Microplastics in aquatic ecosystems of Africa: A comprehensive review and meta-analysis.

Microplastic pollution is a global issue of great public concern. Africa is flagged to host some of the most polluted water bodies globally, but there is no enough information on the extent of microplastic contamination and the potential risks of microplastic pollution in African aquatic ecosystems. This meta-analysis has integrated data from published articles about microplastic pollution in African aquatic ecosystems. The data on the microplastic distribution and morphological characteristics in water, sediments and biota from African rivers, lakes, oceans and seas were extracted from 75 selected studies. Multivariate statistics were used to critically analyze the effects of sampling and detection methods, ecological risks, spatial distribution and similarity of microplastics in relation to the geographical distance between sampling sites. This study found that sampling methods have significant effect on abundance and morphological characteristics of microplastics and that African aquatic ecosystems are highly contaminated with microplastics compared to global data. The most prevalent colors were white, transparent and black, the most prevalent shapes were fibres and fragments, and the most available polymers were polypropylene (PP), polystyrene (PS) and polyethene terephthalate (PET). Microplastic polymers similarity decreased with an increase in geographical distance between sites. Risk levels of microplastics in African aquatic ecosystems were comparatively high, and more than 40 % of water and sediments showed highest level of ecological risk. This review provides recent information on the prevalence, distribution and risks of microplastics in African aquatic ecosystems.

Chitosan-coated nanostructured lipid carriers for effective brain delivery of Tanshinone IIA in Parkinson's disease: interplay between nuclear factor-kappa ß and cathepsin B.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder associated with increased oxidative stress, the underlying vital process contributing to cell death. Tanshinone IIA (TAN) is a phytomedicine with a documented activity in treating many CNS disorders, particularly PD owing to its unique anti-inflammatory and antioxidant effect. However, its clinical utility is limited by its poor aqueous solubility, short half-life, and hence low concentration reaching targeted cells. This work aimed to develop a biocompatible chitosan-coated nanostructured lipid carriers (CS-NLCs) for effective brain delivery of TAN for PD management. The proposed nanosystem was successfully prepared using a simple melt-emulsification ultra-sonication method, optimized and characterized both in vitro and in vivo in a rotenone-induced PD rat model. The developed TAN-loaded CS-NLCs (CS-TAN-NLCs) showed good colloidal properties (size ≤ 200 nm, PDI ≤ 0.2, and ζ-potential + 20 mV) and high drug entrapment efficiency (> 97%) with sustained release profile for 24 h. Following intranasal administration, CS-TAN-NLCs succeeded to achieve a remarkable antiparkinsonian and antidepressant effect in diseased animals compared to both the uncoated TAN-NLCs and free TAN suspension as evidenced by the conducted behavioral tests and improved histopathological findings. Furthermore, biochemical evaluation of oxidative stress along with inflammatory markers, nuclear factor-kabba ß (NF-Kß) and cathepsin B further confirmed the potential of the CS-TAN-NLCs in enhancing brain delivery and hence the therapeutic effect of TAN of treatment of PD. Accordingly, CS-TAN-NLCs could be addressed as a promising nano-platform for the effective management of PD.

Evaluation of antimicrobial and antioxidant activity of zinc oxide nanoparticles biosynthesized with Ziziphus spina-christi leaf extracts.

Background: Due to their simplicity, eco-friendliness, availability and non-toxicity, the greener fabrication of metal and metal oxide nanoparticles has been a highly attractive research area over the last decade. Aim: This study aimed to assess the antioxidant and antimicrobial activities of the green synthesized zinc oxide nanoparticles (ZnO-NPs) using an aqueous leaf extract of Ziziphus spina-christi. Method: The antioxidant property of ZnO-NPs was analyzed by the α, α-diphenyl-ß-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2). Additionally, the diffusion agar method assessed the antimicrobial activities against bacteria and fungi. Results: ZnO-NPs synthesized by Z. spina-christi had shown promising H2O2 and DPPH free radical scavenging actions compared to vitamin C. The ZnO-NPs exhibited significant antibacterial activity against the tested bacteria with various susceptibility as a concentration-dependent effect. The largest zone of inhibition for Staphylococcus aureus (S. aureus) was observed (36 ± 2 mm) compared to Escherichia coli (E. coli) (15 ± 2 mm) by the same concentration of ZnO-NPs. The ZnO-NPs showed remarkable antifungal activity against Aspergillus niger. Conclusion: It can be concluded that, ZnO-NP have been imposed as suitable antimicrobial agent being able to combat both S. aureus and E. coli in vitro.

Right Ventricular Strain Analysis By Tissue Tracking Cardiac Magnetic Resonance Imaging In Pediatric Patients With End-Stage Renal Disease.

PURPOSE: To investigate right ventricular (RV) volume and mass by cardiac magnetic resonance (CMR) and the added value of tissue tracking strain analysis as markers of RV dysfunction in pediatric patients with end-stage renal disease (ESRD) and preserved RV ejection fraction. MATERIALS AND METHODS: Twenty-five children with ESRD and preserved RVEF (>50%) and 10 healthy control children were enrolled. Tissue tracking CMR was used to assess Global Longitudinal, circumferential (GCS), and radial short and long axes (GRS SAX and GRS LAX) RV strains in the patients group compared with controls. Correlations between strain parameters and other CMR parameters and clinical biomarkers were assessed. Binary logistic regression was used to test the independence of cofounders and detect their significance. RESULTS: RV end-diastolic volume and mass (RVMi) were significantly higher in patients (97.2±19.3 mL/m 2 and 26.6±7gr/m 2 ) than control (71±7.8 mL/m 2 and 11.9±2 gr/m 2 , P values 0.000). All RV global strain parameters were significantly impaired in patients compared with control (all P values <0.05). RV Global Longitudinal was significantly correlated to LVEF (r=-0.416, P =0.039), LVEDVi (r=0.481, P =0.015), LVMi (r=0.562, P =0.004), and systolic blood pressure index (r=0.586, P =0.002). RV GRS (LAX) was significantly correlated to LV GCS (r=-0.462, P =0.020) and LV GRS (SAX) (r=0.454, P =0.023). GRS (SAX) and GCS demonstrated the highest diagnostic accuracy (area under curve: 0.82 and 0.81) to detect strain impairment. Univariate binary logistic regression with patients versus control as dependent variables identified LVMi, RV end-diastolic volume, RVMi, weight, body surface area, RV GCS, RV GRS (LAX), RV GRS (SAX), LV GCS, and LV GRS (SAX) as significantly correlated to patients with ESRD. When adjusted to other cofounders in the multivariable model, only RVMi remained as an independent significant cofounder (Odds ratio:0.395, P =0.046). CONCLUSION: RV global strain, volume, and mass by CMR are markers of RV dysfunction in ESRD pediatric patients with preserved RVEF.

The threat of micro/nanoplastic to aquatic plants: current knowledge, gaps, and future perspectives.

Plastics have been recognized as an emerging pollutant and have raised global concerns due to their widespread distribution in the environment and potential harm to living systems. However, research on the threat of micro/nanoplastics (MPs/NPs) to the unique group of aquatic plants is far behind, necessitating a comprehensive review to summarize current research progress and identify future research needs. This review explores the sources and distribution patterns of MPs/NPs in aquatic environments, highlighting their uptake by aquatic plants through roots and leaves, and subsequent translocation via the vascular system facilitated by the transpiration stream. Exposure to MPs/NPs elicits diverse effects on the growth, physiology, and ecological interactions of aquatic plants, with variations influenced by plastic properties, plant species, and experimental conditions. Furthermore, the presence of MPs/NPs can impact the toxicity and bioavailability of other associated toxicants to aquatic plants. This review shows critical knowledge gaps and emphasizes the need for future research to bridge the current understanding of the limitations and challenges posed by MPs/NPs in aquatic ecosystems.

Supervised clustering of peripheral immune cells associated with clinical response to checkpoint inhibitor therapy in patients with advanced melanoma.

Background and purpose: Immune therapy with checkpoint inhibitors (CPIs) is a highly successful therapy in many cancers including metastatic melanoma. Still, many patients do not respond well to therapy and there are no blood-borne biomarkers available to assess the clinical outcome. Materials and methods: To investigate cellular changes after CPI therapy, we carried out flow cytometry-based immune monitoring in a cohort of 90 metastatic melanoma patients before and after CPI therapy using the FlowSOM algorithm. To evaluate associations to the clinical outcome with therapy, we divided the patients based on progression-free survival. Results: We found significant associations with CPI therapy in both peripheral blood mononuclear cell and T-cell subsets, but with the most pronounced effects in the latter. Particularly CD4+ effector memory T-cell subsets were associated with response with a positive correlation between CD27+HLA-DR+CD4+ effector memory T cells in a univariate (odds ratio: 1.07 [95% confidence interval 1.02-1.12]) and multivariate regression model (odds ratio: 1.08 [95% confidence interval 1.03-1.14]). We also found a trend towards stronger accumulation of CD57+CD8+ T cells in non-responding patients. Conclusion: Our results show significant associations between immune monitoring and clinical outcome of therapy that could be evaluated as biomarkers in a clinical setting.

Computed tomography and magnetic resonance imaging of congenital thoracic systemic venous anomalies.

We present the imaging findings of thoracic systemic venous anomalies diagnosed by computed tomography and magnetic resonance imaging. Persistent left superior vena cava is the commonest anomaly of the thoracic systemic veins encountered either incidentally as an isolated finding or associated with congenital heart disease. Inferior vena cava (IVC) interruption with azygos continuation is the second most common anomaly, which may also be isolated or be associated with left isomerism syndrome. The article will also discuss other rarer systemic venous anomalies including retroaortic brachiocephalic vein and IVC drainage into the left atrium. Finally, the impact of pre-procedure reporting of thoracic systemic venous anomalies on the choice of intervention and patient outcome will be addressed.

Left Ventricular Pseudoaneurysm: Unexpected Sequel of Tamponade-Complicated Infectious Pericarditis in Infancy.

Left ventricular pseudoaneurysm (LV-PsA) is a critical finding that could result in a fatal outcome. It may complicate myocardial infarction, cardiac surgery, trauma, or endocarditis but rarely follows pericarditis. We report a case of infectious pericarditis complicated by pericardial tamponade in an infant. After effusion drainage and medical therapy, a large LV-PsA was detected. Successful closure of the pseudoaneurysmá¾½s neck was accomplished using a Gore-tex patch.

Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia.

Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.

Impaired aortic strain and distensibility by cardiac MRI in children with chronic kidney disease.

Renal disease is associated with increased arterial stiffness. The aim was to investigate the effect of renal disease on regional aortic strain and distensibility in children with chronic kidney disease (CKD) by cardiac magnetic resonance imaging (MRI). The study included 30 children with CKD on hemodialysis, and ten healthy control subjects. Using cardiac MRI, maximal and minimal aortic areas were measured in axial cine steady state free precision images at the ascending aorta, proximal descending, and aorta at diaphragm. Regional strain and distensibility were calculated using previously validated formulas. Second reader aortic areas measurements were used to assess inter-observer agreement. Ascending aorta strain was significantly reduced in patients (38.4 ± 17.4%) compared to the control group (56.1 ± 17%), p-value 0.011. Ascending Aorta distensibility was significantly reduced in patients (9.1 ± 4.4 [× 10-3 mm Hg-1]) compared to the control group (13.9 ± 4.9 [× 10-3 mm Hg-1]), p-value 0.006. Strain and distensibility were reduced in proximal descending aorta and aorta at diaphragm but did not reach statistical significance. Only ascending aorta strain and distensibility had significant correlations with clinical and cardiac MRI parameters. Inter-observer agreement for strain and distensibility was almost perfect or strong in the three aortic regions. Aortic strain and distensibility by cardiac MRI are important imaging biomarkers for initial clinical evaluation and follow up of children with CKD.

The role of platelet-rich plasma in microlaryngeal surgery: a randomised, controlled trial.

OBJECTIVE: Platelet-rich plasma has gained interest over the two last decades, mainly because of its role in regenerative medicine. This work aimed to assess the role of intra-operative local application of platelet-rich plasma gel in the improvement of quality of voice after microlaryngeal surgery. METHOD: This was a prospective comparative study that included 40 patients undergoing microlaryngeal surgery for benign vocal fold lesions. There were two groups divided equally into study group A and control group B. The assessment of voice was performed by videostroboscopy and acoustic analysis pre-operatively and at two weeks and one and three months post-operatively. RESULTS: The data demonstrated that all the stroboscopic and acoustic parameters showed significant improvement in both groups. Group A showed significant improvement regarding acoustic parameters at the third post-operative follow up when compared with group B. CONCLUSION: Platelet-rich plasma has a beneficial effect on voice quality following microlaryngeal surgery based in particular on acoustic parameters.

The relevance of left ventricular functions to clinical and metabolic characteristics of prepubertal children with obesity.

BACKGROUND: Paediatric obesity is a worldwide health burden, with growing evidence linking obesity to myocardial function impairments. The study aims to evaluate left ventricular functions among prepubertal obese children to obesity-related clinical and metabolic parameters. METHODS: Between June 2019 and March 2020, 40 prepubertal children with obesity were recruited and compared to 40 healthy controls. Patients were assessed for body mass index z scores, waist circumference, body adiposity by bioimpedance analysis, and obesity-related laboratory tests, for example, serum chemerin. Left ventricular functions were assessed using variable echocardiographic modalities, such as M-mode, tissue Doppler, and two-dimensional speckle tracking. RESULTS: Mean patients' age was 9.25 ± 1.05 years. Left ventricular mass index, E/E', and myocardial performance index were significantly increased in obese children than controls. Although M-mode-derived ejection fraction was comparable in both groups, two-dimensional speckle tracking-derived ejection fraction, global longitudinal strain, and global circumferential strain were significantly lower in cases than controls. Left ventricular mass index displayed a positive correlation with body mass index z score (p = 0.003), fat mass index (p = 0.037), and trunk fat mass (p = 0.021). Global longitudinal strain was negatively correlated with body mass index z score (p = 0.015) and fat mass index (p = 0.016). Serum chemerin was positively correlated with myocardial performance index (p = 0.01). CONCLUSION: Alterations of left ventricular myocardial functions in prepubertal obese children could be detected using different echocardiographic modalities. Chemerin, body mass index z score, fat mass index, and trunk fat mass were correlated with subclinical left ventricular myocardial dysfunction parameters before puberty. Our results reinforce early and strict management of childhood obesity upon detection of changes in anthropometric and body adiposity indices.

Understanding the Aorta-Spine Relation in Idiopathic Scoliosis: Value of Noncontrast CT-Derived Curved Coronal Reformats and 3D Volume Images.

BACKGROUND: Investigating axial position and longitudinal bending of the aorta in relation to spine curvature in adolescent idiopathic scoliosis patients could help surgeons in planning of spine surgeries. METHODS: Noncontrast computed tomography (CT) scans of 27 consecutive patients with adolescent idiopathic scoliosis (19 right and 8 left curves) and 16 control subjects were retrospectively reviewed. Using semiautomated software, centerline was drawn along the descending aorta, and curved reformat was generated. Aorta tortuosity index (TI) was calculated as (centerline length/straight line distance) - 1 × 100. The spine centerline was drawn from T1 to L5, and curve index (CI) was similarly calculated. The aorta centerline angle was measured. Apical vertebral-rotation angle and multilevel aorto-vertebral angles were measured on axial CT. Three-dimensional volume-rendered images of the aorta were generated using a manual region grow function. RESULTS: Mean (± standard deviation) Cobb's angle was 63.8 ± 34.6°. The spine CI of patients (9.7 ± 7.11) was significantly higher than controls (0.28 ± 0.22), P = .00001. Aorta TI in scoliosis was significantly higher than controls (6.4 ± 7.2 versus 0.6 ± 0.5, P = .0001). The aorta centerline angle was steeper in scoliosis than controls (140 ± 26.8° versus 170 ± 3.6°). Correlations were excellent between the aorta TI and each of Cobb's angle, spine CI, and vertebral rotation angle (r = 0.851 to 0.867, all P < .001). Aorto-vertebral angles were significantly different between right scoliosis and left scoliosis patients and control groups at T6, T7, T8, L2, and L3 levels. CONCLUSIONS: Aortic curvature increases in proportion to the degree of scoliosis. The aorta follows the concavity of scoliosis in right and left curves. In the axial CT plane, the aorta in both right and left scoliosis is maximally rotated away from its normal position at T7 and is closest to its normal position at T11 to T12. CLINICAL RELEVANCE: Quantitative evaluation of aortic curvature combined with preoperative reconstructed CT images could be beneficial for surgeons in planning of spine surgeries.

Left Ventricular Strain Analysis by Tissue Tracking- Cardiac Magnetic Resonance for early detection of Cardiac Dysfunction in children with End-Stage Renal Disease.

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in end-stage renal disease (ESRD). Reduction in left ventricular ejection fraction (LVEF) represents late left ventricle (LV) dysfunction. Cardiac MRI myocardial strain analysis is an alternative method for assessment of LV function. PURPOSE: To investigate whether LV strain analysis is more sensitive than LVEF for early detection of systolic dysfunction in children with ESRD. STUDY TYPE: Case control. POPULATION: Thirty-two children with ESRD (median 14 years, 17 females) and 10 healthy control (median 12.5 years, 7 females). FIELD STRENGTH AND SEQUENCES: A 1.5 T /retrospective ECG-gated steady-state free precession (SSFP). ASSESSMENT: LVEF, and indexed LV mass (LVMi) and LV end-diastolic volume (LVEDVi) were measured. Using tissue tracking analysis, LV endocardial and epicardial contours were traced in short and long axes at end diastole to calculate global longitudinal (GLS), circumferential (GCS) and radial (GRS) strains. STATISTICAL ANALYSIS: Cardiac MRI and strain parameters were compared between patients and control, and between subgroup with preserved LVEF and control by Student t-test/Mann Whitney test. Diagnostic accuracy was assessed by Receiver operating characteristic analysis. Strain as predictor of poor outcome (mortality, pulmonary edema, and/or heart failure) within 1-year follow up was investigated by binary logistic regression. RESULTS: Compared to control, cardiac MRI LVEF, LVEDVi, LVMi, GLS, GCS and GRS were significantly impaired in patients. Patients with preserved LVEF had significantly higher LVEDVi, LVMi and significantly impaired GCS and GRS than control. Strain parameters were significantly correlated with LVEF, LVEDVi, and LVMi. GCS and GRS demonstrated greater diagnostic accuracy than GLS (area under curve: 0.89). LVEF, LVMi, GCS, and GRS were correlated with poor outcome. CONCLUSION: Cardiac MRI tissue tracking could identify subclinical LV dysfunction in children with ESRD and still preserved LVEF. Furthermore, LV strain parameters (GCS and GRS) were correlated with future cardiovascular events. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Epicardial and Perihepatic Fat as Cardiometabolic Risk Predictors in Girls with Turner Syndrome: A Cardiac Magnetic Resonance Study

Objective: Turner syndrome (TS) patients are at high risk of cardiometabolic disorders. Cardiometabolic risk factors are more commonly related to visceral rather than total body adiposity. Adipocytokines have been explored as a potential link between obesity and obesity-related cardiometabolic dysfunction. This study explored the validity of epicardial fat-thickness (EFT) and perihepatic fat-thickness (PHFT) measurement as cardiometabolic-risk predictors in TS-girls in relation to standard obesity-indices and metabolic syndrome (MetS) components. Methods: Forty-six TS girls and twenty-five controls (10-16 years) were subdivided into two age-groups (10 to less than 13 and 13-16). Participants were assessed for body mass index (BMI) Z-scores, waist circumference (WC), total-fat mass (FM) and trunk-FM by bioimpedance-technique, EFT and PHFT by cardiovascular magnetic resonance, lipid-profile, homeostasis model assessment of insulin resistance (HOMA-IR), and serum chemerin. MetS was defined according to International Diabetes Federation criteria. Results: Overweight/obesity and MetS were detected in 45.7% and 37% of TS-girls respectively. BMI Z-score, WC, total-FM, trunk-FM, EFT and PHFT values were significantly higher in TS-age groups compared to age-matched control groups, being more pronounced in the older group when TS-girls had been exposed to estrogen. Dyslipidemia, higher HOMA-IR, chemerin, EFT and PHFT values were observed in lean-Turner compared to BMI-Z-matched controls. EFT and PHFT were significantly correlated with chemerin and several components of MetS. EFT at a cut-off-value of 6.20 mm (area under the curve=0.814) can predict MetS in TS-girls. Conclusion: TS-girls displayed an adverse cardiometabolic profile during late childhood and adolescence. EFT and PHFT are emerging cardiometabolic risk predictors in TS-patients. Excess EFT rather than total body adiposity may contribute to altered metabolic profile among lean-Turner patients.

Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models.

The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.

ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.

Left superior vena cava: cross-sectional imaging overview.

Persistent left-sided superior vena cava (PLSVC) is the commonest systemic venous anomaly in the thorax with a reported prevalence of up to 0.5% in otherwise normal population and up to 10% in patients with congenital heart disease (CHD). In the absence of associated CHD, it is usually asymptomatic, discovered incidentally. It may complicate catheter or pacemaker lead placement. PLSVC typically drains into the right atrium through the coronary sinus. In children with CHD, the presence of a PLSVC may affect the choice of certain surgical procedures. PLSVC is significantly more common in association with situs ambiguous than with situs solitus or inversus, up to 60-70%. In patients with situs ambiguous, the drainage of LSVC is variable, more commonly directly into the atria rather than through the coronary sinus (CS). Rarely, there is a PLSVC draining into the CS with absent right SVC. PLSVC draining into the right atrium via the CS will not usually cause blood shunting between the right and the left sides. However, shunting occurs when PLSVC is associated with unroofed CS, or when it directly drains into the left atrium. With an increased use of CT and MRI for chest and cardiac imaging, PLSVC is being more encountered by radiologists than before. In this article, we will discuss the embryology of PLSVC, its anatomic course and drainage pathways, as well as its clinical relevance and relation to congenital heart disease and viscero-atrial situs.