Treatment Regimens Research Articles

Bimekizumab Safe and Effective Self-administration Using 2 mL Devices by Patients with Moderate to Severe Plaque Psoriasis: Results from Two Multicenter, Randomized, Open-label Studies

Introduction: Safe and effective self-injection of subcutaneous bimekizumab (BKZ) in patients with moderate to severe plaque psoriasis using a 1­ mL safety syringe (sy) or auto-injector (AI) has previously been associated with an overall positive patient experience.1 Here, the ability of patients to safely and effectively self-administer subcutaneous BKZ using a 2 mL sy or AI is reported. Methods: DV0002 (North America) and DV0006 (Germany, Hungary and Poland) were sub-studies of the phase 3 open-label extension (OLE) study, BE BRIGHT.1,2 Included patients received BKZ 320 mg every 4 weeks (Q4W) or Q8W based on treatment regimen and Psoriasis Area Severity Index (PASI) response at BE BRIGHT entry. Patients were randomized 1:1 to BKZ-sy-2 mL or BKZ-AI-2 mL, and performed self-injections (after training in the self-injection technique) at baseline and Wk8. Safe and effective self-injection defined as complete dose delivery of BKZ and absence of adverse events related to the device which led to study withdrawal. Primary and secondary objectives were to assess patients’ ability to safely and effectively self-administer BKZ at Wk8 and baseline, respectively. Other objectives included to evaluate patient experience of self-injection, using the injection site pain visual analog scale (VAS; 0 [no pain]–100 [worst possible pain]) and the Self-Injection Assessment Questionnaire (SIAQ; subscale scores ranged 0-10 [higher scores better]), and the post-use structural and mechanical integrity of each device. Data analyzed using two full analysis sets (BKZ-sy-2 mL and BKZ-AI-2 mL) and reported for the combined BKZ dose groups (BKZ Total) using observed cases. Results: In DV0002, 19 patients each were randomized to use BKZ-sy-2 mL and BKZ-AI-2 mL. All patients using BKZ-sy-2 mL (n=19) self-injected BKZ safely and effectively at baseline and Wk8. All (n=19) and 94.7% (n=18/19) of patients using BKZ-AI-2 mL self-injected BKZ safely and effectively at baseline and Wk8, respectively. In DV0006, 44 and 45 patients were randomized to use BKZ-sy-2 mL and BKZ-AI-2 mL, respectively. All patients using BKZ-sy-2 mL (n=44) and BKZ-AI-2 mL (n=45) safely and effectively self-injected BKZ at baseline and Wk8. In DV0002/6, median pre-injection and post-injection SIAQ scores were ≥7.5 across both devices, and >9.0 for feelings about injections, self-image, and injection-site reactions subscales. In DV0002/6, low median VAS scores across both devices indicate variable but generally low pain. All devices maintained their structural and functional integrity post-use. One device deficiency complaint was received. Conclusions: A positive self-administration experience was associated with the 2 mL devices, as reported with 1 mL devices,1 providing patients with an option to self-administer a single injection of BKZ.

Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens

Abstract Background Diffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach. Methods We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy. Results We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction. Conclusion Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.

Prevention and Treatment of Glucocorticoid-Induced Osteoporosis in adults: Recommendations From the European Calcified Tissue Society

Abstract Introduction This report presents the recommendations of the European Calcified Tissue Society (ECTS) for the prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) in adults. Our starting point was that the recommendations be evidence based, focused on non-bone specialists who treat patients with GC and broadly supported by ECTS. Methods The recommendations were developed by global experts. After a comprehensive review of the literature, twenty-five recommendations were formulated, based on quality evidence. For stratifying fracture risk and the most appropriate first line of treatment, we have classified patients into 3 categories: those at medium risk of fractures i.e. adults without a recent (in the last 2 years) history of fracture, those at high risk of fractures i.e. adults with recent history of fracture, and/or at least one vertebral fracture (grade ≥ 2 according to Genant classification), and those at very high risk of fractures i.e. adults aged ≥ 70 years with a recent hip fracture, pelvis fracture, and/or at least one vertebral fracture (grade ≥ 2 according to Genant classification) . The subtopics in the recommendations include Who to assess, How to assess, Who to treat, How to treat, and Follow-up and Monitoring. Results General measures are recommended for all patients who are being prescribed glucocorticoids (GCs) for > 3 months: i.e. calcium and protein intake should be normalized, a 25(OH) vitamin D concentration of 50-125 nmol/L should be attained, and the risk of falls be minimized. 1)Who to assess? (R1-2) A preliminary assessment of fracture risk should be routinely performed in patients likely to receive oral GCs for ≥ 3 months: (i) women and men ≥ 50 years and (ii) patients at increased risk of fracture (history of fragility fracture and/or have comorbidities or are on medications that are frequently associated with osteoporosis. 2)How to assess (fracture risk)? (R3-6) Clinical risk factors including history of fragility fracture, systematic vertebral imaging, and GCs dose-adjusted FRAX, measurement of BMD by DXA, fall risk, and biochemical testing. 3) Who to treat? (R7-12) Anti-osteoporosis treatment is indicated for women and men ≥ 50 years with (i) the presence of a recent history of vertebral and/or non-vertebral fracture (less than 2 years) (ii)and/or a GCs dosage ≥ 7.5 mg/day, (iii)and/or age ≥ 70 years (iv)and/or a T-score ≤ -1.5, (v)and/or 10-year probability risk above the country specific GC dose-adjusted FRAX® thresholds. In premenopausal women and men < 50 years with a Z-score ≤ -2 and/or a history of fragility fracture, it is recommended to refer the patient to a bone specialist. 4) How to treat? (R13-18) In women and men ≥ 50 years, (i) alendronate or risedronate is preferred as the first line of treatment in patients at medium risk of fractures, (ii) zoledronic acid or denosumab in patients at high risk of fractures, and (iii) teriparatide in patients at very high risk of fractures. It is imperative that sequential therapy be implemented in individuals receiving denosumab or teriparatide as their first-line treatment regimen. 5) Follow-up and Monitoring (R19-25): In patients receiving anti-osteoporosis treatment, monitoring of clinical risk factors (e.g., history of fragility fracture), systematic vertebral imaging, fall risk, BMD measurement using DXA, and biochemical testing should be performed regularly during follow-up. Conclusions The new, evidence-based recommendations by the ECTS for the prevention and treatment of GIOP provide clear and pragmatic advice to all health practitioners especially those who are not bone specialists.

Small but mighty: targeted antifungal liposomes of a smaller size are superior in treating cryptococcal meningitis

ABSTRACT Cryptococcal meningoencephalitis (CME) is deadly. CME is responsible for 19% of deaths in AIDS patients, and its global mortality is greater than 60%. The recommended CME therapy requires amphotericin B (AmB), a fungicidal drug targeting fungal ergosterol. AmB also binds to the host’s cholesterol and is highly toxic. Liposomal AmB (AmB-LLs), relative to deoxycholate-solubilized AmB, has lower toxicity and longer tissue retention, but it requires high doses for treatment and its efficacy in treating CME remains unsatisfactory. To improve the effectiveness of AmB-LLs, we previously developed DectiSomes-targeted AmB-LLs decorated with host dectins that recognize fungal polysaccharides. DectiSomes, relative to untargeted AmB-LLs, modestly improve efficacy against systemic cryptococcosis, in contrast to the drastic improvement observed in candidiasis or aspergillosis models. We speculated that limited tissue penetration of the regular-sized DectiSomes might have contributed to the modest improvement in treating systemic cryptococcosis. Here, we discovered that DectiSomes of a smaller size (~50 nm), compared with DectiSomes of the regular size (~100 nm) or untargeted AmB-LLs of either size, had a much better capability in reducing cryptococcal burden of various organs including the brain and in prolonging the survival of mice with systemic cryptococcosis. The performance of small DectiSomes was far superior to all other groups at two different doses of AmB tested. Furthermore, no kidney toxicity was observed in any of the treatment regimens tested. Taken together, our findings indicate that small DectiSomes can be a powerful antifungal delivery platform to drastically improve therapies against the deadly CME. IMPORTANCE Systemic cryptococcosis is fatal even with antifungal interventions. The most effective drug against this disease is amphotericin B (AmB). However, AmB is highly toxic as it binds to fungal ergosterol and also mammalian cholesterol. Liposomal AmB was introduced to the clinic in 1990s because it showed reduced toxicity and longer retention in various organs. However, the dose of AmB required for treatment using liposomal formulation is high and the outcome is far from satisfactory. In our previous work, we generated DectiSomes, dectin-decorated liposomes loaded with AmB that more effectively deliver the drug to the pathogen and enhance antifungal efficacy. However, the improvement in treating systemic cryptococcosis, compared with candidiasis and aspergillosis, is modest. Here, we generated DectiSomes that are half their regular size to improve tissue penetration. We discovered that small DectiSomes are superior in reducing fungal burden in various organs including the brain and in prolonging animal survival.

Results of a Phase 2 Multicenter Study Evaluating the Safety and Tolerability of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective In Part 2 of this study, the primary objective was to determine the optimal dosing regimen for VP-315 by exploring the effects of various dosing schemes on the safety and tolerability of VP-315 in a larger population of subjects with biopsy proven BCC. Methods Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Safety and tolerability were assessed by documenting the occurrence of Treatment Related Adverse Events (TRAEs), including those of special interest, Treatment Related Serious Adverse Events (TRSAEs), discontinuations due to AEs and expected treatment-related cutaneous reactions including tumor necrosis. Results All 82 subjects completed one of the VP-315 treatment regimens for BCC. TRAEs were mostly mild to moderate. AEs included injection site pain (mild 13.4%, moderate 12.2%, severe 1.2%), hypertension (mild 4.9%), hypotension (mild 4.9%), erythema (mild 1.2%, moderate 2.4%), and headache (mild 2.4%). Expected cutaneous reactions were observed. No TRSAEs were reported. Conclusion VP-315 treatment was shown to be safe and well-tolerated when administered once daily 2-3 times per week per tumor for up to 2 weeks using a split dose approach. Given its favorable safety profile, VP-315 warrants continued research as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting. Sponsored by Verrica Pharmaceuticals Inc.

Characteristics and outcome of 73 dogs with iron EDTA molluscicide ingestion in Melbourne, Australia (2013–2019)

IntroductionThe objective of this study was to describe the clinical features, treatments and outcomes of dogs with iron ethylenediaminetetraacetate (EDTA) molluscicide ingestion. We aimed to identify potential predictors of serum iron concentration >54 μmol/L; a cut‐off recommended for initiating treatment of human iron toxicosis.MethodsMedical records across four veterinary hospitals (2013–2019) for dogs with known or suspected iron EDTA molluscicide ingestion were reviewed for signalment, clinical signs, clinicopathological data, treatment regimens and outcomes. Clinical signs of dogs with serum iron concentrations either below or above a cut‐off of 54 μmol/L were compared using Fisher's exact test. Association between serum iron and urine discolouration was tested using logistic regression.ResultsSeventy‐three dogs were included. The most frequent characteristic was abnormal faeces (n = 47, 64%) as determined by rectal examination, with more dogs that had serum iron >54 μmol/L showing this clinical sign (24/35), compared to dogs with serum iron <54 μmol/L (4/13) (P = 0.025). Clinicopathologic abnormalities included increased base excess (n = 20/49, 20%), hyperglycaemia (n = 13/57, 23%) and hyperlactataemia (n = 12/57, 21%). Fifty‐four dogs received deferoxamine chelation (74%), during which 25/42 (60%) dogs had discoloured urine despite all dogs having subsequent iron concentrations <54 μmol/L. Admission serum iron concentration was associated with urine discolouration during hospitalisation (odds ratio 1.046, 95% confidence interval 1.008–1.107, P = 0.011). Sixty‐nine dogs (95%) survived to discharge, with 10 dogs (14%) transferred to another veterinarian.ConclusionsIron EDTA molluscicide ingestion caused predominantly gastrointestinal clinical signs, and abnormal faeces, as well as urine discolouration during chelation therapy, which may indicate an elevation of serum iron concentration on presentation. Outcome was excellent.

Clinical characteristics, progression patterns and treatment outcomes in microsporidial keratoconjunctivitis: a prospective study in Thailand.

To assess the clinical characteristics, progression patterns, and treatment outcomes of microbiologically confirmed microsporidial keratoconjunctivitis (MKC). This prospective cross-sectional study included patients with superficial punctate epithelial keratitis clinically suspected of MKC. Comprehensive slit-lamp examinations were conducted, and corneal scraping was performed for Gram-chromotrope staining and polymerase chain reaction (PCR) analysis. A standardized questionnaire gathered demographic data, clinical features, and risk behaviors. Treatment regimens and corneal findings, including medication and frequency, were documented at each visit. PCR confirmed the diagnosis of MKC in 96 out of 117 eyes (82.1%), identifying Vittaforma corneae in 93.7% of cases, Microsporidium sp. in 4.2%, and Encephalitozoon hellem in 2.1%. All cases exhibited similar characteristics and pattern of progression, including elevated epithelial lesions in diffused distribution (34.1%), typical target lesions (31.3%), and subepithelial infiltrations (41.7%). Treatment with topical moxifloxacin, with or without oral albendazole, followed by topical steroids for subepithelial infiltrates, led to clinical improvement within approximately two weeks, with 52% of patients achieving complete recovery. This study identifies key clinical features and progression patterns in MKC. Topical fluoroquinolone monotherapy, or its combination with topical steroids or oral albendazole, results in favorable visual outcomes without corneal scarring. These insights may inform and enhance clinical management of MKC.

Exploring the impact of mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 on breast cancer cell metabolism.

Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of significant efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide, IMD-0354 and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors. To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Metabolic characterization was carried out using Seahorse XFe96 Bioanalyzer and statistical analysis was carried out via ANOVA. Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested. In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

Combination of rituximab and low-dose glucocorticoids for idiopathic refractory nephrotic syndrome with MCD/FSGS: a single-center prospective cohort study

Background The treatment of idiopathic refractory nephrotic syndrome (IRNS) remains a difficult problem in clinical practice. This study aims to determine the efficacy and safety of combining low-dose glucocorticoids with rituximab in IRNS treatment. Methods This prospective, single-center cohort study enrolled 60 patients who were diagnosed with refractory IRNS with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) and treated at First Affiliated Hospital of Sun Yat-sen University. All patients received a treatment regimen consisting of rituximab (375 mg/m2/week × 4) and low-dose glucocorticoids. Results 46 complete remissions and 4 partial remissions were observed within 6 months of treatment. Within 12 months of treatment, 48 patients achieved complete remission, and 4 achieved partial remission. The complete remission rate for steroid-dependent/frequently relapsing nephrotic syndrome was significantly higher than that for steroid-resistant nephrotic syndrome (88.24% vs. 33.33%, p < .01). Following up for 12 months, 16 patients relapsed, accounting for 30.76% of the total, with a mean time to relapse of 10.97 months. Compared with baseline data, 24-hour urine protein quantification, total cholesterol and triglycerides significantly decreased, while serum albumin, globulin and IgG significantly increased at 12 months after treatment. All follow-ups were without serious adverse events. Twenty-four patients experienced infusion-related adverse reactions, which could be relieved by slowing down the infusion rate or suspending the infusion. Nine patients experienced infection-related adverse reactions; six of them were relieved with antibiotic treatment, and 3 patients were controlled by symptomatic treatment. Conclusions Rituximab combined low-dose glucocorticoids therapy is effective and safe in idiopathic refractory nephrotic syndrome.

Antibiotic Resistance in Mycobacterium Tuberculosis and Non-Tuberculous Mycobacteria

Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) antibiotic resistance presents an important challenge to the treatment of mycobacterial infections. The therapeutic approaches are complicated by the resistance of both MTB and NTM to a variety of antibiotics. Resistance to first-line drugs such as isoniazid, rifampicin, ethambutol, and streptomycin has been consistently increasing in MTB, underscoring the necessity of effective treatment strategies. Conversely, the necessity of species-specific treatment regimens is underscored by the high resistance rates of NTM species, such as Mycobacterium avium complex, M. kansasii, and M. abscessus complex, to commonly used anti-tuberculosis pharmaceuticals. A combination of intrinsic and acquired factors are involved in the mechanisms of antibiotic resistance in these mycobacteria. Features such as biofilm formation, thick cell walls, and reduced drug uptake are responsible for intrinsic resistance in NTM, whereas acquired resistance can develop as a result of protracted antibiotic exposure. Understanding these resistance mechanisms is essential for the development of new therapies and the prevention of the increasing prevalence of drug resistance in mycobacterial infections. The significance of continuous surveillance, species-specific treatment protocols, and the development of novel antimicrobial agents to effectively manage mycobacterial diseases is emphasized by the prevalence of antibiotic resistance in MTB and NTM. This review article focuses on the molecular mechanisms that have resulted in the development of resistance in both MTB and NTMs, as well as the extent to which various classes of antimycobacterial drugs act.

Comparison of clinical performance between late and standard total-body [68Ga]Ga-PSMA-11 in biochemical recurrent prostate cancer.

Enhanced lesion detection in prostate cancer is observed with late [68Ga]Ga-PSMA-11 PET/CT imaging compared to standard [68Ga]Ga-PSMA-11 PET/CT imaging (50-100min p.i.). However, the poor image quality of late imaging using short axial field of view (SAFOV) PET/CT has hindered its sole clinical adoption. Conversely, the image quality of late imaging with a long axial field of view (LAFOV) [68Ga]Ga-PSMA-11 PET/CT fulfills clinical diagnostic requirements. Nonetheless, the diagnostic efficacy of late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis and its impact on treatment decisions, compared to standard LAFOV [68Ga]Ga-PSMA-11 PET/CT, remains unclear. This study aims to compare the rate of PET positivity between late and standard LAFOV [68Ga]Ga-PSMA-11 PET/CT and to evaluate the influence of late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis on treatment decisions relative to standard scans. From January 2021 to April 2024, 127 patients with biochemical recurrence of prostate cancer post-radical prostatectomy were enrolled to undergo both standard and late LAFOV [68Ga]Ga-PSMA-11 PET/CT scans at Shanghai Renji Hospital. We compared the rate of PET positivity between the two modalities at the patient level and across different anatomical regions. We assessed the added diagnostic value of late LAFOV [68Ga]Ga-PSMA-11 PET/CT and its impact on modifying patient treatment plans. The image quality of late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis in all patients met clinical diagnostic requirements. The rate of PET positivity of late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis were significantly higher than those of standard LAFOV [68Ga]Ga-PSMA-11 PET/CT (80.31% [102/127] vs. 65.35% [83/127]; P < 0.001). Late LAFOV [68Ga]Ga-PSMA-11 PET/CT demonstrated higher lesion SUVmax (16.69 ± 16.42 vs. 11.91 ± 10.72, P < 0.001) and TBR (6.26 ± 7.21 vs. 3.44 ± 3.57, P < 0.001) compared to standard LAFOV scans. Additionally, 14.17% (18/127) of patients experienced changes in their treatment regimen due to the superior detection capabilities of late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis compared to the standard scan. The rate of PET positivity of late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis compared to standard LAFOV [68Ga]Ga-PSMA-11 PET/CT highlight its potential as a valuable diagnostic tool for biochemically recurrent prostate cancer. This study paves the way for using late LAFOV [68Ga]Ga-PSMA-11 PET/CT with forced diuresis for prostate cancer imaging in daily clinical practice, facilitating more accurate and timely diagnoses.

Sleep in hospitalized children with cancer: relationship with psychiatric disorders and hospital conditions

Background. Children with cancer often undergo prolonged and recurrent hospitalization, which leads to an increased incidence of sleep disruptions and psychiatric disorders. This study aimed to objectively quantify the prevalence of sleep disruptions in hospitalized pediatric oncology patients and to determine the effects of psychiatric disorders, treatment regimens, and hospital conditions on sleep patterns. Method. This cross-sectional study included 39 children who were undergoing treatment and monitoring in the pediatric oncology inpatient service. Parents completed questionnaires providing information about their child’s sleep patterns, quality of life, and hospital conditions. The children were monitored for five days using actigraphy to record sleep parameters. They were evaluated with a semi-structured interview form (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version-DSM 5-Turkish Adaptation) for psychiatric diagnoses. Results. Sleep disruptions were identified in 27 (69.2%) children with cancer. In addition to adjustment disorder and anxiety disorder psychiatric diagnoses, behavioral problems and emotional symptoms were more common in the group with sleep disruptions. Actigraphy measurements indicated that poor sleep was associated with younger age, recent cancer diagnosis, specific phobias, depression, daytime napping, and frequent vital sign assessments. Conclusion. Sleep problems in hospitalized children with cancer are linked to psychiatric comorbidities, treatment routines, and hospital conditions. By recognizing psychiatric symptoms and optimizing hospital conditions that affect sleep, healthcare providers can enhance the quality of sleep for these children.

The incidence of symptomatic CSF viral escape in patients on antiretroviral therapy in western India: a retrospective cohort study.

Antiretroviral treatment (ART) effectively suppresses viral loads in both plasma and cerebrospinal fluid (CSF). Patients with discordant plasma and CSF viral loads may experience chronic-progressive or fluctuating neurocognitive dysfunctions. This study examined the incidence of symptomatic CSF viral escape (CSFVE) in patients receiving ART. This retrospective cohort study was conducted between 2000 and 2023. The primary outcome measure was the incidence of symptomatic CSFVE. Nonparametric Mann-Whitney U and Fisher exact/χ 2 tests were applied for continuous and categorical variables, respectively. The cumulative incidence function with Gray's test was used to compare the incidence of CSFVE across the treatment regimens. During the study period, 52 of the 8415 patients were diagnosed with CSFVE. The median duration of HIV diagnosis in patients with CSF VE was 150 (12-288) months, with a median nadir CD4 + T-cell count 96.5 (13-601 cells/L)], and 75% of the patients were on a ritonavir-boosted protease inhibitor (PI/r) regimen. The cumulative incidence of symptomatic CSFVE at a follow-up of 14 years was 1% (95% CI, 0-1%). PI/r (HR 34.73; 95% CI 13.5 to 89.4; p < 0.001) and integrase strand transfer inhibitor (INSTI) (HR 3.42; 95% CI 1.94 to 6.02; p < 0.001) regimens were significantly more likely to be associated with CSFVE than the Non-nucleoside reverse transcriptase inhibitors (NNRTIs) regimens. NNRTIs had the lowest risk of CSFVE compared to the PI/r and INSTI regimens. A rapid and complete recovery is possible with symptomatic CSFVE if it is diagnosed and treated early.

Abstract B020: A blood-based multi-omics test for early evaluation of lymphoma treatment effectiveness

Abstract Introduction: The standard clinical assessment for treatment response of lymphoma currently relies on periodic functional imaging examinations. In this prospective study, we utilized a blood-based multi-omics test, SeekInClarity, to evaluate treatment response and predict patient outcomes in the major types of lymphoma. Methods: 116 patients with various lymphoma subtypes were recruited from two clinical centers: The First Affiliated Hospital of Zhengzhou University and Sun Yat-sen University Cancer Center. Blood samples were collected at pre- treatment (baseline) and after two cycles of treatment (landmark) for SeekInClarity analysis, which integrated shallow whole-genome sequencing (sWGS) data of circulating-free DNA (cfDNA), including copy number aberrations (CNA) and fragment size (FS), with seven protein markers. The molecular tumor burden (MTB) score was calculated with SeekInClarity to assess the therapeutic efficacy of patients. Results: At 95.2% specificity, cancer signals were detected in 74.1% (86/116) of patients at baseline. Higher MTB scores were associated with advanced tumor stages, with MTB+ ratios of 31.8%, 63.6%, 84.6%, and 91.2% for stage I, II, III, and IV, respectively. After two cycles of treatment, patients with MTB+ status exhibited significantly poorer progression-free survival (PFS) (HR: 0.13, 95% CI, 0.05-0.33, P &amp;lt; 0.001) and overall survival (OS) (HR: 0.24, 95% CI, 0.06-0.97, P &amp;lt; 0.05) compared to MTB- patients. These trends were consistent across stages, subtypes, and treatment regimens. Traditional biomarkers, lactate dehydrogenase (LDH) and β2-microglobulin (B2M), showed no OS difference between high and low expression groups. The disease progression (PD) rate was 5.2 times higher in the MTB+ group (41.5%) than in the MTB- group (8.0%, P &amp;lt; 0.001), outperforming LDH (1.1 times, 20.7% vs 18.1%, P = 0.15) and B2M (3.1 times, 43.8% vs 14.0%, P = 0.02). All 116 patients, except four with stable disease, were classified as partial or complete response based on imaging at the landmark analysis. However, 13 patients experienced disease progression within six months after treatment. Notably, six (46.2%) were identified earlier through MTB reduction at the landmark. Greater MTB reduction at landmark associated with better OS (P&amp;lt;0.05). Multivariate Cox regression analysis confirmed MTB reduction at landmark as an independent prognostic indicator for PFS, with low reduction indicating a significant increase in disease progression (HR: 0.11, 95% CI: 0.03-0.42, P &amp;lt; 0.001), while other clinical parameters were not significant. Conclusions: This study confirms the clinical utility of SeekInClarity in evaluating lymphoma treatment responses. Reductions in MTB during treatment are associated with patient survival and can predict therapeutic outcomes. Furthermore, post-treatment MTB status after two cycles is an independent prognostic indicator for both PFS and OS. Citation Format: Mao Mao, Wang Xin hua, Li Zhi ming, Chang Yu, Li Shi yong, Wu Wei, Chang Fang yuan, Chang Yin yin, Zhu Dan dan, Zhang Ming zhi. A blood-based multi-omics test for early evaluation of lymphoma treatment effectiveness [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B020.

Cost-effectiveness analysis of trifluridine/tipiracil combined with bevacizumab vs. monotherapy for third-line treatment of colorectal cancer

BackgroundThe combination of trifluridine/tipiracil (FTD/TPI) and bevacizumab has demonstrated promising efficacy and safety in the treatment of colorectal cancer (CRC). This study aims to evaluate the cost-effectiveness of trifluridine/tipiracil combined with bevacizumab vs. trifluridine/tipiracil monotherapy as a third-line treatment regimen for colorectal cancer within the Chinese healthcare system, providing an economic basis for clinical application.MethodsBased on data from the SUNLIGHT Phase III clinical trial, a dynamic Markov model was constructed with a cycle length of 4 weeks and a simulation duration of 10 years. Direct medical costs and quality-adjusted life years (QALYs) were calculated. The incremental cost-effectiveness ratio (ICER) was compared with the willingness-to-pay threshold (WTP = ¥268,200.00/QALY) to assess the economic viability of the treatment regimen. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to verify the robustness of the model results.ResultsThe cost of trifluridine/tipiracil combined with bevacizumab treatment (¥838,492.74) was higher than that of trifluridine/tipiracil monotherapy (¥357,396.97), with greater health benefits (2.45 QALYs vs. 1.54 QALYs). The ICER was ¥527,577.36/QALY, exceeding the willingness-to-pay threshold. One-way sensitivity analysis indicated that drug costs and utility values during the progression-free period significantly impacted model outputs. Probabilistic sensitivity analysis further confirmed the robustness of the results, showing that at a willingness-to-pay threshold of ¥494,000.00, the probability of the combined treatment being cost-effective was 50%.ConclusionTrifluridine/tipiracil combined with bevacizumab, as a third-line treatment for colorectal cancer, does not have a cost-effectiveness advantage compared to trifluridine/tipiracil monotherapy in economic evaluations.

Abstract B050: Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy reveals unexpected complexity and opportunities

Abstract We have developed a version of our "methylation DETection of Circulating Tumour" DNA (mDETECT) assay that is able to sensitively and quantitatively monitor Non-Small Cell Lung Cancer (NSCLC). We used this assay to frequently assess the tumour burden of a small cohort (17 individuals) of patients undergoing first line monotherapy with pembrolizumab for metastatic disease. Patients were tested weekly or biweekly in the period immediately after initiation of treatment with radiological assessment being done at approximately 3 months. Radiologically non-responding patients showed constant or increased mDETECT levels over the 3 month time frame. Responding patients showed 2 different patterns, with some showing dramatically increasing mDETECT levels for a short period of time followed by a rapid decrease. Other responders showed an immediate decrease within the first few week of treatment. In both responder groups these decreases were associated with a longer term response. Continued monitoring did reveal eventual progression in some of these patients with increasing mDETECT levels being seen 4 to 6 months before radiological changes. In some non-responding patients complex responses were seen, with mDETECT levels varying significantly over time. In one non-responding patient the addition of carboplatin to their treatment regime did produce a temporary improvement in their mDETECT levels. Frequent assessment of tumour burden by a liquid biopsy such as mDETECT offers the opportunity to rapidly determine a patient's response to therapy and potentially modify treatments to improve responses. Citation Format: Christopher R Mueller, Keira Parr, Mihaela Mates, Andrew Robinson, Harriet Feilotter, Keira Frosst. Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy reveals unexpected complexity and opportunities [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B050.

HPB SO17 - A rare case of Goblet cell adenocarcinoma of appendix presenting as primary ampullary tumour

Abstract Background Goblet cell adenocarcinoma (GCA), formerly known as goblet cell carcinoid,is a rare appendiceal tumour with amphicrine differentiation that has distinct morphologic and clinical features compared to carcinomas seen elsewhere in the gastrointestinal tract. The tumour histologically resembles both carcinoids and adenocarcinomas. It is found in 0.3–0.9 % of appendectomy specimens; hence, ampullary GCAs are exceptionally uncommon. Method A 57-year-old Caucasian male presented with a two-month history of weight loss, pruritus, and dark urine. His blood tests revealed deranged liver enzymes. His past medical history was unremarkable. Abdominal CT identified a double duct sign, no detectable mass. Endoscopic ultrasound (EUS) revealed a dilated biliary system terminating in a slightly enlarged ampulla (15mm) without any obvious mass lesions. Endoscopic retrograde cholangiopancreatography (ERCP) was performed showing a distal common bile duct (CBD) stricture. Cytology samples were negative for malignancy, and stents were placed in the CBD and pancreatic duct (PD). Pancreaticoduodenectomy was advised given the high risk of malignancy. Results Histopathology report showed clusters of goblet-like mucinous cells in an infiltrative pattern, in addition to classic neuroendocrine tumor morphology, reminiscent of goblet cell adenocarcinoma of the appendix, staged as pT3pN1M0. This is consistent with primary ampullary GCA given the normal appendix on preoprative CT imaging. Conclusion To our knowledge, this is the fourth case of ampullary GCA report in medical literature. There is no consensus on adjunct chemotherapy regimen for systemic treatment. Chicago consensus group (2018) recommends following the colorectal cancer pathway for goblet cell adenocarcinoma. In our experience, given the anatomical location of the tumour and the normal appendix, FOLFIRINOX was offered in line with ampullary adenocarcinoma cancer pathway.

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.

Identifying immunohistochemical biomarkers panel for non-small cell lung cancer in optimizing treatment and forecasting efficacy.

Chemotherapy and immunotherapy for non-small-cell lung cancer (NSCLC) are gaining momentum. However, its long-term efficacy remains limited to only a small fraction of patients. Hence, it is crucial to identify reliable immunohistochemical biomarkers to facilitate the formulation of optimal treatment strategies and to predict therapeutic outcomes. We retrospectively analyzed a cohort of 140 patients diagnosed with NSCLC who received chemotherapy or immunotherapy. Using bioinformatics analysis and machine learning techniques, we assessed the role of immunohistochemical biomarkers and clinical characteristics in developing a predictive model for treatment options and outcomes in this population. Our research has found that immunohistochemical biomarkers can accurately predict treatment regimens and progression-free survival in NSCLC patients with an accuracy rate of 82.1%. We identified an exclusive detection panel for the six vital biomarkers. Of particular note is the role of programmed cell death protein 1 ligand 1 (PD-L1) expression in guiding treatment selection, with high expression predicting better outcomes in the immunotherapy group at a cut-off value of 50%. Non-squamous patients who tested positive for thyroid transcription factor 1 had a longer median progression-free survival, while squamous patients who tested positive for p63 protein or cytokeratin 5/6 expression had a longer median progression-free survival. The results of our study are highly encouraging, as they revealed a significant correlation between immunohistochemical biomarkers, therapeutic regimens, and prognosis. These findings indicate that our immunohistochemical detection panel has great potential for facilitating customization of therapeutic regimens to improve patient care. The insights gained from this study could help clinicians optimize treatment protocols and ultimately enhance clinical outcomes.

Hematological Changes in Newly Diagnosed Pulmonary Tuberculosis Patients on Standard Anti-TB Treatment Regimen and their Influence on Smear Conversion

Pulmonary tuberculosis (PTB) mortality remains high despite the availability of effective anti-TB therapy. Disease and treatment-associated hematological derangements at diagnosis and during therapy might contribute to this high TB mortality rate. This paper aims to determine hematological changes in newly diagnosed pulmonary tuberculosis patients on standard anti-TB treatment regimen and their influence on smear conversion. The study adopted a longitudinal design in which 55 newly diagnosed HIV negative PTB patients were followed up to the fifth month of anti-TB therapy. Blood samples (5ml) were collected for diagnosis during the second and fifth months and analyzed using automated HumaCount 5D hematology analyzer. Data was analyzed using Kruskal-wallis test with Dunn’s multiple comparisons test in Graph-Pad prism version 6.0. Throughout therapy, there was a statistically significant time-dependent decrease in median total white blood cell counts from 6.82x103/ uL at diagnosis to 5.87x103/ uL at the fifth month (P=0.0358). This decrease in total WBC count was majorly driven by significant decrease in the neutrophil numbers from 4.31x103/ uL at diagnosis to 2.97x103/ uL at the fifth month. The proportion of patients who had anemia at the fifth month of treatment increased compared to the second month post intensive phase. There was also a significant decrease in MCV, MCH and MCHC at the second month compared to diagnosis. Moreover, the median platelet count, MPV, PDW and PCT% decreased from 314x103/ uL, 8.9 fL, 10.4 fL and 0.273 at diagnosis to 232x103/ uL, 10.15 fL, 12.5 fL and 0.235 at the fifth month, respectively. High WBC count, high platelet count, low lymphocyte count and low HGB at the end of month two of therapy were shown to increase the likelihood of sputum non-conversion (OR-2.42 (95% Ci 2.07-2.82)), (OR-1.5 (95% Ci 1.01-2.22)), (OR-1 (95% Ci 1-1)) and (OR-2.58 (95% Ci 1.68-3.95)), respectively (P&lt;0.05). A significant number of PTB patients presented with anemia, thrombocytosis and leukocytosis. The proportion of patients with anemia increased over time. The study recommends screening for hematological abnormalities in patients for tailored patient interventions for better clinical outcomes.