Cytidine Deaminase Residual Activity in Serum Is a Predictive Marker of Early Severe Toxicities in Adults After Gemcitabine-Based Chemotherapies

2010 ◽  
Vol 28 (1) ◽  
pp. 160-165 ◽  
Author(s):  
Joseph Ciccolini ◽  
Laetitia Dahan ◽  
Nicolas André ◽  
Alexandre Evrard ◽  
Muriel Duluc ◽  
...  

Purpose Anticipating toxicities with gemcitabine is an ongoing story, and deregulation in cytidine deaminase (CDA) could be associated with increased risk of developing early severe toxicities on drug exposure. Patients and Methods A simple test to evaluate CDA phenotypic status was first validated in an animal model investigating relationships between CDA activity and gemcitabine-related toxicities. Next, relevance of this test as a marker for toxicities was retrospectively tested in a first subset of 64 adult patients treated with gemcitabine alone, then it was tested in a larger group of 130 patients who received gemcitabine either alone or combined with other drugs and in 20 children. Additionally, search for the 435 T>C, 208 G>A and 79 A>C mutations on the CDA gene was performed. Results In mice, CDA deficiency impacted on gemcitabine pharmacokinetics and had subsequent lethal toxicities. In human, 12% of adult patients experienced early severe toxicities after gemcitabine administration. A significant difference in CDA activities was observed between patients with and without toxicities (1.2 ± 0.8 U/mg v 4 ± 2.6 U/mg; P < .01). Conversely, no genotype-to-phenotype relationships were found. Of note, the patients who displayed particularly reduced CDA activity all experienced strong toxicities. Gemcitabine was well tolerated in children, and no CDA deficiency was evidenced. Conclusion Our data suggest that CDA functional testing could be a simple and easy marker to discriminate adult patients at risk of developing severe toxicities with gemcitabine. Particularly, this study demonstrates that CDA deficiency, found in 7% of adult patients, is associated with a maximum risk of developing early severe toxicities with gemcitabine.

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 764
Author(s):  
Shih-Lung Cheng ◽  
Kuo-Chin Chiu ◽  
Hsin-Kuo Ko ◽  
Diahn-Warng Perng ◽  
Hao-Chien Wang ◽  
...  

Purpose: To understand the association between biomarkers and exacerbations of severe asthma in adult patients in Taiwan. Materials and Methods: Demographic, clinical characteristics and biomarkers were retrospectively collected from the medical charts of severe asthma patients in six hospitals in Taiwan. Exacerbations were defined as those requiring asthma-specific emergency department visits/hospitalizations, or systemic steroids. Enrolled patients were divided into: (1) those with no exacerbations (non-exacerbators) and (2) those with one or more exacerbations (exacerbators). Receiver operating characteristic curves were used to determine the optimal cut-off value for biomarkers. Generalized linear models evaluated the association between exacerbation and biomarkers. Results: 132 patients were enrolled in the study with 80 non-exacerbators and 52 exacerbators. There was no significant difference in demographic and clinical characteristics between the two groups. Exacerbators had significantly higher eosinophils (EOS) counts (367.8 ± 357.18 vs. 210.05 ± 175.24, p = 0.0043) compared to non-exacerbators. The optimal cut-off values were 292 for EOS counts and 19 for the Fractional exhaled Nitric Oxide (FeNO) measure. Patients with an EOS count ≥ 300 (RR = 1.88; 95% CI, 1.26–2.81; p = 0.002) or FeNO measure ≥ 20 (RR = 2.10; 95% CI, 1.05–4.18; p = 0.0356) had a significantly higher risk of exacerbation. Moreover, patients with both an EOS count ≥ 300 and FeNO measure ≥ 20 had a significantly higher risk of exacerbation than those with lower EOS count or lower FeNO measure (RR = 2.16; 95% CI, 1.47–3.18; p = < 0.0001). Conclusions: Higher EOS counts and FeNO measures were associated with increased risk of exacerbation. These biomarkers may help physicians identify patients at risk of exacerbations and personalize treatment for asthma patients.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1921-1921 ◽  
Author(s):  
SeungHwan Shin ◽  
JaeHo Yoon ◽  
SeungAh Yahng ◽  
SungEun Lee ◽  
ByungSik Cho ◽  
...  

Abstract Abstract 1921 Background: There is a controversy concerning upper age limit of recipient in allogeneic stem cell transplantation (allo-SCT) of severe aplastic anemia (SAA) because older patients have an increased risk of transplant-related mortality (TRM). Recently, a less toxic regimen comprising reduced dose of cyclophosphamide (CY), fludarabine (Flu), and ATG (Flu/CY/ATG) was introduced for conditioning the patients with SAA scheduled for HLA-identical sibling allo-SCT. We analyzed the outcome of these patients after conditioning with Flu/CY/ATG regimen according to recipient's age. Method: We analyzed 82 consecutive adult patients transplanted from March 2002 to June 2011, followed conditioning with CY (50 mg/kg/day × 2 days), Flu (30 mg/m2/day × 6 days), and ATG (2.5 mg/kg/day × 4 days). Results: The median age of patients was 39 years (range, 13–58 years). 29 (35.4%) patients were very SAA at the time of allo-SCT. Stem cell sources were bone marrow (BM, n=59), peripheral blood stem cell (PBSC, n=12), and BM+PBSC (CD34+ cell selection, n=11). The conditioning regimen was well tolerated, with low TRM (4.9%). Neutrophil engraftment was observed in all patients; the median time to engraftment of neutrophils and platelets was 12 and 17 days, respectively. The 100-day cumulative incidence (CI) of acute graft-versus-host disease (GVHD, grade °Ã2) was 3.7% and 2-year CI of chronic GVHD was 4.4%. With a median follow-up of 3 years, overall survival (OS) and failure-free survival was 93% and 83%, respectively. Seven patients (8.5%) developed delayed graft failure and 6 patients of them have successful durable engraftment after second allo-SCT without TRM. Seven patients died of veno-occlusive disease (n=1), cytomegalovirus pneumonia (n=2), sepsis (n=2), clonal evolution after allo-SCT (n=2, 1 acute myeloid leukemia and 1 myelodysplastic syndrome), respectively. 3-year probability of OS by age group were 88% at less than 20 years old (n=8), 97% at 20–39 (n=34), 92% at 40–49 (n=26), 86% at 50–59 (n=14). There is no significant difference in OS according to age group (p=0.426). Conclusion: These data indicate that the Flu/CY/ATG conditioning regimen is well tolerable with low TRM and CI of GVHD in all age group. Similar OS according to 4-divided age group suggest that patient's age more than 50 years old might be possible candidate for allo-SCT in SAA with Flu/CY/ATG conditioning regimen. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Author(s):  
He-Jie Shi ◽  
Rui-Xia Yuan ◽  
Jun-Zhi Zhang ◽  
Jia-Hui Chen ◽  
An-Min Hu

Abstract BACKGROUND: Midazolam is commonly administered in the intensive care unit (ICU) because of its limited effect on hemodynamics and stable calming and sleep-induction effects. Recent concerns about an increased risk of delirium associated with midazolam have resulted in decreased midazolam usage in the ICU. However, whether midazolam administration within 24 hours prior is related to the occurrence of delirium is still unknown.METHODS: We used real-world data from MIMIC III v1.4, MIMIC-IV v0.4 and eICU Collaborative Research to perform comparisons and assess the associated outcome effectiveness. We performed a systematic study with two cohorts to estimate the relative risks of outcomes among patients administered midazolam within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1:1 matched cohort and to identify potential prognostic factors. The outcomes included mortality, length of ICU stay, length of hospitalization, and odds of being discharged home.RESULTS: Propensity matching successfully balanced covariates for 9,348 patients (4,674 per group). There was no significant difference in hospitalization duration, (P = 0.03). However, compared to no administration of midazolam, midazolam administration was associated with a significantly higher risk for delirium (P<0.001). When compared with no midazolam administration, the use of midazolam, was associated with higher mortality and a longer ICU stay (P<0.001). Patients treated with midazolam were relatively less likely to be discharged home (P<0.001). CONCLUSIONS: Compared with no administration of midazolam, midazolam administration was associated with a difference in the incidence of delirium, mortality, ICU stay and likelihood of being discharged home but was not associated with hospitalization duration. These data suggest that midazolam may not be the preferred sedative drug for patients at risk for delirium.


VASA ◽  
2017 ◽  
Vol 46 (6) ◽  
pp. 484-489 ◽  
Author(s):  
Tom Barker ◽  
Felicity Evison ◽  
Ruth Benson ◽  
Alok Tiwari

Abstract. Background: The invasive management of varicose veins has a known risk of post-operative deep venous thrombosis and subsequent pulmonary embolism. The aim of this study was to evaluate absolute and relative risk of venous thromboembolism (VTE) following commonly used varicose vein procedures. Patients and methods: A retrospective analysis of secondary data using Hospital Episode Statistics database was performed for all varicose vein procedures performed between 2003 and 2013 and all readmissions for VTE in the same patients within 30 days, 90 days, and one year. Comparison of the incidence of VTEs between procedures was performed using a Pearson’s Chi-squared test. Results: In total, 261,169 varicose vein procedures were performed during the period studied. There were 686 VTEs recorded at 30 days (0.26 % incidence), 884 at 90 days (0.34 % incidence), and 1,246 at one year (0.48 % incidence). The VTE incidence for different procedures was between 0.15–0.35 % at 30 days, 0.26–0.50 % at 90 days, and 0.46–0.58 % at one year. At 30 days there was a significantly lower incidence of VTEs for foam sclerotherapy compared to other procedures (p = 0.01). There was no difference in VTE incidence between procedures at 90 days (p = 0.13) or one year (p = 0.16). Conclusions: Patients undergoing varicose vein procedures have a small but appreciable increased risk of VTE compared to the general population, with the effect persisting at one year. Foam sclerotherapy had a lower incidence of VTE compared to other procedures at 30 days, but this effect did not persist at 90 days or at one year. There was no other significant difference in the incidence of VTE between open, endovenous, and foam sclerotherapy treatments.


2019 ◽  
Author(s):  
Cort M. Dorn-Medeiros ◽  
Cass Dykeman ◽  
Timothy Bergquist

This archived data study used results from the New York City Community Health Survey to explore the relationship between interpersonal violence among female sexual minorities (FSM) and their levels of alcohol and tobacco use. A total of 92 FSM were included in the sample population. There was a significant difference in the mean number of alcoholic drinks consumed between FSM who reported past experience of interpersonal violence and those who did not. No difference was found in levels of tobacco use between FSM who reported interpersonal violence and those who did not. Results of the present study support current research indicating FSM may be at increased risk for elevated alcohol use and respective negative life outcomes related to the experience of interpersonal violence.


2019 ◽  
Vol 14 (3) ◽  
pp. 268-279
Author(s):  
Ying Liu ◽  
Zhi Li ◽  
Xinyue Tang ◽  
Min Li ◽  
Feng Shi

Background: A previous genome-wide association study showed that hTERT rs10069690 and rs2736100 polymorphisms were associated with thyroid cancer risk. Objective: This study further investigated the association between increased risk and clinicopathologic characteristics for Papillary Thyroid Carcinoma (PTC) and hTERT polymorphisms rs10069690 or rs2736100 in a Chinese female population. Methods: The hTERT genotypes of 276 PTC patients and 345 healthy subjects were determined with regard to SNPs rs10069690 and rs2736100. The association between these SNPs and the risk of PTC and clinicopathologic characteristics was investigated by logistic regression. Results: We found a significant difference between PTC and rs10069690 (Odds Ratio (OR) = 1.515; P = 0.005), but not between PTC and rs2736100. When the analysis was limited to females, rs10069690 and rs2736100 were both associated with increased risk for PTC in female individuals (OR = 1.647, P = 0.007; OR = 1.339, P = 0.041, respectively). Further haplotype analysis revealed a stimulative effect of haplotypes TC and CA of TERT rs10069690-rs2736100, which increased risk for PTC in female individuals (OR = 1.579, P = 0.014; OR = 0.726, P = 0.025, respectively). Furthermore, the heterozygote A/C of rs2736100 showed significant difference for age (OR = 0.514, P = 0.047). Conclusion: Our finding suggests that hTERT polymorphisms rs10069690 and rs2736100 are associated with increased risk for PTC in Chinese female population and rs2736100 may be related to age. Consistent with US20170360914 and US20170232075, they are expected to be a potential molecular target for anti-cancer therapy.


2017 ◽  
Vol 6 (03) ◽  
pp. 5297
Author(s):  
Vedangi Aaren* ◽  
Godi Sudhakar ◽  
Girinadh L.R.S.

In both developed and developing countries, overuse of alcohol is a considered as the major cause of acute and chronic pancreatitis. Prolonged overconsumption of alcohol for 5–10 years typically precedes the initial attack of acute alcoholic pancreatitis. It is observed that only a minority (around 5%) of alcoholics develop pancreatitis. It is now established that the pancreas has the capacity to metabolize ethanol. Previous studies have shown that there are two major pathways of ethanol metabolism, oxidative and non-oxidative. Oxidative ethanol metabolism involves the conversion of ethanol to acetaldehyde, a reaction that is catalysed by aldehyde dehydrogenase (ADH) with contributions from cytochrome P450 enzyme (CYP2E1) and possibly also catalase. Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (AP). We investigated the association of polymorphisms in ADH enzymes with the alcoholic pancreatitis in North coastal Andhra Pradesh. Patients with alcoholic pancreatitis (AP; n = 100), alcoholic controls (AC; n = 100), and healthy controls (HC; n = 100) were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH2 and ADH3 was done by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism). The products were analysed by gel electrophoresis. The frequency distribution of ADH3*1/*1 genotype was significantly higher in AP group (54%) compared with AC (35%), and HC (42%), and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3*1/*1, ADH3*1/*2, and ADH3*2/*2 genotypes between AC and HC. There was no statistically significant difference between the frequency distribution of ADH2*1/*1, ADH2*1/*2, and ADH2*2/*2 genotypes in AP compared with AC and HC. This study shows that carriers of ADH3*1/*1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3*1/*2 and ADH3*2/*2. 


2020 ◽  
Author(s):  
Dr. Animesh Ray ◽  
Dr. Komal Singh ◽  
Souvick Chattopadhyay ◽  
Farha Mehdi ◽  
Dr. Gaurav Batra ◽  
...  

BACKGROUND Seroprevalence of IgG antibodies against SARS-CoV-2 is an important tool to estimate the true extent of infection in a population. However, seroprevalence studies have been scarce in South East Asia including India, which, as of now, carries the third largest burden of confirmed cases in the world. The present study aimed to estimate the seroprevalence of anti-SARS-CoV-2 IgG antibody among hospitalized patients at one of the largest government hospital in India OBJECTIVE The primary objective of this study is to estimate the seroprevalence of SARS-CoV-2 antibody among patients admitted to the Medicine ward and ICU METHODS This cross-sectional study, conducted at a tertiary care hospital in North India, recruited consecutive patients who were negative for SARS-CoV-2 by RT-PCR or CB-NAAT. Anti-SARS-CoV-2 IgG antibody levels targeting recombinant spike receptor-binding domain (RBD) protein of SARS CoV-2 were estimated in serum sample by the ELISA method RESULTS A total of 212 hospitalized patients were recruited in the study with mean age (±SD) of 41.2 (±15.4) years and 55% male population. Positive serology against SARS CoV-2 was detected in 19.8%patients(95% CI 14.7-25.8). Residency in Delhi conferred a higher frequency of seropositivity 26.5% (95% CI 19.3-34.7) as compared to that of other states 8% (95% CI 3.0-16.4) with p-value 0.001. No particular age groups or socio-economic strata showed a higher proportion of seropositivity CONCLUSIONS Around, one-fifth of hospitalized patients, who were not diagnosed with COVID-19 before, demonstrated seropositivity against SARS-CoV-2. While there was no significant difference in the different age groups and socio-economic classes; residence in Delhi was associated with increased risk (relative risk of 3.62, 95% CI 1.59-8.21)


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii168-ii168
Author(s):  
Antonio Dono ◽  
Kristin Alfaro-Munoz ◽  
Yuanqing Yan ◽  
Carlos Lopez-Garcia ◽  
Zaid Soomro ◽  
...  

Abstract In the 2016 WHO classification of CNS tumors, oligodendrogliomas are molecularly defined by IDH1 or IDH2 mutations and 1p/19q co-deletion. Some reports suggest that PI3K pathway alterations may confer increased risk of progression and poor prognosis in oligodendroglioma. However, factors that influence prognosis in molecularly defined oligodendroglioma (mOGD) have not been thoroughly studied. Also, the benefits of adjuvant radiation and temozolomide in mOGDs remain to be determined. 107 mOGDs diagnosed between 2008-2018 at the University of Texas Health Science Center at Houston (n= 39) and MD Anderson Cancer Center (n= 68) were included. A retrospective review of the demographic, clinical, histologic, molecular, and outcomes were performed. Median age at diagnosis was 37 years and 61 (57%) patients were male. There were 64 (60%) WHO Grade 2 and 43 (40%) WHO Grade 3 tumors. Ninety-five (88.8%) tumors were IDH1-mutant and 12 (11.2%) were IDH2-mutant. Eighty-two (77%) patients were stratified as high-risk: older than 40-years and/or subtotal resection (RTOG 9802). Gross-total resection was achieved in 47 (45%) patients. Treatment strategies included observation (n= 15), temozolomide (n= 11), radiation (n= 13), radiation with temozolomide (n= 62) and other (n= 6). Our results show a benefit of temozolomide vs. observation in progression-free survival (PFS). However, no benefit in PFS or overall survival (OS) was observed when comparing radiation vs. radiation with temozolomide. PIK3CA mutations were detected in 15 (14%) cases, and patients with PIK3CA-mutant mOGDs showed worse OS (10.7-years vs 15.1-years, p= 0.009). Patients with WHO Grade 3 tumors had shorter PFS but no significant difference in OS was observed compared to grade 2. Our findings suggest that mOGDs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS in temozolomide treated patients, adjuvant treatment with radiation or the combination of both, showed no significant advantage in terms of OS.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1580.2-1580
Author(s):  
R. De Angelis ◽  
F. Salaffi

Background:A growing evidence supports the role of microvasculopathy as a primary pathogenic event in systemic sclerosis (SSc). The most commonly used imaging technique to identify microangiopathy in SSc is high magnification videocapillaroscopy (NVC), and reduced capillary density and/or capillary loss, which is a typical feature of “scleroderma microangiopathy”, easily identified by NVC, has been associated with digital ulcers (DUs). Different approaches have been proposed to measure capillary density or capillary loss. Some of these were qualitative methods, others semi-quantitative, others only concerned a limited nailfold area, without ever evaluating the overall density, which is more suitable for quantitative estimate.Objectives:To assess the association between the extent of different values of nailfold capillary density and the presence of DUs and to identify the risk of developing DUs, based on quantitative parameters.Methods:The study involved 54 SSc selected patients (47 women and 7 men, mean age 59.5 years, 50 with limited and 4 with diffuse). The study population came from an ongoing database, that includes clinical and laboratory data of patients with definite SSc. A videocapillaroscope (VideoCap® 3.0, DS Medica, Milan, Italy) with a 200x optical probe was used. During examination, eight fingers (fingers 2–5 of each hand), 4 fields per finger, according to the standard literature were assessed. For each patient, a total of 32 images were collected, then classified as having either “normal”, “non-specific” or the “scleroderma pattern” (SP). Capillary density was defined as the number of capillaries/mm in the distal row, regardless of its shape and morphology. Avascular areas were defined by the absence of loops within a width/area extending over more than 500 microns. For each patient, the SP images were further graded with no/slight reduction of the capillary density (7-9 loops/mm) (NOR), with a well-defined reduction of capillary density (6-4 loops/mm) (RED) and with loss of capillaries (<4) plus avascular areas (AA). Then, the overall percentages were calculated (the number with SP, the number with NOR, with RED and with AA, respect to 32), thus obtaining the quantitative measures. All data were analysed using the MedCalc® version 18.6; 64-bit (MedCalc Software, Mariakerke, Belgium).Results:A total of 1728 images were analyzed. Patients with DUs were 16/54 (29.6%). All patients had a SP, but only five patients showed a SP along the entire nailfold. A comparison between patients with or without DUs showed a significant difference both for the overall extent of AA (p=0.032), and particularly for the overall extent of RED (p<0.001). No significant difference was found regarding the overall extent of the SP (p=0.085). Factor significantly associated with DUs in multivariate analysis was the overall extent of RED (p=0.0286). The ROC curve was very effective at discriminating the capillary feature able to distinguish patients with DUs from patients without DUs. The discriminatory power of the overall extent of RED was very good, with an AUC of 0.948 (95 % CI 0.852 ± 0.990). Then, we calculated the cut-off values of the overall extent of RED for presence/absence of DUs with the highest combination of sensitivity and specificity. The resulting cut-off value (Yourden index of 0.825) was >68.7 (sensitivity 92.31 %; specificity 90.24 %) with a LR+ of 9.46.Conclusion:Our data strongly support that the capillary density between 4 and 6 loops/mm is the best capillaroscopic quantitative measure associated with DUs and able to discriminate the probability of having DUs. If all SSc-specific antibodies and/or other laboratory/clinical parameters are not yet available, the overall capillary density can allow physicians to assess SSc patients easily, regarding DUs and risk for developing DUs.Disclosure of Interests:None declared


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