A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors.

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).

Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia.

Acute leukemia (AL) with a lineage switch (LS) is associated with poor prognosis. The predisposing factors of LS are unknown, apart from KMT2A rearrangements that have been reported to be associated with LS. Herein, we present two cases and review all 104 published cases to identify risk factors for LS. Most of the patients (75.5%) experienced a switch from the lymphoid phenotype to the myeloid phenotype. Eighteen patients (17.0%) experienced a transformation from acute myelogenous leukemia (AML) to acute lymphoblastic leukemia (ALL). Forty-nine (46.2%) patients carried a KMT2A rearrangement. Most of the cases involved LS from B-cell ALL (B-ALL) to AML (59.4%), and 49 patients (46.2%) carried KMT2A-rearrangements. Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

Loss of spontaneous vasomotion precedes impaired cerebrovascular reactivity and microbleeds in a mouse model of cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-ß accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral hemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-ß clearance, may be impaired in CAA. Methods: To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using in vivo 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype littermates from 7 to 14 months of age, tracking amyloid-ß accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18-, and 24-month-old APP23 transgenic mice and wildtype littermates to detect microbleeds and to assess cerebral blood flow and cerebrovascular reactivity with pseudo-continuous arterial spin labeling. Results: We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in wildtype mice with age. This decline corresponded in timing to initial vascular amyloid-ß deposition (∼8-10 months of age), although was more strongly correlated with age than with vascular amyloid-ß burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in APP23 mice by 18 months of age. Additionally, evoked cerebrovascular reactivity was intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. Conclusions: Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target.

Cognitive brain activity before and after surgery in meningioma patients.

Neuropsychological studies have demonstrated that meningioma patients frequently exhibit cognitive deficits before surgery and show only limited improvement after surgery. Combining neuropsychological with functional imaging measurements can shed more light on the impact of surgery on cognitive brain function. We aimed to evaluate whether surgery affects cognitive brain activity in such a manner that it may mask possible changes in cognitive functioning measured by neuropsychological tests. Twenty-three meningioma patients participated in a fMRI measurement using a verbal working memory task as well as three neuropsychological tests focused on working memory, just before and 3 months after surgery. A region of interest based fMRI analysis was used to examine cognitive brain activity at these timepoints within the central executive network and default mode network. Neuropsychological assessment showed impaired cognitive functioning before as well as 3 months after surgery. Neuropsychological test scores, in-scanner task performance as well as brain activity within the central executive and default mode network were not significantly different between both timepoints. Our results indicate that surgery does not significantly affect cognitive brain activity in meningioma patients the first few months after surgery. Therefore, the lack of cognitive improvement after surgery is not likely the result of compensatory processes in the brain. Cognitive deficits that are already present before surgery appear to be persistent after surgery and a considerable recovery period. Our study shows potential leads that comprehensive cognitive evaluation can be of added value so that cognitive functioning may become a more prominent factor in clinical decision making.

Preoperative executive functioning impairments in patients with a meningioma: does a frontal location matter?

Patients with meningiomas frequently exhibit impairments in executive functioning. There are few studies specifically examining the role of frontal meningioma localization in executive functioning impairments. This study examines whether frontally located meningiomas are specifically associated with executive functioning impairments in a large sample of meningioma patients before treatment, using an axis-wise and lobe-based approach to meningioma localization. We retrospectively examined cognitive performances in 353 patients with frontal, frontally-involved and non-frontal meningiomas on a battery of tests including tests of executive functioning. We applied an axis-based approach to meningioma location, in addition to qualitative lobe-based localization. We examined the association between meningioma coordinates on an anterior-posterior axis and continuous cognitive performance scores in univariate correlations and linear regression analyses. We also examined the association between meningioma coordinates on an anterior-posterior axis with cognitive impairments in multivariable logistic regression analyses. Meningioma position on the anterior-posterior axis was only univariately associated with mean performance on the Stroop test Interference ratio and Symbol Digit Coding task. There was no (multivariable) association with impairments on tests of executive or non-executive domains. Increased odds of impairment on executive functioning tasks were associated with left-localization (Verbal Fluency) and larger meningioma volumes (Shifting Attention). We did not find a specific relation between a frontal meningioma location and executive functioning impairments, which may be explained by widespread organization of executive functioning throughout the brain, diffuse cognitive effects of the mass of meningiomas, functional reorganization due to neuroplasticity, or functional involvement of less-anteriorly located frontal areas.

Comparison of the characteristics of the population eligible for lung cancer screening under 2013 and population newly eligible under 2021 US Preventive Services Task Force recommendations.

PURPOSE: In 2021, the United States Preventive Services Task Force (USPSTF) revised their 2013 recommendations for lung cancer screening eligibility by lowering the pack-year history from 30+ to 20+ pack-years and the recommended age from 55 to 50 years. Simulation studies suggest that Black persons and females will benefit most from these changes, but it is unclear how the revised USPSTF recommendations will impact geographic, health-related, and other sociodemographic characteristics of those eligible. METHODS: This cross-sectional study employed data from the 2017-2020 Behavioral Risk Factor Surveillance System surveys from 23 states to compare age, gender, race, marital, sexual orientation, education, employment, comorbidity, vaccination, region, and rurality characteristics of the eligible population according to the original 2013 USPSTF recommendations with the revised 2021 USPSTF recommendations using chi-squared tests. This study compared those originally eligible to those newly eligible using the BRFSS raking-dervived weighting variable. RESULTS: There were 30,190 study participants. The results of this study found that eligibility increased by 62.4% due to the revised recommendations. We found that the recommendation changes increased the proportion of eligible females (50.1% vs 44.1%), Black persons (9.2% vs 6.6%), Hispanic persons (4.4% vs 2.7%), persons aged 55-64 (55.8% vs 52.6%), urban-dwellers(88.3% vs 85.9%), unmarried (3.4% vs 2.5%) and never married (10.4% vs 6.6%) persons, as well as non-retirees (76.5% vs 56.1%) Respondents without comorbidities and COPD also increased. CONCLUSION: It is estimated that the revision of the lung cancer screening recommendations decreased eligibility disparities in sex, race, ethnicity, marital status, respiratory comorbidities, and vaccination status. Research will be necessary to estimate whether uptake patterns subsequently follow the expanded eligibility patterns.

Geometric Analysis of the Gore Excluder Conformable Endoprosthesis in the Infrarenal Aortic Neck: One Year Results of the EXCeL Registry.

OBJECTIVE: The Gore Excluder Conformable Endoprosthesis (CEXC) is designed to treat challenging infrarenal anatomy because of its active angulation control, repositionability, and enhanced conformability. This study evaluated 30 day and one year position and apposition of the CEXC in the infrarenal neck. METHODS: Patients treated with the CEXC between 2018 and 2022 with an available 30 day computed tomography angiography (CTA) were selected from four hospitals in a prospective registry. Endograft apposition (shortest apposition length [SAL]) and position (shortest fabric distance [SFD]) were assessed on the 30 day and one year CTAs. Maximum infrarenal aortic curvature was compared between the pre-operative and post-operative CTAs to evaluate conformability of the CEXC. RESULTS: There were 87 patients with a 30 day CTA, and for 56 of these patients the one year CTA was available. Median (interquartile range [IQR]) pre-operative neck length was 22 mm (IQR 15, 32) and infrarenal angulation was 52° (IQR 31, 72). Median SAL was 21.2 mm (IQR 14.0, 29.3) at 30 days for all included patients. The SAL in 13 patients (15%) was < 10 mm at 30 days, and one patient had a SAL of 0 mm and a type Ia endoleak. There was no significant difference in SAL between patients within and outside instructions for use. The SAL significantly increased by 1.1 mm (IQR -2.3, 4.7; p = .042) at 1 year. The SAL decreased in seven patients (13%), increased in 13 patients (23%), and remained stable in 36 patients (64%). Median SFD was 2.0 mm (IQR 0.5, 3.6) at 30 days, which slightly increased by 0.3 mm (IQR -0.5, 1.8; p = .019) at 1 year. One patient showed migration (SFD increase ≥ 5 mm). Median endograft tilt was 15.8° (IQR 9.7, 21.4). Pre-operative maximum infrarenal curvature was 36 m-1 (IQR 26, 56) and did not significantly change thereafter. CONCLUSION: In most patients, the CEXC was implanted close to the renal arteries, and sufficient (≥ 10 mm) post-operative apposition was acquired at 30 days, which slightly increased at one year. Post-operative endograft tilt was relatively low, and aortic geometry remained unchanged after implantation of the CEXC, probably due to its high conformability.

Somatic polyploidy supports biosynthesis and tissue function by increasing transcriptional output.

Cell size and biosynthetic capacity generally increase with increased DNA content. Polyploidy has therefore been proposed to be an adaptive strategy to increase cell size in specialized tissues with high biosynthetic demands. However, if and how DNA concentration limits cellular biosynthesis in vivo is not well understood, and the impacts of polyploidy in non-disease states is not well studied. Here, we show that polyploidy in the C. elegans intestine is critical for cell growth and yolk biosynthesis, a central role of this organ. Artificially lowering the DNA/cytoplasm ratio by reducing polyploidization in the intestine gave rise to smaller cells with more dilute mRNA. Highly-expressed transcripts were more sensitive to this mRNA dilution, whereas lowly-expressed genes were partially compensated - in part by loading more RNA Polymerase II on the remaining genomes. DNA-dilute cells had normal total protein concentration, which we propose is achieved by increasing production of translational machinery at the expense of specialized, cell-type specific proteins.

Using histopathology latent diffusion models as privacy-preserving dataset augmenters improves downstream classification performance.

Latent diffusion models (LDMs) have emerged as a state-of-the-art image generation method, outperforming previous Generative Adversarial Networks (GANs) in terms of training stability and image quality. In computational pathology, generative models are valuable for data sharing and data augmentation. However, the impact of LDM-generated images on histopathology tasks compared to traditional GANs has not been systematically studied. We trained three LDMs and a styleGAN2 model on histology tiles from nine colorectal cancer (CRC) tissue classes. The LDMs include 1) a fine-tuned version of stable diffusion v1.4, 2) a Kullback-Leibler (KL)-autoencoder (KLF8-DM), and 3) a vector quantized (VQ)-autoencoder deploying LDM (VQF8-DM). We assessed image quality through expert ratings, dimensional reduction methods, distribution similarity measures, and their impact on training a multiclass tissue classifier. Additionally, we investigated image memorization in the KLF8-DM and styleGAN2 models. All models provided a high image quality, with the KLF8-DM achieving the best Frechet Inception Distance (FID) and expert rating scores for complex tissue classes. For simpler classes, the VQF8-DM and styleGAN2 models performed better. Image memorization was negligible for both styleGAN2 and KLF8-DM models. Classifiers trained on a mix of KLF8-DM generated and real images achieved a 4% improvement in overall classification accuracy, highlighting the usefulness of these images for dataset augmentation. Our systematic study of generative methods showed that KLF8-DM produces the highest quality images with negligible image memorization. The higher classifier performance in the generatively augmented dataset suggests that this augmentation technique can be employed to enhance histopathology classifiers for various tasks.

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

Mind the gap! Interdisciplinary approach to anterior chest wall reconstruction after total sternectomy.

BACKGROUND: There are various reconstructive methods after total sternectomy. Reproducibility is scarce due to overall small patient numbers. Therefore we present a standardized, interdisciplinary approach for thoracic and plastic surgery. METHODS: Four patients underwent interdisciplinary chest wall reconstruction with STRATOS® titanium bars and myocutaneous vastus lateralis muscle free flap in our center. RESULTS: All patients reported chest wall stability after reconstruction. They reported good quality of life, no dyspnea, prolonged pain or impairment in lung function from rigid reconstruction. FEV1/FVC was overall better after surgery. Secondary wound healing was not impaired and there was no implant defect in follow up. CONCLUSIONS: We recommend an interdisciplinary surgical approach in chest wall reconstruction after total sternectomy. The combination of rigid reconstruction with titanium bars and a myocutaneous vastus lateralis muscle free flap renders excellent results in patient satisfaction and is objectifiable via spirometry.

Primary MALT lymphoma of the breast: pathological and radiological characteristics.

PURPOSE: Primary Mucosa-associated lymphoid tissue (MALT) lymphoma is a rare diagnosis in the breast, and clinical diagnosis based on radiological features is often challenging. This study aimed to evaluate the clinicopathological, and radiological characteristics of the patients diagnosed with primary breast MALT lymphoma. METHODS: This study examined 18 cases of primary MALT lymphoma of the breast diagnosed at a single tertiary center between January 2002 to December 2020. Medical charts, radiological imaging and original pathology slides were reviewed for each case. RESULTS: All cases were female (gender assigned at birth) and presented with a palpable mass or an incidental imaging finding. Imaging presentation ranged from mammographic asymmetries, circumscribed masses, and ultrasound masses lacking suspicious features. Seventeen cases were biopsied under ultrasound; one received a diagnostic excision biopsy. Microscopic examination of the breast specimens demonstrated atypical small lymphocyte infiltration with plasmacytoid differentiation and rare lymphoepithelial lesions. Immunohistochemistry was performed in all cases and established the diagnosis. Most patients were treated with radiotherapy, and only three were treated with chemotherapy. The median follow-up period was 4 years and 7.5 months, and all patients were alive at the last follow-up. CONCLUSION: Primary MALT breast lymphomas are usually indolent and non-systemic, and local radiotherapy may effectively alleviate local symptoms. Radiological findings show overlap with benign morphological features, which can delay the diagnosis of this unusual etiology. Although further studies involving a larger cohort could help establish the clinical and radiological characteristics of primary breast MALT lymphomas, pathology remains the primary method of diagnosis. TRIAL REGISTRATION NUMBER: University Health Network Ethics Committee (CAPCR/UHN REB number 19-5844), retrospectively registered.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Staged Ventricular Septation of the Double-Inlet Ventricle: How-I-Do-It.

Ventricular septation of the double-inlet ventricle is a largely abandoned operation due to poor historical outcomes. However, there has been renewed interest in septation as an alternative to Fontan palliation given its long-term sequelae. As one of the few centers to revisit septation in the early 1990s, our institution has long-term data on a series of patients with a double-inlet ventricle who underwent biventricular repair. This manuscript is a summary of our approach to staged septation of the double-inlet ventricle, with a focus on patient selection criteria, surgical techniques, perioperative considerations on timing of interventions, and long-term results. We believe that septation of the double-inlet ventricle should be reconsidered in patients with suitable anatomy in light of the known complications of Fontan palliation.

Effective treatment of Clostridioides difficile infection improves survival and affects graft-versus-host disease: a multicenter study by the Polish Adult Leukemia Group.

Clostridioides difficile infection (CDI) is the most common cause of infectious diarrhea after allogeneic hematopoietic cell transplantation (allo-HCT). The impact of CDI and its treatment on allo-HCT outcomes and graft-versus-host disease (GVHD), including gastrointestinal GVHD (GI-GVHD) is not well established. This multicenter study assessed real-life data on the first-line treatment of CDI and its impact on allo-HCT outcomes. Retrospective and prospective data of patients with CDI after allo-HCT were assessed. We noted statistically significant increase in the incidence of acute GVHD and acute GI-GVHD after CDI (P = 0.005 and P = 0.016, respectively). The first-line treatment for CDI included metronidazole in 34 patients, vancomycin in 64, and combination therapy in 10. Treatment failure was more common with metronidazole than vancomycin (38.2% vs. 6.2%; P < 0.001). The need to administer second-line treatment was associated with the occurrence or exacerbation of GVHD (P < 0.05) and GI-GVHD (P < 0.001) and reduced overall survival (P < 0.05). In the multivariate analysis, the risk of death was associated with acute GVHD presence before CDI (hazard ratio [HR], 3.19; P = 0.009) and the need to switch to second-line treatment (HR, 4.83; P < 0.001). The efficacy of the initial CDI treatment affects survival and occurrence of immune-mediated GI-GVHD after allo-HCT. Therefore, agents with higher efficacy than metronidazole (vancomycin or fidaxomicin) should be administered as the first-line treatment.

Long Term Outcomes of the Gore Excluder Low Permeability Endoprosthesis for the Treatment of Infrarenal Aortic Aneurysms.

OBJECTIVE: This study evaluated the long term outcomes of endovascular aneurysm repair using the Gore Excluder Low Permeability (LP) endoprosthesis across high volume Dutch hospitals. METHODS: A retrospective analysis was conducted of patients treated with the Excluder LP for infrarenal abdominal aortic aneurysm (AAA) in four hospitals between 2004 and 2017. Primary outcomes were overall survival, freedom from re-interventions (overall, inside and outside instructions for use, IFU), and AAA sac dynamics: growth (> 5 mm), stabilisation, and regression (< 5 mm). Secondary outcomes were technical success (device deployment), procedural parameters, and re-interventions. Follow up visits were extracted from patient files, with imaging assessed for complications and AAA diameter. RESULTS: Five hundred and fourteen patients were enrolled, with a median (IQR) follow up of 5.0 (2.9, 6.9) years. Survival rates were 94.0% at one year, 73.0% at five years, and 37.0% at 10 years, with freedom from re-interventions of 89.0%, 79.0%, and 71.0%, respectively. 37.9% were treated outside IFU, leading to significantly more re-interventions over 10 years compared with those treated inside IFU (36.0% vs. 25.0%, respectively; p = .044). The aneurysm sac regressed by 53.5% at one year, 65.8% at five years, and 77.8% at 10 years, and grew by 9.8%, 14.3%, and 22.2%, respectively. Patients with one year sac growth had significantly worse survival (p = .047). Seven patients (1.4%) had a ruptured aneurysm during follow up. Over 15 years, type 1a endoleak occurred in 5.3%, type 1b in 3.1%, type 3 in 1.9%, type 4 in 0.2%, and type 2 in 35.6% of patients. CONCLUSION: This multicentre study of real world endovascular aneurysm repair data using the Gore Excluder LP endoprosthesis demonstrated robust long term survival and re-intervention rates, despite 37.9% of patients being treated outside IFU, with type 4 endoleak being rare. Treatment outside IFU significantly increased re-intervention rates and one year sac growth was associated with statistically significantly worse survival.

External Quality Assessment on Molecular Tumor Profiling with Circulating Tumor DNA-Based Methodologies Routinely Used in Clinical Pathology within the COIN Consortium.

BACKGROUND: Identification of tumor-derived variants in circulating tumor DNA (ctDNA) has potential as a sensitive and reliable surrogate for tumor tissue-based routine diagnostic testing. However, variations in pre(analytical) procedures affect the efficiency of ctDNA recovery. Here, an external quality assessment (EQA) was performed to determine the performance of ctDNA mutation detection work flows that are used in current diagnostic settings across laboratories within the Dutch COIN consortium (ctDNA on the road to implementation in The Netherlands). METHODS: Aliquots of 3 high-volume diagnostic leukapheresis (DLA) plasma samples and 3 artificial reference plasma samples with predetermined mutations were distributed among 16 Dutch laboratories. Participating laboratories were requested to perform ctDNA analysis for BRAF exon 15, EGFR exon 18-21, and KRAS exon 2-3 using their regular circulating cell-free DNA (ccfDNA) analysis work flow. Laboratories were assessed based on adherence to the study protocol, overall detection rate, and overall genotyping performance. RESULTS: A broad range of preanalytical conditions (e.g., plasma volume, elution volume, and extraction methods) and analytical methodologies (e.g., droplet digital PCR [ddPCR], small-panel PCR assays, and next-generation sequencing [NGS]) were used. Six laboratories (38%) had a performance score of >0.90; all other laboratories scored between 0.26 and 0.80. Although 13 laboratories (81%) reached a 100% overall detection rate, the therapeutically relevant EGFR p.(S752_I759del) (69%), EGFR p.(N771_H773dup) (50%), and KRAS p.(G12C) (48%) mutations were frequently not genotyped accurately. CONCLUSIONS: Divergent (pre)analytical protocols could lead to discrepant clinical outcomes when using the same plasma samples. Standardization of (pre)analytical work flows can facilitate the implementation of reproducible liquid biopsy testing in the clinical routine.

Five-year outcomes for bell bottom, iliac branch endoprosthesis, and coil and cover approaches from the GREAT registry.

OBJECTIVE: There are a variety of methods used today to treat common iliac aneurysms with endovascular techniques. Of these approaches, little is known about whether a particular limb strategy influences endoleak, reintervention, or aneurysm regression rates. We present 5-year data comparing endoleak, stent graft migration, fracture, aneurysm sac dynamics, and aortic rupture rates among patients treated with bell bottom limbs (BB), iliac branch endoprosthesis (IBE), and coil and cover (CC) approaches from the Global Registry for Endovascular Aortic Treatment registry. Secondary end points were all-cause mortality, stroke, reintervention, and paraplegia. METHODS: Subjects from the GORE Global Registry for Endovascular Aortic Treatment were enrolled over a 5-year period from October 2017 to August 2022. We included 924 subjects in this study. Statistical data was generated on R software and limb groups were compared using the Pearson's χ2 test and the Kruskal-Wallis rank-sum test. RESULTS: We found no statistical difference in endoleak rates, stent graft migration, fracture, or aortic rupture when stratified by limb strategy. There was no difference between limb approaches with regard to aneurysm sac dynamics among those with abdominal aortic aneurysms and common iliac aneurysms. Similarly, no statistical difference between limb strategies was found in all-cause mortality, stroke, paraplegia, or reintervention rates. Among patients that required an additional graft during reintervention, the highest rates were found within the IBE group 8.6%, compared with BB group 2.2% and CC group 1.3% (P = .006). CONCLUSIONS: Overall, there was no difference among limb strategies in endoleak rates, stent graft migration, aneurysm sac dynamics, aortic rupture rates, or our secondary end points. Increased rates of reintervention requiring an additional graft within the IBE group is noteworthy and must be weighed against the adverse effects of hypogastric sacrifice with the CC approach or potentially less advantageous seal zones in the BB approach. This finding suggests that all limb approaches have equivalent effectiveness in managing the aneurysmal common iliac artery; thus, the choice of limb strategy should be individualized and remain at physician discretion. Future research should include a more robust sample size to reproduce these findings.