NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15¹3 and NUDT15¹2 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15¹3 and NUDT15¹2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.     

Locally advanced cervical carcinoma patients treated with chemoradiation followed by radical surgery: clinical response and oncological outcomes according to histotype after propensity score analysis

IntroductionThe aims of this study were to analyze the pathological response, and survival outcomes of adenocarcinoma/adenosquamous (AC/ASC) versus squamous cell carcinoma (SCC) in patients with locally advanced cervical cancer (LACC) managed by chemoradiotherapy followed by radical surgery.MethodsRetrospective, multicenter, observational study, including patients with SCC and AC/ACS LACC patients treated with preoperative CT/RT followed by tailored radical surgery (RS) between 06/2002 and 05/2017. Clinical-pathological characteristics were compared between patients with SCC versus AC/ASC. A 1:3 ratio propensity score (PS) matching was applied to remove the variables imbalance between the two groups.ResultsAfter PS, 320 patients were included, of which 240 (75.0%) in the SCC group, and 80 (25.0%) in the AC/ASC group. Clinico-pathological and surgical baseline characteristics were balanced between the two study groups. Percentage of pathologic complete response was 47.5% in SCC patients versus 22.4% of AC/ASC ones (p < 0.001). With a median follow-up of 51 months (range:1–199), there were 54/240 (22.5%) recurrences in SCC versus 28/80 (35.0%) in AC/ASC patients (p = 0.027). AC/ASC patients experienced worse disease free (DFS), and overall survival (OS) compared to SCC patients (p = 0.019, and p = 0.048, respectively). In multivariate analysis, AC/ACS histotype, and FIGO stage were associated with worse DFS and OS.ConclusionIn LACC patients treated with CT/RT followed by RS, AC/ASC histology was associated with lower pathological complete response to CT/RT, and higher risk of recurrence and death compared with SCC patients. This highlights the need for specific therapeutic strategies based on molecular characterization to identify targets and develop novel treatments.     

Tissue tracking of segmental strain as a predictor of provoked dynamic left ventricular outflow tract obstruction

BackgroundLeft ventricular outflow tract obstruction (LVOTO) is commonly observed in patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy (LVH). Some patients develop LVOTO provoked by physical exertion, and hence termed dynamic LVOTO (DLVOTO). However, its precise prevalence and mechanism are still unclear.AimTwo-dimensional speckle tracking echocardiography (2D STE) seems to be helpful for the detection of early LV structural abnormalities. This study aimed to examine the possible role of segmental as well as global longitudinal strain in identifying DLVOTO non-HCM patients as detected by dobutamine stress echocardiography (DSE).Methods and resultsTwo hundred and fifty patients without structural heart disease had undergone conventional transthoracic echocardiography, 2D STE, and DSE. All patients with non-ischemic evidence were divided into two groups according to the DSE results; DLVOTO (+) and DLVOTO (?).Among 250 patients, 50 patients (36%) had shown DLVOTO after DSE (15 males, 35 females; mean age 55±7years). They were compared with 90 non -LVOTO obstruction patients (43 males, 47 females; mean age 57±6years). Based on multivariate logistic regression analysis, the independent predictors of provoked DLVOTO during DSE were resting basal septal longitudinal strain BS-LS _average (p < 0.001), resting LA reservoir strain (p < 0.001), and systolic LVOT diameter (p = 0.03). Resting BS-LS _average with cut-off - 17.5% was recognized as a critical indicator of DLVOTO, with sensitivity 78%, and specificity 95% (better than systolic LVOT diameter of sensitivity 76%, and specificity 15% and resting LA reservoir strain which showed poor AUC at ROC curve 0.007).ConclusionWe demonstrate that provoked LVOTO during DSE in non HCM symptomatic patients is directly correlated to resting regional LS, where the increased BS-LS of ≥ ?17.5% was a key determinant of LVOT gradient provocation. Assessment of baseline BS-LS _average might be a bedside simple tool for detection of patients with DLVOTO not able to do DSE.     

The prognostic value of elevated neutrophil–lymphocyte ratio for cardiac surgery-associated acute kidney injury: A systematic review and meta-analysis

Background

Patients undergoing cardiac surgery are at significant risk of developing postoperative acute kidney injury (AKI). Neutrophil–lymphocyte ratio (NLR) is a widely available inflammatory biomarker which may be of prognostic value in this setting.

Methods

We conducted a systematic review and meta-analysis of studies reporting associations between perioperative NLR with postoperative AKI. We searched Medline, Embase and the Cochrane Library, without language restriction, from inception to May 2022 for relevant studies. We meta-analysed the reported odds ratios (ORs) with 95% confidence intervals (CIs) for both elevated preoperative and postoperative NLR with risk of postoperative AKI and need for renal replacement therapy (RRT). We conducted a meta-regression to explore inter-study statistical heterogeneity.

Results

Twelve studies involving 10,724 participants undergoing cardiac surgery were included, with eight studies being deemed at high risk of bias using PROBAST modelling. We found statistically significant associations between elevated preoperative NLR and postoperative AKI (OR 1.45, 95% CI 1.18–1.77), as well as postoperative need for RRT (OR 2.37, 95% CI 1.50–3.72). Postoperative NLR measurements were not of prognostic significance.

Conclusions

Elevated preoperative NLR is a reliable inflammatory biomarker for predicting AKI following cardiac surgery.     

Outcomes and risk management in type B aortic dissection patients with acute kidney injury: a concise review

PurposeType B aortic dissection is a rare but life-threatening disease. Thoracic endovascular aortic repair (TEVAR) was widely used for Type B aortic dissection patients in the last decade due to the lower mortality and morbidity compared with open chest surgical repair (OCSR). AKI in type B aortic dissection is a well-recognized complication and indicates poor short-term and long-term outcome. The objective of this concise review was to identify the risk factors and the impact of AKI on type B aortic dissection patients.Methods and resultsA literature search was performed using PubMed, Embase, MEDLINE, and Cochrane Library with the search terms ‘type B aortic dissection’ and ‘acute kidney injury’ (AKI), and all English-language literatures published in print or available online from inception through August 2020 were thoroughly reviewed. Studies that reported relative AKI risks and outcomes in type B aortic dissection patient were included. Major mechanisms of AKI in type B aortic dissection included renal hypoperfusion, inflammation response, and the use of contrast medium. Type B aortic dissection patients with AKI significantly had increased hospital stay duration, need of renal replacement therapy, and 30-d and 1-year mortality.ConclusionsAKI in type B aortic dissection is a well-recognized complication and associated with poor short-term and long-term outcome. Early identification of high-risk patients, early diagnosis of AKI, stabilization of the hemodynamic parameters, avoidance of nephrotoxic drugs, and optimization of the use of contrast agents are the major strategies for the reduction of AKI in type B aortic dissection patients.     

Antioxidant and anti-inflammatory activities of lycopene against 5-fluorouracil-induced cytotoxicity in Caco2 cells

5-fluorouracil (5FU) is widely used to treat colorectal cancer (CC) and its main mechanisms of anticancer action are through generation of ROS which often result in inflammation. Here, we test the effect of Lycopene against 5FU in Caco2 cell line. Caco2 cells were exposed to 3 µg/ml of 5FU alone or with 60, 90, 120 µg/ml of lycopene. This was followed by assessment of cytotoxicity, oxidative stress, and gene expression of inflammatory genes. Our findings showed that Lycopene and 5FU co-exposure induced dose-dependent cytotoxic effect without compromising the membrane integrity based on the LDH assay. Lycopene also significantly enhanced 5FU-induced SOD activity and GSH level compared to control for all mixture concentrations (p < 0.01). Lycopene alone and combination with 5FU-induced expression of IL-1β, TNF-α, and IL-6. Furthermore, IFN-γ expression was significantly enhanced by only mixture of lycopene (90 µg/ml) and 5FU (p < 0.05). In conclusion, Lycopene supplementation with 5FU therapy resulted in improvement in antioxidant parameters such as catalase and GSH levels giving the cell capacity to cope with 5FU-mediated oxidative stress. Lycopene also enhanced IFN-γ expression in the presence of 5FU, which may activate antitumor effects further enhancing the cancer killing effect of 5FU.