Intensification Of Therapy Research Articles

Contemporary treatment of metastatic clear cell renal cell carcinoma

Renal cell carcinoma is one of the mostcommon malignant tumors in Germany with an increasing incidence. Drug therapy is indicated in relapsed or metastatic disease. The article is based on the content of the recent guidelines and aselective literature search. Combination therapies based on acheckpoint inhibitor are the current standard in first-line treatment of metastatic renal cell carcinoma. The median overall survival could thus be extended to > 50months. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score is used for risk classification. When selecting asuitable combination therapy, it is important to consider the advantages and disadvantages for each individual patient. There is currently no standard for follow-up therapies. So far, combination therapies have not shown any significant advantage in second-line treatment. It is recommended to switch to asubstance that has not yet been used. Currently, one purely immuno-oncology combination and four combinations of one immune checkpoint inhibitor and one tyrosine kinase inhibitor (TKI) are approved for first-line therapy in Germany. The added value of further intensification of therapy, in particular through triple combinations or further combination therapy in the second line, has not yet been proven.

Descriptive Evaluation in Outpatient Follow-up of Direct LDL-C in Patient with Elevated Triglycerides and Diabetes

Introduction. An annual fasting lipid panel (FLP) is recommended for patients with diabetes, and more frequent testing is advised when escalating cholesterol-lowering therapy. However, the calculated low-density lipoprotein cholesterol (LDL-C) using the Friedewald equation may be inaccurate when triglycerides (TG) are ≥400 mg/dL. In such cases, providers are required to order a separate direct LDL-C assay to confirm results, which increases the risk of overlooking the need for therapy intensification. Methods. The authors conducted a retrospective chart review across 13 outpatient clinics within a single health system over a five-year period. Patients aged 40-75 years, diagnosed with diabetes, and having at least one invalid LDL-C result were included. The primary outcome assessed the frequency of ordering a direct LDL-C assay within 7 days following an invalid LDL-C. Results. Among 1364 unique cases with invalid FLPs, 97 (7.1%) met the primary outcome. No significant association was identified between provider type and the likelihood of ordering a direct LDL-C. Therapy escalation was not significantly impacted by a direct LDL-C (14.1% direct vs 16.3% indirect) (p=0.6269) or provider type (16% MD/DO, 14.9% PA, 20.4% APRN) (p=0.6871). Conclusions: Our findings indicate that the current practice of manually verifying invalid LDL-C results at this institution may overlook necessary therapeutic intensification to meet guideline-based goals. The addition of a reflex direct LDL-C assay may enhance this process.

Abstract 4138757: Lipid-Lowering Therapy Intensification and Low-Density Lipoprotein Cholesterol Testing Following a Major Cardiovascular Event or Procedure in Adult Patients in the United States

Background: Optimizing lipid-lowering therapy (LLT) use is foundational to reduce atherosclerotic cardiovascular disease (ASCVD) risk, especially among patients who have already experienced an ASCVD event. This study aimed to evaluate the patterns of LLT intensification and LDL-C testing within 12 months following an ASCVD event in US patients. Methods: Adults who experienced an ASCVD event (acute coronary syndrome, coronary revascularization, stable angina, ischemic stroke, transient ischemic attack, or peripheral arterial disease) between January 1, 2016 and December 31, 2022 in the IQVIA Longitudinal Access and Adjudication Data were included. The first instance of LLT intensification after the event was defined as an increase from a low-moderate to high intensity statin, or the initiation of statins, ezetimibe, PCSK9i, or bempedoic acid in addition to a baseline LLT regimen that did not include these medications. Baseline medication use was defined during 6 months before the ASCVD event. Results: Among 6,028,573 patients who had an eligible ASCVD event (mean age: 63.6 years, 51.5% male), 53.9% were not taking any LLT and 43.2% were taking statins only (low-moderate intensity: 26.7%; high intensity: 16.4%) during baseline. Within 1, 3, and 12 months after the event, 16.3%, 21.3%, and 30.0% of patients intensified LLT, respectively. Among patients who intensified LLT within 12 months (n= 1,820,246), the most commonly observed intensification was from no LLT use at baseline to low-moderate (29.0%) or high-intensity statins (43.5%), followed by intensification from low-moderate to high-intensity statins (20.3%). LDL-C values at baseline were available in a subset of 10.7% of patients, with the median being 95 mg/dL (78.9% ≥70 mg/dL). LDL-C values were observed in 17.7% of patients within 12 months after the ASCVD event, with the median being 84 mg/dL (68.3% ≥70 mg/dL). Conclusions: Within 12 months after an ASCVD event, only about one-third of patients intensified LLT and two-thirds did not achieve guideline-recommended LDL-C levels. The results highlight a missed opportunity to reduce recurrent ASCVD events. Future effort is warranted to address the clinical inertia that may be contributing to this unmet need.

Real-world use of androgen-deprivation therapy intensification for metastatic hormone-sensitive prostate cancer: a systematic review.

To conduct a systematic literature review of real-world data (RWD) studies to summarise treatment patterns among men with metastatic hormone-sensitive prostate cancer (mHSPC).While androgen-deprivation therapy (ADT) is a primary treatment strategy for mHSPC, ADT intensification with androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy is recommended by current guidelines and has improved clinical outcomes in the last decade. We searched electronic databases (PubMed; Excerpta Medica dataBASE [EMBASE]) for eligible studies (retrospective or prospective observational RWD studies examining mHSPC treatment patterns) between database inception and July 2023, and manually screened the past 2 years of relevant conference proceedings. Of 2336 retrieved citations, 29 studies met the inclusion criteria, covering North America (United States, n = 21; Canada, n = 2), Europe (n = 8), and Asia (n = 6). Most studies utilised retrospective cohorts (n = 26) and included men with a median age of ≥70 years (n = 20). ADT monotherapy was predominantly used across geographies, followed by ADT + ARPI and ADT + docetaxel in the United States and Europe but not in Asia, where use of each combination remained low. Studies with recent electronic medical record data from cancer centres/registries showed >40% use of ADT + ARPI in the United States and Europe. Abiraterone was the most frequently used ARPI, followed by enzalutamide. Quantitative factors associated with ADT intensification were high disease burden, younger age, Eastern Cooperative Oncology Group performance status score of 0 to 1, fewer comorbidities, and oncologist physician specialty; qualitative factors were patient preference, unsatisfactory response to ADT, ability to tolerate adverse events, and absence of cost barriers. While there was an increasing trend in ADT intensification for mHSPC over the study period across geographies, use remained suboptimal considering the high proportion of patients who were still receiving ADT monotherapy only. These findings highlight the need for interventions to further optimise current mHSPC therapies with high guideline concordance.

Coagulation hemostasis disorders and elevated lipoprotein (a) levels in patients with arterial hypertension and multifocal atherosclerosis

Introduction. Hemostatic disorders may act as additional risk factors in patients with arterial hypertension (AH) and multifocal atherosclerotic lesion (MFAL). Elevated lipoprotein (a) (Lp(a)) levels may exacerbate procoagulant shifts.Aim. To identify disorders in the coagulation link of hemostasis in patients with AH and MFAL, depending on the level of Lp(a).Materials and methods. The study included 219 patients with hypertension and MFAL, median age 59 (53; 66) years, of which 110 patients with stage I–II controlled hypertension (group 1) and 109 patients with stage III controlled hypertension with a history of ischemic stroke. Depending on the level of Lp(a), patients in each group were divided into 2 subgroups with Lp(a) levels < 50 mg/dl and with Lp(a) levels above 50 mg/dl. Patients of both groups received antihypertensive, lipid-lowering, antiplatelet therapy and had comparable values of blood pressure and lipid spectrum.Results. In group 2 patients, procoagulant shifts were significantly more often recorded, despite the constant use of antiplatelet therapy. Violations of hemostasis parameters depending on the level of Lp(a) were observed in subgroups 1b and 2b. According to the results of multiple a posteriori comparisons, the most significant hypercoagulation changes were observed in patients with stroke, as well as with Lp(a) levels > 50 mg/dl.Conclusions. Thus, in some patients with hypertension and MFAL, despite taking antihypertensive, lipid-lowering and antiplatelet therapy, coagulation hemostasis disorders may occur. Elevated Lp(a) levels are combined with more pronounced hemostatic disorders, especially in the presence of a previous stroke. Intensification of antithrombotic therapy may be considered in such patients to prevent cardiovascular complications.

High-dose atorvastatin and rosuvastatin reduce the levels of neutrophil extracellular trap-related proteins in coronary artery disease: association with prothrombotic state.

Neutrophil extracellular trap (NET) formation is involved in atherothrombosis. We sought to investigate whether statins affect neutrophil extracellular traps activation and release (NETosis) in coronary artery disease (CAD), and whether such changes show associations with statin‑induced additional effects. We studied 130 patients with advanced CAD before and at least 6 months after initiation of high‑dose statin therapy with rosuvastatin 40 mg/d or atorvastatin 80 mg/d. The levels of circulating citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and neutrophil elastase (NE) were assessed as proteins associated with NETosis along with thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis inhibitors. Following statin therapy intensification, we observed reduced accumulation of H3cit (-30.4%), MPO (-28.1%), and NE (-25.5%; all P <0.001), all not associated with low‑density lipoprotein cholesterol (LDL‑C) lowering (-25%). However, H3cit level was lower in 50 patients (38.5%) who achieved the target LDL‑C below 1.8 mmol/l (-16.5%; P = 0.004), and in 19 patients (14.6%) with LDL‑C below 1.4 mmol/l (-25.5%; P = 0.001), as compared with the remaining individuals. The reductions in H3cit and MPO levels were associated with a 42.9% decrease in C‑reactive protein (CRP) level on high‑dose statins (R = 0.855; P <0.001 and R = 0.25; P = 0.004, respectively), along with increases in Ks and reduction in thrombin activatable fibrinolysis inhibitor (TAFI) activity, but not with CLT or thrombin generation (all |R|, 0.24-0.4; P <0.01). In multivariable analysis, changes in CRP (β = 0.771; P <0.001), TAFI activity (β = 0.125; P = 0.013), and fibrinogen level (β = 0.106; P = 0.034) were independently associated with a decrease in H3cit concentration. We showed for the first time that high‑dose statins can reduce the level of NET‑related proteins in association with anti‑inflammatory and antithrombotic actions in CAD patients.

Donor-derived cell-free DNA versus left ventricular global longitudinal strain in noninvasive detection of heart allograft injury

Abstract Introduction Invasive endomyocardial biopsy (EMB) is still considered the gold standard method for monitoring heart transplant (HTx) rejection. However, it is associated with potentially serious complications, and its histopathologic interpretation has high interobserver variability. Thus, noninvasive methods for surveillance of the transplanted organ remains of great interest. The noninvasive donor-derived cell-free DNA is a marker of graft injury which can indicate acute rejection, even before the histopathological diagnosis of rejection detected by EMB. The assay has a high negative predictive value for acute rejection. Left ventricular global longitudinal strain (LV GLS) is an emerging marker of subclinical myocardial injury which plays a crucial role in the evaluation of several cardiac diseases; however, its role in HTx injury has so far been poorly investigated. Purpose We aimed to investigate the efficacy of a local laboratory-run dd-cfDNA assay-based heart transplant rejection surveillance programme, and the prognostic and discriminatory performance of LV GLS for subsequent heart allograft injury. Methods HTx recipients without a history of allograft rejection requiring intensification of immunosuppressive therapy were transitioned from our EMB-based surveillance protocol to dd-cfDNA-based rejection surveillance. We assessed the percentage of dd-cfDNA to total cell-free DNA. Injury cut-off was defined by a dd-cfDNA level ≥0.20%, while the severe injury threshold was at ≥0.35%. LV ejection fraction was calculated using 2D Simpson’s method. To derive LV GLS, we analyzed apical 4-chamber, 2-chamber, and long-axis images by 2D speckle tracking echocardiography. Results A total of 244 dd-cfDNA samples were analyzed from 46 patients in fifteen runs performed monthly between October 2022 and December 2023. The dd-cfDNA fraction remained below the injury cut-off in most patients (81%). There were no missed rejection episodes. 88% of routine EMBs that would have otherwise been performed were safely avoided. Eighteen for-cause EMBs were performed based on dd-cfDNA levels suggesting injury. One EMB verified moderate cellular rejection (ISHLT grade 2R) that required steroid pulse therapy. Two EMBs proved mild cellular rejection, one EMB confirmed mild antibody-mediated rejection, while one EMB proved mixed rejection. Thirteen EMBs found no rejection. Mean LVEF was preserved (57.6%±7.6%). Mean LV GLS was -15.1%±2.5% in the whole cohort, while -15.6%±4.7% in recipients with HTx rejection on indication EMB. There was no significant correlation between dd-cfDNA and LV GLS (n=159). Conclusion The noninvasive dd-cfDNA assay is effective in ruling out acute rejection and safely decreases the necessity of invasive surveillance EMBs after HTx. LV GLS is less sensitive in comparison with the dd-cfDNA assay for detection of myocardial injury in the early stages of graft rejection in HTx recipients at low risk for rejection.

High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a)

Abstract Background Early and prompt reduction of low-density lipoprotein cholesterol concentrations (LDL-C) using combination lipid-lowering therapy (LLT) is recommended to lower cardiovascular risk in patients with ischaemic heart disease (IHD) and elevated LDL-C. Lowering LDL-C is also an important cardiovascular risk mitigation strategy in patients with elevated lipoprotein(a) [Lp(a)]. However, it is unknown if combination LLT reduces mortality in patients with elevated Lp(a). Aim To undertake an observational study to investigate the effect of combination LLT using high intensity statin with ezetimibe on cardiovascular outcomes in patients with and without elevated Lp(a). Methods Serum Lp(a) concentrations were measured in 520 consecutively recruited patients with IHD admitted to hospital, half of whom were admitted for acute myocardial infarction. Patients treated with high intensity statin and ezetimibe within the 1st year from admission to hospital (‘HI statin-ezetimibe group’, n=157) were compared with the rest of patients who had less intensive lipid lowering regimen (‘Others group’, n=363) for cardiovascular outcomes. Results During the 2-year follow-up period, 14.6%, 6.5%, and 53.1% of patients had all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) respectively. Median age was 63.5 years and 82.3% were male. Multivariable Cox regression showed that baseline Lp(a) ≥70 nmol/L was associated with increased risk of all-cause mortality (HR 1.97, 95% CI 1.20-3.22, P=0.007). Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ≥70 nmol/L (HR 0.51, P=0.007) or Lp(a) ≥100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ≥70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction &amp;gt;50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a). Conclusion Intensification of lipid-lowering therapy with high-intensity statin and ezetimibe improves cardiovascular outcomes in patients at very high cardiovascular risk, particularly those with elevated Lp(a). Larger studies are required to confirm our findings that this cardiovascular benefit is partially independent of LDL-C lowering.

Efficacy and safety of ambulatory, weekly, high-intensity intravenous diuretic strategy for congestion-refractory heart failure patients: insights from the DEA-HF prospective randomized clinical trial

Abstract Background Congestion and volume overload are strongly associated with low quality of life and pose a significant risk for both rehospitalization and mortality in heart failure (HF) patients. Despite the widespread use of diuretics in HF, the use of weekly, intravenous (IV), high-intensity diuretic treatment has not been prospectively studied in the setting of ambulatory congestion-refractory patients. Purpose To assess the efficacy and safety of weekly high-intensity diuresis regimens in a practical setting of ambulatory day care for chronically congested HF patients. Methods We performed a sub-analysis on data from a prospective, randomized, cross-over controlled study (DEA-HF) originally designed to compare diuresis regimens in the setting of an HF ambulatory daycare unit who had signs of congestion or volume overload despite adherence to guideline-directed medical therapy. Each patient received three different IV diuretic regimens, in one of six randomized sequences: IV furosemide 250mg; IV furosemide 250mg + oral metolazone 5mg; and IV furosemide 250mg + IV acetazolamide 500mg. All regimens given on the same chronological week were pooled, and diuresis efficacy was assessed by measuring excreted urine volume and sodium weight 6 hours post treatment initiation. Additional assessment at one week post each treatment included serum levels of NT-ProBNP, body weight and creatinine as well as congestion score based on the presence of ascites, pleural effusion and pedal edema. Statistical analysis was based on linear mixed models while accounting for the random effect of patient identity. Results A total of 42 patients were recruited. The mean age was 72±9 years, twenty-one subjects (50%) had LVEF ≥ 50%. 74% of patients were NYHA III class. All patients were on contemporary guidelines-directed HF therapy. Analysis of excreted sodium weight and urine volume revealed values of 4202.1±180.1 mg (Mean±SEM) and 1.77±0.07 liter per visit, respectively. No significant differences in efficacy were detected among treatments given in consecutive weeks (P= 0.80 and 0.69 for differences in sodium weight and urine volume, respectively). After 4 weeks, log(NT-ProBNP) was significantly decreased (P=0.044), accompanied by a significant decrease of 2.4±0.62 kg in body weight (P=0.0004) and of 0.92±0.44 points in congestion score (P=0.037). Serum creatinine level was only slightly increased by 0.19±0.04 mg/dl (P=0.0001), demonstrating the overall safety of the high-intensity diuresis strategy. Conclusions In ambulatory, congestion refractory HF patients a strategy based on high-intensity, weekly diuresis therapy was safe and effective for three consecutive weeks. The natriuresis response to the treatments was maintained, NT-ProBNP levels and congestion score were decreased. The strategy may be instrumental for ambulatory HF patients that require diuretic therapy intensification and may allow to prevent hospitalization.

Risk of recurrent ischaemic events in ACS patients with baseline LDL-C below guideline-recommended thresholds: insights from the prospective SPUM-ACS study

Abstract Introduction The 2023 European Society of Cardiology (ESC) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with acute coronary syndromes (ACS), adding ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to achieve recommended target goals (LDL-C&amp;lt;55 mg/dL). Purpose This population-based, real-world study aimed to examine cardiovascular (CV) events in ACS patients with baseline LDL-C levels below current guideline thresholds. Methods ACS patients admitted to four Swiss University Hospitals and enrolled in the multicenter SPUM registry (NCT 01000701) between 2009 and 2017 were followed prospectively until 1 year. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE); i.e., non-fatal stroke, myocardial infarction (MI), and death) at 1 year. Multivariable-adjusted Cox proportional hazard regression models were fit to estimate ischaemic risk among those with LDL-C&amp;lt;55 mg/dL. Results Out of 4’787 ACS patients, 226 patients (4.7%) had baseline LDL-C&amp;lt;55 mg/dL. These patients were older (69.7±11.3 vs 63.4±12.4, p&amp;lt;0.001), more frequently male (20.8%vs 15.9%, p&amp;lt;0.001), had more often traditional CV risk factors (all p&amp;lt;0.001) and were more likely to have a complex history of CV disease, such as previous MI (37.2% vs 10.9%, p&amp;lt;0.001), prior percutaneous (47.8% vs 13.2%, p&amp;lt;0.001) or surgical (15.0% vs 3.5%, p&amp;lt;0.001) coronary revascularization. Inflammatory biomarkers were also higher (hs-CRP, 30.1±63.6 vs 10.7±25.8 mg/L), with most patients being on high-dose statin therapy (82.4% vs 38.7%, p&amp;lt;0.001). At 1 year, patients with LDL-C&amp;lt;55 mg/dL had a higher rate of MACCE (16.4% vs 7.0%, p&amp;lt;0.001), with individual components of the primary endpoint occurring more frequently among these patients (all p&amp;lt;0.001), except for a numerical increase in CE (2.7% vs 1.7%, p=n.s.), as shown in the figure (Panel A). The enhanced MACCE risk persisted after adjustment for potential differences in baseline characteristics, with a 51% (adj. HR 1.51, CI95% 1.05-2.17, p=0.026) increase in MACCE (Panel B). Diabetes, low eGFR and high hs-CRP levels remained independent predictors of MACCE in patients with low baseline LDL-C (all p&amp;lt;0.001). Conclusions Our real-world data confirm that even ACS-patients reaching currently recommended LDL-C thresholds have a substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to further reduce CV risk.Event-risk according to baseline LDL-C

Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection.

Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs. We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir. Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

6849 Insulin Edema in newly diagnosed T1DM Pediatric Patient

Abstract Disclosure: A. Ansar: None. K. McNerney: None. Background: Insulin edema is a rare complication of insulin therapy, especially in the pediatric populations. The pathogenesis is not fully understood but has been linked to Insulin’s role in renal sodium handling and vascular permeability. It has been seen with the initiation of insulin in newly diagnosed patients or the intensification of insulin therapy in those with poor glycemic control.Clinical Case: A previously healthy 12 year old girl presented to the ED with polyuria, polydipsia and fatigue. She was alert and oriented but had kussmaul breathing. She was tachycardic but all other vitals were appropriate. Lab work up showed that she was in DKA with pH 7.07 and bicarbonate 7 mmol/L. Her corrected sodium and electrolytes were normal. Her HbA1C was elevated at 11.7% (4.0-5.6%). Initial fluid resuscitation was performed with 20 mL/kg NS fluids. She was transferred to our Pediatric ICU and was started on the DKA protocol consisting of intravenous insulin infusion at 0.1 unit/kg per hour and 2-bags of dextrose and non-dextrose containing intravenous fluids. She was given a new diagnosis of Type 1 Diabetes. She was transitioned to subcutaneous insulin 22 hours later with multiple daily injections with insulin lispro and glargine, with total dose of insulin at 0.7 unit/kg per day. She was transferred to the general care floor and received diabetes education while in the hospital. On the fifth day after discharge, patient started complaining of leg tightness, puffiness around her eyes and generalized swelling of both feet. She returned to the ED, where she was found to be hemodynamically stable and normotensive with a blood pressure of 113/54 mmHg. Her weight had increased 8.8 kg from the weight at discharge. Her physical exam was notable facial and bilateral periorbital edema, abdominal distension, and 2+ bilateral non-pitting non-tender edema of both legs extending to her medial malleolus. Neurologic exam was performed which was unremarkable. Work up was performed to rule out other causes of edema, including a complete blood count, electrolytes, kidney and liver function tests, all of which were normal. She received 20 mg of furosemide and was instructed to perform fluid restriction to 1 L/m2/day and sodium restriction to &amp;lt;2 grams per day at home. She followed up in clinic 3 days after her ED visit where her weight had decreased by 4.2 kg and her edema had mostly resolved with only 1+ bilateral non-pitting edema. Her total dose of insulin remained at 0.7 unit/kg per day, with acceptable blood glucose levels at home. Her fluid restriction was discontinued and patient was instructed to follow up as usual, and she had no further edema in follow-up. Conclusion: This was a rare case of a newly diagnosed pediatric patient presenting with Insulin edema, which is essential for clinicians to recognize, so they can identify patients presenting with this uncommon side effect to rule out conditions that may present in a similar manner. Presentation: 6/2/2024

7555 Gender-Related Differences in Outcomes of Patients With Diabetic Ketoacidosis: An Analysis of the National Readmission Database

Abstract Disclosure: E. Ahsan: None. C. Lesniak: None. M. Akula: None. K. Hu: None. K. Chalasani: None. R. Ong: None. S. Holland: None. M. Hossain: None. J. Cheng: None. J. Heaton: None. Introduction: Diabetic ketoacidosis (DKA), one of the most serious complications of diabetes, is a significant cause of morbidity and mortality. Hospitalizations for DKA have increased significantly over the past two decades. Despite this, there is a notable absence of data on gender-related variations in the clinical characteristics and outcomes of individuals hospitalized with DKA. Understanding these distinctions is crucial for optimizing disease prevention and care. Thus, the primary aim of this study was to explore whether gender influences the outcomes of DKA. Methodology: We analyzed the National Readmissions Database (NRD) from 2016 to 2020 by evaluating patients admitted with a primary diagnosis of DKA without coma. Patients were included if they were at least 18 years old and admitted between January and November. Patients meeting inclusion criteria were stratified by sex. The groups were assessed for 30-day readmissions, all causes of mortality, length of stay, and total cost. Descriptive statistics, Cox proportional hazards, and adjusted Wald tests were used to compare the groups. Results: Between 2016 and 2020, 642,431 patients met the inclusion criteria with a median age of 44, of which 46.5% were female and 53.5% were male. Early readmission occurred in 33,639.20 females and 31,101.92 males. Cox regression analysis showed a significant difference in readmission risk for female patients than males (HR 1.20, 95% CI 1.17-1.22, P = &amp;lt;0.001). The length of stay was higher in male patients than in female patients (adjusted Wald test, P =&amp;lt;0.001). Inpatient mortality was higher in females than in males (Cox regression analysis, P = 0.009). Total cost was higher in males compared to females (adjusted Wald test, P = &amp;lt;0.001). Conclusion: Regrettably, the majority of studies on diabetic ketoacidosis (DKA) have not given due attention to gender differences. Our study, however, reveals statistically significant variations in in-hospital mortality and 30-day readmission rates between men and women hospitalized with DKA, with women exhibiting higher rates than men. Additionally, the length of stay and total cost were found to be higher for men. To comprehend the underlying reasons for these distinctions, further investigations are warranted. Early introduction and intensification of insulin therapy may prove beneficial for this patient group in mitigating the risk of DKA and other complications associated with diabetes mellitus. Presentation: 6/2/2024

9183 Pituitary Metastasis Of Lung Adenocarcinoma Presenting As Anterior Pituitary Dysfunction

Abstract Disclosure: O. faour: None. M. Kinaan: None. S.K. Suryanarayanan: None. Introduction: The pituitary should not be overlooked as a site for metastasis and can be the first presentation of neoplastic disease in some patients. Most common presenting symptoms: headache, ophthalmoplegia, visual field defect and Arginine Vasopressin Deficiency (AVP-D). We present a case of pituitary metastasis of lung adenocarcinoma presenting as anterior Pituitary dysfunction that also showed partial AVP-D unmasked after starting steroids. Case Description: A 63-year-old male with history of tobacco use, COPD, and hypertension presented with syncope. He reported a 30lbs weight loss within prior 2 months, low energy, increased thirst, and polyuria. Physical exam was significant for cachexia, normal visual field on confrontation, and vital signs of BP 100/61, HR 83, and Weighing 180 lbs. Since he had syncope, Cortisol checked was undetectable and Free T4 was low, He was started on hydrocortisone and levothyroxine. CTA chest revealed a right hilar mass measuring 2.7 x 3 cm. Endobronchial biopsy was consistent with lung adenocarcinoma. MRI of pituitary gland revealed solid hypointense lesion with glandular thickening and diffuse heterogeneity involving most of the pituitary gland measuring up to 16 mm. No cavernous sinus invasion. Pituitary infundibulum showed diffuse thickening and enhancement of the pituitary stalk throughout with Intact posterior pituitary bright spot. Labs showed low LH, cortisol, ACTH, GH, TSH, and ADH. Initially, the patient was able to maintain a euvolemic status through increased water intake; however, he was later found to have partial central AVP-D when steroids were introduced. He responded to the use of Desmopressin, developed hyponatremia after 3 doses. He was started on a combination of carboplatin/pemetrexed/pembrolizumab but had no response and was transferred to palliative care/hospice and passed away within 7months after diagnosis.Discussion:Pituitary metastasis is rare and most commonly occurs in lung and breast cancers. Unfortunately, they are associated with poor prognosis. MRI findings of loss of posterior pituitary bright spot, thickening of the stalk, and dumbbell shape can be helpful in distinguishing between primary pituitary tumors and metastases. PET-FDG scan has limited value. Pituitary metastasis commonly presents with posterior pituitary dysfunction due to direct blood supply. Unmasking or worsening of AVP-D can happen with steroid replacement in patients requiring initiation or intensification of Desmopressin therapy. Treatment involves combination of surgery, radiation therapy, and systemic treatment for the primary cancer which can improve symptoms only but does not improve mortality. Presentation: 6/1/2024

Biomarkers and Prognostic Stratification of Squamous Cell Carcinoma of the Oral Cavity in Young Adults: how to personalize therapeutic management?

Abstract Squamous cell carcinomas (SCCs) of the oral cavity in young adults represent a heterogeneous entity. New prognostic biomarkers are described in the literature. The aim was to identify emerging biomarkers and prognostic stratification factors of young population. Clinical, biological, microbiological, histopathological, and molecular markers statistically associated with overall and disease-free survival (OS) and validated in literature. Young adults &amp;lt; 40 years who were non-smokers showed a marginally worse prognosis, while age &amp;lt; 30 years was unfavorable compared to &amp;gt; 30 years. High rate of Neutrophil-to-lymphocyte ratio (NLR) was associated with decreased 5-year disease-specific survival, PDL1 expression correlated with improved OS and recurrence-free survival, presence of Fusobacterium, Mutations in p53, Cyclin D1, and VEGF was associated with reduced OS. Combining these markers in young adult oral cavity SCCs should be used to adapt the intensification of therapy in addition to the TNM classification and minor histo-prognostic factors.

Fatigue and sensorimotor instability : Neurologically controlled conversion of post-COVID-19 patients

For the treatment of the symptoms of post-COVID-19 syndrome, no causal therapy is currently widely recommended according to evidence-based criteria. The overarching goal of the intervention study over a3-year period (Q1-2021-Q4-2023) was to evaluate the changes in the key symptoms of fatigue and sensorimotor instability through individualized stress-controlled training therapy and through intensified cognitive behavioral therapy. In the 3‑year period 407 vaccinated nucleocapsid positive patients were treated at the Post-COVID-19 Center Lausitz (Senftenberg). In 78(around 19%) fatigue/immunometabolic depression and sensorimotor instability were identified as the leading syndromes. The evaluation of the individualized stress-controlled training therapy was based on the specific post-COVID-19 syndrome and motor fatigue parameters. The secondary psychosomatic syndrome was assessed using cognitive fatigue parameters and cognitive behavioral therapy instruments. The investigation of -parameters influencing behavior took place in Q2-2023-Q4-2023 with aguide-supported qualitative interview among the participants. The post-COVID-19 key symptoms "fatigue," "sensorimotor instability," "neuropsychiatric symptoms," "cardiac/autonomic dysfunction," and "pain" improved significantly in the overall cohort and in the gender-specific analysis. Adeterioration occurred in "secondary psychosomatic symptoms". Atherapeutic effect was demonstrated for all motor fatigue parameters for the entire cohort using the Cohen's dvalue. An intensification of cognitive behavioral therapy achieved positive effects through an increasing development of the patients' own activity and their self-control using persuasion and gamification.

Multiplex analysis of post-Covid cardiorenal complications in patients with type 1 and type 2 diabetes mellitus according to the mobile diagnostic and treatment center (Diamobil)

Patients with diabetes mellitus (DM) are at risk for a higher incidence and severity of COVID-19, as well as its adverse outcomes, including post-Covid syndrome. to assess the incidence of cardiorenal complications in patients with type 1 and type 2 diabetes (T1DM/T2DM) who have had COVID-19, and to analyze the structure and severity of disorders according to examination data at the Diamobil mobile medical diagnostic and treatment center. a cohort of T1DM and T2DM patients examined in Diamobil (n=318), with a confirmed anamnesis of COVID-19 (n=236). The time interval between COVID-19 and the visit to Diamobil was 8.7/8.2 months for T1DM/T2DM. The parameters of the last visit before COVID-19 recorded in the Federal Register of Diabetes (FRD) were used as initial data. Clinical characteristics of patients with T1DM/T2DM: age - 49.2/64.5 years, duration of DM - 22/11 years, proportion of women - 64/73%, respectively. After analysis the data from visits before and after COVID-19 there weren't statistically significant differences in HbA1c levels for both types of DM (before 9.0/8.3%; after 8.4/8.2%, respectively), there was the intensification of glucose lowering therapy (the proportion of patients with T2DM on 2 and 3 component therapy increased by 4.3% and 1.6%, the proportion of patients on insulin therapy by 16%). After COVID-19, there was a statistically significant decrease in glomerular filtration rate (GFR) in T1DM from 88.1 to 62 ml/min/1.73 m2; with T2DM from 74.7 to 54.1 ml/min/1.73 m2. When assessing acute diabetic complications, there was an increase in the frequency of coma in T1DM by 1.5 times, severe hypoglycemia in T1DM by 3 times, and in T2DM by 1.7 times. Analysis of the frequency of cardiorenal complications before and after COVID-19 showed a total increase of 8.5% in T1DM, by 13.2% in T2DM, of which myocardial infarction, ischemic heart disease, and CHF increased in T1DM in the range from 1.5 to 5 times, with T2DM by 1.3 times, the frequency of CKD with T1DM by 1.5 times, with T2DM by 5.6 times. There was a decline of kidney filtration function (decrease in GFR) and an increase in the frequency of cardiovascular complications in both types of diabetes in post-Covid period while patients achieved a stable HbA1c levels by intensifying therapy during the COVID-19 infection. This fact reflects combined damage to the kidney and cardiovascular system as a part of the post-Covid syndrome and determines a key set of measures for the development of preventive strategies.

Integrating Novel Agents Into the Clinical Management of Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) is highly curable at all stages. Research efforts over the past few decades have largely focused on interim PET-adapted strategies for therapy de-escalation or intensification. The overarching goals have been to increase cure rates, minimize potential therapy-related effects, and optimize survivorship. Better understanding of the biology of cHL has led to the development and approval of effective novel agents including the antibody-drug conjugate brentuximab vedotin and the checkpoint inhibitor immunotherapies. In this review, we discuss recent trial results and how these agents are integrated into clinical practice with the goal of further optimizing outcomes.

Whole Lung Irradiation in Rhabdomyosarcoma With Lung Metastases: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Patients with rhabdomyosarcoma with metastatic disease have a poor prognosis despite therapy intensification. The aim of this study was to investigate the efficacy of whole lung irradiation (WLI) in patients with rhabdomyosarcoma and lung metastases. Patients with rhabdomyosarcoma with lung metastases enrolled on four Children's Oncology Group protocols (D9802, D9803, ARST08P1, ARST0431) were retrospectively reviewed. Event-free survival (EFS) and overall survival (OS) were compared between patients who received and did not receive WLI. In 143 patients with rhabdomyosarcoma with lung metastases, 65 patients (45.5%) received WLI and 78 patients (54.5%) did not receive WLI despite protocol requirements. The 5-year EFS was 38.3% (95% CI, 24.8 to 51.8) in patients who received WLI and 25.2% (95% CI, 13.8 to 36.6) in patients who did not receive WLI (P = .0496). The 5-year OS was 45.5% (95% CI, 31.8 to 59.3) in patients who received WLI and 32.4% (95% CI, 20.4 to 44.4) in patients who did not receive WLI (P = .08). In exploratory subgroup analyses, the benefit of WLI on EFS and OS was significant in patients 10 years and older. Other clinical factors associated with EFS on univariable analysis included age, histology FOXO1 fusion status, number of metastatic sites, location of metastatic sites, and Oberlin Score. WLI is associated with improved EFS in patients with rhabdomyosarcoma with lung metastases. These results highlight the potential importance of WLI and need for more stringent protocol compliance for administering WLI.

Practice patterns and predictors of treatment intensification in patients with metastatic castration-sensitive prostate cancer.

Treatment intensification beyond androgen deprivation therapy (ADT) has shown survival benefit in patients with metastatic castration-sensitive prostate cancer (mCSPC). There is a need to better understand how these novel treatments fit in real-world practice. Using electronic medical records and administrative data, a population-based, retrospective cohort study of patients newly diagnosed with de novo mCSPC between 2010 and 2020 in Alberta, Canada, and initiated ADT was conducted. Treatment intensification was defined as the receipt of apalutamide, abiraterone acetate, enzalutamide, or chemotherapy (e.g., docetaxel) within 180 days of ADT initiation. A total of 2515 de novo mCSPC were identified, with 2098 (83%) patients initiating ADT post-diagnosis. Of those, 525 (25%) received intensification beyond ADT. The percentage of patients who were intensified was 3% in 2010-2013 and gradually increased to 67% in 2020. From 2014-2017, docetaxel was the most commonly used approach, although it was supplanted by abiraterone acetate, apalutamide and enzalutamide from 2018 onwards. In multivariable logistic regression analyses of patients diagnosed from 2014-2020, significant predictors of intensification were younger age at diagnosis, lower Charlson comorbidity index, greater number of metastatic sites, shorter time to ADT initiation, referral to a medical oncologist, transurethral resection of the prostate or radiation prior to ADT, and more recent year of diagnosis (all p<0.05). Intensification increased for patients living in rural areas and with higher disease burden in 2018+ compared to 2014-2017. There has been a considerable increase in the use of ADT intensification therapies that correspond with the timing of clinical trial data and approvals of novel agents.