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Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG
(2017) Br J Haematol 178: 547-560
MeSH Terms: Antineoplastic Agents, Benchmarking, Bortezomib, Cardiovascular Diseases, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Dyspnea, Heart Failure, Humans, Multiple Myeloma, Proteasome Inhibitors, Retrospective Studies, Risk Factors
Show Abstract · Added December 2, 2017
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
© 2017 John Wiley & Sons Ltd.
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13 MeSH Terms
Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy.
Jacobson IM, Washington MK, Buti M, Thompson A, Afdhal N, Flisiak R, Akarca US, Tchernev KG, Flaherty JF, Aguilar Schall R, Myers RP, Subramanian GM, McHutchison JG, Younossi Z, Marcellin P, Patel K
(2017) Clin Gastroenterol Hepatol 15: 1087-1094.e2
MeSH Terms: Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Alanine Transaminase, Antiviral Agents, Biopsy, Clinical Trials, Phase III as Topic, Fatty Liver, Female, Hepatitis B e Antigens, Hepatitis B, Chronic, Histocytochemistry, Humans, Liver, Male, Middle Aged, Tenofovir, Young Adult
Show Abstract · Added March 14, 2018
BACKGROUND & AIMS - Despite complete suppression of viral DNA with antiviral agents, in some patients with chronic hepatitis B (CHB), serum levels of alanine aminotransferase (ALT) do not normalize. We investigated factors associated with persistent increases in ALT level in patients with CHB given long-term tenofovir disoproxil fumarate.
METHODS - We analyzed data from 471 hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB participating in 2 phase 3 trials. We identified patients with an increased level of ALT (above the upper limit of normal range) after 5 years (240 weeks) of tenofovir disoproxil fumarate therapy. We analyzed findings from liver biopsy specimens collected from 467 patients (99%) at baseline and 339 patients (72%) at year 5 of treatment; biopsy specimens were evaluated by an independent pathologist. We performed stepwise, forward, multivariate regression analyses of specified baseline characteristics and on-treatment response parameters to identify factors associated with persistent increases in ALT level.
RESULTS - Of the 471 patients, 87 (18%) still had an increased ALT level at year 5 of treatment. Factors associated significantly with a persistent increase in ALT level were a steatosis score of 5% or greater (grade 1 or more) at baseline (odds ratio [OR], 2.236; 95% confidence interval [CI], 1.031-4.852; P = .042) and at year 5 (OR, 3.392; 95% CI, 1.560 ≥ 7.375; P = .002), HBeAg seropositivity at baseline (OR, 3.297; 95% CI, 1.653-6.576; P < .001), and age 40 years or older (OR, 2.099; 95% CI, 1.014-4.342; P = .046). Of the 42 HBeAg-positive patients with steatosis at baseline, 21 (50%) had an increased ALT level at year 5 of treatment. Patients with persistent increases in ALT level were more likely to have an increase in steatosis at year 5 than those with a normal ALT level.
CONCLUSIONS - HBeAg seropositivity and hepatic steatosis contribute to persistent increases in ALT level in patients with CHB receiving suppressive antiviral treatment. ClinicalTrials.gov registration numbers: NCT00117676 and NCT00116805.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Sedentary behavior is associated with colorectal adenoma recurrence in men.
Molmenti CL, Hibler EA, Ashbeck EL, Thomson CA, Garcia DO, Roe D, Harris RB, Lance P, Cisneroz M, Martinez ME, Thompson PA, Jacobs ET
(2014) Cancer Causes Control 25: 1387-95
MeSH Terms: Adenoma, Adult, Age Distribution, Aged, Aged, 80 and over, Arizona, Clinical Trials, Phase III as Topic, Colonoscopy, Colorectal Neoplasms, Double-Blind Method, Female, Humans, Logistic Models, Male, Middle Aged, Neoplasm Recurrence, Local, Sedentary Behavior, Sex Distribution, Sex Factors, Surveys and Questionnaires
Show Abstract · Added December 29, 2014
PURPOSE - The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between physical activity and colorectal adenoma recurrence.
METHODS - Pooled analyses from two randomized, controlled trials included 1,730 participants who completed the Arizona Activity Frequency Questionnaire at baseline, had a colorectal adenoma removed within 6 months of study registration, and had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior, light-intensity physical activity, and moderate-vigorous physical activity on colorectal adenoma recurrence.
RESULTS - No statistically significant trends were found for any activity type and odds of colorectal adenoma recurrence in the pooled population. However, males with the highest levels of sedentary time experienced 47% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary time, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.23 (0.88, 1.74), 1.41 (0.99, 2.01), and 1.47 (1.03, 2.11), respectively (p(trend) = 0.03). No similar association was observed for women.
CONCLUSIONS - This study suggests that sedentary behavior is associated with a higher risk of colorectal adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway.
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American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes.
Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent D, Cortazar P, Garrett-Mayer E, Herbst RS, Lilenbaum RC, Sima C, Venook AP, Gonen M, Schilsky RL, Meropol NJ, Schnipper LE
(2014) J Clin Oncol 32: 1277-80
MeSH Terms: Clinical Trials as Topic, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Humans, Medical Oncology, Societies, Medical, Treatment Outcome, United States
Added March 20, 2014
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8 MeSH Terms
Associations between vitamin D-binding protein isotypes, circulating 25(OH)D levels, and vitamin D metabolite uptake in colon cancer cells.
Hibler EA, Jacobs ET, Stone AD, Sardo CL, Galligan MA, Jurutka PW
(2014) Cancer Prev Res (Phila) 7: 426-34
MeSH Terms: Adult, Aged, Aged, 80 and over, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, DNA, Neoplasm, Double-Blind Method, Female, Genotype, Humans, Male, Middle Aged, Protein Isoforms, Randomized Controlled Trials as Topic, Real-Time Polymerase Chain Reaction, Receptors, Calcitriol, Tumor Cells, Cultured, Ursodeoxycholic Acid, Vitamin D, Vitamin D-Binding Protein
Show Abstract · Added December 29, 2014
Vitamin D metabolites have been extensively studied as cancer chemopreventive agents. Gc-globulin (GC) isotypes, based on rs7041 and rs4588 diplotypes, have varying affinities for 1α,25-dihydroxyvitamin D (1,25(OH)2D) and 25-hydroxyvitamin D (25(OH)D), which may affect circulating metabolite concentration as well as delivery at the cellular level. We evaluated associations between GC isotype and circulating vitamin D metabolite concentrations in 403 ursodeoxycholic acid (UDCA) clinical trial participants. Metabolite uptake was evaluated in human colon cancer (HCT-116) cells treated with ethanol vehicle, 1,25(OH)2D, or 25(OH)D, and with plasma from individuals with known GC isotype. Mammalian-2-hybrid and vitamin D-responsive element-based luciferase assays were used to measure the vitamin D receptor pathway activation as a marker for metabolite uptake. Regression analysis demonstrated significantly lower serum 25(OH)D concentration for clinical trial participants with 1F_2, 1S_2, or 2_2 isotypes (P < 0.01) compared with 1S_1S. Consistent with these in vivo observations, cellular data revealed that 25(OH)D uptake varied less by GC isotype only at the higher concentration tested (P = 0.05), while 1,25(OH)2D uptake differed markedly by GC isotype across concentration and assay (P < 0.01). The 1F_1S and 1F_2 isotypes produced the greatest reporter gene induction with 1,25(OH)2D treatment and, while activation varied less with 25(OH)D, the 2_2 isotype demonstrated increased induction at the lower concentration. These results suggest that vitamin D metabolite concentration and delivery to colon cells may vary not only by GC isotype, but also that certain isotypes may more effectively deliver 1,25(OH)2D versus 25(OH)D. Overall, these results may help identify populations at risk for cancer and potential recipients of targeted chemoprevention.
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Targeting angiogenesis in advanced non-small cell lung cancer.
Lammers PE, Horn L
(2013) J Natl Compr Canc Netw 11: 1235-47
MeSH Terms: Angiogenesis Inhibitors, Antineoplastic Agents, Biomarkers, Carcinoma, Non-Small-Cell Lung, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Humans, Lung Neoplasms, Neoplasm Staging, Neovascularization, Pathologic, Prognosis, Treatment Outcome
Show Abstract · Added June 26, 2014
Lung cancer is the leading cause of cancer-related mortality in the United States. Over the past 40 years, treatments with standard chemotherapy agents have not resulted in substantial improvements in long-term survival for patients with advanced lung cancer. Therefore, new targets have been sought, and angiogenesis is a promising target for non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, is the only antiangiogenic agent currently recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted tyrosine kinase inhibitors are currently under investigation for the treatment of patients with NSCLC. This article summarizes the available clinical trial data on the efficacy and safety of these agents in patients with advanced lung cancer.
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Current therapy and future directions in biliary tract malignancies.
Ciombor KK, Goff LW
(2013) Curr Treat Options Oncol 14: 337-49
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Biliary Tract, Biliary Tract Neoplasms, Chemotherapy, Adjuvant, Cisplatin, Clinical Trials as Topic, Clinical Trials, Phase III as Topic, Combined Modality Therapy, Deoxycytidine, Humans, Neoplasm Recurrence, Local, Retrospective Studies
Show Abstract · Added September 10, 2013
OPINION STATEMENT - Cancers of the biliary tree represent a rare group of diseases with a devastating impact on patients. Gallbladder cancer often is associated with cholelithiasis. Cholangiocarcinoma may arise in the setting of biliary inflammation, such as primary sclerosing cholangitis, but most commonly occurs in patients without a particular risk factor. Surgical removal of biliary cancer is essential for cure, but it is associated with a very high rate of recurrence and for many patients is not possible at the time of diagnosis. Although risk factors differ for each anatomic site, systemic treatment is generally similar. Various adjunctive therapies, such as radiation and embolization, have been investigated for biliary tract cancers with modest success and efforts are ongoing to understand how to optimize these tools. Retrospective series and pooled analysis suggest a benefit for adjuvant treatment following resection, but prospective data are limited. Ongoing and planned phase 3 trials should help to clarify the role of adjuvant chemotherapy and radiation. For advanced disease, chemotherapy improves quality of life and survival, and gemcitabine with cisplatin represents the standard of care. However, all patients ultimately progress on this therapy, so clinical trials of new and better agents are essential to expand the existing treatment options for patients.
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Aflibercept.
Ciombor KK, Berlin J, Chan E
(2013) Clin Cancer Res 19: 1920-5
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Disease-Free Survival, Fluorouracil, Humans, Irinotecan, Leucovorin, Neoplasm Metastasis, Organoplatinum Compounds, Oxaliplatin, Placenta Growth Factor, Pregnancy Proteins, Protein Binding, Randomized Controlled Trials as Topic, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Treatment Outcome, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B
Show Abstract · Added September 10, 2013
Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
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Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement.
Schwarz RE, Berlin JD, Lenz HJ, Nordlinger B, Rubbia-Brandt L, Choti MA
(2013) HPB (Oxford) 15: 106-15
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Chemotherapy, Adjuvant, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Consensus Development Conferences as Topic, Hepatectomy, Humans, Liver Neoplasms, Neoplasm Metastasis, Patient Selection, Practice Guidelines as Topic, Radiotherapy, Adjuvant, Survival Analysis, Treatment Outcome
Show Abstract · Added March 20, 2014
Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.
© 2012 International Hepato-Pancreato-Biliary Association.
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14 MeSH Terms