Intercurrent Illness Research Articles

Use of sodium D, L-3-hydroxybutyrate as adjunct therapy in two siblings with HMG-CoA lyase deficiency

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare autosomal recessive mitochondrial disease characterised by recurrent life-threatening metabolic crises generally presenting in neonates or infancy during catabolic stress triggered by prolonged fasting or intercurrent illness. Acute decompensations with lethargy, vomiting, hypoketotic hypoglycemia and metabolic acidosis may evolve into Reye-like syndrome if untreated, with acute liver failure, hyperammonemic encephalopathy, dilated cardiomyopathy, and death in 20% of cases. Long-term health complications include psychomotor retardation, white matter abnormalities, epilepsy, hepatic steatosis, pancreatitis, cardiomyopathy, and arrythmia. The mitochondrial enzyme catalyses the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, the common final step of ketogenesis and leucine degradation, resulting in diagnostic urinary organic acid pattern (elevated 3-hydroxy-3-methylglutaric, 3-methylgutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids) with the absence of ketonuria, when deficient. Therapeutic interventions include dietary protein or leucine and fat restriction, carnitine supplementation, avoidance of fasting, and use of carbohydrate-based high caloric intake when unwell. We describe the clinical course and diagnostic work-up in two affected siblings, with the proband presenting with severe neonatal onset disease with metabolic acidosis, non-ketotic hypoglycaemia, hyperammonemia and white matter changes on brain MRI. High-risk screening for a younger sibling led to pre-emptive management with good outcomes. Sodium D, L-3-hydroxybutyrate (S-DL-3OHB) was used in both siblings as an adjunct therapy to prevent cerebral dysfunction and cardiomyopathy, with the rationale that decreased ketogenesis in this disorder may impact the major energy source for the brain and heart during starvation. S-DL-3OHB therapy is a well-tolerated and effective therapeutic option for this disorder.

Safe use of the ketogenic diet in an infant with microcephaly, epilepsy, and diabetes syndrome: a case report

BackgroundMicrocephaly, epilepsy, and diabetes syndrome (MEDS) is a rare syndromic form of monogenic diabetes caused by bi-allelic loss of function mutations in IER3IP1. In vitro studies have shown that loss of IER31P leads to apoptosis in both neurons and pancreatic β-cells. Simultaneous management of seizures and diabetes is challenging in patients with MEDS. We present the challenges and successes in the use of ketogenic diet in an infant with insulinopenic diabetes.Case presentationOur term female proband presented at 2 months of age with new onset multifocal seizures followed by the onset of infantile spasms (IS) at 4 months of age. An epilepsy gene panel identified bi-allelic variants, c.239T > G (p.Leu80*) and c.2T > A (initiator codon), in IER3IP1 that were subsequently shown to be inherited in trans. Following initiation of steroid therapy for IS, the patient developed clinically apparent insulin requiring diabetes. Her epilepsy was ultimately refractory to multiple antiseizure medications, thus the ketogenic diet (KD) was initiated. We were able to successfully titrate to a therapeutic KD ratio of 3:1 and maintain a ketotic state without diabetic ketoacidosis (DKA). With intercurrent illnesses, however, the patient had rapid decompensation and mild DKA due to delays in treatment, and for this reason, KD was discontinued after 5 months.ConclusionsWe report two novel IER31P1 mutations in a patient with MEDS and the successful management of the cooccurring conditions of IS and insulinopenic diabetes with the KD. Our experience underscores the importance of careful monitoring during KD as our patient had DKA more easily when on the KD.

908 Factors Affecting Last Minute Cancellation of Elective General Surgical Cases; Preliminary Findings of a QIP

Abstract Introduction Waiting lists for elective general surgeries have been growing steadily over the past few years, with short-notice cancellations affecting both cost and patient safety. There are currently nationwide incentives to cut referral-to-theatre delays and tackle the backlog of over 7 million patients (NHS backlog data analysis - British Medical Association 2022). Aim To identify common causes of short-notice cancellation of elective general surgery lists, and identify targets for intervention for minimisation. Method This audit was registered with the department. Prospectively collected elective general surgery lists between January and November 2022 were compiled and analysed. We coded the reason for cancellation from patient records. For the patients found to be unfit on the day to come in (TCI), we reviewed PAC notes to see whether they had been deemed fit at PAC and how this had changed. Data were coded and analysed on Microsoft Excel on secure Trust computers. Results Between 01/01/2022 and 06/11/2022, 508 (22%) of the scheduled 2300 cases were cancelled, with 235 (10.2%) within 48 hours of their scheduled start date. Acute patient illness and patient unavailability were the most common causes of short notice cancellation of a case (n = 41), followed by time constraints (n = 33), patients not being medically optimised (n = 27) or no longer requiring surgery (n = 21, as well as administrative error (n = 14). Conclusions Targets for intervention following these preliminary audit results included improved patient literature at pre-assessment, clerical chart review in the lead up to the surgery to ensure all administrative tasks have been performed, and a clinical review immediately prior the TCI date to identify any intercurrent illness.

Accuracy of the NADAS Criteria in Helping Establish the Diagnosis in Children With Suspected to Have Congenital Heart Disease

Background : Prevalence of congenital heart disease is approximately 8/1000 live births and majority of them are diagnosed during evaluation of a murmur detected either during a routine follow-up or while assessment during an intercurrent illness. NADAS criteria can be used as screening test with hight a sensitivity and specificity regarding ability to differentiate pathologic from innocent murmurs.
 Aim : The aim of the study was to assess the accuracy of the NADAS criteria in helping to diagnose disease in children suspected of having congenital heart disease.
 Methods : This was a diagnostic study with a cross-sectional approach and Inclusion criteria were children aged 1 month - 12 years from history and physical examination found a history of recurrent ARI, poor nutritional status, failure to thrive, found cardiac murmurs, without/any cyanosis who attended the outpatient cardiology pediatric at Haji Adam Malik General Hospital between Januari - july 2021. Data Analysis was created using the program IBM SPSS Statistics version 25
 Results : 70 children were screened. 60 children were detected to have CHD. 63,3% of the study population in the age group <5 year had a heart disease. All CHD patients had poor nutritional status, abnormal ECG and 88.33% had a history of recurrent ARI, 80% had abnormal chest x-ray, and 55% had abnormal S2. A grade 3 or higher systolic murmur was found in 78.33% of patients had CHD.
 Conclusion : NADAS criteria can be used as a screening test for helping to diagnose disease in children suspected of having CHD with accuracy 87.14%, sensitivity of 88.33%, specificity was 80% when score at 3 (1 major + 2 minor) and AUC value is 0.842.

Patient Characteristics Associated with Hospital Admission or Antiarrhythmic Medication Changes After Emergency Department Evaluation of Supraventricular Tachycardia.

Supraventricular tachycardia (SVT) is a relatively frequent diagnosis in the pediatric emergency department (ED). However, there are no consensus guidelines for ED disposition, and there are limited data on ED outcomes. Better understanding of those who are admitted or have antiarrhythmic medication changes may avoid potentially unnecessary transfers or admissions. Our objective was to identify patient factors associated with discharge from the emergency department without medication initiation or modification after management of SVT in the pediatric ED. A retrospective review of children aged 0-18 years seen in the emergency department for SVT was conducted using electronic medical record data over a ten-year period at a single academic tertiary children's hospital. Patients with congenital cardiac disease or prior cardiac surgeries were excluded. Multivariable logistic regression analysis was used to determine association between patient factors of interest and the primary outcome of admission and secondary outcome of change to antiarrhythmic medications. We analyzed 197 patients encounters. The mean age was 7 years. Of these 104 (52.8%) were admitted to the hospital or discharged with antiarrhythmic medication changes. This primary outcome was associated with younger age (aOR 0.77, 95% CI 0.67-0.86), history of pre-excitation (aOR 5.82, 95% CI 2.01-18.8), intercurrent illness (aOR 3.75, 95% CI 1.27-12.1), number of adenosine doses prior to arrival (aOR 5.45, 95% CI 1.55-22.3), and in-person cardiology consultation (aOR 6.42, 95% CI 2.43-19.4). Nearly half of children treated in a pediatric ED for SVT are discharged without changes in medications. We identified patient factors associated with hospital admission or antiarrhythmic medication changes. These factors represent high value care and can be assessed when considering transfer from a referring facility. Risk stratification using these patient characteristics may reduce potentially avoidable transfers and admissions.

What do older patients know about their medication? A cross-sectional, interview-based pilot study

PurposeThis study sought to analyze the medication knowledge and awareness of medication adjustment options during intercurrent illness (sick day rules) of patients ≥ 70 years treated at a hospital for geriatric medicine in northern Germany.MethodsThe study was designed as a cross-sectional, interview-based pilot study, was approved by the Ethics Committee of Hannover Medical School (No. 10274_BO_K_2022; date of approval: 11 March 2022), and enrolled a convenience sample of 100 patients between May and December 2022.ResultsThe median of the average medication knowledge score in the study population (median age 82 years (IQR 75–87); 71% female) was 5 on a scale from 0 to 6 (IQR 3.8–5.6). Women achieved higher average medication knowledge scores than men (median 5.1 (IQR 4–5.6) vs. median 4.3 (IQR 3.6–5.1); p = 0.012), and patients < 80 years achieved higher average medication knowledge scores than patients ≥ 80 years (median 5.4 (IQR 4.9–5.7) vs. median 4.3 (IQR 3.2–5.3); p < 0.001). Sick day rules were known for only 1.1% of drugs for which sick day rules were applicable. Fifty-two percent of the patients reported that their general practitioner contributed most to their medication knowledge, and 66% considered their daily number of drugs to take adequate.ConclusionOur study showed that medication knowledge of older patients was overall satisfying. Awareness of sick day rules, however, was poor. Future studies should evaluate the clinical benefits of sick day rules and ways of better communicating sick day rules to patients. In this regard, general practitioners may play a decisive role.

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors

Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. ClinicalTrials.gov Identifier: NCT03511391.

Synchronous bilateral idiopathic external auditory canal cholesteatoma: a case report and review of the literature

BackgroundExternal auditory canal cholesteatoma (EACC) is a rare pathological condition representing 0.1% of all new otologic cases. Bilaterality manifests in 10% of EACC cases. Similar disease processes include keratosis obturans (KO) and benign necrotizing otitis externa (BNOE). Diagnostic differentiation may not always be unexacting but does however influence management and eventual outcome. This study aims to briefly review the literature, describe an unusual case of synchronous bilateral primary EACC, and simplify the diagnostic challenges surrounding this disease.Case presentationA 66-year-old man with no relevant family history, no concurrent or intercurrent illnesses, having undergone no relevant surgery, and had visited the Department of Otorhinolaryngology regarding right-sided otorrhoea and aural pruritis 9 years ago. At the time, he was diagnosed clinically with KO. Nine years later after having defaulted follow-up, he presented again with the same symptoms. Oto-microscopy now revealed excavation of the posterior canal wall, keratinous desquamation, and an intact tympanic membrane. Oto-endoscopy demonstrated extension posteriorly into the mastoid segment of the temporal bone. Computed tomography evinced a soft tissue attenuating mass within the excavated sub-adjacent bone, with extension into the mastoid air cell system. The contralateral ear had a smaller epithelial defect of the canal floor with underlying tympanic plate erosion. A closed mastoidectomy with the reconstruction of the posterior canal wall was performed on the right ear. The left ear was managed conservatively with micro-suctioning and aural toilette. Six months post-surgery, however, the reconstructed posterior canal wall underwent necrotic breakdown. The contralateral lesion gradually progressed into a Naim et al. (2005) Stage III EACC.ConclusionThis case illustrates the diagnostic challenge presented by EACC and is unusual regarding its bilaterality. The importance of diagnostic differentiation, both in the management of this disease and in the prevention of its progression, is highlighted. The idea of oto-endoscopy as a routine clinical tool is introduced, and endoscopic images are compared to high-definition computed tomography scans of the affected temporal bones.

Clinically relevant monitoring of long‐term night‐time behaviour and physiology from the homes of people living with dementia

AbstractBackgroundDisturbances of sleep and night‐time behaviours are amongst the most disabling symptoms of dementia. They often increase carers’ burden and the risk of institutionalization. The causes are complex and are difficult to investigate because of a lack of acceptable methods for monitoring behaviours in the home. Here we show that a passive under‐mattress can be used to track changes in night‐time behaviour and physiology, and that a range of digital biomarkers produced are informative in understanding the effects of medication changes, disease progression and intercurrent illness in patients living with dementia (PLWD).MethodWe used contactless Withings Sleep Mattress (WSM) to monitor bed‐occupancy in 4 PLWD (age 74‐93, 3males) enrolled into the CR&amp;T MINDER cohort study. Each participant was tracked over 1000 nights between 2019 and 2021. Minute‐to‐minute timeseries were extracted from WSM to calculate bed occupancy metrics and nocturnal physiology measures (heart and breathing rates (HR/BR)). Raw measures were standardized within subjects by comparing each time point to the mean of the time points that preceded it. We then investigated the relationship between these metrics and clinical events such as infections and medication.ResultThe 4 case studies illustrate the potential of this technology for passive health monitoring in PLWD. High levels of intraindividual variability in behavioural and physiological metrics were observed. Progressive changes in bed occupancy were observed in two patients with frontotemporal dementia and Alzheimer’s disease (Cases 1&amp;2). Intercurrent illness and medications changes influenced the measures. For example, Patient 1 showed progressive night‐time wandering with increasing time spent out of bed, which improved following the initiation of risperidone. Case 2 showed recurrent episodes of heart failure accompanied by increased nocturnal HR. Cases 3 and 4 showed urinary tract infections, which were accompanied by transient changes in bed occupancy measures.ConclusionPassive monitoring of night‐time behaviour and physiology is a simple and cost‐effective way to monitor the effects of medication change and medical events in PLWD. Digital biomarkers derived from these simple measures hold great promise as measures of dementia progression, to enhance dementia care by identifying at risk individuals and as novel clinical outcome measures in clinical trials.

The Maverick trial: A phase 2 study of abivertinib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).

TPS5106 Background: Abivertinib is a potent, small molecule third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), Bruton tyrosine kinase (BTK) receptor, and bone marrow tyrosine kinase gene on chromosome X (BMX). Abivertinib irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor, and also BMX. The adrenal-permissive HSD3B1(1245C) allele, which is present in upwards of 50% of men with prostate cancer, encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from extragonadal precursor steroids and promotes poor clinical outcomes. 3βHSD1 must be phosphorylated by BMX for androgen biosynthesis. Preclinical studies suggest BMX inhibition blocks 3βHSD1, androgen biosynthesis and CRPC in xenograft models. These provide the rationale for use of the combination of abivertinib and abiraterone to block residual androgen synthesis that escapes abiraterone inhibition. Methods: The Maverick Trial is a multicenter, open-label phase 2 study within the US Dept of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC) of abivertinib with abiraterone in pts with mCRPC harboring the adrenal-permissive HSD3B1(1245C) allele (germline heterozygous or homozygous). HSD3B1 status will be confirmed centrally prior to enrollment via CLIA testing at the Cleveland Clinic. The study includes two cohorts: abiraterone-naïve and abiraterone-progressing. There will be cap of 50% of accrual in each cohort for pts heterozygous for the HSD3B1(1245C) allele. An interim futility analysis is embedded in each cohort, and toxicity rates will be continuously monitored for early stoppage according to predefined rules. Pts receive continuous treatment with abivertinib 200 mg BID with abiraterone 1000 mg QD + prednisone 5 mg BID until radiographic progression, unacceptable toxicity, intercurrent illness, or other reason, such as subject withdrawal. The primary endpoint is 6-month rPFS defined as percent of subjects alive and without progression by RECIST version 1.1 for measurable disease and PCWG3 criteria for bone metastases. Secondary and exploratory endpoints include objective response rate, duration of response, PSA progression, pharmacokinetics, pharmacodynamic tissue changes, and mechanisms of response and resistance to therapy via sequential tissue and blood sampling. The study is currently open at 1 site and will activate at 9 additional sites. It is sponsored by Sorrento Therapeutics, Inc, and managed by the Prostate Cancer Clinical Trials Consortium. Trial Registration: NCT05361915 Funding Source: Sorrento Therapeutics, Inc, the trial’s sponsor who is funding the trial. Clinical trial information: NCT05361915 .

Results of a phase 3 study of IVO vs IO for previously untreated older patients (pts) with chronic lymphocytic leukemia (CLL) and impact of COVID-19 (Alliance).

7500 Background: The Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib +/- anti-CD20 antibody obinutuzumab (IO) is a standard frontline regimen for older adults with CLL. BTKi alone do not often lead to complete response (CR) or undetectable minimal residual disease (uMRD), thus are given indefinitely. Smaller trials showed that IO plus venetoclax (IVO) can induce uMRD CRs which may allow successful discontinuation. Methods: Alliance for Clinical Trials in Oncology A041702 is a multicenter trial designed to evaluate if IVO with response-guided discontinuation of I improves progression free survival (PFS) versus IO with indefinite I in treatment-naïve, older CLL pts. IO is given in standard fashion, and in the IVO arm V is added at C3D1 and continued until C14D28. After 14 cycles, pts undergo response evaluation including CT scans and bone marrow biopsy with central MRD assessment by flow cytometry. Pts in IVO arm with uMRD CR discontinue I; all others continue I until progression or unacceptable toxicity. Eligible pts were age ≥70 years (amended to ≥65). Pts had CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no other life-limiting intercurrent illness. Pts were stratified based on Rai stage and +/- del17p13.1 by FISH, and randomized 1:1 to IO:IVO. With 431 evaluable pts, the trial had 90% power to detect significant improvement in PFS using a one-sided log-rank test with one-sided type 1 error rate of 2.5%. The Alliance DSMB approved release of data on Nov 4, 2022 after meeting the protocol defined futility threshold at the second planned event-driven interim analysis. Data were locked on December 15, 2022. Results: Between January 4, 2019 and July 15, 2022, 465 pts were registered (IO:232, IVO:233). Median age was 74; 67% of pts were men. Rai stage 3-4 was seen in 55% and del17p in 13%. With median follow-up of 14 months, PFS of IO was 87.5% compared to 85% on IVO. Events were observed in 29 pts on IO (4 progressions, 23 deaths, 2 pts started other therapy) and 35 on IVO (7 progressions, 28 deaths). The predefined futility boundary was crossed, with a hazard ratio (HR) of 1.20 (95% CI: 0.73-1.97) in favor of IO. COVID-19 was the leading cause of death in both arms, (11 COVID-19 deaths on IO, 19 on IVO), with 13 and 11 additional deaths from other causes, respectively. Censoring pts with COVID-19 related deaths, PFS HR is 0.82 (95% CI: 0.44-1.53) in favor of IVO. Grade 3+ toxicity and discontinuation in year 1 of therapy were similar between arms. Conclusions: This study demonstrates that PFS for IVO is not superior to IO for treatment-naive older CLL pts in the setting of the COVID-19 pandemic. Study treatment is ongoing, and long-term follow-up will determine if there are advantages to IVO, with special attention to MRD and therapy discontinuation. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03737981 .

A phase I trial of diphencyprone for cutaneous neurofibromas in adult patients with neurofibromatosis type 1.

TPS2678 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic tumor predisposition syndrome affecting about 1 in 2500 people. Affected patients develop a variety of skin findings including café-au-lait macules, axillary freckling, and cutaneous neurofibromas (cNFs). These patients also have an increased risk of malignant tumors including gliomas and soft tissue sarcomas. However, the cNFs, of which a patient can have thousands, are often cited as the most burdensome sign. Despite their benign nature, these tumors can be physically bothersome and cause significant emotional distress. To date, there are no effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten that induces a delayed-type hypersensitivity skin reaction, for the treatment of cNFs in adults with NF1. Methods: This trial is enrolling NF1 patients aged 18 and older with at least four cNFs greater than 4mm. Subjects taking systemic immunosuppressants, those with underlying immunodeficiency or uncontrolled intercurrent illnesses, and those who are pregnant or nursing are excluded from the study. DPCP 0.04% ointment is administered topically once weekly to up to 20 cNFs in a localized area for 10 weeks. The primary endpoint is to determine the safety and tolerability of DPCP ointment in the treatment of cNFs. Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. To assess subjective tolerability, subjects score their symptoms, including pain, stinging, burning, and pruritus from 0 (none) to 3 (severe). Efficacy and tumor regression are assessed using the Response Evaluation Criteria in Solid Tumors guidelines in conjunction with photographs and manual tri-axial tumor measurements. Additionally, qualitative assessments are made by the study team using 3D whole-body photography. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a cNF and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints. Quantitative RT-PCR and single-cell RNA sequencing studies will assess gene expression changes in immune and tumor cell-related genes pre- and post-treatment with DPCP. Immunohistochemistry and proteomic profiling will be performed to characterize changes in the tumor microenvironment. Genetic testing for the NF1 germline mutation will be correlated with treatment response. Enrollment is ongoing with a target of 20 participants. Since September 2022, the study has enrolled 12 patients and five have completed the study. Clinical trial information: NCT05438290 .

EGRET: A first-in-human study of the novel antibody-drug conjugate (ADC) AZD9592 as monotherapy or combined with other anticancer agents in patients (pts) with advanced solid tumors.

TPS3156 Background: The epidermal growth factor receptor (EGFR) and mesenchymal-epidermal transition tyrosine kinase receptor (c-MET) are expressed in diverse solid tumors, and function as driver genes in some types. Clinical benefit of bispecific monoclonal antibodies (Ab) targeting these receptors was demonstrated in pts with EGFR mutated (EGFRm) non-small-cell lung cancer (NSCLC), but an ADC targeting these receptors has not been developed. AZD9592 is an ADC with a bispecific Ab targeting EGFR and c-MET. When internalized, AZD9592 releases a topoisomerase 1 inhibitor (TOP1i) warhead that traps TOP1 on DNA, causing double-strand breaks and induction of apoptotic cell death. Preclinical data have demonstrated promising efficacy and safety of AZD9592 in tumors expressing EGFR and c-MET, including but not limited to adenocarcinoma and squamous NSCLC and head and neck squamous cell carcinoma (HNSCC). Methods: EGRET is a phase 1, open-label, multicenter, modular study in pts with advanced solid tumors (NCT05647122). Module 1 will evaluate AZD9592 monotherapy in pts with metastatic NSCLC (mNSCLC) with EGFRm (sensitizing L858R mutation or exon 19 deletions) or EGFR wild-type, or recurrent or metastatic HNSCC. Module 2 will evaluate AZD9592 in combination with osimertinib in pts with EGFRm mNSCLC. Each module will include dose escalation (Part A) and dose expansion (Part B) cohorts. Key inclusion criteria are age ≥18 years, ECOG performance status 0–1, life expectancy ≥12 weeks, measurable disease per RECIST v1.1, and adequate organ and bone marrow function. Key exclusion criteria for both modules include unresolved toxicities of Grade ≥2 (NCI CTCAE v5.0) from prior therapy, uncontrolled intercurrent illness, cardiovascular disorders, history of drug-induced interstitial lung disease or pneumonitis, and previous treatment with a TOP1i ADC or an EGFR- or MET-targeted ADC. Treatment continues until disease progression, initiation of alternative anticancer therapy or unacceptable toxicity. The primary objectives of Part A are to assess safety and tolerability, and to determine the maximum tolerated dose and/or the recommended phase 2 dose of AZD9592 as monotherapy or in combination with osimertinib. The primary objectives for Part B are to evaluate safety and tolerability, and antitumor activity by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary objectives for both Part A and B include assessing AZD9592, as monotherapy and in combination with osimertinib, for efficacy (by ORR, disease control rate, duration of response, and progression-free and overall survival), pharmacokinetics, and immunogenicity. Descriptive statistics will be used for all variables. The study will include sites across the EU, USA, and Asia Pacific; sites in USA and Australia are currently open for enrollment. Clinical trial information: NCT05647122 .

Effectiveness of a starch thickened infant formula with reduced lactose content, probiotics and prebiotics on quality of life and clinical outcome in infants with regurgitation and/or colic.

Regurgitation and colic are quite common in young infants, leading to a reduced quality of life (QoL) and to parental distress. Their management is challenging and aims to effectively reassure and relieve symptoms. This study aimed to assess the effectiveness over 30 days of a starch thickened formula with a reduced lactose content, Limosilactobacillus reuteri (Lactobacillus reuteri) DSM 17938 and FOS/GOS. A real-world prospective multicenter experimental study was conducted in a before-after design within subject. Full term infants 0-5 months with regurgitation or colic or both symptoms and without intercurrent illness were included after parental informed consent and received the studied formula. The primary endpoint was the improvement in QoL using the QUALIN infant's questionnaire. Secondary endpoints were the symptoms outcome and the formula tolerance. Of the 101 infants included (age: 6.2 ± 4.3 weeks), 33 had regurgitation, 34 colic and 34 had both. At D30, the QoL score was improved in 75% of infants in per protocol analysis (n = 68; +8.2 ± 13.7; p < 0.001), more in those with colic or both symptoms. Meanwhile, in intention to treat analysis (all p < 0.001), the daily number of regurgitations decreased by 61% and the weekly number of days with colic by 63% while the daily cumulative duration of crying decreased by 82 ± 106 mn. These improvements were observed within the first week by 89 and 76% of parents, respectively. The study formula associated with reassurance is shown to be quickly effective in the management of infant's regurgitation or/and colic in routine clinical practice. https://clinicaltrials.gov/, identifier NCT04462640.

Topical clobetasol treatment for oral lichen planus can cause adrenal insufficiency.

Glucocorticoids suppress the hypothalamic-pituitary-adrenal axis, which may lead to glucocorticoid-induced adrenal insufficiency. The study aimed to investigate the prevalence of this state in patients with oral lichen planus treated with topical clobetasol propionate. In this cross-sectional study, 30 patients with oral lichen planus receiving long-term (>6 weeks) clobetasol propionate gel 0.025% were invited to participate. Adrenal function was assessed by measuring morning plasma cortisol after a 48-h withdrawal of clobetasol treatment. In patients with plasma cortisol <280 nmol/L, a cosyntropin stimulation test was performed. Twenty-seven patients were included. Twenty-one (78%) patients presented with plasma cortisol ≥280 nmol/L (range 280-570 nmol/L), and six (22%) <280 nmol/L (range 13-260 nmol/L). Five of these six patients underwent cosyntropin stimulation that revealed severe adrenal insufficiency in two patients (cortisol peak 150 nmol/L and 210 nmol/L) and mild adrenal insufficiency in three patients (cortisol peak 350-388 nmol/L). In this study, approximately 20% of patients receiving intermittent topical glucocorticoid treatment for oral lichen planus had glucocorticoid-induced adrenal insufficiency. It is essential for clinicians to be aware of this risk and to inform patients about the potential need for glucocorticoid stress doses during intercurrent illness.

P106 Feasibility Study of Methotrexate use Improvement in Rheumatoid Arthritis using Biomarker Feedback: The MIRA Trial

Abstract Background/Aims MTX non-adherence is associated with reduced response, increased healthcare costs to the NHS and reduced quality of life for the patient. Often the prescriber is unable to determine if a patient is taking their medication as prescribed. There is a need to measure adherence directly to facilitate more precise and objective measurements of adherence to add to the clinicians tools and help to open up honest discussions and supportive interventions with patients. Our group has previously developed a sensitive biochemical assay for the detection of MTX adherence, MIRA is a feasibility trial designed to assess the feasibility of a randomised controlled trial of MTX biochemical adherence biofeedback. Methods MIRA is a prospective multi-centre randomised controlled trial to examine the feasibility of a fully powered randomised controlled trial to examine if a biochemical adherence guided intervention is superior to standard clinical care in RA patients prescribed MTX. RA patients prescribed oral MTX for ≥ two years were randomised 1:1 to receive biochemical adherence biofeedback or control. Clinico-demographics, biochemical MTX adherence and DAS-28 and were measured at baseline and three months. Participants in the intervention cohort were telephoned with their biochemical adherence results and adherence was explored. Ethical approval for MIRA was given by the North West - Haydock Research Ethics Committee (19/NW/0047) and all participants provided written informed consent. Results 57 participants were recruited, withdrawal rate was 14% and reasons given were intercurrent illness, lost contact, withdrawn consent and one patient died during follow-up leaving full outcome data available for 49 participants. Baseline clinico-demographics were similar in control and intervention cohorts (Table 1). Biochemical adherence worsened in the control cohort and improved in the intervention cohort (17 to 30%, 15 to 8% respectively). Change in DAS(CDP)-28 during the trial worsened in the control cohort but improved in the intervention cohort (-0.04 STD 1.26 and 0.38 STD 0.78 respectively). Conclusion The results of the MIRA trial have demonstrated that the use of a biochemical adherence blood test with biofeedback is feasible as part of a clinical trial. The intervention demonstrated early evidence for efficacy justifying the need for a full definitive trial. Disclosure J. Bluett: None. K.L. Hyrich: None. B. Keevil: None. P. Doran: None. A. Barton: None.

Abstract CT014: Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer

Abstract Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr &amp;gt;2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by &amp;gt;2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) &amp;gt;1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with &amp;gt;2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

A Pilot, Prospective, Randomized-Controlled Study to Evaluate the Efficacy and Safety of Arsha Hita™ in the Treatment of Anal Fissures.

Introduction Anal fissures are tears in the anal canal that cause pain, bleeding, and spasms. They can be treated with non-operative options such as sitz baths, local anesthetics, topical nitrates, oral fiber, and calcium channel blockers, but some patients require surgery. Topical nitrates have side effects such as severe headaches, while topical calcium channel blockers can cause itching. There is a need to explore alternative treatments with fewer side effects. This proof-of-concept pilot study aimed to compare the efficacy and safety of a combination of Arsha Hita™ tablets and ointment (Shree Dhootapapeshwar Limited, Mumbai Maharastra, India) (test treatment) with a combination of lidocaine 1.5% w/w + nifedipine 0.3% w/w cream for local application and Isabgol powder (6 g) orally as an active comparator (standard treatment), which is the standard treatment of anal fissures as per the Association of Colon and Rectal Surgeons of India (ACRSI) guidelines. Methodology This study was a single-center, prospective, randomized-controlled study conductedin Karnataka, India. Participants were screened for anal fissures and randomized to receive either standard treatment (Group A) or test treatment (Group B) for 14 days, and were re-evaluated after two, four, and six weeks. The study assessed signs and symptoms related to anal fissures, such as pain post-defecation on Visual Analog Scale (VAS), bleeding per anus grading, wound healing grade, stool consistency, and stool frequency. Compliance, inter-current illness, and concomitant therapy were noted at each visit. The study used independent sample t-tests to compare variables at baseline and chi-square or Fisher's exact tests to compare the number/proportion of participants achieving primary and secondary endpoints. Mann-Whitney U test was used to compare median composite scores at baseline and Visit 4, and Friedman's two-way analysis of variance was used to compare median composite scores across the four visits (p < 0.05 was considered significant). Descriptive analysis was used to assess VAS, bleeding, and healing grades. Results The study included 53 participants with anal fissures, of which 25 out of 27 allocated in Group A (two drop-outs) received standard treatment, and all 26 allocated in Group B received Arsha Hita treatment. At the end of the study, 11 participants in Group B achieved a 90% reduction in composite scores compared to only three patients in Group A (p<0.05). Both groups showed improvement in pain on defecation, severity of bleeding, healing of anal fissure wound, and participant's and physician's global impression score. Group B had significantly better results in terms of VAS score, resolution of per-anal bleeding, and physician's global impression score (p<0.05). There were no adverse events in either group during the six-week treatment period. Conclusion The pilot study provides evidence that the combination of Arsha Hita tablets and Arsha Hita ointment may be more effective and safer for treating anal fissures than the standard treatment. The test treatment group experienced greater pain relief, complete resolution of per-anal bleeding, and better global impression scores than the standard treatment group. These findings suggest the need for further research through larger, randomized controlled trials to determine the efficacy and safety of Arsha Hita in treating anal fissures.

Utilization and Factors Precluding Receipt of Checkpoint Inhibitor Consolidation for Stage III NSCLC in a Large US Academic Health System

ObjectivesWe sought to determine the proportion of patients with stage III non–small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications. Materials and MethodsWe retrospectively identified consecutive patients with unresectable stage III NSCLC treated with definitive cCRT between October 2017 and December 2021 within a large US academic health system. Patients either received consolidation ICIs (ICI group) or did not (no-ICI group). Baseline characteristics and overall survival (OS) of the groups were assessed. Factors predictive of ICI nonreceipt were evaluated using logistic regression. ResultsOf 333 patients who completed cCRT, 229 (69%) initiated consolidation ICIs; 104 (31%) did not. Reasons for ICI nonreceipt included progressive disease post-cCRT (N = 31, 9%), comorbidity or intercurrent illness (N = 25, 8%), cCRT toxicity (N = 23, 7%; 19/23 pneumonitis), and EGFR/ALK alteration (N = 14, 4%). The no-ICI group had worse performance status and a higher rate of baseline pulmonary comorbidity. Larger planning target volume was associated with post-cCRT progressive disease, and higher lung radiation dose with cCRT toxicity. Median OS was 16 months in the no-ICI group and 34.4 months in the ICI group. In the no-ICI group, OS was superior among those with EGFR/ALK alterations (median 44.5 months) and worst among those with progressive disease (median 5.9 months, P < 0.001). Conclusion31% of patients who completed cCRT for stage III NSCLC did not receive consolidation ICIs. Survival amongst these patients is poor, especially for those with progressive disease post-cCRT.

Abstract P4-01-35: A Phase 1 Study of the Oral CDK7 Inhibitor XL102 as a Single Agent and in Combination Therapy in Patients With Advanced Solid Tumors (QUARTZ-101): Initial Results From the Dose-Escalation Stage

Abstract Background: Cyclin-dependent kinase 7 (CDK7) plays a significant role in the cell cycle via activation of CDKs 1, 2, 4, and 6, and regulates transcription via phosphorylation of RNA polymerase II and the estrogen receptor. CDK7 overexpression has been reported in several tumor types, including hormone receptor-positive breast cancer (HR+ BC), triple-negative BC (TNBC), small-cell lung cancer, and epithelial ovarian cancer (EOC). In all major BC subtypes, CDK7 overexpression is associated with poor prognosis. XL102 is a potent, orally bioavailable, highly selective covalent CDK7 inhibitor. QUARTZ-101 is a first-in-human, open-label trial (NCT04726332) evaluating the safety, tolerability, and optimal dose of XL102 as a single agent and in combination regimens in patients with solid tumors, with expansion in subsequent tumor cohorts of advanced HR+ BC, TNBC, EOC, and metastatic castration-resistant prostate cancer (mCRPC). Presented here are initial results from the dose-escalation stage for single-agent XL102 (cohort A). Methods: In the single-agent dose-escalation stage, patients received XL102 orally at multiple dose levels (DLs) using a modified interval 3+3 design: once daily at 20 mg (DL A1), 40 mg (DL A2), 80 mg (DL A3), and 120 mg (DL A4); and twice daily at 40 mg (DL A5). Eligible patients had confirmed inoperable, locally advanced, metastatic, or recurrent solid tumors and ECOG performance status (PS) of 0 or 1; any CNS disease must have been adequately treated and stable for ≥4 weeks. Patients with previous exposure to XL102 or other selective CDK7 inhibitors were excluded, as were patients with uncontrolled, significant intercurrent or recent illness. Prior use of CDK4/6 inhibitors was allowed. The primary objective of dose escalation was to determine the maximum tolerated dose (MTD) and/or recommended dose (RD) of XL102; secondary objectives included safety and tolerability, pharmacokinetics (PK), and drug-drug interactions. Results: At data cutoff of May 13, 2022, twenty patients with various advanced solid tumors (100% stage IV) were enrolled in dose-escalation stage cohort A and treated with single-agent XL102 (DL A1 n=3; A2 n=3; A3 n=7; A4 n=4; A5 n=3). Median age was 67 (range 43–84) years, 85% were female, and 75% had an ECOG PS of 1. Six patients remained on XL102 including 2 treated for &amp;gt;6 months with stable disease, both had received prior CDK4/6 inhibitors (HR+BC and liposarcoma). There were no dose-limiting toxicities at any DL, and MTD/RD has not been determined. Treatment-emergent adverse events (TEAEs) occurred in 95% of patients, with 4 (20%) grade 3 and 0 grade 4 TEAEs; there were no grade 5 treatment-related AEs. Treatment discontinuations were mostly due to radiographic progression (n=8); longest treatment duration was 6.7+ months and ongoing. XL102 demonstrated rapid absorption with a Tmax of approximately 1–2 h and elimination half-life of 5– 8 h. Target occupancy was exposure-dependent and prolonged relative to XL102 PK, consistent with covalent binding to CDK7. Conclusions: Single-agent XL102 was well tolerated at the DLs tested. Updated data, as well as PK results, will be presented. Expansion cohorts in HR+BC, TNBC, EOC, and mCRPC will be initiated once a recommended dose for the expansion-cohort stage is determined. Citation Format: Amita Patnaik, Minal Barve, Manali Bhave, Vivek Subbiah, Drew Rasco, Aarohi Bhatt, Jing Li, Svetlana Andrianova, Geoffrey Shapiro. A Phase 1 Study of the Oral CDK7 Inhibitor XL102 as a Single Agent and in Combination Therapy in Patients With Advanced Solid Tumors (QUARTZ-101): Initial Results From the Dose-Escalation Stage [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-35.