Prolonged Disease Research Articles

A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors.

Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, genes conferring replication stress (RS), or SDH. Patients were recruited to 4 cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient GIST. Patients were treated with berzosertib 240 mg/m2 IV twice per week. Pre and on-treatment biopsies were obtained in cohorts T1-T3. Patients with SDH-mutant GIST had the longest median progression-free survival (PFS) (229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (g-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1-T3, increased expression of SFLN11 on treatment correlated with clinical benefit (HR = 0.045; 95%CI 0.005-0.400). Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.

Combining a WT1 Vaccine (Galinpepimut-S) with Checkpoint Inhibition (Nivolumab) in Patients with WT1-Expressing Diffuse Pleural Mesothelioma (DPM): A Phase I Study

IntroductionWilms’ tumor suppressor protein (WT1) often presents on the surface of diffuse pleural mesotheliomas (DPMs) and is an ideal therapeutic target. Galinpepimut-S (GPS), a tetravalent, non-HLA restricted, heteroclitic WT1-specific peptide vaccine was safe and effective in early phase clinical trials and upregulates T cell suppressive programmed death-ligand 1 (PD-L1) in the tumor microenvironment of other malignancies. A randomized phase II study of adjuvant GPS in patients with DPM trended toward improved median overall survival. MethodsTo further enhance immunogenicity, we combined GPS with nivolumab, an anti-PD1 monoclonal antibody, in an open-label, single-center phase I study, examining tolerability and immunogenicity in patients with previously treated DPM. We enrolled patients with progressive or recurrent DPM treated with at least one course of pemetrexed-based chemotherapy. Patients received 2 doses of GPS followed by 6 doses of GPS with intravenous nivolumab every 2 weeks, and up to 6 additional cycles until disease progression or unacceptable toxicity. ResultsTen patients were treated; 70% experienced mostly mild treatment-related adverse events; 2 experienced a grade ≥3 adverse event. Three (30%) of 10 patients demonstrated vaccine-specific T-cell responses. There were no partial responses; 3 patients had prolonged stable disease with up to 17% decrease in tumor volume. Median progression-free survival was 3.9 months and the median overall survival was 7.4 months. ConclusionsCoadministration of GPS and nivolumab demonstrated a tolerable toxicity profile and induced immune responses in a subset of patients, but initial response and survival benefit were limited possibly due to the small sample size.

Persistent Serous Choroidal and Retinal Detachment After Ab Interno Trabeculotomy for Glaucoma.

We describe a case of serous retinal detachment (SRD) with ciliochoroidal detachment (CCD) that persisted for 2 years and 7 months after minimally invasive glaucoma surgery (MIGS). A 71-year-old woman with primary open-angle glaucoma and cataracts had a central corneal thickness of 489 μm/492 μm and an ocular axis length of 24.05 mm/24.30 mm. She underwent phacoemulsification and intraocular lens implantation in the right eye (OD), along with goniosynechialysis and microhook ab interno trabeculotomy. Postoperative intraocular pressure was 4-6 mmHg in the OD. Five months later, SRD was observed temporally and inferiorly to the macula, with increased choroidal thickness. Best-corrected visual acuity at 5 months was (1.2)/(1.2) (right eye [OD]/left eye [OS]), and intraocular pressure was 6 mmHg/13 mmHg. CCD in the OD was accompanied by choroidal vessel dilation and choroidal vascular hyperpermeability. Two years and 7 months post-surgery, intraocular pressure spiked to 50-54 mmHg but settled at 12 mmHg 1 week later. CCD resolved, and choroidal folds and SRD disappeared, with decreased choroid thickness. Two years and 10 months postoperatively, there was no SRD recurrence at 10 mmHg on two antiglaucoma eye drops, and best-corrected visual acuity remained stable at (1.0)/(1.0). This case suggests that SRD may result from increased choroidal vessel permeability and retinal pigment epithelium dysfunction secondary to prolonged CCD/low IOP after MIGS. The prolonged disease course may be attributed to the balance between aqueous humor excretion and absorption, influenced by the limited size of the cyclodialysis cleft caused by MIGS.

7191 When Pain Is Misdiagnosed: A Case of Parathyroid Carcinoma Masked as Fibromyalgia

Abstract Disclosure: H. Pham: None. P.V. Kumar: None. S. Taylor: None. Parathyroid carcinoma is a rare and aggressive cause of hyperparathyroidism, typically associated with <1% of primary hyperparathyroidism cases. Incidence occurs mainly in the 5th decade of life, with less than 4% of all cases presenting in patients under age 30. Here, we highlight a case involving a 28-year-old woman with fibromyalgia who presented for worsening right shoulder pain in the setting of progressive, poorly characterized pain for the past year. Her initial physical exam was unremarkable aside from a non-tender left sided neck enlargement. However, her laboratory results were significant for corrected serum calcium of 15 mg/dL, serum phosphorus of 2.3 mg/dL, parathyroid hormone (PTH) >2500 pg/mL, and alkaline phosphatase 1604 units/L. X-ray of her right shoulder demonstrated mottled bone concerning for degenerative disease. Thyroid ultrasound revealed a complex cystic lesion posterior to the left thyroid lobe measuring 5.3 x 3.9 x 2.9 cm, worrisome for giant parathyroid adenoma. CT abdomen/pelvis showed diffuse osteosclerosis and innumerable lytic lesions, consistent with osteitis fibrosa cystica, as well as bilateral nephrolithiasis, likely medullary nephrocalcinosis. Her hypercalcemia was treated with aggressive hydration with normal saline and IV pamidronate. She underwent surgical resection of her parathyroid adenoma, which was unfortunately complicated by symptomatic hypocalcemia requiring prolonged care in the ICU. Her calcium levels did improve within a few days, and she was subsequently discharged with close outpatient follow-up. Final pathology report showed predominant thickened trabecular growth pattern with focal vascular invasion consistent with parathyroid carcinoma. Our patient’s case represents a rare presentation of parathyroid carcinoma in a young patient without any additional risk factors. Although atypical, her severe symptomatic hypercalcemia, nephrolithiasis, presence of large neck mass, and diffuse skeletal disease warranted immediate concern for malignant hyperparathyroidism instead of benign adenoma. Delayed diagnosis in our patient led to prolonged bone disease and severe complications. While hungry bone syndrome typically manifests post-parathyroidectomy in patients with end-stage renal disease, our patient experienced this complication in the setting of advanced, untreated hyperparathyroidism. We should consider hypercalcemia and hyperparathyroidism in our differential diagnosis for chronic pain, especially if pain remains uncontrolled with conservative measures. The most appropriate initial test for evaluation of hypercalcemia is a PTH level to distinguish between PTH-dependent and PTH-independent etiologies. Parathyroid carcinoma, even in young patients, should be considered when PTH is >3x upper limit of normal, serum calcium is >14, or skeletal and renal involvement is present. Presentation: 6/3/2024

7960 Clinical Outcomes of Image-Guided Therapies In Patients With Adrenocortical Carcinoma: A Tertiary Referral Center Retrospective Study

Abstract Disclosure: B. Chahla: None. K. Pal: None. V. Balderrama Brondani: None. F. Yaylaci Mert: None. M. Campbell: None. R. Sheth: None. M.A. Habra: None. Background: Image-guided therapies (IGTs) such as cryoablation or embolization are commonly used in oncology, but their role in adrenocortical carcinoma (ACC) is not well-defined. Materials and Methods: A retrospective review of ACC patients treated with IGTs. We assessed time to next line of systemic therapy, disease control rate (DCR), local tumor progression-free survival (LTPFS), and complications of IGTs.Treatment efficacy was assessed based on RECIST v1.1. Complications were categorized based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The study cohort included 26 patients (median age 56 years [range 38-76]; n=18 female) who had 51 IGT sessions to treat 86 lesions. The median Ki-67 is 20 (range 2-79), and median Weiss score is 6 (range 3-9). Seventeen patients received systemic therapy including mitotane, chemotherapy, immunotherapy, and other treatments prior to the first IGT and 10 patients received systemic therapy concurrently with first IGT. IGT modalities included cryoablation (n = 49), microwave ablation (n = 21), combined microwave and bland transarterial embolization (n = 8), bland transarterial embolization alone (n = 3), radioembolization (n = 3), and radiofrequency ablation (n = 2). Treated sites included the liver (n=37), intraperitoneal (n=11), adrenalectomy bed (n=10), lung (n=6), lymph nodes (n=6), retroperitoneal soft tissue (n=6) and other soft tissues (n=10). The median largest pre-IGT anteroposterior tumor dimension was 2.3 cm (range 0.5-8.6). DCR was 81.4% (70 out of 86), of which 66.3% of tumors showed complete response, 18.6% showed progressive disease, 8.1% showed partial response, and 7.0% showed stable disease. LTPFS rates were 73% and 63% at 1 and 2 years, respectively. Fourteen lesions needed re-ablation. Ten patients did not require systemic therapy while 16 patients (61.5%) received new systemic therapy following IGT, with a median time from first IGT to systemic therapy of 12.5 months (95% CI: 8.6 months- upper limit not reached). There was 1 reported CTCAE grade 3 adverse event (biloma) following IGT. Conclusion: IGT use in properly selected ACC lesions is safe and associated with prolonged disease control and delay in the need for systemic therapy. Presentation: 6/2/2024

Factors associated with resorption of calcific deposits in the shoulder with extracorporeal shock wave therapy

BackgroundFocused extracorporeal shock wave therapy (FSWT) is effective for treating calcific tendinitis of the shoulder. However, only a few reports exist on the factors related to calcium resorption after FSWT. Thus, this study aimed to investigate the factors associated with calcium resorption. MethodsIn 117 shoulders with chronic calcific rotator cuff tendinitis, FSWT was administered nine times once every 2 weeks (a total of 16 weeks). After nine sessions of FSWT, the shoulders were radiographed and categorized into complete resorption (CR) and incomplete resorption (ICR) groups. Evaluated parameters included age, duration of disease, Gärtner classification, size of calcium deposits, presence of blood flow around calcium deposits using the Doppler function of the ultrasound imaging system, Japanese Orthopaedic Association (JOA) score, University of California at Los Angeles score, disability of the arm, shoulder, and hand (UCLA) score, and tenderness. ResultsThe CR group included 93 shoulders (79.4%) and the ICR group included 24 shoulders (20.6%). In the two-arm comparison, CR showed significantly longer disease duration (P=.012) and high tenderness (P=.0013). Blood flow around calcium deposits was observed in 79.5% of shoulders in the CR group (P<.0001) and 29.1% in the ICR group. Type 1 Gärtner classification (P=.0009) was observed in 28 shoulders (30.1%) in the CR group and 17 shoulders (70.8%) in the ICR group. The two groups had no significant differences in age, size of calcium deposits, JOA score, or UCLA score. Multiple logistic regression analysis was performed using the following items that showed significant differences: absence of blood flow (odds ratio [OR], 8.51, 95% confidence interval [CI]: 2.24–22.8), Gärtner classification (OR, 5.60, 95%CI: 1.73–13.3), and duration of disease (OR, 1.06, 95%CI: 0.97–1.26). Longer disease duration, Gärtner type 1, and absence of blood flow around calcium deposits resulted in difficulty in calcium resorption. ConclusionPatients with Gärtner type 1 with prolonged disease duration and absence of blood flow around calcium deposits may have difficulty in achieving complete resorption.

153P Long-term effectiveness of risdiplam in non-ambulant SMA patients with prolonged disease duration

153P Long-term effectiveness of risdiplam in non-ambulant SMA patients with prolonged disease duration

Atherosclerosis, cancer and immune checkpoint inhibitors

Immunotherapy has revolutionized the treatment of various cancers leading to a clear survival benefit with cured or long-surviving patients. Atherosclerosis and cancer share risk factors and molecular mechanisms and have as their common thread a state of chronic inflammation linked to a deregulation of the immune system. A growing body of evidence is accumulating on the potential worsening effect of immune checkpoint inhibitors on atherosclerosis, with subsequent worsening of patients' long-term cardiovascular risk. The molecular pathways implicated in the growth and deregulation of atherosclerotic plaques seem to be the same (CTLA-4, PD-1, PD-L1) as those on which the anti-tumor effect is exerted. Owing to the increasing number of cancer patients treated with immunotherapy and the improved survival with the possibility of prolonged disease control, it is necessary to know the potential increase in cardiovascular risk for atherosclerosis-related events and to establish all prevention measures to reduce it.

Tertiary lymphoid structures' pattern and prognostic value in primary adenocarcinoma of jejunum and ileum.

To date, there have been no reports on tertiary lymphoid structures (TLS) in primary adenocarcinoma of jejunum and ileum. In this study, we employed digital pathology image analysis software to classify and quantify TLS, and evaluated the maturity of TLS using immunohistochemistry. Molecular genetics and immunotherapy biomarker detection were performed using next-generation sequencing technology, such as tumor mutational burden (TMB) and microsatellite instability (MSI). The aim of this study was to investigate the presence, location, maturity, association with immunotherapy biomarkers, and prognostic value of TLS in primary adenocarcinoma of jejunum and ileum. Compared to secondary follicle-like TLS (SFL-TLS), intra-tumoral TLS (IT-TLS) were more likely to manifest as early TLS (E-TLS) (P = 0.007). Compared to IT-TLS, SFL-TLS had a higher propensity to occur at the invasive margin(IM) (P = 0.032) and showed a trend towards being more prevalent at the tumor periphery (P = 0.057). In terms of immunotherapy biomarkers, there was a higher trend of IM-TLS density in PD-L1(22C3) score CPS < 1 group compared to PD-L1(22C3) score CPS ≥ 1 group (P = 0.071). TMB-H was significantly associated with MSI-H (P = 0.040). Univariate survival analysis demonstrated a correlation between high SFL-TLS group and prolonged disease free survival (DFS) (P = 0.047). There was also a trend towards prolonged DFS in the E-TLS-high group compared to the E-TLS-low group (P = 0.069). The peri-tumoral TLS (PT-TLS)-high group showed a trend of prolonged overall survival (OS) compared to the PT-TLS-low group (P = 0.090). In conclusion, the majority of TLS were located at the invasive margin and tumor periphery, predominantly consisting of mature TLS, while IT-TLS were mainly immature. Notably, TMB was closely associated with MSI and PD-L1, indicating potential predictive value for immunotherapy in primary adenocarcinoma of jejunum and ileum.

Dynamic evolution of frontal-temporal network connectivity in temporal lobe epilepsy: A magnetoencephalography study.

Temporal lobe epilepsy (TLE) frequently involves an intricate, extensive epileptic frontal-temporal network. This study aimed to investigate the interactions between temporal and frontal regions and the dynamic patterns of the frontal-temporal network in TLE patients with different disease durations. The magnetoencephalography data of 36 postoperative seizure-free patients with long-term follow-up of at least 1 year, and 21 age- and sex-matched healthy subjects were included in this study. Patients were initially divided into LONG-TERM (n = 18, DURATION >10 years) and SHORT-TERM (n = 18, DURATION ≤10 years) groups based on 10-year disease duration. For reliability, supplementary analyses were conducted with alternative cutoffs, creating three groups: 0 < DURATION ≤7 years (n = 11), 7 < DURATION ≤14 years (n = 11), and DURATION >14 years (n = 14). This study examined the intraregional phase-amplitude coupling (PAC) between theta phase and alpha amplitude across the whole brain. The interregional directed phase transfer entropy (dPTE) between frontal and temporal regions in the alpha and theta bands, and the interregional cross-frequency directionality (CFD) between temporal and frontal regions from the theta phase to the alpha amplitude were further computed and compared among groups. Partial correlation analysis was conducted to investigate correlations between intraregional PAC, interregional dPTE connectivity, interregional CFD, and disease duration. Whole-brain intraregional PAC analyses revealed enhanced theta phase-alpha amplitude coupling within the ipsilateral temporal and frontal regions in TLE patients, and the ipsilateral temporal PAC was positively correlated with disease duration (r = 0.38, p <.05). Interregional dPTE analyses demonstrated a gradual increase in frontal-to-temporal connectivity within the alpha band, while the direction of theta-band connectivity reversed from frontal-to-temporal to temporal-to-frontal as the disease duration increased. Interregional CFD analyses revealed that the inhibitory effect of frontal regions on temporal regions gradually increased with prolonged disease duration (r = -0.36, p <.05). This study clarified the intrinsic reciprocal connectivity between temporal and frontal regions with TLE duration. We propose a dynamically reorganized triple-stage network that transitions from balanced networks to constrained networks and further develops into imbalanced networks as the disease duration increases.

Abstract A001: Health expenditure trajectory and gastric cancer incidence in the National Health Insurance Senior Cohort: A nested case-control study

Abstract Background: Gastric cancer is the fourth most common cancer and highly prevalent in South Korea. Given its prolonged disease progression, understanding the impact of health expenditure patterns over time is crucial. This nested case-control study aimed to identify the association between health expenditure trajectory and incidence of gastric cancer. Methods: Data from the National Health Insurance Service Senior Cohort of South Korea were used. Individuals diagnosed with gastric cancer (N = 14,873) were matched to a non-diagnosed group (N = 44,619) in a 1:3 ratio using a nested case-control design. A latent class trajectory analysis was performed to identify the patterns of health expenditure among the matched participants. Furthermore, conditional logistic regression analysis was conducted to examine the relationship between healthcare expenditure trajectories and gastric cancer incidence. Results: Seven distinct health expenditure trajectories over a 5-year period were identified: consistently lowest (13.9%), rapidly increasing (6.4%), gradually increasing (14.1%), consistently second-highest (22.1%), middle-low (17.8%), gradually decreasing (12.8%), and consistently highest (12.9%). Compared to the Middle-low group, individuals in the rapidly increasing (OR = 2.07; 95% confidence interval [CI], 1.90–2.25), consistently lowest (OR = 1.43; 95% CI, 1.33–1.55), gradually increasing (OR = 1.23; 95% CI, 1.15–1.32), and consistently highest (OR = 1.08; 95% CI, 1.01–1.17) groups exhibited a higher risk of developing gastric cancer. Conclusion: Our findings emphasize the importance of monitoring health expenditures to prevent gastric cancer. The categorization of health expenditure by trajectories allowed the identification of specific risk groups that may be targeted by appropriate interventions. Citation Format: Minjee Lee, Ki-Bong Yoo, Woo-Ri Lee. Health expenditure trajectory and gastric cancer incidence in the National Health Insurance Senior Cohort: A nested case-control study [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A001.

Clinical characteristics of pyoderma gangrenosum: Case series and literature review.

Pyoderma gangrenosum (PG) is a neutrophilic skin disease characterized by recurrent painful cutaneous ulcers, often accompanied by inflammatory bowel disease, joint pain, and other systemic damage. This disease is relatively rare in clinical practice and its diagnosis and treatment are often delayed, leading to secondary infections in the skin lesions, prolonged disease course, and increased disease burden on patients. This study retrospectively analyzed the clinical characteristics and treatment strategies of patients with PG admitted to our hospital and conducted a literature review, in order to improve the understanding of the disease among clinical doctors, enable patients to receive better diagnosis and treatment, and ultimately improve patient prognosis. Clinical data of patients diagnosed with PG and hospitalized in Beijing Chaoyang Hospital, Capital Medical University from January 2014 to December 2022 were retrospectively collected. The clinical manifestations, treatment strategies, efficacy, and disease outcomes were analyzed. A total of 14 patients, including 8 males and 6 females, aged 14 to 66 years, were included. Skin lesion types: 13 cases were ulcer-type, 1 case was pustule combined with ulcer-type, and the lower limbs were the most commonly affected areas. All the 14 patients presented with comorbidities. All patients were treated with glucocorticoids, with a daily dose equivalent to 20 to 100 mg prednisone and a median dose of 40 mg. Among them, 3 patients were treated with minocycline in combination, 1 patient was treated with mycophenolate mofetil 0.5 twice daily in combination, 1 patient was treated with cyclophosphamide 0.1 once daily in combination, and 1 patient was treated with thalidomide 0.1 every night in combination. PG is a relatively rare immune-related skin disease. Our small sample data analysis found that male PG is not uncommon in the Chinese population. Systemic glucocorticoids can quickly control the symptoms of PG in most patients with PG. In patients with poor efficacy or limited use of glucocorticoids, immunosuppressive drugs or novel targeted drugs such as biologics or small-molecule drugs should be used in combination as early as possible. Skin lesion care focuses on preventing infection, avoiding surgical debridement, and emphasizing pain management and the symptomatic treatment of comorbidities.

Cognitive States Classification Analysis

Alzheimer's disease is a chronic, prolonged, and irreversible neurodegenerative disease of unknown cause. In recent years growing research interest assumes that by processing data of essential factors effective models can be defined for recognizing and predicting the disease development. The present article aims to propose classification models for the diagnosis of Alzheimer's disease cognitive states. For this aim medical data of biomarkers and cognitive assessment data are used. The novelty of the paper is to explore both the Amyloid/TAU/ Neurodegeneration framework and the biologically determined process of delay between the brain impairment and visibility of its appearances by incorporating these concepts in the model development procedure. The study explores the ability of three classifiers – Random Forest, Extreme Gradient Boosting, and Logistic Regression. Conclusion results have been done by comparison of the grouping abilities in different data spaces. The practical result of the study is helping to determine medical examinations that give accurate results for the diagnosis and prediction of the progression of the disease in possible earlier stages of the disease development.

Retrospective study of ureteral stenosis after holmium laser lithotripsy.

To identify the factors influencing postoperative ureteral stenosis following holmium laser lithotripsy. A retrospective study was conducted of 106 patients who underwent ureteroscopic holmium laser lithotripsy. The effects of variables including stone location, stone size, the duration of surgery, water intake, disease duration, and stone-associated polyps were investigated. Logistic regression analysis revealed significant associations of ureteral stenosis with stone location, stone size, duration of surgery, water intake, disease duration, and stone-associated polyps. Patients with proximal stones, with large stones, who underwent long surgical procedures, who drank a large amount of water, who had long-term disease, and who had stone-related polyps were more likely to develop postoperative ureteral stenosis. Significant perioperative complications of holmium laser lithotripsy are associated with prolonged disease, large ureteral stones, long incarceration periods, and the presence of polyps. Surgeons should consider these risk factors during the preoperative evaluation of patients and surgical planning to minimize the risk of postoperative ureteral stenosis.

Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D.

Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib. Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children. A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children. This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

Pembrolizumab and Cabozantinib in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Long-term Survival Update with a Biomarker Analysis.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis. This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry. With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%-56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%-76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%-81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively]. Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings.

Case series on neuroimaging spectrum of Wilson’s disease: knowing the known and the uncommonly known

BackgroundWilson’s disease is an inherited disease characterized by impaired copper metabolism that causes damage to many organs, including the brain. Patients having neurological involvement usually present with varied neuropsychiatric symptoms. Magnetic resonance imaging (MRI) Brain plays an indispensable role in identifying the structural involvement in these patients, aiding in early accurate diagnosis and timely management. Typically, basal ganglia, thalami and brainstem are involved, with bright claustrum sign, face of giant panda sign and miniature panda signs on MRI.ConclusionsHaving knowledge about the commonly encountered and known MRI brain findings in Wilson’s disease are essential in aiding accurate diagnosis and initiating early management. However, identifying the Atypical MRI brain characteristics is all the more imperative and should be considered in patients with prolonged or severe disease or in patients with rapid clinical progression and in patients showing poor response to treatment.

Real-world outcomes with lurbinectedin in second-line and beyond for small cell lung cancer in Korea.

211 Background: Small-cell lung cancer (SCLC) accounts for approximately 10~15% of all lung cancers and is characterized by a strong tendency for early metastasis, and a poor prognosis. Most patients are diagnosed with extensive disease, with only one-third presenting with earlier-stage disease amenable to potentially curative multimodality therapy. Before the advent of lurbinectedin in 2020, only few options existed for treating patients with SCLC that had progressed after first-line therapy. The sole available second-line option for metastatic SCLC was topotecan, which is associated with hematological toxicities and only modest efficacy. Although lurbinectedin has been added to the arsenal against metastatic SCLC, real-world data on its efficacy has been scarce due to its recent implementation. In this study, we investigated the demographics and clinical outcomes of metastatic SCLC patients treated with lurbinectedin in Korea. Methods: Patients with metastatic SCLC who had failed first-line therapy were identified (n=51) at Yonsei Cancer Center, Seoul, Republic of Korea, and received lurbinectedin at a starting dose of 3.2mg/kg. Efficacy data, including investigator-assessed tumor response, progression data, survival, and demographic information, were recorded. Results: A total of 51 patients were treated with lurbinectedin at a single center in Korea. Thirty-four patients were eligible for assessment. The median age of diagnosis was 68. The overall objective response rate and disease control rate were 20% and 47%, respectively. For patients treated with lurbinectedin in the second-line therapy, the ORR and DCR were 12% and 15% respectively, while the ORR was 18% and DCR was 29% for patients in beyond third-line of therapy. The median progression-free survival was 1.8 months (95% CI 0.38 to 2.08), and the median overall survival was 2.8 months (95% CI 0.55 to 2.70). A patient group with a history of smoking showed prolonged overall survival and disease control rate. The most common adverse effects related to lurbinectedin were anemia (55%), leukopenia (53%), nausea (35%), loss of appetite (25%), general weakness (19%), neutropenia (12%), dizziness (6%), alopecia (6%), phlebitis (3%), thrombocytopenia (3%), pneumonia (3%). Conclusions: The real-world data of lurbinectedin in SCLC patients suggests that it is still a viable option in this disease area with dismal prognosis. [Table: see text]

Sunitinib for the treatment of patients with advanced pheochromocytomas or paragangliomas: The phase 2 non-randomized SUTNET clinical trial

BackgroundMetastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option. MethodsWe conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011–002632-99. ResultsFifty patients were included. At a median follow-up of 71.7 months (IQR 35.4–100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1–69.3) and median PFS was 14.1 months (95 % CI 8.9–25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy. ConclusionSunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile.

Phase 1 study of NEDD8 activating enzyme inhibitor pevonedistat in combination with chemotherapy in pediatric patients with recurrent or refractory solid tumors (ADVL1615)

PurposeThe objective of this study was to determine the recommended Phase 2 dose (RP2D) of pevonedistat, a first in class inhibitor of NEDD8 activating enzyme, in combination with irinotecan (IRN) and temozolomide (TMZ) in children with cancer. MethodsThis Phase 1 study used a rolling 6 design to evaluate escalating doses of pevonedistat in combination with standard doses of IRN and TMZ in pediatric patients with recurrent/refractory solid or CNS tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50 mg/m2) and TMZ (orally, 100 mg/m2), on days 8–12 of a 28-day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN/TMZ on days 1–5 of a 21-day cycle. ResultsThirty patients enrolled; all were eligible and evaluable for toxicity. Six patients each enrolled on pevonedistat dose levels (DL) 1 (15 mg/m2), 2 (20 mg/m2), 3 (25 mg/m2) and 4 (35 mg/m2) as well as an expanded pharmacokinetic (PK) cohort at DL4. The maximum tolerated dose (MTD) was not exceeded. 2/12 (17 %) patients treated at the RP2D (35 mg/m2) experienced a cycle 1 dose limiting toxicity (DLT). IRN is unlikely to affect the pharmacokinetics of pevonedistat. Two patients had a partial response and 6 patients had prolonged stable disease (> 6 cycles). ConclusionsPevonedistat in combination with IRN/TMZ is well tolerated in children with solid or CNS tumors. The RP2D of pevonedistat is 35 mg/m2 on days 1, 3, 5 in combination with IRN/TMZ.