Escalation Of Therapy Research Articles

2805. Extended-Infusion versus Intermittent-Infusion Piperacillin/tazobactam for High Minimum Inhibitory Concentration Pseudomonas aeruginosa Infections

Abstract Background Extended-infusion (EI) piperacillin/tazobactam, compared to intermittent-infusion (II) piperacillin/tazobactam, has been associated with improved clinical outcomes for both critically ill and febrile neutropenic patients. However, there is a paucity of data on whether these clinical benefits apply to broader populations. Infections involving high minimum inhibitory concentration (MIC) Pseudomonas aeruginosa represent an additional group where optimization of pharmacokinetic parameters may impact treatment success. Methods Medical records of adults who received II or EI piperacillin/tazobactam for pneumonia and/or bacteremia caused by Pseudomonas aeruginosa with MIC 8 or 16 mcg/mL were reviewed. The primary outcome was 30-day all-cause mortality. Hospital and/or intensive care unit (ICU) length of stay (LOS) and recurrence of infection were also recorded. Additionally, an escalation of care composite was assessed by need for new ICU transfer, new vasopressor start, new mechanical ventilation, or rescue antibiotic therapy change. Finally, a safety outcome of acute kidney injury (AKI) was recorded. Results A total of 69 patients were included, 31 in the II group and 38 in the EI group. Bacteremia was detected in 19.4% and 23.7% of the II and EI groups, respectively (p = 0.66). Baseline demographics and characteristics of treatment were similar between groups. The most common dosing regimens were 3.375 g IV every 6 hours over 30 minutes and 3.375 g IV every 8 hours over 4 hours. 30-day mortality was 32.3% in the II group and 39.5% in the EI group (p = 0.54). Similarly, hospital LOS (19 versus 15 days, p = 0.27) and ICU LOS (23 versus 15 days, p = 0.15), as well as recurrence (29.4% versus 23.5%, p = 1) and therapy escalation (38.7% versus 47.4%, p = 0.47), were not significantly different between groups. 43.5% of patients in the II group and 40.6% of patients in the EI group developed AKI (p = 0.83). Conclusion The present study found no significant difference in outcomes between piperacillin/tazobactam infusion strategies. However, the small sample size and complex patient factors may have limited the comparison. Disclosures Dustin R. Carr, PharmD, BCPS, BCIDP, Merck: Advisor/Consultant Thomas L. Walsh, MD, Accelerate Diagnostics: Advisor/Consultant Derek N. Bremmer, PharmD, BCIDP, Thermo Fisher Scientific: Advisor/Consultant

2789. Cefepime Versus Non-Cefepime/Non-Carbapenem Therapy for Blood Stream Infections Caused by Non-ESBL-Producing Serratia Marcescens: A Subgroup Analysis of The Carbapenem-Serratia Multicenter Retrospective Cohort Study

Abstract Background Serratia Marcescens causes serious infections. Carbapenems were prescribed due to the bacterium’s ability to develop inducible AmpC-mediated resistance. Recent IDSA guidance recommends ceftriaxone and in high-burden cases, cefepime. Evidence on the role of cefepime in the treatment of Serratia bacteremia is scarce. We aim to evaluate the outcomes of patients who received cefepime-containing empiric and/or definitive therapy (CFCT) to those receiving non-cefepime therapy (NCFCT). Methods This is a sub-analysis of a retrospective study of 7 Massachusetts acute care hospitals from January 1, 2015, to October 31, 2022. We included hospitalized adults (≥18 years) with Serratia Marcescens bacteremia. IRB approval was obtained. Demographics, clinical course characteristics, and choice of antibiotic therapy were collected. Primary outcome was 30-day mortality, and secondary outcome was composite antimicrobial failure (see Definitions in Table 1). Chi Square and Mann-Whitney U tests were computed using SPSS statistical package. Results The original Carbapenem-Serratia study had 73 out of 128 patients who met the inclusion criteria (Figure 1). The non-carbapenem group (n=56) was further studied for the purpose of this subanalysis and was divided into CFCT (n=15) and NCFCT (n=41). The two subgroups were similar in baseline comorbidities, severity measures, and sources of bacteremia (Table 1). Neither 30-day mortality nor the composite outcome of antimicrobial failure were significantly different with relative risks of 0.94 (95% CI 0.16 to 5.3, P=0.948) and 1.21 (95% CI 0.27 to 5.4, P=0.800), respectively. Study exclusion flow-chart with subanlaysis. ESBL phenotypically defined by ceftriaxone resistance (MIC <1). Characteristics and outcomes of patient with Serratia bacteremia treated with a cefepime versus non-cefepime nor carbapenem therapy regimen. * Immunocompromised patients are those receiving immunosuppressants, chemotherapy, or transplants, having HIV with CD4+ T cell count <200 cells/mm3, neutropenia with ANC < 500 cells/mm3, or corticosteroid use with prednisone or equivalent >10 mg for ≥ 14 days. † Hospital-acquired bacteremia is diagnosed when a positive blood culture obtained from patients hospitalized for 48 hours or longer. Healthcare-associated bacteremia was defined as a positive blood culture is obtained within 48 hours of hospital admission and the patient fulfills specific pre-defined criteria utilized in prior studies. Community-acquired bacteremia refers to positive a blood culture obtained within 48 hours after hospital admission in patients who do not fit the criteria for healthcare-associated infections. ‡ Deep seated complicated infection included Infective endocarditis, septic arthritis, osteomyelitis, or epidural abscess § Empiric antibiotic therapy: Antibiotics administered before antimicrobial susceptibility testing (AST) results, with a minimum 48-hour of uninterrupted duration and appropriate dosing. || Definitive antibiotic therapy (i.e., antibiotics administered after the AST results, also with a minimum of 48-hour duration). ¶ Duration of total definitive antibiotic therapy was counted from day of AST results until last day of definitive antimicrobial therapy. # Microbiological failure, microbiological relapse, in- hospital mortality, 30-day mortality, infection-related hospital readmission, or recurrent Serratia bateremia within 30 days. Microbiological failure refers to the growth of Serratia after 48 hours of definitive antibiotic therapy, while microbiological relapse is the regrowth of Serratia after a negative blood culture (Kunz Coyne et al., 2023). Note: Two patients had recurrence of Serratia bacteremia within 30 days, neither were resistant to third generation cephalosporins. Δ Infection-related re-admission was defined when a patient is readmitted not solely for a procedure or surgery, and they experience fever, worsening leukocytosis, or required escalation of antimicrobial therapy from the definitive therapy of the index admission. Conclusion Averting cefepime in the antimicrobial therapy of Serratia bacteremia is not associated with a significant increase in 30-day mortality or the composite outcome of antimicrobial failure. When applicable, a narrower beta-lactam therapy such as ceftriaxone may be appropriate. Limitations include a small sample size, with higher risk for type II error, and overlap in definitive antibiotic therapy. Further prospective studies are needed to confirm these findings, especially in patients with deep-seated infections. Disclosures All Authors: No reported disclosures

Dose escalation in intrathecal baclofen therapy based on disease etiology: Can an a priori target dose be established? A ten-year follow-up study

Context Intrathecal baclofen (ITB) therapy is administered for severe, persistent spasticity that cannot be addressed by oral medication or other treatments. Objective We aimed to evaluate the target dose of ITB for severe, persistent spasticity based on disease etiology. Methods Data at baseline (discharge), 1, and 10 years from 102 patients who received ITB therapy between 1985 and 2011 were retrospectively collected. Patients were divided based on disease etiology (cerebral, spinal, or multiple sclerosis [MS]) to evaluate differences in dose requirements. A comprehensive literature review of the dose trends in ITB therapy was conducted. Results Patients with cerebral spasticity (n = 62) required the highest dose after discharge (102.66 ± 30.9 µg), 1 (402.29 ± 300.2 µg), and 10 years (578.74 ± 421.2 µg). Patients with spinal spasticity (n = 19) required an average of 82.89 ± 30.7 µg baclofen at discharge, 296.3 ± 224.6 µg after 1 year, and 522.63 ± 425.97 µg after 10 years. Patients with MS-related spasticity (n = 21) had a dose of 82.73 ± 39.3 µg baclofen at discharge, 226.95 ± 193.3 µg after 1 year, and 320.6 ± 261.4 µg after 10 years. The differences among the categories were significant after 1 and 10 years of therapy. Conclusions The largest dose escalation occurs within the first year of ITB therapy. Our work provides a guideline for the initial dose setting during the inpatient stay after implantation and potentially expected dosage over the years thereafter, although this must always be adjusted individually.

Abstract 13948: Real World De-Escalation Practices in Genotype Guided P2Y12 Inhibitor Therapy and Pharmacoeconomic Implications

Background: Tailored P2Y12 inhibitor therapy is gaining popularity and is described as a method to balance safe and effective prescribing of clopidogrel. Based on previous work, 28% of our patients with CYP2C19 genotyping do not metabolize clopidogrel effectively (intermediate or poor metabolizers). Aim: We aim to describe the economic impact of a guided P2Y12 inhibitor strategy and the practice of escalation (clopidogrel to ticagrelor/prasugrel) and de-escalation (ticagrelor/prasugrel to clopidogrel) practices at a single health system. We hypothesize a guided approach is economically feasible vs. a universal ticagrelor or prasugrel approach. We also aim to determine how quickly clinicians escalate or de-escalate in response to CYP2C19 results. Methods: 3-year (2020-2022) data was collected from our EMR. Annually an average of 950 patients received CYP2C19 testing to guide P2Y12 inhibitor therapy (n=2799), and an average of 316 patients were either escalated or de-escalated (n=949). Of the 2799 patients, clopidogrel was most often the initial P2Y12 inhibitor (n=2240), followed by ticagrelor (n=525), and prasugrel (n=34). We estimated overall medication and CYP2C19 testing costs over the course of an average year (Figure 1) based on the assumption that over the course of 1-year patients would begin on 30 days of either ticagrelor, prasugrel, or clopidogrel and escalate/de-escalate therapy thereafter as guided by testing. Results: The time to escalation was similar if the CYP2C19 result was ordered before or after the first order for P2Y12 inhibitor therapy, median of 6.2 and 6.5 days respectively (p = .07). There was a difference in time to de-escalation based on time of CYP2C19 testing in comparison to medication ordering with a median time of 32.1 and 8 days when testing was ordered before initiation and after, respectively (p <.001). Conclusion: Overall, clinicians were highly responsive to CYP2C19 test results for both escalation and de-escalation of therapy.

Abstract 12630: Sex Differences in Patients Hospitalized With Acute Pulmonary Embolism - A Single Center Experience

Background: Acute pulmonary embolism (APE) is the third leading cause of cardiovascular death following stroke and myocardial infarction. Data regarding the impact of sex differences on the presentation, management, and outcomes of patients with (APE) remains limited. This study aimed to identify baseline characteristics and treatment strategies in males (M) versus females (F) from a single center experience. Methods: We retrospectively analyzed patients who underwent evaluation by our institutional pulmonary embolism response team for APE between 3/1/2016 and 1/1/2022. Baseline characteristics, biomarkers, and outcomes of interest were compared using Pearson’s Chi-squared test for categorical variables and Wilcoxon rank sum test for continuous variables. Results: The cohort included 886 patients, of whom 48.6% were females. The mean age was (61 ± 16) years. Males were more likely to be smokers (41% vs. 26 %; p<0.001), have a lower Body Mass Index (BMI) (31 ± 9 kg/m 2 , vs 33 ±10; p=0.01) and were more likely to have a history of prior stroke (12% vs 7.9%; p=0.04). The mean brain natriuretic peptide (BNP) on presentation was significantly higher in females (361 ± 624 pg/ml vs 281 ± 505; p=0.019). The mean d-dimer (F: 7,041 ± 6,438 ng/ml vs M: 9,063 ±11,447; p=0.13), troponin I (F: 1.60 ± 15.58 ng/ml vs M: 0.72±4.11; p=0.3), and lactic acid (F: 2.58 ± 3.20 mm/l vs M: 2.42 ± 2.43; p=0.6) were similar between both groups. PE severity (massive: 5.3% vs 6.4%; submissive: 58% vs: 55%; P=0.8) was similar between females and males. There were also no sex-based differences in the use of advanced therapies or outcomes. (Figure 1) Conclusion: In our APE cohort from a single center tertiary care center, sex differences in comorbidity profile (BMI, tobacco use, history of stroke) were observed. Females had a significantly higher BNP consistent with prior published literature. However, there were no sex-based disparities in PE severity, management, escalation of advanced therapies or outcomes.

Abstract 13600: LDL Levels and Lipid Lowering Management Across Age Groups in Mexican Population. Analysis From the Mexican Registry of Cardiovascular Diseases (REMECAR)

Background and Aims: Age is a major determinant of cardiovascular (CV) risk. While younger people are more likely to have lower CV risk they may have other risk factors that can impact the long-term development of cardiovascular disease. Among them, dyslipidemia has a crucial role in the development of atherosclerotic disease (ASCVD). Objective: This analysis aimed to compare LDL levels and lipid lowering management in patients with dyslipidemia across different age groups Methods: The REMECAR registry is a prospective, multicentre, observational study of patients attending to outpatient cardiovascular clinics for diagnostic, and clinical management of cardiometabolic diseases. Patients were classified according to their age group. Results: A total of 6,138 patients with a previous diagnosis of dyslipidemia were included in the analysis. The prevalence of ASCVD and comorbidities progressively increased with older age, while younger patients presented higher proportions of modifiable risk factors (Alcohol consumption, Smoking). Younger patients had significantly higher cholesterol, LDL-c, and triglycerides levels compared with groups >60 years (Figure 1A). Most of the patients <40 did not have any established lipid-lowering therapy (73.4%). This same group also showed higher proportions of patients with LDL>190mg/dL (6.3%) and with triglycerides>500mg/dL (4.8%). Low/Moderate Statin was the most frequent treatment, high-intensity statins were used in less than 20% of all groups despite the increasing prevalence of ASCVD (Figure 1B). Conclusions: A stepwise therapy escalation is reasonable in young patients, as the risk of CV events is not immediately perceived. However, this also prolongs long-term exposure if proper management is not established on time, leading to the progression of the disease. Our results underline the urgent need to improve population awareness, proper follow-up, and optimization of lipid-lowering management.

Abstract 18677: Residual Cardiovascular Risk Reduction Through a Digital App

Introduction: atherosclerotic cardiovascular disease (ASCVD) is the first cause of disability and death globally and represents the main etiological agent of myocardial infarction and ischemic stroke. The causal association between LDL cholesterol (LDL chol) and ASCVD is one of the most consolidated topics of modern medicine: it has gone from the demonstration that high levels of LDL Chol are a necessary condition for atherogenesis to the awareness that "the lower the better" and "the earlier the better" to underline the need for secondary and primary prevention to reduce atherosclerotic burden. Hypothesis: we hypothesized that motivational alerts sent through telemedicine to patients could affect escalation therapy in ASCVD patients. Aim: we evaluated the impact of a digital-APP in dyslipidemia management, and other CV risk factors, but focusing mainly on LDL chol. Methods: fifty dyslipidemic patients (APP_pts; 40 males; mean age 62±9 years; age range 40÷81 yrs) were followed through telemedicine-based APP from March 2022 to May 2023, in comparison with additional 50 dyslipidemic patients (ST_pts; 43 males; mean age 63±9 years; age range 40÷81 yrs) who underwent standard outpatient visits. Patients’ access to digital APP was remotely monitored and reports were used for therapy adjustments. Statistical analysis was performed with GraphPad Prism 7; comparisons were carried out by two-way ANOVA and by chi-square test. Results: baseline LDL chol values were 93,3±36,4 mg/dL, and 90,8±43,8 mg/dL, in APP_pts and in, ST_pts, respectively; six months after enrollment, both cohorts experienced significant reductions (APP_pts, 72,1±35,2 mg/dL, p=0,024; ST_pts, 76,7±38,6 mg/dL, p=0,008) vs baseline. We further subdivided both groups into ischemic and non-ischemic subjects (APP_pts: 26 vs 24; ST_pts : 33 vs 17). Remarkably, telemedicine control showed a 32% reduction in LDL chol for ischemic pts, while ischemic ST_pts gained only 11%. Overall, dyslipidemic control in non-ischemic pts appeared less beneficial (17 vs 15%). Finally, telemedicine-based APP resulted more effective than standard monitoring (p=0,04). Conclusion: aggressive lipid lowering therapies should be implemented with remote patients monitoring, mostly in the post-ischemic setting.

Re-intervention rates and symptom-free survival at 1year after endoscopic versus surgical management of strictures in Crohn's disease: A propensity matched analysis of a prospective inflammatory bowel disease cohort.

Resection for Crohn's disease (CD) related strictures is definitive but carries risk of morbidity, recurrence, and short bowel syndrome. On the contrary, the durability of endotherapy (ET) for CD-related strictures is questionable. Prospective comparative studies are limited. We aimed to prospectively compare the outcomes of ET in CD strictures with a case-matched surgical therapy (ST) cohort. Patients undergoing ET or resection for primary CD strictures (symptomatic, non-traversable, <5cm length, n≤3) between January 2021 and March 2022 in a high-volume tertiary center were compared with regard to recurrent symptoms, escalation of therapy, re-intervention, and re-operation based on propensity matched analysis. Fifty-nine patients [49% ET, 57.6% male, median (years): 34 (15-74)] had ≥12months of follow up. Before propensity matching, cumulative re-intervention rate was significantly higher with ET [34.5% (10/29) vs 3.3% (1/30) ST, P=0.002]. Recurrent symptoms (34.5% vs 26.7%, P=0.42), escalation of medical therapy (27.5% vs 23.3%, P=0.64), and re-operation (7.4% vs 3.1%, P=0.55) were comparable. In propensity matched analysis adjusted for demographics, disease, and stricture characteristics [n=42, 21 each, 62% male, median (years): 32 (15-60)], cumulative probability of re-intervention rates was higher in ET (28.6% vs 4.8%, P=0.042). The cumulative probability of recurrent symptoms (ET: 33.3% vs surgery 33.3%, P=0.93), therapy escalation (ET: 23.8% vs surgery 28.6%, P=0.75), and re-operation (ET: 9.5% vs surgery 4.8%, P=0.57) was similar. ET for CD strictures require higher re-interventions compared with resection although re-operation could be avoided in the majority with comparable symptom free survival at 1year.

A rare presentation of acute myocarditis as a manifestation of adult-onset Still’s disease: a case report

Abstract Background Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory condition characterized by a classical triad of symptoms that include prolonged fever, polyarthritis, and a characteristic salmon-pink skin rash. It can affect a variety of organ systems resulting in many different clinical presentations and is usually a diagnosis of exclusion. Myocarditis complicated by cardiogenic shock is a rare and life-threatening manifestation of AOSD, typically affecting younger patients. There is a limited experience and evidence in how best to manage this challenging patient cohort. Case summary A previously fit and well 22-year-old male presented with fever, arthralgia, and general malaise. On clinical examination, he was pyrexial and hypotensive, requiring vasopressor support for presumed septic shock. Subsequent transthoracic echocardiography and cardiac MRI findings were in keeping with fulminant myocarditis. Further septic and auto-immune screens were negative although he responded well to high-dose intravenous corticosteroids. Attempts to wean immunosuppression were unsuccessful, and his ferritin was markedly elevated (20 233 μg/L). A diagnosis of AOSD was suspected after exclusion of other possible causes. The successful addition of tocilizumab (an interleukin-6 receptor antagonist) therapy allowed for gradual de-escalation of steroid therapy and disease remission, with on-going remission at 18 months on maintenance therapy. Discussion This case highlights the importance of considering AOSD as a rare cause for myocarditis, especially when fever is present, or disease is severe. Failure to improve with first-line therapy involving high-dose corticosteroids, or inability to wean that therapy, should prompt consideration for escalation of therapy, with tocilizumab seemingly an effective treatment option.

Rapid phenotypic antimicrobial susceptibility testing of Gram-negative rods directly from positive blood cultures using the novel Q-linea ASTar system.

Adequate and timely antibiotic therapy is crucial for the treatment of sepsis. Innovative systems, like the Q-linea ASTar, have been developed to perform rapid antimicrobial susceptibility testing (AST) directly from positive blood cultures (BCs). We conducted a prospective study to evaluate ASTar under real-life conditions with a focus on time-to-result and impact on antimicrobial therapy. Over 2 months, all positive BCs that showed Gram-negative rods upon microscopy were tested with the ASTar and our standard procedure (VITEK 2 from short-term culture). Additionally, we included multidrug-resistant Gram-negative bacteria from our archive. Both methods were compared to broth microdilution. In total, 78 bacterial strains (51 prospective and 27 archived) were tested. ASTar covered 94% of the species encountered. The categorical and essential agreement was 95.6% and 90.7%, respectively. ASTar caused 2.4% minor, 2.0% major, and 2.4% very major errors. The categorical agreement was similar to standard procedure. The average time between BC sampling and the availability of the antibiogram for the attending physician was 28 h 49 min for ASTar and 44 h 18 min for standard procedure. ASTar correctly identified all patients who required an escalation of antimicrobial therapy and 75% of those who were eligible for de-escalation. In conclusion, ASTar provided reliable AST results and significantly shortened the time to obtain an antibiogram. However, the percentage of patients that will profit from ASTar in a low-resistance setting is limited, and it is currently unclear if a change of therapy 29 h after BC sampling will have a significant impact on the patient's prognosis.

Healing of the epithelial barrier in the ileum is superior to endoscopic and histologic remission for predicting major adverse outcomes in ulcerative colitis.

Achieving endoscopic remission is a key therapeutic goal in patients with ulcerative colitis (UC) that is associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of endoscopic and/or histologic remission against ileal barrier healing for predicting long-term disease behavior in a large cohort of UC patients in clinical remission. At baseline, UC patients in clinical remission underwent ileocolonoscopy with assessment of ileal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity and ileal barrier healing were scored using validated scores. During subsequent follow-up (FU), patients were closely monitored for clinical disease activity and occurrence of major adverse outcomes (MAO) defined as the following: disease relapse; UC-related hospitalization; UC-related surgery; necessity for initiation or dose escalation of systemic steroids, immunosuppressants, small molecules or biological therapy. Of the 73 UC patients included, 67% experienced MAO during a mean FU of 25 months. The probability of MAO-free survival was significantly higher in UC patients with endoscopic and/or histologic remission compared to patients with endoscopically and/or histologically active disease. Ileal barrier healing on endomicroscopy was highly accurate for predicting the further course of UC and outcompeted endoscopic and histologic remission for predicting MAO-free survival. Ileal barrier healing in clinically remittent UC patients can accurately predict future MAO development and is superior in its predictive capabilities than endoscopic and histologic remission. Ileal barrier healing therefore represents a novel and superior surrogate parameter for stratification of UC patients according to their risk for development of complicated disease behavior. https://classic.clinicaltrials.gov/ct2/show/NCT05157750, identifier NCT05157750.

Precision gestational diabetes treatment: a systematic review and meta-analyses

BackgroundGestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus.MethodsWe conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions.ResultsThere was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis.ConclusionsClinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.

Concurrent Radiation and Deep Hyperthermia Therapy for the Treatment of Recurrent Prostate Cancer

Robustpreclinical and clinical data have established hyperthermia as an effective radiosensitizer which can be used in the setting of recurrent disease to enhance the therapeutic window. We present a single institution experience examining outcomes in recurrent prostate cancer (RPCA) patients treated with concurrent deep hyperthermia (DHT) and radiation (RT). We hypothesized that concurrent DHT and RT would be well tolerated and would provide durable local control without unexpected toxicity. Consecutive RPCA patients treated with concurrent DHT and pelvic RT were retrospectively analyzed. Patients received twice weekly DHT treatments in addition to daily or twice daily (BID) RT. DHT was delivered using a concentric ring radiofrequency phased array system to a target temperature of 40-43°C. Acute and late treatment associated toxicities, graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, were evaluated. Survival and control outcomes were evaluated using the Kaplan-Meier method. Eighteen patients were included for analysis. Median patient age was 69 yrs (64-82 yrs). Fifteen (83%) patients had received prior RT and 12 (67%) patients had undergone radical prostatectomy. At time of treatment, two patients had RPCA which had dedifferentiated to a small cell phenotype. Eight (44%) patients had extra-pelvic disease at time of treatment. Seventeen (94%) patients received proton RT, while 1 (6%) received photon RT. Median RT dose was 49 Gy (range 30-73.8 Gy). Five (28%) patients received BID RT. Fifteen (83%) patients also received sequential or concurrent systemic therapy including androgen deprivation therapy or chemotherapy. A total of 142 DHT treatments were administered (median of 7.5 treatments). Fourteen (78%) patients completed ≥ 75% of planned DHT treatments. Reasons for inability to complete treatment included discomfort and abnormal vital signs during DHT. Only one patient reported Grade 2 pain and pruritus attributed to concurrent RT and DHT. One acute Grade 3 RT toxicity (diarrhea) was reported. No late Grade 3+ toxicities occurred. Of ten patients (56%) treated with curative intent, 8 (44%) had no reported failures at 2-year follow up while two had distant failure and biochemical failure respectively. Three (17%) patients were treated with palliative intent for disease related pain; two reported partial relief and one reported complete pain relief. With a median follow-up of 27 months (1-46 months), 2-year failure free survival was 41.4% (95% CI: 27.8-55%), local control was 76.5% (95% CI 66.2-86.8%) and overall survival was 70.9% (95% CI 58.4-83.3%). Our results suggest that concurrent RT and DHT is well tolerated and allows for safe escalation of local therapy for RPCA, providing patients with durable local control and palliation with an acceptable toxicity profile. Prospective validation is warranted.

Dose Escalation in Esophageal Cancer: Comparing Pre-Accrual and On-Trial Target Volume Delineation in the UK SCOPE2 Trial

The ongoing UK SCOPE2 trial evaluates radiotherapy (RT) dose escalation and PET-guided systemic therapy in esophageal cancer, and has an accompanying RT trials quality assurance (RTTQA) program, evolved through the preceding SCOPE trials. We compare pre-accrual with on-trial individual case review (ICR) target volume delineation (TVD). Prior to recruitment, centers were required to undertake TVD exercises using 3D/4D DICOM datasets with relevant clinical details and a RT planning guidance document (RPGD) provided. Contours were then compared against the RTTQA team-defined gold standard. Exceptions were those who had satisfied QA requirements for a previous esophageal RT trial (NeoSCOPE). For ICRs, prospective reviews (prior RT start, PRs) were undertaken for each center's first submission, plus high-dose cases submitted pending formal safety review. Additional PRs were undertaken at the RTTQA team's discretion. Timely retrospective reviews (within 2 weeks of RT start, TRR) were also undertaken for a random 10% sample. TVDs were assessed for compliance using predefined criteria and the RPGD. Resubmission was requested at reviewer's discretion, usually due to unacceptable variation (UV) from protocol. Clarification was sought before contour approval/resubmission request if appropriate. Review outcomes were then evaluated. PTV6000 was new to SCOPE2, along with a greater emphasis on use of 4DCT than in prior SCOPE trials. A total of 85 pre-accrual cases from 33 UK centers were reviewed, of which 20 (24%) were resubmissions, and 50 (59%) were accepted. 99 TVD UVs were observed in 49 cases, most commonly in CTVB (42/99, 42%), which included editing for normal structures and elective lymph node regions, followed by ITV (4D cases only, 14/52, 27%) and PTV6000 (13/99, 13%). 121 ICRs from 31 UK centers were available for review. 87 (72%) were PRs and 34 (28%) TRRs. 43 (36%) completed the relevant SCOPE2 exercise. 19 (16%) were resubmissions, and 82 (68%) were accepted. 72 UVs were observed in 45 ICRs; again, most commonly in CTVB (34/72, 48%), PTV6000 (high dose arm only, 11/46, 24%) and ITV (4D only, 5/26, 19%). Of the 45 cases where a UV was recorded, 16 (36%) had completed the relevant SCOPE2 pre-accrual. Comparing area of UV on SCOPE2 pre-accrual cases and ICRs, 3 (19%) contours contained the same (2 = CTVB, 1 = PTV6000), 5 (31%) contained different and 8 (50%) had no UVs at pre-accrual. The rate of UV was significantly lower for ICR than for pre-accrual submissions (0.60 and 1.16 respectively, p = 0.001). Significantly fewer UVs in ICR compared with pre-accrual supports a robust, educational RTTQA program through national collaboration and evolving trial series. CTVB, along with newer volumes of ITV and PTV6000, were recurring UV domains and should inform RPGD development and RTTQA for ongoing recruitment and future trials.

Development of a Screening Nomogram for Regional Lymph Node Metastasis Development in Muscle Invasive Bladder Cancer after Multiagent Systemic Therapy

A reliable method of identifying clinically node negative bladder cancer patients at greater risk of developing lymph node metastasis and may require intensified therapy is needed. The purpose of this study was to create a nomogram to quantify the risk for regional lymphatic involvement in non-metastatic muscle invasive bladder cancer. Usingthe National Cancer Database, patients with clinical T2-4N0M0 urothelial carcinoma of the bladder between the years of 2004 - 2020 were selected. All patients completed multiagent chemotherapy followed by surgery for pathologic nodal staging to determine presence or absence of nodal disease. No neoadjuvant radiation therapy was allowed and patients with history of prior malignancies were excluded. Following a 70:30 training to testing data split, baseline variables were assessed using univariate logistic regression. Variables were selected for inclusion in the multivariate logistic regression model using a combination of previously reported findings in the literature and/or if found to have a p-value < 0.05 on univariate analysis. A nomogram was constructed using this final model with assessment using calibration plots and the area under the receiver operating characteristics curve (AUC), respectively. An empiric cut point was chosen at 95% sensitivity to identify patients at "high" and "low" risk for pathologic nodal disease with overall assessment in both cohorts using chi-square. A total of 6194patients were identified for study with a median age of 65 years (IQR = 58 - 71 years). Most patients were male (68.0%) with T2 disease (81.2%). The final multivariate model included age at time of diagnosis (OR = 0.99; 95% CI = 0.99 - 1.00; p = 0.172), time from diagnosis to initiation of chemotherapy (OR = 1.00; 95% CI = 1.00 - 1.01; p = 0.005), papillary histology (OR = 0.85; 95% CI = 0.72 - 1.01; p = 0.068), and clinical T stage (Table 1). Model calibration demonstrated excellent goodness-of-fit with good discrimination (AUC = 0.644). Within the training data, high risk patients were seen to have a twofold increase in pathologic nodal disease (N = 835/3924, 21.2%) when compared to those identified as low risk (N = 38/347, 9.9%) (p < 0.001). Validation within the testing data set demonstrated similar results with pathologic node rates of 22.8% and 7.8% for high- and low-risk patients, respectively (AUC = 0.645, p < 0.001). This study demonstrates a clinically applicable risk stratification tool for identifying patients at risk for developing lymphadenopathy in T2-4 bladder cancer and may help guide future research in selecting patients eligible for escalation of therapy. Future studies should aim to externally validate this tool within prospective cohorts, and seek to determine if this nomogram may provide further prognostic utility.

Definitive Radiotherapy for Oligometastatic and Oligoprogressive Thyroid Cancer

Local consolidative radiotherapy (LCT) for oligometastatic disease is a promising paradigm improving outcomes for various malignancies but has been underexplored for metastatic thyroid cancer. We hypothesize that LCT to distant sites with definitive RT doses can yield favorable outcomes and defer systemic therapy escalation for these patients. We reviewed 96 thyroid cancer patients who received 175 LCT courses from 2010-2022 to 228 metastatic sites, including: thorax (45%), bone (40%), brain (6%), head/neck (5%), and abdomen (3%). Common prescriptions were 50-55Gy/4-5fxs or 56-70Gy/8-10fxs for lung; 52.5-60Gy/15fxs for mediastinum; and 18-24Gy/1fx or 27-30Gy/3fxs for bone. RECIST v1.1 and CTCAE v5.0 were used to define progression and toxicities, respectively. Outcomes were evaluated via Kaplan-Meier and associations examined via Cox proportional hazards modeling. Median age was 63 years (range: 26-92), with 62 oligometastatic cases (total 1-5 sites) and 34 oligoprogressive (with 1-5 growing sites). Primary disease was controlled in all patients, with 39% receiving post-op RT and 66% prior RAI. Histologies included papillary (40%), anaplastic (25%), follicular (12%), medullary (9%), Hurthle (7%), and poorly-differentiated (7%). Median time from initial diagnosis to LCT was 3 yrs (IQR 1-8), and median follow-up from 1st LCT was 21 mos (IQR 9-51). Patients received an average 2 LCT courses (range 1-8) treating 1-4 sites. Median survival (OS) from 1st LCT was 9 yrs (95% CI = 5-14). On multivariable analysis (MVA), worse OS was associated with anaplastic histology (HR 4.6, p<.01), but longer OS was associated with prior RAI (HR 0.33, p = .02) and oligometastatic disease (HR 0.3, p = .01). For anaplastic histology, median OS was 1.2 years vs. 9.3 years for non-anaplastic; 3-yr OS was 36% vs. 88% (log-rank, p<.01). Five-year OS for oligometastatic cases was 75% vs 53% for oligoprogressive (log-rank, p = .04). Median progression free survival (PFS) from 1st LCT was 15.5 mos (95% C I = 11-20). On MVA for all LCT courses, time to any progression (TTP) was negatively associated with anaplastic histology (HR 1.7, p = .02) and 2nd or higher LCT course (HR 1.45, p = .05), but favorably associated with thoracic site (HR 0.49, p<.01). Following later LCT courses, median TTP was 11 mos vs 17 mos for initial LCT course (log-rank, p = .03). After LCT to lung/chest, TTP was 18.6 mos vs 9.5 mos for non-thoracic sites (log-rank, p<.01). Only 6% of failures occurred at previously treated lesions. Most LCT courses (67%) were without ongoing chemotherapy, while 25% entailed continuing the same regimen and 9% had planned treatment post-RT. There were 2 Grade 3 toxicities (pneumonitis and esophagitis) and no Grade 4-5 events. With high local control rates and minimal toxicity, LCT can be a feasible strategy to defer systemic therapy escalation for oligometastatic and oligoprogressive thyroid cancer.

Pretreatment Neurofilament Light Chain Serum Levels, Early Disease Severity, and Treatment Response in Pediatric Multiple Sclerosis.

High disease activity and frequent therapy failure in pediatric multiple sclerosis (MS) make prognostic biomarkers urgently needed. We investigated whether serum neurofilament light chain (sNfL) levels in treatment-naive pediatric patients with MS are associated with early disease severity and indicate treatment outcomes. A retrospective cohort study of patients seen in the Göttingen Center for MS in Childhood and Adolescence, Germany. Inclusion criteria were MS diagnosis according to the McDonald criteria, MS onset <18 years, and available pretreatment serum sample. sNfL levels were analyzed using a single-molecule array assay. Associations with clinical and MRI evidence of disease severity at sampling were evaluated using the Spearman correlations and nonparametric tests for group comparisons. Correlations between pretreatment sNfL and annualized relapse and new T2 lesion rate on first-line therapy, and odd ratios for switch to high-efficacy therapy were assessed. A total of 178 patients (116 women [65%]) with a mean sampling age of 14.3 years were included in the study. Pretreatment sNfL levels were above the ≥90th percentile reported for healthy controls in 80% of patients (median 21.1 pg/mL) and correlated negatively with age, but no correlation was seen with sex, oligoclonal band status, or body mass index. High pretreatment sNfL levels correlated significantly with a high number of preceding relapses, a shorter first interattack interval, a high T2 lesion count, and recent gadolinium-enhancing lesions. Of interest, sNfL levels reflected more strongly MRI activity rather than clinical activity. Pretreatment sNfL levels also correlated significantly with the relapse rate and occurrence of new/enlarging T2 lesions while on first-line injectable therapy. Odds of future therapy escalation increased from 0.14 for sNfL below 7.5 pg/mL to 6.38 for sNfL above 15 pg/mL. In patients with a recent relapse, higher sNfL levels were associated with poorer recovery 3 months after attack. The results of this study have 3 important implications: First, pretreatment sNfL levels are a valuable biomarker for underlying disease activity in pediatric patients with MS. Second, pretreatment sNfL levels in pediatric patients with MS have a predictive value for the response to first-line therapy and the necessity of future therapy escalation. Third, high sNfL levels during a relapse are associated with poor recovery in this age group.

Insurance Approval Delay of Biologic Therapy Dose Escalation Associated with Disease Activity in Patients with Inflammatory Bowel Disease.

Dose escalation of self-injectable biologic therapy for inflammatory bowel diseases may be required to counteract loss of response and/or low drug levels. Payors often require completion of a prior authorization (PA), which is a complex approval pathway before providing coverage. If the initial PA request is denied, clinic staff must complete a time and resource-intensive process to obtain medication approval. This study measured time from decision to dose escalate to insurance approval and evaluated impact of approval time on disease activity. This was a single-center retrospective analysis of adult patients with IBD prescribed an escalated dose of biologic therapy at an academic center with an integrated specialty pharmacy team from January to December 2018. Outcomes included time to insurance approval and the association between approval time and follow-up C-reactive protein (CRP) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores. Associations were tested using linear regression analyses. 220 patients were included, median age 39, 53% female, and 96% white. Overall median time from decision to dose escalate to insurance approval was 7days [interquartile range (IQR) 1, 14]. Approval time was delayed when an appeal was required [median of 29days (IQR 17, 43)]. Patients with a longer time to insurance approval were less likely to have CRP improvement (p = 0.019). Time to insurance approval did not significantly impact follow-up SIBDQ scores. Patients who had a longer time to insurance approval were less likely to have improvement in CRP, highlighting the negative clinical impact of a complex dose escalation process.

Relation between global longitudinal strain and acute rejection in pediatric patients within the first-year post heart transplant

BackgroundAcute rejection leading to graft dysfunction remains a major cause of morbidity and mortality. In adults, assessment of global longitudinal strain (GLS) using speckle tracking echocardiography (STE) has been used as an early marker for graft dysfunction. Studies evaluating GLS in a sizable pediatric transplant population are scarce. ObjectivesWe sought to determine association between GLS and acute rejection within first-year post-transplantation in pediatric patients. MethodsPatients 0 to 18 years old who received heart transplants (HT) at Cleveland Clinic Children's Hospital after April 2013 were identified. Clinical data was collected from pre-transplant evaluation and post-transplant surveillance endomyocardial biopsy (EMB) visit from time of transplantation to one-year post-transplantation. Left ventricular (LV) GLS was measured retrospectively using vendor independent software. Significant rejection was defined by escalation in immunosuppression therapy due to pathology or clinical diagnosis. Trends of GLS were compared between patients with (Group 1) and without (Group 2) rejection, controlled for age. At the visit of rejection diagnosis, GLS rejection measurements were compared to the range of “normal”, non-rejection measurements. ResultsTwenty-seven patients met inclusion criteria. Eight patients (29.6 %) had at least one clinically significant rejection episode. There was no significant difference in GLS at the first endomyocardial biopsy visit between groups. At last biopsy visit, subjects with rejection had significantly worse GLS (p ≤ 0.001). In a mixed effect model, average global, 3-chamber, and 4-chamber systolic strain had significant interaction of group and time (p = 0.016, 0.033, 0.003, respectively). Systolic strain in those views significantly worsened over time in rejection group while remaining stable in non-rejection group. GLS of subjects with rejection were worse and out of the range of “normal” by the time of the third EMB visit. ConclusionsThere was a trend toward worse GLS in those who developed acute rejection within first year post-transplant compared to those without rejection.

Ki67 and prostate specific antigen are prognostic in metastatic hormone naïve prostate cancer

Background For metastatic hormone naïve prostate cancer patients, androgen deprivation therapy (ADT) with escalation therapy including docetaxel and/or androgen targeting drugs is the standard therapy. However, de-escalation is preferable to avoid unnecessary side effects, especially from docetaxel, but markers to identify these patients are lacking. The purpose of the present study was to investigate the potential of PSA and Ki67 immunoreactive scores as prognostic and treatment-predictive markers. Material and methods Prostate biopsies from 92 patients with metastatic hormone naïve PC (PSA > 80 ng/mL or clinical metastases) were immunohistochemically evaluated for PSA and Ki67. Gene expression analysis was performed with Clariom D microarrays to identify the phenotypic profile associated with the immunohistochemistry scores of biopsies. Cox regression analysis for progression free survival after ADT adjustment for age, ISUP, and serum PSA and Kaplan-Meier analyses were performed to assess prognostic values of Ki67, PSA, and the Ki67/PSA ratio. Results The immunohistochemical score for PSA was the strongest prognostic factor for progression-free and overall survival after ADT. Consequently, the ratio between Ki67 and PSA displayed a stronger prognostic value than Ki67 itself. Further, mRNA expression data analysis showed an association between high Ki67/PSA ratio, cell-cycle regulation, and DNA damage repair. In an exploratory sub-analysis of 12 patients treated with early docetaxel as addition to ADT and matched controls, a high Ki67/PSA ratio showed potential to identify those who benefit from docetaxel. Conclusion PSA and Ki67 immunoreactive scores are prognostic in the metastatic hormone-sensitive setting, with PSA being superior. The combination of Ki67 and PSA did not give additional prognostic value. The results suggest immunohistochemical scoring of PSA to have potential to improve identification of patients responding well to ADT alone.