To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on ...the role of prognostic factors for treatment selection and the long-term risk of second cancers.
The PORTEC trial (1990–1997) included 714 patients with Stage IC Grade 1–2 or Stage IB Grade 2–3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat.
426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio HR 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02).
The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.
Plant—soil feedback affects performance and competitive ability of individual plants. However, the importance of plant—soil feedback in historical contigency processes and plant community dynamics is ...largely unknown. In microcosms, we tested how six early-successional plant species of secondary succession on ex-arable land induced plant-specific changes in soil community composition. Following one growth cycle of conditioning the soil community, soil feedback effects were assessed as plant performance in soil of their own as compared to soil from a mixture of the other five early-successional species. Performance was tested in monocultures and in mixed communities with heterospecific competition from mid-successional species. The role of soil microorganisms was determined by isolating the microbial component from the soil community, re-inoculating microorganisms into sterilized substrate, and analyzing plant biomass responses of the early- and mid-successional species. Plant—soil feedback responses of the early-successional species were negative and significantly increased when the plants were grown in a competitive environment with heterospecifics. In monocultures, three early-successional species experienced negative feedback in soil with a history of conspecifics, while all early-successional species experienced negative feedback when grown with interspecific competition. Interestingly, the nonnative forb Conyza canadensis showed the weakest soil feedback effect. Biomass production of the early-successional plant species was profoundly reduced by the microbial inocula, most strongly when exposed to inocula of conspecific origin. Molecular characterization of the fungal and bacterial rhizosphere communities revealed a relationship between plant biomass production and the composition of the dominant fungal species. Furthermore, our results show that, in early secondary succession, the early-successional plant species induce changes in the soil microbial community composition that cause historical contingency effects in dominance patterns of mid-succession plant communities. We conclude that feedback between early-successional plant species and soil microorganisms can play a crucial role in breaking dominance of early-successional plant communities. Moreover the influences on soil microorganism community composition influenced plant community dynamics in the mid-successional plant communities. These results shed new light on how feedback effects between plants and soil organisms in one successional stage result in a biotic legacy effect, which influences plant community processes in subsequent successional stages.
Introduction
Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether ...quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings.
Methods
A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan.
Results
Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median −62 % with IQR −87 to −39 %) compared to the control group (median +27 % with IQR −32 to +104 %,
p
= 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95 % CI 74.2–100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR −11–25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14–117).
Conclusion
In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI.
Endometrial carcinoma (EC) is traditionally diagnosed by a histopathological assessment of an endometrial biopsy, leaving up to 30% of patients undiagnosed due to technical failure or an inadequate ...amount of tissue. The aim of the current study is to assess whether mutational analysis of cervical cytology or pipelle endometrial biopsies improves the diagnostic accuracy of traditional histopathological diagnosis of EC. This prospective multicentre cohort study included patients surgically treated for EC or a benign gynaecological condition (control group). A Pap brush sample, cervicovaginal self‐sample, pipelle endometrial biopsy and surgical specimen of either the EC or normal endometrium were obtained. A targeted next‐generation sequencing panel was used to analyse these samples for mutations in eight genes. Sensitivity, specificity and predictive values were calculated. Fifty‐nine EC patients and 31 control patients were included. In these patients, traditional histopathological diagnosis by pipelle had a sensitivity of 79% and a specificity of 100%. For EC patients, 97% of surgical specimens contained at least one mutation. Mutational analysis of Pap brush samples, self‐samples and pipelle endometrial biopsies yielded a sensitivity of 78, 67 and 96% with a specificity of 97, 97 and 94%, respectively. Combining one of these three methods with histopathological pipelle endometrial biopsy evaluations yielded a sensitivity of 96, 93 and 96%, respectively. Our study has shown that mutational analysis of either cervical cytology or pipelle endometrial biopsies improves diagnosis of EC. Prospective validation will support implementation in clinical practice.
What's new?
Diagnosing endometrial cancer generally relies on histopathological analysis of endometrial biopsy samples. However, these tests are inconclusive in up to 30% of patients. To find a better way, these authors tested whether genetic analysis of endometrial or cervical samples could boost the diagnostic accuracy of the test. They tested 59 EC patients and 31 controls for 8 different genetic mutations using tissue from either Pap brush samples, pipelle biopsies, or self‐samples. Combining histopathology with mutation testing increased sensitivity from 79% to 93‐97%.
Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ...ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC.
Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome.
A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the ‘high and advanced/metastatic’ risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO ‘high and advanced/metastatic’ were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression.
The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification.
•Abnormal expression of p53/L1CAM/ER/PR is strongly correlated with higher ESMO-ESGO-ESTRO risk classification groups.•Within the ‘high-advanced/metastatic’ risk group, abnormal expression of p53/L1CAM/ER/PR was most predictive for outcome.•p53-abn, ER/PR- and ‘high-advanced/metastatic’ risk group were independently associated with reduced DSS.•IHC biomarkers have important additional prognostic relevance in both patients with and without lymph node metastasis.
Increasing evidence suggests that community-level responses to human-induced biodiversity loss start with a decrease of interactions among communities and between them and their abiotic environment. ...The structural and functional consequences of such interaction losses are poorly understood and have rarely been tested in real-world systems. Here, we analysed how 5 years of progressive, size-selective exclusion of large, medium, and small vertebrates and invertebrates-a realistic scenario of human-induced defaunation-impacts the strength of relationships between above- and belowground communities and their abiotic environment (hereafter ecosystem coupling) and how this relates to ecosystem functionality in grasslands. Exclusion of all vertebrates results in the greatest level of ecosystem coupling, while the additional loss of invertebrates leads to poorly coupled ecosystems. Consumer-driven changes in ecosystem functionality are positively related to changes in ecosystem coupling. Our results highlight the importance of invertebrate communities for maintaining ecological coupling and functioning in an increasingly defaunated world.
Oestrogen receptor (ER) expression is a prognostic biomarker in endometrial cancer (EC). However, expression does not provide information about the functional activity of the ER pathway. We evaluated ...a model to quantify ER pathway activity in EC, and determined the prognostic relevance of ER pathway activity.
ER pathway activity was measured in two publicly available datasets with endometrial and EC tissue, and one clinical cohort with 107 samples from proliferative and hyperplastic endometrium and endometrioid-type EC (EEC) and uterine serous cancer (USC). ER pathway activity scores were inferred from ER target gene mRNA levels from Affymetrix microarray data (public datasets), or measured by qPCR on formalin-fixed paraffin-embedded samples (clinical cohort) and related to ER expression and outcome.
ER pathway activity scores differed significantly throughout the menstrual cycle supporting the validity of the pathway test. The highest ER pathway scores were found in proliferative and hyperplastic endometrium and stage I EEC, whereas stage II-IV EEC and USCs had significantly lower levels. Low ER pathway activity was associated with recurrent disease, and added prognostic value in patients with low ER expression.
The ER pathway test reflects activity of the ER pathway, and may improve prediction of outcome in EC patients.
Summary Background After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as ...effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. Methods In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. Findings At median follow-up of 45 months (range 18–78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1·8% (95% CI 0·6–5·9) for VBT and 1·6% (0·5–4·9) for EBRT (hazard ratio HR 0·78, 95% CI 0·17–3·49; p=0·74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5·1% (2·8–9·6) for VBT and 2·1% (0·8–5·8) for EBRT (HR 2·08, 0·71–6·09; p=0·17). 1·5% (0·5–4·5) versus 0·5% (0·1–3·4) of patients presented with isolated pelvic recurrence (HR 3·10, 0·32–29·9; p=0·30), and rates of distant metastases were similar (8·3% 5·1–13·4 vs 5·7% 3·3–9·9; HR 1·32, 0·63–2·74; p=0·46). We recorded no differences in overall (84·8% 95% CI 79·3–90·3 vs 79·6% 71·2–88·0; HR 1·17, 0·69–1·98; p=0·57) or disease-free survival (82·7% 76·9–88·6 vs 78·1% 69·7–86·5; HR 1·09, 0·66–1·78; p=0·74). Rates of acute grade 1–2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12·6% 27/215 vs 53·8% 112/208). Interpretation VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. Funding Dutch Cancer Society.
Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.
...Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.
Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. Four patients demonstrated tumor response on MRI, one with complete regression and still alive after 8 years. Most serious adverse events were attributed to increased intracranial pressure caused by either an inflammatory reaction responding to steroid treatment or viral meningitis being transient and self-limiting. Often viral DNA concentrations in CSF increased over time, peaking after 2 to 4 weeks and remaining up to 3 months. Concomitantly Th1- and Th2-associated cytokine levels and numbers of CD3+ T and natural killer cells increased. Posttreatment tumor specimens revealed increased numbers of macrophages and CD4+ and CD8+ T cells. No evidence of viral shedding in excreta was observed.
CED of Delta24-RGD not only in the tumor but also in surrounding brain is safe, induces a local inflammatory reaction, and shows promising clinical responses.
To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation ...Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial.
Between 1990 and 1997, 714 patients with stage IC grade 1 to 2 or IB grade 2 to 3 EC were randomly allocated to pelvic external-beam radiotherapy (EBRT) or no additional treatment (NAT). HRQL was evaluated with the Short Form 36-Item (SF-36) questionnaire; subscales from the European Organisation for Research and Treatment of Cancer (EORTC) PR25 module for bowel and bladder symptoms and the OV28 and CX24 modules for sexual symptoms; and demographic questions. Analysis was by intention-to-treat.
Median follow-up was 13.3 years. The 15-year actuarial locoregional recurrence rates were 5.8% for EBRT versus 15.5% for NAT (P < .001), and 15-year overall survival was 52% versus 60% (P = .14). Of the 351 patients confirmed to be alive with correct address, 246 (70%) returned the questionnaire. Patients treated with EBRT reported significant (P < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after EBRT (day and night use, 42.9% v 15.2% for NAT; P < .001). Patients treated with EBRT reported lower scores on the SF-36 scales "physical functioning" (P = .004) and "role-physical" (P = .003).
EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower physical and role-physical functioning, even 15 years after treatment. Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC.
PDF
