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Metastasis‐associated in colon cancer 1 (MACC1) and S100 calcium‐binding protein A4 (S100A4) are prominent inducers of tumor progression and metastasis. For the first time, we systematically tracked circulating serum levels of MACC1 and S100A4 transcripts in the course of surgery and chemotherapy and analyzed their clinical relevance for ovarian cancer. MACC1 and S100A4 transcripts were quantified in a total of 318 serum samples from 79 ovarian cancer patients by RT‐qPCR and digital droplet PCR, respectively. MACC1 and S100A4 transcripts were significantly elevated in serum of ovarian cancer patients, compared to healthy controls (P = 0.024; P

Poster-Abstract

Poster-Abstract

Supplemental material for "No Long-Term Effects of Antenatal Synthetic Glucocorticoid Exposure on Epigenetic Regulation of Stress-Related Genes" by S. Müller, D. Moser, L. Frach, P. Wimberger, K. Nitzsche, S.-C. Li, C. Kirschbaum and N. Alexander submitted to the Journal of Clinical Endocrinology and Metabolism (JCEM)

Since the publication of the updated German guideline in 2015, the recommendations for performing pelvic lymphadenectomy (LAE) in patients with vulvar cancer (VSCC) have changed considerably. The guideline recommends surgical lymph node staging in all patients with a higher risk of pelvic lymph node involvement. However, the current data do not allow the population at risk to be clearly defined, therefore, the indication for pelvic lymphadenectomy is still not clear. There are currently two published German patient populations who had pelvic LAE which can be used to investigate both the prognostic effect of histologically verified pelvic lymph node metastasis and the relation between inguinal and pelvic lymph node involvement. A total of 1618 patients with primary FIGO stage ≥ IB VSCC were included in the multicenter AGO CaRE-1 study (1998-2008), 70 of whom underwent pelvic LAE. During a retrospective single-center evaluation carried out at the University Medical Center Hamburg-Eppendorf (UKE), a total of 514 patients with primary VSCC treated between 1996-2018 were evaluated, 21 of whom underwent pelvic LAE. In both cohorts, around 80% of the patients who underwent pelvic LAE were inguinally node-positive, with a median number of three affected groin lymph nodes. There were no cases of pelvic lymph node metastasis without inguinal lymph node metastasis in either of the two cohorts. Between 33-35% of the inguinal node-positive patients also had pelvic lymph node metastasis; the median number of affected groin lymph nodes in these patients was high (> 4), and the maximum median diameter of the largest inguinal metastasis was > 40 mm in both cohorts. Pelvic lymph node staging and pelvic radiotherapy is therefore probably not necessary for the majority of node-positive patients with VSCC, as the relevant risk of pelvic lymph node involvement was primarily found in node-positive patients with high-grade disease. More, ideally prospective data collections are necessary to validate the relation between inguinal and pelvic lymph node involvement.

The approval of trastuzumab emtansine (T-DM1) was conducted without pertuzumab as previous therapy. Efficacy data on T-DM1 following pertuzumab treatment are therefore limited. This study explores this issue in a real-world setting. Within the prospective PRAEGNANT (Prospective Academic Translational Research Network for the Optimization of the Oncological Health Care Quality in the Advanced Setting) metastatic breast cancer registry (NCT02338167), patients in all therapy lines receiving any kind of treatment were eligible for inclusion. This report describes patient characteristics and progression-free survival (PFS) in human epidermal growth factor receptor 2 (HER2)-positive patients receiving T-DM1 after pertuzumab treatment. Seventy-six patients were identified, 39 of whom received T-DM1 as second-line therapy, 25 as third-line, and 12 as fourth-line therapy or higher. Pertuzumab was mostly administered as a first-line treatment (n = 61, 80.3%). The median PFS in all patients was 3.5 months (95% CI: 2.8&ndash, 7.8), in second-line treatment, 7.7 months (95% CI: 2.8&ndash, 11.0), in third-line, 3.4 months (95% CI: 2.3&ndash, not reached (NR)), and in fourth-line therapy or higher, 2.7 months (95% CI: 1.2&ndash, NR). T-DM1 was mainly administered second-line after pertuzumab, but also in more heavily pretreated patients. The PFS in higher therapy lines appears to be shorter than in second-line.

The authors wish to clarify that the authors Aljosa Mandic, Katarina Koprivsek, and Goran Malenkovic are also affiliated with Faculty of Medicine Novi Sad, University of Novi Sad, Serbia, as well as Gynecologic Oncology Department Clinic for Operative Oncology, Institute of Oncology of Vojvodina, Serbia.

The authors wish to clarify that the authors Aljosa Mandic, Katarina Koprivsek, and Goran Malenkovic are also affiliated with Faculty of Medicine Novi Sad, University of Novi Sad, Serbia, as well as Gynecologic Oncology Department Clinic for Operative Oncology, Institute of Oncology of Vojvodina, Serbia.

Additional file 6: Suppl. Fig. 6. Uncropped Western Blots for Fig. 2a. The figure shows all original uncropped blots. As some membranes were used to simultaneously detect Ras and cleaved PARP (after cutting), the pictures here also include the Ras original blots used for Fig. 1a to keep the originality. All original blots for GAPDH are also included. Representative cropped GAPDH images are shown in Fig. 2a.

Additional file 8: Suppl. Fig. 8. Uncropped Western Blots for Supplementary Figure 4b.

Additional file 2: Suppl. Fig. 2. Statins and zoledronic acid (ZOL) do not modulate the expression of B-cell lymphoma 2 (BCL-2), but downregulate survivin (SVV) in A2780 cells. A2780 cells were treated with increasing concentrations of atorvastatin (ATO), simvastatin (SIM), rosuvastatin (ROSU) or ZOL for 24 h. Expression of BCL-2 and SVV was assessed by real-time-PCR. Data are shown as mean ± SEM of at least three individual experiments. *p < 0.05; **p < 0.01; ***p < 0.001 vs. respective control (0 μM).

Additional file 1: Suppl. Fig. 1. The colony-forming ability of IGROV1 cells is significantly impaired by simvastatin (SIM). IGROV1 cells were seeded in 6-well plates (200 cells/cavity) and treated with atorvastatin (ATO), SIM, rosuvastatin (ROSU) or zoledronic acid (ZOL) for 9-10 days. The resulting colonies were stained with a crystal violet solution. a. The crystal violet staining was eluted with 10% SDS and the absorbance was measured at 595 nm. b. Counting of the colonies (absolute numbers). c. Representative pictures of the colonies. Data are shown as mean ± SEM of at least three individual experiments. *p < 0.05 vs. respective control (C).

Additional file 7: Suppl. Fig. 7. Uncropped Western Blots for Supplementary Figure 3a.

Additional file 5: Suppl. Fig. 5. Uncropped Western Blots for Fig. 1a. The figure shows all original uncropped blots. As some membranes were used to simultaneously detect Ras and cleaved PARP (after cutting), the pictures here also include the cleaved PARP original blots used for Fig. 2a to keep the originality. All original blots for GAPDH are also included. Representative cropped GAPDH images are shown in Fig. 1a.

Additional file 3: Suppl. Fig. 3. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) specifically rescue farnesylation or geranylgeranylation and vitality upon mevalonate pathway inhibition in IGROV1 and A2780 cells. a. IGROV1 cells were treated with simvastatin (SIM; 10 μM) or zoledronic acid (ZOL; 50 μM), and supplemented with either FPP (50 μM) or GGPP (50 μM). Farnesylation of Ras, geranylgeranylation of Rap1A and cleavage of poly (ADP-ribose) polymerase (cPARP) were assessed by western blotting. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as loading control. The figures show representative blots which were cropped from original images. Full-length blots are presented in Suppl. Fig. 7. Images were detected using GelCapture 7.0.18 software. b. A2780 cells were treated with atorvastatin (ATO), SIM, rosuvastatin (ROSU) or ZOL and supplemented with 10 μM of either FPP or GGPP for 48 h. Cell vitality was assessed by CellTiterBlue® assay. Data are shown as mean ± SEM of at least three individual experiments. *p < 0.05; **p < 0.01; ***p < 0.001 vs. respective control (C). #p < 0.05; ##p < 0.01; ###p < 0.001 vs. respective treatment (-).

Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine–carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ?1 or, Breast Cancer Research Foundation, BCRF; Pfizer; AstraZeneca; Merck; Roche; Samsung; Merck Sharp and Dohme, MSD; Eisai, JC reports personal fees and research funding paid to his institution from Roche, AstraZeneca, Merck Sharp & Dohme, and Eisai; personal fees from Celgene, Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin, Novartis, Pfizer, Samsung Bioepis; research funding paid to his institution from Ariad Pharmaceuticals, Bayer Healthcare, F Hoffman-La Roche, Guardanth Health, Piqur Therapeutics, Puma C, and Queen Mary University of London, outside the submitted work. In addition, JC has a MedSIR patent pending. DWC reports research support from Merck during the conduct of the study; research support paid to his institution from Merck, Pfizer, and GlaxoSmithKline; personal fees from Merck, Roche–Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Puma, Agenda, Exact Sciences, and Dynamo Therapeutics, outside the submitted work. In addition, DWC has a Biomarkers of TTK inhibitors patent pending. HSR reports funding for sponsored studies paid to the University of California San Francisco from Pfizer, Novartis, Lilly, Roche–Genentech, Macrogenics, OBI, Merck, Eisai, Immunomedics, Daiichi Sankyo, Seattle Genetics, and Odonate; travel support for educational meetings from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and Macrogenics; and consulting fees from Samsung and Puma, outside the submitted work. S-AI reports grants from AstraZeneca, Eisai, Pfizer, Roche, and Daewoong; an advisory role for AstraZeneca, Amgen, Eisai, Hanmi, Novartis, Lily, MedPacto, Pfizer, and Roche; and travel expenses for presentation from Novartis, outside the submitted work. CG reports Advisory Board fees from Merck Sharp & Dohme and Roche; and speaker's bureau fees from Bristol Myers Squibb and AstraZeneca, outside the submitted work. CHB reports grants and fees from Merck Sharp & Dohme for clinical research consulting during the conduct of the study; consulting–advisory role fees from Boehringer Ingelheim, GlaxoSmithKline, and Bayer; consulting–advisory role fees and grants for clinical research from Novartis, Pfizer, Roche–Genentech, Eisai, Merck Sharp & Dohme, and AstraZeneca; grants for clinical research from Abbvie, Amgen, Astellas Pharma, Bristol Myers Squibb, Celgene, Covance, Lilly, Medication, Merck Serono, and PharmaMar; grants for academic research projects from CPO, Pontificia Universidade Católica do Rio Grande do Sul, Latin American Cooperative Oncology Group, Grupo Brasileiro Estudos Câncer Mama, and Instituto Nacional de Câncer-Brazil, outside the submitted work. HI reports a grant from Merck Sharp & Dohme during the conduct of the study; honoraria and consulting fees from Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Eisai, and Chugai; and a grant from Chugai, outside the submitted work. NM reports honoraria and research funding paid to his institution from Chugai, AstraZeneca, Pfizer, Eli-Lilly, Eisai, Takeda, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, and Daiichi Sankyo, outside the submitted work. EG reports non-financial support from Merck Sharp & Dohme during the conduct of the study; honoraria, consulting–advisory fees and meeting support from Novartis, Roche, Bristol Myers Squibb, and Pfizer; and honoraria from AstraZeneca and Astellas, outside the submitted work. SL reports research funding or consulting fees paid to her institution from Bristol Myers Squibb, Roche–Genentech, Puma Biotechnology, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, Eli Lilly, Aduro Biotech, GI Therapeutics, AstraZeneca, and GlaxoSmithKline; and non-remunerated consultancy for Bristol Myers Squibb, Roche–Genentech, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, and AstraZeneca, outside the submitted work. In addition, SL is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. ZG, JZ, GA, and VK are employees of Merck Sharp & Dohme and own stock or stock options in Merck. PS reports consultancy fees from Pfizer, AstraZeneca, Novartis, Roche, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; consultancy fees to his spouse from Genentech and Roche; and grants or funding to his institution from Roche, Genentech, Oncogenex, Novartis, Astellas, and AstraZeneca, outside the submitted work. All other authors declare no competing interests., The authors thank the patients, their families and caregivers for participating in this trial, all of the investigators and site personnel, and the following employees of Merck Sharp & Dohme: Wilbur Pan, Deborah Card, Eleanor Readinger, Shana Hamm, Roger Maxwell, and Krystal Bourdon, for collection of data, supervision of research, provision of study materials or patients or administrative or logistical support; Aline Galvao, for collection of data, supervision of research, administrative or logistical support, and review of imaging data related to the primary end point; Donna Letizia, for collection of data and imaging expertise; Jennifer Kimmel, for study management; Mercedes Bustamante, for data collection and management; Xuan Zhou and Madhusudhan Reddy Papasani, for statistical expertise; Christine McCrary Sisk, for medical writing and editorial assistance; and Joseph C Naggar and Michele McColgan, for administrative or logistical support.