Patient Tolerance Research Articles

Impact of UGT1A1*28 polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3.

717 Background: SN-38, the active metabolite of irinotecan, is cleared by the liver enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and biliary excretion. UGT1A1*28 (genotype 7/7) homozygosity is associated with reduced activity of UGT1A1 and a recommendation for dose adjustment of non-liposomal irinotecan, a component of the FOLFIRINOX regimen. In this post-hoc analysis, we analyzed the impact of UGT1A1*28 homozygosity on the incidence and profile of treatment-emergent adverse events (TEAEs) among patients enrolled in NAPOLI 3 (NCT04083235). Methods: Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. UGT1A1*28 status was evaluated in all patients before enrollment. All patients, regardless of UGT1A1*28 status, received the full starting dose of liposomal irinotecan and followed the same dose reduction rules. This exploratory analysis of TEAEs by UGT1A1*28 status was descriptive; statistical analyses were not performed. Results: Overall, 83 patients (11.0%) were homozygous for UGT1A1*28 , among whom the incidence of TEAEs was similar to patients with non-homozygous status (Table). The most frequently reported TEAEs (≥ 40%) among the homozygous group (vs the overall NAPOLI 3 population) were diarrhea (59.0% vs 70.5%), nausea (56.4% vs 59.5%), vomiting (46.2% vs 39.7%) and anemia (41.0% vs 26.2%) in the NALIRIFOX arm and nausea (45.5% vs 42.7%), fatigue (45.5% vs 37.7%), diarrhea (45.5% vs 36.7%) and anemia (40.9% vs 40.4%) in the Gem+NabP arm. Conclusions: The incidence of TEAEs, including TEAEs leading to death, was similar between patients with homozygous and non-homozygous UGT1A1*28 status, in both treatment arms. The profile of TEAEs was consistent with that of the overall NAPOLI 3 population. UGT1A1*28 status did not substantially influence the safety profile or subsequent need for dose reductions of liposomal irinotecan in NAPOLI 3. Clinical trial information: NCT04083235 . UGT1A1*28 homozygous UGT1A1*28 non-homozygous TEAE, n (%) NALIRIFOX (n = 39) Gem+NabP (n = 44) NALIRIFOX (n = 328) Gem+NabP (n = 331) Any 39 (100.0) 44 (100.0) 327 (99.7) 328 (99.1) Related to any drug 39 (100.0) 41 (93.2) 310 (94.5) 308 (93.1) Grade ≥ 3 31 (79.5) 34 (77.3) 288 (87.8) 288 (87.0) Serious 24 (61.5) 24 (54.5) 176 (53.7) 168 (50.8) Leading to treatment discontinuation 15 (38.5) 10 (22.7) 103 (31.4) 100 (30.2) Leading to dose reduction of any drug 23 (59.0) 14 (31.8) 182 (55.5) 174 (52.6) Leading to interruption of any drug 1 (2.6) 1 (2.3) 15 (4.6) 3 (0.9) Leading to death 2 (5.1) 4 (9.1) 20 (6.1) 19 (5.7)

Teleguided photocoagulation treatments across continents with a remotely programmed laser for retinal diseases.

Diabetic retinopathy and retinal vein occlusion represent two prevalent vision-threatening retinal diseases. Retinal laser therapy still plays an important role in treating these conditions, but its successful administration often requires referral to specialized centers and retina experts. It is, therefore, essential to develop a new treatment methodology that enables patients to benefit from the expertise of specialists from reference centers. For this purpose, we investigated the feasibility of teleguided photocoagulation conducted across continents to determine if different ophthalmologists can consensually devise and safely execute treatment plans remotely. Two patients from Italy (Europe) with diabetic retinopathy and one from Arizona (USA) with central retinal vein occlusion underwent retinal photocoagulation using Navilas® 577s with remote teleguidance from the corresponding continental counterpart. The process included remote planning and execution, supported by an audio connection for real-time communication. Teletreatment success criteria included treatment plan completion, patient tolerance, remote connection stability, and technical quality. All treatments have been successfully performed with accurate spot application and no technical issues. Follow-ups at three weeks confirmed positive outcomes for each patient. Remote teleguided retinal photocoagulation appears feasible, offering a promising tool for global collaborations in retina care and potential benefits to regions with limited access to expert supervision.

Beamion BCGC-1: A phase Ib/II trial of the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (BI 1810631) + trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) for patients with metastatic breast cancer (mBC) and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC).

TPS509 Background: Approximately 15% of mGEAC tumors overexpress HER2. Currently, the HER2-targeted antibody-drug conjugate (ADC), T-DXd, is approved in mGEAC as a second-line or later-line treatment option following the failure of prior trastuzumab-containing therapy. Zongertinib (BI 1810631) is a novel, orally administered HER2-selective TKI that spares EGFR. In a Phase I trial (NCT04886804), zongertinib showed encouraging tolerability and efficacy in patients with HER2 aberration-positive advanced solid tumors, including mGEAC. Beamion BCGC-1 (NCT06324357) is a Phase Ib/II dose escalation/optimization trial investigating zongertinib plus T-DXd or T-DM1 in patients with HER2+ mGEAC or mBC. Here we focus on the mGEAC cohorts, in which patients will receive zongertinib in combination with T-DXd. Methods: Across the whole trial, approximately 240 patients will be enrolled from approximately 48 sites in 6 countries. In the mGEAC cohorts, approximately 80 patients with histologically/cytologically confirmed locally advanced/metastatic, unresectable, HER2-positive, pre-treated mGEAC will be enrolled. All patients must have investigator-assessed progression and documented HER2-positive disease (overexpressed and/or amplified; confirmed by immunohistochemistry and in situ hybridization). In Phase Ib, approximately 20 patients will receive escalating doses of zongertinib plus a fixed approved dose of T-DXd (6.4 mg/kg, once every 21 days). Dose escalation will be guided by a Bayesian Logistic Regression Model, with overdose control. In Phase Ib, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (first 21-day cycle); secondary endpoints include objective response (RECIST v1.1), DLTs during the on-treatment period and pharmacokinetics. In Phase II, up to 60 patients with mGEAC will be randomized 1:1 to receive one of two zongertinib dose levels (dose levels informed by Phase Ib), plus a fixed approved dose of T-DXd. In Phase II, the primary endpoint is objective response; secondary endpoints include progression-free survival, disease control, treatment-emergent adverse events leading to dose reduction, pharmacokinetics and patient-reported outcomes. Patients will remain on treatment until disease progression, undue toxicity or any other protocol-defined stopping criterion. Enrollment is ongoing. Clinical trial information: NCT06324357 .

Phase II study of neoadjuvant NALIRIFOX followed by chemoradiation with paclitaxel and carboplatin in locally advanced gastroesophageal cancer.

452 Background: We performed a single-arm phase II study of neoadjuvant NALIRIFOX and chemoradiation (CRT) with concurrent carboplatin/taxol (C/T) followed by surgery in patients with locally advanced gastroesophageal (GE) cancer. Methods: Patients were enrolled on an NCI sponsored, prospective, single arm study (NCT04656041). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive GE junction or esophageal cancer, ECOG PS ≤1, age 18+, and life expectancy > 3 months. Exclusion criteria included: metastatic disease, prior chemotherapy or RT, or prior targeted therapy for diagnosis. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed feasible to be encompassed within a RT field. Laparoscopy was not required. Pts were treated with neoadjuvant NALIRIFOX x 4-8 cycles pending patient tolerance and physician discretion, restaging, CRT (50.4 Gy in 28 fractions) with concurrent C/T, restaging, followed by surgical resection. Dose reductions were at discretion of the treating physician. The primary study endpoint was the pathologic complete response rate following neoadjuvant treatment with NALIRIFOX and CRT with concurrent C/T. Major pathologic response (mPR) was defined as Tumor Regression Grade 0 and 1. Secondary endpoints included: 1) acute toxicity; 2) clinical response per RECIST criteria; 3) PFS and 4) OS. Results: From June 2021 to October 2023, 40 patients were enrolled. Median age was 64 (range: 47-82), and 31 patients were male (78%). All patients started NALIRIFOX, and the median number of NALIRIFOX received was 5 (range: 1-8). Reasons for discontinuation of NALIRIFOX were: physician discretion (n=29), subject withdrew from treatment (n=2), progressive disease (n=1), death (n=1). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to NALIRIFOX were 55%, 35%, and 13% respectively. 35 patients started chemoRT (88%) and 33 patients completed chemoRT (83%). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to chemoRT were 86%, 11%, and 9% respectively. Of 33 who completed chemoRT, two patients declined surgery (including 1 with clinical CR), and 31 (78%) patients went for surgical exploration. No patients were found with intraoperative metastases. Therefore, 31 (78%) patients underwent surgical resection. In total, 9 patients had pCR (29% in resected cohort, 23% in ITT cohort) and 15 had a major PR (48% in resected cohort, 38% in ITT cohort). In total, 10 (25% in ITT) patients had pCR or clinically CR at 1 year. Conclusions: Neoadjuvant NALIRIFOX followed by CRT is feasible with acceptable rates of treatment completion and grade 3+ toxicity. In our phase II trial, the rate of pCR is promising and further studies incorporating this regimen should be considered. Clinical trial information: NCT04656041 .

Cardiac allograft tolerance can be achieved in nonhuman primates by donor bone marrow and kidney cotransplantation.

Long-term, immunosuppression-free allograft survival has been induced in human and nonhuman primate (NHP) kidney recipients after nonmyeloablative conditioning and donor bone marrow transplantation (DBMT), resulting in transient mixed hematopoietic chimerism. However, the same strategy has consistently failed in NHP heart transplant recipients. Here, we investigated whether long-term heart allograft survival could be achieved by cotransplanting kidneys from the same donor. Cynomolgus monkeys were transplanted with heart allografts alone or heart and kidney allografts from the same major histocompatibility complex (MHC)-mismatched donors. All animals except one received DBMT, either at the same time or after a 2- to 4-month delay, plus short-term costimulation blockade and calcineurin inhibitor treatment. Long-term, immunosuppression-free heart allograft survival was consistently achieved in heart/kidney, but not heart-alone, recipients. This was not associated with greater donor/recipient histocompatibility or altered lymphoid cell reconstitution after conditioning. The maintenance of tolerance after heart/kidney transplantation was associated with the presence of forkhead box P3 (Foxp3+) regulatory T cell (Treg)-rich organized lymphoid structures in kidneys but not hearts. Substituting high-dose erythropoietin treatment for kidney transplantation was unsuccessful, suggesting that it was not the sole mechanism of action. RNA sequencing analysis revealed that gene expression in hearts from tolerant recipients closely resembled that in hearts from chronically immunosuppressed recipients but differed markedly from rejecting allografts and naïve hearts. A version of this protocol may be able to induce tolerance in patients with end-stage heart and kidney failure who require combined heart and kidney transplantation.

P0391 The impact of point of care ultrasound on time to initiating advanced therapy in IBD (GUIDE-IBD): A randomised controlled trial

Abstract Background Intestinal ultrasound is an accurate tool for assessing inflammatory bowel disease activity1. Previous studies showed point-of-care ultrasound (POCUS) can impact treatment decisions in 48% of appointments2. Early diagnosis and treatment improves outcomes in Crohn’s disease (CD). We aimed to investigate if POCUS in the IBD clinic led to earlier initiation of advanced therapies using a randomised controlled trial. Methods Patients attending an IBD clinic at a UK tertiary referral centre with known or suspected IBD (with a high likelihood) were eligible. During the primary clinic appointment clinicians’ investigation and treatment decisions were recorded. Immediately following this they were randomised 1:1 to POCUS or standard of care (SOC). The POCUS group then had further review with an option to alter treatment decisions. The primary end-point was time to initiating definitive therapy (in days) (new/changed immunomodulator, advanced therapy or surgery only). Secondary end-points included clinical score (HBI, SCCAI), calprotectin and patient tolerability. Patients were followed for 12 months. Results 122 patients were enrolled between 1st June and 1st November 2023. Median age was 25 years (16-79) and 50% male with a final diagnosis of 87 CD, 23 UC, 4 IBD-U and 8 non IBD (new referrals). 63 had POCUS and 59 SOC. POCUS was performed by one of two sonographers (one gastroenterologist and one radiologist). 65 (53%) were on advanced therapy or immunomodulators at baseline. 99 (81%) had advanced therapy, immunomodulators or surgery during the study period. Mean time to definitive treatment decision was 43 days with POCUS compared to 92 days in SOC (p<0.01). 65 (53%) patients had a change of, or started a new therapy and mean time to treatment initiation was also significantly shorter in the POCUS group, 75 days, compared to SOC, 131 days (p=0.033). In a sub-group of 20 new referrals, 12 were diagnosed with IBD. Mean time to treatment initiation was shorter with POCUS (82 vs 151 days). Steroid prescriptions at the baseline appointment were significantly higher in the POCUS group, 11/63 vs 2/59 (p = 0.012). Any change to treatment in the POCUS group occurred in 29/63 (46%) patients. Scans took an average of 7.5 minutes with 100% patient acceptability. Conclusion POCUS leads to earlier IBD-related decision making which translates into earlier initiation of effective therapy. This should, in turn, lead to improved care with shorter time to remission and reduced complications. Pathways to incorporate POCUS into routine clinical practice to optimise its effectiveness need further evaluation. This will require collaborative training and working across multiple specialties to effectively deliver this service. References (1)Taylor SA, Mallett S, Bhatnagar G, et al. Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn’s disease (METRIC): a multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(8):548-558. doi:10.1016/S2468-1253(18)30161-4 (2)Bots S, De Voogd F, De Jong M, et al. Point-of-care Intestinal Ultrasound in IBD Patients: Disease Management and Diagnostic Yield in a Real-world Cohort and Proposal of a Point-of-care Algorithm. J Crohns Colitis. 2022;16(4):606-615. doi:10.1093/ecco-jcc/jjab175

P1188 Real-world quality of life experience of subcutaneous infliximab use in children with Inflammatory Bowel Disease (IBD) at a tertiary paediatric centre

Abstract Background Subcutaneous infliximab (SC-IFX) use offers relative pharmacokinetic stability and efficacy and safety profiles comparable to intravenous-infliximab (IV-IFX) in adult patients with IBD (1-4). Regular hospital admissions for infusions have an impact Quality of Life (QoL), impacting work and school commitments as well as increasing financial burden. Aim to assess tolerability and QoL in patients switched from IV to SC infliximab collected 12 weeks after the switch. Methods A prospectively identified cohort of 33 children with IBD commenced 120mg fortnightly SC-IFX dosing between February to July 2024 in an Australian tertiary paediatric IBD service. QoL and medication tolerability questionnaires (SIAQ and Costs For Patient’s questionnaire) included assessment of tolerability, convenience, satisfaction along with data about travel time and costs were completed at week 12. Assessment of disease activity, inflammatory biomarkers and therapeutic drug monitoring occurred 4 weekly for the first 12 weeks. Results 31(94%) patients completed the 12-week study treatment period. 21 patients (68%) responded to the QOL questionnaires. Satisfaction with SC treatment was 20 (95%) across respondents, only 1 patient reporting ‘somewhat dissatisfied’ experience. 18 (85%) described ease of administration, with 3 (14%) finding injections "not easy". Respondents described financial impacts to be greatest, followed by time-commitment for attendance, loss of school and work time for attendance for infusions. Nearly 2/3 caregivers required formal leave from employment to facilitate infusion attendance, and 1/3 of patients required full day off school. 100% described a definite or probable willingness to continue SC injections beyond the 12-week period. Conclusion We describe the largest cohort of children with IBD prescribed SC-IFX with short-term follow-up. There was high treatment persistence with the drug. QOL data demonstrates high patient satisfaction, with positive impacts on patient quality-of-life with treatment described. Our real-world experience of paediatric SC-IFX use suggests this well tolerated and preferable alternative to IV-IFX dosing in children in with IBD. Further large-cohort and long-term paediatric data is required. References 1)Schreiber S, Ben-Horin S, Leszczyszyn J et al. Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease. Gastroenterology 2021; 160: 2340-53. 2)Buisson A, Nachury M, Bazoge M et al. Long-term effectiveness and acceptability of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel disease treated with intensified doses: The REMSWITCH-LT study. Aliment Pharmacol Ther 2024; 59: 526-34. 3)Gianolio L, Armstrong K, Swann E et al. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy. J Pediatr Gastroenterol Nutr 2023; 77: 235-9. 4)Gianolio L, Armstrong K, Swann E et al. OC5 Effectiveness and safety of switching to subcutaneous infliximab in paediatric inflammatory bowel disease patients on established intravenous biosimilar infliximab maintenance therapy: real world data from a regional cohort. Frontline Gastroenterology 2024; 15: A4-A.

P0332 Optimization and assessment of colonoscopy preparation in Inflammatory Bowel Disease: a comprehensive single-center analysis with focus on disease-specific factors

Abstract Background Colonoscopy remains a cornerstone in inflammatory bowel disease (IBD) management, yet comprehensive data on preparation quality and tolerability in this specific population remains limited. We aimed to evaluate bowel preparation efficacy, tolerability, and colonoscopy outcomes in IBD patients while analyzing disease-specific influencing factors. Methods We conducted a prospective single-center study of 78 IBD patients (45 ulcerative colitis [UC] and 33 Crohn’s disease [CD]) undergoing routine colonoscopy surveillance. All patients received a split-dose 4L polyethylene glycol preparation. We collected comprehensive data including clinical parameters, Boston Bowel Preparation Scale (BBPS) scores, sedation requirements, and procedure tolerability using Visual Analogue Scale (VAS, 0-100mm). Disease activity was assessed using standardized endoscopic scores. Results Mean age was 47.2 ± 14.5 years for UC and 43.8 ± 13.9 years for CD patients. Adequate bowel preparation (BBPS ≥6) was achieved in 85.7% (67/78) of patients, with a mean total BBPS score of 6.3 ± 1.4. Female patients showed slightly higher preparation quality scores compared to males (BBPS 6.5 ± 1.3 vs 6.1 ± 1.4, p=0.12), though this difference was not statistically significant. Complete colonoscopy was successfully performed in 93.6% (73/78) of cases. No significant differences in BBPS scores were observed between UC and CD patients (6.4 ± 1.5 vs 6.2 ± 1.3, p=0.62), or between patients with active disease versus those in remission (6.3 ± 1.4 vs 6.2 ± 1.5, p=0.85). Preparation tolerability was rated as good or excellent (VAS ≥70) in 76.9% (60/78) of patients, with similar ratings between genders (females: 77.8%, males: 75.9%, p=0.83). Notably, 32.1% (25/78) of IBD patients required increased sedation compared to standard doses, with a higher proportion in CD patients (42.4%, 14/33) compared to UC patients (24.4%, 11/45, p=0.047), and in female patients (37.2%, 16/43) compared to males (25.7%, 9/35, p=0.038). Disease-related factors including disease duration, location, and previous surgery did not significantly impact preparation quality. Conclusion Our study demonstrates that high-quality bowel preparation can be achieved in IBD patients regardless of gender and disease characteristics, with good tolerability rates. However, increased sedation requirements, particularly in CD patients and females, should be anticipated. These findings support the implementation of standardized preparation protocols in IBD patients while emphasizing the need for personalized sedation strategies based on both disease and demographic factors.

High-Risk Plaque Characteristics in Patients with Suspected Stable Coronary Artery Disease and Impaired Glucose Tolerance: A Coronary Computed Tomography Angiography Study

Impaired glucose tolerance (IGT), a prediabetic state, is a known risk factor for coronary artery disease (CAD). Low-attenuation plaque (LAP) lesions are associated with a high risk of coronary events. We aimed to evaluate high-risk plaque characteristics in LAP lesions between patients with IGT and normal glucose tolerance (NGT) in patients suspected for stable CAD. Coronary computed tomography angiography (CCTA) identified LAP lesions and assessed plaque volumes, burdens, and high-risk plaque features. Glycemic tolerance was stratified using oral glucose tolerance tests. Among 148 patients, 202 LAP lesions were identified, with 93 patients classified as NGT and 55 as IGT. Patients with IGT had a significantly higher prevalence of LAP lesions compared with NGT (p = 0.007). LAP volume was higher in IGT (16.46 ± 12.52 mm3) compared with NGT (12.66 ± 9.72 mm3, p = 0.01), but this association did not persist in multivariate analysis. The LAP burden was greater in IGT (10.79 ± 6.84%) than NGT (8.62 ± 5.93%, p = 0.02), and the napkin-ring sign was more frequent in IGT (12%) versus NGT (5%, p = 0.02); these associations remained significant in multivariate analysis. Patients with IGT had a higher LAP burden and higher frequency of napkin-ring signs. These findings may help explain the common occurrence of prediabetes in patients with acute myocardial infarction.

P0570 Role of dynamic contrast-enhanced ultrasound (D-CEUS) in predicting clinical remission to advanced therapy in ulcerative colitis - a monocenter prospective pilot study

Abstract Background Ulcerative Colitis (UC) is a chronic inflammatory disease characterized by periods of relapse and remission. While colonoscopy is currently the gold standard for assessing disease activity, its invasiveness, low patient tolerance and associated risks make it unsuitable for frequent monitoring of intestinal inflammation. Despite these challenges, a "treat-to-target" approach is crucial in the era of biological therapies. Intestinal Ultrasound (IUS) offers a non-invasive, cost-effective and well-tolerated alternative to monitor treatment response. Indeed, the Milan Ultrasound Criteria (MUC), based on B-mode and color-doppler parameters, have been recently developed to assess disease activity in UC1,2. Dynamic Contrast-Enhanced Ultrasound (D-CEUS) allows visualization of tissue microvascularization, providing objective quantitative parameters derived from time-intensity curve analysis, potentially representing a promising tool to quantify bowel inflammation. The aim of our study was to assess the role of D-CEUS in predicting 6 months clinical remission to advanced therapies (biologic and small molecules). Methods We prospectively enrolled consecutive UC patients starting a new advanced treatment for clinical practice. Patients underwent IUS, D-CEUS and clinical assessment at baseline and at 8 (T1), 16 (T2) and 24 (T3) weeks after starting treatment. According to STRIDE-II consensus3, clinical remission at T3 was defined as partial Mayo score <3 and no subscore <1. Time-intensity curves were analyzed through VueBox® software (figure 1). Patients needing surgery or treatment change before T3 were classified as "non-responders". Logistic regression analysis was performed to evaluate the predictive role of D-CEUS in achieving clinical remission at T3. Statistical significance was defined as p<0.05. Results 40 patients were enrolled (mean age 39±13 years, 60% males), 44.4% (n=18) of which had previously failed at least one line of advanced therapy. At T3, 50% of patients achieved clinical remission (n=20). Univariate logistic regression analyses showed that reductions of Peak Enhancement (PE) and Wash-in Perfusion Index (WiPI) at T2 were predictive of clinical remission at T3 (OR=0.99, p=0.032 and OR=0.25, p=0.036 respectively). Moreover, the percentage changes between T2 and T0 (△% T2 – T0) of PE and WiPI were associated with 6 months clinical remission (OR=0.19 p=0.019 and OR=0.26 and p=0.04, respectively). Lastly, our results confirmed the value of MUC (at T1 and T2) in predicting clinical remission at T3 (OR=0.62, p=0.03 and OR=0.73, p=0.048, respectively). Conclusion D-CEUS provides early predictors of 6 months clinical remission in UC patients treated with advanced therapies.

P0521 Accuracy of a non-invasive approach in monitoring pediatric inflammatory bowel disease: interim-analysis of a prospective multicenter italian study

Abstract Background Ileocolonoscopy is the gold standard for diagnosing and monitoring pediatric IBD. However, it has limitations, including high costs, invasiveness, and the inability to visualize the small bowel (SB) and assess transmural involvement. Magnetic resonance enterography (MRE), while not the gold standard, is recognized as a key tool for evaluating the SB. Its limitations include high costs, the requirement for oral contrast—which reduces patient tolerance—and longer procedure times. To provide less invasive monitoring, especially in children, non-invasive methods such as capsule endoscopy (CE) and ultrasound (US) have been developed. We aimed to evaluate the accuracy of these non-invasive techniques (US and CE) in monitoring pediatric IBD. Methods This study represents an interim analysis of the prospective multicenter protocol GR-2019-12370621. Consecutive children with IBD were enrolled. At baseline, 6 and 12 months, UC children underwent ileocolonoscopy (IC), CE and US, while CD children underwent IC and EGD, MRE, CE and US. For the terminal ileum in CD and the colon in UC and CD, IC was the gold- standard. For the SB (jejunum, proximal and mid-ileum) MRE was the comparator to assess the presence of active disease. EGD served as the gold standard for duodenum. Sensitivity (Se), specificity (Sp), negative and positive predictive value (NPV and PPV) and accuracy of CE and US were determined for CD and UC in an ITT analysis. Results Thirty-one patients (16 CD and 15 UC) were enrolled as of the retrieval date (04/10/2024). For UC, 31 IC, 31 CE and 30 US procedures were performed. In CD, a total of 40 endoscopies, 30 CEs, 12 US procedures, and 36 MREs were available. In UC, CE showed a Se of 85%, Sp 100%, NPV of 87%, PPV of 100%, and an accuracy of 92.8%. The Se, SP, NPV, PPV and accuracy of US were 63%, 100%, 70%, 100% and 80%, respectively. The combination of CE and US increased accuracy up to 93.1% (Table 1).For CD: the combined accuracy of CE and US was 100% for the terminal ileum, 80% for the jejunum, 69% for the proximal ileum, and 75% for the mid ileum. The accuracy of CE for the colon in CD was 82.1% (Table 2). Conclusion Non-invasive monitoring achieves an accuracy of 93% compared to endoscopy in UC. For CD, it demonstrates excellent accuracy for the terminal ileum (100%) and fair accuracy for the colon (82.1%) compared to the invasive counterpart. However, reduced accuracy in the small intestine, ranging from 69% to 80%, may be influenced by the lack of a definitive gold standard for this segment. The low PPV of the CE, particularly for jejunum and proximal ileum, could be explained by the detection of mucosal lesion not visible by the comparator (MRE).

Prognostic values of intracellular cell-related genes in esophageal cancer and their regulatory mechanisms

Esophageal cancer is a grave malignant condition. While radiotherapy, often in conjunction with chemotherapy, serves as a cornerstone in the management of locally advanced or metastatic cases, patient tolerance and treatment resistance frequently hinder its efficacy. Cell-in-cell structures, prevalent in various tumors, have been linked to prognosis. Hence, investigating the prognostic significance and regulatory mechanisms of genes related to these intracellular structures in esophageal cancer is imperative. The Cancer Genome Atlas (TCGA) Esophageal Cancer (ESCA) dataset served as the training set for the analysis. Differentially expressed genes (DEGs) in ESCA samples were identified, with those related to intercellular structures designated cell-in-cell-related differential expression genes (CIC-related DEGs). Cox regression analysis was employed to identify prognostic genes, categorizing samples into high- and low-risk groups based on median risk scores. Validation was conducted using the GSE53624 risk model. Established methodologies included morphological mapping, enrichment analysis, immune infiltration analysis, prognostic gene expression validation, molecular docking, and Reverse Transcription Polymerase Chain Reaction (RT-PCR) validation. Thirty-eight intersecting genes were identified between the disease and normal groups in ESCA samples. Stepwise multivariate Cox analysis pinpointed three prognostic genes: androgen receptor (AR), C-X-C motif chemokine ligand 8 (CXCL8), and epidermal growth factor receptor (EGFR). The risk model’s applicability was confirmed in the GSE53624 dataset, revealing eight significantly different immune-related gene sets. Prognostic gene expression validation demonstrated significant differences between the disease and normal groups in both datasets. The proteins corresponding to the three prognostic genes interacted with gefitinib and osimertinib. RT-PCR results corroborated the differential expression of prognostic genes in esophageal cancer tissues. This study identified AR, CXCL8, and EGFR as prognostic genes and demonstrated their molecular interactions with gefitinib and osimertinib, providing a foundation for ESCA diagnosis and treatment.

Comparison of Hepatic Function and Chemotherapy-Induced Side Effects Between Pegylated Liposomal Doxorubicin (PLD), Topotecan (TOPO), and Gemcitabine in Platinum-Resistant Ovarian Cancer (PROC).

Background/Objectives: Platinum-resistant ovarian cancer (PROC) is a major therapeutic challenge, as it responds poorly to standard platinum-based treatment, has limited treatment options, and offers a generally unfavorable prognosis. Chemotherapeutic agents like pegylated liposomal doxorubicin (PLD), topotecan (TOPO), and gemcitabine (GEM) are used for this setting, but with varying efficacy and toxicity profiles, leading to an increasing need to understand the optimal balance between treatment effectiveness and tolerability for improving patient outcomes. This study evaluates the efficacy and side effects of PLD, TOPO, and GEM, focusing on progression-free survival (PFS), overall survival (OS), and safety profiles. Methods: We conducted a retrospective observational study that included 856 PROC patients treated with PLD (n = 383), TOPO (n = 352), or GEM (n = 121) at the OncoHelp Oncology Center from January 2018 to December 2023. Inclusion criteria encompass diagnosis, prior platinum therapy, and Eastern Cooperative Oncology Group (ECOG) status (0-2). Treatment protocols followed standard dosing, with adjustments for toxicity. Primary endpoints included PFS and OS, with safety assessed by incidence of grade 3 and 4 toxicities per CTCAE v5.0. Kaplan-Meier analysis and Cox regression were used to compare survival, and statistical significance was set at p < 0.05. Results: TOPO showed higher toxicity than PLD and GEM, including liver damage, hematological and non-hematological side effects, while PLD induced more skin toxicity. In terms of survival, minor differences were seen between the three chemotherapeutic agents, with a slight advantage for PLD for better disease control. Conclusions: Given the comparable results in OS across the regimens, treatment decisions should be based on other factors such as patient tolerance and quality of life.

Selpercatinib – a new option for a precision approach to the treatment of medullary thyroid cancer

Introduction. Multikinase inhibitors are used to treat nonresectable locally advanced and/or metastatic medullary thyroid cancer (MTC). However they are characterized by high toxicity associated with kinase inhibition. Selective RET inhibitor selpercatinib demonstrates high selectivity and tolerance which makes it a promising agent for MTC treatment.Aim. To evaluate selpercatinib effectiveness and tolerance in patients with metastatic MTC associated with a mutation in the RET gene.Materials and methods. The study included 9 patients with metastatic MTC and mutation in the RET gene who received treatment with selpercatinib 160 mg 2 times a day. The drug effectiveness was evaluated every 2–3 months based on the results of multispiral computed tomography of the whole body and tumor marker (calcitonin and carcinoembryonic antigen) levels.Results. Median duration of therapy was 29 months overall response rate was 78 %; complete response was observed in 56 % of patients. After 12 months of therapy progression-free survival was 100 %; after 24 months it was 89 %. Persistent decrease in calcitonin level (by more than 90 %) was achieved in all patients. The most common adverse events were arterial hypertension and insignificant creatinine increase.Conclusion. The results of therapy show significant improvement in the rate of objective response and progression[1]free survival which makes selpercatinib a preferential treatment choice in this category of patients.

Contribution of nebulized budesonide before bronchoscopy, a prospective clinical study.

This study evaluated the efficacy of adding budesonide to nebulized lidocaine in patients undergoing flexible bronchoscopy (FB) under topical anaesthesia. Patients aged ≥18years, scheduled for FB under topical anaesthesia were randomized into two groups: the combination group received a pre-treatment of 2ml 1mg budesonide with 5ml 2% lidocaine, whilst the lidocaine group received 5ml 2% lidocaine with 2ml saline solution, both administered via nebulization. Blood pressure (BP), heart rate, and percutaneous oxygen saturation were recorded before, during, and 10min after FB. The Visual Analogue Scale (VAS) and Wong-Baker FACES Pain Rating Scale (FPS-R) were used to evaluate cough severity, discomfort, willingness to accept reoperation, and the operator's satisfaction with patient cooperation. In addition, the duration of the procedure, total lidocaine dosage instilled through the bronchoscope during the procedure, and types of procedures performed were documented. Compared to the lidocaine group, the combination group showed lower maximum systolic and diastolic BP, higher minimum percutaneous oxygen saturation, and lower cough and discomfort severity scores. Operator's satisfaction, as measured via the VAS or FPS-R, was greater in the combination group, which also exhibited shorter procedure times and required lower lidocaine dosages. There were no significant differences between the groups in terms of willingness to accept reoperation or types of procedures performed. In patients undergoing FB with topical anaesthesia, pre-treatment with a combination of nebulized lidocaine and budesonide is more effective than nebulized lidocaine alone. Key message What is already known on this topic? Flexible bronchoscopy (FB) with topical anaesthesia remains a common practice in many settings, although it can cause significant discomfort for patients. What this study adds? Pre-treatment with a combination of nebulized budesonide and lidocaine was more effective and safer than nebulized lidocaine alone for improving patient tolerance during FB. How this study might affect research, practice, or policy? In settings where conscious sedation is not feasible, the combined nebulization of lidocaine and budesonide may offer an optimized approach for FB, enhancing patient comfort and procedural efficiency.

Kneeling tolerance when using quadriceps tendon autograft for anterior cruciate ligament reconstruction is superior to hamstring tendon autograft.

To investigate kneeling tolerance in patients undergoing hamstring (HT) versus quadriceps (QT) anterior cruciate ligament reconstruction (ACLR) and investigate correlation with patient-reported outcome measures (PROMs). After recruitment and randomisation, 112 patients (HT = 55; QT = 57) underwent ACLR. Patients were assessed at 6, 12 and 24 months using the Kneeling Tolerance Test, which evaluates patient-reported pain in a position of both 90 (KT90) and 110 (KT110) degrees of knee flexion. PROMs collected included the International Knee Documentation Committee (IKDC) questionnaire and the ACL Return to Sport after Injury (ACL-RSI) questionnaire. Kneeling tolerance at KT90 and KT110 improved (p < 0.05) for both graft types across all time points. There was no difference in KT90 scores between groups at 6 or 12 months. At 24 months, kneeling tolerance was superior in the QT group (mean HT 93 ± 9 vs. QT 98 ± 5; p = 0.003). For KT110 scores, a statistically significant difference was noted at 6 (mean HT 80 ± 25 vs. QT 89 ± 12; p = 0.027), 12 (mean HT 90 ± 13 vs. QT 95 ± 10; p = 0.040) and 24 months (mean HT 92 ± 10 vs. QT 97 ± 5; p = 0.003). The ACL-RSI was significantly correlated with KT90 and KT110 at 24 months (r = 0.40, p < 0.001; r = 0.40, p < 0.001). Other PROMs demonstrated significant weak-to-moderate correlations with kneeling tolerance. Patients undergoing ACLR with a QT versus HT autograft report superior kneeling tolerance up to 2 years postsurgery, more prominent in deeper (110°) knee flexion. A strong correlation with ACL-RSI was demonstrated at 2 years. ACTRN12618001520224p (Australian New Zealand Clinical Trials Registry). Level 1.

Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution.

Fluoropyrimidines are metabolized in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. About 7% of the European population is a carrier of DPYD gene polymorphisms associated with reduced DPD enzyme activity. To assess the prevalence of DPYD polymorphisms and their impact on fluoropyrimidine tolerability in Italian patients with gastrointestinal malignancies. A total of 300 consecutive patients with a diagnosis of gastrointestinal malignancy and treated with a fluoropyrimidine-based regimen were included in the analysis and divided into two cohorts: (1) 149 patients who started fluoropyrimidines after DPYD testing; and (2) 151 patients treated without DPYD testing. Among the patients in cohort A, 15% tested only the DPYD2A polymorphism, 19% tested four polymorphisms (DPYD2A, HapB3, c.2846A>T, and DPYD13), and 66% tested five polymorphisms including DPYD6. Overall, 14.8% of patients were found to be carriers of a DPYD variant, the most common being DPYD6 (12.1%). Patients in cohort A reported ≥ G3 toxicities (P = 0.00098), particularly fewer nonhematological toxicities (P = 0.0028) compared with cohort B, whereas there was no statistically significant difference between the two cohorts in hematological toxicities (P = 0.6944). Significantly fewer chemotherapy dose reductions (P = 0.00002) were observed in cohort A compared to cohort B, whereas there was no statistically significant differences in chemotherapy delay. Although this study had a limited sample size, it provides additional information on the prevalence of DPYD polymorphisms in the Italian population and highlights the role of pharmacogenetic testing to prevent severe toxicity.

Population Pharmacokinetics of Sotorasib in Healthy Subjects and Advanced Solid Tumor Patients Harboring a KRASG12C Mutation from Phase 1 and Phase 2 Studies.

Sotorasib is a novel KRASG12C inhibitor that has shown robust efficacy, safety, and tolerability in patients with KRASG12C mutation. The objectives of the population pharmacokinetic (PK) analysis were to characterize sotorasib population PK in healthy subjects and patients with advanced solid tumors with KRASG12C mutation from 6 clinical studies, evaluate the effects of intrinsic and extrinsic factors on PK parameters, and perform simulations to further assess the impact of identified covariates on sotorasib exposures. A two-compartment disposition model with three transit compartments for absorption and time-dependent clearance and bioavailability well described sotorasib PK. Sotorasib exposure increased in a less-than-dose proportional manner across the evaluated 180mg to 960mg dose range. Disease burden, measured by Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size, were identified as significant covariates on clearance. Lower disease burden was associated with higher clearance (and thus lower sotorasib exposure). Low albumin was found to be associated with lower clearance of sotorasib. Use of PPIs was associated with reduced sotorasib exposures. Although sex, race, and high fat meal were significantly associated with PK parameters, their impact on exposures were not clinically relevant. Other evaluated covariates, including body weight, age, renal impairment (evaluated by chronic kidney disease stage score) and hepatic impairment (evaluated by NCI criteria) were not statistically significant. Greater baseline disease burden and low albumin were associated with lower sotorasib clearance; based on the established efficacy and safety profiles from clinical trials, the estimated magnitude of these effects does not warrant a dose adjustment.

Association between preoperative exercise tolerance and unplanned readmission in patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma: a retrospective analysis

BackgroundDespite advances in treatment, the incidence of postoperative complications following pancreatectomy remains high, leading to frequent hospital readmissions. Therefore, this study aimed to investigate the relationship between preoperative exercise tolerance and the likelihood of unplanned readmission in patients with pancreatic ductal adenocarcinoma.MethodsThis retrospective analysis included 88 patients who underwent pancreatectomy at a single institution between July 2019 and September 2022 and focused on patients with pancreatic ductal adenocarcinoma. Patients’ preoperative exercise tolerance was assessed using the 6-minute walk distance (6 MWD).ResultsThe study found a 22.7% readmission rate within 1 year, with the median 6 MWD being significantly lower in readmitted patients than in those who were not readmitted (390.0 m versus 436.5 m; p < 0.01). A 6 MWD cut-off of 425 m was a strong predictor of readmission, with lower preoperative exercise tolerance associated with a higher risk of readmission.ConclusionsEnhancing preoperative physical reserves through exercise therapy may reduce readmission rates and improve patient outcomes. Further research with larger sample sizes is required to confirm these findings.

Polyamine Content of Enteral Nutrition Formulas: Effect of Daily Intake on the Feeding Tolerance of Patients During the First Week in the Intensive Care Unit

Enteral nutrition (EN) formulas are necessary for critically ill patients to meet their metabolic requirements. Polyamines (putrescine, spermidine, and spermine) are crucial dietary components, with spermidine being particularly interesting due to its multiple proposed benefits. The requirements for and intake of polyamines have yet to be investigated in adult patients hospitalised in intensive care units (ICUs) who are exclusively fed via commercial EN formulas. The aim of this study was to determine the polyamine content and other biogenic amines of EN formulas and the total intake and gastric residual volume (GRV) in adult ICU patients during their first seven days of hospitalisation. The amines were analysed in 16 EN formulas using high-performance liquid chromatography (HPLC). The clinical data of eight patients of both sexes aged 47 to 77 admitted to the ICU were analysed. Differences existed among the analysed EN formulas. The N-acetyl putrescine content was higher than that of the remaining amines. The daily intake of polyamines in the ICU was less than 100 μmol (the dietary intake is above 400 μmol). An inverse correlation existed between total daily polyamine intake and daily GRV, without effects from other biogenic amines being analysed. Polyamine intake in critically ill patients receiving EN is low and could impact these patients’ feeding tolerance. These findings underscore the need for further research to explore the clinical implications of increasing the polyamine content of EN formulas.