Impact of Blood Sampling Methods on Blood Loss and Transfusion After Pediatric Cardiac Surgery: An Observational Study.

OBJECTIVES: The aims of this study were to assess the impact of the closed-loop sampling method on blood loss and the need for blood transfusion in pediatric patients following cardiac surgery. DESIGN: Retrospective observational study. SETTING: A single tertiary center. PARTICIPANTS: All pediatric patients younger than 4 years old who were admitted to the pediatric intensive care unit (PICU) after cardiac surgery were enrolled. The study included 100 pediatric patients in the conservative (postimplementation) group and 43 pediatric patients in the nonconservative group (preimplementation). INTERVENTIONS: Observational. MEASUREMENTS: The primary outcome was the volume of blood loss during the PICU follow-up period. The secondary outcomes were the requirement for blood transfusion in each group, duration of mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay, and mortality. MAIN RESULTS: In the conservative (postimplementation) group, blood loss during the follow-up period was 0.67 (0.33-1.16) mL/kg/d, while it was 0.95 (0.50-2.30) mL/kg/d in the nonconservative (preimplementation) group, demonstrating a significant reduction in blood loss in the conservative group (p = 0.012). The groups showed no significant differences in terms of the required blood transfusion volume postoperatively during the first 24 hours, first 48 hours, or after 48 hours (p = 0.061, 0.536, 0.442, respectively). The frequency of blood transfusion was comparable between the groups during the first 24 hours, first 48 hours, or after 48 hours postoperatively (p = 0.277, 0.639, 0.075, respectively). In addition, the groups did not show significant differences in the duration of mechanical ventilation, length of ICU stay, length of hospital stay, or mortality. CONCLUSIONS: The closed-loop sampling method can be efficient in decreasing blood loss during postoperative PICU follow-up for pediatric patients after cardiac surgeries. However, its application did not reduce the frequency or the volume of blood transfusion in these patients.

Insights Into MRI Neuroimaging Patterns of COVID-19 in Children: A Retrospective Comprehensive Analysis.

RATIONALE AND OBJECTIVES: Neurological complications associated with coronavirus disease (COVID-19) have been reported in children; however, data on neuroimaging findings remain limited. This study aimed to comprehensively examine neuroimaging patterns of COVID-19 in children and their relationship with clinical outcomes. MATERIALS AND METHODS: This retrospective cross-sectional study involved reviewing the medical records and MRI scans of 95 children who developed new neurological symptoms within 2-4 weeks of clinical and laboratory confirmation of COVID-19. Patients were categorized into four groups based on guidelines approved by the Centers for Disease Control and Prevention (CDC). Initial brain/spinal MRI was performed. Images were reviewed by three blinded radiologists, and the findings were analyzed and categorized based on the observed patterns in the brain and spinal cord. Follow-up MRI was performed and analyzed to track lesion progression. RESULTS: Encephalopathy was the most common neurological symptom (50.5%). The most common initial MRI involvement patterns were non-confluent multifocal hyperintense white matter (WM) lesions (36.8%) and ischemia (18.9%). Most patients who underwent follow-up MRI (n = 56) showed complete resolution (69.9%); however, some patients developed encephalomalacia and myelomalacia (23.2% and 7.1%, respectively). Non-confluent hyperintense WM lesions were associated with good outcomes (45.9%, P = 0.014), whereas ischemia and hemorrhage were associated with poor outcomes (44.1%, P < 0.001). CONCLUSION: This study revealed diverse neuroimaging patterns in pediatric COVID-19 patients. Non-confluent WM lesions were associated with good outcomes, whereas ischemia and hemorrhage were associated with poorer prognoses. Understanding these patterns is crucial for their early detection, accurate diagnosis, and appropriate management.

Surgical Management of Primary Anorectal Melanoma: Is Less More?

PURPOSE: Ano-uro-genital (AUG) Mucosal Melanoma UK guidelines recommended a less radical surgical strategy for anorectal melanoma (ARM) where possible. We report our experience of ARM consistent with that approach including clinical presentation, intervention undertaken and prognosis. METHODS: We present a retrospective study of 15 consecutive patients with ARM surgically treated between November 2014 and April 2023. Patients were divided into the two surgery types: wide local excision (WLE, n = 9) and abdominoperineal resection (APR, n = 6). Data on demographics, diagnosis, treatment and oncological outcomes were assessed between the groups. RESULTS: The mean age was 65.3 ± 17.4 years and 6 (40.0%) were female patients. Nine patients (60.0%) were diagnosed with stage I and six patients (40.0%) with stage II disease. R0 margins were achieved in all cases. The overall mean length of stay was lower following WLE compared to APR (2.6 ± 2.4 days versus 14.0 ± 9.8 days, p = 0.032). Two complications were observed in the WLE group compared to four complications after APR (p = 0.605). Five patients (55.5%) developed local/distant recurrence in the WLE group compared to three patients (50.0%) in the APR group (p = 0.707), with a median overall survival of 38.5 (12-83) months versus 26.5 (14-48) months, respectively. CONCLUSIONS: Achieving clear margins by the least radical fashion may have equivalent oncological outcomes to radical surgery, potentially reducing patient morbidity and preserving function. In our experience, the surgical management of ARM consistent with the 'less is more' approach adhering to AUG guidelines has acceptable outcomes.

Robotic Versus Conventional Unicompartmental Knee Surgery: A Comprehensive Systematic Review and Meta-Analysis.

Robotic-assisted surgery is a computer-controlled technique that may improve the accuracy and outcomes of unicompartmental total knee arthroplasty (TKA), a partial knee replacement surgery. The purpose of a meta-analysis about robotic-assisted versus conventional surgery for unicompartmental TKA is to compare the effectiveness of these two methods based on the current evidence. Our meta-analysis can help inform clinical decisions and guidelines for surgeons and patients who are considering unicompartmental TKA as a treatment option. We searched four online databases for studies that compared the two methods until March 2023. We used RevMan software to combine the data from the studies. We calculated the mean difference (MD) and the 95% confidence interval (CI) for each outcome, which are statistical measures of the difference and the uncertainty between the two methods. We included 16 studies in our analysis. We found that robotic-assisted surgery had a better hip-knee-ankle angle, which is a measure of how well the knee is aligned, than conventional surgery (MD = 0.86, 95% CI = 0.16-1.56). We also found that robotic-assisted surgery had a better Oxford Knee score, which is a measure of how well the knee functions, than conventional surgery (MD = 3.03, 95% CI = 0.96-5.110). This study compared the results of conventional and robotic-assisted unicompartmental knee arthroplasty in 12 studies. We concluded that robotic-assisted surgery may have some benefits over conventional surgery in terms of alignment and function of the knee. However, we did not find any significant difference between the two methods in terms of other outcomes, such as pain, range of motion, health status, and joint awareness. Therefore, we suggest that more research is needed to confirm these results and evaluate the long-term effects and cost-effectiveness of robotic-assisted surgery.

Effects of obstructive sleep apnea on non-alcoholic fatty liver disease in patients with obesity: a systematic review.

INTRODUCTION: Obesity has been linked to non-alcoholic fatty liver disease (NAFLD), a widespread chronic liver ailment, as well as obstructive sleep apnea (OSA). The development of NAFLD is influenced by repeated intermittent hypoxia, a feature of OSA. METHODS: This systematic review (SR) investigated CENTRAL, PubMed, and EMBASE databases. The endpoint of this SR was to assess which OSA-related indicators could predict the presence of NAFLD and the effect of bariatric metabolic surgery (BMS) on improving OSA and NAFLD over time. RESULTS: Compared to previous SRs published in 2013, 14 new publications were added to our SR, alongside studies conducted prior to 2013. The SR ultimately included 28 studies (18 cross-sectional and 10 cohort trials). In the majority of studies, significant correlations were observed between OSA, OSA-related outcomes, and NAFLD. However, the apnea-hypopnea index (AHI) alone proved to be an inadequate predictor of NAFLD. Instead, respiratory and metabolic changes were found to alleviate oxidative stress induced by hypoxemia. Six studies involved patients who underwent BMS, with one evaluating patients before and after BMS, revealing associations between increased OSA and NAFLD improvement following BMS. Six months after surgery, 100% of patients in the mild-to-moderate OSA group were free from fatty liver, and an 89% reduction was observed in the severe OSA group. CONCLUSION: For the first time, BMS has been tested in treating both OSA and NAFLD pre and postoperative with positive results. Further research, ideally with histological and functional data, is needed to confirm these findings. The SR identified 14 distinct liver outcome tests; however, high heterogeneity and incomplete data precluded a meta-analysis. It is imperative to pay greater attention to the influence of OSA-related factors and uniformity in liver outcomes testing concerning NAFLD. To accomplish this, study designs should be enhanced by incorporating more comprehensive pre- and postoperative evaluations, extending follow-up periods, and employing a more consistent methodology for liver diagnosis in patients with obesity.

The Use of Indocyanine Green and Near-Infrared Fluorescence Imaging Versus Blue Dye in Sentinel Lymph Node Biopsy in Cutaneous Melanoma: A Retrospective, Cohort Study.

BACKGROUND: The use of indocyanine green (ICG) and near-infrared fluorescence imaging is a promising option for sentinel lymph node (SLN) mapping in cutaneous melanoma. The study objective was to compare the performance of ICG and blue dye at detecting SLNs with radioisotope nanocolloid (technetium-99). METHODS: Between April 2018 and June 2022, 293 consecutive patients with cutaneous melanoma (Breslow thickness ≥ 0.8 mm) underwent wide local excision and SLN biopsy. Patients were divided into group A (ICG; n = 122) and group B (blue dye; n = 163). All patients underwent SPECT/CT imaging preoperatively. SLN detection parameters and complications were compared between the groups. RESULTS: A total of 285 patients had complete data and were included in the analysis. The median age was 62.0 (range 10-91) years, and 139 (48.8%) were female patients. The mean Breslow thickness was 2.6 mm, 89 (31.2%) patients had ulceration, and 179 (62.8%) patients had mitosis ≥ 1 mm2. The mean number of SLNs detected per patient in group A was 1.58 and group B was 1.48. In groups A and B, the SLN detection rate was 96.7% versus 89.6% (p = 0.022) and the pathological SLN detection rate was 92.3% versus 97.1% (p = 0.481), respectively. CONCLUSIONS: ICG had a higher SLN detection rate and equal pathological SLN detection rate to blue dye. ICG may not be inferior to blue dye and is a useful adjunct to radioisotope in SLN biopsy in cutaneous melanoma.

A Frequency Reconfigurable Folded Antenna for Cognitive Radio Communication.

In this work, a spectrum-sensing monopole antenna was used to operate in different frequency bands for cognitive radio applications. The proposed antenna consists of a folded monopole antenna with a partial ground plane, and it can be used for various wireless technologies operated at various frequencies from 1.5 to 3.5 GHz. The suggested antenna was printed on a RO4003 substrate with 3.38 permittivity and an overall size of 60 × 60 × 0.813 mm3. To achieve reconfigurability of the antenna, PIN diodes (HPND-4005) were inserted at different lengths along the antenna to obtain the desired performance. The antenna was fabricated and experimentally tested to validate the simulation outcomes, and distinct consistency between the simulation and measurement outcomes was obtained. Computer simulation tool (CST) software was used to design and simulate the suggested antenna and then the model was fabricated to validate the simulation outcomes.

Filtenna with Frequency Reconfigurable Operation for Cognitive Radio and Wireless Applications.

A reconfigurable wideband monopole antenna is introduced in this paper for cognitive radio and wireless applications. The reconfigurability was achieved by four varactor diodes embedded in the band pass filter (BPF) structure which was integrated with the suggested antenna through its feed line. The simulated impedance characteristics coped with the measured ones after fabricating the suggested model with/without the reconfigurable BPF. Furthermore, the model achieved the desired radiation characteristics in terms of radiation pattern with acceptable gain values at the selected frequencies within the achieved frequency range (1.3-3 GHz).

Bosniak classification version 2019: a prospective comparison of CT and MRI.

OBJECTIVE: To assess the diagnostic accuracy and agreement of CT and MRI in terms of the Bosniak classification version 2019 (BCv2019). MATERIALS AND METHODS: A prospective multi-institutional study enrolled 63 patients with 67 complicated cystic renal masses (CRMs) discovered during ultrasound examination. All patients underwent CT and MRI scans and histopathology. Three radiologists independently assessed CRMs using BCv2019 and assigned Bosniak class to each CRM using CT and MRI. The final analysis included 60 histopathologically confirmed CRMs (41 were malignant and 19 were benign). RESULTS: Discordance between CT and MRI findings was noticed in 50% (30/60) CRMs when data were analyzed in terms of the Bosniak classes. Of these, 16 (53.3%) were malignant. Based on consensus reviewing, there was no difference in the sensitivity, specificity, and accuracy of the BCv2019 with MRI and BCv2019 with CT (87.8%; 95% CI = 73.8-95.9% versus 75.6%; 95% CI = 59.7-87.6%; p = 0.09, 84.2%; 95% CI = 60.4-96.6% versus 78.9%; 95% CI = 54.4-93.9%; p = 0.5, and 86.7%; 95% CI = 64.0-86.6% versus 76.7%; 95% CI = 75.4-94.1%; p = 0.1, respectively). The number and thickness of septa and the presence of enhanced nodules accounted for the majority of variations in Bosniak classes between CT and MRI. The inter-reader agreement (IRA) was substantial for determining the Bosniak class in CT and MRI (k = 0.66; 95% CI = 0.54-0.76, k = 0.62; 95% CI = 0.50-0.73, respectively). The inter-modality agreement of the BCv219 between CT and MRI was moderate (κ = 0.58). CONCLUSION: In terms of BCv2019, CT and MRI are comparable in the classification of CRMs with no significant difference in diagnostic accuracy and reliability. KEY POINTS: • There is no significant difference in the sensitivity, specificity, and accuracy of the BCv2019 with MRI and BCv2019 with CT. • The number of septa and their thickness and the presence of enhanced nodules accounted for the majority of variations in Bosniak classes between CT and MRI. • The inter-reader agreement was substantial for determining the Bosniak class in CT and MRI and the inter-modality agreement of the BCv219 between CT and MRI was moderate.

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial.

BACKGROUND: Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. METHODS: This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. RESULTS: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). CONCLUSIONS: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial.

BACKGROUND: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1. METHODS: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574. FINDINGS: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response. INTERPRETATION: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies. FUNDING: Forma Therapeutics.

Prognostic Role of Porphyromonas gingivalis Gingipain Rgp and Matrix Metalloproteinase 9 in Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: The oral bacteria involved in the development of periodontitis alter the tissue conditions and modify immune responses in a way that may also influence tumor development. We investigated the prevalence of R gingipain (Rgp), a key virulence factor of the oral pathobiont Porphyromonas gingivalis, and the tissue-destructive enzymes matrix metalloproteinase 8 (MMP-8) and 9 (MMP-9) in 202 unselected consecutive oropharyngeal squamous cell carcinoma (OPSCC) samples. We further investigated the relationships between these factors and human papillomavirus (HPV) status, Treponema denticola chymotrypsin-like proteinase (Td-CTLP) immunoexpression, clinical parameters, and patient outcome. PATIENTS AND METHODS: Clinicopathological data were derived from university hospital records. Rgp, MMP-8, and MMP-9 immunoexpression was evaluated by immunohistochemistry; the immunohistochemistry of Td-CTLP and HPV has been described earlier for this patient series. Cox regression analysis including death by causes other than OPSCC as a competing risk served to assess sub distribution hazard ratios. RESULTS: In multivariable survival analysis, positive tumoral MMP-9 immunoexpression predicted poor prognosis among all patients [sub distribution hazard ratio (SHR)=2.4; confidence interval (CI)=1.2-4.4, p=0.008], and especially among those with HPV-negative OPSCC (SHR=3.5; CI=1.7-7.3, p=0.001). Positive immunoexpression of Rgp in inflammatory cells was associated with favorable outcome among all patients (SHR=0.5, CI=0.2-0.9, p=0.021) and among those with HPV-negative disease (SHR=0.4, CI=0.2-0.9, p=0.022). CONCLUSION: Our results suggest that tumoral MMP-9 may be related to poor outcome in OPSCC, especially in HPV-negative disease, while Rgp immunoexpression in inflammatory cells is associated here with better disease-specific survival (DSS).

One-year results of minimally invasive fusion surgery of the sacroiliac joint as an alternative treatment after failed endoscopic thermal coagulation.

BACKGROUND: While pain in the severe sacroiliac joint (SIJ) is a common cause of lower back pain, SIJ disease is often overlooked as a diagnosis. OBJECTIVE: This study examines the extent of sufficient long-term pain relief and functional improvement in patients with SIJ syndrome that are treated with thermocoagulation. Some patients treated with thermocoagulation noted initial improvement, but the functionality and pain relief had limited duration and efficacy. Patients with insufficient improvement were recommended to undergo fusion surgery as an option for better and longer lasting results. METHOD: Patients with a long history of back or pelvic problems were selected for the study. Endoscopic thermal coagulation of the SIJ was carried out. The follow-up examinations took place after 1, 3, 6, 12 months. In patients with insufficient pain relief and functionality after thermocoagulation, a fusion surgery was performed. The results of the fusion surgery were documented over a 12-month follow-up period. To carry out the statistical evaluation visual analog scale (VAS), Oswestry-Disability-Index (ODI) and the consumption of opioids were recorded. RESULTS: Forty-eight patients were included. The mean VAS values 12 months after thermocoagulation were 68.9. The ODI after 12 months was very near or somewhat higher than their baseline prior to the thermocoagulation. Thus, a fusion surgery was recommended. Thirty-three patients agreed to the fusion operation. The VAS values 12 months after fusion surgery decreased to 53.1. Analogous to the VAS values, the Oswestry index (ODI) showed a significant improvement after the fusion operation. CONCLUSION: The success of surgical intervention in 88% of the SIJ syndrome patients with inadequate results 12 months after thermocoagulation proves the superiority of SIJ fusion surgery. This study showed long-lasting pain relief by an average of 65% and a median improvement in functional impairments of 60%. In view of these results, fusion surgery should be considered for patients without sufficient success of thermocoagulation.

Bronchopleural Fistula as a Complication in a COVID-19 Patient Managed With Endobronchial Valves.

Bronchopleural fistula (BPF) is associated with high morbidity if left untreated. Although rare, the frequency of BPF in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is becoming recognized in medical literature. We present a case of a 64-year-old male with BPF with persistent air leak due to SARS-CoV-2 pneumonia treated with Spiration Valve System endobronchial valve (EBV). An EBV was placed in the right middle lobe with successful cessation of air leak. In conclusion, the use of EBVs for BPF with persistent air leaks in SARS-CoV-2 patients who are poor surgical candidates is effective and safe.

Exploring the Conformational Landscape of the Neh4 and Neh5 Domains of Nrf2 Using Two Different Force Fields and Circular Dichroism.

The nuclear factor erythroid 2-related factor 2 (Nrf2)-ARE transcriptional response pathway plays a critical role in protecting the cell from oxidative stresses via the upregulation of cytoprotective genes. Aberrant activation of Nrf2 in cancer cells can confer this cytoprotectivity, thereby reducing the efficacy of both chemotherapeutics and radiotherapies. Key to this antioxidant pathway is the interaction between Nrf2 and CREB binding protein (CBP), mediated by the Neh4 and Neh5 domains of Nrf2. Disruption of this interaction via small-molecule therapeutics could negate the effects of aberrant Nrf2 upregulation. Due to the disordered nature of these domains, there remains no three-dimensional structure of Neh4 or Neh5, making structure-based drug design a challenge. Here, we performed 48 µs of unbiased molecular dynamics (MD) simulations with the Amber99SB*-ILDNP and CHARMM36m force fields and circular dichroism (CD) spectropolarimetry experiments to elucidate the free-state structures of these domains; no previous data regarding their conformational landscapes exists. There are two main findings: First, we find Neh5 to be markedly more disordered than Neh4, which has nine residues in the middle of the domain showing α-helical propensity, thus pointing to Neh4 and Neh5 having different binding mechanisms. Second, the two force fields show strong differences for the glutamic acid-rich Neh5 peptide but are in reasonable agreement for Neh4, which has no glutamic acid. The CHARMM36m force field agrees more closely with the CD results.

Mitral valve replacement in dilated cardiomyopathy: A valid option?

BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and dysfunction. The association with significant mitral regurgitation worsens the prognosis. CASE REPORT: A 2-year-old girl presented with DCM and severe mitral regurgitation. She had a history of viral myocarditis at the age of 4 months, necessitating recurrent hospital admissions for management of intractable heart failure, pneumonia, and failure to thrive. The decision was taken to proceed for mitral valve surgery, which ended with mitral valve replacement. Over 3 years of follow-up after surgery, there was significant improvement in her weight gain and she improved clinically. There were still recurrent admissions, but mostly for adjustment of her deranged anticoagulation medications. CONCLUSION: Mitral valve surgery might be indicated in selected patients with DCM.

Expression and Role of E-Cadherin, ß-Catenin, and Vimentin in Human Papillomavirus-Positive and Human Papillomavirus-Negative Oropharyngeal Squamous Cell Carcinoma.

Oropharyngeal squamous cell carcinoma (OPSCC) is subclassified by the World Health Organization into two different entities: human papillomavirus (HPV)-positive and HPV-negative tumors. HPV infection promotes the epithelial-to-mesenchymal transition (EMT) and transformation of keratinocyte stem cells into cancer stem cells. EMT is a crucial process in the carcinogenesis of epithelial-derived malignancies, and we aimed to study the role of its markers in OPSCC. This study consists of 202 consecutive OPSCC patients diagnosed and treated with curative intent. We examined E-cadherin, ß-catenin, and vimentin expression using immunohistochemistry and compared these with tumor and patient characteristics and treatment outcome. We found that the cell-membranous expression of ß-catenin was stronger in HPV-positive than in HPV-negative tumors, and it was stronger in the presence of regional metastasis. The stromal vimentin expression was stronger among HPV-positive tumors. A high E-cadherin expression was associated with tumor grade. No relationship between these markers and survival emerged. In conclusion, ß-catenin and vimentin seem to play different roles in OPSCC: the former in the tumor tissue itself, and the latter in the tumor stroma. HPV infection may exploit the ß-catenin and vimentin pathways in carcinogenic process. More, ß-catenin may serve as a marker for the occurrence of regional metastasis.

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

PURPOSE: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. METHODS: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. RESULTS: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. CONCLUSION: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study.

OBJECTIVES: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines. MATERIALS AND METHODS: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available. RESULTS: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB ≥ 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002). CONCLUSION: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.