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Journal of Clinical Oncology : Official... Dec 2021To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).
METHODS
In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and mutation status.
RESULTS
Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% 49.3%). Both groups received full chemotherapy dose intensity.
CONCLUSION
The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Case-Control Studies; Chemoradiotherapy; Colorectal Neoplasms; Embolization, Therapeutic; Female; Follow-Up Studies; Humans; Irinotecan; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Prognosis; Survival Rate; Yttrium Radioisotopes
PubMed: 34541864
DOI: 10.1200/JCO.21.01839 -
The New England Journal of Medicine Nov 2023
Topics: Humans; Liver; Liver Transplantation; Metabolism, Inborn Errors; Neoplastic Syndromes, Hereditary; Rare Diseases; Glucagon
PubMed: 37991861
DOI: 10.1056/NEJMe2310332 -
The New England Journal of Medicine Nov 2023Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia....
Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.
Topics: Female; Humans; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Glucagon; Hypertension, Portal; Hypertrophy; Liver Cirrhosis; Liver Transplantation; Genetic Diseases, Inborn; Pancreatic Diseases; Glucagon-Secreting Cells
PubMed: 37991855
DOI: 10.1056/NEJMoa2303226 -
Journal of Gastroenterology and... Aug 2023
Review
Topics: Humans; Glucagon; Mutation; Pancreatic Neoplasms
PubMed: 36698259
DOI: 10.1111/jgh.16104 -
Drugs Jun 2021Statins are a group of lipid-lowering drugs that inhibit cholesterol biosynthesis and have anti-inflammatory, anti-tumor, and immunomodulatory properties. Several lines... (Review)
Review
Statins are a group of lipid-lowering drugs that inhibit cholesterol biosynthesis and have anti-inflammatory, anti-tumor, and immunomodulatory properties. Several lines of evidence indicate that statins regulate multiple proteins associated with the regulation of differing cellular pathways. The 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolism homeostasis with effects on cellular processes including apoptosis and the inflammatory responses through several pathways. Recently, it has been shown that statins can affect the AMPK pathway in differing physiological and pathological ways, resulting in anti-cancer, cardio-protective, neuro-protective, and anti-tubercular effects; additionally, they have therapeutic effects on non-alcoholic fatty liver disease and diabetes mellitus-associated complications. Statins activate AMPK as an energy sensor that inhibits cell proliferation and induces apoptosis in cancer cells, whilst exerting its cardio-protective effects through inhibition of inflammation and fibrosis, and promotion of angiogenesis. Furthermore, statin-associated AMPK activation leads to decreased lipid accumulation and decreased amyloid beta deposition in the liver and brain, respectively, and may have therapeutic effects on the liver and neurons. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of statins in different pathological conditions.
Topics: AMP-Activated Protein Kinases; Angiogenesis Inducing Agents; Animals; Apoptosis; Cardiovascular Diseases; Cell Line, Tumor; Cell Proliferation; Fibrosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Inflammation; Neoplasms; Nervous System Diseases
PubMed: 33939118
DOI: 10.1007/s40265-021-01510-4 -
World Journal of Gastroenterology Dec 2021Impressive survival outcome of our previous study in unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass microspheres transarterial...
Disease control and failure patterns of unresectable hepatocellular carcinoma following transarterial radioembolization with yttrium-90 microspheres and with/without sorafenib.
BACKGROUND
Impressive survival outcome of our previous study in unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass microspheres transarterial radioembolization (TARE) with/without sorafenib according to individuals' disease burden, , intrahepatic tumor load (IHT) and adverse disease features (ADFs) might partly be confounded by other treatments and underlying hepatic function. Therefore, a dedicated study focusing on treatment response and assessment of failure patterns might be a way to improve treatment outcome in addition to patient selection based on the disease burden.
AIM
To assess the tumor response, disease control and patterns of disease progression following TARE with/without sorafenib in unresectable HCC patients.
METHODS
This retrospective study was conducted in successful TARE procedures with available pre- and post-treatment imaging studies ( = 169). Three treatment subgroups were (1) TARE only () for IHT ≤ 50% without ADFs, , macrovascular invasion, extrahepatic disease (EHD) and infiltrative/ill-defined HCC ( = 63); (2) TARE with sorafenib () for IHT > 50% and/or presence of ADFs ( = 81); and (3) TARE only for patients who could not receive sorafenib due to contraindication or intolerance () ( = 25). Objective response rate (ORR; consisted of complete response (CR) and partial response (PR)), disease control rate (DCR; consisted of CR, PR and stable disease) and failure patterns of treated, intrahepatic and extrahepatic sites were assessed using the modified response evaluation criteria in solid tumors. Time to progression (TTP) was calculated from TARE to the first radiologic progression at any site using Kaplan-Meier method. Identification of prognostic factors for TTP using the univariate Kaplan-Meier method and multivariate Cox proportional hazard model were performed in major population subgroups, and .
RESULTS
The median radiologic follow-up time was 4.4 mo (range 0.5-48.8). In treated area, ORR was highest in (53.1%), followed by (41.3%) and (16%). In intrahepatic area, DCR remained highest in (84%), followed by (79.4%) and (44%). The overall DCR was highest in (79.4%), followed by (71.6%) and (40%). Dominant failure patterns were intrahepatic for both (44.5%) and (38.4%). Extrahepatic progression was more common in (32%) and (40%) than in (12.7%). TTP was longest in 8.6 mo; 95%CI: 3.4-13.8, followed by (5.1 mo; 95%CI: 4.0-6.2) and 2.7 mo; 95%CI: 2.2-3.1). Pre-existing EHD (HR: 0.37, 95%CI: 0.24-0.56, < 0.001) was a sole prognostic factor for TTP in with no prognostic factor for TTP in .
CONCLUSION
TARE with/without sorafenib according to individuals' disease burden provided DCR approximately 70% with intrahepatic progression as dominant failure pattern. Extrahepatic progression was more common in procedures with initially high disease burden.
Topics: Carcinoma, Hepatocellular; Embolization, Therapeutic; Humans; Liver Neoplasms; Microspheres; Retrospective Studies; Sorafenib; Treatment Outcome; Yttrium Radioisotopes
PubMed: 35068861
DOI: 10.3748/wjg.v27.i47.8166 -
The Biochemical Journal Aug 2020The detailed metabolic characterization of the glucagon receptor (Gcgr)V369M+/+ mutant mice described in Lin et al. in the Biochemical Journal is of interest and...
The detailed metabolic characterization of the glucagon receptor (Gcgr)V369M+/+ mutant mice described in Lin et al. in the Biochemical Journal is of interest and resulting in the expected metabolic profile. We would like to point out that these mice might also be extremely useful as a precision medicine model of mild Mahvash disease, a rare hereditary pancreatic neuroendocrine tumor syndrome characterized by inactivating mutations in the glucagon receptor. Further characterization of pancreas morphology and histology in the GcgrV369M+/+ mice at more advanced ages will be critically important to understand mild Mahvash disease in humans.
Topics: Animals; Glucagon; Humans; Metabolic Diseases; Mice; Mutation; Precision Medicine; Receptors, Glucagon
PubMed: 32785645
DOI: 10.1042/BCJ20200522 -
The New England Journal of Medicine Dec 2023
PubMed: 38118047
DOI: 10.1056/NEJMx230012 -
Oral Oncology Nov 2020Complex interactions take place during cancer formation and progression. In this regard, there has been increasing focus on the non-malignant cells that make up the... (Review)
Review
Complex interactions take place during cancer formation and progression. In this regard, there has been increasing focus on the non-malignant cells that make up the tumour microenvironment (TME), and how they interact with malignant tumour cells. TME is highly heterogeneous and has a major influence on tumour behaviour and therapy response. Cancer-associated fibroblasts (CAFs), one of the main components of the TME, establish dangerous liaisons with cancer cells and other components of the TME to shape a tumour-supportive environment in many types of cancer. Head and neck squamous cell carcinoma (HNSCC) encompass the malignant neoplasms arising from the mucosal lining of the oral cavity, pharynx and larynx. The TME of HNSCC contributes to tumour progression and this stromal compartment may be an interesting target for treatment. There is an emerging picture of the behaviour of CAFs in HNSCC; how they affect and are affected by the TME. We aim to summarise and discuss the current understanding of CAFs in head and neck cancer, exploring CAF activation and heterogeneity, and interaction with cancer cells and other cells within the TME.
Topics: Actins; Animals; Biomarkers; Cancer-Associated Fibroblasts; Cytokines; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Energy Metabolism; Epithelial-Mesenchymal Transition; Exosomes; Fibroblasts; Head and Neck Neoplasms; Humans; MicroRNAs; Neoplastic Stem Cells; Papillomavirus Infections; Tumor Microenvironment
PubMed: 33011636
DOI: 10.1016/j.oraloncology.2020.104972 -
GE Portuguese Journal of... Jun 2024Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly... (Review)
Review
Portuguese Pancreatic Club Perspectives on Pancreatic Neuroendocrine Neoplasms: Diagnosis and Staging, Associated Genetic Syndromes and Particularities of Their Clinical Approach.
Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly owing to improvement in the detection of small asymptomatic tumours with imaging. Early detection and proper classification and staging are essential for the prognosis and management of panNENs. Histological evaluation is mandatory in all patients for the diagnosis of panNEN. Regarding localization and staging, multiphasic contrast-enhanced computer tomography is considered the imaging study of choice. Nevertheless, several other diagnostic modalities might present complementary information that can help in diagnosis and staging optimization: magnetic resonance imaging, somatostatin receptor imaging using positron emission tomography in combination with computed tomography (PET/CT), PET/CT with fluorodeoxyglucose (F-FDG), and endoscopic ultrasound. Approximately 10% of panNENs are due to an inherited syndrome, which includes multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis type 1 (NF-1), tuberous sclerosis complex, and Mahvash disease. In this review, the Portuguese Pancreatic Club summarizes the classification, diagnosis, and staging of panNENs, with a focus on imaging studies. It also summarizes the characteristics and particularities of panNENs associated with inherited syndromes.
PubMed: 38836119
DOI: 10.1159/000534641