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Endocrinologia Y Nutricion : Organo de... 2011To elucidate the pathogenetic mechanisms of a mutant P86S glucagon receptor (GCGR) in causing a novel human disease (Mahvash disease).
BACKGROUND AND AIM
To elucidate the pathogenetic mechanisms of a mutant P86S glucagon receptor (GCGR) in causing a novel human disease (Mahvash disease).
MATERIAL AND METHOD
Enhanced green fluorescent protein (EGFP)-tagged WT and P86S GCGR were expressed in HEK 293 or H1299 cells either transiently or stably. Receptor localization and internalization, and cell apoptosis were studied by fluorescence microscopy, and calcium signaling by Rhod-3 labeling. Gene expression was assayed by RT-PCR or Western blot. Cell fate was determined by live cell imaging.
RESULTS
Unlike WT GCGR, P86S was partially localized to the plasma membrane and partially in the cytoplasm as previously reported and did not undergo internalization upon glucagon treatment. P86S did not elicit calcium response after treatment with 1 μM glucagon. Cells transiently expressing P86S exhibited more apoptosis than those expressing WT GCGR (18.3% vs 2.1%, P<0.05) but the X-box binding protein 1 mRNA cleavage, a marker of endoplasmic reticulum (ER) stress, was not evident, suggesting that the apoptosis did not result from ER stress. Cells stably expressing P86S did not exhibit apoptosis and a quarter of them harbored a novel inclusion body-like circular structure that was marked by P86S and ER residential proteins. These circular ER bodies were not seen in cells expressing WT GCGR or transiently expressing P86S and were not affected by treatment with proteasome inhibitor or microtubule depolymerizer, suggesting that they do not represent aggresome structures. The circular ER bodies could fuse and split to form new bodies.
CONCLUSION
The naturally-occurring P86S mutant GCGR exhibits abnormal receptor internalization and calcium mobilization, and causes apoptosis. The novel dynamic circular ER bodies may be adaptive in nature to nullify the toxic effects on P86S. These findings provide further insights into the pathogenetic mechanisms of Mahvash disease.
Topics: Apoptosis; Calcium Signaling; Cell Line; Cell Membrane; Cyclic AMP; Endocytosis; Endoplasmic Reticulum; Glucagon; Glucagon-Secreting Cells; Humans; Hyperplasia; Hypoglycemia; Mutation, Missense; Neoplastic Syndromes, Hereditary; Neuroendocrine Tumors; Pancreatic Neoplasms; Point Mutation; Receptors, Glucagon; Recombinant Fusion Proteins
PubMed: 21680267
DOI: 10.1016/j.endonu.2011.04.002 -
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 -
Molecular Genetics and Metabolism... Dec 2018Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in...
Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in adults with pancreatic α cell hyperplasia and PNETs. We describe a 7-year-old girl with persistent hyperaminoacidemia, notable for elevations of glutamine (normal ammonia), alanine (normal lactate), dibasic amino acids (arginine, lysine and ornithine), threonine and serine. She initially was brought to medical attention by an elevated arginine on newborn screening (NBS) and treated for presumed arginase deficiency with a low protein diet, essential amino acids formula and an ammonia scavenger drug. This treatment normalized plasma amino acids. She had intermittent emesis and anorexia, but was intellectually normal. Arginase enzyme assay and sequencing and deletion/duplication analysis were normal. Treatments were stopped, but similar pattern of hyperaminoacidemia recurred. She also had hypercholesterolemia type IIa, with only elevated LDL cholesterol, despite an extremely lean body habitus. Exome sequencing was initially non-diagnostic. Through a literature search, we recognized the pattern of hyperaminoacidemia was strikingly similar to that reported in the knockout mice. Subsequently the patient was found to have an extremely elevated plasma glucagon and a novel, homozygous c.958_960del (p.Phe320del) variant in . Functional studies confirmed the pathogenicity of this variant. This case expands the clinical phenotype of GCGR defect in children and emphasizes the clinical utility of plasma amino acids in screening, diagnosis and monitoring glucagon signaling interruption. Early identification of a GCGR defect may provide an opportunity for potential beneficial treatment for an adult onset tumor predisposition disease.
PubMed: 30294546
DOI: 10.1016/j.ymgmr.2018.09.006 -
JAMA Oncology Jun 2022Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent... (Clinical Trial)
Clinical Trial
IMPORTANCE
Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing.
OBJECTIVE
To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs.
DESIGN, SETTING, AND PARTICIPANTS
This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021.
INTERVENTIONS
Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal.
MAIN OUTCOMES AND MEASURES
The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point.
RESULTS
Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively.
CONCLUSIONS AND RELEVANCE
In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03074513.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Humans; Neuroectodermal Tumors, Primitive; Neuroendocrine Tumors; Prospective Studies; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 35389428
DOI: 10.1001/jamaoncol.2022.0212 -
Journal of Gastrointestinal Surgery :... Jun 2016The risk of colorectal liver metastases (CLM) disappearing on cross-sectional imaging has increased with advances in preoperative chemotherapy, but <50 % of...
BACKGROUND
The risk of colorectal liver metastases (CLM) disappearing on cross-sectional imaging has increased with advances in preoperative chemotherapy, but <50 % of disappearing CLM demonstrate complete pathological response.
OBJECTIVE
The aim of this study was to evaluate the role of fiducial marker placement before potentially curative treatment of CLM at risk of disappearing with chemotherapy.
METHODS
All consecutive patients who underwent fiducial placement for tracking of CLM at a tertiary center were reviewed.
RESULTS
Among 1377 patients undergoing CLM resection between 2005 and 2015, 35 patients underwent fiducial placement. Three patients were excluded due to disease progression. The study population comprised 32 patients who underwent fiducial placement in 41 CLM. Among the 41 marked CLM, 34 (83 %) were located >10 mm deep in the liver parenchyma, 25 (61 %) were in the right liver, and median size was 12 mm (range, 6-20 mm). No complication occurred after fiducial placement. After chemotherapy, 19 (46 %) of the 41 marked metastases disappeared on cross-sectional imaging. All fiducial-tracked CLM were treated with resection (n = 31) or ablation (n = 10). After median follow-up of 14 months (range, 0-64 months), no local recurrences were observed.
CONCLUSION
Fiducial placement represents a safe procedure that facilitates accurate localization for resection or ablation of small CLM at risk of disappearing with chemotherapy.
Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fiducial Markers; Follow-Up Studies; Hepatectomy; Humans; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Retrospective Studies; Treatment Outcome
PubMed: 26791387
DOI: 10.1007/s11605-016-3079-1 -
Radiology. Artificial Intelligence Sep 2019Some patients with hepatocellular carcinoma (HCC) are more likely to experience disease progression despite transcatheter arterial chemoembolization (TACE) treatment,...
PURPOSE
Some patients with hepatocellular carcinoma (HCC) are more likely to experience disease progression despite transcatheter arterial chemoembolization (TACE) treatment, and thus would benefit from early switching to other therapeutic regimens. We sought to evaluate a fully automated machine learning algorithm that uses pre-therapeutic quantitative computed tomography (CT) image features and clinical factors to predict HCC response to TACE.
MATERIALS AND METHODS
Outcome information from 105 patients receiving first-line treatment with TACE was evaluated retrospectively. The primary clinical endpoint was time to progression (TTP) based on follow-up CT radiological criteria (mRECIST). A 14-week cutoff was used to classify patients as TACE-susceptible (TTP ≥14 weeks) or TACE-refractory (TTP <14 weeks). Response to TACE was predicted using a random forest classifier with the Barcelona Clinic Liver Cancer (BCLC) stage and quantitative image features as input as well as the BCLC stage alone as a control.
RESULTS
The model's response prediction accuracy rate was 74.2% (95% CI=64%-82%) using a combination of the BCLC stage plus quantitative image features versus 62.9% (95% CI= 52%-72%) using the BCLC stage alone. Shape image features of the tumor and background liver were the dominant features correlated to the TTP as selected by the Boruta method and were used to predict the outcome.
CONCLUSION
This preliminary study demonstrates that quantitative image features obtained prior to therapy can improve the accuracy of predicting response of HCC to TACE. This approach is likely to provide useful information for aiding HCC patient selection for TACE.
PubMed: 31858078
DOI: 10.1148/ryai.2019180021 -
Journal of Gastrointestinal Surgery :... Sep 2023To evaluate the impact of salvage locoregional therapy (salvage-LT) on survival of hepatocellular carcinoma (HCC) patients presenting with intrahepatic tumor progression...
PURPOSE
To evaluate the impact of salvage locoregional therapy (salvage-LT) on survival of hepatocellular carcinoma (HCC) patients presenting with intrahepatic tumor progression following radiotherapy.
METHODS
This single-institution retrospective analysis included consecutive HCC patients having intrahepatic tumor progression following radiotherapy during 2015-2019. Overall survival (OS) was calculated from the date of intrahepatic tumor progression after initial radiotherapy by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariable and multivariable analyses. An inverse probability weighting was used to estimate treatment effect of salvage-LT considering confounding factors.
RESULTS
A total of 123 patients (mean age ± SD, 70 years ± 10; 97 men) were evaluated. Among those, 35 patients underwent 59 sessions of salvage-LT, including transarterial embolization/chemoembolization (n = 33), ablation (n = 11), selective internal radiotherapy (n = 7), and external beam radiotherapy (n = 8). At a median follow-up of 15.1 months (range, 3.4-54.5 months), the median OS was 23.3 months in patients who received salvage-LT and 6.6 months who did not. At multivariate analysis, ECOG performance status, Child-Pugh class, albumin-bilirubin grade, extrahepatic disease, and lack of salvage-LT were independent predictors of worse OS. After inverse probability weighting, salvage-LT was associated with a survival benefit of 8.9 months (95% CI: 1.1, 16.7 months; p = 0.03).
CONCLUSIONS
Salvage locoregional therapy is associated with increased survival in HCC patients suffering from intrahepatic tumor progression following initial radiotherapy.
Topics: Male; Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Retrospective Studies; Chemoembolization, Therapeutic; Combined Modality Therapy; Salvage Therapy; Treatment Outcome
PubMed: 37268830
DOI: 10.1007/s11605-023-05712-x -
European Journal of Cancer (Oxford,... Oct 2018Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor...
BACKGROUND
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear.
METHODS
ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain- and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of activation of EGFR signalling as well as on exosome production and exosomal phospho-EGFR.
RESULTS
ANXA1 was found to be downregulated in head and neck cancer tissues, both at mRNA and protein level. Its anti-proliferative effects were mediated through the intracellular form of the protein. Importantly, ANXA1 downregulation resulted in increased phosphorylation and activity of EGFR and its downstream PI3K-AKT signalling. Additionally, ANXA1 modulation affected exosome production and influenced the release of exosomal phospho-EGFR.
CONCLUSIONS
ANXA1 acts as a tumour suppressor in HNSCC. It is involved in the regulation of EGFR activity and exosomal phospho-EGFR release and could be an important prognostic biomarker.
Topics: Annexin A1; Cell Proliferation; ErbB Receptors; Exosomes; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Mutation; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tumor Suppressor Proteins
PubMed: 30142511
DOI: 10.1016/j.ejca.2018.07.123 -
Cardiovascular and Interventional... Feb 2020Peptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on...
PURPOSE
Peptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on cumulative hepatotoxicity. The aim of this sub-analysis was to investigate hepatotoxicity of yttrium-90 resin microspheres radioembolization in patients who were previously treated with PRRT.
METHODS
Patients treated with radioembolization after systemic radionuclide treatment were retrospectively analysed. Imaging response according to response evaluation criteria in solid tumours (RECIST) v1.1 and clinical response after 3 months were collected. Clinical, biochemical and haematological toxicities according to common terminology criteria for adverse events (CTCAE) v4.03 were also collected. Specifics on prior PRRT, subsequent radioembolization treatments, treatments after radioembolization and overall survival (OS) were collected.
RESULTS
Forty-four patients were included, who underwent a total of 58 radioembolization procedures, of which 55% whole liver treatments, at a median of 353 days after prior PRRT. According to RECIST 1.1, an objective response rate of 16% and disease control rate of 91% were found after 3 months. Clinical response was seen in 65% (15/23) of symptomatic patients after 3 months. Within 3 months, clinical toxicities occurred in 26%. Biochemical and haematological toxicities CTCAE grade 3-4 occurred in ≤ 10%, apart from lymphocytopenia (42%). Radioembolization-related complications occurred in 5% and fatal radioembolization-induced liver disease in 2% (one patient). A median OS of 3.5 years [95% confidence interval 1.8-5.1 years] after radioembolization for the entire study population was found.
CONCLUSION
Radioembolization after systemic radionuclide treatments is safe, and the occurrence of radioembolization-induced liver disease is rare.
LEVEL OF EVIDENCE
4, case series.
Topics: Adult; Aged; Aged, 80 and over; Brachytherapy; Female; Humans; Liver Neoplasms; Male; Microspheres; Middle Aged; Neuroendocrine Tumors; Receptors, Peptide; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Treatment Outcome; Yttrium Radioisotopes
PubMed: 31646375
DOI: 10.1007/s00270-019-02350-2 -
European Radiology Experimental Jan 2023To evaluate the feasibility of a novel approach for predicting hepatocellular carcinoma (HCC) response to drug-eluting beads transarterial chemoembolization (DEB-TACE)...
A novel method for predicting hepatocellular carcinoma response to chemoembolization using an intraprocedural CT hepatic arteriography-based enhancement mapping: a proof-of-concept analysis.
BACKGROUND
To evaluate the feasibility of a novel approach for predicting hepatocellular carcinoma (HCC) response to drug-eluting beads transarterial chemoembolization (DEB-TACE) using computed tomography hepatic arteriography enhancement mapping (CTHA-EM) method.
METHODS
This three-institution retrospective study included 29 patients with 46 HCCs treated with DEB-TACE between 2017 and 2020. Pre- and posttreatment CTHA-EM images were generated using a prototype deformable registration and subtraction software. Relative tumor enhancement (T) defined as the ratio of tumor enhancement to normal liver tissue was calculated to categorize tumor response as residual (T > 1) versus non-residual (T ≤ 1) enhancement, which was blinded compared to the response assessment on first follow-up imaging using modified RECIST criteria. Additionally, for tumors with residual enhancement, CTHA-EM was evaluated to identify its potential feeding arteries.
RESULTS
CTHA-EM showed residual enhancement in 18/46 (39.1%) and non-residual enhancement in 28/46 (60.9%) HCCs, with significant differences on T (3.05 ± 2.4 versus 0.48 ± 0.23, respectively; p < 0.001). The first follow-up imaging showed non-complete response (partial response or stable disease) in 19/46 (41.3%) and complete response in 27/46 (58.7%) HCCs. CTHA-EM had a response prediction sensitivity of 94.7% (95% CI, 74.0-99.9) and specificity of 100% (95% CI, 87.2-100). Feeding arteries to the residual enhancement areas were demonstrated in all 18 HCCs (20 arteries where DEB-TACE was delivered, 2 newly developed collaterals following DEB-TACE).
CONCLUSION
CTHA-EM method was highly accurate in predicting initial HCC response to DEB-TACE and identifying feeding arteries to the areas of residual arterial enhancement.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Retrospective Studies; Treatment Outcome; Chemoembolization, Therapeutic; Tomography, X-Ray Computed; Angiography
PubMed: 36717474
DOI: 10.1186/s41747-022-00315-8