Risk of hepatotoxicity with concurrent statin and tyrosine kinase inhibitor (TKI) or mTOR inhibitor (mTORi) in patients with metastatic renal cell carcinoma (mRCC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 610-610
Author(s):  
Trang H. Au ◽  
Erin B. Bailey ◽  
Shiven B. Patel ◽  
Srinivas Kiran Tantravahi ◽  
Neeraj Agarwal ◽  
...  

610 Background: TKIs and statins alone can cause liver injury. When used together, there is additive risk for hepatotoxicity, as seen with pazopanib and simvastatin, and the potential for discontinuing TKI therapy. Liver enzyme abnormalities are also associated with mTORi. Hepatotoxicity from concurrent use of statins as a class with TKI or mTORi as a class in real world practice in mRCC has not been reported. Methods: This observational cohort study included adult patients treated with a TKI or mTORi for mRCC at the Huntsman Cancer Institute from 2004-2014. We performed a treatment line analysis. For each treatment line, CTCAE criteria were used to categorize maximum AST, ALT, and total bilirubin. Highest grade of any liver enzyme was compared between TKI with and without statin and between mTORi with and without statin (Fisher’s Exact test). Results: A total of 162 treatment lines were included. For TKI and statin, the three most common treatment line combinations were sunitinib and simvastatin (7), sunitinib and atorvastatin (4), and pazopanib and simvastatin (3). For mTORi and statin, the three most common treatment line combinations involved simvastatin with temsirolimus (7) and everolimus (3). Prevalence of hepatotoxicity is shown in the table. Conclusions: Our results show a trend toward significance in the prevalence of hepatotoxicity with concomitant mTORi and statin versus mTORi alone, perhaps explained by mTORi-mediated competitive inhibition of simvastatin (sensitive CYP 3A4 substrate). There was no difference in hepatotoxicity for TKI with or without statin, although there were few pazopanib and simvastatin combinations. Study limitations include the small sample size, limited number of TKI or mTORi and statin combinations, and retrospective study design. A larger study is needed to validate these findings. [Table: see text]

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 608-608
Author(s):  
Trang H. Au ◽  
Erin B. Bailey ◽  
Shiven B. Patel ◽  
Srinivas Kiran Tantravahi ◽  
Neeraj Agarwal ◽  
...  

608 Background: PPIs may reduce TKI bioavailability resulting in reduced efficacy, shortened time on TKI treatment, and disease progression. Axitinib, sorafenib, and pazopanib exhibit pH-dependent solubility. Esomeprazole reduced the AUC and Cmax of pazopanib by 40%, but there was no significant interaction for sorafenib with omeprazole or axitinib with rabeprazole. In real world practice, the effect of PPIs as a class on the efficacy of TKIs as a class in mRCC has not been reported. Methods: This observational cohort study evaluated adult patients treated with a TKI for mRCC. Time on TKI treatment was defined as TKI initiation date to date of discontinuation, change in therapy, lost to follow-up, or death. We performed a treatment line analysis. Time on TKI treatment was compared between patients with and without concurrent PPI (Kaplan-Meier, log-rank). Results: Analysis included 128 treatment lines, including 49 TKI with PPI and 79 TKI with no PPI treatment lines. TKIs included sunitinib, pazopanib, sorafenib, and axitinib. PPIs included omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole. The three most common TKI/PPI combinations involved omeprazole with sunitinib (26), pazopanib (13), and axitinib (3). No difference in time on TKI treatment with PPI (median 8.7 months) and with no PPI (median 7.0 months, p = 0.41) was observed. In pazopanib treatment lines, no difference in time on treatment was observed in those treated with omeprazole or esomeprazole (n = 14, median 4.8 months) compared to those without PPI (n = 18, median 1.7 months, p = 0.22). Conclusions: Among the TKI/PPI combinations evaluated, there was no difference in time to TKI discontinuation with or without concurrent PPI. This suggests that concurrent PPI does not affect time to discontinuation of TKI. Study limitations include the small sample size, limited number of TKI/PPI combinations, and retrospective study design. A larger study is needed to validate these findings.


CNS Spectrums ◽  
2017 ◽  
Vol 23 (4) ◽  
pp. 278-283 ◽  
Author(s):  
Anja Elliott ◽  
Thibault Johan Mørk ◽  
Mikkel Højlund ◽  
Thomas Christensen ◽  
Rasmus Jeppesen ◽  
...  

ObjectiveAntipsychotics are associated with a polymorphic ventricular tachycardia, torsades de pointes, which, in the worst case, can lead to sudden cardiac death. The QT interval corrected for heart rate (QTc) is used as a clinical proxy for torsades de pointes. The QTc interval can be prolonged by antipsychotic monotherapy, but it is unknown if the QTc interval is prolonged further with antipsychotic polypharmaceutical treatment. Therefore, this study investigated the associations between QTc interval and antipsychotic monotherapy and antipsychotic polypharmaceutical treatment in schizophrenia, and measured the frequency of QTc prolongation among patients.MethodsWe carried out an observational cohort study of unselected patients with schizophrenia visiting outpatient facilities in the region of Central Jutland, Denmark. Patients were enrolled from January of 2013 to June of 2015, with follow-up until June of 2015. Data were collected from clinical interviews and clinical case records.ResultsElectrocardiograms were available for 65 patients, and 6% had QTc prolongation. We observed no difference in average QTc interval for the whole sample of patients receiving no antipsychotics, antipsychotic monotherapy, or antipsychotic polypharmaceutical treatment (p=0.29). However, women presented with a longer QTc interval when receiving polypharmacy than when receiving monotherapy (p=0.01). A limitation of this study was its small sample size.ConclusionsWe recommend an increased focus on monitoring the QTc interval in women with schizophrenia receiving antipsychotics as polypharmacy.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5037-5037
Author(s):  
Zhen Wang ◽  
Elaine Zhai ◽  
Aleksic Sandra ◽  
Kibola Adam ◽  
Richard May ◽  
...  

Abstract Background: The American Association of Blood Banks (AABB) 2012 Guidelines recommend a restrictive transfusion strategy of 7 g/dL to 8 g/dL in asymptomatic, hemodynamically stable patients (pts) and for Hgb less than 8 g/dL in pts with preexisting cardiovascular disease. [1] Additional recommendations based on expert opinion include transfusion at threshold Hgb of 7 g/dL for hemodynamically stable ICU pts and Hgb less than 10 g/dL in pts with symptomatic anemia. We examined adherence to these guidelines and for differences in outcomes between restrictive and non-restrictive approaches at an academic hospital. Methods: We performed an IRB-approved retrospective review of all pts admitted to the Internal Medicine Service at University Hospital in Newark, New Jersey from July 1st to November 30th 2015 who received RBC transfusions. Charts were abstracted for demographic information, past medical history, indication for transfusion, presence of signs or symptoms of anemia (chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart failure), pre-transfusion Hgb, number of units transfused, and post-transfusion hgb. Outcomes were defined as requirement for additional transfusions, infections, cardiovascular events, adverse transfusion reactions, and death within 30 days of transfusion. Each transfusion was categorized as either adherent or non-adherent to the guidelines. Difference in outcomes between groups (adherent vs non-adherent) was tested using chi-square and Fisher's exact test with SAS studio version 3.4 (Cary, NC). Results: We reviewed 318 RBC transfusion records for 210 pts (median age: 55±17 years) with 157 (49%) transfusions in male and 161 (51%) in female pts. Site was ICU for 86 and the ward for 232 transfusions. The leading indication was acute bleeding (121 or 38%; pre-transfusion Hgb 6.9±1.3g/dL), followed by asymptomatic anemia (107 or 33%; pre-transfusion Hgb 6.8±0.8g/dL), and symptomatic anemia (91 or 29%; pre-transfusion Hgb 6.6±0.8g/dL). Of the 107 pts with asymptomatic anemia, 37 had pre-existing heart disease. Within this group, 35 were transfused at Hgb < 8g/dL (adherence of 95%). Seventy of the 107 transfusions were performed in pts without pre-existing cardiac disease. Fifty-nine were transfused at hgb < 7g/dL with an adherence of 84%. In the ICU, 21 of the 27 transfusions occurred for hgb < 7 g/dL in hemodynamically stable pts with an adherence of 78%. There were 91 transfusions for symptomatic anemia and all were adherent (100%). Regarding 30 day post-transfusion outcomes, there were 140 (44%) with subsequent transfusions; 54 (14%) infections; 7 (2.2%) cardiovascular events; 8 (2.5%) transfusion adverse reactions; 27(8%) deaths. No difference was detected for 30 day outcomes between the adherent group and the non-adherent group. (Table 1) Transfusion of at least 2unitsRBC in asymptomatic, symptomatic, and active bleeding pts were 25% (27/107), 44% (40/91), 57% (69/120) respectively. No difference in outcomes was found for the group receiving only 1 unit RBC (restrictive) compared to the group receiving 2 or more units RBC (non-restrictive). (Table 1) Conclusion: The majority of transfusions (92%) performed adhered to current guideline. While the restrictive approach was not associated with more complications or mortality, this study is limited by the small sample size and further work is being done. Acknowledgment: The authors are grateful to Dr. Koshy, Director of Blood Bank at University Hospital, for assistance. Reference: 1. Carson, J. L. et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 157, 49-58 (2012). Disclosures Chang: Johnson and Johnson: Other: Stock; Amgen: Other: Research; Boehringer Ingelheim: Other: Research.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4611-4611
Author(s):  
Axel Bex ◽  
Thomas Powles ◽  
Christian U. Blank ◽  
Simon Chowdhury ◽  
Simon Horenblas ◽  
...  

4611 Background: There is concern that interruption of tyrosine kinase inhibitors (TKI) triggers disease progression (PD) and metastasis. This is based on preclinical models and observation of rapid PD in the postsurgical treatment break in patients pretreated with TKI. Little is known about the frequency of PD during postsurgical TKI interruption and its outcome. These data may have implications for neoadjuvant or presurgical treatment concepts. Methods: Of 66 patients from two closed phase II trials investigating 2-3 months presurgical sunitinib for primary metastatic clear-cell RCC, 45 were evaluated in this retrospective analysis because they had absence of PD prior to planned surgery and underwent CN (35 [78%] MSKCC intermediate and 10 [22%] poor risk). Patients had CT scans at the end of pretreatment and at 4 weeks post-nephrectomy before restarting sunitinib. In patients with postsurgical RECIST PD at 4 weeks when compared to the preoperative CT scan overall survival (OS) was measured from the time of nephrectomy and compared to patients without treatment break PD. Results: Median OS of 45 patients from the time of surgery was 22 months (13.0-31.5 months). Overall 14 patients progressed during treatment break (31%), with new sites of disease in 5/14 (35%). Reintroduction of sunitinib resulted in disease stabilisation or better in 13. Patients with poor risk were represented in the progressors (n=4[28%]) and non-progressors (n=6 [19%]) (p=0.7 fishers exact test). The hazard ratio (HR) for death associated with PD during treatment break was 1.90 (95% CI 0.89-4.08). OS for non-progressors was 25 months (15-NA) and 13 months (6-27) for progressors. Conclusions: A significant proportion of patients develop PD upon sunitinib withdrawal in a 4 week recovery period following CN. In view of the small sample size these data suggest a strong trend toward treatment break PD being associated with a poor outcome. It is not clear whether this PD is related to interruption of TKI, surgery or a combination of factors. The EORTC SURTIME trial investigates treatment break PD after immediate CN and CN after sunitinib and may answer this question.


2021 ◽  
Vol 27 ◽  
Author(s):  
Bing Lv ◽  
Jing Chen ◽  
Xiao-Liang Liu

Background: Anlotinib is a new tyrosine kinase inhibitor developed in China that targets the receptors for vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and stem cell factor. Therefore, anlotinib inhibits tumor angiogenesis, representing a new therapeutic alternative for lung cancer. Hypertension is one of its most common adverse effects, leading to discontinuation of the drug and limited clinical usefulness. Objective: The present review aims to summarize the evidence on the prevalence, physiopathology, and management of anlotinib-induced hypertension, as well as its effect on the cancer prognosis. Method: Searches in Medline, Cochrane Central Library, and Embase were performed using the following terms: anlotinib, adverse effect, hypertension, clinical trial, vascular endothelial growth factor, and antiangiogenic drugs. Citations were also identified by checking the reference sections of selected papers. Results: Except for a phase I clinical trial with a small sample size (n = 6), almost all the clinical trials on anlotinib have reported the development of anlotinib-induced hypertension. In these trials, the incidence of hypertension ranged from 13% to 67.7%, and that of grade 3/4 hypertension ranged from4.8% to 16%. Alterations in nitric oxide, endothelin-1, microvascular rarefaction, selective vasoconstrictions, and renal injury have been cited as potential mechanisms leading to anlotinib-induced hypertension. When needed, treatment may include general hygienic measures and pharmacotherapy in some cases. Conclusions: To effectively manage anlotinib-induced hypertension, early prevention, a reasonable dosage regimen, and appropriate treatment are critical to effectively manage anlotinib-induced hypertension. Additionally, anlotinib-induced hypertension may be considered a marker for predicting efficacy.


2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S29-S30
Author(s):  
Anu S Maharjan ◽  
Gwendolyn McMillin ◽  
Moh’d Khushman ◽  
Girijesh Patel

Abstract Introduction The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation. Here we genotyped a larger cohort of a mixed racial background to explore the incidence of DPYD*9A variant and to further study the genotype-phenotype correlation. Methods Genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13, and DPYD*9B) and the DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies (GI) treated with fluoropyrimidines, using TaqMan chemistry. The prevalence of different DPYD variants was further analyzed in 1,283 retrospective data from ARUP laboratories. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v 5.0). Fisher’s exact test was used for statistical analysis. Results In total, 1,283 were retrospectively reviewed for DPYD variants. Four patients (0.31%) carried DPYD c.-1590T>C, 10 patients (0.55%) carried DPYD c.1679T>G (*13), 36 patients (2.8%) carried DPYD c.2846A>T, and 527 patients (41.1%) carried DPYD c.85T>C (*9A). In the GI cancer cohort, DPYD variants were identified in 61 patients (54%), showing similar prevalence as the retrospective analysis. Caucasians represented 54% and African Americans represented 43%. Twenty-eight patients (46%) were females. Heterozygous DPYD*9A was identified in 46 patients (41%) and homozygous DPYD*9A was identified in 11 patients (10%). DPYD*2A was identified in 3 patients and DPYD*9B was identified in 2 patients (one patient had double heterozygous *9A and *9B). Grade 3 to 4 toxicities were experienced in 26 patients with mutant DPYD*9A (3 patients had homozygous DPYD*9A) and in 20 patients with no identified DPYD mutation (P = .7035). In patients who received full-dose fluoropyrimidines (N = 85), grade 3 to 4 toxicities were experienced in 22 patients with mutant DPYD*9A (2 patients had homozygous DPYD*9A) and in 17 patients with no identified DPYD mutation (P = .8275). Conclusion In the GI cancer population, the DPYD*9A variant was identified in 54% of patients. The correlation between DPYD*9A variant and DPD clinical phenotype was not significant. The noticeable correlation that was previously reported is likely due to small sample size and selection bias.


2015 ◽  
Author(s):  
Wilson Wen Bin Goh

Network-based analysis methods can help resolve coverage and inconsistency issues in proteomics data. Previously, it was demonstrated that a suite of rank-based network approaches (RBNAs) provides unparalleled consistency and reliable feature selection. However, reliance on the t-statistic/t-distribution and hypersensitivity (coupled to a relatively flat p-value distribution) makes feature prioritization for validation difficult. To address these concerns, a refinement based on the fuzzified Fisher exact test, Fuzzy-FishNet was developed. Fuzzy-FishNet is highly precise (providing probability values that allows exact ranking of features). Furthermore, feature ranks are stable, even in small sample size scenario. Comparison of features selected by genomics and proteomics data respectively revealed that in spite of relative feature stability, cross-platform overlaps are extremely limited, suggesting that networks may not be the answer towards bridging the proteomics-genomics divide.


2021 ◽  
Vol 9 ◽  
Author(s):  
Archana Priyadarshi ◽  
Gemma Lowe ◽  
Vishal Saddi ◽  
Amit Trivedi ◽  
Melissa Luig ◽  
...  

Background: The administration of live microbiota (probiotic) via enteral route to preterm infants facilitates intestinal colonization with beneficial bacteria, resulting in competitive inhibition of the growth of pathogenic bacteria preventing gut microbiome dysbiosis. This dysbiosis is linked to the pathogenesis of necrotizing enterocolitis (NEC), an acquired multi-factorial intestinal disease characterized by microbial invasion of the gut mucosa, particularly affecting preterm infants. Probiotic prophylaxis reduces NEC; however, variations in strain-specific probiotic effects, differences in administration protocols, and synergistic interactions with the use of combination strains have all led to challenges in selecting the optimal probiotic for clinical use.Aim: To compare any differences in NEC rates, feeding outcomes, co-morbidities in preterm infants receiving single or two-strain probiotics over a 4-year period. The two-strain probiotic prophylaxis was sequentially switched over after 2 years to the single strain probiotic within this 4-year study period, in similar cohort of preterm infants.Methods: During two consecutive equal 2-year epochs, preterm infants (&lt;32 weeks and or with birth weight &lt;1,500 g) receiving two-strain (Lactobacillus acidophilus and Bifidobacterium bifidum) and single strain (Bifidobacterium breve M-16 V,) probiotic prophylaxis for prevention of NEC were included in this retrospective, observational study. The primary outcome included rates of NEC; secondary outcomes included prematurity related co-morbidities and feeding outcomes. Time to reach full enteral feeds was identified as the first day of introducing milk feeds at 150 ml/kg/day.Results: There were 180 preterm infants in the two-strain, 196 in the single strain group from the two equal consecutive 2-year epochs. There were no differences in the NEC rates, feeding outcomes, all-cause morbidities except for differences in rates of retinopathy of prematurity.Conclusion: In our intensive-care setting, clinical outcomes of single vs. two—strain probiotic prophylaxis for prevention of NEC were similar. Although our study demonstrates single strain probiotic may be equally effective than two-strain in the prevention of NEC, small sample size and low baseline incidence of NEC in our unit were not sufficiently powered to compare single vs. two-strain probiotic prophylaxis in preventing NEC. Further clustered randomized controlled trials are required to study the effects of single vs. multi-strain probiotic products for NEC prevention in preterm infants.


Polymers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 4340
Author(s):  
Katarzyna Mańka-Malara ◽  
Maciej Trzaskowski ◽  
Dominika Gawlak

Polymeric liners are materials commonly used in prosthodontics to reshape denture surfaces contacting the soft tissues of the oral cavity. The aim of the study was to determine the impact of different cleaning methods on two polymeric materials used in prosthodontics as non-adhesive permanent liners. The material for the research consisted of samples made from Mollosil Plus (Detax, Ettlingen, Germany)—direct polysiloxan liner; and Plastitanium (Pressing Dental, San Marino, Republic of San Marino)—an injection-molded liner. A total of 198 samples were made, 99 of each assessed material. They were exposed to different cleaning methods—a toothbrush, a toothbrush and soap, a toothbrush and toothpaste (BlendaMed, Procter&Gamble, Cincinnati, OH, USA), a toothpaste and denture cleaning paste (Protefix Hygiene Denture Paste, Queisser Pharma, Germany), denture cleansing tablets (Protefix Hygiene Cleaning Tablets, Queisse Pharma, Germany), and a disinfecting spray (Aftermat, Port Jefferson Station, New York City, NY, USA)—for 1 min, 5 min, 10 min, and 15 min. The image acquisition was performed with scanning electron microscopy and samples were analyzed for the homogeneity of their surfaces—the presence of holes, grooves, precipitate, and small and large separating pieces of the material marking departures from this homogeneity. For each type of damage, one point was given. Continuous data from two groups were compared with Mann–Whitney U testing. Due to a small sample size and distribution of variables other than normal, to compare more than two groups, Kruskal–Wallis testing with post hoc analysis (Dunn test with Bonferroni correction) was used. Categorical data were compared with the chi-square test and the Fisher’s exact test. The Mollosil Plus material should be decontaminated with the use of a toothbrush or toothbrush with soap, while Plastitanium material should be disinfected. Plastitanium samples are more susceptible to damage during the decontamination procedures than Mollosil Plus.


Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Katherine Duello ◽  
Jay P Nagel ◽  
William D Freeman ◽  
Joseph L Blackshear ◽  
David A Miller

Introduction: Elevations of troponin after subarachnoid hemorrhage (SAH) frequently occur and are associated with cardiopulmonary complications. The time to peak elevation remains poorly described in terms of the natural history after SAH. Our two objectives were to define the temporal profile of troponin T elevation after SAH and correlate levels of troponin T with baseline neurological status. We hypothesized that troponin T would peak early after initial presentation. Methods: We reviewed the medical records of all aneurysmal and non-traumatic SAH patients from March 2011-December 2012. Troponin T from patients with ≥ 2 values was recorded with respect to SAH symptom onset. Patients with ≥ 1 Troponin T value were stratified according to admission Glasgow Coma Scale (GCS). GCS was dichotomized to > 8 or ≤ 8. Fisher’s exact test was performed comparing elevated peak troponin T (≥0.01 ng/ml) versus normal against GCS status cutoffs > 8 or 8 or less. Results: We identified 124 patients who had both troponin T and GCS reported, and 30 patients had ≥2 troponin T measurements within the first 40 hours of hospitalization. The median time to peak troponin T in these patients was 11.2 hours with a standard deviation of 6.2 hours (Range: 4.9-35.0 hours). Elevated troponin T was seen in 52 of 124. GCS of ≤ 8 was present in 43 of 124. Patients with elevated levels of troponin T had a greater chance of lower GCS [Odds ratio = 4.8 (95% CI: 2.2 to 10.7)] (P= <0.0001). Conclusions: The median time to peak troponin T after SAH injury was 11 hours. There was a statistically significant association between troponin T elevation and worse neurologic status at presentation (GCS ≤ 8). Although our small sample size found large variation in time to peak troponin, it supports the hypothesis that troponin peaks early after the initial presentation. Future studies using troponin elevation as a biomarker should focus on sample acquisition at the time of admission and in the first 1-2 days.


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