Risk for pelvic metastasis and role of pelvic lymphadenectomy in node-positive vulvar cancer - results from the AGO-VOP.2 QS vulva study

Simple Summary In node-positive vulvar squamous cell cancer, questions of when and how to perform pelvic lymphadenectomy (LAE) as well as the optimal extent of pelvic treatment in general have been surrounded by considerable controversy. In Germany, systematic pelvic LAE is currently recommended as a staging procedure in patients at risk for pelvic nodal involvement in order to prevent morbidity caused by pelvic radiotherapy (RT) in patients without histologically-confirmed pelvic involvement. However, the population at risk for pelvic metastases remains insufficiently described, resulting in the potential overtreatment of a considerable proportion of patients with groin-positive disease. This applies to the indication to perform surgical staging but also to adjuvant RT of the pelvis without previous pelvic staging. Our study aims to describe the risk for pelvic lymph node metastasis with regard to positive groin nodes and to clarify the indication criteria for pelvic treatment in node-positive vulvar cancer. Abstract The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b

Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Die Rolle der Mastzelle im murinen Sepsismodell Cecal Ligation and Puncture (CLP) anhand der Carboxypeptidase A

Seit 1996 wird den Mastzellen durch Freisetzung entzündungsfördernder Zytokine eine wichtige Rolle bei der Initiierung der Abwehr einer bakteriell-induzierten Sepsis zugeschrieben. Die momentanen Mastzellmodelle - basierend auf Kit-Mutationen - haben einige Nachteile, weil auch andere Organsysteme betroffen sind. In der Arbeit soll die Auswirkungen der Mastzelllosigkeit anhand eines neuen Mausstamms (Mc-cpa cre/+) mit selektiven Mastzellmangel gezeigt werden. Im zweiten Teil soll die Rolle der Mastzell-Carboxypeptidase A (Mc-cpa) untersucht werden. Diese katalysiert den Abbau von Endothelin-1, einem starken Vasokonstriktor, welcher in der Sepsis stark erhöht ist und durch Minderperfusion weitere Komplikationen fördert. Als experimentelles Sepsismodell wird die Cecal Ligation and Puncture (CLP) gewählt. Die Konzentrationen ausgewählter Zytokine im Serum wird mit Hilfe eines Bead-Assays bestimmt. Die neuen mastzelllosen Mc-cpa cre/+-Tiere überlebten eine induzierte Sepsis besser als die bisher bekannten mastzelllosen WBB6F1 Kit W/Wv-Tiere (p<0,001) mit signifikant niedrigeren Konzentrationen an proinflammatorischen Zytokinen (p=0,002). Im Vergleich zu den Wildtyptieren zeigen die Mc-cpa cre/+-Tiere ein ähnliches Verhalten bei Überleben und Zytokinkonzentrationen. Bei den Tieren ohne Carboxypeptidase A zeigt sich im Vergleich zum Wildtyp kein signifikanter Unterschied bezüglich Überleben und Zytokinkonzentrationen. Das unterschiedliche Überleben der beiden mastzelllosen Stämme stellt die bisher zentrale Rolle der Mastzellen im Rahmen der Sepsis in Frage. Unter Berücksichtigung der gewonnenen Ergebnisse und der Literatur scheint der bisher gezeigte Effekt der Mastzellen eher durch die Mutation des Kit-Gens und die daraus folgenden Begleitveränderungen erklärbar. Für die Mastzell-Carboxypeptidase A als Abbauprotease des toxischen Endothelin-1 konnte aufgrund der interexperimentellen Varianz kein eindeutiger Effekt auf den Verlauf der Sepsis gezeigt werden

Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses

Circulating tumor cells (CTCs) traverse vessels to travel from the primary tumor to distant organs where they adhere, transmigrate, and seed metastases. To cope with these challenges, CTCs have reached maximal flexibility to change their differentiation status, morphology, migratory capacity, and their responses to genotoxic stress caused by metabolic changes, hormones, the inflammatory environment, or cytostatic treatment. A significant percentage of breast cancer cells are defective in homologous recombination repair and other mechanisms that protect the integrity of the replication fork. To prevent cell death caused by broken forks, alternative, mutagenic repair, and bypass pathways are engaged but these increase genomic instability. CTCs, arising from such breast tumors, are endowed with an even larger toolbox of escape mechanisms that can be switched on and off at different stages during their journey according to the stress stimulus. Accumulating evidence suggests that DNA damage responses, DNA repair, and replication are integral parts of a regulatory network orchestrating the plasticity of stemness features and transitions between epithelial and mesenchymal states in CTCs. This review summarizes the published information on these regulatory circuits of relevance for the design of biomarkers reflecting CTC functions in real-time to monitor therapeutic responses and detect evolving chemoresistance mechanisms

Is there evidence behind pre- or perioperative cognitive training in gynaecological patients on the prevention of perioperative cognitive dysfunction? A review

Purpose!#!Perioperative cognitive dysfunction can be observed in all age groups of patients. Sometimes, this is more stressful to the patient than the actual surgical wound. Enhanced recovery after surgery pathways screen for patients at risk and lead to early post-surgical intervention. To prevent cognitive dysfunction, a prehabilitation approach might be useful.!##!Methods!#!This systematic literature review provides an overview on the current knowledge on prehabilitation for cognitive dysfunction for gynaecological patients by searching the National Library of Medicine (PubMed) in February 2020 to identify publications regarding presurgical cognitive training with three different search terms.!##!Results!#!501 articles were identified and after screening for eligibility five were left for further analysis. Generally, cognitive function is split into several cognitive aspects like anxiety or memory, speed, attention, flexibility or problem-solving functions. Each of these aspects can/need to be trained to show an improvement after general anaesthesia. Training possibilities range from relaxation methods via music, one-on-one personal training sessions to electronically supported training units.!##!Conclusion!#!Prehabilitation of the cognitive function can be split in different cognitive domains. Each of these domains seem to be influenced by training. The training itself can be based on applications or known relaxation methods or even old-fashioned board games. The evidence is, however, still low and there is a need for further studies