Intensive Therapy Research Articles

Neuroprotective and neuroregenerative drugs after severe traumatic brain injury : Anarrative review from aclinical perspective.

Traumatic brain injuries cause enormous individual and socioeconomic burdens. Survivors frequently struggle with motor handicaps as well as impaired cognition and emotion. In addition to the primary mechanical brain damage, complex secondary mechanisms are the main drivers of functional impairment. Many of these pathophysiological mechanisms are now well known: excitotoxic amino acids, breakdown of the blood-brain barrier, neuroinflammation with subsequent damage to cell organelles and membranes, cerebral edema, and apoptotic processes triggering neuronal death; however, paracrine resilience factors may counteract these processes. Specific neuroprotective and neuroregenerative intensive care therapies are few. This review highlights medical approaches aimed at mitigating secondary damage and promoting neurotrophic processes in severe traumatic brain injury. Some pharmacologic attempts that appeared very promising in experimental settings have had disappointing clinical results (progesterone, cyclosporineA, ronopterin, erythropoietin, dexanabinol). Thus, the search for drugs that can effectively limit ongoing posttraumatic neurological damage is ongoing. Some medications appear to be beneficial: N‑methyl-D-aspartate receptor (NMDA) antagonists (esketamine, amantadine, Mg++) reduce excitotoxicity and statins and cerebrolysin are known to counteract neuroinflammation. By supporting the impaired mitochondrial energy supply, oxidative processes are inhibited and neuroregenerative processes, such as neurogenesis, angiogenesis and synaptogenesis are promoted by citicoline and cerebrolysin. First clinical evidence shows an improvement in cognitive and thymopsychic outcomes, underlined by own clinical experience combining different therapeutic approaches. Accordingly, adjuvant treatment with neuroprotective substances appears to be apromising option, although more randomized prospective studies are still needed.

Clinical manifestations, prognostic factors, and outcomes of adenovirus pneumonia after allogeneic hematopoietic stem cell transplantation

BackgroundSevere pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT.MethodsTwenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan–Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses.ResultsThe incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17–609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia.ConclusionsWe first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy.

25years of lipid-lowering therapy: secular trends in therapy of coronary patients.

Guidelines on dyslipidemia and lipid-lowering therapy (LLT) over the years recommend lower low-density lipoprotein cholesterol (LDL-C) goals by more intense therapy. Nevertheless, LDL‑C has increased in the general population. Real-world trends of LLT medication as well as of LDL‑C levels in cardiovascular high-risk patients are unclear. From 2158 patients who were referred for elective coronary angiography, lipid medication was analyzed at admission in three cardiovascular observational studies (OS) over the last 25years: OS1: 1999-2000, OS2: 2005-2008 and OS3: 2022-2023. The three studies were performed at the same cardiology unit of atertiary care hospital in Austria. The proportion of patients without LLT significantly decreased from OS1 through OS2 to OS3 (49.4%, 45.6%, and 18.5%, respectively, ptrend < 0.001). Moreover, the percentage of patients under high-intensity statin treatment significantly increased from 0% to 5.1%, and 56.5% (ptrend < 0.001). Significantly more patients became treated by more than one compound (OS1: 1.8%, OS2: 1.6%, OS3: 31.2%; ptrend < 0.001). In the latest OS3, atrend to fixed-dose combination of statins with ezetimibe was observed. Mean LDL‑C levels decreased from 129 mg/dL over 127 mg/dL to 83 mg/dL, respectively (ptrend < 0.001). Of the patients on high-intensity therapy 34% met the recent ESC/EAS goals (LDL-C < 55 mg/dL), but only 3% on non-intense therapy. We conclude that during the observational period of aquarter of acentury, treatment intensity increased and LDL‑C levels improved considerably. Guidelines apparently matter in this high-risk population and are considered by primary care physicians.

Renal function and natriuresis-guided diuretic therapy-a pre-specified analysis from the PUSH-AHF trial.

In a randomized controlled trial, we recently showed that a natriuresis-guided diuretic approach improved natriuresis and diuresis in patients with acute heart failure (HF). In this pre-specified analysis, we investigated the association between (worsening) renal function, outcomes and the effect of intensive natriuresis-guided loop diuretic therapy as compared with standard of care. The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) trial randomized patients to natriuresis-guided diuretic therapy or standard of care. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at fixed timepoints, and worsening renal function (WRF) was assessed at 72 h. The primary outcome was the interaction between randomized treatment allocation, baseline eGFR and the dual primary outcome of PUSH-AHF: total natriuresis at 24 h and time to all-cause mortality or HF rehospitalization at 180 days. In 309 patients, median baseline eGFR was 53 (35-73) ml/min/1.73 m2, and 58% had eGFR <60 ml/min/1.73 m2. Baseline eGFR did not significantly modify the treatment effect of natriuresis-guided diuretic therapy on natriuresis at 24 h (p for interaction = 0.730). However, baseline eGFR significantly modified the effect on all-cause mortality and HF rehospitalization (p for interaction = 0.017): the risk of this second primary outcome was lower in patients with lower eGFR who were randomized to the natriuresis-guided group. In the natriuresis-guided arm, eGFR decreased more (-11.0 vs. -6.91 ml/min/1.73 m2; p = 0.002) during the first 3 days, but this effect was attenuated at discharge (-10.3 vs. -8.69 ml/min/1.73 m2; p = 0.38). WRF was more frequently observed in patients randomized to natriuresis-guided treatment, but was not associated with worse clinical outcomes. Natriuresis-guided diuretic treatment improved diuresis and natriuresis irrespective of baseline eGFR and occurrence of WRF, was effective even in patients with low eGFR, and the observed effect on eGFR was transient and not associated with worse clinical outcomes.

A Tissue Distribution Study of Propafenone in an Intentional Fatal Poisoning Case

Propafenone (PPF) belongs to the class 1C antiarrhythmics and can cause electrocardiogram-associated adverse/toxic effects. Cases of PPF intoxication are rarely investigated. We developed a novel and selective GC-MS/MS method for the determination of PPF and its tissue distribution in an intentional fatal poisoning case, which is applicable to PPF quantification in the range of therapeutic to lethal concentrations in complex post-mortem samples. A simple and effective sample pretreatment was applied to all analyzed samples. PPF was determined without the need for dilution, even in highly complex samples containing a wide range of analyte concentrations. Quantification was performed using the standard addition method, developed and validated according to the ICH M10 guidelines. The obtained results indicated that the PPF concentration in the serum from blood taken while alive, before therapy, was the highest ever reported in the literature. Despite the intensive therapy after the patients’ admission, the PPF concentrations in the lungs, spleen, femoral blood and cardiac blood were fatal or abnormally high. On the other hand, the concentrations in the liver and skeletal muscle were lower or approximately the same as observed in cases with therapeutic doses. To the best of our knowledge, the distribution of PPF has not been investigated in fatal intoxication cases and can be helpful in clinical or forensic toxicology.

Predictors of cardiovascular risk in familial hypercholesterolemia.

Familial Hypercholesterolemia is associated with an increased risk of cardiovascular disease. The current international guidelines of the main scientific societies consider that all people with familial hypercholesterolemia have a high or very high cardiovascular risk. However, the occurrence of atherosclerotic cardiovascular disease is very heterogeneous in this population. Stratifying risk within people with familial hypercholesterolemia is essential to identify individuals who require intensive cholesterol-lowering therapies. In the last year, several studies have been published focusing on the contribution of diabetes to familial hypercholesterolemia, the role of stroke, as a manifestation of atherosclerotic disease, and the external validation of the SAFEHEART risk equation in the English population diagnosed with Familial Hypercholesterolemia. It is necessary the development of a tool that allows us to identify, in a simple, reproducible, and universal way, patients who may have a high risk of suffering a cardiovascular event and who are susceptible to more intensive treatments to reduce cholesterol levels.

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.

The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

Intensive Cognitive Behavioral Therapy for Adolescents with Anorexia Nervosa Outcomes before, during and after the COVID-19 Crisis

Studies comparing treatment outcomes in patients with eating disorders before and during the coronavirus (COVID-19) pandemic have yielded conflicting results. Furthermore, no study has yet evaluated treatment outcomes in adolescent patients with anorexia nervosa before, during and after the crisis. Hence, this study investigated the outcomes of an intensive Cognitive Behavioral Therapy-Enhanced (CBT-E) program on adolescents with anorexia nervosa consecutively treated before (n = 64), during (n = 37) and after (n = 31) the period of emergency spanning 8 March 2020 to 31 March 2022. Results show consistent and similar improvements in eating disorder psychopathology, general psychopathology and body mass index-for-age percentiles across all three periods, with approximately 60% of patients maintaining a full response at the 20-week follow-up, suggesting that treatment efficacy remained robust. Overall, the study underscores the effectiveness of intensive CBT-E as a viable treatment option for adolescents with anorexia nervosa, even during and after unprecedented challenges such as those posed by the COVID-19 pandemic.

Monocytic Differentiation of Human Acute Myeloid Leukemia Cells: A Proteomic and Phosphoproteomic Comparison of FAB-M4/M5 Patients with and without Nucleophosmin 1 Mutations

Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased responsiveness) and possibly also bromodomain inhibition (increased responsiveness). FAB-M4/M5 patients are heterogeneous with regard to genetic abnormalities, even though monocytic differentiation is common for patients with Nucleophosmin 1 (NPM1) insertions/mutations; to further study the heterogeneity of FAB-M4/M5 patients we did a proteomic and phosphoproteomic comparison of FAB-M4/M5 patients with (n = 13) and without (n = 12) NPM1 mutations. The proteomic profile of NPM1-mutated FAB-M4/M5 patients was characterized by increased levels of proteins involved in the regulation of endocytosis/vesicle trafficking/organellar communication. In contrast, AML cells without NPM1 mutations were characterized by increased levels of several proteins involved in the regulation of cytoplasmic translation, including a large number of ribosomal proteins. The phosphoproteomic differences between the two groups were less extensive but reflected similar differences. To conclude, even though FAB classification/monocytic differentiation are associated with differences in responsiveness to new targeted therapies (e.g., Bcl-2 inhibition), our results shows that FAB-M4/M5 patients are heterogeneous with regard to important biological characteristics of the leukemic cells.

An interpretable framework to identify responsive subgroups from clinical trials regarding treatment effects: Application to treatment of intracerebral hemorrhage.

Randomized Clinical trials (RCT) suffer from a high failure rate which could be caused by heterogeneous responses to treatment. Despite many models being developed to estimate heterogeneous treatment effects (HTE), there remains a lack of interpretable methods to identify responsive subgroups. This work aims to develop a framework to identify subgroups based on treatment effects that prioritize model interpretability. The proposed framework leverages an ensemble uplift tree method to generate descriptive decision rules that separate samples given estimated responses to the treatment. Subsequently, we select a complementary set of these decision rules and rank them using a sparse linear model. To address the trial's limited sample size problem, we proposed a data augmentation strategy by borrowing control patients from external studies and generating synthetic data. We apply the proposed framework to a failed randomized clinical trial for investigating an intracerebral hemorrhage therapy plan. The Qini-scores show that the proposed data augmentation strategy plan can boost the model's performance and the framework achieves greater interpretability by selecting complementary descriptive rules without compromising estimation quality. Our model derives clinically meaningful subgroups. Specifically, we find those patients with Diastolic Blood Pressure≥70 mm hg and Systolic Blood Pressure<215 mm hg benefit more from intensive blood pressure reduction therapy. The proposed interpretable HTE analysis framework offers a promising potential for extracting meaningful insight from RCTs with neutral treatment effects. By identifying responsive subgroups, our framework can contribute to developing personalized treatment strategies for patients more efficiently.

CLINICAL RELEVANCE OF HIGH SENSITIVITY C-REACTIVE PROTEIN IN ACUTE MYOCARDIAL INFARCTION PATIENTS

Objectives: Poor cardiovascular outcomes have been linked to high-sensitivity C-reaction protein (hs-CRP), a biomarker of residual inflammatory risk. Whether or not a patient has diabetes mellitus, evaluate the relationship among hs-CRP levels estimated at hospital admission and in-hospital consequences and death. Methods: This prospective cohort study included 100 acute myocardial infarction (AMI) patients with both non-ST elevation myocardial infarction (STEMI) and STEMI who were admitted to the cardiac care critical care unit intensive therapy unit. Results: Diabetics had a considerably higher incidence of hypertension (p=0.001) and dyslipidemia (p=0.001) compared to non-diabetics. Diabetics exhibited a significantly higher mean hs-CRP level (6.76±1.12 vs. 3.65±0.98 mg/dL; p=0.01) than non-diabetics. Meanwhile, compared to non-diabetics, diabetics utilized significantly more aspirin (p=0.001), beta-blockers (p=0.001), angiotensin receptor blockers (ARBs) (p=0.01), and statins (p=0.001). Furthermore, compared to those with hs-CRP &lt;3 mg/L, those with hs-CRP ≥3 mg/dL had a significantly higher incidence of dyslipidemia (p=0.001) and hypertension (p=0.001). Conclusion: The results of the current study demonstrated that hs-CRP upon admission is a valid predictor of hospital morbidity and death in patients with AMI who are diabetic or non-diabetic. Individuals with diabetes showed greater CRP levels than non-diabetic AMI patients did.

The First Two Years of COVID-19 Hospitalization Characteristics and Costs: Results from the National Discharge Registry

Background: The COVID-19 pandemic has emerged as the primary global health challenge of the new millennium. Understanding its impact on health systems and learning from these experiences are crucial for improving system resilience against future health crises. This paper examines hospitalizations related to COVID-19 in Italy from 2020 to 2021, with a specific focus on the costs associated with these admissions. Design and methods: This is a retrospective, population-based study of Italian hospitalizations of patients diagnosed with COVID-19 during the 2020–2021 period, using data extracted from the National Hospital Discharge Registry. The outcome variables considered include hospital admissions, costs, and length of stay. Results: In Italy, hospitalizations for COVID-19 totaled 357,354 in 2020 and 399,043 in 2021, with the transfer rate being three times higher than that of other patients. Hospitalizations were predominantly concentrated in the northern regions, especially during the first year. Mortality rates increased with age, while hospitalization rates peaked in the youngest and oldest age groups. The financial impact of COVID-19 hospitalizations was approximately €3.1 billion in 2020 and €3.6 billion in 2021. The cost per admission was around €8000 for standard care and €24,000 for intensive therapy in both years. Conclusion: Conducting a cost-benefit analysis of implementing a protective pad around the entire health system, which leverages networks of family doctors and nurses connected in real-time, could be an important step in strengthening health system resilience.

Abstract PO1-15-12: Circulating tumor DNA (ctDNA) for prediction of pathologic complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: WSG-Keyriched-1 trial

Abstract Background ctDNA testing is emerging as an important biomarker in early breast cancer (eBC). However, its value in prediction of tumor response to de-escalated, chemotherapy-free neoadjuvant therapy (NAT) remains underexplored. In WSG-Keyriched-1 (NCT03988036), a single-arm phase 2 trial, we investigated for the first time a chemotherapy-free NAT with dual HER2 blockade and pembrolizumab in HER2- enriched HER2+ eBC. In this pre-specified translational analysis, we evaluated whether ctDNA measurement could predict pCR. Methods 48 patients (pts) with HER2 2+ (ISH+) or 3+ eBC (stage I-III) and HER2-enriched subtype by PAM50 were included. Pts received pembrolizumab (200 mg), trastuzumab biosimilar (loading dose (LD) 8 mg/kg bodyweight (BW), maintenance dose (MD) 6 mg/kg BW), and pertuzumab (LD 840 mg/kg BW, MD 420 mg/kg BW) q3w for 12 weeks. Primary objective was pCR (ypT0/is ypN0). ctDNA was analyzed in 92 plasma samples collected from 31 pts at baseline (BL) and week 3 of NAT and 30 pts at end of treatment (EOT). Sequencing libraries with unique molecular identifiers were constructed from cell-free DNA and hybridization panels with ≤50 patient-specific somatic mutations from tumor sequencing were used for enrichment. Libraries were sequenced to an ultra-high depth of 100,000×. Sequencing data was analyzed using a combination of public pipelines (megSAP and umiVar2 for mapping and deduplication) and custom in-house scripts (to extract the allele counts for patient-specific variants). To reduce the error rate, only corrected reads with ≥4 duplicates were used. p-value for ctDNA detection was calculated using the total variant count, depth and sample-specific error. Association between ctDNA with pCR and other clinical parameters were assessed with Chi-square or Fisher’s exact test and univariable logistic regression. Additionally, bivariable logistic regressions for pCR were performed with ctDNA and either cT, cN, or grade. Results ctDNA was detected (ctDNA+) in 58.0% (n=18/31) of pts at BL, 9.7% (n=3/31) at week 3, and 10% (n=3/30) at EOT. ctDNA was cleared by week 3 in 83.3% of pts (n=15/18). Compared with ctDNA-negative cases (ctDNA-) at BL, those ctDNA+ more often had cT2-3 disease (94.4%, n=17/18, vs 38.5%, n=5/13; p=.001) and lymph node involvement (61.1%, n=11/18, vs 0%, n=0/13; p&amp;lt; .001). 72.2% (n=13/18) of ctDNA+ and 61.5% (n=8/13) of ctDNA- cases at BL were grade 3 (p=.53). Each of the 3 pts who remained ctDNA+ at week 3 was node-positive; all pts remaining ctDNA- at week 3 were node-negative. pCR rate was 38.9% (n=7/18) in ctDNA+ vs 76.9% (n=10/13) in ctDNA- pts at BL (p=.067), 0% (n=0/3) in ctDNA+ vs 60.7% (n=17/28) in ctDNA- at week 3 (p=.081), and 33.3% (n=1/3) in ctDNA+ vs 59.3% (n=16/27) in ctDNA- at EOT (p=.565). pCR rate was highest in pts who remained ctDNA- throughout week 3 (76.9%, n=10/13), compared to pts with ctDNA cleared by week 3 (46.7%, n=7/15), and pts remaining ctDNA+ (0%, n=0/3, p=.024). ctDNA at BL was predictive for pCR in univariable analysis (odds ratio, OR 0.22, 95%CI 0.04- 0.93, area under curve, AUC=0.69). Bivariable models including ctDNA and grade yielded the highest accuracy for analyses with ctDNA at BL (AUC=0.77), week 3 (AUC=0.79), and with ctDNA change from BL to week 3 (AUC=0.87). Conclusions Absence of ctDNA prior to and during NAT, as well as early clearance of ctDNA associates with a higher pCR rate in eBC pts with HER2-enriched intrinsic subtype treated with chemotherapy-free pembrolizumab plus dual HER2 blockade. These results are in line with prior data with more intensive therapy from I-SPY 2 and NeoALTTO trials in HER2+ eBC and indicate that ctDNA analysis during NAT appears feasible for real- time monitoring of response to treatment and could be used to guide escalation/de-escalation strategies. Further trials with a larger number of pts and pre-designed follow-up are needed to confirm the role of ctDNA for prediction of tumor response and relapse. Citation Format: Monika Graeser, Sherko Kuemmel, Oleg Gluz, Christopher Schroeder, Leon Schuetz, Olga Kelemen, Stephan Ossowski, Katarzyna Jozwiak, Mattea Reinisch, Athina Kostara, Iris Scheffen, Kerstin Lüdtke-Heckenkamp, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens-Uwe Blohmer, Matthias Christgen, Stephan Bartels, Hans-Heinrich Kreipe, Enrico Pelz, Ulrike Nitz, Peter Schmid, Nadia Harbeck, Andreas Hartkopf. Circulating tumor DNA (ctDNA) for prediction of pathologic complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: WSG-Keyriched-1 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-12.

Abstract PO2-15-02: Personalized circulating tumor DNA (ctDNA) monitoring can early identify disease progression and predict prognosis in patients with breast cancer undergoing neoadjuvant therapy

Abstract Background: Circulating tumor DNA (ctDNA) analysis offers a non-invasive method to assess tumor burden during treatment. Although some data have been reported on the use of ctDNA in neoadjuvant therapy (NAT) for breast cancer (BC), there is a lack of data on neoadjuvant efficacy and prognosis in China specifically using tumor-informed personalized ctDNA monitoring panel. Methods: We performed personalized ctDNA analyses at different time of NAT (before, during, and after) in 19 patients with Stage IIA-IIIB BC. WES was conducted on tumor tissues, and single nucleotide variants (SNVs) (20-40) were selected for each patient to ensure accurate and sensitive detection of individual ctDNA(Shanghai OrigiMed Co., Ltd.). Results: A total of 19 BC patients, 6 HER2-negative and 13 HER2-positive, were enrolled at the Breast Center, Fourth Hospital of Hebei Medical University (China) from June 2022 to May 2023. The median age of the patients was 53 (min-max: 28-64) years old. Through WES, it was discovered that 78.5% (3377/4303) of the mutated genes were unique to each patient. Additionally, 96.1% (637/663) of the selected tumor-informed SNVs were VUS variants. These findings suggest that tumor-informed ctDNA monitoring is more effective than panel-based ctDNA monitoring in BC. Among the patients, 84% (16/19) completed baseline blood collection, 63% (12/19) completed blood collection after NAT and 42% (8/12) patients completed blood collection after the surgery. The baseline positivity rate was 100%, and the baseline ctDNA variant allele frequency was significantly associated with T stage and N stage (both p &amp;lt; 0.01). This suggests that designing a panel based on puncture samples is feasible for ctDNA analysis. The detection of ctDNA before surgery after NAT correlated with the postoperative ctDNA status. Patients with persistently negative ctDNA during NAT were associated with pathologic complete response (pCR), although the difference was not statistically significant due to the small sample size (n=7). In 84% of patients, dynamic changes in ctDNA aligned with imaging findings, indicating a correlation between ctDNA and disease progression. A 56-year-old patient with HER2-negative stage IIIC BC had persistent ctDNA positivity during NAT. Imaging evaluation showed disease progression, with ctDNA allele frequency increasing 18 days before detection on imaging. After surgical tumor removal, the pathology assessment revealed a change in HER2 status from negative to positive. The patient received adjuvant chemotherapy combined with HER2-targeted therapy, resulting in a transition from positive to negative ctDNA status. The disease has remained stable for nearly 9 months. A 29-year-old patient with HER2-positive stage IIIA BC underwent NAT for 8 cycles. Due to drug intolerance, the treatment was interrupted multiple times during the first 4 cycles, and ctDNA remained positive. After modifying the treatment regimen in the 5th cycle, ctDNA became negative until the patient underwent surgery. The postoperative pathology evaluation revealed a pCR. Conclusions: Personalized ctDNA monitoring is more effective than panel-based ctDNA (a predefined set of cancer-associated genes) monitoring in BC. The status of ctDNA before and after surgery following NAT may be correlated, suggesting that patients with positive ctDNA before surgery may benefit from intensive therapy. More importantly, dynamic changes in ctDNA closely align with radiological findings, enabling early detection of disease progression and guiding treatment modifications. Citation Format: Yunjiang Liu, Chao Shi, Xiangmei Zhang, Xiaofei Ren, Shang Wu, Yaxian Wang, Yue Che, Zanmei Xu, Fei Pang. Personalized circulating tumor DNA (ctDNA) monitoring can early identify disease progression and predict prognosis in patients with breast cancer undergoing neoadjuvant therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-02.

Abstract PO4-18-10: Randomized controlled trial of Young, Empowered &amp; Strong (YES), a web-based patient-reported symptom monitoring and self-management portal for adolescent and young adult (AYA) breast cancer (BC) survivors

Abstract Background: BC is the most common malignancy diagnosed in AYAs. AYAs develop more biologically aggressive BC and present at more advanced stages, necessitating more intensive therapy with curative intent. While acute physical sequelae often resolve following initial treatment, the long-term physical and psychosocial impact of BC on a survivor’s life may worsen or emerge in survivorship. This impact includes symptoms (e.g., sexual problems, anxiety, fatigue, stress, sleep issues, hot flashes) as well as concerns unique to, or accentuated by, being young (e.g., fertility, genetics, childrearing, educational/work attainment). With provider attention to these issues often sub-optimal, strategies that empower patients have the potential to improve their well-being. To engage and activate AYA BC survivors, we developed YES, a web-based portal that leverages electronic patient-reported outcomes (ePROs) to facilitate self-monitoring and management of symptoms/AYA concerns. In contrast to ePRO models dependent on clinician interaction, our approach emphasizes self-management of chronic survivorship concerns outside of the clinic environment. This model is grounded in the reality that most clinicians have limited bandwidth to address these needs and considers that AYAs can have competing demands (e.g., missing work, child-care) that may make accessing in-person support challenging. Methods: The YES study is a randomized controlled trial of the YES intervention vs. usual care. YES supports participants to 1) self-monitor needs/symptoms; and 2) provides a repository for information and resources on self-management of symptoms/AYA concerns. Eligibility criteria include: female, age 15-39 years at diagnosis, stage 0-III BC, within 3 years of diagnosis, no recurrent/second primary BC, no other malignancy since BC diagnosis, and English speaking. Participants randomized to the YES arm are prompted through a monthly text or email to complete an ePRO assessment regarding current symptoms/AYA concerns. For each symptom/concern endorsed, information/resources to address the symptom/concern is automatically provided via the YES portal. The portal is monitored, and providers are contacted if participants report severe distress or suicidality. YES also provides peer support via a chat room and self-support through a journaling platform in the portal. Participants in the usual care group are offered access to YES for up to 3 months at the end of their 9-month study participation. All participants complete a REDCap survey with validated measures of quality of life (QOL), symptoms, and other PROs at baseline, 3, 6, and 9 months after randomization and provide a dried blood spot specimen via a self-administration kit at baseline and 6 months. The primary study aim is to determine the efficacy of YES vs. usual care in improving life quality measured by the QOL in Adult Cancer Survivors [QLACS] scale at 6 months post-randomization. With a planned sample size of 360 participants, the study will have ≥90% power to detect a 6-point mean change (6 months vs. baseline) in the cancer-specific QLACS score between arms. Secondary outcomes include efficacy of YES in reducing symptoms/AYA concerns at 6 months and sustainability of the effects of YES at 9 months. Repeated measures regression will be used with link functions selected based on the type of outcome data analyzed. Exploratory aims will evaluate moderators and mediators of intervention efficacy and the effects of YES on inflammatory biomarkers. At study completion, a subset of 30 participants diverse in age, race, ethnicity, and gender identity are invited to participate in an interview to understand their survivorship preferences/concerns and to understand how the portal supported their self-management. The YES trial opened to enrollment in 9/2021. As of 6/2023, 245 participants are enrolled. Clinical Trials Information: NCT04906200 Citation Format: Shoshana Rosenberg, Yue Zheng, Dawn Hershman, Craig Snow, Kate Dibble, Magnolia Contreras, Noel Roma, Nabihah Tayob, Michelle Naughton, Ann Partridge. Randomized controlled trial of Young, Empowered &amp; Strong (YES), a web-based patient-reported symptom monitoring and self-management portal for adolescent and young adult (AYA) breast cancer (BC) survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-10.

Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type two diabetes: the Veterans Affairs Diabetes Trial

BackgroundIntensive glycemic control reduced the risk of coronary artery disease (CAD) events among White ACCORD study participants with the haptoglobin (Hp)2-2 phenotype, and not among participants without the Hp2-2 phenotype. It is unknown whether these results persist in a population with more severe diabetes. MethodsHaptoglobin phenotype was measured in 1746 (97%) samples from the Veterans Affairs Diabetes Trial (VADT) randomized controlled trial. Multivariable-adjusted Cox regression models assessed the effect of intensive therapy on CAD risk among participants with and without the Hp2-2 phenotype separately and when stratified within pre-specified race/ethnicity-based subgroups. Time-varying (achieved) HbA1c data (<7.0% or ≥8.0% compared to 7.0-7.9, updated every 3 months) were also analyzed in relation to CAD risk within each phenotype. Results567 (32.5%) participants had the Hp2-2 phenotype. Compared to standard therapy, intensive glycemic control was not associated with risk of CAD among participants with the non-Hp2-2 or the Hp2-2 phenotype or for any race/ethnicity-based group. Compared to HbA1c of 7.0-7.9%, having HbA1c <7.0% was not associated with CAD risk for either phenotype or among any race/ethnicity-based group. Having HbA1c ≥8.0% was associated with an increased risk of CAD among Hispanic participants without the Hp2-2 phenotype (HR= 3.61, 95% CI: 1.54-8.41, p-interaction=0.53). ConclusionThe effect of intensive glycemic therapy on CAD events was not dependent on Hp phenotype in the VADT study of veterans with severe diabetes who may represent a population where Hp phenotype information would not be useful for personalizing diabetes management. However, further research is needed to determine if these results are conclusive.

Morbidity and mortality in patients with stage IV pancreatic adenocarcinoma and acute cholangitis: Outcomes and risk prognostication

BackgroundAcute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in patients with stage IV PDAC. MethodsWe conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality. ResultsOne hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0–5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3–92.5), 37 % (95 % CI, 29.3–46.6 %) and 18.9 % (95 % CI, 13.1–27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC. ConclusionsAC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.

Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110)

The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS= 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS= 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS= 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P= 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P= 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P= 0.022). We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.

Rate of Change in Cardiac Magnetic Resonance Imaging Measures Is Associated With Death in Duchenne Muscular Dystrophy.

Cardiovascular disease is the leading cause of death among patients with Duchenne muscular dystrophy (DMD). Identifying patients at risk of early death could allow for increased monitoring and more intensive therapy. Measures that associate with death could serve as surrogate outcomes in clinical trials. Duchenne muscular dystrophy subjects prospectively enrolled in observational studies were included. Models using generalized least squares were used to assess the difference of cardiac magnetic resonance measurements between deceased and alive subjects. A total of 63 participants underwent multiple cardiac magnetic resonance imaging and were included in the analyses. Twelve subjects (19.1%) died over a median follow-up of 5 years (interquartile range, 3.1-7.0). Rate of decline in left ventricular ejection fraction was faster in deceased than alive subjects (P<0.0001). Rate of increase in indexed left ventricular end-diastolic (P=0.0132) and systolic (P<0.0001) volumes were higher in deceased subjects. Faster worsening in midcircumferential strain was seen in deceased subjects (P=0.049) while no difference in global circumferential strain was seen. The rate of increase in late gadolinium enhancement, base T1, and mid T1 did not differ between groups. Duchenne muscular dystrophy death is associated with the rate of change in left ventricular ejection fraction, midcircumferential strain, and ventricular volumes. Aggressive medical therapy to decrease the rate of progression may improve the mortality rate in this population. A decrease in the rate of progression may serve as a valid surrogate outcome for therapeutic trials.

Efficacy of Mom’s Belief Integrated Therapy Protocol (MBITP) based therapies across multiple therapy centers serving neurodivergent populations

Long term and intensive therapy that can provide for a multimodal comprehensive approach has been found to be an effective modality for children presenting with varied kinds of Neurodevelopmental delays, concerns and diagnosis. In India and in the world at large there are millions of Neurodivergent children who are in need of high-quality Psychological therapeutic services that are easily accessible. Varied therapy centers provide such a solution in which the child is at the very core of the therapeutic process. The primary objective of the study was to measure the effectiveness of the center based in-person intervention for children with Neurodivergent needs. A pre-post T-test analysis demonstrates that even with as less as 2 hours of weekly therapies such as Speech, OT and Behaviour therapy-based interventions within a span of 3 months of providing quality therapy there has been significant positive progress for children in all five domains of development, as hypothesized.