Treatment Interruption Research Articles

Lessons Learned in Eliciting Systematic Participant Perspectives in a Combination HIV Cure Research Trial.

Current trials toward an HIV cure involve combination strategies aimed at achieving durable antiretroviral treatment (ART)-free viral control or HIV elimination, many relying on analytical treatment interruptions (ATIs) to evaluate efficacy. Given the physical, psychosocial, and interpersonal risks associated with ATIs, it is critical to monitor participants' experiences so that support can be provided when needed. While qualitative approaches have been used in similar settings, we designed and implemented a series of short, closed-ended participant surveys in the University of California, San Francisco-amfAR trial, a single-arm multi-intervention HIV cure-related trial with an extended ATI. Surveys were administered at relevant trial timepoints to capture participants' (n = 10) perspectives and experiences. These included their understanding of the trial, motivations, expectations, perceived risks, benefits, and burdens of trial participation, and their perspectives on restarting ART and partner protections. We describe these data using descriptive statistics and summarize lessons learned from implementing quantitative surveys in this complex trial. Our data indicate that all respondents understood the scientific goals and requirements of participating in the trial. Most were motivated to help advance research but many expressed anxiety about participating. During the trial, respondents had limited side effects, discomfort, and trial burnout. Those who completed surveys at ART restart reported mixed (positive and negative) feelings and challenges (e.g., missed doses) when restarting ART. Participants offered various methods for partner protection during ATIs and at ART restart. Many respondents expressed future willingness to participate in a similar HIV cure trial. While the number of respondents was small, these findings are consistent with concerns identified in guidance regarding these types of trials as well as qualitative findings from earlier studies. Moreover, we demonstrated that it is feasible to implement quantitative evaluations of participants' experiences. Such approaches should be implemented in future HIV cure trials to optimize human-centered research implementation.

Impact of Breast Cancer Systemic Therapies on Fertility

Abstract Purpose of Review This review examines the impact of breast cancer treatments on fertility in young women and explores strategies for fertility preservation. It highlights what is known about the effects of chemotherapy, hormonal therapies, and targeted treatments for breast cancer on ovarian function, emphasizing the importance of integrating fertility preservation into oncology care. Recent Findings Systemic treatments, including chemotherapy and targeted agents like PARP inhibitors and CDK4/6 inhibitors, have the potential to significantly affect ovarian reserve and fertility. As treatment protocols become more prolonged, patients may consider treatment interruption to attempt pregnancy, and studies such as the POSITIVE trial offer new insights into the safety of pregnancy after breast cancer. Summary Personalized fertility preservation strategies are essential for optimizing outcomes in young breast cancer patients. Ongoing research to better understand the effects of treatment on future fertility, as well as mitigation strategies, is necessary to support informed decision-making and improve quality of life.

Gemcitabine and cisplatin induction chemotherapy followed by concurrent chemoradiotherapy for stage III-IVA nasopharyngeal carcinoma: A real-world study.

This study aims to evaluate the efficacy of combining induction chemotherapy with concurrent chemoradiotherapy for patients with stage III-IVA nasopharyngeal carcinoma (NPC), particularly focusing on cases associated with Epstein-Barr virus infection. The primary focus is on treatment response and disease control. This retrospective cohort study analyzed data from 81 patients with stage III-IVA NPC (excluding T3N0M0) treated with gemcitabine and cisplatin as induction chemotherapy, followed by concurrent chemoradiotherapy at the Vietnam National Cancer Hospital. Patient data and follow-up information were collected between June 2021 and June 2024, focusing on disease-free survival (DFS) as the primary outcome and secondary outcomes including factors affecting DFS and treatment-related toxicity. In the initial 3-month period, 76 out of 81 patients achieved a complete response, and five patients achieved a partial response. The follow-up period averaged 18.7 ± 5.3 months, with a 2-year DFS rate of 77.6%. Key factors influencing DFS included patient age, N stage, disease stage, and treatment interruptions. Grade 3 toxicities observed included neutropenia (17.3%) and mucositis (32.1%), while grade 4 toxicity was limited to nausea (2.4%). Additionally, 2.6% of patients experienced delayed grade I-II toxicities, with some presenting grade III anorexia. Our findings suggest that gemcitabine and cisplatin induction chemotherapy, followed by chemoradiotherapy, may result in a high response rate and effective disease control with manageable toxicity. However, further research is needed to evaluate long-term outcomes and potential delayed adverse effects to confirm these initial observations.

A phase 1 trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, balstilimab (FOLFOX-3B) in microsatellite stable metastatic colorectal cancer.

180 Background: Botensilimab (BOT) is a novel Fc fragment engineered CTLA4 inhibitor designed to boost innate and adaptive immune response. The combination of BOT and the PD-1 antibody balstilimab (BAL) has been associated with durable and deep responses in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Given the potential synergistic activity between checkpoint inhibitors and oxaliplatin and VEGF(R) inhibitors, we performed a phase 1 clinical trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, and balstilimab (FOLFOX-3B). Methods: We enrolled ECOG performance status 0-1 patients (pts) with measurable MSS mCRC, up to 2 prior lines of therapy, and without progression following prior oxaliplatin. FOLFOX was given at a fixed dose, every 2 weeks, across the study: folinic acid at 400 mg/m 2 x 2 hours (hr), oxaliplatin at 85 mg/m 2 x 2 hr, and fluorouracil at 2400 mg/m2 x 46 hrs. BOT was administered at 2 dose levels (DL) of 25 mg and 75 mg IV Q6 weeks x 2. BAL was administered at a fixed dose of 240 mg IV Q2 weeks. The study followed a 3 x 3 escalation design with up to 9 patients per DL. A dose level was deemed safe if < 1 out of 6 pts or < 2 out of 9 pts had a DLT (expansion to 9pts only if 2 DLTs encountered in the 1 st 6 pts). The DLT period consisted of 6 weeks. Pts should have received all intended BOT/BAL and FOLFOX doses in the 1 st 6 weeks to be deemed DLT-evaluable. Results: 14 pts were enrolled on study: 9/14 with liver metastatic disease, 5/14 RAS -mutated, all TMB low. 7 were treated on DL1 and 7 on DL2. 6/7 pts at DL1 had received 1-2 prior lines of therapy, 4 of whom included oxaliplatin. 6/7 of pts at DL2 had 1-2 prior systemic therapy, all of whom received prior oxaliplatin. No DLT were noted at DL1 or DL2. 1 pt at each DL was not DLT-evaluable as they were not able to receive all intended therapy due to treatment interruptions. Grade (G)2 and above immune related toxicities included: one pt at DL1 with transient G3 AST/ALT elevation and transient G2 colitis (resolved with steroids and infliximab), one pt at DL1 with G2 hypothyroidism and one patient at DL2 with G2 hyperthyroidism. At DL1, 4/7 had a partial response (PR) - including 2/4 with prior oxaliplatin exposure. At DL2, 6/7 pts had a PR – including 5/6 with prior oxaliplatin exposure. 3 patients proceeded to surgical resection or ablation and are currently followed with observation only. In the combined cohort of DL1 and DL2, the median progression free survival (PFS) is 8 months and remains unreached for DL2. Overall survival outcome has not matured at the time of this analysis. Conclusions: FOLFOX-3B with BOT at 75 mg IV Q6 weeks x 2 in combination with BAL 240 mg Q2 weeks is well-tolerated and is associated with promising clinical activity with 5/6 PR and prolonged PFS. The study was amended to explore additional DL that explore higher doses of BOT (150 mg) or longer duration of BOT 75mg (4 doses). Clinical trial information: NCT05627635 .

Evaluation of gemcitabine and carboplatin dosing in patients with cisplatin-ineligible metastatic urothelial carcinoma

The National Comprehensive Cancer Network Bladder Cancer Guidelines recommend carboplatin and gemcitabine first-line treatment in patients with cisplatin-ineligible, metastatic urothelial cancer (mUC) -- a Category 1 recommendation. For these patients, the median overall survival is 9.3 months. While carboplatin is purported to offer a more tolerable side-effect profile, many patients still require dose-reductions, dose-delays, and hospitalizations. Given the inability for mUC patients to tolerate this palliative regimen, we aim to determine whether initiating therapy with a lower dose regimen is justified. A single-institution retrospective analysis was conducted to review eligible patients treated with carboplatin plus gemcitabine from May 2014 through October 2022. Data collected via manual chart review included patient baseline characteristics, chemotherapy doses, reductions, delays, toxicities, and effectiveness. Forty-three patients met inclusion criteria. Nineteen patients (44%) required ≥ 1 dose reduction during therapy. Twenty-six patients (60%) started with a full-dose regimen, and 14 (54%) of those patients required a dose reduction during treatment. Seventeen patients (40%) started with a reduced-dose regimen, and 5 (29%) of those patients required a dose reduction during treatment. No patients received the anticipated 6 cycles at full dose, but 14% completed 6 cycles with dose reductions. One patient (2%) was able to tolerate >80% relative dose intensity of both carboplatin and gemcitabine. Cisplatin-ineligible mUC patients were unable to tolerate full-dose carboplatin and gemcitabine. As this is a palliative regimen, it would be pertinent to consider starting therapy at a reduced dose to minimize treatment interruptions, dose omissions and side effects.

The Impact of Aging on Measurement of Continuity of Treatment Among Children Living With HIV in the PEPFAR Supported Program in Kenya.

To reduce HIV-related morbidity and mortality among children living with HIV (CLHIV), continuity of treatment is critical. We sought to understand how aging out among CLHIV in Kenya impacts estimates of treatment continuity. A retrospective cohort analysis was performed on deidentified individual-level data from the Kenya National Data Warehouse for all clients who initiated and/or received antiretroviral therapy between the periods of October 2018 and September 2022 [US Government fiscal years (FYs) 2019-2022]. CLHIV previously on treatment and those newly initiating treatment were included in the analysis. Outcomes included aging out of childhood (turning 15 years old), interruption in treatment, return to treatment and remaining active on treatment. The number of active CLHIV on treatment at the end of FY 2019 was 44,628. This changed to 48,218, 48,262 and 44,780 representing 8%, 0% and -7% cohort growth/reduction at the end of FYs 2020, 2021 and 2022, respectively. Among those who were on treatment at the beginning of each FY, aging out of childhood accounted for 53%, 61% and 72% of the total cohort reductions for the periods 2020, 2021 and 2022, respectively. Interruptions in treatment accounted for proportions ranging from 5% to 9% among those active on treatment, while those who aged out of childhood ranged between 11% and 13%. Among those who returned to treatment in each FY, the proportions who remained active at the end of the FY varied from 72% to 76%. Accounting for aging out of childhood can improve program estimates of their true rates of interruptions of treatment in children, as they work to achieve epidemic control among CLHIV.

SIV monoclonal antibody administration spanning treatment interruption in macaques delays viral rebound and selects escape variants

HIV-1 envelope broadly neutralizing antibodies represent a promising component of HIV-1 cure strategies. To evaluate the therapeutic efficacy of combination monoclonal antibodies (mAbs) in a rigorous nonhuman primate model, we tested different combinations of simian immunodeficiency virus (SIV) neutralizing mAbs in SIVmac251-infected rhesus macaques. Antiretroviral therapy-suppressed animals received anti-SIV mAbs targeting multiple Env epitopes spanning analytical treatment interruption (ATI) in 3 groups (n = 7 each): i) no mAb; ii) 4-mAb combination; and iii) 2-mAb combination. Each mAb was administered at 15 mg/kg, and both mAb-treated groups received ITS103.01, a highly potent CD4-binding site targeting antibody. mAb treatment delayed viral rebound, lowered rebound viremia setpoint and viral diversity, and extended animal lifespan. Compared to controls, for which viremia rebounded 2 wk following ATI, mAb infusion delayed rebound for both groups (P = 0.0003). Animals that received the 4-mAb regimen rebounded 3 to 6 wk post-ATI while the 2-mAb regimen rebounded 5 to 22 wk post-ATI. Envelope escape mutations emerged in rebound virus of mAb-treated animals that abrogated neutralization by ITS103.01, the most potent in the cocktail. These data demonstrate in vivo antiviral activity of SIV mAbs in the context of ATI via immune pressure dominated by the most potent mAb and highlight their potential in adjunctive therapeutic studies.

Inhibition of p75NTR/p53 axis by ambrisentan suppresses apoptosis and oxidative stress-mediated renal damage in a cisplatin AKI model.

Cisplatin (CP) is a potent antineoplastic agent that triggers nephrotoxicity as a major adverse effect which can cause treatment interruptions and limitations to its clinical use. Nephrotoxicity associated with CP involves inflammation, oxidative stress and apoptosis in kidney tubules. The objective of this work was to assess the effect of the blockade of endothelin-1 (ET-1) receptor with ambrisentan (Amb) on altered renal function induced by CP. Swiss albino mice were assigned into control, CP, CP/Amb-5 and CP/Amb-10 groups. Ambrisentan improved kidney function (serum creatinine and BUN) and histopathological changes in comparison to CP-treated group. Ambrisentan significantly reduced protein expression of p75NTR and JNK influencing renal apoptosis as evidenced by reducing p53, caspase-3 and Bax level and elevating Bcl-2 level (p<0.05 vs CP group). Moreover, vasodilatory effect of ambrisentan was indicated by significant increase in level of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) (p<0.05 vs CP group). Ambrisentan also significantly restored oxidative balance in renal tissues as evidenced by reduced malondialdehyde and increased total antioxidant capacity and superoxide dismutase activity, in addition to decreasing nitric oxide levels (p<0.05 vs CP group). This protective effect of ambrisentan might be mediated through the downregulation of death receptor, P75NTR that in turn restores renal blood flow and oxidative balance and regulates p53, VEGF/eNOS, NF-κB, and bcl-2/Bax/caspase-3 signaling.

P-1076. Describing the clinical characteristics, treatment patterns, and outcomes in hospitalized pneumonia patients treated with Ceftolozane/Tazobactam (C/T): Insights from the SPECTRA Study

Abstract Background This sub-analysis of the SPECTRA (Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam [C/T] Real-world Analysis) study aimed to describe the clinical characteristics, treatment patterns, and outcomes of hospitalized pneumonia patients treated with ceftolozane/tazobactam (C/T).Table 1.Patient characteristics and Microbiology2 Immunocompromised defined as: ‘Immunocompromised present’ [raw item] or ‘Hematologic Malignancy present’ or ‘Solid Tumor present’ or ‘Transplant=Yes’. Methods SPECTRA was a multicenter observational study conducted in 7 countries. It included adult patients (age≥18yrs) who received ≥48-hours C/T treatment (n=617). Retrospective data were extracted from medical records covering a 6-month period prior to the index date, up to 30 days after the last dose of C/T or until death. Descriptive statistics were used to analyze clinical success, all-cause in-hospital mortality (ACHM), intensive care unit (ICU) admission, length of stay (LOS) in the subcategory of pneumonia (n=182).Table 2.Outcomes with Ceftolozane/tazobactam and Treatment duration (days) (Treatment interruptions not included)*Other conditions: Bile duct anostomic leakage, Brain-vascular hemorrhagic accident, CMV infection, Encephalic Death, Hemorrhage, Invasive fungal infection, Necrotizing pancreatitis, Post operative complication, Renal amyloidosis, Spontaneous rupture of the spleen, Septic shock, Hemodynamic dysfunction, Kidney failure, Stable angina grade I-II CCS, Probable Clostridium difficile colitis, Progression of AML, Refractory Hypoxemia, Refractory hematologic malignancy, Subarachnoid Hemorrhage, Solid tumor, Tracheobronchitis Results The median duration of C/T treatment was 11.0 days, median time from index hospitalization admission to C/T initiation was 19.0 days, and from the first microbiological sample to C/T initiation 6.0 days. All-cause in-hospital mortality was 32.4% (n=59), with a median time from the index to death of 28.0 days. The causes of death included sepsis (38.9%) and pneumonia (18.6%) and 67% (n=122) patients were admitted to the ICU during the index hospitalization. Pseudomonas aeruginosa (PSA) was the most commonly isolated pathogen (88% of patients), with MDR PsA present in 68.4% (n=80) of pneumonia patients. Conclusion In hospitalized patients with pneumonia treated with C/T in a real-world setting, clinical characteristics, treatment patterns, and outcomes provide insights into the use and effectiveness of C/T. Disclosures Emre Yucel, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) David Paterson, bioMerieux: Grant/Research Support|bioMerieux: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Grant/Research Support|Shionogi: Honoraria Florian Thalhammer, MD, MSD: Advisor/Consultant Stefan Kluge, Prof. Dr. med., Merck &amp; Co: Advisor/Consultant|Merck &amp; Co: Board Member Mike Allen, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) Brune Akrich, MD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) Yanbing Zhou, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company)

Improved measurement precision for cancer cardiotoxicity screening using fully automated analysis

Abstract Background Serial surveillance screening for cardiotoxicity demands measurement precision to detect dysfunction early and avoid inappropriate treatment interruptions. 3D LVEF and GLS imaging are therefore recommended, or CMR where image quality is suboptimal [1]. Automated (AI) analysis of CMR has demonstrated ‘superhuman’ precision [2], however the impact of AI on echocardiographic precision is unknown. Purpose To compare human versus AI analysis for LVEF and GLS using echocardiography in oncology patients at risk of cardiotoxicity. Methods Adult oncology patients underwent same day repeat echocardiography (GE Vivid9 machine) using recommended protocols (ethics 16/LO/1815). Manual analysis by a single blinded expert observer was compared to AI analysis (of 2D images) using two commercial AI packages (AI1, AI2) and a third AI package currently undergoing regulatory approval (AI3). A subset of patients also underwent paired same day CMR, analysed using commercial software (Circle CVI). Primary outcome measure was mean absolute difference (MAD) between repeat scans, and within subject co-efficient of variation (WSCoV), minimal detectable difference (MDD) and Bland-Altman limits of agreement were also analysed. Statistical analysis was performed in R, with n=10,000 bootstrap to estimate confidence intervals. MAD was compared with a Mann-Whitney U test. Results 61 cancer patients (median age 51, 84% female) underwent same day repeat echocardiography. Image quality was graded acceptable for LVEF analysis by humans in 92% cases for 2D and 74% of 3D images. AI analysis was feasible in 96% (AI1), 93% (AI2) and 100% (AI3) of adequate 2D studies. Median LVEF across the group was 58% (IQR 50 – 66%). MAD for 2D LVEF (n=56) was similar between humans and AI software packages AI1, AI2 and AI3 respectively (4.2% [3.5-49] vs 4.8% [3.7–5.9], 5.2% [4.2-6.4], 3.5% [2.7-4.2]), Figure 1 and Table 1. However for LVEDV and LVESV, AI3 had significantly lower MAD (6.8ml [5.5-8.1] vs 11.8ml [9.5-14.2] and 3.4ml [2.7-4.1] vs 6.5ml [5.3-7.7], p&amp;lt;0.001) compared with humans. MDD for EDV was 10.5ml [8.2-12.3] for AI3 vs 20ml [16.1-23.4] for human 2D LVEF (p&amp;lt;0.05). For GLS, MAD was similar between humans, AI2 and AI3 though significantly higher for AI1 (2.6% [2.2-3.0] vs 1.4% [1.1-1.7], p&amp;lt;0.001). For participants (48) with matched CMR paired data, MAD for CMR LVEF was significantly lower than human, AI1 and AI2 for LVEF, LVEDV and LVESV respectively [p&amp;lt;0.05], but not significantly different to AI3 for LVEF (3.9% [3.2-4.7] vs CMR 2.9% [2.3-3.4] or 3D 3.3% [2.7-3.9] p&amp;gt;0.05). Conclusion In oncology patients at risk of cardiotoxicity, newer fully-automated AI based echocardiography analysis improves measurement precision, with similar performance to 3D echocardiography and approaching CMR. Feasible even with challenging images, this should improve both confidence and efficiency for cardiotoxicity surveillance in cancer patients.

P-1321. The Infectious Disease Needs of Adult Ukrainian Refugees in a Tertiary Centre in the West of Ireland

Abstract Background Since February 2022 6.5 million have fled Ukraine; 104’ 870 to Ireland (2% of Irish population) [1, 2] The surge in those seeking temporary protection, coupled with infectious disease epidemiology in Ukraine; high prevalence of blood borne viruses and TB has placed strain on host countries' health services. [3, 4] 18 ‘840 (18% of National total, 0.37% of Irish population) are accommodated within our catchment area. The objective of this study was to evaluate case complexity, barriers to access and impact on service by this population. HIV, HCV and HBV prevalence, control and management Methods We performed a retrospective chart review using our electronic patient record, compiled data on a protected spreadsheet and results were collated. Tuberculosis prevalence, susceptibility, site and management Results 123 adult Ukrainian refugees have newly attended our service since February 2022 - April 2024, 2.03 new patients weekly; 63/123 (51.2%) are female. The mean age is 44.7 years (18 - 79). 76 (61.8%) have HIV (PLWH); 68 (89.5%) known diagnoses; 39 (57.3%) of whom were virally suppressed on ART and 27 (40%) were viraemic as a result of treatment interruption, 2 (2.9%) had no blood testing with us. 7 (5.7%) were newly diagnosed following arrival to Ireland; 4 (57%) with advanced disease (mean CD4 Count 285 IU/mL [28 - 753]). Thirty two (42%) PLWH are co-infected with HCV, 4 (5.3%) with HBV. 37 (30%) attended with HCV mono-infection, 9 (7.3%) with HBV mono-infection. 17 PLWH (22.4%) report previously treated TB. We have seen 4 (3.25%) cases of active TB; three of MDR pulmonary disease and results are pending for the fourth case. 4, 10.5% of women living with HIV in this cohort have had pregnancies; 2 (5.3% of WLH) are currently pregnant (both live in Donegal; average 165.6 miles from clinic). The average distance traveled to our clinic is 64.6 miles (Range 0.62 - 189); based on current geographic distribution of the group 50.4% (62/123) can access public transport that would allow them to reach our clinic within 2 hours. There was no significant association between access to public transport and missed clinic appointments (p = 0.64). 115/123 (93.5%) have a need for an interpreter. Since February 2022 26 (21%) have required hospital admission with an average length of stay of 22.9 days and a total of 597 bed days used. Conclusion We have identified significant case complexity and ongoing high ID service need for this cohort. Cohort Demographics Disclosures All Authors: No reported disclosures

Validity of one-time phantomless patient-specific quality assurance in proton therapy with regard to the reproducibility of beam delivery.

Patient-specific quality assurance (PSQA) is a crucial yet resource-intensive task in proton therapy, requiring special equipment, expertise and additional beam time. Machine delivery log files contain information about energy, position and monitor units (MU) of all delivered spots, allowing a reconstruction of the applied dose. This raises the prospect of phantomless, log file-based QA (LFQA) as an automated replacement of current phantom-based solutions, provided that such an approach guarantees a comparable level of safety. To retrieve a reliable LFQA conclusion from a one-time plan delivery before treatment initiation, deviations between planned and logged parameters must either be persistent over all following treatment fractions or, in case of random fluctuations, must not have a relevant impact on the reconstructed dose distribution. We therefore investigated the reproducibility of log file parameters over multiple patient treatment fractions and compared the reconstructed dose distributions. Log file variability was examined at both spot parameter and integral dose levels. The log files of 14 patient treatment plans were analyzed retrospectively for a total of 339 delivered fractions. From the recorded x/y position and MU parameters per spot, the respective mean difference to the planned value (accuracy) and the standard deviation (reproducibility) were calculated for 108,610 planned spots. The dose distributions reconstructed from the log files of each fraction were evaluated against the planned fraction dose using 3D gamma index analysis. The dose-based gamma pass rate was correlated with a new spot-based log file pass rate . Beam timing information from the log files was used to quantify the total plan/field delivery time stability after excluding machine interlocks. The mean spot-wise accuracy with respect to distance from planned positions and MUs was (0.6±0.3)mm and (0.0001±0.0023) MU, respectively. The mean reproducibility of the observed single spot deviations was (0.2±0.1) mm and (0.0004±0.0004) MU (mean±standard deviation). These variations resulted in minimal changes in the reconstructed fraction dose with (2mm/2%)>99% for all studied fractions. Results for more sensitive criteria (1mm/1%) were plan-specific, but on average>92.6% per plan and correlated with (1mm) pass rates (0.51≤rPearson≤0.99). Field delivery times were reproducible within±4 s (2σ) and no treatment interruptions were observed in 92.8% of cases. The log file records of plan-relevant spot parameters are well-reproducible over multiple fractions and deviations have no dosimetrically relevant impact on the reconstructed fraction doses. Results of a one-time pre-treatment LFQA are considered as valid for the entire treatment course and there is no concern in this regard to replace state-of-the-art phantom measurements in the current PSQA workflow.

Palliative Radiotherapy in Metastatic Breast Cancer Patients on CDK4/6 Inhibitors: Safety Analysis

Purpose: CDK4/6 inhibitors require meticulous monitoring due to their potential to cause hematological toxicities and hepatotoxicity. This study evaluates the safety of combining CDK4/6 inhibitors with palliative radiotherapy in patients with metastatic hormone receptor-positive and HER2-negative breast cancer. Patients and Methods: This study included 188 patients treated with CDK4/6 inhibitors between January 2021 and June 2024. Data on patient demographics, tumor characteristics, and treatment interventions were extracted from medical records. The primary focus was on the incidence of grade ≥ 3 hematologic toxicities and hepatotoxicity, assessed according to CTCAE 5.0 criteria, in those receiving concurrent palliative radiotherapy. Results: With a median follow-up of 18.5 months, the 18-month PFS and OS rates were 67% and 85%, respectively. The median age was 57.5 years, and 79% of patients were post-menopausal. Bone and liver metastases were present in 66% and 23% of patients, respectively. Concurrent palliative radiotherapy was administered in 25% of the cohort. The incidence of grade ≥ 3 hematologic toxicity was comparable between those who received radiotherapy and those who did not. Ribociclib use was associated with lower rates of grade 3 hematologic toxicity (OR: 0.37), neutropenia (OR: 0.41), dose interruptions (OR: 0.30), and dose reductions (OR: 0.37). Pre-menopausal status was linked to fewer dose reductions (OR: 0.17). Rates of treatment interruption, dose reduction, and withdrawal were 55%, 24%, and 2%, respectively. Conclusions: The concurrent use of CDK4/6 inhibitors and palliative radiotherapy does not increase the incidence of hematological adverse events in patients with metastatic breast cancer.

P1127 Comparative study of Subcutaneous and Intravenous Infliximab in Inflammatory Bowel Disease: Interim analysis of a prospective single center cohort (The SWITCH study)

Abstract Background Randomized control studies have demonstrated the efficacy of subcutaneous infliximab (IFX SC) compared to placebo. However, real-life evidence remains scarce on the impact of this switch on effectiveness, safety, pharmacokinetics (PK), and quality of life in IBD management. Methods This is a 1 year longitudinal prospective single center cohort study (EC: P2021/570) comparing 2 groups: IBD patients remaining on IFX Intravenous (IV) (IV group) and patients switching from IFX IV to SC (SC group). The study population included patients in clinical, biological and endoscopic remission on IFX IV maintenance. Decision to switch to SC or to remain on IV was based on patient preference. The primary outcome was the proportion of IBD patients with drug sustainability. Drug sustainability was defined as the absence of treatment interruption or modifications in the IFX regimen. The secondary outcomes were safety, PK and quality of life (via IBDQ). At each timepoint, IFX Trough Levels (TL) were measured using ELISA. Results Sixty-eight IBD patients met the inclusion criteria with 42 patients switching to SC. At last IV infusion, all patients were treated at 5 mg/kg with regimen of every 8 (n=49), 6 (n=9) and 4 (n=10) weeks. Demographics of SC and IV groups were comparable as shown in Table 1. At the time of this interim analysis, the mean follow-up was 37 weeks ± 20. Drug sustainability was not different in the 2 groups (p=0.45). The reasons for loss of drug sustainability were flare disease (n=4), neoplasia (n=1), pregnancy (n= 1) or patient choice (n=4). At last IV infusion and baseline, both IV and SC groups had similar TL distributions but as soon as patients were switched to SC (SC group), IFX TL were significantly different from patients maintained in IV (IV group) at each timepoint (Figure 1a). Strikingly, in the SC group, median IFX TL at week 8 was significantly lower in patients failing drug sustainability (Figure 1b) (10.7 μg/mL, IQR (7.3-14.1) vs 27.5 μg/mL, IQR (25.8-45), (p= 0.007)). Neither the overall quality of life assessed via IBDQ nor the specific IBDQ domains (GI, systemic, social, or emotional) showed significant differences between the SC and IV groups. Although the incidence of IFX-related adverse events was higher in the SC group, the difference was not statistically significant (74% vs 41%; p=0.07). Injection site reactions were the most common and specific adverse event in the SC group. Conclusion This study demonstrates comparable drug sustainability between IFX SC and IV in a remitter IBD population. Among SC patients, week 8 IFX levels were predictive of drug sustainability. While SC treatment showed a trend toward higher adverse events, injection site reactions were the most common and specific to the SC group References This interim analysis of SWITCH study demonstrates comparable drug sustainability between IFX SC and IV in a remitter IBD population. Among patients switched to SC, week 8 IFX trough levels were predictive of drug sustainability. While SC treatment showed a trend toward higher adverse events, injection site reactions were the most common and specific to the SC group.

A comparative analysis in monitoring 24-hour urinary copper in wilson disease: sampling on or off treatment?

Background & AimTwenty-four-hour urinary copper excretion (24 h-UCE) is the standard diagnostic tool for dose adjustments in maintenance therapy in Wilson disease (WD) patients. Guidelines lack data if both variants of 24 h-UCE measurement (with or without 48 h of treatment interruption) are equally interpretable.MethodsEighty-four patients with a confirmed diagnosis of WD treated with chelators (50% of patients with D-Penicillamine and 50% with trientine) and with pairwise 24-h-UCE values on-therapy and off-therapy were included in the analysis. Pairwise urinary sampling between October 2022 (T0) and a 12-month FU (T2) was compared, and exchangeable copper (CuEXC) was additionally measured at T0.ResultsAmong the 84 patients, 65% had predominant hepatic symptoms, the median age was 42 years, and 58% were female. At T0, patients were in the stable maintenance phase, with a median treatment duration of 21.9 years. The levels of the biochemical markers liver and copper metabolism remained stable over the 12-month observation period for all patients. 24 h-UCE off-therapy significantly decreased from T0 to T2 (p = 0.03), whereas no statistically significant differences were detected for 24 h-UCE after therapy. Both sampling methods did not correlate. CuEXC was significantly correlated with 24 h-UCE after 48 h of dose interruption (p = 0.018) but not with 24 h-UCE after therapy. A total of 46% of the 24 h-UCE value pairs were discordant, laying out the aimed therapeutic ranges given in current international guidelines.ConclusionOff-therapy 24 h-UCE reflects the “free” copper pool more accurately than does urinary sampling. The study shows discordant results for both sampling methods in approximately half of the patients, revealing that interpretation of 24 h-UCE with respect to chelator-dosing decisions should be performed with caution.

Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies

The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of ‘placebo’ controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13–25), 21 (IQR:15–28), and 32 (IQR:20–35), respectively. PTC defined as pVL <50 copies/mL at day 84 occurred in 4% (n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design.

COVID-19-Related Discontinuation Impact on Patient-Reported Outcomes in Long-Term Thermal Therapy: A Single-Center Observational Study at Saturnia Thermal Springs.

Thermal therapy represents a well-established therapeutic approach for chronic musculoskeletal and respiratory conditions. To date, no studies have investigated the clinical effects of treatment interruption in thermal medicine. We aimed to evaluate the clinical impact of COVID-19 lockdown-induced thermal therapy discontinuation through validated patient-reported outcomes. This single-center observational, retrospective study (March 2020-June 2024) evaluated 97 patients receiving standardized thermal therapy at Saturnia Thermal Springs. Treatment protocols included balneotherapy, mud therapy, and inhalation treatments in cycles of 12-15 sessions, with maintenance protocols every 4-6 months. Primary outcomes were assessed through VAS and SF-36 PCS, with EQ-5D and PSQI as secondary outcomes. Significant clinical deterioration occurred during treatment interruption (p < 0.001) in 77.7% of patients. Recovery patterns were duration-dependent, with the 6-7-year cohort showing faster recovery (mean time to baseline: 2.8 months) compared to the 3-5-year cohort (4.6 months). Effect sizes were substantial across all outcomes (Cohen's d > 1.0), with EQ-5D scores showing duration-dependent improvement (mean improvement in 6-7-year cohort: 0.27). Thermal therapy interruption precipitates quantifiable clinical deterioration, with recovery patterns significantly influenced by pre-existing treatment duration. These findings support the essential nature of treatment continuity in thermal therapy protocols.

Evaluating the Quality of Real-World Data on Adherence to Oral Endocrine Therapy in Breast Cancer Patients: How Real Is Real-World Data?

The aim of this study was to compare estimates of adherence to oral endocrine therapy (OET) based on real-world data (RWD) and on clinical evaluation in people diagnosed with breast cancer in the public healthcare system in Catalonia (Spain). We conducted two retrospective cohort studies. Cohort 1 (RWD) consisted of women diagnosed with breast cancer in 2021 in the public healthcare system of Catalonia (Spain). Sources of RWD were the pharmacy billing register, hospital discharge records, and the Catalan health division's central insurance registry. Nonadherence was defined as below 80% adherence in the first year of treatment. Data for cohort 2 came from two population-based cancer registries in Girona and Tarragona (Catalonia), with diagnoses from 2007 to 2011. We evaluated the impact of variables missing from RWD, such as stage and hormonal status. Analyses were performed using a chi-square test and logistic regression, with results stratified by age group and drug type. Nonadherence at one year was 10.9% in cohort 1 and 11.3% in cohort 2. When we reviewed the medical records of a selection of nonadherent women from cohort 1, we found only 59.4% had documented treatment interruptions. Reasons for interruptions in the patients from RWD cohort included adverse effects (48.8%), patient decision (40.0%), medical reasons (29.4%), and other clinical causes (14.7%). Women aged under 50 years and those receiving tamoxifen or a sequential regimen had lower adherence. Determinants associated with nonadherence were similar in both approaches used. This study confirms the validity of estimating adherence with RWD from the Spanish national health system, although when combined with reviewing medical records, this may provide more reliable and higher-quality data. The RWD method provides valuable evidence to help oncologists discuss adherence with their patients.

A Real-World Comparison of the Safety Profile for Immune Checkpoint Inhibitors in Oncology Patients.

Background/Objectives: Owing to the growing use of immune checkpoint inhibitors (ICIs) in the treatment of cancer, a wide spectrum of toxicity has arisen among cancer patients. Yet, limited ICI toxicity-related research is currently conducted in our region. Methods: This is a retrospective observational study conducted on adult cancer patients who received at least one cycle of ICI single therapy. Toxicity profiles of different ICI monotherapies were described and compared, and their association with different risk factors was assessed. SPSS version 28 was used for statistical analyses, and p < 0.05 was considered statistically significant. Results: A total of 428 patients were treated with anti-PD1 (nivolumab [n = 221, 51.6%] and pembrolizumab [n = 126, 29.5%]) or anti-PD-L1 (atezolizumab [n = 78, 18.2%] and durvalumab [n = 3, 0.7%]). Pneumonia was the most common complication (10%), followed by acute kidney injury (AKI; 8.2%) and hepatitis (7.9%). The proportion of hepatitis cases was significantly higher among atezolizumab compared to nivolumab-, pembrolizumab-, and durvalumab-treated patients (17.95% vs. 7.7% vs. 2.4% vs. 0.0%, respectively; p < 0.001). Gastrointestinal complication (colitis) was detected in 3.3% of patients with a significant difference between treatment groups (4.5%, 1.6%, 1.3%, and 33.3% in nivolumab, pembrolizumab, atezolizumab, and durvalumab, respectively; p = 0.008). Cardiac complications occurred in 1.2% of patients with a significant difference between treatment groups (0.5% in the nivolumab, 3.8% in the atezolizumab, 33.3% in the durvalumab, and none in the pembrolizumab groups (p < 0.001)). Musculoskeletal side effects, including both arthralgia and fatigue, were the most-reported side effects by 39.5% of patients, with significantly higher arthralgia complainers only in nivolumab (7.7%) compared to other treatment groups (0%, 2.6%, and 0% in pembrolizumab, atezolizumab, and durvalumab, respectively, p = 0.007). Hepatic, cardiovascular, hematological, respiratory, renal, gastrointestinal complications, thyroid complications, and dermatological side effects were found to occur on weeks 6, 7.5, 8, 8, 10, 10, 10.5, and 12 after treatment initiation, respectively, with no significant difference between treatment groups. Despite that, hepatitis and AKI tended to occur earlier with atezolizumab (week 2, p = 0.084) and pembrolizumab (week 2, p = 0.062), respectively, compared to their comparators. The female gender and a history of hepatitis were found to increase the odds of hepatic complication with anti-PD1 or anti-PD-L1 use [OR = 2.71; 95% CI 1.07-6.85, OR = 11.14; 95% CI 3.46-35.88, respectively]. Previous exposure to cancer therapy only was found to increase the odds of developing pneumonia among the treated patients [OR = 3.08; 95% CI 1.12-8.85]. Having hematological malignancy influenced the odds of hematological complications positively (either neutropenia or thrombocytopenia) compared to solid malignancies when patients were treated with anti-PD1 or anti-PD-L1 [OR = 17.18; 95% CI 4.06-72.71]. Finally, the female gender was found to positively associate with the odds of nausea/vomiting and fatigue secondary to anti-PD1 or anti-PD-L1 administration [OR = 2.08; 95% CI 1.34-3.21, OR = 1.65; 95% CI 1.09-2.51, respectively]. On the other hand, previous exposure to cancer therapy was found to reduce the risk of having arthralgia with anti-PD1 or anti-PD-L1 administration [OR = 0.344; 95% CI 0.121-0.974]. Conclusions: Treatment with anti-PD1 or anti-PD-L1 was associated with a spectrum of complications and side effects. Several risk factors have been identified to impact their occurrence. ICI toxicities and risk factors influencing their odds should be recognized and considered in clinical practice, as this could help in individualizing therapeutics regimens and avoiding treatment interruption.

The Role of Intravenous Selexipag in Managing PAH and Bridging Gaps in Oral Treatment: A Narrative Review.

Pulmonary arterial hypertension (PAH) is a rare and potentially fatal condition characterized by progressive increases in blood pressure in the arteries of the lungs. Oral selexipag, approved by the Food and Drug Administration (FDA) in 2015 for the treatment of PAH, targets prostacyclin receptors on pulmonary arterial vascular smooth muscle and endothelial cells to improve blood flow through the lungs and reduce pulmonary vascular resistance. Oral selexipag is effective, but may be discontinued due to factors like side effects, emergency conditions, or inability to take oral medication, potentially leading to severe adverse events, such as rebound pulmonary hypertension and right heart failure. To address treatment interruptions, intravenous (IV) selexipag was introduced as an alternative for patients who are temporarily unable to take oral medications. IV selexipag bypasses hepatic metabolism, requiring a 12.5% higher dose compared to the oral form to achieve similar therapeutic effects. It is administered via IV infusion twice daily over 80minutes, typically for short-term use. However, caution is needed when prescribing selexipag to patients with hepatic or renal issues, and it is contraindicated with strong CYP2C8 inhibitors. A Phase III clinical trial confirmed that switching between oral and IV selexipag was safe, with comparable efficacy and tolerability, though it was limited by small sample size and short duration. Given the risks of treatment interruption and the complexity of managing PAH, this review provides essential insights into the practical use of IV selexipag as a bridging therapy. Furthermore, it calls for larger clinical trials to refine dosing strategies, explore long-term outcomes, and identify patient populations most likely to benefit from IV selexipag.