Treatment Phase Research Articles

Abstract C044: Single cell RNA-sequencing coupled with lineage tracing identifies novel clonal populations associated with immunotherapy resistance

Abstract Although immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, many individuals either show no response or eventually develop acquired resistance. This variability could be linked to differences in the tumor immune microenvironment, pre-existing drug-resistant cells or treatment induced changes in melanoma cell states. Using single cell RNA sequencing (scRNA-seq) coupled with heritable barcodes, this study aims to lineage trace changes in melanoma transcriptional cell states and map changes in the tumor immune microenvironment to uncover if preexisting and/or therapy-induced melanoma transcriptional cell states lead to resistance to ICIs. In this study, we used YUMMER1.7 mouse melanoma cells which were transduced with barcodes under conditions that allow delivery of a single unique barcode to each cell, this served as a cell lineage tag. Each barcode is heritable and stably transcribed into RNA molecules so that individual barcoded cells can be matched with a gene expression profile from scRNA-seq outputs. The barcoded cells were subcutaneously injected into C57BL/6 mice, and once tumors were established, mice were treated with 3 cycles of anti-PD-1 and anti-CTLA-4 therapy. Lineage tracing and scRNA-seq analyses were performed on tumors harvested prior to treatment, early on treatment (Day 6), during minimal residual disease (Day 13) and upon relapse. Early on treatment (Day 6)- two tumour groups were harvested, those that responded well and others that only partially responded. Our results showed that during the early on treatment phase (Day 6) tumors that responded well and those that only partially responded displayed distinct barcodes. Additionally, prevalent barcoded cells identified at the minimal residual disease phase were also dominant upon relapse. Analysis of the transcriptional states is underway to determine if ICI therapy induces transcriptional heterogeneity in sensitive and tolerant cells and if a particular or several transcriptional states lead to relapse. This study will potentially identify predictive response biomarkers and vulnerabilities of ICI naïve and resistant cells that could be targeted to improve outcomes for melanoma patients. We will also identify neoadjuvant approaches, to remove the inherent heterogeneity within the tumor cell population, facilitating a more uniform sensitivity to ICIs. Citation Format: Reem Saleh, Riyaben Patel, Dane Vassiliadis, Fayrouz Hammal, Benjamin Blyth, Xin Du, Katie Fennell, Mark A. Dawson, Grant A. McArthur, Karen Sheppard. Single cell RNA-sequencing coupled with lineage tracing identifies novel clonal populations associated with immunotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C044.

Parental and Pediatric Perspectives during the Cancer Trajectory: A Systematic Review

Background: The cancer journey is a complex and emotionally challenging experience for both children diagnosed with cancer and their parents. Understanding the perspectives of both groups can provide critical insights into improving care, psychological support, and overall quality of life during treatment and survivorship. Objectives: This systematic review aims to synthesize existing literature on the perspectives of both pediatric cancer patients and their parents throughout the cancer trajectory, focusing on emotional, psychological, and social aspects. It seeks to highlight key themes and identify gaps in research for potential future studies. Methods: A comprehensive search was conducted across PubMed, C.I.N.A.H.L., PsycINFO, and Scopus for studies published between 2013 and 2023. Eligible studies included those addressing pediatric patients with cancer, their parents, and their experiences during diagnosis, treatment, and post-treatment phases. The studies were critically appraised using the P.R.I.S.M.A. guidelines, and thematic analysis was applied to extract key findings. Results: A total of 6 studies met the inclusion criteria, revealing both parents and children experience anxiety, fear, and uncertainty, especially during diagnosis and treatment initiation. Parental distress often mirrors or exceeds the child’s emotional challenges. Parents seek clear and transparent communication with healthcare providers, while children often desire age-appropriate information about their condition and treatment. Parents and children adopt a range of coping mechanisms, including reliance on healthcare professionals, family support, and religious or spiritual beliefs. Parents express concern about the long-term impact of treatment on the child's health, education, and social life. Pediatric patients often focus on maintaining normalcy, friendships, and school participation during treatment. Both groups emphasize the importance of emotional and psychological support from healthcare teams, family, and peer support networks during the cancer journey. Conclusion: The review underscores the profound emotional and psychological burden of cancer on both pediatric patients and their parents. Effective communication, individualized support systems, and addressing the unique needs of both parties are critical for improving overall well-being during the cancer trajectory. Further research is needed to explore interventions that can mitigate distress and enhance coping strategies for parents and children.

The Punch Graft Technique: A Simplified Protocol for Three-Dimensional Peri-Implant Soft and/or Hard Tissue Augmentation in a Single Step.

This article describes a clinical protocol utilizing soft tissue augmentation alone or in combination with guided bone regeneration (GBR), introducing simultaneous application of the one abutment one time concept for three-dimensional reconstruction of the deficient ridge. Soft and hard tissue quality and dimensions are fundamental elements for long lasting results in implant dentistry. Different techniques have been described for soft and hard tissue augmentation at time of implant placement presenting favorable results. However, multiple abutment disconnections during the prosthetic phase of treatment can compromise the results achieved during surgery. The purpose of this article is to present a surgical protocol that allows three-dimensional ridge reconstruction involving soft tissue augmentation alone, or in combination with hard tissue augmentation in one single step with the use of an one-time intermediate abutment as an anchorage device for the regenerative materials. Two clinical cases utilizing the proposed protocol are also presented, demonstrating favorable results. The application of the proposed protocol simplifies the surgical phase of treatment, protects the achieved result and enables a favorable outcome in decreased time. Utilising an intermediate abutment as an anchorage device at time of surgery can be proven an easy to apply and biologically favorable alternative way to other methods of soft tissue graft stabilization proposed in the past.

A SPINAL TRAUMA, A TUMOR AND EVERYTHING IN BETWEEN

Introduction Burkitt lymphoma is a male predominant (3:1 male:female ratio) aggressive B-cell non-Hodgkin lymphoma that can present as a sporadic variant with meningeal involvement in about 20% of cases. Therefore, it can manifest with neurologic deficits due to compression of the spinal cord or spine nerve root. Case Report We report the case of a 6 years-old girl who presented in the emergency department following a traumatic vertebral injury (fall from around 1.5 meters) with no spinal cord involvement. She accused upper back pain, walking and orthostatism difficulties and manifested a light to moderate inferior paraparesis (MCR 3/5) The MRI revealed a space-occupying epidural mass between T1-T4, severely compressing the spinal cord initially thought to be an epidural hematoma. Emergency surgery was performed with duro-radicular decompression and mass excision through a T1-T4 laminotomy followed by a laminoplasty. The unveiled mass was white, minimally vascularized and adherent to the dura raising the suspicion of a tumor. Postoperatively the patient exhibited significant neurological improvement with resolution of the paraparesis and normal gait restoration. Three weeks later, the patient returned with complaints of abnormal gait, lumbar pain radiating in the right lower leg and upon examination a light right lower limb monoparesis (MRC 4/5) following another traumatic event. Emergency MRI of the whole spine with contrast was requested just as the pathologist in charge of the case suggested a diagnosis of Burkitt lymphoma, prompting a whole-body MRI. A severe recurrence was noted at the site of the previous lesion along with a new lumbar lesion, and several intraabdominal, intrathoracic, ovarian tumor sites with diffuse infiltration of the bone marrow. The patient was urgently referred to the pediatric oncology department and started on steroidal anti-inflammatory treatment and chemotherapy. Conclusions Burkitt lymphoma involving the nervous system in children requires increased medical attention during the clinical, histopathological examination and treatment phase, due to the association with advanced disease and, although rare, should be considered as a differential diagnosis in pediatric patients with epidural lesions. The management of such lesions demands a solid collaboration between neurosurgeon, pediatrician, pathologist and oncologist for an early diagnosis and proper treatment.

OGC SO15 - Utility of radiological re-staging following neo-adjuvant chemotherapy and its impact on oncological outcomes in resectable gastric adenocarcinoma

Abstract Background The current perioperative chemotherapy regimen that comprises the multimodal treatment strategy for gastric cancer consists of Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel. Despite improvement in outcomes at a population level, real-world data suggests that ≤40% of patients show a poor/no response to the neoadjuvant phase of treatment. Identification of these poor/non-responders may facilitate a re-evaluation of their treatment strategy and prevent potentially futile surgery. Radiological re-staging following neoadjuvant treatment is routinely performed despite its debatable accuracy and benefits. This study aimed to define the accuracy of radiological re-staging and its impact on survival following neoadjuvant treatment for resectable GC. Method Patients with resectable gastric cancer who completed 4 cycles of neoadjuvant FLOT and underwent resectional surgery with curative intent between 2018 and 2022 were retrospectively identified. All patients were clinically staged with gastroscopy, CT and staging laparoscopy. The index radiological/clinical stage at diagnosis was compared to the radiological re-staging following neoadjuvant treatment. Patient were re-staged with either a CT or PET-CT. Both were then compared with the final pathological stage to assess for correlation between the radiological and pathological stage. A survival analysis was then performed to evaluate the impact of radiological-pathological staging discrepancy on overall survival Results A total of 65 consecutive patients met the inclusion criteria of this study. On comparison of the index clinical stage with the radiological re-stage post-neoadjuvant treatment, 71% had concordant stages, 25% were downstaged, and 4% were upstaged. On comparison of the index clinical stage with the final pathological stage, 35% had concordant stages, 38% were upstaged and 27% were down staged (Cohen kappa = -0.224, 95% CI -0.390, -0.058). Discrepancy between clinical stage and radiological re-stage did not influence survival. However, discrepancy between clinical and pathological stage highlighted survival differences where upstaged patients had reduced survival (p = 0.018). Conclusion The accuracy of clinical staging compared to final pathological staging in the setting of aggressive tumour biology remains undefined. Radiological re-staging following neoadjuvant treatment proves to be an unreliable tool for assessing treatment response and does not predict long-term survival outcomes. These findings highlight the importance of accurate staging and the need for more precise methods of evaluating treatment response. This may enhance decision-making, individualise treatment regimens, and improve patient outcomes.

Longitudinal assessment of thyroid function in dogs with hypoadrenocorticism: Clinical outcomes and prevalence of autoantibodies.

Knowledge about primary hypoadrenocorticism coexisting with immune-mediated thyroiditis (Schmidt's syndrome) in dogs is limited. To evaluate thyroid function in dogs with naturally occurring hypoadrenocorticism before and during treatment. Sixty-six client-owned dogs. Measurement of canine thyroid stimulating hormone (cTSH), total thyroxine (T4), free thyroxine, and autoantibodies against thyroglobulin, T4, and total triiodothyronine. Thirty-eight dogs were assessed before and 28 during treatment. Follow-up data were available for 24/38 and 17/28 dogs, with median follow-up duration of 3.8 years (range, <1.0-8.8 years) and 4 years (range, 1.1 weeks to 10.5 years), respectively. Canine thyroid stimulating hormone was above the reference range at the time of diagnosis of hypoadrenocorticism in 10 of 38 dogs but decreased into the reference range in 7 for which follow-up data was available. Hypothyroidism was confirmed in 5 dogs at a median age of 11 years (range, 7-15 years). In 4 dogs, the condition was diagnosed after a median treatment duration of 5.75 years (range, 2.6-10 years), while in 1 dog, the diagnosis was made concurrently. One dog had detectable thyroid autoantibodies. Hypothyroidism occurs as a rare concurrent condition in dogs with hypoadrenocorticism, potentially at any phase of treatment. Close monitoring of cTSH levels in these dogs could be beneficial, as early changes might indicate the onset of hypothyroidism. The low prevalence of detectable thyroid autoantibodies suggests that nonimmune mechanisms might contribute to thyroid dysfunction.

Abstract 4134327: Efficacy and safety of aprocitentan in patients with resistant hypertension receiving at least 4 antihypertensive medications including beta (β) blockers

Background: Aprocitentan, a dual ET A /ET B endothelin receptor antagonist, was recently FDA-approved for use in combination with other drugs for the treatment of hypertension not adequately controlled on other antihypertensive drugs. β-blockers are used for the prevention of cardiovascular events and have antihypertensive effects. All subjects in the PRECISION study were hypertensive at screening despite receiving ≥3 antihypertensives, with 63.5% on ≥4 and 16.8% on ≥5 antihypertensives. All were switched to a standardized fixed dose triple combination of amlodipine/valsartan/hydrochlorothiazide; and the 456 patients (62.5% of the 730 total) who were on β-blockers at screening continued throughout the study as well. Of these, 173 (37.9%) had a history of ischemic heart disease and 106 (23.2%) a history of congestive heart failure, vs 52 (19%) and 37 (13.5%) not receiving β-blockers. This preplanned subgroup analysis assessed the efficacy and safety of aprocitentan in patients with resistant hypertension on the triple combination with or without β-blockers. Methods: Changes from baseline (BL) in office systolic blood pressure (SBP) and diastolic BP (DBP) were assessed at Week 4, the end of the double-blind treatment phase with aprocitentan 12.5 mg or 25 mg per day or placebo, and at Week 36, at the end of the single-blind aprocitentan 25 mg treatment phase. Results: There was no difference in the efficacy of aprocitentan when patients were on a β-blocker or not. In patients on β-blockers, 12.5 mg and 25 mg aprocitentan decreased SBP from BL to Week 4 by mean -14.9 mmHg and -14.9 mmHg, respectively, vs -11.2 mmHg in the placebo group; and in patients without β-blockers by -16.5 mmHg and -14.9 mmHg vs -11.8 mmHg. Similar results were seen at Week 36, as compared with BL for both subgroups, and at Week 4 for DBP (Table 1). In patients on β-blockers, the incidence of edema/fluid retention at Week 4 was 9.9%, 19.3% and 2.8% in the aprocitentan 12.5 mg, 25 mg and placebo groups, respectively, as compared with 7.6%, 16.7%, and 1.0% in patients without β-blockers. In both subgroups, most events occurred during the first 8 weeks of treatment. The incidence of edema/fluid retention with aprocitentan was comparable with that of the placebo group in both subgroups thereafter. Conclusions: Aprocitentan is effective in lowering BP and has a good safety and tolerability profile in patients with resistant hypertension who are taking 4 or more antihypertensive drugs including β-blockers.

JCCG ALL-B12: Evaluation of Intensified Therapies With Vincristine/Dexamethasone Pulses and Asparaginase and Augmented High-Dose Methotrexate for Pediatric B-ALL.

The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework. Patients age 1-19 years with newly diagnosed B-ALL were enrolled in this study. These patients were stratified into standard-risk (SR), intermediate-risk (IR), and high-risk (HR) groups. Randomized comparisons assessed the effectiveness of vincristine (VCR)/dexamethasone pulses in the SR group, evaluated the effects of L-asparaginase (ASP) intensification in the IR group, and compared standard consolidation including block-type treatment with experimental consolidation with high-dose methotrexate (HD-MTX) intensified with VCR and ASP in the HR group. Of 1,936 patients enrolled, 1,804 were eligible for the experimental treatment. The overall 5-year event-free survival and overall survival rates were 85.2% (95% CI, 83.5 to 86.8) and 94.3% (95% CI, 93.1 to 95.3), respectively. The cumulative incidence of relapse and postremission nonrelapse mortality was 13.2% (95% CI, 11.6 to 14.8) and 0.6% (95% CI, 0.3 to 1.0), respectively. Random assignment in the SR group showed no significant benefit from pulse therapy. In the IR group, ASP intensification had limited effects. In the HR group, standard block therapy and HD-MTX yielded equivalent outcomes. The ALL-B12 trial achieved favorable outcomes in a nationwide cohort by stratifying treatment on the basis of risk and balancing treatment intensity. This study not only demonstrated that existing standard of care can be further refined but also indicated that improvement in outcomes with intensified chemotherapy has reached a plateau.

ADVANCES IN BONE REMODELING AND CLEAR ALIGNERS IN ORTHODONTICS

The use of clear aligners in orthodontics represents a significant advancement in dental treatment, allowing effective tooth movement with a less invasive approach compared to traditional fixed appliances. Clear aligners not only facilitate the alignment of teeth but also promote changes in the supporting alveolar bone. The success of these movements relies on the surrounding bone's response to mechanical stress during treatment, involving processes of bone resorption and deposition. Research has demonstrated that advancements in digital technology, such as 3D modeling and artificial intelligence, enhance the planning of tooth movements, making bone remodeling more predictable. Sophisticated algorithms simulate aligner forces on the alveolar bone, optimizing each treatment phase. However, limitations persist in complex cases where specific movements, like extrusion and rotation, require precise force control. Recent studies by Guo et al. (2023) and Abogabal et al. (2023) evaluated the effects of clear aligners on alveolar bone dimensions during orthodontic treatment, finding a greater occurrence of bone defects after treatment. They highlighted the differences in bone height changes between aligners and fixed appliances, indicating that clear aligners might have less impact on bone height. Innovative approaches such as low-intensity pulsed ultrasound (LIPUS) and high-frequency vibration (HFV) have also been investigated for their potential to enhance treatment outcomes. Research indicates that daily vibration may reduce the time required for dental correction while increasing levels of cytokines and markers for bone remodeling. Overall, the integration of digital tools and innovative techniques in orthodontics is crucial for improving treatment efficacy, addressing challenges in complex cases, and ultimately enhancing patient experience and satisfaction.

CTNI-40. PSYCHOLOGICAL DOMAINS CORRELATE WITH ADHERENCE IN TTFIELDS TREATMENT OF GLIOBLASTOMA

Abstract INTRODUCTION Adherence is critical to the success of the treatment with Tumor Treating Fields (TTFields) for Glioblastoma Multiforme (GBM). Previously found factors influencing treatment adherence in general are social support, belief in the efficacy of treatment, communication with physicians, anxiety, and depression. We propose those five factors predict adherence to TTFields treatment since, to our knowledge, no systematic data exists for this treatment. METHODS We conducted a longitudinal study and included 25 patients with newly diagnosed GBM who received treatment with TTFields. Participants were invited to take part in six structured interviews, each four weeks apart, during their treatment with TTFields, assessing the five factors expected to influence treatment adherence over time. RESULTS We found a significant impact of communication, anxiety, and depression on treatment adherence with TTFields. Furthermore, also the time point during treatment (days of treatment) was significantly related to adherence. Better physician communication and a higher level of anxiety were associated with higher adherence and higher depression with less adherence. A higher belief in efficacy showed a trend toward significantly improving treatment adherence. When results were separately compared for early, middle, and later 90-day treatment phases, factors seemed to be differentially influential, with belief in efficacy being significantly relevant in the first, efficacy, communication, and anxiety in the second, and depression in the third phase of treatment with TTFields. CONCLUSIONS Our findings not only confirm the predictive role of psychosocial factors in treatment adherence but also provide specific targets for psychological interventions. This suggests that by addressing these factors, healthcare providers can potentially increase treatment adherence among GBM patients. Moreover, our results indicate that these interventions may be most effective when tailored to the specific phase of treatment, offering a practical approach for healthcare providers.

CTNI-21. PIVOTAL, PHASE 2B RENEU TRIAL OF MIRDAMETINIB IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMA (NF1-PN): A SPOTLIGHT ON PATIENTS ACHIEVING DEEP RESPONSE

Abstract BACKGROUND Patients with NF1-PN in the phase 2b ReNeu trial (NCT03962543) of mirdametinib in adults (N=58, ≥18y) and children (N=56, 2-17y) had a deeper median (range) best reduction (adults: -41% [-90% to 13%]; children: -42%, [-91% to 48%]) from baseline in target PN volume than previously published in trials of other agents in NF1-PN. METHODS In the 24-cycle (1-cycle=28d) treatment phase, objective response rate (ORR) was the percentage with confirmed objective responses (OR) of ≥20% target PN volume reduction from baseline on consecutive MRIs (by blinded independent central review). This analysis includes patients achieving deep response (&amp;gt;50% best reduction from baseline in target PN volume) regardless of OR and inclusive of patients in the long-term follow-up. Exploratory analysis of baseline characteristics compared patients with deep response and patients with ≤50% volume reduction. RESULTS ORR was 41% (24/58) in adults and 52% (29/56) in children treated with mirdametinib. 62% (15/24) of adults and 52% (15/29) of children who achieved OR had deep response. To further characterize deep response, 2 adults and 3 children with deep response without confirmation or in long-term follow-up were included. Of those with a deep response, 35% (6/17) of adults and 72% (13/18) of children were investigator-defined as having progressing PN. Patients achieved deep response regardless of baseline age, sex, target PN volume, tumor location, or progression status. For adults and children, median time to best percent change from baseline in PN volume for patients achieving deep response was 25.4 and 21.8mo; for patients with reductions of ≥20% to ≤50% was 15.3 and 15.2mo; for patients with reductions of &amp;lt;20% was 7.8 and 4.2mo, respectively. CONCLUSIONS Patients had a similar likelihood of achieving deep response across assessed baseline characteristics. A trend between deep response and longer treatment duration suggests a benefit of prolonged therapy with mirdametinib.

Final diagnoses and mortality rates in ambulance patients administered nebulized β2-agonists bronchodilators.

To assess final diagnoses and mortality rates (30day and 1year) in patients treated with the inhaled bronchodilator salbutamol by ambulance personnel, and to establish its role as an identifier of moderate to severe respiratory distress in the prehospital phase of treatment. In a descriptive retrospective observational study, patients experiencing respiratory distress and treated with inhaled bronchodilators, specifically salbutamol, in the prehospital setting within the Central Denmark Region during 2018-2019 were included. The study included 6318 ambulance transports, comprising 3686 cases of acute exacerbation of chronic obstructive pulmonary disease (AECOPD), 234 with community-acquired pneumonia (CAP), 320 with heart disease (HD), 233 adults with asthma, 1674 with various other primary ICD-10 diagnoses (other ≥ 18years), and 171 patients under 18years. The 30day mortality rate for all patients was 10.7% (95% CI 9.8-11.6), with zero deaths within 30days among adults with asthma and those under 18. Excluding low mortality groups, AECOPD patients had the lowest 30day mortality at 10.2% (95% CI 9.1-11.3), and HD patients the highest at 15.3% (95% CI 10.6-19.9). The 1-year overall mortality rate increased to 32.1% (95% CI 30.2-34.0), with mortality staying low for asthma and under-18 groups, while differences between other groups lessened and became insignificant. Patients requiring inhaled bronchodilator treatment in ambulances exhibit notably high mortality rates at 30days and 1year, except for those with asthma or under 18. The need for prehospital bronchodilators could serve as a clear and unmistakable marker for moderate to severe respiratory distress, enabling early intervention.

BIOM-25. MOLECULAR PROFILING PREDICTS EARLY AND LATE PROGRESSION IN GLIOBLASTOMA

Abstract Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 6% surviving more than 5 years. To date, there are few non-invasive clinical biomarkers to predict response to first – line treatment. Chemical exchange saturation transfer (CEST) MRI may have the potential to fill this gap. CEST MRI is sensitive to treatment-induced changes and changes in tumor metabolism. Our team has obtained CEST data for patients before, during and after the end of standard chemoradiation treatment, and found that CEST provides markers of early response and can identify early, standard and late progressors before treatment initiation. In this study, we aimed to establish molecular profiles of early, standard and late progressors with IDH wild-type glioblastoma. Patients (n=180) with primary, IDH wild-type glioblastoma were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from matched normal and tumour pairs and processed for whole genome sequencing, enzymatic methyl-seq and gene expression analysis using Nanostring. Clinical variables such as age, extent of resection, sex, ECOG status and MGMT promoter methylated were also collected. A survival analysis was conducted using the Kaplan-Meier method with log-rank tests. Univariate and multi-variate hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models. Early progressors reported a median progression-free survival (PFS) of 142 days compared to 832 days in late progressors (p&amp;lt;0.0001). Early progressors also harbored distinct and statistically significant differences in gene expression and genomic alterations, namely in DNA damage repair, glucose transport and arginine metabolism pathways. A gene signature was prognostic of PFS and overall survival. Collectively, this data has the potential to serve as a radiogenomic biomarker to assess treatment response before or within early phases of treatment and allow for individual tailoring of the treatment plan.

QOL-08. HEALTH-RELATED QUALITY-OF-LIFE (HRQOL) IN ADULTS AND CHILDREN WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMA (NF1-PN) TREATED WITH MIRDAMETINIB: PIVOTAL, PHASE 2B RENEU TRIAL

Abstract Patients with NF1-PN experience pain and other symptoms that negatively impact functioning and quality-of-life. We present patient- and parent proxy-reported HRQoL outcomes from ReNeu (NCT03962543), a pivotal, phase 2b trial of mirdametinib, an investigational MEK1/2 inhibitor, in adults and children (≥2 y) with NF1-PN causing morbidities. Fifty-eight adults and 56 children received mirdametinib (2 mg/m2 BID; 3-weeks-on/1-week-off, 28-d cycles). Change in HRQoL was assessed by Pediatric QoL Inventory (PedsQL) 4.0 Generic Core Scales from baseline across the 24-cycle treatment phase; change from baseline at Cycle 13 (C13) was a prespecified secondary endpoint. PedsQL is a HRQoL measure for adults and children with a Total Score (TS) and 4 subscales: physical, emotional, social, and school/work. Items are reported on a 0-100 scale (higher scores=better HRQoL). Clinically meaningful improvement was defined as change from baseline &amp;gt;9.7 points for adults, &amp;gt;8.5 points for child self-report, and &amp;gt;9.0 points for parent proxy-report. PedsQL-TS improvement (least-squares mean, LSM [SE] change) from baseline at C13 was 3.9 (1.6; P=.018; n=34) for adults, 4.0 (2.4; P=.096; n=38) for children by self-report, and 5.6 (1.9; P=.005; n=43) by parent proxy-report. PedsQL-TS improvements for adults and children by parent proxy-report (not by children self-report) were observed early (at C5 and C3, respectively) and sustained through C24. Clinically meaningful improvement in PedsQL-TS from baseline at C13 was achieved by 37% (10/27) adults, 45% (13/29) children by self-report, and 47% (15/32) children by parent proxy-report (among patients who could have achieved a clinically meaningful change from baseline). Significant (P&amp;lt;.05) improvement from baseline to C13 was reported for physical (adults, children, and parent proxy-report), school/work (adults), and emotional and social (parent proxy-report) subscales. Adults and children (by parent proxy-report) with NF1-PN had clinically meaningful, early, and sustained improvement in HRQoL over the course of mirdametinib treatment.

Therapeutic effects of pentoxifylline in propionic acid-induced autism symptoms in rat models: A behavioral, biochemical, and histopathological study.

The role of propionic acid (PPA) in eliciting behaviors analogous to autism in rat models is a documented phenomenon. This study examines the therapeutic implications of pentoxifylline-an agent traditionally used for peripheral vascular diseases-on these autism-like behaviors by modulating brain proteins and reducing pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) in a rat model. This research involved 30 male Wistar albino rats, which were divided into three distinct groups: a baseline control set, a PPA-treated cluster receiving a 250 mg/kg/day dose of PPA via intraperitoneal injection for a span of five days followed by saline orally, and a PPA group administered an oral dose of pentoxifylline at 300 mg/kg/day over 15 days. Subsequent to the treatment phase, euthanasia was carried out for the extraction of brain and blood samples, which were then analyzed for histopathological and biochemical markers. The pentoxifylline-treated subjects demonstrated a significant mitigation in the manifestation of autistic-like behaviors, as assessed through a triad of social interaction tests. A noteworthy decline in TNF-α levels was observed, alongside a significant rise in the concentration of adenosine triphosphate and nerve growth factor in brain tissue (p < 0.05). Histopathological analysis underscored a reduction in oxidative stress and a significant preservation of neuronal cell types, specifically pyramidal neurons in the hippocampal CA1 and CA3 regions and Purkinje cells in the cerebellum (p < 0.001). Pentoxifylline treatment has been found to effectively reduce the behavioral symptoms associated with autism, as well as biochemical and histopathological disruptions induced by PPA in rat models, highlighting its potential as a neurotherapeutic agent.

ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma.

Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults. ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Assessment of Optimal Treatment Strategies and Their Outcomes in T3N1 Rectal Cancers.

Background:This study compares the outcomes of a surgery first vs a neoadjuvant treatment strategy in T3N1M0 rectal cancers. Methods:This was a single-centre retrospective cohort study of patients admitted for curative treatment of T3N1 rectal cancer. Patients with pre-treatment T3N1 and pathological T3N1 disease were included in the study. Patients were divided into two groups depending on whether they had surgery or neoadjuvant therapy as their initial phase of treatment. Primary outcome measures were local recurrence and distant recurrence. Secondary outcomes were disease-free survival (DFS) and overall survival (OS). Tabulated results were analyzed with appropriate statistical tests. Results:One hundred and ten patients were initially selected. Fourty-eight were finally included after excluding patients who did not meet the staging criteria or were not eligible for curative treatment. Twenty-nine patients underwent surgery, and 19 patients with neoadjuvant therapy as their first treatment. No local recurrence was noted in either group, with a distant recurrence noted in group 2 (6.9%) and group 1 (5.26%) cases among the surgery-first and neoadjuvant-first groups, respectively. Disease-free survival and overall survival were 29.5 and 30 months for the surgery-first group and 22 and 22 months for the neo-adjuvant group, respectively. Conclusions:Outcomes in the surgery-first group were non-inferior to that of the neoadjuvant group. A threatened circumferential resection margin (CRM) on pretreatment staging warrants neoadjuvant therapy to ensure an R0 resection. Extramural vascular invasion (EMVI), being a negative prognostic factor, doesn't preclude a surgery-first approach.

The effects of spondylodiscitis on the inflammation burden in infective endocarditis.

This study investigates the effects of spondylodiscitis on the inflammation burden in infective endocarditis patients. Aprospective, observational study was conducted between September 2018 and October 2022 in anon-surgical teaching hospital. Patients with adefinite or possible and treated as infective endocarditis were recruited from the Alkmaar Endocarditis Team meetings. Spondylodiscitis was diagnosed based on symptoms and radiological findings. The inflammation burden was defined as the area under the C‑reactive protein (CRP) curve. 174 consecutive patients with infective endocarditis were included (mean age73years, 34.5% female). Concomitant spondylodiscitis was present in 32patients (18%), frequently associated with Streptococcus species (38%). At admission, the mean level of CRP was significantly higher in patients with concomitant spondylodiscitis (p = 0.004). The median CRP area under the curve was significantly higher in spondylodiscitis patients (4.2 × 106 min.mg/l [1.2 × 105 - 1.6 × 107 min.mg/l] vs 2.0 × 106 min.mg/l [8.7 × 104 - 1.6 × 107 min.mg/l], p < 0.001). This difference remained during the whole treatment period. At 6months of follow-up, rates of mortality and relapse of infective endocarditis were not significantly different. The prevalence of spondylodiscitis in non-referred patients with infective endocarditis was 18%. Endocarditis patients with spondylodiscitis had an increased inflammation burden at and during admission. This difference in normalisation of CRP levels was particularly apparent in the final phase of antibiotic treatment but not related to infectious complications. Despite an augmented inflammation burden, spondylodiscitis was not associated with mortality, cardiac surgery or infectious relapse.

Efficacy of Complexity-Based Target Selection for Treating Morphosyntactic Deficits in Children With Developmental Language Disorder and Children With Down Syndrome: A Single-Case Experimental Design.

Selecting targets for morphosyntactic intervention is a critical component of treatment planning. The complexity approach suggests that, by treating a complex morphosyntactic target, improvements will occur for the treated structure and for related, simpler structures. This study evaluated the efficacy of the complexity approach for treating morphosyntactic deficits by targeting a complex BE verb question structure for children with developmental language disorder (DLD) and children with Down syndrome (DS) and observing its impact on treated and untreated BE verb structures. We also explored whether etiology impacted our participants' treatment responses. Three participants with DLD and three with DS received treatment for the BE verb question structure in the context of a single-case multiple-baseline design across participants. Accuracy of production for the treated structure and untreated BE verb structures was measured across baseline, treatment, and posttreatment phases. Treatment of the complex BE verb question structure resulted in change on the treated structure for three participants (i.e., two with DLD and one with DS). Generalization of treatment to untreated, related BE verb structures occurred for all six participants. Outcomes indicated participants from both etiologies benefited from treatment. This study provides evidence supporting the use of a complexity-based approach for selecting morphosyntactic treatment targets for children with DLD and children with DS. Additional research is needed to identify specific characteristics that may influence individual treatment responses. https://doi.org/10.23641/asha.27018124.

Progress on the Mechanisms and Neuroprotective Benefits of Dexmedetomidine in Brain Diseases.

Dexmedetomidine, a highly specific α2 agonist, has been extensively utilized in clinical sedation and surgical anesthesia since its introduction in 2000 due to its excellent sympatholytic, sedative, and analgesic effects. This review aimed to identify new approaches for the treatment of patients with brain disorders by thoroughly describing the mechanism of action of dexmedetomidine and examining its neuroprotective effects from the standpoints of basic and clinical research. The PubMed and Web of Science databases were searched using the keywords dexmedetomidine and related brain diseases, although relevant articles from the last decade were included for detailed summarization and analysis. Dexmedetomidine has shown strong neuroprotective effects, such as protection of the blood-brain barrier, decreased neuronal death, maintained hemodynamic stability, and reduced postoperative agitation and cognitive dysfunction. Furthermore, dexmedetomidine has been shown to exert various neuroprotective effects, including anti-inflammatory and antioxidative stress effects, modulation of autophagy, and reduction of apoptosis in cerebral diseases. Dexmedetomidine acts as a neuroprotective agent against brain diseases during all phases of treatment. However, clinical trials with larger sample sizes are required to optimize dosage and dosing strategies.