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Objectives: Part 1 of the RUBY trial (NCT03981796) demonstrated improved survival in patients with primary advanced or recurrent endometrial cancer (EC) treated with dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel. Here, we examine additional efficacy and safety data from patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) EC in the RUBY trial., Methods: Patients were randomized 1:1 to dostarlimab 500 mg or placebo plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo every 6 weeks for up to 3 years. In the dMMR/MSI-H population of RUBY Part 1, analysis of progression-free survival by investigator assessment compared with blinded independent central review, sensitivity analyses of the source-verified population compared with the randomized population, and analysis of safety in this population were completed., Results: In total, 118 patients with dMMR/MSI-H were enrolled in the RUBY trial (53, dostarlimab arm; 65, placebo arm). At the first interim analysis, a 72% reduction in the risk of progression or death (P < 0.0001) was seen with dostarlimab plus carboplatin-paclitaxel by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which was consistent with blinded independent central review per RECIST v1.1. Likewise, sensitivity analyses of the source-verified dMMR/MSI-H population compared with the randomized dMMR/MSI-H population were consistent for progression-free survival and overall survival. Safety results seen in the dMMR/MSI-H population were similar to those previously reported for the overall population., Conclusions: All primary and secondary efficacy assessments demonstrate the consistent benefit of dostarlimab plus carboplatin-paclitaxel. The improvements seen in survival and the manageable safety profile support the favorable benefit-risk profile for dostarlimab plus carboplatin-paclitaxel in patients with dMMR/MSI-H primary advanced or recurrent EC., Competing Interests: Declaration of competing interest Matthew A. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, and Merck. David Cibula reports participation on an advisory board from Akesobio, AstraZeneca, GSK, MSD, Novocure, Roche, Seagen, and Sotio. David M. O'Malley reports grants from Ajinomoto, BMS, Cerulean Pharma, GOG Foundation, INC Research, InVentiv Health Clinical, Iovance Biotherapeutics, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA International, Serono, Stemcentrx, Tracon Pharmaceuticals, and Yale University; has been a consultant/advisory board member for AbbVie, Ambry, Amgen, Array Biopharma, Clovis Oncology, EMD Serono, Ergomed, Janssen/Johnson & Johnson, Myriad Genetics, Novocure, Regeneron, Tarveda, and VentiRx; was a member of a steering committee for Genentech/Roche and Merck; and received personal fees from Agenus, Eisai, GSK and ImmunoGen. Ingrid Boere reports institutional research grant from GSK and institutional advisory board meeting fees from AstraZeneca and GSK. Mark S. Shahin reports institutional grants from AstraZeneca, GSK, and Merck; honoraria from AstraZeneca, GSK, Merck, and Seagen; expert testimony fees from Robinson & Havens PSC, Lexington, KY; advisory board fees from Seagen; and board member for Unite for Her. Antonella Savarese reports institutional funding and provision of study materials from GSK and MSD; institutional funding and provision of study material for other clinical trials from GSK and MSD; honoraria from GSK and MSD; support for attending meetings and/or travel from GSK, MSD, and PharmaMar; and advisory board honoraria from Eisai and MSD. Dana M. Chase reports consultant fees from AstraZeneca and GSK and honoraria from AstraZeneca, GSK, ImmunoGen, and Seagen/Genmab. Lucy Gilbert reports institutional grants from Alkermes, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Esperas, GOG Foundation, GSK, ImmunoGen, IMV, K-Group Beta, Karyopharm Therapeutics, MSD, Mersana Therapeutics, Novocure GmbH, OncoQuest Pharmaceuticals, Roche, Shattuck Labs, Sutro BioPharma, and Tesaro; consulting fees from GSK and Merck; honoraria from CanariaBio, Eisai, Eisai-Merck, GOG Foundation, GSK, ImmunoGen, Kora Healthcare, and Merck; travel support from EndomEra, GOG Foundation, GSK, Merck, and Zentalis; and participation on a data safety monitoring board or advisory board from CanariaBio, Eisai, Eisai-Merck, GOG Foundation, GSK, ImmunoGen, Kora Healthcare, and Merck. Destin Black reports institutional grant fees from GSK; fees for being a member of GOG Partners Investigational Council; and medical director/owner of Trials365, LLC. Jørn Herrstedt reports consultant fees from Elsai. Sudarshan Sharma has nothing to disclose. Stefan Kommoss reports grants from GSK; consulting fees from AstraZeneca, Eisai, GSK, MSD, and Roche; and participating on a data safety monitoring board or advisory board for AstraZeneca, GSK, MSD, and Roche. Michael A. Gold has nothing to disclose. Anna M. Thijs has nothing to disclose. Kari Ring has nothing to disclose. Magnus Frödin Bolling reports press-release comment fees from GSK. Joseph Buscema reports honorarium for participation in an advisory committee from GSK. Sarah E. Gill has nothing to disclose. Paul Nowicki has nothing to disclose. Nicole Nevadunsky has nothing to disclose. Michael Callahan has nothing to disclose. Lyndsay Willmott reports speakers' bureau fees from AstraZeneca, Eisai, ImmunoGen, Merck, and Seagen and advisory board fees from AstraZeneca, ImmunoGen, and Seagen. Carolyn McCourt reports personal royalties <$200 annually from UpToDate and personal honoraria of $200 from the Washington University OB/Gyn annual symposium. Caroline Billingsley has nothing to disclose. Sharad A. Ghamande reports institutional fees from the Georgia Cancer Center for trial and consulting and speakers' bureau fees from GSK and Eisai. Zangdong He, Morad Marco Balas, and Shadi Stevens are employees of GSK. Evelyn Fleming has nothing to disclose. Mansoor Raza Mirza reports reports consulting fees from AstraZeneca, Biocad, GSK, Karyopharm Therapeutics, Merck, Roche, and Zailab; speakers' bureau fees from AstraZeneca and GSK; research funding (to institution) from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm Therapeutics (stocks/shares, member of board of directors)., (Copyright © 2024. Published by Elsevier Inc.)

Objective: In the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin-paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin-paclitaxel, with manageable toxicity, in patients with primary advanced or recurrent endometrial cancer. Here we report on patient-reported outcomes in the mismatch repair-deficient/microsatellite instability-high population, a secondary endpoint in the trial., Methods: Patients were randomized 1:1 to dostarlimab+carboplatin-paclitaxel or placebo+carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo monotherapy every 6 weeks for ≤3 years or until disease progression. Patient-reported outcomes, assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Endometrial Cancer Module, were prespecified secondary endpoints. A mixed model for repeated measures analysis, a prespecified exploratory analysis, was conducted to generate least-squares means to compare between-treatment differences while adjusting for correlations across multiple time points within a patient and controlling for the baseline value. Results are provided with 2-sided, nominal p values., Results: Of 494 patients enrolled, 118 were mismatch repair-deficient/microsatellite instability-high. In this population, mean change from baseline to end of treatment showed visual improvements in global quality of life (QoL), emotional and social function, pain, and back/pelvis pain for dostarlimab+carboplatin-paclitaxel. Meaningful differences (least-squares mean [standard error]) favoring the dostarlimab arm were reported for change from baseline to end of treatment for QoL (14.7 [5.45]; p=0.01), role function (12.7 [5.92]); p=0.03), emotional function (14.3 [4.92]; p<0.01), social function (13.5 [5.43]; p=0.01), and fatigue (-13.3 [5.84]; p=0.03)., Conclusions: Patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin-paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin-paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin-paclitaxel as a standard of care in this setting., Trial Registration: ClinicalTrials.gov NCT03981796., Competing Interests: Competing interests: GV reports consulting fees from GSK; honoraria from AstraZeneca, GSK, and MSD; travel support from AstraZeneca and PharmaMar; participation in advisory boards for AstraZeneca, Eisai, GSK, and MSD. MAP reports consulting fees from GSK, Tesaro, Merck, Eisai, SeaGen, Clovis Oncology, and AstraZeneca. SH reports consulting fees from AstraZeneca, Eisai, GSK, and MSD and honoraria from AstraZeneca and GSK. EMM reports advisory board meeting fees from AstraZeneca, GSK, and Tempus; honoraria from OncLive and Opinions in Gyn Malignancies; and support for attending meetings from Opinions in Gyn Malignancies and OncLive. ZN reports honoraria from Sofmedica, AstraZeneca, and MSD; support for attending meetings from Sofmedica and Preglem; participation on a data safety monitoring board or advisory board for AstraZeneca and Richter Gedeon; stock options from Richter Gedeon; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from AstraZeneca. RH reports honoraria from GSK, AstraZeneca, Clovis Oncology, Eisai, and Merck. DD reports receiving consulting fees from AstraZeneca, GSK/Tesaro, Roche, Eisai Germany, and MSD Oncology; honoraria for advisory roles from Roche, AstraZeneca, GSK/Tesaro, Intuitive Surgical, KLS Martin, MSD, PharmaMar, and Seagen; and travel support from AstraZeneca. TM reports honoraria from Immunogen. LG reports institutional grants from Alkermes, AstraZeneca, Clovis Oncology, Esperas, IMV, ImmunoGen, Karyopharm, MSD, Mersana, Novocure, OncoQuest Pharmaceuticals, Pfizer, Roche, and Tesaro; consulting fees from Merck; honoraria from Alkermes, AstraZeneca, Eisai, Eisai-Merck, and GSK. BA reports honoraria from AstraZeneca, Eisai, GSK, MSD, Norartis, and Roche; support for attending meetings from AstraZeneca, GSK, and Roche; participation on a data safety monitoring board or advisory board for Eisai, GSK, MSD, Roche, and Sanofi Aventis. RG reports participation on a data safety monitoring board or advisory board for Pionyr Pharmaceuticals and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Bausch+Lomb. NC reports advisory board fees for Aadii, GSK, Kartos, Novita Pharmaceuticals, Tarveda Therapeutics, Toray, Umoja, and Zentalis. BJM reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers’ bureau honoraria from AstraZeneca, Clovis Oncology, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis Oncology, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and President of GOG Partners. AS reports royalties as an UptoDate reviewer. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, SeaGen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, Atossa, Clovis Oncology, Deciphera, Elevar Therapeutics, I-Mab Biopharma, Merck, Mersana, Sutro Biopharma, Tesaro/GSK, and Toray; support for attending meetings from GOG Foundation; advisory board fees from Arquer Diagnostics, AstraZeneca, Atossa, Clovis Oncology, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-Mab Biopharma, Lilly, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Toray, and VBL Therapeutics; and noncompensated leadership fees from NYOB Society Secretary, SGO Clinical Practice Committee Chair, and SGO COVID-19 Taskforce Co-Chair. AAS reports support paid to her institution from GSK for the present IGCS abstract; institutional grant support from AbbVie, Aravive, AstraZeneca, Clovis Oncology, Eisai, Ellipses, I-Mab Biopharma, Immunogen, Merck, Oncoquest/Canaria Bio, Roche/Genentech, Seagen, TapImmune, Tesaro/GSK, and VBL Therapeutics; honoraria from @Point of Care Clinical Care Options Curio Science, Peerview, Bio ASCEND, RTP, GOG Foundation (Highlight reel), and GOG Foundation Symposium; patent issued for 'blood based biomarkers in ovarian cancer'; noncompensated participation on a data safety monitoring board/advisory board from AstraZeneca, Clovis Oncology, Gilead, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, and OncoQuest; uncompensated leadership roles with SGO, AAOGF, and NRG and compensated role from GOG; receipt of medical writing support from AstraZeneca; and uncompensated Clinical Trial Steering Committees for the AXLerate trial (Aravive), AtTEnd trial (Hoffman-LaRoche), Oval Trial (VBL Therapeutics), FLORA-5 trial (CanariaBio), and QPT-ORE-004 (CanariaBio). DC reports consultant fees from AstraZeneca and GSK and honoraria from AstraZeneca, GSK, Seagen/Genmab, and Immunogen. MRM reports consulting fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zai Lab; speakers’ bureau fees from AstraZeneca and GSK; research funding (to institution) from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors). DB reports institutional grant fees from GSK; fees for being a member of GOG Partners Investigational Council; and medical director/owner of Trials365. AMT, KPP, EF, OZ, LML, IP, and SS have nothing to disclose. OM, VV, and JG are employees of GSK., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype -guided targeted therapy to improve survival without compromising quality of life., Study Design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness., Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jurgen Piek reports equipment, drugs, or supplies was provided by InnoSIGN. Phyllis van der Ploeg reports a relationship with Catharina Research Fund that includes: funding grants. Cynthia Hendrikse reports a relationship with Catharina Research Fund that includes: funding grants. Phyllis van der Ploeg reports a relationship with InnoSIGN that includes: funding grants. Cynthia Hendrikse reports a relationship with InnoSIGN that includes: funding grants., (© 2024 The Authors. Published by Elsevier Ltd.)

Introduction: Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs and pharmacokinetics in this setting. This study aims to explore these parameters in patients with isolated unresectable colorectal PM who receive repetitive ePIPAC-OX as a palliative monotherapy., Methods and Analysis: This multicentre, open-label, single-arm, phase II study is performed in two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM. Eligible patients are adults who have histologically or cytologically proven isolated unresectable PM of a colorectal or appendiceal carcinoma, a good performance status, adequate organ functions and no symptoms of gastrointestinal obstruction. Instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled ePIPAC-OX (92 mg/m 2 body surface area (BSA)) with intravenous leucovorin (20 mg/m 2 BSA) and bolus 5-fluorouracil (400 mg/m 2 BSA) every 6 weeks. Four weeks after each procedure, patients undergo clinical, radiological and biochemical evaluation. ePIPAC-OX is repeated until disease progression, after which standard palliative treatment is (re)considered. The primary outcome is the number of patients with major toxicity (grade ≥3 according to the Common Terminology Criteria for Adverse Events v4.0) up to 4 weeks after the last ePIPAC-OX. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, minor toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, pharmacokinetics of oxaliplatin, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical and macroscopic tumour response., Ethics and Dissemination: This study is approved by an ethics committee, the Dutch competent authority and the institutional review boards of both study centres. Results are intended for publication in peer-reviewed medical journals and for presentation to patients, healthcare professionals and other stakeholders., Trial Registration Number: NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: In patients with diabetes treated with sunitinib symptomatic hypoglycaemia has been reported. To explore the mechanism of this adverse effect we performed a prospective study to investigate the effect of sunitinib on insulin concentration, insulin clearance and insulin sensitivity., Methods: We studied the early effects of sunitinib on insulin sensitivity and insulin clearance with a hyperinsulinaemic euglycaemic clamp (insulin infusion rate 60 mU m−2 min−1; steady-state 90–120 min) in patients with renal cell carcinoma before and 1 week after the start of sunitinib 50 mg day−1. Insulin sensitivity index (SI) was defined as steady-state glucose disposal divided by the steady-state plasma insulin., Results: Ten patients (one with diabetes, treated with metformin) were included in the study protocol. Steady-state insulin concentrations during the clamp increased after 1 week of sunitinib (from 128.9 ± 9.0 mU l−1 to 170.8 ± 12.8 mU l−1, P < 0.05; 95% CI on difference − 64.3, −19.6). The calculated insulin sensitivity index decreased from 0.22 ± 0.04 before to 0.18 ± 0.02 μmol kg−1 min−1 per mU l−1 insulin (P < 0.05; 95% CI on difference 0.07, 0.08). As the insulin infusion rate was similar for both clamps, the increased steady-state insulin concentration indicates reduced insulin clearance., Conclusion: Sunitinib affects insulin clearance which could possibly lead to overexposure to insulin in patients using insulin or insulin-secretion stimulating agents.

Background: Tyrosine kinase inhibitors targeting angiogenesis have become an important part of the treatment of patients with several types of cancer. One of the most reported side effects of vascular endothelial growth factor receptor (VEGFR)-targeted therapies is hypertension. In this study, we hypothesized that the development of hypertension in patients treated with sunitinib, a multitargeted tyrosine kinase inhibitor, is preceded by reduced endothelium-dependent vasodilation. Moreover, we hypothesized that this endothelial dysfunction is a result of impaired nitric oxide release., Method: In a placebo-controlled experiment, we determined vascular responses in isolated mesenteric arteries of rats (n = 26) after 7 days of sunitinib treatment., Results: Sunitinib reduced endothelium-dependent vasodilation, but not endothelium-independent vasodilation. Moreover, we observed that the difference in endothelium-dependent vasodilation between controls and sunitinib-treated animals disappeared in the presence of N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide antagonist. In patients with metastatic renal cell carcinoma, before and 1 week after start of sunitinib, the endothelium-dependent vasodilator response to intra-arterial acetycholine and the endothelium-independent vasodilator response to intra-arterial sodium nitroprusside was assessed with venous occlusion plethysmography. No changes in forearm blood flow ratios were observed. Mean arterial pressure did significantly increase from 101.9 ± 3.8 to 106.1 ± 2.6 mmHg after 1 week and further to 115.8 (±4.9) mmHg after 2 weeks of treatment., Conclusion: In animals, this study confirms that exposure to high concentrations of sunitinib reduces endothelium-dependent vasodilation by reducing endothelial release of nitric oxide. In humans, however, reduced endothelium-dependent vasodilation does not precede the development of hypertension in patients treated with sunitinib.

Concerns have been raised about the development of heart failure in patients treated for cancer with angiogenesis inhibitors, such as the tyrosine kinase inhibitor sunitinib. Patients with previous coronary artery disease and hypertension have an increased risk of developing heart failure. Therefore, we studied the effect of sunitinib on the contractility of isolated human atrial trabeculae and the effect on recovery after ischemic stimulation. After informed consent, the atrial appendage of patients undergoing cardiac surgery was harvested and isolated trabeculae were placed in an organ bath with a force transducer. During electrical stimulation, contractile force was measured during normal pacing or after simulated ischemia. Of each patient, one trabecula was perfused with control and one with sunitinib. Contractile force (expressed as percentage of baseline force) declined over time to 57 ± 8 and 73 ± 20% after 150 min of stimulation for solvent- and sunitinib-treated trabeculae, respectively (mean ± SE; n = 8; p > 0.1). After simulated ischemia and reperfusion, contractile force was 40 ± 6% in the control compared to 39 ± 6% in the sunitinib-treated trabeculae during the last final 5 min of reperfusion (n = 12; p > 0.1). Sunitinib at low, but clinically relevant, concentrations does not have a direct effect on function of human atrial cardiomyocytes nor does it attenuate the recovery in contractile force of atrial cardiomyocytes after a period of ischemia. A direct and acute toxic effect on cardiomyocytes does not explain the development of heart failure in patients treated with sunitinib.

Background: The use of therapeutic monoclonal antibodies for clinical purposes has significantly increased in recent years, and so has the need to monitor antibody concentrations. This may be achieved using the well-established enzyme linked immunoassay (ELISA) methods; however, these assays are subject to a variety of interferences., Methods: In the present study, the authors have tested the ELISA methods for quantifying bevacizumab (BVZ) to investigate this interference. Three different ELISA methods were used and exhibited similar characteristics., Results: The detection limits of the ELISA methods varied from 0.05 to 0.07 ng/mL. To monitor assay performance, BVZ was measured in a control sample during each run. The BVZ concentration in the control sample was 15.4 μg/mL, the within-run imprecision (CV) and between-run CV were 4.3% and 10.4% (direct ELISA), 5.2% and 12.9% (indirect/Rabbit ELISA), and 3.9% and 9.1% (indirect/Chicken ELISA). The assays exhibited good precision and parallelism in serial dilutions of samples and a mean recovery of 98% (range, 78%-118%)., Conclusions: The authors show that the degree of interference by using direct and indirect target immobilization depends heavily on the method of target immobilization on the surface of the ELISA plate, and is patient-specific. The results highlight pitfalls of potential relevance to sandwich-type assays, and an approach to rectify such problems. This approach will yield a valid assay protocol for the measurement of monoclonal therapeutic antibodies in case no target is available for direct immobilization.

Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. Hypertension is the most reported side effect of angiogenesis inhibitors interfering with vascular endothelial growth factor signaling. In this study, we test the hypothesis that circulating vascular endothelial growth factor at physiological concentrations is essential to preserve normal endothelial control of vasomotor tone. In 7 healthy male volunteers, infusion of bevacizumab (monoclonal vascular endothelial growth factor antibody) into the brachial artery for 15 minutes (144 μg/dL forearm volume per minute) did not affect forearm vasodilator tone as measured with venous occlusion strain gauge plethysmography. In a separate group of 12 male volunteers, a similar bevacizumab infusion reduced the vasodilator response to 2 dosages of acetylcholine from (mean ± SE) 440 ± 157% and 926 ± 252% to 169 ± 40% and 612 ± 154% (P<0.05). Finally, in a third group of 12 volunteers, bevacizumab did not alter the percentage increase in forearm blood flow during infusion of sodium nitroprusside at dosages equipotent to acetylcholine. Bevacizumab acutely and specifically reduced endothelium-mediated vasodilation at local concentrations that resemble plasma concentrations after systemic exposure to bevacizumab. This observation suggests a physiological role for vascular endothelial growth factor in maintaining normal endothelial control of vasomotor tone. The role of the endothelium in the mechanism of bevacizumab-induced hypertension deserves further exploration.

Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive neoplasm that mostly occurs in young males. No curative treatment options currently exist for this type of tumor and long-term survival remains poor. In vitro rapamycin induces apoptotic death of JN-DSRCT-1 cells, a possible model for desmoplastic small round cell tumors in which the EWS gene is fused to the WT1 gene. We therefore demonstrate the prolonged activity of temsirolimus, an mTOR-inhibitor, in a patient with DSRCT.