Long-term Clinical Outcomes Research Articles

Charting heterogeneity and spatial landscape of consensus molecular subtypes in colorectal cancer.

e15647 Background: High inter-patient heterogeneity and spatial diversity within tumors represent significant challenges to improving outcomes in colorectal cancer (CRC). Despite elucidation of consensus molecular subtypes (CMS), little progress has been made in translating this knowledge into clinical gain. Intratumoral CMS heterogeneity remains a relatively unexplored area and understanding of the interplay between subtypes holds promise for improving prognostication. We leverage spatial transcriptomics (ST) to enhance understanding of CMS heterogeneity and spatial distribution, with the goal of advancing personalized therapy through high resolution molecular sub-typing. Methods: ST using the 10x Genomics Visium platform was performed on paraffin-embedded CRC specimens for which comprehensive clinicopathological and long-term clinical outcome data were available. ST data were deconvoluted with respect to CMS single-cell RNA sequencing (scRNA-seq) data, yielding maps of CMS landscapes at a resolution of 55 microns. A pre-trained deep learning model was used to identify distinct CRC tissue classes (tumor epithelium, stroma, etc.) within H&E images, enabling spatial correlation of histomorphology with CMS. Cellular composition within these CMS maps was quantified through deconvolution of six major cell types using reference scRNA-seq data. Pseudo-bulk samples were generated from the ST data to evaluate CMS behaviors and compute pathway activities. Results: 40 CRC patients were assayed using ST and H&E profiling (13, 8, 14, and 5 from stages 1-4, respectively). Median follow-up was 112 months (Range 1–192). Intratumoral CMS heterogeneity was evident in all patients, with diverse CMS compositions. Using Simpson diversity index to quantify this heterogeneity, we observed significant correlation of heterogeneity with disease specific survival (DSS) (p = .03). CMS landscapes displayed spatial patterns that were distinct among tissue categories (average F1-score: testing = .92, validation = .89. Tissue categories based on deep learning from H&E images). Tumors with higher levels of CMS1 or 4 were associated with worse outcome. Stratification by the composite CMS biomarker (CMS1+CMS4)/(CMS2+CMS3) yielded significant separation of the Kaplan-Meier curve for DSS (p = .018). Conclusions: This study demonstrates that CRC tumors contain significant intratumoral CMS heterogeneity that is not detectable using bulk classification methods. Spatial patterns in CMS transcriptional topographies correlate with H&E-derived morphology, suggesting the potential for estimating CMS composition from histopathological features. Importantly, we show that spatially composite CMS-derived biomarkers possess strong prognostic potential. The capacity to decode CMS topographic patterns and associate these with clinical outcome offers great potential to advance personalized therapy for CRC.

Staged Surgical Treatment of the Giant Pituitary Neuroendocrine Tumors

To investigate the long-term clinical outcomes of staged surgical resection in giant Pituitary Neuroendocrine Tumors(pitNET).Method We performed a retrospective analysis of the clinical data of 16 patients who underwent surgery. The patients were diagnosed and underwent surgery at the Department of Neurosurgery of Shiyan Taihe Hospital from January 2013 to March 2021. Among the cases, 12 patients underwent primarily transsphenoidal surgery followed by secondary transcranial surgery, while 4 patients underwent primarily transsphenoidal surgery followed by secondary transsphenoidal surgery. Before the surgery, all patients underwent a pituitary MRI scan, pituitary hormone level examination, visual acuity, and visual field examination. A pituitary MRI was rechecked within 1 week after the operation. A tumor resection rate of 100% on MRI was considered as a total resection, between 90% to 100% as a subtotal resection, and lower than 90% as a partial resection. After the surgery, regular clinical visits and telephone or internet platform follow-ups were conducted. Outcome In our clinical investigation, after staged surgery 10 patients had a total resection, 5 had a subtotal resection, and 1 had a partial resection depending on the tumor size and invasion. The clinical outcomes showed that 1 case suffered from postoperative intracranial infection, 1 case had decreased visual acuity, and 6 cases experienced decreased pituitary function after surgery.Postoperative complications were cured after symptomatic treatment, except for 1 patient who experienced decreased vision and 1 patient sufferred hypopituitarism required long-term oral levothyroxine tablet treatment. No cases of intracranial hemorrhage or death were caused by intentionally staged resection surgery. Conclusion Staged surgery for giant pitNET is a safe and effective clinical surgery strategy.

Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.

Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done. To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances. We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic NTRK gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility. In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab. In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.

Correlation between metastatic site and immunotherapy efficacy in patients with advanced dMMR/MSI colorectal cancer: Real-World Italian multicentric retrospective study (Colon-MSI).

e15544 Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The Colon-MSI study aimed to describe a cohort of MSI mCRC pts treated with ICIs before Italian pembrolizumab approval and to evaluate the efficacy, safety, and possible predictive factors of response in a real-world setting. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs before June 30, 2023, in 16 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. We explored the correlation between clinicopathological factors, survival outcomes, and treatment response. Results: Between January 2021 and June 2023, we reported 83 consecutive pts with data available. Among all, the median age was 61 years (23-86), 42 (51%) were female, and 45 (54%) had a ECOG PS 0; 35 (42%) pts were at stage IV at diagnosis, and 61 (74%) had right colon tumor site. The most common metastatic sites were liver (35%), lymph nodes (43%), peritoneum (31%), and lung (15%); 48 (58%) pts had a single metastatic site. 33 (39%) pts had a mucinous adenocarcinoma, 32 (39%) BRAF mutated, 32 (39%) RAS mutated, and 26% presented a Lynch syndrome. The majority of pts (69%) were pre-treated, and 26 pts (31%) received ICIs in first line. Nivolumab alone or plus Ipilimumab, and Pembrolizumab, were administered in 23 (28%), 3 (4%), and 57 (68%) pts, respectively. The median follow-up was 23 (1-65) months (m) and the median duration of treatment was 23 m (0-65) with 27 pts still ongoing. Treatment-related severe toxicities (G3 or G4) were observed only in 5.6% of pts. The median OS and PFS were not reached; the mean OS was 45.6 m (IC 95% 39.6-51.6) and the mean PFS was 38.8 m (IC 95% 32.5-45.1). Complete response (CR) was observed in 20 pts (24%), partial response (PR) in 28 (34%), stable disease (SD) in 19 (23%) and progression disease (PD) in 16 (19%). Overall response (ORR) was observed in 48 pts (57.8%; 95 %IC 0.31- 0.53), and disease control rate in 67 pts (80.7%; 95% IC 0.11– 0.29). Lung metastatic site was associated with poorer outcome in terms of OS (p = 0.001, HR 3.88 IC 95% 1.7-8.9), PFS (p = 0.045 HR = 2.31 IC95% 1-5.2), and ORR (p = 0.015 OR = 6.19 IC95% 1.4-26.9). Significantly worse PFS was also observed in pts with liver metastasis (p = 0.009 HR = 2.5 IC 95% 1.3-4.9). Conclusions: Our data confirm that ICIs are effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest an unfavorable correlation between lung and liver metastasis and the ICI response. Further biomolecular analysis will be provided in the future.

Use of circulating tumor DNA (ctDNA) to affect the adjuvant or post-adjuvant treatment of patients with stage III and high-risk stage II resected colon cancer: The ERASE-CRC project by GONO.

TPS3644 Background: Three or 6 months of fluoropyrimidines plus oxaliplatin is the standard adjuvant therapy for stage III and high-risk stage II colon cancer, but 20-25% of patients relapse. CtDNA is a promising biomarker of minimal residual disease (MRD) after primary tumor resection and a potential guide in the adjuvant treatment decision-making process. Indeed, ctDNA-positivity after surgery or at the end of adjuvant therapy is associated with higher risk of recurrence. Intensifying the adjuvant and/or the post-adjuvant treatment could be a valuable strategy in these cases. CtDNA clearance has been suggested as a predictor of long-term clinical outcome. Methods: ERASE-CRC is a prospective, open-label, multicentre study, including three phase 2 trials enrolling ctDNA-positive patients with radically resected stage III or high-risk stage II (one major prognostic factor or at least two minor prognostic factors) adenocarcinoma of the colon or intraperitoneal rectum. CtDNA is centrally assessed through a tissue-informed method, F1Tracker. In the phase II ERASE-CRC Part 1 study, patients that are ctDNA-positive after surgery (2-6 weeks) are randomized 1:1 to 6 months of either FOLFOX or CAPOX at investigators’ choice (standard arm) versus FOLFOXIRI (experimental arm). In the phase II single arm ERASE-HER2 study, ctDNA-positive patients with HER2 amplified and RAS wild-type tumors received FOLFOX plus trastuzumab and tucatinib for 12 cycles. In the phase II ERASE-CRC Part 2 study, ctDNA-positive patients after the end of an oxaliplatin-based adjuvant therapy (either in the context or outside ERASE-CRC Part 1 or ERASE-HER2) are randomized 1:2 to observation (standard arm) or trifluridine/tipiracil for 6 cycles (experimental arm). The primary endpoint is the clearance rate of ctDNA after the adjuvant (ERASE-CRC Part 1 and ERASE-HER2) or the post-adjuvant treatment (ERASE-CRC Part 2). 300 patients will be randomized in ERASE-CRC Part 1 to detect a 15% difference in ctDNA clearance rate between the experimental and the standard arm with expected clearance rates of 65% and 50%, respectively, and 1-sided alpha and beta errors of 0.05 and 0.2, respectively. 18 patients will be enrolled in ERASE-HER2 to observe a ctDNA clearance rate of 80% with the targeted treatment ( versus 50% expected), and ctDNA clearance should be observed in 13 cases to consider the strategy promising. Finally, 159 patients will be randomized in ERASE-CRC Part 2 to detect a 15% difference in ctDNA clearance rate between the experimental and the standard arm with 20% and 5% expected clearance rates respectively, and 1-sided alpha and beta errors of 0.05 and 0.2, respectively. Approximately 40 Italian Oncology Units are participating in the study. Currently, 19 and 8 patients have been randomized in ERASE-CRC Part 1 or 2, respectively. NCT05062889. Clinical trial information: NCT05062889 .

Breast Cancer Index re-stratifies 21-gene assay risk groups for late distant recurrence and extended endocrine therapy benefit: Results from the BCI Registry Study.

529 Background: Patients with hormone receptor-positive (HR+) breast cancer face a prolonged risk for late distant recurrence (DR), even after 5 years of adjuvant endocrine therapy. The BCI (Breast Cancer Index, Biotheranostics) is a genomic assay that provides the risk of late DR and predicts the likelihood of benefit from extended endocrine therapy (EET) based on the H/I (HOXB13/IL-17BR) ratio. The 21-gene RS (Recurrence Score; Oncotype DX, Exact Biosciences) test provides the 9-year risk of DR and the benefit from adjuvant chemotherapy (CT) in HR+/HER2− breast cancer. However, the RxPONDER trial showed that RS was not predictive of CT benefit in premenopausal women with N1 disease. Here, we investigated the concordance between BCI prognostic score and H/I versus RS in HR+/HER2- patients from the BCI Registry study. Methods: The BCI Registry study is a prospective, multi-institutional study to evaluate the long-term clinical outcome, decision impact and medication adherence in early-stage HR+ breast cancer patients. Based on TAILORx and RxPONDER results, RS stratified patients into four risk groups: Age ≤ 50, No CT benefit (RS ≤ 15); Age ≤ 50, CT benefit (RS>15); Age > 50, No CT benefit (RS ≤ 25); and Age > 50, CT benefit (RS > 25). Kendall’s correlation coefficient (R) was used to estimate the correlation between BCI prognostic score, BCI (H/I) and RS as continuous variables. Results: BCI and RS results were reported for 847 patients (76% T1; 59% grade II; 85% N0). H/I classified 559 patients (66%) as H/I-Low and 288 (34%) as H/I-High, respectively, while BCI prognostic risk scores classified 434 patients (51%) as low-risk and 413 (49%) as high-risk for late DR. RS classified 30 patients (4%) as Age ≤ 50, No CT benefit, 38 (5%) as Age ≤ 50, CT benefit, 665 (78%) as Age > 50, No CT benefit and 114 (13%) as Age > 50, CT benefit. When analyzed as continuous variables, BCI H/I and prognostic score showed a weak correlation with RS with R=0.18 and R=0.2, respectively. Based on categorical groups, H/I had low concordance with RS for younger women (Age ≤ 50) but showed some correlation with RS for older women (Age > 50). Among those older than Age 50, H/I identified 31% of those with no CT benefit as likely to benefit from EET while 39% of those with CT benefit as not likely to benefit from EET. Conclusions: BCI H/I and prognostic risk scores exhibited low concordance with RS risk categories. H/I consistently re-stratified RS risk categories into distinct H/I-Low and -High groups, further substantiating that prediction of CT benefit does not equate to prediction of EET benefit. [Table: see text]

Clinical outcomes of upfront combination therapy for portopulmonary hypertension

BackgroundLimited data exists on upfront combination therapy for portopulmonary hypertension. We evaluated the clinical efficacy, long-term outcomes, and safety of upfront combination therapy in patients with portopulmonary hypertension. MethodsWe performed a retrospective, single-center cohort study involving a final analysis of 33 consecutive patients diagnosed with portopulmonary hypertension who were taking pulmonary arterial hypertension-specific medication. We compared hemodynamic parameters, risk profiles, composite clinical worsening events, and safety between monotherapy (n = 23) and upfront combination therapy (n = 10). ResultsTwenty-seven patients (82 %) were classified into the Child–Pugh A stage. The change ratios of pulmonary vascular resistance (−32 % vs. −57 %, P = 0.006) were significantly better with upfront combination therapy. Upfront combination therapy also showed significant improvement in risk profiles. Kaplan–Meier analysis showed that the composite event-free rate was significantly lower in patients who received upfront combination therapy than in those who received monotherapy (P = 0.016), although no statistical differences were observed in all-cause death. In the univariate Cox proportional hazards analysis, upfront combination therapy was a factor for decreasing composite clinical worsening outcomes (hazard ratio 0.190, 95 % confidence interval 0.042–0.854; P = 0.030). No significant hepatic impairments were observed over 2 years of follow-up in the upfront combination group. ConclusionsIn patients with portopulmonary hypertension, upfront combination therapy significantly improved symptoms and short-term hemodynamics, and reduced long-term clinical worsening events without serious adverse effects. This study's findings suggest that patients with portopulmonary hypertension presenting with mild hepatic impairment benefit from upfront combination therapy.

Is location more determining than WHO grade for long-term clinical outcome in patients with meningioma in the first two decades of life?

To identify factors for tumor relapse and poor outcome in patients with meningiomas in the first two decades of life. All patients ≤ 21years of age who underwent resection of ameningioma at the department of neurosurgery, Medical University of Vienna between 1989 and 2022 were included in this retrospective study. Clinical and radiological data were extracted from the medical records. Outcome and tumor relapse were analyzed for tumor location, histological findings and extent of resection. In this study 18 patients were included, 6 meningiomas were located in the skull base, 5 in the convexity and 7 in other locations including intraventricular and spine (2 patients each), falx, intraparenchymal and optic nerve sheath. Most frequent symptoms were seizures and cranial nerve palsy. In total 56% of the meningiomas were World Health organization (WHO) grade1, 39% grade2 and 5% grade3. Gross total resection was achieved in 67%. The overall relapse rate was 61% and 50% underwent repeat surgery. All patients with convexity meningiomas became seizure free and had afavorable outcome. Relapse and clinical outcome were independent of WHO grade among the whole cohort but the outcome significantly depended on the WHO grade when patients with skull base meningiomas were analyzed as asubgroup. The relapse rate was significantly higher in cases of skull base location (100% vs. 42%, p = 0.038) and after subtotal resection (100% vs. 42%, p = 0.038). Clinical outcome was also significantly worse and the rate of complications was higher in patients with skull base meningiomas. Patients with convexity meningiomas in the first two decades of life have agood outcome due to high chance of gross total resection. Patients with skull base meningioma are at high risk of relapse and poor outcome, particularly those with WHO grades2 and 3. Subtotal resection in patients with skull base location is probably the main reason for this difference.

Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del.

Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1β (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1β and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes.

Assessing the impact of wheat varieties and processing methods on diabetes risk: A systematic review

Diabetes mellitus remains a major global health challenge, with diet playing a critical role in both its management and prevention. Among dietary factors, wheat-based products are staple foods worldwide, yet their impact on diabetes risk is influenced by the variety of wheat and the methods used in its processing. This systematic review aims to synthesize existing research on how different wheat varieties and their processing methods affect the risk of diabetes. We conducted a comprehensive search of multiple databases, selecting studies that met predefined inclusion criteria focused on wheat characteristics and diabetes outcomes. Our review categorizes wheat varieties based on their genetic profiles and glycemic indices, and examines how traditional and modern processing methods, such as milling and fermentation, alter these properties and influence health outcomes. Preliminary findings suggest that whole grains and ancient wheat varieties often have lower glycemic responses compared to refined and genetically modified strains. Additionally, processes like stone grinding and fermentation have been shown to improve glycemic profiles and potentially lower diabetes risk. This review highlights significant gaps in current research, particularly in long-term clinical outcomes and comparisons of genetic variations. We discuss the implications for dietary guidelines and propose directions for future research to better understand and utilize wheat's nutritional potential in diabetes prevention.

Long-term Safety and Efficacy of the Derivo Embolization Device in aSingle-center Series.

This study analyzes the long-term clinical and angiographic outcomes of the Derivo Embolization Device (DED), an advanced flow diverter device with an electropolished surface, for the treatment of intracranial aneurysms. Aconsecutive series of 101 patients (mean age: 58years, 72% female) treated with the DED for 122 aneurysms at asingle center between 2017 and 2023 was retrospectively analyzed for major (change in National Institutes of Health Stroke Scale [NIHSS] score ≥ 4points) and minor (change in NIHSS score < 4points) neurological events, procedural morbidity (increase of at least one point on the modified Rankin Scale), and angiographic results. There were 14(11%) recurrent aneurysms, 15(12%) ruptured aneurysms, 26(21%) posterior circulation aneurysms and 16(13%) fusiform or dissecting aneurysms. Device deployment failed in 1case (1%). Procedure-related symptomatic procedural complications consisted of 2(2%) major events (1major stroke and 1vessel perforation with intracranial hemorrhage and infarction) and 6minor events (6minor strokes). Procedural morbidity was 5%. There were no late ischemic or hemorrhagic events during follow-up. Complete and favorable aneurysm occlusion was achieved in 54% (40/74) and 62% (46/74) at amean of 5months, 71% (27/38) and 87% (33/38) at amean of 12months, and 76% (25/33) and 97% (32/33) at amean of 35months, respectively. The results demonstrate progressive aneurysm occlusion beyond 12months after DED implantation with an almost 100% favorable occlusion rate. Procedural morbidity was low and there were no late complications.

Clinical Outcome of Lumbar Hybrid Surgery in a Consecutive Series of Patients with Long-term Follow-up.

This was a retrospective study combined with attempted prospective patient contact to collect current data. The purpose of this study was to investigate long-term clinical outcome of patients undergoing lumbar hybrid surgery (total disc replacement (TDR) at one level and fusion at an adjacent level. Many patients with symptomatic lumbar disc degeneration are affected at more than one level. Lumbar TDR was introduced as a fusion alternative; however, some disc levels are not amenable to TDR and fusion is preferable at such levels. Hybrid surgery was introduced as an option to fusing multiple levels. A consecutive series of 305 patients undergoing lumbar hybrid surgery was identified beginning with the first case experience in 2005. Operative and clinical outcome data including visual analog scales (VAS) assessing back and leg pain, Oswestry Disability Index (ODI), and re-operations were collected. The mean follow-up duration was 67.1 months. There were statistically significant improvements (P<0.01) in the mean values of all three clinical outcome measures: VAS back pain scores improved from 6.7 to 3.3; leg pain improved from 4.3 to 2.0; and ODI scores improved from 45.5 to 24.6. There were no significant differences in pain and function scores for patients with minimum 10-year follow-up vs. those with shorter follow-up duration. Re-operation occurred in 16.1% of patients, many of which involved removal of posterior instrumentation at the fusion level (6.2% of study group, 38.8% of re-operations). Re-operation involving the TDR level occurred in 9 patients (2.9%), only 3 of which (1.0%) involved TDR removal/revision. This study supports that for many patients with multilevel symptomatic disc degeneration, hybrid surgery is a viable surgical option. Significant improvements were demonstrated in pain and function scores with no diminished improvement in scores among patients with more than 10-year follow-up.

Neonatal heart transplantation in the United States: Trends and outcomes.

Heart transplantation in the neonatal period is associated with excellent survival. However, outcomes data are scant and have been obtained primarily from two single-center reports within the United States. We sought to analyze the outcomes of all neonatal heart transplants performed in the United States using the United Network for Organ Sharing (UNOS) dataset. The UNOS dataset was queried for patients who underwent infant heart transplantation from 1987 to 2021. Patients were divided into two groups based on age - neonates (<=31 days), and older infants (32 days-365 days). Demographic and clinical characteristics were analyzed and compared, along with follow up survival data. Overall, 474 newborns have undergone heart transplantation in the United States since 1987. Freedom from death or re-transplantation for neonates was 63.5%, 58.8% and 51.6% at 5, 10, and 20 years, respectively. Patients in the newborn group had lower unadjusted survival compared to older infants (p < .001), but conditional 1-year survival was higher in neonates (p = .03). On multivariable analysis, there was no significant difference in survival between the two age groups (p = .43). Black race, congenital heart disease diagnosis, earlier surgical era, and preoperative mechanical circulatory support use were associated with lower survival among infant transplants (p < .05). Neonatal heart transplantation is associated with favorable long-term clinical outcomes. Neonates do not have a significant survival advantage over older infants. Widespread applicability is limited by the small number of available donors. Efforts to expand the donor pool to include non-standard donor populations ought to be considered.

Correlation between asymmetrical vein sign of SWI and long-term clinical outcomes in patients with middle cerebral artery ischemic stroke.

To evaluate the association of asymmetrical cortical vein sign (ACVS) and asymmetrical medullary vein sign (AMVS) on susceptibility-weighted imaging (SWI) with 90-day poor outcomes in patients with unilateral middle cerebral artery acute ischemic stroke (AIS) after conservative drug treatment. Clinical data for the participants included age, sex, smoking, alcohol, hypertension, diabetes, hyperlipidemia, coronary heart disease, NHISS-admission, and NHISS-discharge scores. Participants underwent magnetic resonance imaging (MRI) within 12h of hospital admission, including conventional scan sequences and a SWI sequence. Poor prognosis was defined as a modified Rankin scale (mRS) ≥ 3 at 90days. A total of 108 patients were included from January 2021 to March 2022. Twenty-seven (25%) patients had a poor outcome at 90days. Univariate analysis indicated that diabetes, NHISS-admission, NHISS-discharge, DWI-ASPECTS, SWI-ASPECTS, FLAIR-ASPECTS, and AMVS + were associated with 90-day poor outcome. Multivariate regression analysis showed that AMVS + was associated with 90-day poor outcome from the three models (OR = 3.57, P = 0.006; OR = 3.74, P = 0.005; OR = 5.14, P = 0.0057). However, no significant association was found between ACVS + and 90-day poor outcome. AMVS might be a helpful neuroimaging predictor for poor outcome at 90days compared to ACVS in drug-conserving treatment of patients with unilateral middle cerebral artery ischemic stroke.

To cast or not to cast? Postoperative care of ankle fractures: a meta-analysis of randomized controlled trials.

Postoperative care of ankle fractures treated with open reduction and internal fixation (ORIF) is a debated topic. A meta-analysis of Randomized Controlled Trials was conducted with the aim of comparing early mobilization and weightbearing to traditional postoperative protocols. A systematic search of electronic databases was conducted according to the PRISMA guidelines. Only randomized clinical trials were included. Data about clinical outcome, time to return to work and complications were extracted and summarized. Meta-analyses were performed. Twenty studies for a total of 1328 patients were included. Early mobilization was compared to immobilization in 724 patients: the two groups did not significantly differ in terms of short- and long-term clinical outcome (p = 0.08 and p = 0.41, respectively). However, early mobilization resulted to be significantly associated with faster return to work (p = 0.047). Early weightbearing was compared to nonweightbearing in 1088 patients. While the clinical difference between the two groups was not significant at short term (p = 0.08), it was significant at long term (p = 0.002). No other significant differences, in particular regarding complications, were highlighted between different groups. Early motion, early weightbearing and traditional postoperative protocols are all safe strategies after ORIF for unstable ankle fractures. Early mobilization is significantly associated with faster return to work and early weightbearing improves long term clinical outcome.Level of evidence: I.

Impact of early surgical complications on kidney transplant outcomes.

Kidney transplantation (KT) improves clinical outcomes of patients with end stage renal disease. Little has been reported on the impact of early post-operative surgical complications (SC) on long-term clinical outcomes following KT. We sought to determine the impact of vascular complications, urological complications, surgical site complications, and peri-graft collections within 30days of transplantation on patient survival, graft function, and hospital readmissions. We conducted a single-centre, observational cohort study examining adult patients (≥ 18years) who received a kidney transplant from living and deceased donors between January 1st, 2005 and December 31st, 2015 with follow-up until December 31st, 2016 (n = 1,334). Univariable and multivariable analyses were performed with Cox proportional hazards models to analyze the outcomes of SC in the early post-operative period after KT. The cumulative probability of SC within 30days of transplant was 25%, the most common SC being peri-graft collections (66.8%). Multivariable analyses showed significant relationships between Clavien Grade 1 SC and death with graft function (HR 1.78 [95% CI: 1.11, 2.86]), and between Clavien Grades 3 to 4 and hospital readmissions (HR 1.95 [95% CI: 1.37, 2.77]). Early SC following KT are common and have a significant influence on long-term patient outcomes.

Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders.

We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children.

Incidence and outcome of periinterventional atrial fibrillation in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention

Abstract Background Peri-interventional atrial fibrillation (AF) may be detected in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). Data on the thromboembolic risk and long-term clinical outcome in patients with AF limited to the peri-interventional period is scarce. Purpose To assess the incidence and impact on long-term clinical outcome of peri-interventional de-novo AF in STEMI patients. Methods and Results This retrospective single-center cohort study included all patients who underwent PCI between January 2016 and November 2020 (n=491) due to STEMI. Patients were stratified to three cohorts of AF status: Pre-existing AF: n=42 [8.6%], newly diagnosed peri-interventional AF: n=56 [11.4%] and no AF: n=393 [80.0%]. Patients with newly diagnosed peri-interventional AF as well as patients with pre-existing AF had in median a mild-moderately reduced left ventricular ejection fraction (LVEF), patients in sinus rhythm in median a normal LVEF. During the average follow-up time of 4.7 years (min. 2 years, max. 7 years) the rate for readmission for AF or occurrence of AF without hospital admission was increased in patients with peri-interventional de-novo AF or pre-existing AF (n=6 [10.7%], n=10 [23.8%]) compared to those in sinus rhythm n=22 [5.6%] (p&amp;lt;0,001) The occurrence of ischemic stroke was higher in patients with peri-interventional de-novo AF (n=2 [3.6%] or with pre-existing AF (n=2 [4.8%]) compared to those in sinus rhythm (n=6 [1.5%]. (p=0.256) The risk of cardiovascular death was significantly higher in patients with newly diagnosed peri- interventional AF compared to patients with pre-existing or no AF (n=13 [23.2%], n=5 [11.9%], n= 37 [9.4%]) (p=0.009). In the patient group with peri-interventional de-novo AF, only 25.0% (n=13) received long-term oral anticoagulation therapy (OAK). The rate of stroke in patients who received OAK after peri- interventional de-novo AF was 7.7% (n=1) compared to those without OAK 2.6% (n=1). Conclusion Peri-interventional AF is a frequent finding in STEMI patients undergoing primary PCI. Patients with peri-interventional AF had a significantly increased risk for an adverse cardiovascular outcome. Optimal secondary prophylactic measures appear mandatory in this patient population. The significance of long-term OAK therapy is to be determined.

Residual Coronary Risk Factors Associated With Long-Term Clinical Outcomes in Patients With Coronary Artery Disease Treated With High- vs. Low-Dose Statin Therapy - REAL-CAD Substudy.

It remains unclear which comorbidities, other than lipid parameters, or combination of comorbidities, best predicts cardiovascular events in patients with known coronary artery disease (CAD) treated with statins. Therefore, we aimed to identify the nonlipid-related prognostic factors and risk stratification of patients with stable CAD enrolled in the REAL-CAD study. Blood pressure, glucose level, and renal function were considered as risk factors in the 11,141 enrolled patients. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unstable angina. The secondary composite endpoint was the primary endpoint and/or coronary revascularization. A significantly worse prognosis at the primary endpoint was observed in the estimated glomerular filtration rate (eGFR) ≤60 group, and the combination of eGFR ≤60 and HbA1c ≥6.0 was the worst (hazard ratio (HR) 1.66; P<0.001). However, even in the eGFR >60 group, systolic blood pressure (SBP) ≥140 mmHg met the secondary endpoint (HR 1.33; P=0.006), and the combination of eGFR ≤60 and HbA1c ≥6.0 was also the worst at the secondary endpoint (HR 1.35; P=0.002). Regarding nonlipid prognostic factors contributing to the incidence of cardiovascular events in statin-treated CAD patients, renal dysfunction was the most significant, followed by poor glucose control and high SBP.

The phenomenon of drug-coating embolism during lower extremity endovascular interventions with paclitaxel-coated balloon.

There is a risk of distal embolization lower extremity endovascular interventions. Possibly a drug-coating embolism caused by coating detachment from intravascular devices. This review focuses on providing updated information on distal embolism in endovascular revascularization of lower extremity arteries, including the use of drug-coated balloons. Drug-coating embolism is a special case of distal embolization during recanalization of the arteries of the lower extremities. Preclinical studies have demonstrated embolization of drug-coated balloons during angioplasty of lower extremity arteries. However, the clinical role of drug-coating embolism is not completely clear. A 2020 meta-analysis found an increased risk of major lower extremity amputation after drug-coated balloon angioplasty in patients with critical limb ischemia. But long-term research is emerging to support the safety of using these devices. Perhaps a more thorough assessment of the quality of life and the degree of compensation of lower limb ischemia with an intraoperative assessment of the frequency of peripheral embolizations using ultrasound emboli detection, as well as microcirculation with transcutaneous oximetry and laser Doppler flowmetry of the operated lower limb will allow a more detailed study of the phenomenon of drug-coating embolism and its impact on long-term clinical outcomes. According to the results of preclinical studies, the use of paclitaxel-coated balloons leads to an increase in the concentration of paclitaxel in distal skeletal muscles. However, paclitaxel concentration in skeletal muscle was significantly higher in first-generation DCBs. The non-target effects of drug-coating balloon are not fully understood and require further study. Understanding the phenomenon of drug-coating embolism can help physicians to better assess the patient risk and to minimize complications.