Search

Purpose: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN)., Methods: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences., Results: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL., Conclusion: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL., Competing Interests: Brian SlomovitzConsulting or Advisory Role: Clovis Oncology, AstraZeneca, Genentech, Incyte, Agenus, GlaxoSmithKline, GOG Foundation, Myriad Genetics, Merck, Eisai Ignace VergoteConsulting or Advisory Role: Amgen, AstraZeneca, Clovis Oncology, Carrick Therapeutics, Deciphera, Elevar Therapeutics, Genmab, GlaxoSmithKline, Immunogen, Jazz Pharmaceuticals, Mersana, MSD, Novocure, OCTIMET Oncology NV, Oncoinvent, Sotio, Verastem, Zentalis, Roche, MillenniumResearch Funding: Roche, Genmab, Amgen, OncoinventTravel, Accommodations, Expenses: Roche, AstraZeneca, Tesaro, Amgen, MSD/Merck Mats BrännströmStock and Other Ownership Interests: EUGIN Sweden Martin WidschwendterStock and Other Ownership Interests: Sola Diagnostics, BreOva HealthPatents, Royalties, Other Intellectual Property: Patents relevant for risk prediction or diagnosis of women's cancers Paul A. DiSilvestroConsulting or Advisory Role: AstraZeneca, AgenusResearch Funding: Janssen Oncology, Tesaro, AstraZeneca, Genentech, AbbVie Robert MannelConsulting or Advisory Role: Tesaro Dorry BollResearch Funding: AstraZeneca David CibulaConsulting or Advisory Role: AstraZeneca, Sotio, Roche, GlaxoSmithKline Diane ProvencherConsulting or Advisory Role: AstraZeneca, GlaxoSmithKlineResearch Funding: AstraZeneca, AbbVie Ingo B. RunnebaumConsulting or Advisory Role: AbbVie (I), Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Oncgnostics, Tesaro Preben KjølhedeResearch Funding: Leo Pharma AB Katharina E. KieserHonoraria: AstraZenecaConsulting or Advisory Role: MerckResearch Funding: AstraZeneca Nicola M. SpirtosResearch Funding: AbbVie, AstraZeneca, Genentech/Roche, Clovis Oncology, Seattle GeneticsPatents, Royalties, Other Intellectual Property: Application No. PCT/US 2019/19465 Cannabis Based Therapeutic and Method of Use Application No, US Patent 0024098766 Compounds Cannabidiol and Flavanones 63/047550 (July 1, 2020) 63/055458 (July 23, 2020) David M. O'MalleyConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute, Agenus, Marker Therapeutics, Eisai, Genelux, Iovance Biotherapeutics, Ambry Genetics, Tarveda Therapeutics, Leap Therapeutics, Myriad Genetics, GlaxoSmithKline, Regeneron, Sorrento Therapeutics, Rubius Therapeutics, Elevar Therapeutics, Novartis, Seagen, BBI Healthcare, Arquer Diagnostics, Toray Medical, Takeda, InxMed, Celsion, Roche Diagnostics MSAResearch Funding: Amgen, AstraZeneca, Genentech/Roche, Regeneron, Immunogen, Janssen Research & Development, Clovis Oncology, EMD Serono, Ergomed, Ajinomoto, Cerulean Pharma, PharmaMar, Array BioPharma, Bristol Myers Squibb, Agenus, Tesaro, TRACON Pharma, Genmab, Seattle Genetics, Iovance Biotherapeutics, Leap Therapeutics, Merck, AbbVie/Stemcentrx, AbbVie, Mersana, Eisai, BBI Healthcare, Sumitomo Dainippon Pharma Oncology Mario M. LeitaoHonoraria: Intuitive SurgicalConsulting or Advisory Role: Intuitive Surgical, Ethicon/Johnson & Johnson, Medtronic, TakedaResearch Funding: KCITravel, Accommodations, Expenses: Intuitive Surgical Melissa A. GellerResearch Funding: Tesaro, Genentech, FATE Therapeutics, Morphotek, Bayer Karl TamussinoOther Relationship: Medtronic Daniel H. TobiasConsulting or Advisory Role: Ethicon Jayanthi S. LeaConsulting or Advisory Role: Roche Brynhildur EyjolfsdottirOther Relationship: Intuitive Surgical Krishnansu S. TewariHonoraria: Tesaro, Clovis OncologyConsulting or Advisory Role: Roche/Genentech, Tesaro, Clovis Oncology, AstraZenecaSpeakers' Bureau: Roche/Genentech, AstraZeneca, Merck, Tesaro, Clovis OncologyResearch Funding: AbbVie, Genentech/Roche, Morphotek, Merck, RegeneronTravel, Accommodations, Expenses: Roche/Genentech Ranjit ManchandaHonoraria: AstraZeneca Linda Van LeConsulting or Advisory Role: EyePoint Pharmaceuticals, Novartis, Advarum, Neurotech, Iveric, Gemini Therapeutics, NaegisResearch Funding: GOG Partners Trial Bradley J. MonkLeadership: US OncologyHonoraria: AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoID, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Geistlich Pharma, Genmab/Seattle Genetics, ImmunoGen, Immunomedics, Incyte, Iovance Biotherapeutics, Laekna Health Care, Merck, Mersana, Myriad Pharmaceuticals, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Senti Biosciences, Takeda, Tarveda Therapeutics, Tesaro/GSK, Vavotar Life Sciences, Vascular Biogenics, Vigeo Therapeutics, GOG Foundation, Starton Therapeutics, Elevar Therapeutics, Novocure, Gradalis, Karyopharm TherapeuticsConsulting or Advisory Role: AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Geistlich Pharma, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Immunomedics, Incyte, Iovance Biotherapeutics, Laekna Health Care, Merck, Mersana, Myriad Pharmaceuticals, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Senti Biosciences, Takeda, Tarveda Therapeutics, Tesaro/GSK, Vavotar Life Sciences, Vascular Biogenics, Vigeo Therapeutics, Gradalis, Karyopharm Therapeutics, Sorrento Therapeutics, NovocureSpeakers' Bureau: Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, Tesaro/GSK, MerckResearch Funding: Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, Tesaro, Morphotek, Pfizer, Advaxis, AstraZeneca, Immunogen, Regeneron, Nucana Carien L. CreutzbergConsulting or Advisory Role: MerckResearch Funding: Elekta, Varian Medical SystemsNo other potential conflicts of interest were reported.

Background: The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required., Methods: A cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease., Results: We have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, p < 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman's Rank Order Correlation: ρ = - 0.3914, p < 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease., Conclusions: These data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients.

The initial steps of the electrochemical reduction of CO2 at Pt electrodes were computationally investigated at the molecular level. Simulations were performed with density functional theory using the B3LYP functional and effective core potential basis sets. The surface was modeled through two clusters comprising 13 and 20 atoms. An implicit solvation model was used to describe solvation effects for two different solvents: water and acetonitrile. It was found that CO2 adsorption is highly favored on negatively charged clusters and takes place passing from a well-defined transition state. The computational evidence suggests that the electrodic CO2 adsorption reaction may be described as a concerted process in which an electron-transfer reaction takes place contextually to CO2 adsorption. Also, the present results suggest that the formation of the CO2(•–) aqueous species is significantly unfavored from an energetic standpoint and that its main fate, if formed, would be most likely that of getting adsorbed again on the Pt surface. The calculation of the pKa of adsorbed CO2(–) showed that its protonation reaction is thermodynamically favored in most electrochemical conditions used for CO2 reduction. Also, it was found that the free-energy difference between adsorbed formate and adsorbed COOH favors the latter, suggesting that the interconversion kinetics of these two species at a Pt surface may play an important role in determining the system reactivity. A tentative global mechanism able to describe the CO2 reactivity on Pt surfaces is proposed.