Upper Limit Of Normal Research Articles

The strategic use of biopsy in the diagnosis of coeliac disease in adults

BackgroundThe paediatric guidelines support the use of the ‘No Biopsy Approach’ in the diagnosis of coeliac disease (CD). We aimed to determine the correlation between anti tissue transglutaminase (anti-TTG serology) ≥10 times the upper limit of normal (ULN), using the Celikey ® ELiA assay and histological findings. Our secondary aim was to determine the safety of this approach in our centre. MethodsA retrospective analysis of adult patients referred to a tertiary referral centre with raised anti-TTG titres and/or histological changes of coeliac on D2 biopsies between 2014 – 2019. Excluded patients were those who did not have a biopsy performed, or whose biopsy was unavailable for review, selective IgA deficiency, and gluten elimination prior to biopsy. Biopsies were classified according to Marsh, by two independent pathologists, blinded to the anti-TTG titre. Results164 patients had positive anti-TTG serology and duodenal biopsy in our centre prior to starting a gluten free diet (GFD) in the period 2014 - 2019. Of these 164 patients (median age 40yrs, 62% female), 68 (33%) had an anti-TTG titre ≥10 x ULN, 99% of which had a Marsh grading ≥ 3 and 1% had a Marsh of 2 on biopsy. 91% had either a normal index gastroscopy or findings of mild gastritis/oesophagitis. ConclusionsWe found a 98.5% positive predictive value (PPV) of determining CD (i.e., Marsh ≥ 3) in those with an anti-TTG ≥10 x ULN. In those with moderate to high-risk clinical suspicion of CD we propose that duodenal biopsy is unnecessary for diagnosis.

Development of prediction model for alanine transaminase elevations during the first 6 months of conventional synthetic DMARD treatment

Frequent laboratory monitoring is recommended for early identification of toxicity when initiating conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). We aimed at developing a risk prediction model to individualize laboratory testing at csDMARD initiation. We identified inflammatory joint disease patients (N = 1196) initiating a csDMARD in Turku University Hospital 2013–2019. Baseline and follow-up safety monitoring results were drawn from electronic health records. For rheumatoid arthritis patients, diagnoses and csDMARD initiation/cessation dates were manually confirmed. Primary endpoint was alanine transaminase (ALT) elevation of more than twice the upper limit of normal (ULN) within 6 months after treatment initiation. Computational models for predicting incident ALT elevations were developed using Lasso Cox proportional hazards regression with stable iterative variable selection (SIVS) and were internally validated against a randomly selected test cohort (1/3 of the data) that was not used for training the models. Primary endpoint was reached in 82 patients (6.9%). Among baseline variables, Lasso model with SIVS predicted subsequent ALT elevations of > 2 × ULN using higher ALT, csDMARD other than methotrexate or sulfasalazine and psoriatic arthritis diagnosis as important predictors, with a concordance index of 0.71 in the test cohort. Respectively, at first follow-up, in addition to baseline ALT and psoriatic arthritis diagnosis, also ALT change from baseline was identified as an important predictor resulting in a test concordance index of 0.72. Our computational model predicts ALT elevations after the first follow-up test with good accuracy and can help in optimizing individual testing frequency.

Systematic review with meta-analysis: Significant histological changes among treatment-naïve chronic hepatitis B patients with normal alanine aminotransferase levels by different criteria.

The upper limits of normal (ULNs) of ALT are not consistent across the major international guidelines which may affect the eligibility for antiviral therapy for chronic hepatitis B (CHB). To estimate the proportions of histological changes among treatment-naïve patients with CHB within differently defined ALT ULNs. We searched PubMed and Embase up to May 15th, 2023, to identify studies of treatment-naïve CHB patients with liver biopsies. We pooled proportions of moderate to severe necroinflammation, significant fibrosis, and cirrhosis in those patients within different ALT ULNs by using random-effect models. We included 23 studies with 4010 participants. Within ALT ULN at 40 IU/L, the pooled proportions of moderate to severe necroinflammation, significant fibrosis, and cirrhosis were 33% (95% CI: 26%-42%), 32% (95% CI: 27%-38%), and 3% (95% CI: 1%-5%), respectively. Within ALT ULN at 30 IU/L for men and 19 IU/L for women, the pooled proportion of significant fibrosis remained at 30% (95% CI: 25%-34%; 432 participants). However, it was 21% (95% CI: 11%-37%; 361 participants) even in those within ALT ULN at 20 IU/L. Subgroup analyses suggested a significantly higher proportion of significant fibrosis among studies with prospective design or enrolled patients' mean age >35 or >40 years. Significant histological changes occurred in approximately 1/3 of treatment-naïve CHB patients within ALT ULN at 40 IU/L, whereas the proportion of significant fibrosis was approximately 1/5 even in those within ALT ULN at 20 IU/L.

Association between troponin level and medium-term mortality in 20 000 hospital patients

IntroductionCardiac troponin (cTn) concentrations above the manufacturer recommended upper limit of normal (ULN) are frequently seen in hospital patients without a clinical presentation consistent with type 1 myocardial infarction, and...

Situation of HDV Infection in Adult Hepatitis B Patients at The Outpatient Clinic of Pasteur Institute in Ho Chi Minh City

Hepatitis D virus (HDV) infection, also known as delta virus, has been identified as a crucial risk factor contributing to severe complications among hepatitis B patients. Such complications arise as HDV accelerates the progression towards cirrhosis, exacerbates the risk of decompensated cirrhosis, and increases mortality rates compared to non-HDV hepatitis B infections. Despite its clinical significance, data on HDV infection remains scarce, and exhibits marked regional disparities in Viet Nam. This study endeavors to explore HDV co-infection in adult hepatitis B patients. A descriptive cross-sectional investigation was conducted, involving 539 hepatitis B subjects attending the Outpatient Clinic of the Pasteur Institute in Ho Chi Minh City between October 2021 and May 5, 2022. The study sample featured three hepatocellular carcinoma (HCC) patients, 148 patients with elevated alanine aminotransferase (ALT) levels, and nine patients whose ALT levels exceeded five times the upper limit of normal (ULN). Additionally, 11 patients reported a history of blood transfusion, while no participants had any history of intravenous drug use. Remarkably, the study did not document any instances of HDV co-infection among the subjects. These findings suggest that HDV screening may not be a routine recommendation for patients diagnosed with moderate or mild hepatitis B, particularly when presenting with low-risk factors. Further research is warranted to better understand the prevalence of HDV co-infection in this population and to guide the development of evidence-based screening guidelines.

HyperCKemia: An early sign of childhood-onset neutral lipid storage disease with myopathy

Neutral lipid-storage disease with myopathy (NLSDM) is an autosomal recessive neuromuscular disorder caused by mutations in PNPLA2, and the average age at onset is 30 years. To date, only eight patients with childhood-onset NLSDM have been reported in detail. We investigated 3 unreported patients with NLSDM detected in childhood and reviewed 8 childhood-onset and 82 adult-onset patients with NLSDM documented in the literature. In the childhood-onset cohort, NLSDM presented initially as asymptomatic or paucisymptomatic hyperCKemia in 6/11 patients, and follow-up data showed onset of muscle weakness in 6/11 childhood-onset patients. In the adult-onset cohort, 95.1% (78/82) of patients showed muscle weakness. Cardiac involvement developed in 6/11 childhood-onset patients. Hepatomegaly was observed in 3/11 childhood-onset patients. Serum creatine kinase levels were elevated greater than five-fold of the upper limit of normal (ULN) in most childhood-onset patients and were elevated to less than ten-fold of the ULN in most adult-onset patients. Peripheral blood smears and muscle biopsies showed cytoplasmic lipid droplets in leukocytes and myocytes. NLSDM can present in children with asymptomatic or paucisymptomatic hyperCKemia before the onset of muscle weakness. The presence of lipid droplets in leucocytes (Jordans' anomaly) aids in diagnosing and confirming the pathogenicity of PNPLA2 variants of uncertain significance. There were no clear genotype-phenotype correlations in patients with NLSDM.

The Role of Blood Pressure Load in Ambulatory Blood Pressure Monitoring in Adults: A Literature Review of Current Evidence.

The blood pressure load (BPL) is commonly defined as the percentage of readings in a 24-h ambulatory blood pressure monitoring (ABPM) study above a certain threshold, usually the upper normal limit. While it has been studied since the 1990s, the benefits of using this index have not been clearly demonstrated in adults. We present the first review on the associations of BPL with target organ damage (TOD) and clinical outcomes in adults, the major determinants for its role and utility in blood pressure measurement. We emphasize studies which evaluated whether BPL has added benefit to the average blood pressure indices on ABPM in predicting adverse outcomes. PubMed search for all English language papers mentioning ABPM and BPL. While multiple studies assessed this question, the cumulative sample size is small. Whereas the associations of BPL with various TODs are evident, the available literature fails to demonstrate a clear and consistent added value for the BPL over the average blood pressure indices. There is a need for prospective studies evaluating the role of BPL in blood pressure measurement. The current literature does not provide sound support for the use of BPL in clinical decisions.

Case Report: Case report: An unusual presentation of granulomatosis with polyangiitis

Aim: We are reporting a case of an unusual presentation of granulomatosis with polyangiitis (GPA) with liver involvement. Case presentation: A 45-year-old male patient presented with erythematous plaques on the face and bilateral nasal obstruction. On physical examination, the patient had a ring-shaped squamous plaque on the face. The laboratory findings revealed an accelerated erythrocyte sedimentation rate at 100 mm/h, an elevated C-reactive protein at 66 mg/L, hyper gamma globulinemia 16 g/L and an elevated alkaline phosphatase (twice the upper normal limit). The craniofacial and thoracoabdominal computed tomography (CT) -scans showed ethmoid and maxillary sinusitis, low facial bone density, multiple mediastinal and hilar lymphadenopathy, diffuse small pulmonary nodules, and hepatomegaly. A cutaneous lesion biopsy, the nasal mucosa, and the liver showed a chronic inflammatory granulomatosis process with necrosis. Serum anti-neutrophil cytoplasmic antibody (ANCA) against PR3 was positive. The clinical, biological, radiological, and histological findings substantiated the diagnosis of GPA. The patient received systemic steroids combined with cyclophosphamide pulses on days 1, 14 and 28 and then he was lost to follow-up. Two-years later, he presented with a cardiac failure and skin ulcer in the right lower limb. A nasal endoscopic exam showed nasal septum cartilage perforation with resorption of the middle and inferior nasal concha. Two weeks later, he developed a diffuse alveolar hemorrhage and was therefore transferred to the intensive care unit but died of respiratory failure 3 days later. Conclusion: Clinicians should be aware of GPA atypical clinical manifestations.

Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study

Background Type 2 diabetes mellitus (T2DM) patients are at high risk of cardiovascular (CV) events. Factor XI (FXI) is associated with arterial thromboembolism, including myocardial infarction (MI), stroke, and CV mortality. The role of FXI in T2DM is unknown. We investigated whether plasma FXI is associated with CV events in T2DM patients in long-term observation.MethodsIn 133 T2DM patients (aged 66 ± 8 years, 40.6% women, median T2DM duration 5 [2–10] years) we assessed plasma FXI levels, along with fibrin clot properties, thrombin generation, and fibrinolysis proteins. A composite endpoint of MI, stroke, or CV death, as well as CV mortality alone were assessed during a median follow-up of 72 months.ResultsPlasma FXI above the 120% upper normal limit was detected in 25 (18.8%) patients and showed positive association with LDL cholesterol and thrombin activatable fibrinolysis inhibitor, but not glycated hemoglobin, inflammatory markers or thrombin generation. The composite endpoint (n = 21, 15.8%) and CV death alone (n = 16, 12%) were more common in patients with elevated FXI (hazard ratio [HR] 10.94, 95% confidence interval [CI] 4.46–26.87, p < 0.001 and HR 7.11, 95% CI 2.61–19.31, p < 0.001, respectively). On multivariable analysis, FXI remained an independent predictor of the composite endpoint and CV death, regardless of concomitant coronary artery disease.ConclusionsTo our knowledge, this study is the first to show that in T2DM patients, elevated FXI could predict major CV events, including mortality, which suggest that anti-FXI agents might be a potential novel antithrombotic option in this disease.

Outcomes in patients with BRAFV600-mutated melanoma and brain metastases at baseline treated with dabrafenib plus trametinib.

Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited. DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAFV600-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS). Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively). Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes.

Sensitivity and specificity of thromboelastography for hyperfibrinolysis: Comparison of TEG 5000 and TEG 6S CK LY30 systems.

The sensitivity and specificity of clot lysis at 30 minutes after maximum clot strength (LY30), as measured by thromboelastography (TEG), for clinically significant hyperfibrinolysis have not been compared across the 2 US Food and Drug Administration-approved instruments (the TEG 5000 and TEG 6s [Haemonetics]). We performed a retrospective, single-center analysis of these 2 instruments using the kaolin (CK) reagent. Local verification studies showed that the TEG 5000 and TEG 6s CK LY30 upper limits of normal (ULNs) were distinct (5.0% and 3.2%, respectively). Retrospective analysis of patient data showed that abnormal LY30 was 6 times more prevalent with the TEG 6s than with the TEG 5000 instrument. LY30 was a significant predictor of mortality with both instruments (TEG 6s: receiver operating characteristic [ROC] area under the curve [AUC] = 0.836, P ≤ .0001; TEG 5000: ROC AUC = 0.779, P = .028). The optimal LY30 cut point was determined based on these mortality data for each instrument. The TEG 6s showed superior mortality prediction than the TEG 5000 at lower LY30 levels (≥10%), with likelihood ratios of 8.22 and 2.62 for the TEG 6s and TEG 5000, respectively. Patients with a TEG 6s CK LY30 of 10% or higher were significantly more likely to die, receive cryoprecipitate, receive transfusions, or receive massive transfusion than patients with a TEG 6s LY30 of 3.3% to 9.9% (all P < .01). Patients with a TEG 5000 LY30 of 17.1% or higher were significantly more likely to die or use cryoprecipitate (P < .05); transfusion and massive transfusion protocol were not significantly different. Whole blood spiking studies showed that 70 ng/mL tissue plasminogen activator (tPA) achieved an average LY30 of approximately 10% for both instruments. CK LY30 above the ULN is a sensitive but not specific cutoff for hyperfibrinolysis. At least moderately elevated CK LY30 carries more clinical portent on the TEG 6s instrument than on the TEG 5000. These TEG instruments are not sensitive to low concentrations of tPA.

Characterization and Short-Term Outcome of Potential Celiac Disease in Children.

Background and Objectives: Potential Celiac Disease (PCD) is defined by positive celiac serology without villous atrophy. We aimed to describe the short-term outcome of pediatric PCD while consuming a gluten-containing diet (GCD). Materials and Methods: Retrospective analysis of pediatric PCD patients continuing GCD, between December 2018-January 2022. Baseline demographics, celiac serology and duodenal biopsy results were reviewed. Follow-up data included repeated serology and biopsy results when performed. Minimum follow-up was 12 months unless celiac disease (CeD) was diagnosed earlier. Results: PCD was diagnosed in 90 children (71% females) with a mean age of 7.2 (range 1.8-16.5) years. Baseline anti-tissue transglutaminase (TTG) levels were above 10 times the upper limit of normal (ULN) in 17/90 (18.9%), 3-10 × ULN in 56/90 (62.2%) and 1-3 × ULN in 17/90 (18.9%). During follow-up, the mean time was 17.6 (range 5-35) months, TTG normalized in 34/90 (37.8%), was stable in 48/90 (53.3%), and increased or remained >10 × ULN in 8/90 (8.9%). In 20/90 (22.2%) patients, a repeat endoscopy was performed, leading to CeD diagnosis in 12/20 (60%). Thus, at the end of follow-up, CeD was diagnosed in 12/90 (13.3%). In patients with TTG >10 × ULN at diagnosis, TTG normalized in 5/17, decreased to 3-10 × ULN in 8/17, and remained above 10 × ULN in 4/17. Conclusions: During the short-term follow-up of pediatric PCD patients, less than 15% progressed to CeD. A third had normalized TTG levels, including children with TTG >10 × ULN, indicating the need for periodic serological and histological follow-up among PCD patients.

Endoscopic endonasal approach for acromegaly: surgical outcomes using 2018 consensus criteria for remission.

The primary aim is to analyze the endoscopic endonasal surgical results in short-term and two-year follow-ups according to the 11th Acromegaly Consensus statement (2018). Indeed, prognostic factors and complications were analyzed. 40 patients who underwent endoscopic endonasal surgery by acromegaly between 2013 to 2020 was analyzed. Patients were considered in remission if an upper limit of normal (ULN) IGF-1 was less than 1.0 at the six-month and two-year follow-ups. Moreover, we assessed the Knosp grade, tumor volumetry, ULN, T2 signal in MRI, reoperation, and complications. The mean age of admission was 46.7 years. Thirty-two patients were in remission after six months of surgery (80%), decreasing to 76.32% at the two-year follow-up. All microadenomas presented remission (n = 6). Regarding the complications, three patients had permanent panhypopituitarism (7.5%); postoperative cerebrospinal fluid (CSF) leaks did not occur in this series. The hyperintense signal on the T2 MRI and a higher tumor volumetry were the single predictor's factors of non-emission in a multivariate regression logistic analysis (p < 0.05). Preoperative hormone levels (GH and IGF-1) were not a prognostic factor for remission. The re-operated patients who presented hypersignal already had a high predictor of clinical-operative failure. The endoscopic endonasal surgery promotes high short-term and two-year remission rates in acromegaly; the tumor's volumetry and the T2 hypersignal were statistically significant prognostic factors in non-remission - the complications presented at similar rates in comparison to the literature. In invasive GH-secreting tumors, we should offer these patients a multi-disciplinary approach to improve acromegalic patients' remission rates.

Hepatitis B reactivation: A possible cause of coronavirus disease 2019 vaccine induced hepatitis

Coronavirus disease 2019 (COVID-19) vaccines were rapidly implemented globally and vaccine-associated immune-related hepatitis was recently reported. We aim to investigate its impact in regions endemic of chronic hepatitis B (CHB). We retrospectively collected patients who developed hepatitis within 90 days after COVID-19 vaccination in Taiwan. The mechanisms of hepatitis included vaccine induced liver injury (VILI) and immune-related hepatitis, which are direct liver injuries defined as aspartate or alanine aminotransferase (AST or ALT) increased ≥ 5-fold upper limit of normal (ULN) and/or AST or ALT ≥ 3-fold of ULN with concurrent total bilirubin ≥ 2-fold of ULN. Indirect liver injury due to HBV reactivation was defined as HBsAg reverse seroconversion or significant rise in HBV DNA level. The demographics, clinical data, and course of hepatitis were compared statistically. Twenty-five patients were included with a median age of 54. The culprit vaccines were ChAdOx1 nCoV-19 (n=9), mRNA-1273 (n=12), and BNT162b2 (n=4). The characteristics of hepatitis were comparable regardless of vaccine subtypes. The median onset of hepatitis was 25 days post vaccination, with a peak of 10-fold ALT-increase. The etiologies included HBV reactivation (n=10), VILI (n=10), and immune-related hepatitis (n=5). HBV reactivation accounts for 90% of vaccine-induced hepatitis in patients of CHB (n=10), and two patients died. Patients with initial AST levels >500 U/L increased 27-fold risks of liver injury greater than moderate severity compared with those without. COVID-19 vaccine induced hepatitis is a clinical significant complication, and HBV reactivation may account for a possible mechanism.

Gender-related differences in aortic diameters: why do we use the same cutoff?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patient’s body size and gender are major determinants of aortic dimensions. Even though female gender is associated with smaller aortic dimensions, surgery indication for thoracic aorta aneurysms is still based mainly on absolute diameters without considering gender. Therefore, if 4 cm is the number which allows us to discriminate aortic dilation in women is still controversial. Objective to compare the upper limit of normal (ULN) and Z score between genders in the population of the MATEAR Study (prospective nationwide multicenter registry in Argentina) and to determine the usefulness and fairness of the guideline’s recommendations about aortic diameters in women. Methods It was a prospective nationwide registry (53 centers). We included 1,000 healthy adult individuals (mean age: 38.3±12.7 years) being 553 women (56.7% Caucasian, 38.3% Native Americans). Echocardiograms were performed in all patients measuring aortic dimensions at 6 levels following the current standard recommendations: aortic annulus, aortic sinuses, sinotubular junction (STJ), proximal ascending aorta, aortic arch, and proximal descending aorta. Absolute diameters and indexed diameters by body surface area and height were compared between men and women, as well as the estimated ULN in order to analyze discrepancies of the recommended ULN (4cm) in female individuals. Results Table 1 shows the baseline characteristics of the study population by gender. The mean age was similar in both sexes (39.1±13.4 years in women and 37.2±12.3 years in men). Women had lower values in all anthropometric parameters, they were 13 cm shorter than men, and had lower left ventricular diameters, ventricular mass, septal thickness and medium blood pressure. The aortic measures at the six levels revealed that women had lower absolute aortic diameters in all aortic segments. However, when the indexed parameters were analyzed in the aortic root and STJ, women presented lower height indexed diameters but higher BSA/indexed diameters (Table 2 and Figure 1). Regarding the Z score evaluation, we found that the recommended ULN (4 cm) was higher in women than men, with a Z score equivalent to 3.61 and 2.34 respectively. Moreover, in our registry 3.62 cm was the ULN in women which corresponded to a Z score of 2.5. Conclusions As was suggested in previous studies aortic diameter indexed by height or BSA appear to be the most appropriate measurements for considering aortic dilatation. In our registry, women showed lower absolute aortic diameters in all segments placing the recommended ULN of 4cm as a misguided value for considering aortic dilatation in women. Therefore, gender should always be taken into account when defining aortic dilatation.

#5359 DETECTING NEONATAL AKI BY SERUM CYSTATIN-C

Abstract Background and Aims Serum creatinine is not a sensitive biomarker for acute kidney injury (AKI) in neonates. Unlike creatinine, cystatin-C (Cys-C) does not cross the blood placental barrier and the serum level in the neonates is not significantly impacted by the gestation age, birthweight, and the age during the first four weeks after birth. Therefore, serum Cys-C may be a better marker neonatal AKI than serum creatinine. We aimed to assess the performance of serum Cys-C as an alternative biomarker for detecting neonatal AKI. Method This is a large multicenter cohort study including 52,333 hospitalized neonates. First, we assess the impacts of gestational age, birthweight, and days after birth on the level of Cys-C, and estimated the upper normal limit (UNL) and the reference change value RCV of serum Cys-C in neonates. Then, we proposed a Cys-C based criteria (CyNA) for detecting neonatal AKI based on both Cys-C level and the change in Cys-C using UNL and RCV as the cutoffs, respectively. Finally, we assessed the performance of CyNA in detecting neonatal AKI and the association of CyNA-detected AKI with the risk of in-hospital death, and compared the performance with that using the KDIGO creatinine criteria. Results Cys-C level in neonates did not vary with gestational age and birthweight, and remained relatively stable during the neonatal period (Figure 1). The UNL of Cys-C was 2.2 mg/L and the RCV (for Cys-C ratio) was 1.25. CyNA criteria defines AKI by a serum Cys-C of ≥2.2 mg/L (UNL) or an increase in Cys-C of ≥25% (RCV) during the neonatal period. Among 52,333 neonates 6,336 (12.1%) AKI cases were detected by CyNA criteria, of whom 96 (1.5%) died. In comparison, 202 (0.44%) death events occurred in 45,997 neonates who did not have AKI. After adjusting all comorbidities, CYNA-detected AKI was associated with a significantly increased risk of in-hospital mortality (adjusted HR 2.91, 95% confidence interval, 2.24 to 3.78). Among 45,839 neonates that had measurement of both Cys-C and SCr, 4,513 (9.8%) had AKI detected by CyNA only, 373 (0.8%) by KDIGO only, and 381 (0.8%) by both criteria (Table 1). After adjusting admission to ICU and comorbidities, AKI detected by CyNA only (C+/K-) was associated with a significantly increased risk of in-hospital mortality compared with those without AKI by both criteria (C-/K-), with an adjusted hazard ratio of 2.86 (95% CI, 2.02 to 4.04). In comparison, the HR for those detected by KDIGO only (C-/K+) was lower at 2.15 (95% CI, 0.96 to 4.81). Neonates with AKI detected by both criteria (C+/K+) had the highest risk of in-hospital mortality (HR 4.86, 95% confidence interval, 2.84 to 8.29). Conclusion Serum Cys-C is a robust and sensitive biomarker for detecting neonatal AKI. CyNA is 5.5 times more sensitive than the modified KDIGO in detecting neonates who are at an elevated risk of in-hospital mortality.

#3911 DIETARY OXALIC ACID INTAKE AND PLASMA OXALIC ACID CONCENTRATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims High oxalic acid concentration may be caused by genetic disorders, enteric diseases, but also by kidney insufficiency per se. It may result in kidney oxalic acid stones, kidney function decline, and failure. This study aimed to investigate whether dietary oxalic acid intake influences plasma oxalic acid concentration in a population undergoing kidney transplantation. Method Dietary oxalic acid intake was assessed using a Food Frequency Questionnaire. Based on frequency and portion size, average daily oxalic acid intake in the past year and in the last 24 hours was calculated. A blood sample for determination of plasma oxalic acid concentration was drawn on the operation ward before transplantation. For multivariable analysis seventeen recipient related variables were gathered. Results 418 patients were included. The median age of the participants was 62 year, 60% were male, all had an eGFR &amp;lt;20 ml/min/1.73 m2, and 66% were on dialysis with a median dialysis vintage of 13 months. The median plasma oxalic acid concentration was 32.2 µmol/L (range 4.6-243.2). In 98.3% of patients oxalic acid concentration was above the upper limit of normal. The average oxalic acid intake was 199 mg/day (range 4-1599), while it was 138 mg/day in the last 24 hours before transplantation (range 0-3906). Multivariable linear regression analysis showed that plasma oxalic acid concentrations were significantly higher in recipients with higher average (p&amp;lt;0.001) and last 24 hours oxalic acid intake (p = 0.002), lower age (p&amp;lt;0.001), lower residual diuresis (p&amp;lt;0.001), higher body mass index (p&amp;lt;0.001), longer dialysis vintage (p = 0.032), hemodialysis (p&amp;lt;0.001), and peritoneal dialysis (p&amp;lt;0.001) versus preemptive status. Conclusion In pre-kidney transplant patients, plasma oxalic acid concentration is above upper normal limit in 98.3% of patients and is multifactorially determined. As all other factors are not modifiable, the only way to decrease plasma oxalic acid concentration is dietary restriction.

Expanding eligibility criteria for renal and liver function in NCI-sponsored immunotherapy clinical trials.

e13610 Background: Stringent eligibility criteria can slow accrual, impede evaluation of potentially promising anticancer therapies, and limit applicability of trial results to the larger population. Immuno-Oncology (IO) clinical trials utilizing anti-PD1/PDL1 monoclonal antibodies (mAb) are ideal candidates to broaden organ function (fcn) eligibility, as their kinetics are independent of renal or hepatic fcn. Herein we present an analysis of the current landscape of renal and hepatic eligibility criteria in NCI CTEP-sponsored IO clinical trials to determine if these meet the recommended guidelines for broadened criteria. Methods: We conducted a retrospective analysis of renal and hepatic fcn eligibility criteria of NCI-sponsored IO trials in the CTEP networks initiated by the data cut-off date of 4/24/22. At least one treatment arm on all included trials had an anti-PD1/PDL1 mAb either alone or in combination with other agents. ASCO and Friends of Cancer Research (ASCO/Friends) recommendations and the NCI broadened eligibility criteria were used to assess the trials. ASCO/Friends broadens inclusion criteria for renal fcn to a creatinine clearance (CrCl) of &gt; 30 mL/min but gives no specific hepatic fcn cutoff. NCI recommends broadened criteria to glomerular filtration rate (GFR) of ≥ 60 mL/min/1.73m2 for the Experimental Therapeutics Clinical Trials Network and all phase 1 trials or GFR ≥ 50 mL/min/1.73m2 for National Clinical Trials Network (NCTN) trials, unless safety data exists for lower renal fcn values, and no lower than 30 mL/min/1.73m2. NCI suggests hepatic fcn criteria with total bilirubin ≤ institutional upper limit of normal (ULN) and AST/ALT ≤ 3 × ULN. CrCl and GFR were deemed interchangeable in this analysis. Results: A total of 182 IO trials were identified. Of these, 45 (25%) required CrCl &gt; 30 mL/min. Three trials (2%) allowed for CrCl &lt; 30 mL/min: one trial each requiring CrCl &gt; 25 mL/min, 20 mL/min, and 15 mL/min. One trial had no renal criteria. Ninety-five trials (52%) were compliant with the suggested NCI template guidance but not ASCO/Friends: 20 trials with CrCl &gt; 60 mL/min, 48 trials with &gt; 50 mL/min, 10 trials with &gt; 45 mL/min, and 17 trials with &gt; 40 mL/min as the renal eligibility criteria. Thirteen trials (7%) did not abide by either guidance: 6 NCTN trials with CrCl &gt; 60 mL/min and 4 trials requiring CrCl &gt; 70 mL/min. Serum creatinine alone was utilized for renal fcn in 22 trials. For hepatic criteria, 82 trials (45%) complied with NCI recommendations. The other 100 trials (55%) did not utilize the suggested NCI template cutoff for AST/ALT of 3 x ULN, but 81 of these trials allowed for AST/ALT at 2.5 x ULN with 27 of the 81 trials allowing for 5 x ULN for AST/ALT if liver metastases were present. Conclusions: Our results demonstrate that clinical trials have updated toward broadening hepatic eligibility criteria but require further guidance to facilitate a less cautious approach with renal fcn.

The Prognostic Value of Cardiac Troponin in a Contemporary Cohort of Patients With First-Time Myocardial Infarction

The prognostic value of cardiac troponin following myocardial infarction (MI) is well documented; however, the benefit in a predominantly revascularised cohort is less certain. This study reported the prognostic role of peak cardiac troponin in the Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS). Due to varying troponin assays across hospitals, peak troponin data from the index admission were standardised as the peak troponin divided by the upper limit of normal (ULN) for each troponin assay (“peak troponin ratio”). Troponin ratio was categorically investigated (≤1, >1–10, >10–100, >100 over ULN) and as a continuous variable. The relationship between troponin and all-cause death or cardiovascular readmission was investigated using Cox regression including restricted cubic splines. Models were adjusted for the MENZACS clinical summary score (comprising 20 clinical factors including age and sex), ethnicity, and log2 N-terminal pro B-type natriuretic peptide (NT-proBNP). A total of 1,876 patients admitted with first-time MI from 2015 to 2019 were included (mean age 61 years, 21% women, 43% ST-elevation MI, 57% non-ST elevation MI); 99% received coronary angiography and 88% were revascularised during the index admission. Peak troponin ratio was 1% ≤1, 19% >1–10, 36% >10–100,and 44% >100. The NT-proBNP increased with increasing troponin category. Overall, 20% patients died or were readmitted over a median of 3.5 years. After multivariable adjustment, peak troponin ratio was not associated with death or readmission (Figure 1). Peak troponin was not an independent predictor of death or cardiovascular readmission in a highly revascularised cohort of patients in New Zealand surviving admission for a first-time MI.

A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced melanoma: Poor-prognosis subgroup analysis.

9548 Background: Co-blockade of LAG-3 improves the effectiveness of anti-PD-1 treatment (Tx) in advanced melanoma (Mel) patients (pts). We previously reported high clinical activity of the combination immunotherapy of anti-LAG-3 (fianlimab) and anti-PD-1 (cemiplimab) in pts (N = 80) with anti–PD-1/PD-ligand (L)1-naïve advanced Mel enrolled in two expansion phase 1 cohorts. The objective response rate (ORR) (N = 80) and disease control rate (DCR) was 63.8% and 80.0%, respectively with median duration of response (mDOR) not reached (NR). Factors associated with poor prognosis include elevated lactate dehydrogenase (LDH) levels and sites of metastases, including liver or other visceral organs (M1c). Here we present updated efficacy data in poor prognosis pts from three phase 1 advanced Mel expansion cohorts: cohort 6 and 15 of anti-PD-(L)1/systemic Tx-naïve pts and cohort 16 of pts previously exposed to adjuvant (adj) or neo-adj systemic Tx including anti-PD-1. Methods: Pts with advanced Mel (excluding uveal Mel) were treated with fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (+ additional 12 months if clinically indicated). Tumor measurements were assessed by RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 40 pts each in cohort 6 and 15, and 18 pts in cohort 16 (total N = 98) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff. In the adj/neo-adj setting, 23.5% of pts had received prior systemic Tx for Mel including 15.3% with prior exposure to immune checkpoint inhibitors (iCPIs). Median follow up was 12.6 months and median Tx duration was 32.9 weeks. ORR among all 98 pts and in 15 pts with prior iCPIs was 61.2% and 60.0%, respectively. In pts with LDH &gt; upper limit of normal (ULN) (N = 32, 32.7%), ORR, DCR, and mDOR were 53.1%, 71.9%, and NR (95% CI, 7.4– not estimated [NE]), respectively, and median progression-free survival (mPFS) was 11.8 months (95% CI, 3.7–NE). In pts with liver mets at baseline (BL) (N = 21, 21.4%), ORR, DCR, and mDOR were 42.9%, 57.1%, and 9.0 months (95% CI, 2.8–NE), respectively, and mPFS was 4.2 months (95% CI, 1.2–NE). In pts with any M1c disease and LDH &gt; ULN at BL (N = 17, 17.3%), ORR, DCR, mDOR were 35.3%, 58.8%, and NR (95% CI, 5.7–NE), respectively, and mPFS was 7.1 months (95% CI, 1.2–NE). Overall, 43.9% and 32.7% of pts reported grade ≥3 Tx-emergent adverse events (TEAEs) and serious TEAEs. Correlative biomarkers analyses are in progress and will be included in the presentation. Conclusions: The combination of fianlimab and cemiplimab showed high activity in pts with advanced Mel and poor prognosis features at BL. The ORR and DCR observed in these subgroups compare positively with the available data for approved combinations of iCPIs in the same clinical setting. A phase 3 trial (NCT05352672) of fianlimab + cemiplimab in Tx-naïve advanced Mel pts is ongoing. Clinical trial information: NCT03005782 .