Reference Cohort Research Articles

Preoperative Anemia as a Risk Factor for Postoperative Complications After Open Reduction Internal Fixation of Distal Radius Fractures

The incidence of distal radius fractures (DRFs) in the United States is more than 640,000 cases per year and is projected to increase. The overall prevalence of anemia in the United States increased from 5.71% in 2005 to 6.86% in 2018. Therefore, preoperative anemia may be an important risk factor to consider before surgical fixation of a distal radius fracture. The purpose of this study was to investigate preoperative anemia and its association with short-term complications after surgical treatment of DRFs. The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent open reduction internal fixation (ORIF) of DRFs between 2015 and 2020. The initial pool of patients was divided into cohorts based on preoperative hematocrit. Multivariate logistic regression, adjusted for all significantly associated patient demographics and comorbidities, was used to identify associations between preoperative anemia and postoperative complications after ORIF of DRFs. A total of 22,923 patients who underwent ORIF of DRFs were identified in National Surgical Quality Improvement Program from 2015 to 2020. Of the 12,068 patients remaining after exclusion criteria, 9,616 (79.7%) patients were included in the normal cohort, 2,238 (18.5%) patients were included in the mild anemia cohort, and 214 (1.8%) patients were included in the severe anemia cohort. Compared with the reference cohort, patients with any anemia were independently associated with higher rates of reintubation (odds ratio [OR], 6.51; 95% confidence interval [CI], 1.29-32.80; P= .023), blood transfusion (OR, 11.83; 95% CI, 3.95-35.45; P < .001), septic shock (OR, 10.76; 95% CI, 1.19-97.02; P= .034), readmission (OR, 2.10; 95% CI, 1.60-2.76; P < .001), nonhome discharge (OR, 2.22; 95% CI, 1.84-2.68; P < .001), and mortality (OR, 2.70; 1.03-7.07; P= .043). Preoperative anemia, both mild and severe, were clinically significant predictors for postoperative complications within 30-day after ORIF of DRFs. Severe anemia was associated with higher rates of blood transfusion, nonhome discharge, and mortality compared with mild anemia. Prognostic III.

Immune checkpoint status and oncogenic mutation profiling of rectal cancer after neoadjuvant chemotherapy (KSCC1301-A2).

Immune checkpoint inhibitors (ICIs) are less effective in mismatch repair (MMR)-proficient (pMMR) colorectal cancers (CRCs) than in MMR-deficient CRCs. Here, we investigated changes in the tumor microenvironment after neoadjuvant chemotherapy (NAC) without radiotherapy in locally advanced rectal cancer (LARC) and the potential of ICIs as therapeutic agents for pMMR CRCs. This was an ad hoc analysis of a KSCC1301 randomized phase II trial in which patients with untreated resectable LARC were randomly assigned to receive S-1 and oxaliplatin or folinic acid, 5-fluorouracil, and oxaliplatin as NAC. Forty-nine patients were studied in this ad hoc analysis. As a reference cohort, we assessed 25 rectal cancer patients who underwent surgery without NAC outside the randomized trial. Immune checkpoint molecules (ICMs; PD-1, PD-L1, CTLA-4, LAG3), tumor-infiltrating lymphocytes (TILs; CD8, FOXP3), and other related proteins were evaluated by immunohistochemistry. Next-generation sequencing (NGS) using Oncomine™ Comprehensive Assay version 3 was conducted in 23 patients. The expression levels of PD-1, CTLA-4, and LAG3 in the NAC group were significantly higher than in reference patients (p < 0.001). Additionally, the infiltration of CD8+ and FOXP3+ T cells, and the CD8/FOXP3 ratio were significantly higher in the NAC group than in reference patients (p < 0.0001). NGS analysis revealed no specific gene alteration related to TILs or ICMs. We demonstrated changes in the tumor immune microenvironment after NAC in pMMR rectal cancer. NAC was associated with increased expression of ICMs and TILs. Rectal cancer could be susceptible to combined immunotherapy with chemotherapy.

Survival and Economic Impact of Rapid Prostate-Specific Antigen Doubling Time in Patients With Nonmetastatic Castration-Resistant Prostate Cancer.

In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), prostate-specific antigen doubling time (PSADT) is associated with risk of metastasis and survival. This study evaluated the association of PSADT with clinical and economic outcomes in a real-world setting among patients with nmCRPC not receiving novel hormonal therapy (NHT), using 2-month PSADT thresholds. We retrospectively identified Veterans Health Administration patients with nonmetastatic prostate cancer and ≥2 PSA increases after medical/surgical castration (2012-2016). The third measurement was the index (CRPC) date. Patients with ≥3 postindex PSA measurements, including index, were followed until death or ≥12 months until disenrollment, study end, or death, and grouped into 2-month cohorts based on postindex PSADT. Cox regression models assessed association between PSADT, time to metastasis, and death. Healthcare resource utilization and costs were evaluated. Among 2800 evaluable patients, median follow-up was 30 months and median PSADT was 17 months. Relative to the reference cohort (PSADT >12 months), all cohorts had significantly higher metastasis risk. PSADT ≤10-month cohorts had significantly greater mortality risk than the reference; hazard ratios (95% confidence intervals) ranged from 12.3 (9.2, 16.4) in the PSADT ≤2-month cohort to 1.3 (0.9, 2.0) in the >10 to ≤12-month cohort. Total costs were significantly higher for cohorts up to and including the PSADT >8 to ≤10-month cohort, than for the reference cohort. Mean per patient per month all-cause medical plus pharmacy costs were $6623, $4768, and $4049 in the PSADT ≤2-month, >2 to ≤4-month cohort, and >4 to ≤6-month cohorts, respectively, versus $1911 in the PSADT >12-month cohort (P <0.05). Most patients with nmCRPC have PSADT >12 months and a long natural history. For those with shorter PSADT, the risk of metastasis, death, and costs increased. These data can help select patients for NHT and conversely those who can safely delay NHT for nmCRPC.

Elucidating genetic diversity and population structure of Alpine x Beetal goats using pedigree analysis

Pedigree analysis is essential for effective management of the breeding program and to keep the inbreeding under acceptable limits. Alpine x Beetal is a crossbred population of goats, bred at National Dairy Research Institute (NDRI) Karnal for last five decades. This germplasm is adapted to the tropical climate and has high milk potential as well as prolificacy. Objective of this study was to elucidate the genetic diversity and population structure in the flock of the Alpine x Beetal goats. The data were collected from the Animal Genetics and Breeding Division of ICAR-NDRI, Karnal for 5656 animals from the year 1971–2021. Animals born between 2014 and 2017 were 283, considered as reference cohort. Results revealed that the average generation interval was 3.40 years for the complete pedigree. The average inbreeding coefficient and the average relatedness for the whole population were 4.77% and 7.84%, respectively, and 9.65% and 11.98% respectively, for the reference population. High inbreeding coefficient and average relatedness in the reference cohort demonstrated the impact of closed gene pool and demands immediate intervention for management of genetic diversity in the closed nucleus under study. Ancestors contributing 50% of the gene pool were 8 for the complete pedigree which illustrates that few ancestors were responsible for genetic diversity in the flock. This resulted in the decline of effective population size (51.39). Effective number of founders (fe), ancestors (fa), and founder genomes equivalents (fg) were 24, 12, and 4.17, respectively. The (fe/fa) ratio in the reference population was 2 indicating the occurrence of the bottleneck effect in the flock. To lessen inbreeding and augment genetic diversity in the flock, the use of sires with lower average relatedness and the use of appropriate mating strategies are recommended.

Secular trends of low birth weight, preterm birth, and small for gestational age in Shanghai from 2004 to 2020: an age-period-cohort analysis

BackgroundAlthough highly heterogeneous among countries, the incidence rates of low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) have been increasing globally over the past two decades. To better understand the cause of these secular trends, this study aimed to investigate the effects of age, period, and birth cohort on LBW, PTB, and SGA rates in Shanghai.MethodsData from 2,958,695 singleton live births at 24–41 gestational weeks between 2004 and 2020 were obtained for this study. Age-period-cohort models based on Poisson regression were used to evaluate the independent effects of maternal age, delivery period, and maternal birth cohort on the trends in LBW, PTB, and SGA.ResultsThe overall prevalence rates of LBW, PTB, and SGA were 2.9%, 4.7%, and 9.3%, respectively, and significant changes were observed (average annual change: + 10.7‰, + 9.1‰, -11.9‰) from 2004 to 2020. Cohort effect increased steadily, from 1960 (risk ratio [RR] = 0.71, 95% confidence interval [CI]: 0.65–0.78) to 1993 (RR = 0.97, 95% CI: 0.94–1.01) for LBW and from 1960 (RR = 0.69, 95% CI: 0.64–0.75) to 2004 (RR = 1.02, 95% CI: 0.94–1.12) for PTB. A strong cohort effect was found with the highest risk of SGA (RR = 1.82, 95% CI: 1.72–1.93) in 1960 and the lowest risk (RR = 0.57, 95% CI: 0.54–0.61) in 2004, compared with the reference cohort of 1985. There was a “U-shaped” maternal age effect on LBW and PTB and a weak period effect on the three birth outcomes.ConclusionsOur findings suggested a significant independent effect of age, period, and birth cohort on the three birth outcomes. The increasing rates of LBW and PTB motivated us to focus on young and advanced pregnant women. Meanwhile, the prevalence of SGA decreased steadily, illustrating the need for further research on the mechanisms underlying these trends.

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer

Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. ClinicalTrials.gov Identifier: NCT04863924.

High-throughput microfluidic blood testing to phenotype genetically linked platelet disorders: an aid to diagnosis

AbstractLinking the genetic background of patients with bleeding diathesis and altered platelet function remains challenging. We aimed to assess how a multiparameter microspot-based measurement of thrombus formation under flow can help identify patients with a platelet bleeding disorder. For this purpose, we studied 16 patients presenting with bleeding and/or albinism and suspected platelet dysfunction and 15 relatives. Genotyping of patients revealed a novel biallelic pathogenic variant in RASGRP2 (splice site c.240-1G>A), abrogating CalDAG-GEFI expression, compound heterozygosity (c.537del, c.571A>T) in P2RY12, affecting P2Y12 signaling, and heterozygous variants of unknown significance in the P2RY12 and HPS3 genes. Other patients were confirmed to have Hermansky-Pudlak syndrome type 1 or 3. In 5 patients, no genetic variant was found. Platelet functions were assessed via routine laboratory measurements. Blood samples from all subjects and day controls were screened for blood cell counts and microfluidic outcomes on 6 surfaces (48 parameters) in comparison with those of a reference cohort of healthy subjects. Differential analysis of the microfluidic data showed that the key parameters of thrombus formation were compromised in the 16 index patients. Principal component analysis revealed separate clusters of patients vs heterozygous family members and control subjects. Clusters were further segregated based on inclusion of hematologic values and laboratory measurements. Subject ranking indicated an overall impairment in thrombus formation in patients carrying a (likely) pathogenic variant of the genes but not in asymptomatic relatives. Taken together, our results indicate the advantages of testing for multiparametric thrombus formation in this patient population.

First live birth before surgical verification of endometriosis-a nationwide register study of 18324 women.

First live birth before surgical verification of endometriosis-a nationwide register study of 18324 women.

Predictors of specialist somatic healthcare utilization among older people with intellectual disability and their age-peers in the general population: a national register study

ObjectivesTo compare somatic healthcare usage among older people with intellectual disabilities (ID) to that of their age-peers in the general population, taking into account health and demographic factors, and to...

DNA methylation-based classifier differentiates intrahepatic pancreato-biliary tumours.

Differentiating intrahepatic cholangiocarcinomas (iCCA) from hepatic metastases of pancreatic ductal adenocarcinoma (PAAD) is challenging. Both tumours have similar morphological and immunohistochemical pattern and share multiple driver mutations. We hypothesised that DNA methylation-based machine-learning algorithms may help perform this task. We assembled genome-wide DNA methylation data for iCCA (n=259), PAAD (n=431), and normal bile duct (n=70) from publicly available sources. We split this cohort into a reference (n=399) and a validation set (n=361). Using the reference cohort, we trained three machine learning models to differentiate between these entities. Furthermore, we validated the classifiers on the technical validation set and used an internal cohort (n=72) to test our classifier. On the validation cohort, the neural network, support vector machine, and the random forest classifiers reached accuracies of 97.68%, 95.62%, and 96.5%, respectively. Filtering by anomaly detection and thresholds improved the accuracy to 99.07% (37 samples excluded by filtering), 96.22% (17 samples excluded), and 100% (44 samples excluded) for the neural network, support vector machine and random forest, respectively. Because of best balance between accuracy and number of predictable cases we tested the neural network with applied filters on the in-house cohort, obtaining an accuracy of 95.45%. We developed a classifier that can differentiate between iCCAs, intrahepatic metastases of a PAAD, and normal bile duct tissue with high accuracy. This tool can be used for improving the diagnosis of pancreato-biliary cancers of the liver. This work was supported by Berlin Institute of Health (JCS Program), DKTK Berlin (Young Investigator Grant 2022), German Research Foundation (493697503 and 314905040 - SFB/TRR 209 Liver Cancer B01), and German Cancer Aid (70113922).

Delays to surgery and worse outcomes: The compounding effects of social determinants of health in non–small cell lung cancer

ObjectiveTo quantify the compounding effects of social determinants of health on time to surgery (T2S) and clinical outcomes. MethodsThe National Cancer Database was queried for treatment-naïve patients with cT1-4N0-1M0 non–small cell lung cancer undergoing (bi)lobectomy or pneumonectomy between 2006 and 2016 with 1 to 180 days T2S, the number of days between diagnosis and surgery; surgical delays were defined as statistically significant increased T2S compared with a reference cohort. Social determinants of health factors prognostic for surgical delays were identified using multivariable regression. The 30-/90-day mortality and 5-year survival estimates were calculated using logistic and Cox regressions, respectively. ResultsIn total, 110,005 patients met inclusionary criteria. Multivariable analysis identified race, insurance, and facility type as factors with significant 3-way interaction: T2S of one depended on the others. Income and education also contributed to delays. Privately insured (private) non-Hispanic White patients at academic medical centers (AMCs) were the reference with T2S of 44.1 days. At AMCs, private Black patients had significant delays to surgery (54.7 days; P < .0001), as did Medicaid and uninsured Black patients (58.5 days; P < .0001, 59.4 days; P < .0001, respectively). The 15-day surgical delays were associated with statistically significant 5% increased 30-day mortality odds (confidence interval [CI], 1.03-1.08), 6% increased 90-day mortality odds (CI, 1.04-1.08), and 4% decrease in hazard of death at 5 years (CI, 1.04-1.05). ConclusionsIn treatment-naïve patients with cT1-4N0-1M0 non–small cell lung cancer, Black race, Medicaid, uninsured status, and AMCs generate compounding surgical delays with increased 30-/90-day mortality and decreased 5-year survival. Thoracic surgeons can leverage these facility and demographic-specific insights to standardize time to surgery and begin mitigating underlying disparities.

Implications of Tumor Surgery in Horseshoe Kidneys: A Comparative Study of Outcomes and Surgical Practices

To contrast surgical outcomes of Horseshoe Kidney (HSK) patients with localized renal masses suspected of cancer with nonfused nonectopic kidney patients, emphasizing safe surgical practices for HSKs. The study examined solid tumors from the Mayo Clinic Nephrectomy registry between 1971 and 2021. Each HSK case was matched to three non-HSK patients based on various factors. The outcomes measured included complications within 30days of surgery, change in estimated glomerular filtration rate, and overall, cancer-specific, and metastasis-free survival rates. Thirty of the 34 HSKs had malignant tumors compared with 90 of the 102 patients in the nonfused nonectopic referent cohort. Accessory isthmus arteries were present in 93% of HSK cases, with 43% exhibiting multiple arteries and 7% with 6 or more arteries. Estimated blood loss and surgery duration were significantly higher in HSKs (900 vs 300mL, P=.004; 246 vs 163minutes, P<.001, respectively). The HSK group demonstrated an overall complication rate of 26% (vs 17% in referents, P=.2) and a median change in estimated glomerular filtration rate at 3months of -8.5 (vs -8.1 in referents, P=.8). At 5-year follow-up, survival rates for HSK patients were 72%, 91%, and 69% for overall, cancer-specific, and metastasis-free survival, respectively. The corresponding rates were 79%, 86%, and 77%, respectively, for matched referent patients (P>.05). HSK tumor management is technically challenging with higher blood loss; however, the data demonstrate comparable outcomes for patients with HSK tumors, including complications and survival, to those without HSKs in experienced centers.

Health-related quality of life of adult, non-surgically treated patients with idiopathic scoliosis and curves above 45°: a cross-sectional study at an average follow-up of 30years.

Previous studies on the natural history of moderate to severe idiopathic scoliosis show contradictory results. Some studies reported an increased incidence of back pain and disability in severe curves, while other studies reported no difference in health-related quality of life (HRQoL) compared to age-matched adult controls. None of these studies addressed HRQoL using currently recommended and validated questionnaires. To examine the long-term HRQoL in non-surgically treated adult idiopathic scoliosis patients with a curve of 45° or higher. In this retrospective cohort study, all patients were retrospectively identified in the hospital's scoliosis database. Patients (1) with idiopathic scoliosis; (2) born before 1981 (to ensure 25-year follow-up after skeletal maturity); (3) with a curve of 45° or more by Cobb's method at the end of growth; and (4) no spinal surgical treatment were selected. Patients received digital questionnaires of the Short Form-36, Scoliosis Research Society-22, Oswestry Disability Index and Numeric Rating Scale. Outcomes of the SF-36 were compared with a national reference cohort. Additional measures with questions regarding choice of education and occupation were used. Forty-eight of 79 (61%) eligible patients completed the questionnaires, at an average follow-up time of 29.9 ± 7.7years. Their average age was 51.9 ± 8.0, and median Cobb angle at adolescence was 48.5°. Five of the eight SF-36 subdomains were significantly lower in the scoliosis group compared to the nationwide cohort: physical functioning (73 vs 83, p = 0.011), social functioning (75 vs 84, p = 0.022), role physical functioning (63 vs 76, p = 0.002), role emotional functioning (73 vs 82, p = 0.032), and vitality (56 vs 69, p = < 0.001). The scoliosis-specific SRS-22r score of the patients was 3.7 ± 0.7 on a 0-5 scale. The mean NRS score for pain of all patients was 4.9 ± 3.2, and eight patients (17%) reported a NRS of 0 and 31 (65%) a NRS above 3. At the Oswestry Disability Index, 79% of the patients reported minimal disabilities. Thirty-three patients (69%) reported that their scoliosis had influenced their choice of education. Fifteen patients (31%) reported that their scoliosis had influenced their choice of work. Patients with idiopathic scoliosis and curves of 45° or higher have reduced HRQoL. Although many patients experience back pain, the disability reported on the ODI was limited. Scoliosis had noteworthy effect on choice of education.

#5413 FRONTIER-1: A PHASE 2B STUDY OF IL-33 BLOCKADE IN DIABETIC KIDNEY DISEASE

Abstract Background and Aims Several biomarkers of inflammation have been correlated with poor renal outcomes and mortality in DKD. However, an effective, well-tolerated treatment of progressive renal disease driven by inflammation has remained elusive. Inhibition of IL-33 may provide a novel opportunity to address this unmet medical need in high-risk patients. Here, we: 1) show that tozorakimab, a high-affinity IL-33-neutralizing mAb, promotes glomerular health in inflammation; 2) describe the clinical study to test tozorakimab in patients with DKD; 3) present participant baseline characteristics; and 4) evaluate inflammation-associated biomarker in FRONTIER-1 and four external validation cohorts. Method FRONTIER-1 (NCT04170543) is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2DM with an eGFR of 25-75 mL/min/1.73 m2 and a UACR in the range of 100-3,000 mg/g. All participants are expected to receive an ACEi/ARB for &amp;gt; 6 weeks before the treatment period. Approximately 565 patients from multiple countries will be randomized to four dose levels of tozorakimab, or volume-matched placebo dosed subcutaneously every 28 days over a 24-week treatment period. All participants will receive 10 mg dapagliflozin Day 85-168. The primary objective of the study is to evaluate the effect of tozorakimab on albuminuria. Secondary objectives are to assess the safety and tolerability of tozorakimab with and without SGLT2i, evaluate the effect of tozorakimab in combination with ACEi or ARB with and without SGLT2i on albuminuria, and describe the PK and immunogenicity of tozorakimab. Key exploratory objective is to assess baseline and treatment-response for urine and/or circulating biomarkers of inflammation, including hsCRP, IL-33/sIL1RL1, CCL2, and TNFR-1/2. Biomarker response was, furthermore, evaluated in pre-clinical models of DKD, and respective distributions and risk were assessed in four independent DKD cohorts (N &amp;gt; 200). Results Transcriptomic profiling of kidney biopsies from patients with DKD indicated a significant glomerular up-regulation of IL-33. Inhibition of IL-33 signalling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model of DKD. This was associated with improved glomerular endothelial health as indicated by decreased cellular inflammation and reduced release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFR-1, and CCL2. Hence, FRONTIER-1 was started in 2019. So far, all trial groups are well-balanced and in line with our expectations for this patient population (N = 574). At baseline, &amp;gt; 95% were receiving ACEi/ARBs and approximately 25% were receiving SGLT2i. The mean eGFR was 47.8 ml/min/1,73 m2 (+/- 14.7) and mean UACR was 765 mg/g (+/- 775). The inflammatory state of participants at baseline was assessed in circulation and urine by hsCRP, TNFR-1 and CCL2 (N &amp;gt; 146). Comparison to independent reference cohorts (N &amp;gt; 200) confirmed elevated risk in DKD patients with high urinary TNFR-1 and CCL2 and showed that 6-week treatment of dapagliflozin did not alter these biomarkers significantly. Conclusion Taken together, inhibition of IL-33 may be beneficial in patients with DKD on standard of care, who have elevated biomarkers of inflammation such as TNFR-1 and/or CCL2. This hypothesis is currently being tested in the FRONTIER-1 phase 2b clinical study. To identify the patients most likely to benefit from immunomodulatory treatment with tozorakimab, the study will conduct a retrospective analysis of albuminuria and inflammatory biomarkers. The primary analysis of the study is planned for the second half of 2023.

HGG-15. HIGH-GRADE GLIOMAS OCCURRING IN TEENAGERS AND YOUNG ADULT PATIENTS COMPRISE NOVEL MOLECULAR SUBGROUPS

Abstract High-grade gliomas (HGG) arise in any central nervous system location, in adults and children, with a poor prognosis. HGGs in teenagers and young adults (TYA) are understudied; this project aimed to characterise these tumours and identify potential therapeutic targets. HGG samples (n=195, FFPE/FF, 13-30 years) were collected, excluding well-characterised entities (histone/IDH-mutant). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package), n=195) classified cases against a reference cohort. Calibrated scores guided workflows to characterise mutational landscapes including RNA-based ArcherDx fusion panel (n=112), whole exome sequencing (n=84), and histological reviews in parallel. Well-characterised entities (n=50, including IDH-mutant tumours (n=18), PXA (n=12)) were excluded. Of the cases scoring &amp;gt;0.6, 64% classified as paediatric-type subgroups (pedHGG-RTK1A/B/C (30%), pedHGG-MYCN (10%), pedHGG-A/B (7%), pedHGG-RTK2A (6%)). 29% classified as subgroups more frequently seen in adults (GBM-MES (12%), GBM-RTK1/2 (3%)). 54% classified with a score &amp;lt;0.6. 38% cases were assigned to novel, recently identified, poorly-characterised subgroups with distinct methylation profiles and molecular features (HGG-B, HGG-E, ANTCON, GBM-CBM). Frequency comparisons to publicly available methylation data showed GBM-MES-ATYP tumours are TYA age-specific, in contrast to adult age-specific GBM-MES-TYP. Copy number profiling identified frequent changes across the cohort, including chromosomal gains (chr1q (54%), chr2 (22%), chr7 (41%)) and losses (chr10 (40%), chr13 (64%)). Focal amplifications included PDGFRA (12%), CDK4 (7%), MYCN/ID2 (3%), MYC (2%) and EGFR (0.7%) and the most common focal deletion was CDKN2A/p16 (12%). The most frequent glioma-associated somatic variants included TP53, PDGFRA, EGFR, and NF1. BCOR alterations were enriched compared to adult and paediatric reference cohorts. 10% cases showed a hypermutator phenotype, enriched in HGG-E. CDK4 amplifications were recurrent in GBM-RTK1 and GBM-CBM. Histology showed variable cytological and architectural features within novel subgroups. TYA HGG comprise novel subgroups with distinct methylation profiles and molecular characteristics, representing opportunities to refine future treatment.

High Hospital-related Costs at the End-of-life in Patients With Multiple Myeloma: A Single-center Study.

High Hospital-related Costs at the End-of-life in Patients With Multiple Myeloma: A Single-center Study.

Measuring Expiratory Diaphragm Activity: An Electrifying Tool to Guide Positive End-Expiratory Pressure Strategy in Critically Ill Children?

Measuring Expiratory Diaphragm Activity: An Electrifying Tool to Guide Positive End-Expiratory Pressure Strategy in Critically Ill Children?

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: The optimal treatment for very elderly patients (pts) with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) remains controversial. R-mini-CHOP is an established standard of care in elderly patients with DLBCL, with a 2 yr OS of 59% and PFS of 47% (Peyrade et al., Lancet Oncol 2011). We present our final data from this prospective Phase II study of ibrutinib, rituximab and mini-CHOP in pts ≥75 yrs with newly diagnosed DLBCL. Methods: Pts received six 21-day cycles of ibrutinib 560 mg daily and R-mini-CHOP (Rituximab 375 mg/m2, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg on day 1 & prednisone 40 mg/m2 or 100 mg/d × 5) followed by an additional two 21 day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). Primary endpoints were deliverability and 2 year overall survival (OS). Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed Peyrade reference OS (59%) and PFS (47%) rates. Results: Eighty pts were recruited from Nov 2015 to Nov 2018. One died prior to receiving treatment and is not included in the analysis. Median age was 82 yrs (75–95); 81% stage III/IV; 54% age adjusted IPI 2–3. With a median follow-up of 35.5 months (m) (0.2, 71.7) (data cut 6 September 2022), there was a non-significant trend towards improvement in 2-year OS of 68% (55.6%, 77.4%) compared to the reference Peyrade cohort of 59% (p = 0.11). Median OS was 72 m (95% CI 35 m to not reached (NR)). Median 2-year PFS of 60.0% (47.7%, 70.3%) was significantly improved compared to the reference cohort of 47% (p = 0.03), with a median PFS of 40 m (95% CI 20.41, NR). Overall response assessment assessed by investigators at the end of treatment was 76% (61/80 pts), with a complete response rate of 70% (56/80 pts). All 6 cycles of R-mini-CHOP were completed in 63/79 pts (80%) and 57/79 pts (71%) completed all 8 cycles of therapy. The median Average Relative Total Dose and Average Relative Dose Intensity for the entire regimen was 97% (IQR 82, 100; 88, 100). 34/79 pts (43%) have died, 17 due to progressive disease and 5 were treatment-related. 67% pts experienced an SAE. Most common AEs were infections and diarrhoea (majority grade 1–2). In the EORTC QLQ-C30 there was an improvement in functional and symptom scales and on the EQ-5D-5L survey, there was a significant improvement in the median health state classification score and median visual analogue scale thermometer score over time. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Janssen-Cilag Pty Ltd. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract. E. Verner Research funding: Janssen-Cilag Pty Ltd. E. Hawkes Consultant or advisory role: Janssen-Cilag Pty Ltd. T. Cochrane Consultant or advisory role: Janssen Cilag Pty Ltd. C. Y. Cheah Consultant or advisory role: Janssen-Cilag Pty Ltd. Honoraria: Janssen-Cilag Pty Ltd. M. K. Gandhi Research funding: Janssen-Cilag Pty Ltd. B. E. Butcher Other remuneration: Janssen Cilag Pty Ltd. J. Trotman Research funding: Janssen-Cilag Pty Ltd.

Long-term survival with IDH wildtype glioblastoma: First results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419).

2016 Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the cut-off of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 not otherwise specified) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O6-methylguanine DNA methyltransferase ( MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p&lt;0.001) and had a high rate of MGMT promoter unmethylated tumors. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Never relapsing patients often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma. Clinical trial information: NCT03770468 .

Potential predictive biomarker for response to radiotherapy and CXCL12 inhibition in glioblastoma in the phase I/II GLORIA trial.

2048 Background: Standard of care (SOC) treatment achieves poor clinical outcomes in patients with glioblastoma (GBM), particularly in the absence of MGMT promoter hypermethylation. Preclinical models suggest that GBM recurrence is facilitated by CXCL12-mediated recruitment of bone marrow-derived cells capable of vasculogenesis after radiotherapy (RT). We have recently reported favorable safety and feasibility data of the phase I/II GLORIA trial, which combines RT and the CXCL12-neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) in patients with newly diagnosed, incompletely resected or unresected GBM lacking MGMT promoter hypermethylation (NCT04121455). Here we report on clinical outcomes and their correlation with potential biomarkers. Methods: 10 patients with newly diagnosed incompletely resected (n=8) or biopsied (n=2) GBM with ECOG≤2, age≥18 and without MGMT promoter hypermethylation were enrolled. All patients received standard RT (60 Gy in 30 fractions or 40.05 Gy in 15 fractions) and escalating dose levels of continuous (24/7) i.v. infusions of NOX-A12 for 26 weeks. While the previously reported primary endpoint was safety, secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Biomarker assessment was performed with a six-plex immunofluorescence staining (CODEX) of neuropathologically confirmed tumor areas of pretreatment tissues for CXCL12, CD31 (endothelial cells), GFAP (glioma cells), CD68 (macrophages, microglia), aSMA (pericytes), Ki-67 (proliferating cells) and a nuclear marker. An independent patient cohort treated with SOC (n=15) matched by clinical and histopathological features was used for comparisons of efficacy and biomarker assessment. Results: Median PFS of the GLORIA cohort was 5.7 (range 1.9–8.5) months and the median OS was 12.7 (4.7–18.4) months. Biomarker analyses revealed that a higher frequency of CXCL12 expressing endothelial and glioma cells (EG12 score) significantly correlated with PFS (r=0.87; p=0.005) in patients treated with RT and NOX-A12, but not with SOC (r=-0.10; p=0.724). GLORIA patients with a high EG12 score (median classifier) had a significantly longer PFS than those with lower scores (3.0 vs. 6.0 months; p=0.031) and a trend towards prolonged OS (11.1 vs. 15.8 months; p=0.075). These correlations were not seen in the reference cohort treated with SOC (PFS: 6.0 vs. 4.6 months; p=0.502; OS: 10.0 vs. 9.6 months; p=0.243). Conclusions: We show superior clinical efficacy of RT and NOX-A12 in patients with high frequency of CXCL12 expressing endothelial and glioma cells, suggesting the use of the EG12 score as a novel predictive biomarker for CXCL12-directed therapies in GBM. Clinical trial information: NCT04121455 .