Cumulative Dose Research Articles

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be < 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

6810 Successful Insulin Allergy Desensitization To Humalog During The Second Trimester Of Pregnancy

Abstract Disclosure: J. Noreña: None. S. Seav: None. S. Jiang: None. S. McGhee: None. M. Tan: None. M. Basina: None. Background: Insulin allergy is rare, occurring in only 0.1 to 3% of people with insulin-treated diabetes. During pregnancy, this incidence is even lower due to a relative immunosuppressive state. Currently, there are no standardized insulin allergy desensitization protocols for this specific patient population. Clinical Case: A 39-year-old female (G4P3003) with T2DM and multiple prior medication allergies presented to the antepartum unit in her 17th week of pregnancy due to hyperglycemia and reported insulin allergy to NPH insulin.Patient was initially diagnosed with gestational diabetes during her third pregnancy, requiring NPH insulin which she seemed to tolerate well at the time. She remained medication-free for two years post-delivery but later developed T2DM with an A1c of 6.8%. Metformin and Jardiance, previously prescribed, were discontinued upon confirmation of her current pregnancy. She opted to manage her diabetes through diet and exercise alone, but her A1c rose to 7.0%, prompting the initiation of NPH.Following the first dose of NPH at home, she experienced a localized burning sensation at the injection site associated with facial flushing, followed by a diffuse, pruritic, erythematous rash on her face, chest, abdomen, and bilateral arms. Due to her history of anaphylaxis to other drugs (mainly antibiotics), she was admitted to the hospital for monitoring. Inpatient attempts with lower doses of NPH and then a trial of glargine triggered new rash episodes. Work-up revealed negative insulin antibodies, low IgG, and a normal CBC. She was started on Humalog to cover basal dose administered every 6 hours and additional prandial injections, which she tolerated prior to discharge. One week later, she developed a new local erythematous reaction at the Humalog injection site followed by a generalized rash which led to her readmission.Allergy was consulted and facilitated a successful desensitization protocol to Humalog. The protocol included escalating doses of insulin administered every 30 minutes (0.1u, 0.2u, 0.4u, 0.8u, 1u, 2u, 3u, 3u) to achieve a pre-determined cumulative dose of 10.5 units. Patient tolerated the protocol well and was discharged with q6h Humalog for basal coverage in addition to prandial doses with plan to transition to insulin pump therapy with Humalog soon. Conclusion: This unique case demonstrates how insulin desensitization can be a safe and successful strategy to help achieve insulin tolerance and glycemic control during pregnancy. Election of an insulin, such as Humalog, that can achieve the one-hour post-prandial glucose target during pregnancy and also provide effective basal coverage should be considered as desensitization can only be done with one insulin type at a time. Presentation: 6/2/2024

Radionuclides determination by alpha (210Po, 228,230,232Th) and gamma (226,228Ra, 137Cs, 40K) spectrometry in children's food in Croatia with assessment of cumulative ingestion dose for infants

This work presents comprehensive results of alpha (210Po, 228,230,232Th) and gamma (40K, 226,228Ra, 137Cs) radioactivity measurements in selected food typically consumed by infants (< 1 year) in Croatia. The samples of readily available infant’s food on Croatian market were categorized according to the growth of an infant, from their first nourishment: adapted powdered milk, to their first solid food. The aim was to estimate ingestion doses and the potential radiological risks for infants. In addition to anthropogenic radionuclides, the study focused on naturally occurring radionuclides often underrepresented in similar researches. 40K prevails in activity concentrations in all types of samples. 210Po was determined in all sample types reaching up to 502 mBq/kg. Maximum values of activity concentrations for 228Ra, 226Ra and Th isotopes were 230 mBq/kg, 1.29 Bq/kg and 52 mBq/kg, respectively. The most important contributors to the annual effective dose were 40K, 226Ra, 210Po and 228Ra contributing with 29 % 28 %, 24 % and 17 %, respectively. Th isotopes contributed with less than 2 %, while the contribution of anthropogenic radionuclides 137Cs and 90Sr were negligible (less than 1 %). Cumulative effective ingestion dose for infants was calculated to be 0.69 mSv/y, which is below the recommended limiting dose of 1 mSv/y. Largest proportion comes from the intake of fruit (33 %), followed by the intake of vegetables 19 %) and cereals 19 %). Although national radioactivity monitoring programs usually focus on anthropogenic radionuclides, this study highlights that naturally occurring radionuclides are dominant contributors to the cumulative effective ingestion dose in infants. Overall, the estimated cumulative effective ingestion dose for infants from consuming food available in Croatia is below recommended dose limits and therefore does not present a radiological concern.

Evaluation of cumulative dose distributions from external beam radiation therapy using CT-to-CBCT deformable image registration (DIR) for cervical cancer patients.

To investigate dose differences between the planning CT (pCT) and dose calculated on pre-treatment verification CBCTs using DIR and dose summation for cervical cancer patients. Cervical cancer patients treated at our institution with 45Gy EBRT undergo a pCT and 5 CBCTs, once every five fractions of treatment. A free-form intensity-based DIR in MIM was performed between the pCT and each CBCT using the "Merged CBCT" feature to generate an extended FOV-CBCT (mCBCT). DIR-generated bladder and rectum contours were adjusted by a physician, and dice similarity coefficients (DSC) were calculated. After deformation, the investigated doses were (1) recalculated in Eclipse using original plan parameters (ecD), and (2) deformed from planning dose (pD) using the deformation matrix in MIM (mdD). Dose summation was performed to the first week's mCBCT. Dose distributions were compared for the bladder, rectum, and PTV in terms of percent dose difference, dose volume histograms (DVHs), and gamma analysis between the calculated doses. For the 20 patients, the mean DSC was 0.68±0.17 for bladder and 0.79±0.09 for rectum. Most patients were within 5% of pD for D2cc (19/20), Dmax (17/20), and Dmean (16/20). All patients demonstrated a percent difference>5% for bladder V45 due to variations in bladder volume from the pCT. D90 showed fewer differences with 19/20 patients within 2% of pD. Gamma rates between pD and ecD averaged 94% for bladder and 94% for rectum, while pD and mdD exhibited slightly better performance for bladder (93%) and lower for rectum (85%). Using DIR with weekly CBCT images, the MIM deformed dose (mdD) was found to be in close agreement with the Eclipse calculated dose (ecD). The proposed workflow should be used on a case-by-case basis when the weekly CBCT shows marked difference in organs-at-risk from the planning CT.

Investigation of 5-fluorouracil cardiotoxicity in combinational therapy: Influence of risk factors and demographics in a Pakistani population.

5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat various types of cancers. Although widely used, it has consistently been attributed to cardiotoxicities after administration. The purpose of this study was to assess the parameters and predictors of cardiotoxicities associated with various 5-FU-based chemotherapeutic protocols in patients with GI/colorectal cancer, as well as the correlation of these cardiotoxic events with age, sex, cumulative dose, and risk factors such as obesity, hypertension, and family history of cardiac diseases. A prospective study consisting of 396 patients of both sexes was conducted in the oncology ward of Nishtar Hospital in Multan, Pakistan. Patients were grouped according to the therapeutic protocol they received (5-FU monotherapy or in combination, with different dosing regimens). Electrocardiography and serum troponin levels were used to assess 5-FU-induced cardiotoxicity. In cases where cardiotoxicity was detected, 5-FU treatment was interrupted; nitroglycerin, nitrates, and calcium channel blockers were administered; and cardiac monitoring was initiated. 5-FU was discontinued in all cases of acute myocardial infarction. Of the 396 patients, 28.5% reported different cardiotoxic symptoms after receiving various 5-FU-containing protocols. 35% had anginal pain, 13% suffered a myocardial infarction, 11% developed hypertension, and 10% presented heart failure. Patients receiving 5-FU combination therapy showed cardiotoxic events that were significantly different from those on 5-FU monotherapy. Based on the ECG results, only the QTc-d interval increased significantly (p < 0.001) after therapy. 68% of the patients had troponin levels > 2 ng/mL at the end of treatment. Pre-existing cardiac diseases, treatment duration, smoking, and obesity were found to be influential components in the development of cardiotoxicity, and patients with cancer should be closely monitored during 5-FU chemotherapy.

Proton Pump Inhibitors Worsen Colorectal Cancer Outcomes in Patients Treated with Bevacizumab

Background: Approximately one-third of patients with advanced colorectal cancer (CRC) and treated with bevacizumab are prescribed proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs). However, there is limited data on the effects of PPIs and H2RAs in these patients. To investigate the oncological outcomes of PPI and H2RA use in CRC patients treated with bevacizumab, we performed a retrospective cohort study using the Taiwan National Health Insurance Research Database and Taiwan Cancer Registry Database from 2005 to 2020. Methods: In CRC patients treated with bevacizumab, the PPI users and H2RA users were matched with patients without acid-reducing agents (ARAs) by 1:4 propensity score matching. PPI users and H2RA users were matched with propensity scoring in a 1:1 ratio. We divided patients into 4 cumulative PPI dosage levels to assess the dose–response relationship. The primary endpoints were 5-year overall survival and cancer-specific survival. Results: Compared with ARA non-users, both H2RA users and PPI users were associated with reduced overall survival. PPI users were associated with more significant negative effects on overall survival. Compared with H2RA users, PPI users were associated with lower 5-year overall survival (aHR: 1.19, 95% CI: 1.09–1.31) and cancer-specific survival (aHR: 1.20, 95% CI: 1.09–1.31). A similar dose–response relationship was observed for PPI users in terms of 5-year overall survival and cancer-specific overall survival. Conclusions: Compared to H2AR use, PPI use was associated with dose-dependent poorer oncological outcomes in metastatic CRC patients treated with bevacizumab.

Small-molecule mediated MuRF1 inhibition protects from doxorubicin-induced cardiac atrophy and contractile dysfunction

Cancer chemotherapy induces cell stress in rapidly dividing cancer cells to trigger their growth arrest and apoptosis. However, adverse effects related to cardiotoxicity underpinned by a limited regenerative potential of the heart limits clinical application: In particular, chemotherapy with doxorubicin (DOXO) causes acute heart injury that can transition to persisting cardiomyopathy (DOXO-CM). Here, we tested if MuRF1 inhibition (“MuRFi”) was able to attenuate DOXO-CM. To mimic DOXO chemotherapy, we treated mice over four weeks with five DOXO injections, resulting in a cumulative dosage of 25 mg/kg. At day 28, mice had lower body and heart weights, reduced cardiac cross-sectional myofibrillar areas (CSAs), and disturbed functional ejection fractions (EFs) and fractional shortenings (FS) as indicated by echocardiography (ECHO). In contrast, mice with a 1 g/kg Myomed#205 spiked diet, a previously described experimental MuRFi therapy, showed lower DOXO-CM at day 28, and also reduced acute DOXO cardiac injury at day 7 (single DOXO dose; 15 mg/kg). Underlying molecular signatures using Western blot (WB) assays showed at day 28 reduced phospho-AKT (AKTp) and phospo-4EBP1 (4 EBP1p) levels following DOXO that were normalized following MuRFi treatment. Taken together, our data suggest that MuRFi treatment is suitable to attenuate DOXO-CM by preserving AKTp and 4 EBP1p levels in DOXO stressed cardiomyocytes, thereby supporting de novo protein translation and cardiomyocyte survival under translational arrest stress.

Postnatal Steroids Use for Bronchopulmonary Dysplasia in a Quaternary Care NICU.

Intercenter variation and trends in postnatal steroids (PNS) use among preterm infants for prevention or treatment of bronchopulmonary dysplasia (BPD) is known. Understanding intracenter PNS use patterns facilitate implementation of center-specific change interventions to optimize outcomes.This study aimed to (i) quantify the proportion of infants who received PNS, and describe the timing, type, trends over time, regimen used, and deviations, and (2) describe the clinical characteristics and unadjusted outcomes of infants who received PNS. This was a cohort study in a quaternary neonatal intensive care unit including infants born at less than 33 weeks, and who received PNS for prevention or treatment of BPD between 2011 and 2021. Following data were included: proportion of babies who received PNS; type of PNS; age at initiation and duration; trends over time; deviation from published regimen; morbidity, mortality, and cointerventions. One hundred and eighty four infants (8% of <33 week' infants) received PNS. The median (interquartile range [IQR]) gestational age and birth weight were 25 (24-26) weeks and 720 (625-841) grams, respectively. The median (IQR) day of initiation and duration of PNS use were 29 (19-38) and 10 (10-22) days, respectively. One hundred and fifty-seven (85%) infants received dexamethasone (DX) and 22 (12%) received hydrocortisone as the first PNS course, and 71 (39%) infants received multiple courses. The proportion of infants receiving PNS remained unchanged, but the cumulative median dose received for BPD per patient increased by 56%. Nearly one-third of cumulative PNS dose came from PNS used for non-BPD indications. Forty-six percent infants had a deviation from published regimen (±20% deviation in duration or ±10% deviation in dose). Survival, survival without major morbidity, moderate-to-severe BPD, and technology dependence at discharge were 87, 2, 91, and 67%, respectively. Increased variation in PNS use, deviation from published regimen, and concurrent PNS exposure from non-BPD indication offer insights into implementing interventions to improve processes. · In this quaternary NICU, 8% of infants born before 33 weeks were administered postnatal steroids (PNS).. · The percentage of infants given PNS remained stable; however, the cumulative dose per patient for BPD rose.. · The study identified targeted interventions to minimize clinical practice variations at the center..

Liver fibrosis in inflammatory arthritis patients treated with methotrexate and hydroxychloroquine: A FIB-4 index analysis.

To evaluate the risk of liver fibrosis and associated factors with the non-invasive fibrosis score-4 (FIB-4) index in patients with inflammatory arthritis using methotrexate (MTX). Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were followed up in the rheumatology outpatient clinic, who were on methotrexate only and for whom FIB-4 index was could be calculated at methotrexate initiation and follow-up were included. The FIB-4 index was calculated according to the following formula: age (years) × AST(IU/L)/(platelet count(10 (9)/L) × √ALT(IU/L)). The patients' demographics, comorbidities, other treatments, cumulative MTX dose, and reasons for MTX cessation were assessed. For the multivariate analysis, possible factors associated with intermediate-high risk FIB-4 index at last visit were determined. A total of 107 patients were enrolled in the study, of whom 82 (76.6%) had RA and 25 (23.4%) had PsA. At the initiation of MTX, 24 (22.4%) patients had intermediate-high risk FIB-4 index. Comorbidities and the rate of ≥3-4 Charlson comorbidity index were more common in patients with intermediate-high risk FIB-4 index. A total of 37 (34.5%) patients had intermediate-high risk FIB-4 index at the last visit after median 3.6 (0.3-22.06) years follow-up. The median cumulative MTX dose was 2550 mg (1050-13.991). Cumulative MTX dose [OR 1.18 (1.01-1.33), p = .03] and diabetes mellitus [OR 4.60 (1.74-12.50), p = .002] were associated factors with intermediate-high risk FIB-4 index. The concomitant use of hydroxychloroquine (HCQ) was found to be a low-risk factor for FIB-4 index [OR 0.28 (0.10-0.78) p = .015]. The FIB-4 index is a non-invasive method that can be used in daily rheumatology practice for the evaluation and follow-up of patients who will use methotrexate. Comorbidities and cumulative MTX dose seem to be related with the risk of liver fibrosis. Concomitant use of HCQ with MTX may reduce the risk of liver fibrosis.

Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections.

Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections. This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients. In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections. BZDR initiation was associated with increased risks of serious infections,even when considering unmeasured familial confounding and confounding by indication. The exact pathways through which BZDRs may affect immune function, however, remain unclear. Further studies are needed to explore the neurobiological mechanisms underlying the association between BZDR use and serious infections, as it can lead to safer therapeutic strategies for patients requiring BZDR.

Quantifying corticosteroid burden in chronic rhinosinusitis with nasal polyps: A retrospective US database study

BackgroundReal-world burden data on systemic corticosteroid (SCS) use in chronic rhinosinusitis with nasal polyps (CRSwNP) are limited. ObjectiveThis study's objective was to describe the real-world burden of SCS in CRSwNP. MethodsThis retrospective cohort study included commercial/Medicare Advantage with Part D health plan members from the Optum Research Database with a first medical claim (index) for CRSwNP (January 2015 to July 2020). Primary outcomes/variables included SCS use, healthcare resource utilization (HCRU) and costs during the 12-month follow-up period. Outcomes were analyzed overall (N=21,172) and stratified by baseline comorbid asthma status and sinus surgeries during follow-up. ResultsOverall, 64.7% and 41.0% of patients used all-cause and CRSwNP-related SCS respectively, and 36.0% had ≥1 oral corticosteroid (OCS) burst (≥20 mg for 3–28 days); SCS use was higher in patients with asthma and those with a NP-related surgery (1, 2, ≥3) versus without. The mean (SD) all-cause cumulative OCS dose was 303.3 (675.0) mg/year and 23.5% had a cumulative annual dose ≥400 mg; these values were higher (p<0.001) in patients with versus without comorbid asthma (514.9 [956.1] vs. 247.5 [567.0]; 36.9% vs. 19.9%). All-cause and CRSwNP HCRU and costs increased with increasing number of surgeries; mean (SD) all-cause total medical costs were $14,472 (38,915), $26,909 (40,800), $29,816 (41,677), and $31,558 (37,143) with 0, 1, 2, and ≥3 surgeries, respectively. ConclusionThese data highlight the significant burden of SCS use in CRSwNP, particularly in patients with comorbid asthma and suggest a need to reduce SCS exposure.

Evaluation of Dexmedetomidine Withdrawal and Management After Prolonged Infusion

Dexmedetomidine is often used for longer than its labeled indication of 24 hours, raising concerns for potential withdrawal. Data are limited regarding this syndrome in adult patients. This study aimed to further characterize dexmedetomidine withdrawal in critically ill adult patients after prolonged use. This was an institutional review board-approved, single-center, retrospective chart review conducted at a tertiary academic medical center. Adult intensive care unit (ICU) patients on dexmedetomidine for ≥72 hours in 2019 were screened for inclusion. Exclusion criteria were interruption of dexmedetomidine for >6 hours, indications for dexmedetomidine other than sedation, or patients with neurological or burn injury. The major end point was the incidence of dexmedetomidine withdrawal, defined as meeting ≥2 of the following criteria within 24 hours of discontinuation: newly positive Confusion Assessment Method for ICU, Richmond Agitation Sedation Scale score of ≥+2, hypertension, and tachycardia. Minor end points were incidence of individual withdrawal signs as previously described, additional sedatives or antipsychotics required, dose and duration of dexmedetomidine infusion, length of ventilation, ICU and hospital length of stay, and new onset of the following: fever, vomiting, loose stools/diarrhea, diaphoresis, or seizure. Of the 152 patients included, dexmedetomidine withdrawal occurred in 54 patients (35.5%). Rebound hypertension was the most common withdrawal sign (47 patients [87.0%]). In the withdrawal group, significantly more patients required additional β-blockers (29 [53.7%] vs 10 [10.2%]; P < 0.01), were reinitiated on dexmedetomidine (16 [29.6%] vs 10 [10.2%]; P < 0.01), and required a start or increased dose of clonidine (6 [11.1%] vs 3 [3.1%]; P = 0.04). There was no significant difference in the cumulative dose or duration of dexmedetomidine between the groups. Length of ventilation was longer in the withdrawal group (171 hours [83.7-280.8 hours] vs 159 hours [149.0-335.7 hours]; P < 0.01), but there was no difference in ICU or hospital length of stay. Prolonged use of dexmedetomidine was associated with withdrawal syndrome in 35.5% of patients in our study. Larger trials are needed to confirm the risk factors for dexmedetomidine withdrawal and identify measures to prevent withdrawal.

Serum Carnitine Concentrations and Cardiac Function in Pediatric, Adolescent and Young Adult Oncology Patients Receiving High-Dose Anthracyclines

OBJECTIVE Anthracycline chemotherapy agents have significant dose-dependent cardiotoxic effects. ­Carnitine, a non-essential amino acid, is involved in long chain fatty acid oxidation, and carnitine deficiency can result in cardiomyopathy and cardiac arrhythmias. If administered concurrently with chemotherapy, carnitine supplementation could be a potential strategy to prevent cardiotoxicity. However, the association between serum carnitine concentrations and anthracycline cardiotoxicity during cancer treatment in the childhood, adolescent, and young adult (CAYA) age range has not been established. METHODS This prospective pilot cohort study characterized changes in serum carnitine concentrations and cardiac function before, during, and approximately 1 year after large-dose anthracycline therapy in newly diagnosed CAYA cancer patients. RESULTS Among 21 patients with a mean cumulative anthracycline dose exposure of 409 mg/m2 of ­doxorubicin equivalents, left ventricular ejection fraction and relative wall thickness decreased, indicating an overall decline in cardiac function. A reversible decrease in serum carnitine concentrations was also observed. A non-statistically significant positive correlation was observed; for every 1 mmol/L decrease in serum carnitine concentration, there was a 0.09% decrease in LVEF (p = 0.2). CONCLUSIONS These findings from this small pilot study suggest that there may be a relationship between serum carnitine concentrations and cardiac function after anthracycline therapy that should be evaluated in larger studies.

Sublingual Administration of Tacrolimus is Safe and Provides Similar Drug Exposure to Per-oral Route in Liver Transplant Recipients During Early Postoperative Period–A Large, Retrospective, Observational Study

BackgroundPer-oral(PO) administration of Tacrolimus(TAC) results in inadequate trough levels in early post-operative period in liver-transplant(LT) recipients who undergo Roux-en-Y hepaticojejunostomy for biliary reconstruction. Sublingual administration(SL) of tacrolimus provides an alternative route in such patients. ObjectiveTo assess feasibility and safety of SL tacrolimus in adult LT-recipients in early post-operative period and to compare therapeutic efficacy of SL administration of tacrolimus vs.PO route. Patients and MethodSingle-centre, retrospective, observational study carried out in adult living donor liver transplant(LDLT) recipients between January 2022 till December 2022. Recipients who underwent Roux-en-Y hepaticojejunostomy for biliary reconstruction, received tacrolimus through SL route till post-operative day(POD)5 as they were kept nil per oral constituted the study group while recipients who underwent duct-to-duct(D-D) anastomosis for biliary reconstruction were allowed orally from POD1 and received PO-tacrolimus were chosen as controls. Feasibility and safety of SL-Tacrolimus was assessed in terms of patient acceptance, need to discontinue SL-Tacrolimus, incidence of local adverse effects and systemic adverse events like neurotoxicity and nephrotoxicity. Therapeutic efficacy was evaluated by comparing median trough levels(TAC level) achieved and incidence of graft rejection between two groups. Results212 patients underwent LT during the study period of which 125 were included(58 in SL-group and 67 in PO-group). Both groups had comparable baseline characteristics. In SL-group, all patients tolerated SL-Tacrolimus well and no local adverse events were observed. Patients with SL-Tacrolimus administration achieved higher median TAC level(ng/ml) vs.PO route(5.85 vs 5(p=0.06)) despite similar median cumulative tacrolimus dose before assessing TAC-level. 50% patients achieved TAC level ≥6ng/ml in SL-group vs. 35.8% in PO-group(p=0.14). Incidence of neurotoxicity, nephrotoxicity and graft rejection during hospital stay were similar in both the groups(p=0.56,0.82 and 0.28 respectively). ConclusionSL-tacrolimus is safe and provides similar trough levels to PO-tacrolimus and may be considered as viable alternative whenever inadequate TAC-levels are anticipated through per-oral route.

Risks of Circulatory Diseases among Korean Radiation Workers Exposed to Low-dose Radiation.

High-dose radiation has been widely recognized as a risk factor for circulatory diseases. There is increasing evidence for risk of circulatory diseases in response to low and moderate radiation doses in recent years, but the results are not always consistent. We aimed to evaluate the associations between low-dose radiation exposure (<0.1 Gy) and the incidence of circulatory disease in a large cohort of Korean radiation workers. We collected data from a cohort of 187,001 radiation workers monitored for personal radiation dose since 1984 and linked with the National Health Insurance Service data from 2002 to 2021. Excess relative risks (ERRs) per 100 mGy were calculated to quantify the radiation dose-response relationship. The mean duration of follow-up was 13.3 years. A total of 12,705 cases of cerebrovascular disease (CeVD) and 19,647 cases of ischemic heart disease (IHD) were diagnosed during the follow-up period (2002-2021). The average cumulative heart dose was 4.10 mGy, ranging from 0 to 992.62 mGy. The ERR per 100 mGy with 10-year lagged cumulative heart doses was estimated at -0.094 (95% CI -0.248, 0.070) for CeVD and -0.173 (95% CI -0.299, -0.041) for IHD. The ERRs were not significantly changed after adjusting for confounding factors such as smoking, income, blood pressure, body mass index, and blood glucose level. A linear quadratic model was found to provide a better fit for the ERR of CeVD and IHD than a linear model (P = 0.009 and 0.030, respectively). There were no statistically significant variations in ERR/100 mGy estimates for either CeVD or IHD in terms of sex, attained age, and duration of employment; however, heterogeneity in the ERR/100 mGy estimates for CeVD among occupations was observed (P = 0.001). Our study did not find conclusive evidence supporting the association between occupational low-dose radiation and an increased risk of circulatory diseases. The significant negative ERR estimates for IHD need further investigation with a more extended follow-up period.

A cross-sectional study of associations between the 13C-sucrose breath test, the lactulose rhamnose assay, and growth in children at high risk of environmental enteropathy

BackgroundEnvironmental enteropathy’ (EE) is common among children who are highly exposed to enteric pathogens in low-resource settings. We optimised and validated a stable isotope-based breath test of intestinal sucrase activity (13C-SBT) as a non-invasive test of carbohydrate digestion and metabolism. ObjectivesThe primary objective of this study was to assess the relationship between the 13C-SBT and the lactulose/rhamnose ratio (LR) and growth in children. Secondary objectives were to assess the relationship between the 13C-SBT and additional biomarkers of EE. We also characterised the relationship between the 13C-SBT and child sex anddietary diversity, and household socioeconomic status and food security. MethodsIn this cross-sectional study, 12-to-15-month-old children were recruited in Bangladesh, India, Kenya, and Peru. Children were assessed with a 4-hour 13C-SBT and a 90-minute LR test. Plasma was collected for the determination of citrulline and the kynurenine/tryptophan ratio. Length and weight were measured, and other variables were assessed through questionnaires. For a subset of children, anthropometry was re-measured after three months. inear regression was used to examine associations corresponding to each objective. ResultsThree sites generated 13C-SBT breath curves that enabled pooled analysis. Differences in 13C-SBT breath curves, LR ratios, and other EE biomarkers were observed between sites. No associations were observed for 13C-SBT summary measures and LR, or child growth (e.g., association between LR and cumulative percent dose recovered at 90 minutes (cPDR90): -0.39, 95%CI: -1.79, 0.70). Length-for-age and weight-for-age were positively associated with the time to 50% of dose recovered (T50) (0.05, 95%CI: 0.01, 0.09, and 0.05, 95%CI: 0.02, 0.07, respectively), and dietary diversity was associated with T50 and cPDR90(-0.10, 95%CI: -0.18, -0.02 and 2.67, 95%CI: 0.47, 4.88, respectively). ConclusionsIn children at risk of EE there were no associations between the 13C-SBT, LR or other EE biomarkers encompassing different pathophysiological domains of EE. Trial Registryhttps://clinicaltrials.gov/study/NCT04109352

Outcomes of CEM43 in Predicting Thermal Damage Induced by Focal Laser Ablation in Controlled Ex Vivo Experiments: A Comparison to Histology and MRI.

Focal laser ablation (FLA) serves as a targeted therapy for prostate cancer (PCa). Clinical studies have demonstrated significant variations in ablation volumes with consistent fiber configurations. Consequently, a prediction model is needed for the safe application of FLA in treating PCa. This study aimed to evaluate the reproducibility of FLA-induced temperature profiles in controlled ex vivo experiments using clinical laser treatment protocols. Additionally, it sought to examine the effectiveness of the CEM43 model in predicting the zone of irreversible damage (ZID) and to compare these findings with outcomes derived from the Arrhenius model. Freshly excised postmortem human prostate and porcine liver specimens were used for controlled ex vivo ablation. Tissues were secured in a Perspex sample holder for precise placement of the laser fiber and thermocouples. FLA was conducted with a 1064-nm Nd:YAG laser at 3 W in continuous-wave mode for 10 min. Pre- and post-FLA 3D T1-weighted 7 T MRI scans were obtained to assess the treatment area. Whole-mount hematoxylin and eosin histological slides were prepared and digitized. On histology, the ZID was defined as the total of vaporized, carbonized, and coagulated tissue. A 2D thermal development map was created from temperature data, using bi-cubic interpolation. The cumulative equivalent thermal isoeffect dose at 43°C in minutes (CEM43) model was applied to predict the ZID, with 240 equivalent minutes (240-CEM43) used as the damage threshold. Additionally, the Arrhenius thermal model was used for comparison of CEM43 results. Predicted ZIDs were compared to MRI and histology. FLA treatment was performed on ex vivo human prostate samples (n = 2) and porcine liver specimens (n = 5). For human prostate tissue, FLA did not result in an identifiable ZID upon histological macroscopic examination or a lesion on MRI. Ex vivo porcine liver samples showed a clearly demarcated oval-shaped hyperintense lesion surrounding the laser fiber tip on post-FLA MRI. The MRI lesion (range 1.6-2.1 cm2) corresponded with the shape and location of the ZID on histology, but was smaller (median 1.7 vs. 3.2, p = 0.02). Histological examination of porcine liver samples revealed ZIDs ranging from 2.1 to 4.1 cm2, whereas 240-CEM43-predicted ZIDs ranged from 3.3 to 3.8 cm2. Although the median 240-CEM43-predicted ZID was not significantly larger than the histology ZID (3.8 vs. 3.2 cm2, p = 0.22), it tended to overpredict the histological results in most experiments. The median Arrhenius-predicted ZID was similar to the histologicalZID (3.2 vs. 3.2 cm2, p = 0.56), but varied in size when comparing individual experiments (range 2.5-3.2 cm2). FLA on ex vivo human prostate showed no thermal damage on histopathology or MRI. Ex vivo porcine liver FLA resulted in identifiable ZID on histology and lesions on MRI. 240-CEM43 generally overestimated the ZID and had less variability compared to histology. Results from the Arrhenius model were in better agreement with the histology findings, but still did not predict the individual FLA-induced histological thermal damage. Inter-experiment ZID variability underlines the need for developing a more comprehensive predictive dosimetry model for FLA in PCa treatment.

Geographic residence of patients with medication-related osteonecrosis of the jaw.

135 Background: Bone-modifying agents (BMAs) are utilized to reduce the risk of skeletal-related events in patients with bone metastases. Medication-related osteonecrosis of the jaw (MRONJ) is a rare but difficult to treat adverse event of BMAs. There are known patient and treatment related risk factors for development of ONJ, however, little is known on social and geographic risks. In patients with bone metastases and concurrent MRONJ, we seek to describe differences in patient's geographic residence (rural versus urban) with other social factors as secondary outcomes. Methods: We conducted a retrospective chart review of Atrium Health Wake Forest Baptist Comprehensive Cancer Center patients in the date range of 01/01/2013 to 11/01/2023. Included were patients with metastatic breast cancer, metastatic prostate cancer or multiple myeloma who had a diagnosis of MRONJ. We recorded Rural-Urban Commuting Area (RUCA) codes, the Area Deprivation Index (ADI), age, race, ethnicity, smoking status, alcohol use, body mass index, insurance status, type of cancer, type of BMA, and cumulative dosing of BMAs. Patients were defined as rural or urban based on criteria from the health resources and services administration website. Relative socioeconomic advantage versus disadvantage was determined by the patients’ ADIs with a decile rank from 1-10 for state ADIs and a percentile rank of 1-100 for national ADIs. SAS software (version 9.4) was used for data analysis (2023, SAS Institute Inc, Cary, NC). Results: A total of 88 patients met inclusion criteria. 64% of patients lived in urban areas and 36% in rural. Demographic features of the identified patients are listed in table 1. MRONJ patients from both urban and rural areas had an above average national and state ADI, with a trend toward higher ADIs in rural locations compared to urban locations; mean of 6.7 vs 5.3 state ADI and mean 70.6 vs 62.0 national ADI, for rural and urban patients respectively. There were no statistically significant differences between rural and urban patients in any of the demographic or health-related characteristics we examined. Conclusions: Patients with bone metastases and MRONJ in our cohort demonstrate relative socioeconomic disadvantage in comparison to national and state averages. In comparing the rural with urban patients, however, we observed relatively similar profiles. Patient characteristics by rural/urban status. Rural (n=32) Urban (n=56) Age in years (mean, sd) 64 (11.3) 65 (10.9) Sex, N (%) Male 19 (59) 29 (52) Female 13 (41) 27 (48) Race, N (%) Non-Hispanic White 30 (93.8) 40 (71.4) Non-Hispanic Black 1 (3.1) 11 (19.6) Hispanic 1 (3.1) 3 (5.4) Non-Hispanic Asian 0 (0.0) 1 (1.8) Other 0 (0.0) 1 (1.8) State ADI (mean, sd) 6.7 (2.4) 5.5 (2.7) National ADI (mean, sd) 70.6 (16.9) 62.0 (23.8) Former/current smoker, N (%) 18 (56.3) 25 (44.6) Medicaid/Medicare, N (%) 16 (50.0) 16 (28.6) Months on BMA (mean, sd) 37.2 (35.5) 40.3 (38.2)

MO48-2 Cardiotoxicity after high cumulative dose of anthracyclines in adults with advanced soft tissue sarcomas: a meta-analysis

MO48-2 Cardiotoxicity after high cumulative dose of anthracyclines in adults with advanced soft tissue sarcomas: a meta-analysis

Efficacy and safety of oral versus intravenous cyclophosphamide in treatment of connective tissue disease-related interstitial lung disease.

Interstitial lung disease (ILD) resulting from connective tissue disease (CTD) greatly undermines people's health. Cyclophosphamide (CYC) is a widely used agent in treating CTD-ILD. We compared the efficacy and safety of oral and intravenous CYC in CTD-ILD treatment. The retrospectively enrolled CTD-ILD patients were divided into the oral and intravenous CYC groups. The chest high-resolution computed tomography examination, forced vital capacity (FVC), lung carbon monoxide diffusion capacity (Dlco) determinations, and 6 min walk test (6MWT) were performed pre-treatment and at the 3rd, 6th, and 12th months posttreatment. Radiographic ILD severity was assessed using the Warrick score. Krebs Von den Lungen-6, surfactant protein A (SP-A), SP-D, and erythrocyte sedimentation rate (ESR) before and at the 12th month post-treatment were determined. CYC cumulative dose and occurrence of adverse reactions during treatment were recorded. CYC cumulative dose in the intravenous CYC group was reduced. Compared with oral CYC treatment, intravenous CYC caused decreased Warrick score and increased FVC and 6MWT at the 6th month, and elevated DLco at the 3rd and 6th months posttreatment. SP-A, SP-D and ESR levels in both groups were reduced 12 months posttreatment, with a more evident decrease in the intravenous CYC group. Intravenous CYC had lower total adverse reaction incidence. Compared with oral CYC, intravenous CYC decreases Warrick score and increases FVC and 6MWT at 6 months posttreatment, and reduces SP-A, SP-D, and ESR levels after 12 months of treatment, which shows low CYC cumulative dose and adverse reaction incidence in treating CTD-ILD.