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1. FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma

Author

Kirsten B. Goldberg, Lola Fashoyin-Aje, William F. Pierce, Marc R. Theoret, Sirisha Mushti, Paul G. Kluetz, Richard Pazdur, Yuan Li Shen, Leah Her, Leigh Marcus, Sandra Casak, Steven Lemery, and Joyce Cheng

Subjects
0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Abdominal pain, Constipation, Colorectal cancer, Nausea, medicine.medical_treatment, Pembrolizumab, Neutropenia, Antibodies, Monoclonal, Humanized, DNA Mismatch Repair, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, medicine, Humans, Drug Approval, Aged, Neoplasm Staging, Aged, 80 and over, Chemotherapy, business.industry, Middle Aged, medicine.disease, United States, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Vomiting, Female, Microsatellite Instability, medicine.symptom, business, Colorectal Neoplasms
Abstract

The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4–32.4) versus 8.2 months (95% CI: 6.1–10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45–0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0–30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.

Published
2021

2. Coronary artery calcification and aortic valve calcification in patients with kidney failure: a sex-disaggregated study

Author

Liam J. Ward, Agne Laucyte-Cibulskiene, Leah Hernandez, Jonaz Ripsweden, GOING-FWD Collaborators, Peter Stenvinkel, and Karolina Kublickiene

Subjects
Calcification, Calcific aortic valve disease, Cardiovascular disease, Chronic kidney disease, Inflammation, Oxidative stress, Medicine, Physiology, QP1-981
Abstract

Abstract Background Chronic kidney disease (CKD) is linked to an increased cardiovascular disease (CVD) burden. Albeit underappreciated, sex differences are evident in CKD with females being more prone to CKD development, but males progressing more rapidly to kidney failure (KF). Cardiovascular remodelling is a hallmark of CKD with increased arterial and valvular calcification contributing to CKD. However, little is known regarding sex differences in calcific cardiovascular remodelling in KF patients. Thus, we hypothesise that sex differences are present in coronary artery calcification (CAC) and aortic valve calcification (AVC) in patients with KF. Methods KF patients, males (n = 214) and females (n = 107), that had undergone computer tomography (CT) assessment for CAC and AVC were selected from three CKD cohorts. All patients underwent non-contrast multi-detector cardiac CT scanning, with CAC and AVC scoring based on the Agatston method. Baseline biochemical measurements were retrieved from cohort databases, including plasma analyses for inflammation markers (IL-6, TNF, hsCRP) and oxidative stress by skin autofluorescence measuring advanced glycation end-products (AGE), amongst other variables. Results Sex-disaggregated analyses revealed that CAC score was associated with age in both males and females (both p

Published
2023
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3. FDA Approval Summary: Eribulin for Patients with Unresectable or Metastatic Liposarcoma Who Have Received a Prior Anthracycline-Containing Regimen

Author

Christy L. Osgood, Patricia Keegan, Richard Pazdur, Leah Her, Meredith K. Chuk, Lan Huang, Kun He, and Marc R. Theoret

Subjects
0301 basic medicine, Leiomyosarcoma, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Metastatic Liposarcoma, Dacarbazine, Population, Liposarcoma, Disease-Free Survival, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Humans, Anthracyclines, Neoplasm Metastasis, education, Furans, Drug Approval, Aged, Neoplasm Staging, Aged, 80 and over, education.field_of_study, business.industry, Ketones, Middle Aged, medicine.disease, Surgery, Regimen, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Female, business, medicine.drug, Eribulin
Abstract

On January 28, 2016, the FDA approved eribulin (Halaven; Eisai Inc.) for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. The approval was based on results from a single, randomized, open-label, active-controlled trial (Trial E7389-G000-309) enrolling 452 patients with advanced, locally recurrent or metastatic liposarcoma or leiomyosarcoma. Patients were randomized to eribulin 1.4 mg/m2 intravenously (i.v.) on days 1 and 8 or dacarbazine 850, 1,000, or 1,200 mg/m2 i.v. on day 1 of a 21-day cycle. There was a significant improvement in overall survival [OS; HR, 0.75; 95% confidence interval (CI), 0.61–0.94; P = 0.0119, stratified log-rank] for the overall population. Estimated median OS was 13.5 months (95% CI, 11.1–16.5) in the eribulin arm and 11.3 months (95% CI, 9.5–12.6) in the dacarbazine arm (HR, 0.75; 95% CI, 0.61–0.94; P = 0.011).There were no differences in PFS for the overall population. The effects of eribulin were limited to patients with liposarcoma (n = 143) based on preplanned, exploratory subgroup analyses of OS (HR, 0.51; 95% CI, 0.35–0.75) and progression-free survival (PFS; 0.52; 95% CI, 0.35–0.78). Response rates in both treatment arms were less than 5% in the overall population and in the liposarcoma subgroup. The safety profile was similar to that previously reported for eribulin. The FDA determined that, based on the data reviewed, the benefit–risk assessment for eribulin is positive for patients with advanced, pretreated liposarcoma. Clin Cancer Res; 23(21); 6384–9. ©2017 AACR.

Published
2016

4. Blood–brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins

Author

Leah Hernandez, Liam J. Ward, Samsul Arefin, Thomas Ebert, Agne Laucyte-Cibulskiene, GOING-FWD Collaborators, Olof Heimbürger, Peter Barany, Lars Wennberg, Peter Stenvinkel, and Karolina Kublickiene

Subjects
Medicine, Science
Abstract

Abstract Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.

Published
2022
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5. Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease: focus on sex-specific associations with vascular outcomes and all-cause mortality

Author

Agne Laucyte-Cibulskiene, Liam J. Ward, Thomas Ebert, Giulia Tosti, Claudia Tucci, Leah Hernandez, Alexandra Kautzky-Willer, Maria-Trinidad Herrero, Colleen M. Norris, Louise Pilote, Magnus Söderberg, Torkel B. Brismar, Jonaz Ripsweden, Peter Stenvinkel, Valeria Raparelli, Karolina Kublickiene, and The GOING-FWD Consortium

Subjects
Biomarkers, Calcification, Cardiovascular disease, Chronic kidney disease, End stage kidney disease, TMAO, Medicine, Physiology, QP1-981
Abstract

Abstract Background Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification—features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. Methods ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. Results Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p

Published
2021
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