Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.

• MeSH
• Quinolines * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Phenylurea Compounds * administration & dosage   therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   mortality   secondary   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sunitinib * administration & dosage   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

OBJECTIVE: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. METHODS: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. RESULTS: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. SIGNIFICANCE: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

• MeSH
• Child MeSH
• Electroencephalography * methods   MeSH
• Epilepsy MeSH
• Focal Cortical Dysplasia MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Malformations of Cortical Development, Group I * surgery   complications   diagnostic imaging   MeSH
• Malformations of Cortical Development surgery   complications   diagnostic imaging   MeSH
• Adolescent MeSH
• Positron-Emission Tomography MeSH
• Child, Preschool MeSH
• Drug Resistant Epilepsy * surgery   diagnostic imaging   physiopathology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

AIMS: Cardiac resynchronization therapy (CRT) is guideline recommended for the treatment of symptomatic heart failure (HF) with reduced left ventricular ejection fraction and prolonged QRS. However, patients with common comorbidities, such as persistent/permanent atrial fibrillation (AF), are often under-represented in clinical trials. METHODS: The Strategic Management to Optimize Response to Cardiac Resynchronization Therapy (SMART) registry (NCT03075215) was a global, multicentre, registry that enrolled de novo CRT implants, or upgrade from pacemaker or implantable cardioverter defibrillator to CRT-defibrillator (CRT-D), using a quadripolar left ventricular lead in real-world clinical practice. The primary endpoint was CRT response between baseline and 12 month follow-up defined as a clinical composite score (CCS) consisting of all-cause mortality, HF-associated hospitalization, New York Heart Association (NYHA) class and quality of life global assessment. RESULTS: The registry enrolled 2035 patients, of which 1558 had completed CCS outcomes at 12 months. The patient cohort was 33.0% female, mean age at enrolment was 67.5 ± 10.4 years and the mean left ventricular ejection fraction was 29.6 ± 7.9%. Notably, there was a high prevalence of mildly symptomatic patients (NYHA class I/II 51.3%), non-left bundle branch block (LBBB) morphology (38.0%), AF (37.2%) and diabetes mellitus (34.7%) at baseline. CCS at 12 months improved in 58.9% (n = 917) of patients; 20.1% (n = 313) of patients stabilized and 21.0% (n = 328) worsened. Several patient characteristics were associated with a lower likelihood of response to CRT including older age, ischaemic aetiology, renal dysfunction, AF, non-LBBB morphology and diabetes. Higher HF hospitalization (P < 0.001) and all-cause mortality (P < 0.001) were observed in patients with AF. These patients also had lower percentages of ventricular pacing than patients in sinus rhythm at baseline and follow-up (P < 0.001, both). A further association between AF and non-LBBB was observed with 81.4% of AF non-LBBB patients experiencing an HF hospitalization compared with 92.5% of non-AF LBBB patients (P < 0.001). Mortality between subgroups was also statistically significant (P = 0.019). CONCLUSIONS: This large, global registry enrolled a CRT-D population with higher incidence of comorbidities that have been historically underrepresented in clinical trials and provides new insight into factors influencing response to CRT. As defined by CCS, 58.9% of patients improved and 20.1% stabilized. Patients with AF had particularly worse clinical outcomes, higher HF hospitalization and mortality rates and lower percentages of ventricular pacing. High incidence of HF hospitalization in patients with AF and non-LBBB in this real-world cohort suggests that ablation may play an important role in increasing future CRT response rates.

• MeSH
• Global Health MeSH
• Ventricular Function, Left * physiology   MeSH
• Quality of Life * MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Registries * MeSH
• Aged MeSH
• Cardiac Resynchronization Therapy * methods   MeSH
• Heart Failure * therapy   physiopathology   mortality   MeSH
• Stroke Volume * physiology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

PURPOSE: To evaluate treatment outcomes and toxicity in patients with stage T1-3N0M0 oral cancer treated with surgery followed by high-dose-rate brachytherapy (HDR-BT). METHODS AND MATERIALS: Retrospective study of 50 patients with stage T1-T3N0 tongue and floor-of-mouth cancer who underwent tumour excision (+ elective neck dissection) followed by postoperative HDR-BT due to the presence of negative prognostic factors (close or positive resection margins, lymphovascular and/or perineural invasion, deep invasion). The plastic tube technique (dose: 18 x 3 Gy b.i.d.) was used. Survival outcomes, toxicity, and prognostic factors were evaluated. RESULTS: At a median follow-up of 81 months (range, 4-121), actuarial 5-year local control (LC), nodal control (NC) and progression-free survival (PFS) rates were 79%, 69%, and 64%. After salvage treatment (surgery + external beam radiotherapy), LC, NC, and PFS increased to 87%, 77%, and 72.3%, respectively. Five-year overall survival and cancer-specific survival (CSS) rates were 73% and 77%. Treatmentrelated toxicity included two cases of mandibular osteoradionecrosis and five cases of small soft tissue necrosis. T stage was significantly correlated with nodal control (p=0.02) and CSS (p=0.04). Tumour grade correlated with DFS (p=0.01). CONCLUSION: Postoperative HDR-BT 18 x 3 Gy b.i.d. seems to be an effective method in patients with T1-3N0M0 oral cancer with negative prognostic factors after tumour resection.

• MeSH
• Brachytherapy * methods   MeSH
• Radiotherapy Dosage * MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Mouth Neoplasms * radiotherapy   pathology   surgery   MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging * MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Introduction. Vagal nerve stimulation (VNS) is a therapeutical option for the treatment of drug-resistant epileptic patients. The response to VNS varies from patient to patient and is difficult to predict. The proposed study is based on our previous work, identifying relative mean power in pre-implantation EEG as a reliable marker for VNS efficacy prediction in adult patients. Our study has two main tasks. Firstly, to confirm the utility of relative mean power as a feature correlating with VNS efficacy in children. The second is to validate the applicability of our prediction classifier, Pre-X-Stim, in the pediatric population. Material and Methods. We identified a group of children with drug-resistant epilepsy. We included only children in whom EEG contained photic stimulation (Task 1) or was recorded based on the defined acquisition protocol used for development Pre-X-Stim (Task 2). Relative mean powers were calculated. VNS responders and non-responders were compared based on relative mean powers' values. In the next step, we evaluate the utility of our classifier, Pre-X-Stim, in the children population. Results: We identified 57 children treated with VNS - 17 patients were recruited for the Task 1 and 7 patients for the Task 2. When focusing on relative mean powers in EEG spectra, we observed statistically significant differences in theta range. The Pre-X-Stim algorithm was able to predict VNS efficacy correctly in 6 out of 7 patients (the accuracy 83.3%, the sensitivity 75%, the specificity 100%). Conclusions. Based on our results, it seems that children and adults share a similar pattern of EEG relative mean power changes. These changes can be used for pre-implantation prediction of VNS efficacy.

• MeSH
• Child MeSH
• Electroencephalography * methods   MeSH
• Epilepsy * therapy   physiopathology   MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Drug Resistant Epilepsy * therapy   physiopathology   MeSH
• Scalp MeSH
• Vagus Nerve Stimulation * methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND AND OBJECTIVES: Enhanced Recovery After Surgery (ERAS) guidelines for Radical Cystectomy (RC) were published over ten years ago. Aim of this systematic review is to update ERAS recommendations for patients undergoing RC and to give an expert opinion on the relevance of each single ERAS item. METHODS: A systematic review was performed to identify the impact of each single ERAS item on RC outcomes. Embase and Medline (through Pubmed) were searched systematically. Relevant articles were selected and graded. For each ERAS item, a level of evidence was determined. An e-Delphi consensus was then performed amongst an international panel with renowned experience in RC to provide recommendations based on expert opinion. KEY FINDINGS AND LIMITATIONS: Preoperative medical optimization and avoiding bowel preparation are highly recommended. Robotic-assisted RC with intracorporeal urinary diversion is moderately recommended and can help in applying other ERAS items, such as early mobilization. Medical thromboprophylaxis should be administered and nasogastric tube should be removed at the end of surgery. Perioperative fluid restriction as well as opioid-sparing anesthesia protocols should be implemented. Generally, consensus was reached on most ERAS items, with the exception of epidural anesthesia (no consensus), resection site drainage (consensus against), and type of urinary drainage. Limitations include the lack of a multidisciplinary approach to the present consensus, giving however a highly specialized surgical opinion on ERAS. CONCLUSIONS: and clinical implications: The current study updates ERAS recommendations for patients undergoing RC and suggests application of ERAS by a panel of experts in the field.

• MeSH
• Early Ambulation MeSH
• Surgeons MeSH
• Cystectomy * methods   MeSH
• Urinary Diversion methods   MeSH
• Humans MeSH
• Urinary Bladder Neoplasms surgery   MeSH
• Robotic Surgical Procedures MeSH
• Practice Guidelines as Topic MeSH
• Enhanced Recovery After Surgery * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Systematic Review MeSH

Therapeutic plasma exchange (PLEX) is an adjunctive treatment for patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and kidney involvement. Little is known about the effect of PLEX on early changes in kidney function. This post-hoc analysis of the PEXIVAS trial investigated the effects of PLEX on changes in kidney function within 12 months. PEXIVAS was a randomized controlled trial recruiting 691 patients with ANCA-associated glomerulonephritis, of whom 349 underwent PLEX and 342 received no-PLEX. The primary outcomes of this post hoc study of PEXIVAS were change in estimated glomerular filtration rate (eGFR) from baseline and recovery of kidney function (defined as eGFR increase of 15ml/min/1.73m2 or more). Baseline eGFR was 21.7 ± 20.3 and 20.6 ± 18.7 ml/min/1.73m2 in the PLEX and no-PLEX groups, respectively. Mean improvements in eGFR at weeks two, four, and eight after initiation of therapy were greater for the PLEX vs. the no-PLEX groups. The greatest significant difference in recovery of kidney function in the PLEX compared to the no-PLEX groups was at week four (relative risk (RR): 1.41; 95% confidence interval:1.09-1.82). Increased eGFR or recovery of kidney function at week four were significantly associated with lower risk for end-stage kidney disease at week 52 (RR: 0.96: 0.95-0.97, and RR: 0.29: 0.16-0.52; respectively). Neither changes in eGFR nor recovery of kidney function differed by reduced- compared to standard-dose glucocorticoid group. Overall, our study indicates that PLEX improves early kidney function in patients with ANCA-associated glomerulonephritis.

• MeSH
• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis * physiopathology   therapy   drug therapy   complications   immunology   diagnosis   MeSH
• Adult MeSH
• Glomerulonephritis * physiopathology   immunology   therapy   blood   MeSH
• Glucocorticoids * therapeutic use   administration & dosage   MeSH
• Glomerular Filtration Rate * MeSH
• Kidney * physiopathology   drug effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Recovery of Function MeSH
• Aged MeSH
• Plasma Exchange * MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

OBJECTIVES: Despite increasing interest, prospective data on the use of degradable starch microsphere-transarterial chemoembolization (DSM-TACE) in the management of patients with unresectable HCC are still scarce. The objective of the HepaStar study was to collect prospective safety and effectiveness data in a prospective multicenter observational study. MATERIALS AND METHODS: Between January 2017 and December 2022, consecutive participants with unresectable or recurrent HCC treated with DSM-TACE as standard of care at 6 participating centers in Europe were enrolled. Tumor response was evaluated according to the mRECIST criteria. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were assessed by using Kaplan-Meier analysis and Common Terminology Criteria for Adverse Events, version 5. Liver function deterioration was assessed by monitoring changes in liver blood tests during the follow-up. RESULTS: Seventy-nine participants (median age, 69 years (IQR, 51-87 years); 67 men (85%)) were enrolled and treated. The median follow-up time was 18 months (IQR 9.5-38.0 months). The estimated median OS and PFS for the entire cohort was 32 months (CI, 95% 21-NaN) and 9 months (CI, 95% 7-NaN), respectively. Eleven (13.9%) participants experienced at least one grade 3 or 4 AE. The most frequent grade 3-4 AE was elevated bilirubin (2.2%, 5 of 79). Deterioration of bilirubin, AST, ALT, and albumin were observed in 24.1%, 23.7%, 19%, and 24% of participants, respectively. CONCLUSION: DSM-TACE achieves promising survival in patients with unresectable or recurrent HCC. This technique shows a favorable safety profile both in terms of treatment-related AEs and liver function deterioration. KEY POINTS: Question Although degradable starch microspheres transarterial chemoembolization is widely used in clinical practice across Europe, prospective data on its application in hepatocellular carcinoma patients remains limited. Findings Degradable starch microspheres transarterial chemoembolization results in promising survival rates, good tumor response rates, and low rates of treatment-related adverse events. Clinical relevance In patients with unresectable hepatocellular carcinoma, degradable starch microspheres transarterial chemoembolization represents a safe and effective alternative to more well-established chemoembolization techniques like conventional transarterial chemoembolization and drug-eluting beads transarterial chemoembolization.

• MeSH
• Chemoembolization, Therapeutic * methods   MeSH
• Carcinoma, Hepatocellular * therapy   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Microspheres MeSH
• Liver Neoplasms * therapy   mortality   MeSH
• Prospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Starch * administration & dosage   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

BACKGROUND: Various explicit screening tools, developed mostly in central Europe and the USA, assist clinicians in optimizing medication use for older adults. The Turkish Inappropriate Medication use in oldEr adults (TIME) criteria set, primarily based on the STOPP/START criteria set, is a current explicit tool originally developed for Eastern Europe and subsequently validated for broader use in Central European settings. Reviewed every three months to align with the latest scientific literature, it is one of the most up-to-date tools available. The tool is accessible via a free mobile app and website platforms, ensuring convenience for clinicians and timely integration of updates as needed. Healthcare providers often prefer to use their native language in medical practice, highlighting the need for prescribing tools to be translated and adapted into multiple languages to promote optimal medication practices. OBJECTIVE: To describe the protocol for cross-cultural and language validation of the TIME criteria in various commonly used languages and to outline its protocol for clinical validation across different healthcare settings. METHODS: The TIME International Study Group comprised 24 geriatric pharmacotherapy experts from 12 countries. In selecting the framework for the study, we reviewed the steps and outcomes from previous research on cross-cultural adaptations and clinical validations of explicit tools. Assessment tools were selected based on both their validity in accurately addressing the relevant issues and their feasibility for practical implementation. The drafted methodology paper was circulated among the study group members for feedback and revisions leading to a final consensus. RESULTS: The research methodology consists of two phases. Cross-cultural adaptation/language validation phase follows the 8-step approach recommended by World Health Organization. This phase allows regions or countries to make modifications to existing criteria or introduce new adjustments based on local prescribing practices and available medications, as long as these adjustments are supported by current scientific evidence. The second phase involves the clinical validation, where participants will be randomized into two groups. The control group will receive standard care, while the intervention group will have their treatment evaluated by clinicians who will review the TIME criteria and consider its recommendations. A variety of patient outcomes (i.e., number of hospital admissions, quality of life, number of regular medications [including over the counter medications], geriatric syndromes and mortality) in different healthcare settings will be investigated. CONCLUSION: The outputs of this methodological report are expected to promote broader adoption of the TIME criteria. Studies building on this work are anticipated to enhance the identification and management of inappropriate medication use and contribute to improved patient outcomes.

• MeSH
• Humans MeSH
• Inappropriate Prescribing statistics & numerical data   prevention & control   MeSH
• Aged MeSH
• Potentially Inappropriate Medication List * MeSH
• Cross-Cultural Comparison MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Advancing the retrograde microcatheter (MC) into the antegrade guide catheter during retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) can be challenging or impossible, preventing guidewire externalization. OBJECTIVES: To detail and evaluate all the techniques focused on wiring to achieve intubation of the distal tip of a microcatheter, balloon, or stent with an antegrade or retrograde guidewire, aiming to reduce complications by minimizing tension on fragile collaterals during externalization and enabling rapid antegrade conversion in various clinical scenarios. METHODS: We describe the two main techniques, tip-in and rendezvous, and their derivatives such a facilitated tip-in, manual MC-tip modification, tip-in the balloon, tip-in the stent, deep dive rendezvous, catch-it and antegrade microcatheter probing. We provide case studies that demonstrate the effectiveness of these techniques in complex scenarios involving extreme vessel angulation, severe calcification, fragile collaterals, and challenging retrograde MC crossing without externalization. CONCLUSION: The development of advanced variants along with traditional techniques to establish retrograde guidewire connection and antegrade conversion has led to the establishment of a cohesive group of methods known as portal techniques. These approaches serve as strategic advantages in retrograde CTO-PCI, providing a valuable and feasible alternative to conventional retrograde connection techniques, particularly when those techniques fail. Their ability to avoid the externalization process reduces potential damage to collateral channels and the ostium of the donor artery, potentially leading to a reduction in complication rates.

• MeSH
• Angioplasty, Balloon, Coronary instrumentation   adverse effects   MeSH
• Chronic Disease MeSH
• Equipment Design MeSH
• Percutaneous Coronary Intervention instrumentation   adverse effects   MeSH
• Coronary Occlusion * diagnostic imaging   therapy   physiopathology   MeSH
• Humans MeSH
• Miniaturization MeSH
• Cardiac Catheters * MeSH
• Stents * MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH