Management Of Toxicity Research Articles

Local Anesthetics, Local Anesthetic Systemic Toxicity (LAST), and Liposomal Bupivacaine.

Local anesthetics have played a vital role in the multimodal analgesia approach to patient care by decreasing the use of perioperative opioids, enhancing patient satisfaction, decreasing the incidence of postoperative nausea and vomiting, decreasing the length of hospital stay, and reducing the risk of chronic postsurgical pain. The opioid-reduced anesthetic management for perioperative analgesia has been largely successful with the use of local anesthetics during procedures such as peripheral nerve blocks and neuraxial analgesia. It is important that practitioners who use local anesthetics are aware of the risk factors, presentation, and management of local anesthetic systemic toxicity (LAST).

SOGUG-Vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.

4576 Background: Nivolumab (nivo) 1mg/kg plus ipilimumab (ipi) 3mg/kg achieved the highest ORR (42.4%) in refractory metastatic urothelial carcinoma (mUC) with a manageable safety profile. The addition of nivo and ipi subsequently to first-line chemotherapy (CT) could consolidate the clinical benefit. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of ipi 3 mg/kg and nivo 1 mg/kg (Q3W) for 4 cycles followed by nivo maintenance therapy (Q4W) in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line platinum-based CT (at least 4-6 cycles of CT). Autoimmune disease, immune deficiency, and symptomatic brain metastasis were excluded. The primary endpoint is Progression Free Survival (PFS) in intention-to-treat and PD-L1 populations. Secondary endpoints include: objective response rate (ORR), duration of response (DoR), overall survival (OS), overall survival from 1st dose of CT (cOS), progression-free survival from 1st dose of CT (cPFS), safety and translational biomarker analysis. Sample size was estimated using a Simon II stage design for 4-months PFS rate (H0= 40%; H1= 60; α= 0.05; β= 80%; attrition 10%), requiring 25 patients in the 1st stage and up to 66 in total. Here we report the interim analysis for 1st stage. Results: As of January 2024, the 1st accrual stage was completed with 25 evaluable patients. Baseline characteristics are outlined in the table. With a median follow-up of 6.8 months (95% CI: 6.2-10.5), the 4-m PFS rate was 64% (95% CI: 47.7-85.9) and the median PFS was 4.3 months (95% CI: 3.2-NR). The median cPFS was 9.4 months (95% CI: 8-NR). The 6-m OS rate was 76.4% (95% CI: 60-97.2), while median cOS was 15.4 months (95% CI: 15.4-NR). The median duration of treatment was 2.6 months (95% CI: 2.1, 5.7). Nivo and ipi were permanently discontinued due to toxicity in 3 (12%) and 1 (4.2%) patients, respectively. Nivo doses were delayed in 8 (32%) patients and ipi in 3 (12%) for management of toxicity. Grade ≥3 toxicities were reported in 8 (32%) patients, being the most common: Immune-mediated hepatitis (8%), ALT/AST increased (8%) and diarrhea (8%). Conclusions: Maintenance treatment with nivo and ipi showed preliminary efficacy consolidating clinical benefit to CT with a manageable safety profile. The 4-m PFS rate surpassed the futility threshold in the interim analysis and the accrual in Stage II is underway. Final survival results are awaited. Clinical trial information: NCT05219435 . [Table: see text]

A phase IV study of ApricityCARE program for cancer adverse events rapid evaluation to improve treatment outcomes of ethnic/racial minority patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI).

TPS1642 Background: ICI have changed the treatment landscape of NSCLC, with many now FDA approved in not just advanced, but even early-stage disease. With the increase in ICI use, the incidence of immune-related adverse effects (irAEs) has also risen, occurring in up to 16% of ICI-treated patients. Prompt recognition and timely management are necessary to avert potential poor outcomes from direct toxicity and/or early treatment discontinuation. However, existing barriers to access care that disproportionately impact racial and ethnic minority patients may amplify challenges in early, effective management of irAEs. Using technology-enabled health interventions in a culturally competent manner can improve access to health care resources and reduce health disparities. These platforms need to be optimized at the technology and health literacy level of underserved minority communities and adapted to meet the community's needs. Methods: We have designed a multi-center phase IV clinical trial to 1) assess factors related to suboptimal and optimal use of the ApricityCARE, a virtual first-response clinical support (or coverage) to provide 24/7 symptom monitoring and side effect management and 2) determine the impact of the program on ICI toxicity management for NSCLC patients receiving ICIs in a highly diverse community. Eligible patients are those with a confirmed diagnosis of NSCLC who self-identify as a member of an ethnic minority or underserved population, prescribed for any treatment regimen that includes an ICI. The study entails a 50-patient run-in phase with two focus group discussions, stratified on a Likert-type scale based on the frequency of utilization, to determine factors impacting usability of the ApricityCare program. This data will inform optimal implementation of ApricityCare for the randomized phase of the study, where 230 patients will be assigned 1:1 to use of ApricityCare versus standard of care. The run-in phase of the study is currently accruing at Columbia University, and is planned to open at NYU, Mount Sinai, and Montefiore (NCT05812274). Clinical trial information: NCT05812274 .

Electronic patient-reported outcome measures (E-Proms): Results of the H2020 CAPABLE project for patients with metastatic renal cell cancer (mRCC).

11045 Background: E-Proms were shown to benefit both survival and quality of life (QoL) of cancer patients. So far, E-Proms have been mostly implemented as the electronic version of validated, paper-based questionnaires typically administered at follow-up visits. Benefits of telemedicine systems that put symptom reporting within a wider framework embracing a holistic view of a patient's wellbeing are still under-investigated. Methods: Thirty mRCC patients were enrolled in the CAPABLE project intervention cohort during 2023. They were provided with the CAPABLE smartphone app, and with a smartwatch able to monitor vital parameters, physical activity, and sleep. The app acts as a virtual coach, allowing patients to enter any symptom they experience through an interface inspired by both CTACE and proCTCAE. Immediate feedback on whether to contact or not a doctor is generated according to the symptom severity. Patient’s data are matched with the ESMO guidelines for toxicity management, a selection of which was computerized within CAPABLE, and any generated recommendation is shown to the patient. The app manages the symptom follow up, periodically prompting the patient to report any change, and it also promotes activities aimed at improving patients’ education, mental wellbeing and lifestyle. All the entered data may be visualized by doctors at the hospital. The CAPABLE cohort was compared with a control cohort of 77 mRCC patients, enrolled in 2021/2022, who underwent standard care. All patients filled in a set of questionnaires measuring QoL, satisfaction, nutritional and psychological status at enrollment (T0), after 3 months (T1) and after 6 months (T2). A focus group with the CAPABLE cohort was held close to the end of the study. In this report the primary outcome, i.e. EORTC QLQ-C30 score for QoL, is discussed, together with qualitative results from the focus group. Results: The analysis shows an increase in the average QoL for the CAPABLE cohort (80.7 vs 84.9), and a slight decrease in the controls (80 vs 77), with a statistically significant interaction between time and cohort (p < 0.05). Considering QLQ-C30 subscales, CAPABLE patients showed less fatigue and improved social and role functioning. As from the focus group, the app was perceived as effective and useful. More connection with the patient’s clinical pathway and more personalization according to specific treatments were highlighted as needed improvements. Conclusions: This study shows that E-Proms may be effectively included in a comprehensive and engaging system for remote management of mRCC patients. Clinical trial information: NCT06161233 .

Cisplatin and capecitabine as definitive chemoradiation for squamous cell carcinoma of the anal canal (SCCAC): A prospective cohort.

e15503 Background: SCCAC is a rare disease. The standard of care treatment with curative intent is chemoradiation (CRT) with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-Fluoracil (5-FU). Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are frequently unavailable in underdeveloped countries. CCDP and capecitabine are widely available, but there is no prospective data about the feasibility and efficacy of this combination in a definitive SCCAC CRT setting. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP 60mg/m2 D1 and D29 plus Capecitabine 825mg/m2 BID in a population without MMC and infusional pump access. Eligible patients (pts) had T2-4, N0-3, and M0 disease candidates for a full curative CRT regimen. The study data were prospectively collected using REDCap. The primary endpoint was the response by RECIST v.1.1 at 24 weeks(w). The secondary endpoints included toxicity by CTCAE v.5.0, adherence, PFS, and OS. Results: We enrolled 40 consecutive pts between Aug/2019-Dec/2022 in a tertiary cancer center in Brazil. The median age was 61y, the majority were stage III (n = 31, 77.5%) and ECOG 1 (n = 20, 50%). HIV+ serology was observed in 11 pts (27,5%). All patients received CRT, with a median dose of 54Gy in the primary tumor and 45Gy in the elective nodes. At 8w, 35% (n = 14) had a complete response (CR), 50% (n = 20) partial response (PR), and 2.5% (n = 1) progressive disease (PD). At 6 months, CR was observed in 55% (n = 22), PR in 22.5% (n = 9), and PD in 10% (n = 4). 11 pts had disease recurrence, and six died. 1y OS was 94.7% (IC95%: 80.7- 98.6%), and 1y PFS was 75.3% (IC95%:57.8 - 86.3%). Colostomy-free survival at one year was 89.6% (IC95%: 74.7 - 95.9%). Median PFS and OS were not reached with a 2-year median follow-up. Regarding toxicities, radiodermatitis was observed in 94% (n = 36), nausea in 90% (n = 36), and diarrhea in 65% (n = 26). Any grade 3/4 toxicity was present in 27.5% (n = 11), being the majority of radiodermatitis. Four older pts (average age 73y) had definitive suspension of treatment due to toxicity, 06 pts were hospitalized because of a skin infection, and one died due to treatment toxicity. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, older populations require extra attention to early toxicities management.

Usefulness of lipid emulsion for the management of cardiac toxicity in acute flecainide overdose

Usefulness of lipid emulsion for the management of cardiac toxicity in acute flecainide overdose

Mechanisms and management of CAR T toxicity.

Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities.

Current understanding and management of CAR T cell-associated toxicities.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. AsCAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities.

Synergy of plant growth promoting rhizobacteria and silicon in regulation of AgNPs induced stress of rice seedlings

Silver Nanoparticles (AgNPs), as an emerging pollutant, have been receiving significant attention as they deepen the concern regarding the issue of food security. Silicon (Si) and plant growth-promoting rhizobacteria (PGPR) are likely to serve as a sustainable approach to ameliorating abiotic stress and improving plant growth through various mechanisms. The present study aims to evaluate the synergistic effect of Si and PGPRs on growth, physiological, and molecular response in rice seedlings (Oryza sativa) under AgNPs stress. Data suggested that under AgNPs exposure, the root and shoot growth, photosynthetic pigments, antioxidant enzymes (CAT and APX), expression of antioxidant genes (OsAPX and OsGR), silicon transporter (OsLsi2), and auxin hormone-related genes (OsPIN10 and OsYUCCA1) were significantly decreased which accompanied with the overproduction of reactive oxygen species (ROS), nitric oxide (NO) and might be due to higher accumulation of Ag in plant cells. Interestingly, the addition of Si along with the AgNPs enhances the level of ROS generation, thus oxidative stress, which causes severe damage in all the above-tested parameters. On the other hand, application of PGPR alone and along with Si reduced the toxic effect of AgNPs through the improvement of growth, biochemical, and gene regulation (OsAPX and OsGR, OsPIN10 and OsYUCCA1). However, the addition of L-NAME along with PGPR and silicon drastically lowered the AgNPs induced toxicity through lowering the oxidative stress and maintained the overall growth of rice seedlings, which suggests the role of endogenous NO in Si and PGPRs mediated management of AgNPs toxicity in rice seedlings.

Proton pump inhibitors are detrimental to overall survival of patients with glioblastoma: Results from a nationwide real-world evidence database

Abstract Background Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity during glioblastoma (GBM) treatment, but were recently identified as strong inducers of aldehyde dehydrogenase-1A1 (ALDH1A1). ALDH1A1 is a primary metabolic enzyme impacting the outcome of chemotherapy, including temozolomide. High expression of ALDH1A1 is associated with poor prognosis in multiple cancers, suggesting PPIs may have a negative impact on survival. Methods Real-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients with known IDH1/2 mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications including MGMT methylation status, age, sex, duration of corticosteroid use, extent of resection, starting standard-of-care, and PPI use. Results EMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs (51%) had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 vs. 40.1 months). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI: 1.15–2.44], P = .007). Conclusions Evidence from a nationwide cancer registry has suggested PPIs have a negative impact on OS for GBM patients, particularly those with MGMT promoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving chemoradiotherapy.

Co-exposure to gamma-hydroxybutyrate is associated with attenuated neuropsychiatric and stimulant effects of metamfetamine

Introduction Acute metamfetamine toxicity is characterized by stimulant effects and neuropsychiatric disturbance, which is attenuated by gamma-aminobutyric acid type A receptor agonists including benzodiazepines. We utilized clinical registry data to examine the effect of co-exposure to a gamma-aminobutyric acid type B receptor agonist (gamma-hydroxybutyrate) in illicit drug cases with analytically confirmed exposure to metamfetamine. Methods The Emerging Drugs Network of Australia Victoria is an ethics board-approved prospective registry collecting clinical and analytical data (utilising blood samples) on emergency department illicit drug presentations. Comparison groups were defined by analytically confirmed exposure: lone metamfetamine, metamfetamine plus gamma-hydroxybutyrate, metamfetamine plus benzodiazepine, metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine. Cases with co-exposure to other stimulants or sedatives were excluded. Results Median metamfetamine blood concentrations were significantly greater in metamfetamine plus gamma-hydroxybutyrate (n = 153, median = 0.20 mg/L, interquartile range: 0.10–0.32 mg/L, 95 per cent confidence interval: 0.20–0.23 mg/L) and metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine (n = 160, median = 0.20 mg/L, interquartile range: 0.10–0.30 mg/L, 95 per cent confidence interval: 0.20–0.30 mg/L) positive groups compared to gamma-hydroxybutyrate negative groups including metamfetamine (n = 81, median = 0.10 mg/L, interquartile range: 0.05–0.21 mg/L, 95 per cent confidence interval: 0.09–0.18 mg/L) and metamfetamine plus benzodiazepine (n = 73, median = 0.10 mg/L, interquartile range: 0.06–0.20 mg/L, 95 per cent confidence interval: 0.09–0.20 mg/L) groups (P < 0.0004). Presenting heart rate in metamfetamine plus gamma-hydroxybutyrate cases (n = 153, median = 72 beats per minute, interquartile range: 63–86 beats per minute, 95 per cent confidence interval: 70–78 beats per minute) was significantly lower than metamfetamine plus benzodiazepine cases (n = 73, median = 84 beats per minute, interquartile range: 73–98 beats per minute, 95 per cent confidence interval: 80–90 beats per minute, P < 0.0001), and lone metamfetamine cases (n = 81, median = 110 beats per minute, interquartile range: 87–131 beats per minute, 95 per cent confidence interval: 93–120 beats per minute, P < 0.0001). Presenting temperature in metamfetamine plus gamma-hydroxybutyrate cases (median = 35.8 °C, interquartile range: 35.0–36.2 °C, 95 per cent confidence interval 35.6–35.9 °C) was significantly lower than metamfetamine plus benzodiazepine cases (median 36.2 °C, interquartile range 35.7–36.6 °C, 95 per cent confidence interval, 36.0–36.4 °C, P = 0.017), and lone metamfetamine cases (median = 36.5 °C, interquartile range: 35.8–37.1 °C, 95 per cent confidence interval: 36.2–36.7 °C, P < 0.0001). Median presenting systolic blood pressure was significantly (P ≤ 0.001) lower in benzodiazepine positive groups (metamfetamine plus benzodiazepine median = 120 mmHg, interquartile range: 109–132 mmHg, 95 per cent confidence interval: 116–124 mmHg and metamfetamine plus benzodiazepine plus gamma-hydroxybutyrate median = 124 mmHg, interquartile range: 110–137 mmHg, 95 per cent confidence interval: 120–129 mmHg). Incidence of sedation (Glasgow Coma Scale less than 9) was significantly greater in metamfetamine plus gamma-hydroxybutyrate cases (63 per cent) compared to metamfetamine plus benzodiazepine cases (27 per cent, P < 0.0001) and lone metamfetamine cases (15 per cent, P < 0.0001). Incidence of agitation was significantly lower in metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine cases (17 per cent, P < 0.0001) and metamfetamine plus gamma-hydroxybutyrate cases (34 per cent, P = 0.0004) compared to lone metamfetamine cases (58 per cent). Discussion Differences in gamma-aminobutyric acid type A and B receptor physiology may offer a gamma-aminobutyric acid type B agonist-facilitated alternative pharmacodynamic mechanism able to attenuate metamfetamine stimulant and neuropsychiatric toxicity. Conclusion Metamfetamine intoxicated patients with analytically confirmed co-exposure to gamma-hydroxybutyrate had significantly reduced heart rate, body temperature and incidence of agitation compared to patients with lone metamfetamine exposure. Metamfetamine intoxicated patients with analytically confirmed co-exposure to a benzodiazepine had significantly reduced systolic blood pressure compared to patients with lone metamfetamine exposure. We hypothesize that gamma-aminobutyric acid type B receptor agonists may be beneficial in the management of acute metamfetamine toxicity.

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy. The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS. Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management. Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy. What Did We Do? We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines. Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes. The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1. We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual. We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS. What Does This Mean? Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality. To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.

Abstract PO1-10-10: Leveraging technology to optimize symptom management and patient empowerment in routine breast cancer care: implementation of a remote patient monitoring (RPM) pathway across 24 hospitals in Europe

Abstract Background: In clinical trials, RPM has been proven to improve the quality of life and toxicity management for patients receiving systemic treatment and is recommended by international guidelines for routine clinical practice (Di Maio et al., Ann Oncol 2022). Resilience is an oncology-specific RPM system (CE marked, class IIa medical device - mobile application [app] or web interface) which prompts patients to complete a weekly survey including core symptoms from NCI’s PRO-CTCAE questionnaire. Severe or worsening symptoms trigger an alert notification sent to the patient’s care team. In addition to the RPM system, the mobile app offers a large pool of breast cancer-specific educational, self-management, and patient empowerment resources that are personalized according to symptoms reported, disease stage, and treatments received. Here we present the implementation of the Resilience RPM pathway in routine breast cancer care across 24 highly diverse cancer centers. Methods: The implementation process followed a phasic process of Exploration, Preparation, Implementation, and Sustainability that involved close collaboration with technology providers, hospital managers, and care teams at participating cancer centers to coordinate, train, provide technical assistance, and respond to site-specific needs. In addition, monthly webinars offered participating centers an opportunity to share best practices and ways to overcome implementation barriers. A dedicated platform with educational RPM resources for healthcare providers was also available. A process evaluation according to the RE-AIM framework was performed assessing the reach, adoption, implementation, and maintenance of the RPM pathway in routine care. The effectiveness of the pathway was assessed as the ability of the care team to timely respond to alerts. Aggregated system level metric of RPM was collected covering patients with breast cancer under active systemic treatment followed by Resilience from 01-11-2021 to 29-06-2023. Usage data of mobile app resources was tracked from 01-01-2023 to 29-06-2023. Qualitative assessments with focus groups complemented this evaluation. Results: 985 patients, 1% male, 99% female, with a median age of 57y (range: 21-95y; P25-75 38.5-64.5y), were registered across 24 cancer centers. In the last 6 months, the predominant RPM interface chosen by patients was the mobile app (64.1 vs 35.9% for the web platform). Adherence to weekly ePRO reporting was 89.4% in the mobile app and 86.6% in the web platform. The median time from prompt receipt to survey completion was 5.6 hours. The median time for the nurse navigator (NN) to process an alert was 3h50min. Most alerts (91%) were handled directly by NN with 9% requiring the support of a physician. The mean number of individual content consumed per patient was 13 (6744 resources/523 pts, 100% of app users accessed resources). Preferred formats of content delivery were written articles (66.5%), followed by videos (23.1%) and podcasts (10.4%). Most assessed contents referred to: symptom management advice (16%), followed by information about breast cancer disease characteristics (12.5%), supportive care strategies (11.5%), self-guided exercises of mindfulness-based stress reduction (9.4%), and breast cancer treatment journey (8.3%). Qualitative assessments of the app interface, educational content, and self-management programs revealed high levels of satisfaction. The RPM pathway is sustained in the 24 cancer centers and implementation is expanding to additional centers. Conclusion: The Resilience RPM pathway was successfully implemented in routine care across a diverse group of cancer centers with elevated levels of patient engagement and responsiveness from NN. In addition, patients accessed evidence-based educational and empowerment resources, adapted to their medical profile according to their preferences and learning style. Citation Format: Maria Alice Franzoi, Arlindo R Ferreira, Juliette Fanton d'Andon, Thomas Grellety, Eliane Ithurbide-Dachary, Laura Polastro, Laurence Caravella, Joseph Rodriguez, Nathanaelle Leprevier, Elsa Blanchard, Stéphane Remy, Belen d' Ythurbide, Romain Rivoirard, Raoudha Boughzala, Joana M Ribeiro, Ines Vaz Luis. Leveraging technology to optimize symptom management and patient empowerment in routine breast cancer care: implementation of a remote patient monitoring (RPM) pathway across 24 hospitals in Europe [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-10.

Abstract PO3-12-05: Patient (pt)-provider communication challenges about side effects/toxicities from metastatic breast cancer (mBC) treatments

Abstract Introduction: Treatment decisions for ER+/HER2- mBC may be influenced by pt knowledge about treatment side effects, which is shaped by pt-provider communication. We conducted a survey of pts with ER+/HER2- mBC to better understand pt expectations and experiences of treatment toxicities, the extent they were discussed by the pts’ medical team (MT), and the sources/types of side effect information pts prefer. Methods: The 55-question, online ESR1 QUAlity of Life Survey 3 (EQUALS 3) survey was emailed to US pts from the Cure Media Group and authors’ contacts, and posted to private BC Facebook and Twitter pt groups for 2 weeks in June 2023. Eligible pts had ER+/HER2- mBC and reported changing treatments due to progression. Pts received a $10 gift card at survey completion. Survey answers were descriptively summarized. Results: 213 pts completed the survey; they were &amp;lt; 60 yrs of age (77%), White (44%) or Hispanic/Latino (48%), peri-/postmenopausal (54%), and urban-area residents (51%); and had college education (71%) and household income &amp;gt;$50K (66%). Most pts were on 2nd (36%) or 3rd+ (51%) therapy lines. Current mBC treatments were endocrine therapy ± targeted agent (70%), antibody-drug conjugate (8%), chemotherapy (11%), and others (10%). Most pts’ oncologists were female (65%), BC specialists (51%), and from an academic hospital (61%). Only half (49%) of surveyed pts felt extremely/very comfortable discussing side effects with their MT. Although 86% felt well informed about treatment toxicities, MTs did not proactively ask about pts’ greatest concerns on side effects for 15% of pts, nor about what side effects pts would find tolerable or intolerable for 25%. Oncologist/MT inquired about acceptability of side effects most often with treatment change (25%) or when brought up by the pt (20%), and at every single visit for only 19% of pts. Most pts felt extremely prepared for treatment toxicities (78%) and well prepared to manage them (86%), but 19% of pts still felt that their MT did not provide optimal guidance on managing potential side effects. Pt-centered conversations were most often missing: what rare but serious side effects to expect (44%), how to deal with potential side effects (39%), and what common side effects to expect (32%). Pts also reported that the likelihood of experiencing side effects (40%), what rare but serious side effects to expect (39%), and how to deal with potential side effects (28%) were not well presented. To facilitate treatment decisions, pts would like more time discussing treatment options (48%) or side effects (39%); additional written or visual resources on side effects (29%, 23%, respectively) or efficacy (39%, 8%); and the ability to ask questions and receive meaningful answers (39%), talk to other pts (20%), or listen to videos of their stories (11%). Pt testimonials (45%), toxicity descriptions/examples (42%), and toxicity management strategies (36%) were the most common additional forms of information that pts would like to have had on side effects. Conclusion: In this survey of pts with ER+/HER2- mBC, not all pts were comfortable discussing treatment toxicities with their MT, but MTs are mostly addressing side effects. However, there is still room for communication improvement and additional forms of toxicity information are needed for optimal decision-making. Despite generally feeling well prepared for toxicities, a significant proportion of pts report that the range and specifics of side effects and how to manage them were missing or not well presented in MT discussions. This survey highlights the need to improve both provider and pt education with the goal of effectively communicating toxicity specifics of mBC therapies, as well as the need for standardized pt education tools detailing risks and benefits of mBC therapies to assist pts in shared decision-making conversations. Citation Format: Sarah Sammons, Jane Meisel, Timothy Pluard, Kelly Shanahan, Fumiko Chino, Dario Trapani, Dominic Carroll, Monica Kozlowski, Elizabeth Attias, Nicole Kuderer. Patient (pt)-provider communication challenges about side effects/toxicities from metastatic breast cancer (mBC) treatments [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-05.

Insights into Prospects of Novel NSAID Prodrugs in the Management of Gastrointestinal Toxicity: A Perspective Review.

Non-steroidal anti-inflammatory drugs (NSAIDs) have a long history in the healthcare system due to their therapeutic potential. These NSAIDs cause ulcerogenicity, stomach pains, gastrointestinal hemorrhage, mucosa bleeding, and pancreatitis when used moderately and consistently. With researchers, managing the aforementioned adverse effects therapeutically is getting increasingly difficult. One method for creating NSAID moieties with low penetration as well as ulcerogenic properties is the prodrug technique. During the oral consumption of NSAID-prodrugs, ulcerations, intestinal hemorrhage, and mucosa hemorrhage have significantly decreased. Considering this background, this review focussed on NSAID prodrugs as well as their justifications, the pathogenesis of NSAIDs inducing gastrointestinal toxicity, and the role of different antioxidants and spacer groups. Prodrug moieties have more advantages over parent medicines concerning both solubility and lipophilicity. In general, NSAID-class prodrugs can successfully treat both acute and long-term inflammation and aches without causing ulcerotoxicity and related gastrointestinal side effects, which reduces their burden from the pharmacoeconomic perspective.

Addressing the Challenges of PD-1 Targeted Immunotherapy in Cancer Treatment

Background: Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) axis have revolutionized cancer treatment, demonstrating remarkable clinical efficacy across multiple malignancies. However, their broader applicability and therapeutic potential remain constrained by several challenges. Objective: This review aims to provide a comprehensive overview of the current challenges associated with PD-1 targeted immunotherapy, encompassing resistance mechanisms, patient selection, toxicity management, and the development of novel combination strategies. Methods: A comprehensive literature search was conducted across PubMed, Embase, and Web of Science databases to identify and critically analyze studies investigating the challenges and limitations of PD-1 targeted immunotherapy in cancer treatment. Results: The primary challenges identified include: (1) Intrinsic and acquired resistance mechanisms, such as alterations in antigen presentation, tumor microenvironment factors, and immune cell dysfunction; (2) Lack of reliable predictive biomarkers for patient selection and response monitoring; (3) Immune-related adverse events and their effective management; (4) Optimization of combination regimens with other immunotherapies, targeted therapies, or conventional treatments; (5) Financial and accessibility barriers limiting the broader implementation of immunotherapy. Conclusion: PD-1 targeted immunotherapy has transformed cancer treatment, addressing the current challenges is imperative to maximize its therapeutic potential and broaden its applicability. Ongoing research efforts focused on elucidating resistance mechanisms, developing predictive biomarkers, managing toxicities, and exploring novel combination strategies hold promise for overcoming these limitations. Interdisciplinary collaborations and continued investment in immunotherapy research are essential to ensure that the benefits of these groundbreaking therapies are accessible to a wider patient population.

The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials.

Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.

Management of Dry Eye Toxicity After Treatment With 177Lu-PSMA-617 Radioligand Therapy

Treatment options for patients with metastatic castration-resistant prostate cancer include use of radioligand therapy with 177Lu-PSMA-617. 177Lu-PSMA-617 is used to target prostate cancer cells selectively by targeting prostate specific membrane antigen (PSMA); however, PSMA is also expressed on lacrimal glands among other tissues. Herein, we report on a case of a Common Terminology Criteria for Adverse Events version 5 grade 3 dry eye event with concomitant blepharitis after administration of 177Lu-PSMA-617. The patient was managed with neomycin-polymyxin-dexamethasone 3.5-10000-0.1 ophthalmic suspension, artificial tears, lubricating ointments, lid scrubs, and oral antihistamines.

Phytosomes in herbal formulation: an updated review

Phytosomes, a phospholipid-based self-assembled delivery system, can improve oral bioavailability of polyphenolic compounds. These systems, prepared by reacting polyphenolic phytoconstituents with phospholipid, can enhance the passage of lipophilic herbal constituents across the lipid membrane. Phytosomes are used in various herbal drugs like Ginkgo biloba,Camellia sinensis. Recent advancements in phytosomes technology have led to the development of transdermal routes for delivering phytoconstituents. These products are increasingly used in dietary supplements for homeostatic management of inflammation, toxicities, cancers, and weight loss. This technique increases the hydrophilicity of highly lipophilic drugs, making them suitable for drug delivery and allowing hydrophilic phytoconstituents to cross biological membranes. Researchers are exploring the transdermal route as a potential way to deliver phytoconstituents, which are increasingly being used in dietary supplements for homeostatic management of various diseases. We will explore an updated review of Phytosomes in herbal formulation.

Nephroprotective activity of Bilwadi Agada in Cypermethrin Induced Nephrotoxicity in Wistar Rats

Introduction: One of the most potent and widely used formulations of Agadatantra is Bilwadi Agada mentioned in the context of management of envenomation from snake in Ayurveda. The same formulation is also indicated in multiple ailments like poisoning from other animals or insects and even is general conditions of fever. Nephroprotective activity has been demonstrated by Bilwadi Agada and the same was evaluated in this experiment in Wistar rats induced by cypermethrin Aim: To evaluate the nephroprotective activity of Bilwadi Agada in toxicity induced by cypermethrin in wistar albino rats. Materials and Methods: According to OECD guidelines 407, the induction of sub‑acute toxicity was done and effect of Bilwadi Agada was evaluated in wistar albino rats. Results: Degenerative changes in kidneys were found to be increased in lower dose level but moderate reversal was observed in higher dose. Conclusion: The thorough analysis of the results shows that the test drug at double the therapeutic dose causes moderate reversal of toxicant induced changes, thereby providing evidence for presence of nephroprotective activity against cypermethrin toxicity. Thus, therapeutic effects of Bilwadi Agada along with suitable cytoprotectant will be beneficial in the management of Cypermethrin toxicity.