Multislice computerized tomography coronary angiography can be a comparable tool to intravascular ultrasound in evaluating "true" coronary artery bifurcations.

Aim: Coronary bifurcation atherosclerosis depends on its angles, flow, and extensive branching. We investigate the ability of CT coronary angiography (CTCA) to determine atherosclerotic plaque characteristics of "true" bifurcation compared with intravascular ultrasound (IVUS) and the influence on side branch (SB) fate after percutaneous coronary intervention (PCI). Methods and results: The study included 70 patients with 72 "true" bifurcations. Most of the bifurcations were in the left anterior descending-diagonal (Dg) territory [50 out of 72 (69.4%)]. Longitudinal plaque evaluation at the polygon of confluence [carina and 5 mm proximal and distal in the main branch (MB)] showed that carina side MB and SB plaque had occurred with the lowest incidence with fibro-lipid structure (115 ± 63 HU and 89 ± 73 HU, p < 0.001 for all). Bland-Altman analysis showed a discrepancy in measuring mainly the lumen area between CTCA and IVUS in proximal MB [lumen 5.10, 95% CI (95% confidence interval, 4.53-5.68) mm2, p < 0.001; vessel -1.42, 95% CI (-2.63 to -0.21) mm2, p = 0.023], carina MB [lumen 3.74, 95% CI (3.37-4.10) mm2, p < 0.001; vessel -0.48, 95% CI (-1.45 to 0.48) mm2, p = 0.322], and distal MB [lumen 4.72, 95% CI (4.27-5.18) mm2, p < 0.001; vessel 0.62, 95% CI (-0.53 to 1.77) mm2, p = 0.283]. A significant correlation existed between average plaque density on CTCA with a percentage of calcified plaque on IVUS tissue characterization (proximal r = 0.307/p = 0.024, carina 0.469/0.008, distal 0.339/0.024, minimal lumen diameter 0.318/0.020). Circumferential plaque in the proximal MB segment remained an independent predictor of SB compromise [OR 3.962 (95% CI 1.170-13.418)]. Conclusion: Detection and characterization of atherosclerotic plaque by CTCA in non-left main "true" coronary bifurcations can provide useful information about bifurcation anatomy and plaque distribution that can predict outcomes after provisional stenting, thus guiding the interventional strategy to bifurcation PCI.

Redox Status and Telomere-Telomerase System Biomarkers in Patients with Acute Myocardial Infarction Using a Principal Component Analysis: Is There a Link?

In the present study, we examined redox status parameters in arterial and venous blood samples, its potential to predict the prognosis of acute myocardial infarction (AMI) patients assessed through its impact on the comprehensive grading SYNTAX score, and its clinical accuracy. Potential connections between common blood biomarkers, biomarkers of redox status, leukocyte telomere length, and telomerase enzyme activity in the acute myocardial infarction burden were assessed using principal component analysis (PCA). This study included 92 patients with acute myocardial infarction. Significantly higher levels of advanced oxidation protein products (AOPP), superoxide anion (O2•-), ischemia-modified albumin (IMA), and significantly lower levels of total oxidant status (TOS) and total protein sulfhydryl (SH-) groups were found in arterial blood than in the peripheral venous blood samples, while biomarkers of the telomere-telomerase system did not show statistical significance in the two compared sample types (p = 0.834 and p = 0.419). To better understand the effect of the examined biomarkers in the AMI patients on SYNTAX score, those biomarkers were grouped using PCA, which merged them into the four the most contributing factors. The "cholesterol-protein factor" and "oxidative-telomere factor" were independent predictors of higher SYNTAX score (OR = 0.338, p = 0.008 and OR = 0.427, p = 0.035, respectively), while the ability to discriminate STEMI from non-STEMI patients had only the "oxidative-telomere factor" (AUC = 0.860, p = 0.008). The results show that traditional cardiovascular risk factors, i.e., high total cholesterol together with high total serum proteins and haemoglobin, are associated with severe disease progression in much the same way as a combination of redox biomarkers (pro-oxidant-antioxidant balance, total antioxidant status, IMA) and telomere length.

Computed Tomography Versus Invasive Coronary Angiography in Patients With Diabetes and Suspected Coronary Artery Disease.

OBJECTIVE: To compare cardiac computed tomography (CT) with invasive coronary angiography (ICA) as the initial strategy in patients with diabetes and stable chest pain. RESEARCH DESIGN AND METHODS: This prespecified analysis of the multicenter DISCHARGE trial in 16 European countries was performed in patients with stable chest pain and intermediate pretest probability of coronary artery disease. The primary end point was a major adverse cardiac event (MACE) (cardiovascular death, nonfatal myocardial infarction, or stroke), and the secondary end point was expanded MACE (including transient ischemic attacks and major procedure-related complications). RESULTS: Follow-up at a median of 3.5 years was available in 3,541 patients of whom 557 (CT group n = 263 vs. ICA group n = 294) had diabetes and 2,984 (CT group n = 1,536 vs. ICA group n = 1,448) did not. No statistically significant diabetes interaction was found for MACE (P = 0.45), expanded MACE (P = 0.35), or major procedure-related complications (P = 0.49). In both patients with and without diabetes, the rate of MACE did not differ between CT and ICA groups. In patients with diabetes, the expanded MACE end point occurred less frequently in the CT group than in the ICA group (3.8% [10 of 263] vs. 8.2% [24 of 294], hazard ratio [HR] 0.45 [95% CI 0.22-0.95]), as did the major procedure-related complication rate (0.4% [1 of 263] vs. 2.7% [8 of 294], HR 0.30 [95% CI 0.13 - 0.63]). CONCLUSIONS: In patients with diabetes referred for ICA for the investigation of stable chest pain, a CT-first strategy compared with an ICA-first strategy showed no difference in MACE and may potentially be associated with a lower rate of expanded MACE and major procedure-related complications.

HDL Subclasses and the Distribution of Paraoxonase-1 Activity in Patients with ST-Segment Elevation Acute Myocardial Infarction.

The aim of this multicentric study was to assess the impacts of oxidative stress, inflammation, and the presence of small, dense, low-density lipoproteins (sdLDL) on the antioxidative function of high-density lipoprotein (HDL) subclasses and the distribution of paraoxonase-1 (PON1) activity within HDL in patients with ST-segment elevation acute myocardial infarction (STEMI). In 69 STEMI patients and 67 healthy control subjects, the lipoproteins' subclasses were separated using polyacrylamide gradient (3-31%) gel electrophoresis. The relative proportion of sdLDL and each HDL subclass was evaluated by measuring the areas under the peaks of densitometric scans. The distribution of the relative proportion of PON1 activity within the HDL subclasses (pPON1 within HDL) was estimated using the zymogram method. The STEMI patients had significantly lower proportions of HDL2a and HDL3a subclasses (p = 0.001 and p < 0.001, respectively) and lower pPON1 within HDL3b (p = 0.006), as well as higher proportions of HDL3b and HDL3c subclasses (p = 0.013 and p < 0.001, respectively) and higher pPON1 within HDL2 than the controls. Independent positive associations between sdLDL and pPON1 within HDL3a and between malondialdehyde (MDA) and pPON1 within HDL2b were shown in the STEMI group. The increased oxidative stress and increased proportion of sdLDL in STEMI are closely related to the compromised antioxidative function of small HDL3 particles and the altered pPON1 within HDL.

Telomere-telomerase system status in patients with acute myocardial infarction with ST-segment elevation - relationship with oxidative stress.

Introduction: Telomeres are protective chromosomal ends. Short telomeres are a proven biomarker of biological aging. We aimed to find an association of telomere length and telomerase activity in circulating leukocytes and thromboaspirates of patients with acute myocardial infarction. Furthermore, association of the telomere-telomerase system with oxidative stress markers (as common risk factors for coronary artery disease (CAD)) was tested. Material and methods: Patients were selected from the patients admitted to the intensive care unit with acute myocardial infarction with ST-segment elevation (STEMI), with the following inclusion criteria - STEMI patients between 18 and 80 years old of both genders and candidates for primary percutaneous coronary intervention, with infarction pain present for a maximum of 12 h. In all the patients leukocyte telomere length, telomerase activity and scores related to oxidative-stress status (Protective, Damage and OXY) were evaluated. Results: Patients were divided into different groups: with stable angina pectoris (AP) (n = 22), acute myocardial infarction with: STEMI (n = 93), non-obstructive coronary arteries (MINOCA) (n = 7), blood vessel rupture (n = 6) at three time points, and compared to the group of 84 healthy subjects. Telomerase activity was significantly higher in all CAD sub-groups compared to the control group (AP = 0.373 (0.355-0.386), STEMI = 0.375 (0.349-0.395), MINOCA = 0.391 (0.366-0.401), blood vessel rupture = 0.360 (0.352-0.385) vs. CG = 0.069 (0.061-0.081), p < 0.001), while telomeres were significantly shorter in STEMI, MINOCA and blood vessel rupture groups compared to the control group (STEMI = 1.179 (0.931-1.376), MINOCA = 1.026 (0.951-1.070), blood vessel rupture = 1.089 (0.842-1.173) vs. CG = 1.329 (1.096-1.624), p = 0.030]. Values of OXY score were significantly higher in STEMI and MINOCA patients compared to the control group and AP patients (5.83 (4.55-7.54) and 10.28 (9.19-10.72) vs. 4.94 (3.29-6.18) and 4.18 (2.58-4.86), p < 0.001). Longer telomeres and higher telomerase activity were found in thromboaspirates, compared to the peripheral blood leukocytes in the same patients (1.25 (1.01-1.84) vs. 1.18 (0.909-1.516), p = 0.036; and 0.366 (0.367-0.379) vs. 0.366 (0.367-0.379), p < 0.001, respectively). In addition, telomere length and telomerase activity had good diagnostic ability to separate STEMI patients from healthy persons. Conclusions: Leukocyte telomere length and telomerase activity can differentiate CAD patients from healthy persons, and relate CAD to oxidative stress.

Stereotactic body radiation therapy in the treatment of cancer patients with oligometastatic disease: a real world study.

PURPOSE: Stereotactic body radiation therapy (SBRT) is a treatment modality with curative intent for oligometastatic cancer patients, commonly defined by a low-burden metastatic disease with 1-5 systemic metastases. Better knowledge of the clinical profile and prognostic factors in oligometastatic cancer patients could help to improve the selection of candidates who may obtain most benefits from SBRT. The objective of this study was to describe the clinical data and outcome in term of overall survival (OS) of patients with oligometastatic disease treated with SBRT over a 6-year period. METHODS: From 2013 to 2018, 284 solid tumor cancer patients with 1-5 oligometastases underwent SBRT at a large university-affiliated oncological center in Barcelona, Spain. Variables related to the patient profile, tumor, oligometastatic disease, and treatment were evaluated. RESULTS: A total of 327 metastatic tumors were treated with SBRT. In 65.5% of cases, metachronous tumors were diagnosed at least 1 year after diagnosis of the primary tumor. The median age of the patients was 73.9 years and 66.5% were males. The median follow-up was 37.5 months. The most common primary tumors were lung and colorectal cancer, with lung and bone as the most commonly treated metastatic sites. Ninety-three percent of patients showed a Karnofsky score (KPS) between 80 and 100. Adenocarcinoma was the most common histological type. The median overall survival was 53.4 months, with 1-, 2- and 5-year survival rates of 90.5%, 73.9% and 43.4%, respectively. Overall survival rates of breast (67.6 months, 95% CI 56.4-78.9), urological (63.3 months, 95% CI 55.8-70.8), and colorectal (50.8 months, 95% CI 44.2-57.4) tumors were higher as compared with other malignancies (20 months, 95% CI 11.2-28.8 months) (p < 0.001). Patients with Karnofsky score (KPS) of 90 and 100 showed a significantly better survival than those with impaired performance status (p = 0.001). CONCLUSION: SBRT appears to be well tolerated and safe approach in oligometastatic patients. Patients with good performance status and with primary breast, urological and colorectal cancer have higher OS compared with other malignancies. More studies are necessary to evaluate the prognostic factors in oligometastatic disease (OMD) in order to select patients who could benefit more from this therapeutic approach.

Long-term outcomes of spinal SBRT. Is it important to select the treatment time?

PurposeSBRT (stereotactic body radiation therapy) is widely used as a curative treatment in tumoral lesions and has become a fundamental tool for the treatment of spine metastasis. In this study, we present survival and toxicity outcomes of spine SBRT after a 2-year follow-up.Methods/patientsData from spine SBRT treatments performed at our institution between March 2012 and February 2020 was collected. Medical records, including demographic, primary tumor, and treatment characteristics were reviewed. Patient follow-up included clinical evaluation, imaging, and blood tests. Toxicity was recorded according to CTCAE v4.0.ResultsWe analyzed 73 consecutive spine SBRT treatments in 60 patients. 39.7% of the cases had primary breast cancer and 23.3% had prostate cancer. Most cases (87.7%) were treated with a single SBRT fraction of 16 Gy. Median follow-up was 26.1 months (range 1.7–78.6), and 1- and 2-year overall survival (OS) rates were 96.9% and 84.2%, respectively. Local control (LC) rates at 1- and 2-years were 76.3% and 70.6%, respectively. Multivariate analysis identified histology as a prognostic factor for both OS and LC. Patients who underwent spine SBRT 6 months after the spinal lesion diagnosis had LC at 2 years of 88%, vs 61.7% for those who underwent SBRT before this period. No grade III or higher toxicity was reported. The vertebral compression fracture (VCF) rate was 4.1%.ConclusionSpine SBRT at our institution showed a 2-year LC of 70.6%, without G3 toxicities. Delaying SBRT at least 6 months to administer systemic treatment was related to an improvement in local control.

Desmoid-type fibromatosis of paranasal sinuses with intracranial extension in a child-acase-based review.

PURPOSE: Desmoid-type fibromatosis (DF) is clonal fibroblastic proliferation that arises in the deep soft tissues, tends to reoccur, and is locally invasive. Desmoid-type fibromatosis of paranasal sinuses with intracranial extension is a rare condition that is even rarer in a small child. We aim to share with the reader our literature review, decision-making, and endoscopic endonasal operation procedure that combined gained us favorable results against this benign tumor with unpredictable natural history and disease course. CASE REPORT: We describe the decision-making process in the management of a 3-year-old boy with a history of sudden vision loss and vomiting. MR showed an expansive well-delineated homogeneous tumor in the sphenoid sinus with intracranial extension and optic nerves compression. The diagnosis of a sporadic form of desmoid-type fibromatosis was made using genetic testing of tumor tissue. A total gross removal was carried out with endoscopic endonasal microsurgical approach. At a 3-month follow-up, the patient is without any signs of recurrance. CONCLUSION: The treatment of children with desmoid-type fibromatosis requires a multidisciplinary approach by clinicians experienced with the management of pediatric cancer. While the desmoid-type fibromatosis is a benign, locally invasive tumor, observation should be the first step in the management. In case of life-threatening or symptomatic cases, operations that preserve function and structure should be the first choice for this benign tumor with unpredictable natural history and disease course.

Oxidative Stress and Inflammatory Markers PTX3, CypA, and HB-EGF: How Are They Linked in Patients With STEMI?

We investigated circulating levels of inflammatory biomarkers pentraxin-3 (PTX3), cyclophilin A (CypA), and heparin-binding epidermal growth factor-like growth factor (HB-EGF); oxidative stress; and antioxidant status markers in the patients with ST-segment elevation acute myocardial infarction (STEMI) to better understand a relationship between inflammation and oxidative stress. We examined the impact of oxidative stress on high values of inflammatory parameters. The study included 87 patients with STEMI and 193 controls. We observed a positive correlation between PTX3 and HB-EGF (ρ = 0.24, P = .027), CyPA, and sulfhydryl (SH) groups (ρ = 0.25, P = .026), and a negative correlation between PTX3 and SH groups (ρ = -0.35, P = .001) in patients with STEMI. To better understand the effect of the examined parameters on the occurrence of high concentrations of inflammatory parameters, we grouped them using principal component analysis. This analysis identified the 4 most contributing factors. Optimal cutoff values for discrimination of patients with STEMI from controls were calculated for PTX3 and HB-EGF. An independent predictor for PTX3 above the cutoff value was a "metabolic-oxidative stress factor" comprised of glucose and oxidative stress marker prooxidant-antioxidant balance (odds ratio = 4.449, P = .030). The results show that higher PTX3 values will occur in patients having STEMI with greater metabolic and oxidative stress status values.

The association of mechanical dyssynchrony and resynchronization therapy with survival in heart failure with a wide QRS complex: a two-world study.

Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35-0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups-they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17-0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22-0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25-0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.

Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models.

BACKGROUND: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. METHODS: In in vitro and in vivo HCC models, we tested regorafenib's effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. RESULTS: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. CONCLUSION: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio.

Circulating levels of inflammatory parameters pentraxin-3, cyclophilin and heparin-binding epidermal growth factor-like growth factor in patients with ST-elevation myocardial infarction.

Inflammatory biomarkers - pentraxin-3 (PTX3), cyclophilin A (CypA) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) were examined in patients with ST-segment elevation myocardial infarction (STEMI) undergoing revascularization with primary percutaneous coronary intervention (pPCI) and stent implanting. Investigated parameters were compared between patients with and without obstructive coronary artery disease (CAD). In addition, their changes were tested in circulation before and immediately after pPCI. The study group consisted of 81 STEMI patients. Patients were classified in the STEMI-CAD group if they had significant obstructive CAD or in MINOCA group if they had no significant stenosis. In STEMI-CAD patients inflammatory parameters were determined prior to and after pPCI intervention. Immediately after pPCI, in STEMI-CAD patients levels of PTX3 were significantly lower (1.52 vs. 2.17 µg/L, p < .001), while the levels of HB-EGF (14.61 vs. 12.03 pg/L, p < .001) and CyPA (15.95 vs. 8.62 µg/L, p < .001) were significantly higher compared to levels before pPCI. STEMI-CAD patients had lower PTX3 values 2.17 µg/L (1.55-5.10 µg/L) than MINOCA patients 5.06 µg/L (2.77-6.7 µg/L), p = .046. Diagnostic accuracy of PTX3 for discrimination MINOCA from STEMI-CAD patients was low (area under receiver operating characteristic curve = 0.770). Evaluation of PTX3 values may be helpful in the understanding of MINOCA aetiology but they couldn't distinguish stenosis severity in STEMI patients. Inflammatory biomarkers significantly changed after pPCI but the possibility of clinical use of these biomarkers needs to be evaluated in a larger prospective study.

Antiapoptotic BCL-2 proteins determine sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma.

Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.

Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent.

Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755-66. ©2018 AACR.

Mechanical dispersion is associated with poor outcome in heart failure with a severely depressed left ventricular function and bundle branch blocks.

OBJECTIVES: Bundle branch blocks (BBB)-related mechanical dyssynchrony and dispersion may improve patient selection for device therapy, but their effect on the natural history of this patient population is unknown. METHODS: A total of 155 patients with LVEF ≤ 35% and BBB, not treated with device therapy, were included. Mechanical dyssynchrony was defined as the presence of either septal flash or apical rocking. Contraction duration was assessed as time interval from the electrocardiographic R-(Q-)wave to peak longitudinal strain in each of 17 left ventricular segments. Mechanical dispersion was defined as either the standard deviation of all time intervals (dispersionSD) or as the difference between the longest and shortest time intervals (dispersiondelta). Patients were followed for cardiac mortality during a median period of 33 months. RESULTS: Mechanical dyssynchrony was not associated with survival. More pronounced mechanical dispersiondelta was found in patients with dyssynchrony than in those without. In the multivariate regression analysis, patients' functional class, diabetes mellitus and dispersiondelta were independently associated with mortality. CONCLUSIONS: Mechanical dispersion, but not dyssynchrony, was independently associated with mortality and it may be useful for risk stratification of patients with heart failure (HF) and BBB. Key Messages Mechanical dispersion, measured by strain echocardiography, is associated with poor outcome in heart failure with a severely depressed left ventricular function and bundle branch blocks. Mechanical dispersion may be useful for risk stratification of patients with heart failure and bundle branch blocks.

Electrophysiological Studies to Detect Peripheral Neuropathy in Children Treated With Vincristine.

Patients treated with vincristine predictably develop peripheral neuropathy. The aim of our study was to investigate the pattern of vincristine-induced neuropathy in children by nerve conduction studies and somatosensory-evoked potentials (SSEPs). We included data from 39 children who received vincristine for various pediatric malignancies, and we performed initial and follow-up (after a minimum of 4 doses of vincristine 1.5 mg/m) conduction studies in 27 patients and SSEPs studies in 34 patients. On follow-up the most prevalent symptoms were paresthesias (44%) and constipation (22%), and the most common neurological sign was impaired myotatic reflexes (89%). Performing nerve conduction studies we found that significant reductions were measured for distal amplitudes, distal latencies were prolonged, and conduction velocities were relatively preserved. The most pronounced differences in amplitudes and distal latencies were measured in the peroneal nerves. Changes of SSEPs studies were subtle. Vincristine-induced neuropathy presents with primary axonal involvement and is more pronounced on motor neurons. We found a trend between higher age and higher dose and the degree of neuropathy in our group of patients.

Acute pancreatitis as a complication of childhood cancer treatment.

Acute pancreatitis (AP) is now well recognized as a possible complication of childhood cancer treatment, interrupting the chemotherapy regimen, and requiring prolonged hospitalization, possibly with intensive care and surgical intervention, thereby compromising the effect of chemotherapy and the remission of the underlying malignant disease. This review summarizes the current literature and presents the various etiological factors for AP during chemotherapy as well as modern trends in the diagnosis and therapy of AP in children.

Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma.

Evasive mechanisms triggered by the tyrosine kinase inhibitor sorafenib reduce its efficacy in hepatocellular carcinoma (HCC) treatment. Drug-resistant cancer cells frequently exhibit sphingolipid dysregulation, reducing chemotherapeutic cytotoxicity via the induction of ceramide-degrading enzymes. However, the role of ceramide in sorafenib therapy and resistance in HCC has not been clearly established. Our data reveals that ceramide-modifying enzymes, particularly glucosylceramide synthase (GCS), are upregulated during sorafenib treatment in hepatoma cells (HepG2 and Hep3B), and more importantly, in sorafenib-resistant cell lines. GCS silencing or pharmacological GCS inhibition sensitized hepatoma cells to sorafenib exposure. GCS inhibition, combined with sorafenib, triggered cytochrome c release and ATP depletion in sorafenib-treated hepatoma cells, leading to mitochondrial cell death after energetic collapse. Conversely, genetic GCS overexpression increased sorafenib resistance. Of interest, GCS inhibition improved sorafenib effectiveness in a xenograft mouse model, recovering drug sensitivity of sorafenib-resistant tumors in mice. In conclusion, our results reveal GCS induction as a mechanism of sorafenib resistance, suggesting that GCS targeting may be a novel strategy to increase sorafenib efficacy in HCC management, and point to target the mitochondria as the subcellular location where sorafenib therapy could be potentiated.

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation.

BACKGROUND & AIMS: Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis. METHODS: HSCs were obtained from WT and Axl(-/-) mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl(-/-) mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. RESULTS: In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl(-/-) mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. CONCLUSIONS: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.