analysis of three prospective trials from the NOGGO study group.

OBJECTIVE: Patients with platinum-resistant ovarian cancer (PROC) have a high need for reliable prognostic markers. Since significance of primary platinum resistance (PPR) versus secondary platinum resistance (SPR) was identified for patients receiving anti-angiogenic therapy, it has not been confirmed for chemotherapy only. METHODS: PROC patients from 3 prospective trials of the NOGGO study group (TOWER, NOGGO-Treosulfan, and TRIAS) were included in this meta-analysis. Exploratory Cox and logistic regression analyses were performed to correlate progression-free survival (PFS) and overall survival (OS) with the timing when platinum resistance developed. RESULTS: Of 477 patients, 264 (55.3%) were classified as PPR, compared to 213 (44.7%) with SPR. For patients receiving chemotherapy only, SPR was associated with a significantly longer median PFS of 3.9 compared to 3.1 months for PPR (hazard ratio [HR]=0.78; p=0.015). SPR versus PPR was confirmed to be an independent prognostic factor for better PFS in multivariate analysis (HR=0.74; p=0.029). Benefit from adding sorafenib to chemotherapy was mainly seen in PPR (HR=0.40; p<0.001) compared to SPR patients (HR=0.83; p=0.465). CONCLUSIONS: Prognostic significance of SPR versus PPR could be elucidated for patients receiving chemotherapy only. In contrast to bevacizumab, the multi-kinase inhibitor sorafenib exhibits profound therapeutic efficacy in PPR patients indicating potential to overcome this negative prognostic impact.

Empirical analysis of the text structure of original research articles in medical journals.

Successful publishing of an article depends on several factors, including the structure of the main text, the so-called introduction, methods, results and discussion structure (IMRAD). The first objective of our work is to provide recent results on the number of paragraphs (pars.) per section used in articles published in major medical journals. Our second objective is the investigation of other structural elements, i.e., number of tables, figures and references and the availability of supplementary material. We analyzed data from randomly selected original articles published in years 2005, 2010 and 2015 from the journals The BMJ, The Journal of the American Medical Association, The Lancet, The New England Journal of Medicine and PLOS Medicine. Per journal and year 30 articles were investigated. Random effect meta-analyses were performed to provide pooled estimates. The effect of time was analyzed by linear mixed models. All articles followed the IMRAD structure. The number of pars. per section increased for all journals over time with 1.08 (95% confidence interval (CI): 0.70-1.46) pars. per every two years. The largest increase was observed for the methods section (0.29 pars. per year; 95% confidence interval (CI): 0.19-0.39). PLOS Medicine had the highest number of pars. The number of tables did not change, but number of figures and references increased slightly. Not only the standard IMRAD structure should be used to increase the likelihood for publication of an article but also the general layout of the target journal. Supplementary material has become standard. If no journal-specific information is available, authors should use 3/10/9/8 pars. for the introduction/methods/results/discussion sections.

H3K4me3 Is a Potential Mediator for Antiproliferative Effects of Calcitriol (1α,25(OH)2D3) in Ovarian Cancer Biology.

Posttranslational histone modification plays an important role in tumorigenesis. Histone modification is a dynamic response of chromatin to various signals, such as the exposure to calcitriol (1α,25(OH)2D3). Recent studies suggested that histone modification levels could be used to predict patient outcomes in various cancers. Our study evaluated the expression level of histone 3 lysine 4 trimethylation (H3K4me3) in a cohort of 156 epithelial ovarian cancer (EOC) cases by immunohistochemical staining and analyzed its correlation to patient prognosis. The influence of 1α,25(OH)2D3 on the proliferation of ovarian cancer cells was measured by BrdU proliferation assay in vitro. We could show that higher levels of H3K4me3 were correlated with improved overall survival (median overall survival (OS) not reached vs. 37.0 months, p = 0.047) and identified H3K4me3 as a potential prognostic factor for the present cohort. Ovarian cancer cell 1α,25(OH)2D3 treatment induced H3K4me3 protein expression and exhibited antiproliferative effects. By this, the study suggests a possible impact of H3K4me3 expression on EOC progression as well as its relation to calcitriol (1α,25(OH)2D3) treatment. These results may serve as an explanation on how 1α,25(OH)2D3 mediates its known antiproliferative effects. In addition, they further underline the potential benefit of 1α,25(OH)2D3 supplementation in context of ovarian cancer care.

PD-L1 expression and survival in p16-negative and -positive squamous cell carcinomas of the vulva.

AIM: Programmed death-ligand 1 (PD-L1) has become a widely used predictive biomarker for therapy with checkpoint inhibitors in a variety of cancers. Here, we studied the expression of PD-L1 in squamous cell carcinomas of the vulva (SCCV) with regard to HPV status via its surrogate marker p16. Additionally, the status of PD-L1 and p16 were analyzed for prognostic information and potential correlation to tumor-infiltrating lymphocytes (TILs). METHODS: PD-L1 was analyzed in 128 cases of SCCV using the tumor proportion score (TPS), the immune cell score (ICS) and the combined positive score (CPS). Cases were immunostained for p16 and analyzed for stromal TILs. PD-L1, p16, and TILs were compared to clinico-pathological parameters and patient's survival. RESULTS: TPS ≥ 50% and CPS ≥ 50 were correlated to a worse grading (p = 0.028 and p = 0.031), but not to FIGO-stage. CPS ≥ 50 was associated to a worse prognosis with overall survival (p = 0.021) but was not correlated to the progression-free survival. P16-positivity was correlated to a longer progression-free survival (p = 0.006) and overall survival (p = 0.023). PD-L1 expression was independent from p16 status. TILs ≥ 50% were present in 24% of the cases and were strongly correlated to PD-L1 (TPS p = 0.02, ICS p < 0.001, CPS p = 0.001). CONCLUSION: Our data demonstrate that PD-L1 expression is frequent in SCCV and independent from p16 status. High PD-L1 expression was associated with an unfavorable outcome whereas p16-positivity turned out to be an independent positive prognostic factor.

Comprehensive analysis of PD-L1 expression, HER2 amplification, ALK/EML4 fusion, and mismatch repair deficiency as putative predictive and prognostic factors in ovarian carcinoma.

Most ovarian carcinomas (OC) are characterized by poor prognosis, particularly the most frequent type high-grade serous carcinoma. Besides PARP inhibitors, target-based therapeutic strategies are not well established. We asked the question which other therapeutic targets could be of potential value and, therefore, analyzed a large cohort of OC for several predictive factors. Two hundred eighty-eight (288) cases of OC including the major histological types were analyzed by immunohistochemistry for PD-L1HER2, ALK, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. HER2 amplification and ALK/EML4 fusion were assessed by fluorescence in situ hybridization. The most frequent finding was PD-L1 expression ≥ 1% in 19.5% of the cases, which correlated with a significantly better overall survival in multivariate analysis (p < 0.001). HER2 amplification was detected in 11 cases (4%), all high-grade serous carcinomas. Amplification of HER2 did not correlate with patients' survival. ALK/EML4 fusion was found in two cases (0.74%): one high-grade serous and one endometrioid carcinoma. MMR deficiency was only present in one case of stage IV high-grade serous carcinoma. Subsets of high-grade serous carcinomas show PD-L1 expression and HER2 amplification, respectively, and, therefore, could qualify for immune checkpoint inhibitor therapy or anti HER2 therapy. PD-L1 is also of prognostic impact. ALK/EML4 fusion is very rare in OC and not a putative therapeutic target.

The ARID1A, p53 and ß-Catenin statuses are strong prognosticators in clear cell and endometrioid carcinoma of the ovary and the endometrium.

AIM: The objective of this study was to evaluate the prognostic value of ARID1A, p53, p21, p16 and ß-Catenin in endometrioid and clear cell ovarian and endometrial carcinomas. MATERIALS AND METHODS: 97 tumors were available for analysis of ARID1A, p53, p21, p16 and ß-Catenin with the techniques of tissue microarray and immunohistochemistry. 32 were ovarian carcinomas and 65 were endometrial carcinomas. RESULTS: Endometrioid ovarian carcinomas showed negative staining for ARID1A (a) and p21 (b), aberrant expression of p53 (c) and p16 (d) and ß-Catenin positive nuclear expression (e) respectively in 19% (a), 100% (b), 28.6% (c), 52.4% (d) and 4.8% (e) of all cases. In the group of clear cell ovarian carcinomas it was 63.6% (a), 100% (b), 81.8% (c), 54.5% (d) and 0% (e). For endometrioid uterine carcinomas it was 75.7% (a), 94.9% (b), 30.5% (c), 52.1% (d) and 6.8% (e) and for clear cell uterine carcinomas it was 8.6% (a), 100% (b), 50% (c), 100% (d) and 0% (e). Survival analysis showed that negative expression of ARID1A, p53 aberrant expression and ß-Catenin nuclear positive staining are independent negative prognosticators in both, clear cell and endometrioid carcinoma, regardless of ovarian or uterine origin. Cox-Regression analysis showed them again as negative prognostic factors. Furthermore, we found a significant correlation between ARID1A and ß-Catenin expression in endometrioid uterine tumors. CONCLUSION: The analyzed gynaecological carcinoma showed a distinct expression scheme of proteins that are associated with tumor suppression. We may conclude that ARID1A, p53 and ß-Catenin are the strongest prognostic factors by analyzing a subgroup of tumor suppressor genes in clear cell and endometrioid subtypes of ovarian and endometrial cancer and may be used along with traditional morphological and clinical characteristics for prognosis.

COMPLIANCE AND ADHERENCE OF PATIENTS WITH DIABETIC MACULAR EDEMA TO INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN DAILY PRACTICE.

PURPOSE: We assessed differences in compliance and adherence (lateness of patients, visual acuity, reasons for abstaining) between patients with diabetic macular edema (DME) and patients with age-related macular degeneration (AMD), both under anti-vascular endothelial growth factor therapy. METHODS: We included 136 patients with DME (36% women, 65 years, 22 visits, 13.9 injections, and 29.9 months of follow-up) and 109 patients with AMD (59% women, 76 years, 20 visits, 14.7 injections, and 22.3 months of follow-up) (minimum follow-up of 12 months and at least 5 injections). We assessed missed appointments (lateness >14 days) and therapy break-offs (lateness >100 days). All delayed patients were called and interviewed for abstaining reasons. RESULTS: Forty-six percent of patients with DME and 22% of patients with AMD had at least one break-off. Thirty-five percent of patients with DME and 50% of patients with AMD were always on schedule. In patients with DME, there was significant correlation (P = 0.017) between the number of break-offs and change of visual acuity. In 60% DME and 38% AMD of break-off cases, visual acuity was worse than the before break-off. The most common reason for abstaining was comorbidities (33% AMD and 20% DME). CONCLUSION: There are significant differences between patients with AMD and DME regarding compliance and adherence, which also affects outcome. Strategies to tie patients with DME to costly intravitreal therapy need to be developed to improve outcomes and efficacy.

LEF1 is preferentially expressed in the tubal-peritoneal junctions and is a reliable marker of tubal intraepithelial lesions.

Recently it has been reported that serous tubal intraepithelial carcinoma (STIC), the likely precursor of ovarian/extra-uterine high-grade serous carcinoma, are frequently located in the vicinity of tubal-peritoneal junctions, consistent with the cancer-prone features of many epithelial transitional regions. To test if p53 (aka TP53)-signatures and secretory cell outgrowths (SCOUTs) also localize to tubal-peritoneal junctions, we examined these lesions in the fallopian tubes of patients undergoing salpingo-oophorectomy for sporadic high-grade serous carcinomas or as a prophylactic procedure for carriers of familial BRCA1 or 2 mutations. STICs were located closest to the tubal-peritoneal junctions with an average distance of 1.31 mm, while SCOUTs were not detected in the fimbriated end of the fallopian tube. As many epithelial transitional regions contain stem cells, we also determined the expression of stem cell markers in the normal fallopian tube, tubal intraepithelial lesions and high-grade serous carcinomas. Of those, LEF1 was consistently expressed in the tubal-peritoneal junctions and all lesions, independent of p53 status. All SCOUTs demonstrated strong nuclear expression of ß-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, ß-catenin was preferentially located in the cytoplasm of cells comprising STICs and p53 signatures, suggesting WNT-independent function of LEF1 in those lesions. Both frequency of LEF1 expression and ß-catenin nuclear expression correlated with the worst 5-year patient survival, supporting important role of both proteins in high-grade serous carcinoma. Taken together, our findings suggest the existence of stem cell niche within the tubal-peritoneal junctions. Furthermore, they support the notion that the pathogenesis of SCOUTs is distinct from that of STICs and p53 signatures. The location and discrete patterns of LEF1 and ß-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions.

Cancer of the ovary, fallopian tube, and peritoneum: a population-based comparison of the prognostic factors and outcomes.

PURPOSE: The objective was to compare the prognostic factors and outcomes among primary ovarian cancer (OC), fallopian tube cancer (FC), and peritoneal cancer (PC) patients in a population-based setting. METHODS: We analysed 5399 OC, 327 FC, and 416 PC patients diagnosed between 1998 and 2014 in the catchment area of the Munich Cancer Registry (meanwhile 4.8 million inhabitants). Tumour site differences were examined by comparing prognostic factors, treatments, the time to progression, and survival. The effect of the tumour site was additionally analysed by a Cox regression model. RESULTS: The median age at diagnosis, histology, and FIGO stage significantly differed among the tumour sites (p < 0.001); PC patients were older, more often diagnosed with a serous subtype, and in FIGO stage III or IV. The time to progression and survival significantly differed among the tumour sites. When stratified by FIGO stage, the differences in time to progression disappeared, and the differences in survival considerably weakened. The differences in the multivariate survival analysis showed an almost identical outcome in PC patients (HR 1.07 [0.91-1.25]) and an improved survival of FC patients (HR 0.63 [0.49-0.81]) compared to that of OC patients. CONCLUSION: The comparison of OC, FC, and PC patients in this large-scale population-based study showed differences in the prognostic factors. These differences primarily account for the inferior outcome of PC patients, and for the improved survival of FC compared to OC patients.

Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030.

Past patterns of cancer disease and future changes in the demographic structure have a major influence on the projected incidences of human malignancies. In Germany, nearly a quarter of men and 20% of women die of cancer, and it is estimated that in Germany around 51% men and 43% women will develop cancer during lifetime. Here, we project the cancer incidence case number as well as the number of deaths for the most common cancers in the German population for the years 2020 and 2030. By 2030, prostate cancer will be the most common malignancy, surpassing breast cancer. Lung cancer will rank third most frequent cancer and will remain the most common cause of cancer-related mortality. Additionally, our projections show a marked increase in liver cancer cases with a continuous rise in liver cancer-related deaths. Finally, we project a constant increase in the incidence of pancreatic cancer. Based on our projections, pancreatic cancer will surpass colorectal and breast cancer to rank as the second most common cause of cancer-related deaths in Germany by 2030.

Outcome of gastric cancer in the elderly: a population-based evaluation of the Munich Cancer Registry.

BACKGROUND: Gastric cancer accounts for 5 % of cancer deaths. Proportions of older stomach cancer patients are increasing. Despite the still poor prognosis, standardised treatment has achieved improvements; nonetheless it is questionable whether all age groups have benefitted. Age and outcome need to be examined in a population-based setting. METHODS: Analyses included Munich Cancer Registry (MCR) data from 8601 invasive gastric cancer patients, diagnosed between 1998 and 2012. Tumour and therapy characteristics and outcome were analysed by two age groups (<70 vs. ≥70 years). Survival was analysed using the Kaplan-Meier method and relative survival was computed as an estimation for cancer-specific survival. Additional landmark analyses were conducted by calculating conditional survival of patients who survived more than 6 months. RESULTS: Fifty-nine per cent of the cohort were ≥70 years old. These patients had tumours with a slightly better prognosis and were treated with less radical surgery and adjuvant therapy than younger patients. The 5-year relative survival was 40 % for the youngest (<50 years) and 23 % for the oldest patients (≥80 years). Survival differences were diminished or eliminated after landmark analyses: The 5-year relative survival in age groups 50-59, 60-69 and 70-79 years was comparable (between 48 and 49.6 %) and slightly worse in the youngest and oldest (45 %), which may be explained by more aggressive tumours and effects of cellular senescence, respectively. CONCLUSION: The treatment and care of elderly gastric cancer patients in the MCR catchment area seems appropriate: if a patient's general condition allows oncologic resection and chemotherapy, it is conducted and the result is comparable between age groups.

Level of hospital care and outcome of gastric cancer: a population-based evaluation of the Munich Cancer Registry.

BACKGROUND: Gastric cancer accounts for 5 % of cancer deaths. Successful implementation of guideline-recommended treatment procedures should result in population-based outcome improvements despite the still poor prognosis. In this context, the objective of this study was to compare the outcome of gastric cancer by different levels of hospital care. MATERIALS AND METHODS: Total of 8,601 patients with invasive gastric cancer documented between 1998 and 2012 by the Munich Cancer Registry were evaluated. Tumour and therapy characteristics and outcome were analysed in regard to five levels of hospital care: three levels were defined for general hospitals (level I-III), while university hospitals and speciality hospitals were grouped as separate classes. Survival was investigated using the Kaplan-Meier-method, computing relative survival, and by multivariate Cox proportional hazard regression. RESULTS: The average age differed between 66 years in university hospitals and 75 years in hospitals providing a basic level of care (level I). No survival differences were found for patients treated in different levels of hospital care in 75 % of the patient cohort, namely the M0 patients. A better survival could only be shown for patients with M1 at diagnosis when treated in a university or level III hospital compared to those treated in other hospitals. CONCLUSION: The outcome difference of M1 patients is most likely caused by selection effects concerning health status differences and not by processes of health care attributable to level of hospital care. Thus, this study demonstrates and confirms appropriate treatment and care of gastric cancer over all levels of hospital care.