Line Treatment Research Articles

Promoting sleep health during pregnancy for enhancing women’s health: a longitudinal randomized controlled trial combining biological, physiological and psychological measures, Maternal Outcome after THERapy for Sleep (MOTHERS)

BackgroundSleep is vital for maintaining individuals’ physical and mental health and is particularly challenged during pregnancy. More than 70% of women during the gestational period report insomnia symptoms. Sleep dysfunction in the peripartum increases the risk for a cascade of negative health outcomes during late pregnancy, birth, and postpartum. While psychological interventions are considered the first line treatment for sleep difficulties, they are still scarcely offered during pregnancy and there is a lack of longitudinal research combining psychological and physiological indices.MethodsThe present protocol outlines a randomized controlled trial aimed at testing the long-term effectiveness of an automatized digitalized psychoeducational intervention for insomnia for expectant mothers complaining insomnia symptoms without comorbidity. Outcomes include physiological, hormonal, and subjective indices of maternal psychopathology, stress, and emotional processes, and sleep and wellbeing of the family system.The trial is part of a longitudinal study evaluating expectant mothers from early pregnancy (within the 15th gestational week) to 6-months postpartum through 6 observational phases: baseline (BSL), 6- and 12-weeks from BSL (FU1-FU2), 2-to-4 weeks after delivery (FU3), and 3- and 6-months after delivery (FU4-5). We plan to recruit 38 women without sleep difficulties (Group A) and 76 women with sleep difficulties (Group B). Group B will be randomly assigned to digital psychological control intervention (B1) or experimental psychoeducational intervention targeting insomnia (B2). At 3 time points, an ecological-momentary-assessment (EMA) design will be used to collect data on sleep and emotions (diaries), sleep-wake parameters (actigraphy) and stress reactivity (salivary cortisol). We will also test the DNA methylation of genes involved in the stress response as biomarkers of prenatal poor sleep. Information on partner’s insomnia symptoms and new-borns’ sleep will be collected at each stage.DiscussionThe proposed protocol aims at testing an easily accessible evidence-based psychoeducational intervention for expectant mothers to help them improving sleep, health, and wellbeing in the peripartum. The results could improve the understanding and management of sleep difficulties and peripartum depression.Trial registrationThe study protocol has been registered on 22 April 2024 with ClinicalTrials.gov Protocol Registration and Results System (PRS), ID: NCT06379074. Protocol version: April 23, 2024.

Combined low-dose isotretinoin and long-pulsed nd: YAG laser in the treatment of post-acne erythema

Post-acne erythema (PAE) is a bothering skin condition that emerges from inflammatory acne and persists after its resolution. It is characterized by telangiectasia and erythematous macules. the role of 1064-nm Nd: YAG when combined with low-dose isotretinoin in the acne erythema treatment. forty-eight PAE patients were involved in the study. They were divided into two groups; group (A) patients administering a low dose of oral isotretinoin (10 mg/day) and underwent a total of six two-week interval sessions of 1064 ND-YAG laser treatment, group (B) patients administering a low dose of oral isotretinoin (10 mg/day) only. All adverse effects experienced during the course of therapy were documented, and photos were taken before the start of the treatment and following the end of the treatment duration. Following the completion of the therapeutic intervention, a significant improvement in clinical condition was observed in both groups, with more improvement in group (A) compared to group (B) as evidenced by a notable improvement in the score on the Clinician Erythema Assessment Scale (CEAS) and also a significant decrease in the mean value of optical density of the erythema. combined 1064-nm Nd: YAG with low-dose isotretinoin may be an efficient and secure line in the PAE treatment. Also, the combined therapy had superior results when compared to low-dose isotretinoin alone.

FUNCTIONAL OUTCOME OF GIANT CELL TUMOR OF DISTAL RADIUS AFTER EN-BLOC RESECTION AND NON-VASCULARIZED FIBULAR BONE GRAFTING

Introduction: Giant cell Tumors (GCT) are relatively common lesions that are most often encountered in middle aged women [Salunke AA, Shah J, Warikoo V, Chakraborty A, Pokharkar H, Chen Y, Pruthi M, Pandit J. Giant cell tumor of distal radius treated with ulnar translocation and wrist arthrodesis. J Orthop Surg 2017 25(1): 2309499016684972, 2017, https://doi.org/10.1177/2309499016684972 ]. As 25% of these are usually locally aggressive, early diagnosis, and treatment are of paramount importance [Dorfman HD, Czerniak B. Bone Tumors. St. Louis, Mosby (1998)]. Due to the high incidence of local recurrence following simple curettage, it is no longer a preferred line of treatment. In recent times, extended curettage, wide resection or en-bloc resection with bone grafting have supplanted simple curettage [Şirin E, Akgülle AH, Topkar OM, Sofulu Ö, Baykan SE, Erol B. Mid-term results of intralesional extended curettage, cauterization, and polymethylmethacrylate cementation in the treatment of giant cell tumor of bone: A retrospective case series. Acta Orthop Traumatol Turc 54(5): 524–529, 2020, https://doi.org/10.5152/j.aott.2020.19082 ]. Case Scenario: A 22-year-old female patient presented to the OPD with a swelling in her right wrist which she noticed two years back. The swelling gradually increased to the size of a lemon at presentation and was initially painless but eventually became painful. The patient was evaluated based on clinical history, examination, and radiography. A clinical and radiological diagnosis of GCT of the distal radius was made. FNAC was done to confirm the same. Further, the lungs were screened for metastasis. She underwent en-bloc resection of the lesion followed by reconstruction with non-vascularized proximal fibular autograft secured with a DCP and [Formula: see text] -wires. The excised specimen was dispatched for Fig. 1. The swelling at presentation histopathological examination and confirmed to be a Giant Cell Tumor. Regular follow-up schedule was initiated at 2 weeks, 6 weeks, 3 months, 1 year, 36 weeks, and 2 years postoperatively. Her functional outcome was monitored by assessing the wrist range of movements and the Mayo wrist scores. Results: The patient’s Mayo wrist scores showed an increasing trend during follow-up, indicating improved functional outcomes. Recurrence was not noted during the follow-up period. Discussion: Tumor in the distal radius metaphyseoepiphyseal region is commonly associated with extracompartmental involvement, cortical invasion, and pathologic fracture [Yang YF, Wang JW, Huang P, Xu ZH. Distal radius reconstruction with vascularized proximal fibular autograft after en-bloc resection of recurrent giant cell tumor. BMC Musculoskelet Disord 17(1): 346, 2016. https://doi.org/10.1186/s12891-016-1211-8 ]. Hence, curettage is not an optimal method in the distal radius. Thus, wide excision is the optimal choice of treatment. However, this creates a defect at the distal end of the radius. The preferred options for the management of the defect comprise of osteoarticular allografts, vascularized grafts, non-vascularized bone grafts, and custom-made prostheses [Saini R, Bali K, Bachhal V, Mootha AK, Dhillon MS, Gill SS. En bloc excision and autogenous fibular reconstruction for aggressive giant cell tumor of distal radius: a report of 12 cases and review of literature. J Orthop Surg Res 6 : 14, 2011, https://doi.org/10.1186/1749-799X-6-14 ]. Vascularized bone grafts have been proposed to have a better union rate and lesser complication rate as compared to non-vascularized options. Thus, with our case report, we would like to highlight the effectiveness of the non-vascularized proximal fibular autograft in the reconstruction following en bloc excision of the distal radius. Conclusion: Hence, en-bloc resection and non-vascularized fibular bone grafting is a valuable method of treatment of GCTs of the distal radius. It is also associated with low recurrence rates and improved wrist function in the course of follow-up.

Fertility preservation in lymphoma patients treated with immunochemotherapy regimens with or without radiotherapy: results of a retrospective multicenter Italian study (Ferty care)

This is a retrospective, multicentric study, aimed to describe the real-life application of fertility preservation methods during treatment in female lymphoma patients, aged 18–40 years old, diagnosed between Oct 1st/2010 and May 31st/2018. Among 414 women included, median age was 28 years old, histologies were: HL 74%, PMBCL 13%, DLBCL 10%, others 3%. First line treatments were: ABVD in 295 (71%), R-CHOP like in 102 (25%), higher intensity regimens in 17 (4%) cases. Fertility preservation strategies were: GnRHa in 315 (78%), Oral Contraceptive in 41 (10%), oocytes and ovarian tissue cryopreservation in 55 and 42 patients, respectively. After therapy, we observed a restored regular period in 293 (70%) and premature ovarian failure (POF) in 33 (8%), Furthermore we recorded 43 pregnancies, all spontaneous with 5 years median follow-up. Median age at diagnosis and number of lines of treatment correlate with higher rate of amenorrhea, risk of POF and menopause (p < 0.001).

Epigallocatechin gallate modulates ferroptosis through downregulation of tsRNA-13502 in non-small cell lung cancer

Ferroptosis, an iron-dependent regulated cell death mechanism, holds significant promise as a therapeutic strategy in oncology. In the current study, we explored the regulatory effects of epigallocatechin gallate (EGCG), a prominent polyphenol in green tea, on ferroptosis and its potential therapeutic implications for non-small cell lung cancer (NSCLC). Treatment of NSCLC cell lines with varying concentrations of EGCG resulted in a notable suppression of cell proliferation, as evidenced by a reduction in Ki67 immunofluorescence staining. Western blot analyses demonstrated that EGCG treatment led to a decrease in the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) while increasing the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4). These molecular changes were accompanied by an increase in intracellular iron, malondialdehyde (MDA), and reactive oxygen species (ROS), alongside ultrastructural alterations characteristic of ferroptosis. Through small RNA sequencing and RT-qPCR, transfer RNA-derived small RNA 13502 (tsRNA-13502) was identified as a significant target of EGCG action, with its expression being upregulated in NSCLC tissues compared to adjacent non-tumorous tissues. EGCG was found to modulate the ferroptosis pathway by downregulating tsRNA-13502 and altering the expression of key ferroptosis regulators (GPX4/SLC7A11 and ACSL4), thereby promoting the accumulation of iron, MDA, and ROS, and ultimately inducing ferroptosis in NSCLC cells. This study elucidates EGCG’s multifaceted mechanisms of action, underscoring the modulation of ferroptosis as a viable therapeutic approach for enhancing NSCLC treatment outcomes.

Timely care for age-related macular degeneration: a qualitative study among retina specialists in Israel

BackgroundAge-related macular degeneration (AMD) affects quality of life and independence, and its incidence and prevalence are increasing due to ageing of the population. Access to effective timely treatment can improve vision and reduce incidence of blindness. This study aimed to explore the perspectives of ophthalmologists in the Israeli public healthcare system regarding timely treatment of AMD patients.MethodsQualitative semi-structured interviews were conducted in 2020-2021 with 22 senior ophthalmologists, from 10 general hospitals and from two HMOs, representing different geographic regions. All interviewees specialize in retinal diseases and work with AMD patients. Interviews discussed patient pathways involved in the diagnosis and treatment of AMD, access to care, and obstacles to timely care. Thematic analysis was conducted.ResultsBased on the interviews, we describe the usual referral and treatment pathways. Themes included regional disparities, long wait times in some areas, a lack of retina specialists, differences in referral pathways, inappropriate use of emergency department to obtain timely treatment, and second-line treatment not fully covered by insurance, most affecting the weakest segments of the population.ConclusionsLoss of vision incurs high health and societal costs. In the context of insufficient medical manpower in Israel, the healthcare system will need to assess future resources to cope with accumulating burden of AMD cases over time in an ageing population. Precise referral information, and simultaneous referral to imaging and retinal clinics, may minimize delays in treatment. Awareness of AMD symptoms and the importance of early intervention could be highlighted by campaigns, particularly among high-risk groups.Highlights• Interviews with hospital-based and community ophthalmologists showed regional disparities in AMD treatment, with long wait times and a lack of retina specialists in some areas.• Differences in referral pathways, inappropriate use of emergency department to obtain timely treatment, and second line treatment not fully covered by insurance were highlighted.• The healthcare system will need to assess future resources to cope with accumulating burden of AMD cases over time in an ageing population• Precise referral information, and simultaneous referral to imaging and retinal clinics, may minimize delays in treatment.• Awareness of AMD symptoms and the importance of early intervention should be emphasized in high-risk groups.

Switching to an Intravitreal Dexamethasone Implant after Intravitreal Anti-VEGF Therapy for Diabetic Macular Edema: A Review.

Among working-age people, diabetic retinopathy and diabetic macular edema are currently considered the main causes of blindness. Nowadays, intravitreal injections are widely acknowledged as a significant milestone in ophthalmology, especially for the treatment of several retinal diseases, including diabetic macular edema. In particular, anti-vascular endothelial growth factor (VEGF) agents are typically the first line of treatment; however, monthly injections are required, at least, during the loading dosage. Notably, an intravitreal 0.7 mg dexamethasone (DEX) implant (Ozurdex®, AbbVie Inc., North Chicago, IL, USA) is considered a legitimate substitute treatment for diabetic eyes that have not responded to anti-VEGF treatment. In fact, clinical trials and real-life studies have demonstrated the effectiveness and safety of an intravitreal DEX implant in treating such conditions over a period of three to six months. For this reason, wisely selecting diabetic patients might be crucial to decreasing the load of injections in clinics and hospitals. The purpose of this review is to analyze the available scientific literature to highlight the benefits, efficacy, and clinical criteria for choosing whether to switch from intravitreal anti-VEGF therapy to an intravitreal DEX implant in diabetic macular edema.

Gut-directed hypnosis and hypnotherapy for irritable bowel syndrome: a mini-review.

Irritable bowel syndrome (IBS) is a frequent health condition which can be associated with functional disability and reduced health-related quality of life. IBS is classified as a disorder of the brain-gut axis. IBS is a very heterogenous condition with regards to the underlying pathophysiological mechanisms, the clinical picture and the amount of functional impairment. Within a biopsychosocial model of IBS psychosocial factors can play a role in the in the predisposition, triggering and development of chronicity. Somatic or psychosocial or a mixture of both factors might predominate in an individual patient. Gut-directed hypnosis is a special type of medical hypnosis combining standardised gut-directed suggestions (hypnosis) with suggestions tailored to the psychological characteristics of the patient (hypnotherapy). Of brain-gut behavioral therapies, cognitive bahvioral-based interventions and gut-directed hypnosis have the largest evidence for both short-term and long-term efficacy in controlled trials for IBS and are recommended by current European and North American gastroenterology guidelines as second line treatment options. Standardised gut-directed hypnosis is available by audiotapes and can be part of a multicomponent self-management approach by digital health applications. It can be used - based on the patient's preferences-as first line therapy for mild forms of IBS. Severe forms of IBS require face-to-face interdisciplinary management. Standardised gut-directed hypnosis and hypnotherapy tailored to the individual patient can be part of this approach.

Workshop write up: responsible use of parasiticides

Parasiticides are the first line of treatment and prevention of ectoparasitic infections and are among the most prescribed medications in small animal practice. Many ectoparasiticide products are available, with an excellent record of safety and efficacy, significantly improving the quality of life of companion pets. In recent years, there have been concerns about the environmental impact of (and development of resistance to) these drugs. The future of ectoparasite control hinges on the responsible use of ectoparasiticides. In this workshop session, Hany Elsheikha explored ways to improve knowledge, awareness, attitudes and behaviours regarding the judicious usage of parasiticides.

A randomized controlled trial and prospective cohort investigating antivenom for red-bellied black snake envenomation

Introduction Antivenom is first line treatment for snake envenomation worldwide, despite few placebo controlled clinical trials demonstrating effectiveness. We aimed to investigate whether early antivenom in red-bellied black snake (Pseudechis porphyriacus) bites would prevent systemic myotoxicity. Methods We undertook a multicentre randomized placebo-controlled trial of antivenom for red-bellied black snake bites with patients recruited from the Australian Snakebite Project (July 2014 to June 2020). In addition, we report all patients with red-bellied black snake bites during the same period, comparing the same outcomes. Patients over 2 years of age with definite red-bellied black snake bites and early systemic effects were randomized to receive 50 per cent glucose (placebo) or tiger snake antivenom within 6 hours post-bite, or in the cohort group received antivenom determined by the treating clinician. The primary outcome was the proportion of patients with myotoxicity (peak creatine kinase activity >1,000 U/L). Secondary outcomes were: area under the curve of total creatine kinase elevation over 48 hours, presence of venom post-antivenom, and adverse reactions. We analyzed both the randomized control trial patients and the combination of randomized control trial and cohort patients. Results Fifteen patients were recruited to the randomized controlled trial, and a cohort of 68 patients who were not randomized were included in the analysis. After treatment, two of seven patients given placebo had a peak creatine kinase activity >1,000 U/L versus none of the eight given antivenom (difference in favour of antivenom; 29 per cent; 95 per cent confidence interval:-18 per cent to +70 per cent; P = 0.2). The median area under the curve of total creatine kinase elevation over 48 hours in patients given placebo was 0 U/L*h (interquartile range: 0–124 U/L*h), which was not significantly different to those given antivenom: 197 U/L*h (interquartile range: 0–66,353 U/L*h; P = 0.26). Venom was not detected post-antivenom in six patients with measured venom concentrations given antivenom. Two patients given antivenom had immediate hypersensitivity reactions, one severe anaphylaxis, and another had serum sickness. Combining randomized and not randomized patients, three of 36 (8 per cent) administered antivenom less than 6 hours post-bite had a peak creatine kinase activity >1,000 U/L versus 17/47 (36 per cent) patients not receiving antivenom less than 6 hours post-bite (difference in favour of antivenom 29 per cent; 95 per cent confidence interval: 8 per cent to 44 per cent; P < 0.004). Overall, 13/36 (36 per cent) patients administered antivenom within 6 hours had hypersensitivity reactions, six severe anaphylaxis (17 per cent). Discussion We found that early antivenom was effective in red-bellied black snake bites, and only three patients need to be given antivenom within 6 hours to prevent myotoxicity in one (number needed to treat = 3). However, one in three patients administered antivenom developed a hypersensitivity reaction, and one in six had severe anaphylaxis. The major limitation of this study was the small number of patients recruited to the randomized controlled trial. Conclusion Administration of antivenom in red-bellied black snake envenomation within 6 hours post-bite appeared to decrease the proportion of patients with myotoxicity, but a third of patients had adverse reactions.

Efficacy of immunotherapy in first-line treatment for non-small cell lung cancer with HER2 mutation: Results from LC-SCRUM-Asia.

8629 Background: HER2 mutations occur in 2–4% of non-small cell lung cancer (NSCLC) patients. Previous studies with small cohorts have showed poor clinical outcomes in HER2-mutant NSCLC patients treated with immune checkpoint inhibitors (ICIs). However, in these previous studies, ICIs had not been used as the first line treatment in advanced NSCLC. Thus, the clinical outcomes in HER2-mutant NSCLC patients treated with ICIs in the first line treatment are still unclear. Methods: Using a large-scale clinical-genomic database of LC-SCRUM-Asia, the clinical-genomic characteristics and therapeutic outcomes of NSCLC patients harboring HER2 mutations were investigated. Tumor mutation burden (TMB) in tumors with HER2 mutations was compared to tumors with EGFR mutations or ALK fusions. Results: From March 2015 to June 2023, 15,251 NSCLC patients enrolled in LC-SCRUM-Asia. HER2 mutations were detected in 402 patients (2.6%). The most common subtype of HER2 mutations was exon 20 in-frame insertions (Ex20ins) (79%), followed by tyrosine kinase domain other than Ex20ins (10%), extracellular domain (7%) and transmembrane domain (3%). The most common Ex20ins was Y772_A775dupYVMA (66%), followed by G776delinsVC (14%), G778_P780dupGSP (7%). A total of 268 patients had received platinum-based chemotherapy with ICI (Chemo-ICI, n = 95) or without ICI (Chemo-alone, n = 173) until October 2022. The median follow-up periods were 18.5 and 19.9 months in the patients received Chemo-ICI and Chemo-alone, respectively. The patients received Chemo-ICI showed a significantly longer progression-free survival (PFS) compared to those received Chemo-alone (median 8.5 vs 6.3 months, HR [95%CI]: 0.66 [0.50–0.88], p &lt; 0.005). In multivariate analysis, the addition of ICI to platinum-based chemotherapy was an independent better prognostic factor for PFS. There was no significant difference in the overall survival between the patients received Chemo-ICI and Chemo-alone (median 31.1 vs 23.3 months, HR [95%CI]: 0.80 [0.57 – 1.12]). The overall response rates were 34.7% and 35.3% in the patients received Chemo-ICI and Chemo-alone, respectively. Tumors with HER2 mutations showed a higher TMB (median 4.22 mut/Mb) and a higher percentage of TMB≥10 mut/Mb (12.3%) compared to tumors with EGFR mutations (median 2.54 mut/Mb and 1.0%, respectively) or ALK fusions (median 2.52 mut/Mb and 0.8%, respectively). The subtype of HER2 mutations showed no significant difference in the clinical outcomes of Chemo-ICI and Chemo-alone. Conclusions: Our large cohort demonstrated that the addition of ICI to platinum-based chemotherapy as first line treatment may improve PFS in NSCLC patients with HER2 mutations. Relatively high TMB may contribute to prolongation of PFS with ICI.

Efficacy of trifluridine/tipiracil in 3rd or 4th line of treatment in patients with advanced or metastatic colorectal cancer: A real-world data analysis with subgroups exploration.

e15576 Background: Patients with unresectable mCRC can achieve long-term overall survival (OS) thanks to modern systemic treatment and subsequent lines of therapy. With effective 1st, 2nd and next lines of therapy, their condition often allows further lines of treatment. Since publication of RECOURSE study, one of the most frequently used drugs in the 3rd or 4th line is trifluridine/tipiracyl (FTD/TPI). There is limited data on optimal selection of patients in order to obtain the greatest therapeutic gain with the least toxicity. The aim of this study was to find and define groups of patients who would benefit most from this treatment in a real-world mCRC patient population. Methods: Consecutive patients with unresectable or metastatic colorectal cancer (mCRC) started treatment with FTD/TPI between 1/Sep/2019 and 31/Dec/2023. Clinical factors including age, gender, primary location of colorectal cancer, BRAF, RAS and MSI-H status, ECOG performance status, baseline CEA level, location of metastases, response to treatment and AEs occurrence were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Jan/2024. Results: 822 medical records of patients with mCRC were analyzed. In total 261 patients treated with FTD/TPI were enrolled. 204 (78%) patients were treated with FTD/TPI in 3rd line (L3) and 57 (22%) in the 4th line (L4). Patients with RASmt were statistically more numerous in the L3 group; no other statistically significant differences in baseline characteristics was found between L3 and L4 groups. Estimated median OS (mOS) was 10.2 and 14.4 months in L3 and L4 group, respectively; no statistical significance was found between them (p = 0.0866; HR = 1.34, Cl 95% 0.9-1.9). Estimated median PFS (mPFS) was 7.4 and 4.6 months in L3 and L4 group, respectively, and statistically significant differences in mPFS was found in the L3 group in comparison to L4 (p = 0.0079; HR = 0.65, Cl 95% 0.5-0.9). Disease progression (PD) was found in 187 (92%) and 50 (88%) patients in the L3 and L4 group, respectively. PD was most common reason for discontinuing therapy. Most frequent serious AEs of grade 3 or higher were diarrhea, neutropenia and weakness. There were no grade 5 AEs and toxicity rarely led to discontinuation of FTD/TPI therapy. 102 (39%) patients were qualified for next line sequential systemic treatment after L3 or L4. Conclusions: Patients with mCRC who were treated with FTD/TPI in the 3rd line had better PFS than patients treated in 4th line, but mOS was statistically non-significantly better in L4 than L3, which requires further analysis. FTD/TPI is an effective therapy in subsequent lines of treatment for mCRC patients with acceptable toxicity.

Real-world outcomes of osimertinib in Peruvian patients with advanced NSCLC with EGFR T790M-positive: A multi-institutional experience.

e20605 Background: Osimertinib is the standard of care for advanced NSCLC patients with EGFR T790M-positive whose disease has progressed to EGFR TKI therapy, however, the knowledge on the real benefit of these therapies in the Latin American setting remains unclear due the lack of access in the most countries. The aim of this study is to evaluate the outcomes of Osimertinib as sencond line treatment of advanced NSCLC patients with EGFR T790M-positive in a real-world Peruvian setting. Methods: This is a retrospective study of advanced NSCLC patients with EGFR T790M-positive treated with osimertinib at seven Peruvian institutions between July 2018 and May 2023. Outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and OS from the start of first-line treatment to death. Results: We analyzed 41 T790M-positive patients with a median age of 60 years (range 36-87y), most of them were females (65.9%), 17.1% had smoking history and 19.5% biomass exposition as a main risk factor. About diagnosis and clinical features, T790M mutation was detected by liquid biopsy in 29.3% of cases, 36 patients (87.8%) had status performance 0 - 1 (ECOG) and 10 (24.4%) presented brain metastases as progression to the previous line of treatment. About outcomes, the ORR was 70.8%; with a median follow-up of 36 months, the median PFS was 15.2 months (95% IC, 9.6 - 20.7) and median OS since the start osimertinib was 16.3 months (95% IC, 7.6 - 24.9), no differences were found regarding the presence of brain metastases (p = 0.06 and p = 0.32) or type of mutation (p = 0.27 and p = 0.46) in both PFS and OS. Median OS from the start of first-line treatment was 46.6 months (95% IC, 34.5 - 58.7). As supplementary analysis, in the same period of time, 11 T790M-positive patients who did not receive osimertinib as second line of treatment achieved a median OS from the start of first-line treatment of 23.5 months (95% IC, 16.5 - 30.5). This OS was significantly lower compared to those who did receive osimertinib (p = 0.001). Conclusions: This study confirms the efficacy of osimertinib in the real world when used as a second line of treatment in T790M-positive patients, in addition the feasibility of osimertinib in this setting may significantly impact the survival.

Validation of article analysis by ChatGPT: Using a cohort of patients with EGFR mutation-positive non-small cell lung cancer treated with first-line osimertinib.

e20542 Background: The rapid advancement of large language models like ChatGPT has shown potential in various fields, including medicine. However, their applicability in clinical practice, especially in complex medical knowledge interpretation, remains unclear. This study developed a framework for article analysis, retrieval of additional information, and knowledge updating using ChatGPT and tested its clinical validity by comparing it to clinical data. Methods: To simplify the prompt to ChatGPT by selecting monotherapy, patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) who had received 1st -line treatment with Osimertinib, were included in this study. ChatGPT analyzed published FLAURA trial data and developed a scoring system for predicting treatment efficacies for comparison with clinical data. Treatment efficacies were evaluated by using progression-free survival (PFS) and overall survival (OS). ChatGPT searched for papers needed to update the scoring system and extracted 5 papers. To reduce the bias of the search, the extraction of papers by ChatGPT was repeated 10 times and the top 5 papers were selected. The revised scoring system, incorporating insights from these 5 papers, was applied to data from Shizuoka Cancer Center (1st-line osimertinib initiated during 2018-2022.3). The clinical validity of analyses by ChatGPT was evaluated in terms of whether the scoring system reflects clinical practice. Analysis with ChatGPT was performed using GPT4 and natural language prompts. Results: Based on the FLAURA study, ChatGPT created a scoring system consisting of the following items: EGFR mutation type, presence of CNS metastasis, smoking history, sex, and performance status (PS). ChatGPT extracted two prospective studies and three retrospective studies. The scoring system, updated by ChatGPT included EGFR mutation type: exon 19 del /L858R (3/1point), sex: female/male (2/1), smoking history: never-smoker/smoker (2/1), CNS metastases: without/with (2/1), PS 0/1/2/3/4 (2/1/0/-1/-2), age: &lt; 75/≥ 75 years (2/1) PD-L1 expression &lt; 50%/≥ 50% (2/0); liver metastasis, without/with (2/0). Group A showing better efficacies to treatment was defined as patients with a cutoff value of 11 or higher. The scoring system was fitted to validate cohort (140 patients without missing scoring system items). Group A (n = 98, ≥11points) outperformed Group B (n = 42, &lt; 11) in both PFS and OS (medianPFS 22.6 months vs. 9.7 months HR 0.32, 95% CI 0.20-0.50, p &lt; 0.0001, medianOS 54.4 months vs. 21.7 months HR 0.28, 95%CI 0.16-0.49, p &lt; 0.0001). Conclusions: The scoring system created by using ChatGPT reflected the efficacies in a cohort of EGFR-positive NSCLC patients treated with 1st-line osimertinib. The framework for article analysis, retrieval of additional information, and knowledge update using ChatGPT is potentially applicable to other cohorts.

Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial.

e16158 Background: PD-1 or PD-L1 inhibitors plus chemotherapy as the first-line treatment has been proven to be effective in improving the prognosis of advanced biliary tract cancer (BTC) patients. However, there is still considerable demand for further improvement of BTC patients’ prognosis. This trial aims to evaluate the efficacy and safety of Cadonilimab (PD-1/CTLA-4, a bi-specific antibody) plus gemcitabine and cisplatin for patients with advanced BTC in first -line treatment. Methods: In this phase II, single-arm trial, we will enroll 65 patients with previously untreated, unresectable, locally advanced or metastatic BTC, including intrahepatic or extrahepatic cholangiocarcinoma (ICC/ECC) and gallbladder carcinoma (GBC). Participants received Cadonilimab (10 mg/kg, days 1, every three weeks) plus gemcitabine (1000 mg/m2, days 1, 8, Q3W), and cisplatin (25 mg/m2, days 1, 8, Q3W) for up to eight cycles, followed by Cadonilimab (10 mg/kg, days 1, Q3W) until disease progression or unacceptable toxicity. Treatment response was evaluated with image-based assessment according to response evaluation criteria insolid tumors (RECIST) version 1.1. by two experienced experts and further explored multiple methods, such as 3D visualisation and Spectral computed tomography Scan. The primary endpoint was the objective response rate (ORR); the secondary endpoints are disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included associations between response, molecular characteristics, and the immune microenvironment. Results: Between June 30, and January 31, 2024, a total of 30 patients have undergone at least one imaging evaluation. 66.7% of these patients were diagnosed with ICC, 23.3% with GBC, and 10% with ECC. The mean age was 58.4 years, and 60% of the patients were male. 24 (80%) patients had metastasis. Among them, 1 (3.3%) patient acheived complete response (CR), 15 (50%) patients had partial response (PR) and 8 (26.7%) patients presented with stable disease (SD). The ORR was 53.3% and the DCR was 80%. The most common treatment-related adverse events (TRAEs) of any grade were rash (80%) and anaemia (76.7%). Grade 3 TRAEs were observed in 66.7% of the patients. The most frequent grade 3 TRAEs were anaemia (33.3%), and leukocytopenia (33.3%). No grade 4 or 5 events were observed. All patients were microsatellite stable (MSS), and the median TMB was 2.88 (0-109.44) Muts/Mb. Conclusions: Cadonilimab plus gemcitabine and cisplatin shown a promising efficacy and acceptable safety profile as first-line treatment for advanced BTC patients. Clinical trial information: NCT05978609 .

Efficacy of post-lenvatinib treatments in patients (pts) with advanced renal cell carcinoma (aRCC).

4538 Background: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of post-lenvatinib therapies in pts with aRCC. Methods: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Pts having received treatment post lenvatinib exposure were eligible and divided into two cohort: pts post-1st line lenvatinib (2nd line cohort) and pts post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results: Overall, 84 pts received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. All pts received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 9.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most pts were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed pts (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. Most pts received 2nd line everolimus + lenvatinib (97%) (ORR 39%, median TTF 5.9 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most pts were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for pts progressing on lenvatinib-based therapies.

Treatment trends for metastatic urothelial carcinoma across eight Mexican centers: A global oncology perspective.

11171 Background: Urothelial carcinoma represents 3% of new cancer cases globally. Metastatic urothelial carcinoma (mUC) poses a notable challenge to healthcare systems, given its treatment complexity and high mortality. These challenges are magnified in resource-constrained settings. We aim to describe treatment trends for mUC across public and private Mexican centers. Methods: Retrospective study across 8 referral centers. Adults with mUC from 01/2001-12/2021 were included. We assessed clinical records, demographics and comorbidities. We recorded subject eligibility for first line platinum therapy, treatment lines received, and access to novel drugs. Descriptive statistics were used for demographics, treatment details and outcomes. Survival analysis was performed, including Kaplan Meier curves and Cox proportional hazards model. Results: We found 342 cases of mUC, 76% were male, with a median age of 67 years. Median follow-up was 8.4 months. Among those that received a first line (n=223, 65%), regimens used were cisplatin-based chemotherapy (n=100, 45%), carboplatin-based chemotherapy (n=87, 39%), gemcitabine (n=5, 2.2%), immunotherapy (n=4, 1.8%) or unspecified (n=27, 12%). Most causes of cisplatin ineligibility were ECOG ≥2 (41%) and glomerular filtration rate &lt;60 ml/min (33%). Of those who received upfront platinum therapy (n=187), 65% received &gt;3 cycles (n=121), 20% received 2 or 3 cycles (n=38) and 15% received 1 cycle (n=28). Progression as best response was found in 47% (n=88). Avelumab maintenance was only used in 14/99 eligible patients (14.1%). The proportion of individuals receiving a second, third or more lines was 24.6%, 8.8% and 3.5%, respectively. The most common second line treatment was chemotherapy (64.4%) followed by immunotherapy (28.6%). Median overall survival (mOS) was 11.8 months. Treatment notably impacted mOS, favoring those who received a first line(16.7 vs. 4.6 months, p&lt;0.0001). Stratified analysis showed worse mOS for those with visceral disease (17.1 vs 10.3 months, p=0.0065) and ECOG ≥2 (17.6 vs 5.8 months, p&lt;0.001).These features correlated with higher mortality, while first line treatment was associated with lower mortality. Conclusions: These data represent the first effort to delineate treatment trends of mUC in Mexico. First line treatment rates were higher than those described worldwide (35-60%1). Further, cisplatin-eligibility was higher compared to reports of high-income countries. Considerable rates of progression to platinum therapy were found, likely due to aggressive disease. This study highlights the limited access to novel treatments, showed by the infrequent use of avelumab maintenance, immunotherapy or targeted agents. [Table: see text]

DREAMM-7 update: Subgroup analyses from a phase 3 trial of belantamab mafodotin (belamaf) + bortezomib and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM).

7503 Background: Patients (pts) with RRMM and poor prognostic features, such as high-risk cytogenetics or disease refractory to major drug classes, have an unmet need. In DREAMM-7 (NCT04246047), BVd demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit vs standard-of-care (SOC) DVd in pts with RRMM and ≥1 prior line of treatment (LOT). We present further analyses from DREAMM-7 to better understand efficacy in key subgroups. Methods: Pts with ≥1 prior LOT were randomized (1:1) to BVd, B 2.5 mg/kg IV Q3W + V 1.3 mg/m2 (D1, 4, 8, 11 of 21-day cycles [C]; up to 8 C) and d 20 mg (D1, 2, 4, 5, 8, 9, 11, 12; up to 8 C), or DVd, D 16 mg/kg (21-day C: C1-3, Q1W; C4-8, Q3W; Q4W from C9 on)—V and d schedules were the same. The primary endpoint was independent review committee–assessed PFS. Secondary endpoints include overall survival (OS), duration of response, and overall response rate (ORR). Pts with high-risk cytogenetics had ≥1 of t(4;14), t(14;16), or del(17p13). Results: The intent to treat (ITT) included 494 pts: BVd, n=243; DVd, n=251. Median PFS (mPFS) in the ITT was 36.6 mo with BVd vs 13.4 mo with DVd (HR, 0.41; 95% CI, 0.31-0.53; P&lt;.00001). ORR in the ITT was 82.7% (95% CI, 77.4%-87.3%) with BVd and 71.3% (65.3%-76.8%) with DVd. BVd had a higher complete response rate vs DVd (34.6% vs 17.1%). At baseline, 79 pts (33%) in the BVd arm and 87 pts (35%) in the DVd arm were refractory to lenalidomide (LEN). In the LEN-refractory subgroup, mPFS favored BVd (25.0 mo; 95% CI, 18.1 mo to NR) vs DVd (8.6 mo; 6.4-13.5 mo) (HR, 0.31; 95% CI, 0.19-0.48). A higher ORR was reported with BVd (84%; 95% CI, 73.5%-90.9%) vs DVd (61%; 49.9%-71.2%) in LEN-refractory pts. In the BVd and DVd arms, 67 (28%) and 69 (27%) pts had ≥1 high-risk cytogenetic abnormality. In the high-risk cytogenetic subgroup, the mPFS was 33.2 mo (95% CI, 20.3 mo to NR) with BVd vs 10.5 mo (7.6-13.4 mo) with DVd (HR, 0.31; 95% CI, 0.18-0.52). ORR favored BVd (85%; 95% CI, 74.3%-92.6%) vs DVd (67%; 54.3%-77.6%) in this subgroup. Additional data including other subgroup analyses will be presented. More deaths occurred with DVd (35%) than BVd (22%) in the ITT; neither arm reached median OS (HR, 0.57; 95% CI, 0.40-0.80; nominal P=.00049). In the ITT, all pts in both arms had ≥1 AE, and 95% (exposure-adjusted rate [exp-adj], 69 per 100 person-years [PY]) of BVd pts and 76% (exp-adj, 62 per 100 PY) of DVd pts reported grade 3/4 AEs. Serious AEs were reported in 50% (exp-adj, 36 per 100 PY) of BVd pts vs 37% DVd (exp-adj, 30 per 100 PY) pts. Ocular AEs were more frequent with BVd vs DVd (79% vs 29%). Conclusions: In DREAMM-7 BVd demonstrated PFS benefit over DVd with an mPFS improvement of 23 mo in pts with RRMM and ≥1 prior LOT. These results, demonstrating efficacy benefit in key subgroups with a high unmet need, support BVd as a potential new SOC in this setting. Clinical trial information: NCT04246047 .

Overlapping and non-overlapping indications for checkpoint inhibitors in the US.

11057 Background: Since the first checkpoint inhibitor was approved in 2014, this class of cancer drug has revolutionized the treatment of several malignancies. As of January 2024, 11 checkpoint inhibitors have been approved by the US Food and Drug Administration (FDA), each with its own particular indications. We assessed the overlap of approved indications, which has implications for competition and price negotiation by payers. Methods: In this cross-sectional study, we evaluated the FDA-approved indications for 11 checkpoint inhibitors as of January 2024. Indications were defined by cancer tissue type (or mutation status for non-tumor-type indications), stage, and line of treatment (first-line, second-line, third-line, or fourth-or-greater-line). Non-overlapping indications were defined as those with only a single drug approved; for overlapping indications, we tabulated the number of approved drugs. Results: The 11 FDA-approved checkpoint inhibitors were associated with 43 distinct indications, ranging from 2 (retifanlimab, toripalimab, and tremelimumab) to 35 (pembrolizumab) indications per drug. Fifteen (43%) indications were non-overlapping. Pembrolizumab had 11 non-overlapping indications (e.g., certain breast, cervical, and urothelial cancers); all other drugs had between 0 and 2 non-overlapping indications (Table). Among the 28 overlapping indications, 15 (54%) had approvals for 2 drugs, 9 (32%) had approvals for 3 drugs, 3 (11%) had approvals for 4 drugs, and 1 (3%; non-small cell lung cancer) had approvals for 7 of the 11 drugs. Conclusions: Checkpoint inhibitors are FDA-approved for a total of 43 different indications, but most indications were included on the labeling of 3 or fewer drugs in this class. Over 1 in 3 indications had only 1 approved drug, most commonly pembrolizumab. This limited overlap of indications suggests that manufacturers may avoid seeking approval for indications that already have multiple approved drugs of the same class, which may decrease competition and lead to sustained high drug prices. To provide patients with better information about the checkpoint inhibitor most appropriate for their cancer, the NIH could fund, and the FDA could encourage, more direct comparative effectiveness trials. [Table: see text]

LIBRETTO-432: A phase 3 study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive (RET+) NSCLC.

TPS8115 Background: Around 30% of NSCLC patients (pts) present with stage IB-IIIA disease. Standard treatment options are definitive locoregional therapies w/wo chemotherapy (CT) and/or immunotherapy, followed by surveillance until disease recurrence. Targeted therapies are standard for metastatic NSCLC with driver alterations and recent Phase III trial data has emerged in support of their use in the adjuvant setting for stage IB-IIIA (ADAURA and ALINA). RET is a key oncogenic driver in NSCLC and a promising target for adjuvant targeted therapy. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, recently demonstrated longer PFS than platinum-based CT as 1L treatment in pts with RET+ advanced NSCLC (Zhou et al. NEJM 2023). LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating efficacy and safety of adjuvant selpercatinib v Placebo in pts with RET+ Stage IB-IIIA NSCLC following completion of definitive therapies with curative intent, and other adjuvant therapy if indicated (NCT04819100). Methods: Pts (n≈170) will be randomized (1:1) to selpercatinib BID [160mg ≥50kg; 120mg &lt; 50kg], or Placebo, in continuous 28-day cycles for a maximum treatment duration of 3y. Stratification factors include disease stage (IB/II/IIIA) and prior definitive therapy. Treatment will continue until disease recurrence/progression, unacceptable toxicity, or another protocol-defined reason. Crossover is allowed for Placebo pts who experience disease recurrence/progression. Key eligibility criteria include age ≥18 y; histologically confirmed Stage IB/II/IIIA NSCLC; RET+ tumor by PCR/NGS; prior definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed from definitive therapy completion to randomization is 26 w. Key exclusion criteria are evidence of other known oncogenic drivers; SCLC; and disease recurrence/progression following definitive therapy. Primary endpoint is investigator-assessed event-free survival (IAEFS) in the primary analysis population (pts with Stage II-IIIA). EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include IAEFS in the overall population (pts with Stage IB-IIIA) and OS in both primary analysis and overall populations. Non-gated secondary efficacy endpoints include BICR-assessed EFS, BICR and investigator-assessed time to distant disease recurrence in the CNS, and PFS on next line of treatment. Recruitment is ongoing, with enrollment across ~170 sites and 30 countries. Results from this trial will further inform the value of RET inhibition and genomic testing for adjuvant NSCLC pts. Clinical trial information: NCT04819100 .