Dose Of Therapy Research Articles

Abstract PO3-11-12: A Pragmatic Randomized Trial Comparing Morning versus Evening Dosing of Endocrine Therapy for Early Breast Cancer: Final Results (REaCT-CHRONO Study)

Abstract Background. Interventions to improve tolerability and adherence to endocrine therapy (ET) are critical to the global improvement of breast cancer (BC) survivorship. The optimal time of day to take ET in terms of quality of life, side effects and adherence is unknown. This study compared a morning dose versus an evening dose of ET in patients with early-stage BC (EBC). Methods. In this pragmatic, open-label, multicenter trial, patients with hormone receptor-positive (HR+) EBC were randomized (1:1) to receive either a morning dose (within 1 hour of the patient wake up time) or an evening dose of ET (within 1 hour of patient bedtime). The primary endpoint was endocrine toxicity/tolerability measured by the change in total Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) score from baseline (commencement of ET) to 12 weeks. The secondary endpoints included: ET toxicity/tolerability and quality of life (FACT-ES and FACT-B) from baseline to 4, 8, 12 and 52 weeks, non-persistence or non-adherence, and patient timing preference. Results. Between June 2021 and March 2022, 245 eligible patients were randomized, 122 to morning (122/245, 49.8%) and 123 to evening (123/245, 50.2%) dosing. Mean age was 61 [standard deviation (sd) 11.9], 181 patients (73.9%) were postmenopausal, 188 (76.7%) received tamoxifen, 58 (23.7%) received an aromatase inhibitor and 22 (9%) received luteinizing hormone-releasing hormone. The mean changes in the FACT-ES score from baseline to 12 weeks following the beginning of ET were -2.0 (sd=14.3) vs -5.4 (sd=16.8) in the morning vs evening arms respectively (Wilcoxon two-sample rank sum test p-value=0.22). Also, the proportion of patients with a clinically important increase (Fisher’s exact test p-value=0.54 0.89) or decrease (p-value= 0.89) in FACT-ES Scores was not statistically different between the arms. At 52 weeks, the mean changes in the FACT-ES score from baseline were -2.5 (sd=18.8) vs -4.8 (sd=15.5) in the morning vs evening arms respectively (p-value=0.23). There was no statistical difference in FACT-ES and FACT-B scores over the 52 weeks of the study. At 12 weeks, 94.5% (69/79) vs 98.7% (78/79) were still taking the ET (p-value=0.2), whereas at 52 weeks, 92.1% (58/63) vs 85.4% (41/48) were still taking ET (p-value=0.36), in the morning vs evening arms respectively. Also, 13.7% (10/73) vs 7.6% (6/79) and 3.2% (2/62) vs 12.5% (6/48) interrupted their ET at least once, in the morning vs evening arms, at 12 and 52 weeks respectively. At week 52, 57.9% (62/107) in the morning arm vs 13.5% (14/104) in the evening arm strongly preferred an ET morning dose, whereas 7.5% (8/107) vs 42.3% (44/104) strongly preferred an ET evening dose. No significant preference changes were observed in dose timing from baseline to week 52 (p-value=0.081). Conclusions. These results suggest no significant difference in quality of life or adherence if ET is taken in the morning or in the evening. Patients should be reassured that they can take ET at their preferred time. Clinical Trial Registration: NCT04864405 Table 1. Mean changes between FACT scores at 12 weeks and 52 weeks from baseline for patients receiving ET morning vs evening dose. A positive value indicates the FACT score increased over time. FACT ES: Endocrine Subscale; FACT B: breast Citation Format: Marie-France Savard, Mohammed Ibrahim, Gregory Pond, Deanna Saunders, Lisa Vandermeer, Lesley Fallowfield, Terry Ng, Arif Awan, Sandeep Sehdev, Ana-Alicia Beltran-Bless, Mark Clemons. A Pragmatic Randomized Trial Comparing Morning versus Evening Dosing of Endocrine Therapy for Early Breast Cancer: Final Results (REaCT-CHRONO Study) [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 PO3-11-12.

Abstract PO1-13-01: Safety profiles of Chinese breast cancer patients who received abemaciclib in MONARCH plus and monarchE study

Abstract Aim: Abemaciclib demonstrated efficacy with tolerable safety profile in Chinese patients (CN pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) and high-risk early breast cancer (EBC). The overall safety profile of abemaciclib in Chinese ABC and EBC pts was consistent with overall population in the MONARCH plus and monarchE studies. To better understand the safety of abemaciclib in CN pts, beyond the previously reported most frequent adverse events (AEs), we report a comprehensive summary of other selected AEs in CN pts in the two trials. Methods: Study designs of MONARCH plus (NCT02763566) and monarchE (NCT03155997) studies were reported previously. To report detailed characteristics of a selected AE profile, including alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased, fatigue, nausea, and vomiting, data were pooled across all CN pts from these two phase 3 studies. The safety population was defined as all randomized patients receiving at least 1 dose of Abemaciclib or endocrine therapy. Data cutoff time is May 18, 2020 and July 1, 2022, respectively. Results: Among 6052 participants in the overall safety population, 875 CN pts (14.5%) were included (512/3100 abemaciclib, 363/2952 placebo). CN pts treated with abemaciclib indicated consistent AE profiles in combination with different endocrine therapies (aromatase inhibitors or Fulvestrant). Detailed characteristics of selected AEs are summarized in table. No deaths due to the selected AEs were reported in CN pts. Conclusion: The selected AEs of abemaciclib group were in low severity with limited grade 3-4 events. Those AEs were tolerable and generally manageable in CN pts in the MONARCH plus and monarchE trials. Citation Format: Zhimin Shao, Qingyuan Zhang, Quchang Ouyang, Qiang Liu, Jifeng Feng, Hui-Ping Li, Xiaojia Wang, Ning Liao, Liu Yang, Qinyi Zhu, Chenxi Qian, Zefei Jiang. Safety profiles of Chinese breast cancer patients who received abemaciclib in MONARCH plus and monarchE study [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 PO1-13-01.

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, > 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE >= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [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 PS17-08.

Abstract PO5-03-06: Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy

Abstract Introduction: Neoadjuvant systemic therapy (NAT) has been the standard-of-care of stage II-III, locally advanced triple-negative breast cancer (TNBC). However, about 50% of TNBC patients achieve a pathological complete response (pCR) to conventional neoadjuvant chemotherapy (NAC)1. Recently approved combination of NAC with the immunotherapy pembrolizumab, has improved the pCR rate by 7.5%2, although with a 44% risk of immune-related adverse reaction3. Aside from the need to develop new therapies with higher efficacy and lower toxicity, a critical barrier to improving TNBC response is the lack of rigorous ways to personally tailor therapeutic regimens. We seek to address this challenge by employing digital twins (i.e., mathematical models that provide virtual representation of individual patients and predict the changes at future time points) to systematically evaluate individual TNBC patient’s response to different NAT regimens, thereby patient-specifically optimizing treatments. Methods: A TNBC cohort (n = 139) from the ARTEMIS trial (NCT02276433)4 was used for this study. All patients received 4 cycles of Adriamycin/Cytoxan (A/C) every 2 weeks, followed by 12 cycles of weekly Taxol or experimental therapy in Phase II trials. All patients had surgery after NAT and post-surgical pathology to assess response status. For each patient, longitudinal MRIs were collected before, during, and after A/C. We have developed digital twins to integrate the longitudinal MRIs with a mechanism-based model to accurately predict TNBC response5. The model was based on a reaction-diffusion equation that describes the change in tumor cellularity due to migration, proliferation, and drug-induced death. With parameters personalized using MRIs, the patient-specific model (i.e., digital twin) significantly improved the accuracy to predict pCR5. We investigated patient-specific treatment optimization on 37 (19 pCR, 18 non-pCR) chemo-sensitive patients (≥ 70% volume decrease after A/C) who received only NAC. We evaluated the effect of altering the A/C/Taxol schedules on patient response. Specifically, each patient’s digital twin was used to predict the patient’s response to 128 clinically reasonable schedules of A/C/Taxol; i.e., 8 candidate A/C schedules combining with 16 candidate Taxol schedules (Table 1). The predicted response (pCR or non-pCR) from each alternative schedule was compared to the patient response from the actual treatment. Results: Without changing the total dose, shortening the duration of A/C/Taxol administration increased the treatment efficacy. The effectiveness of altering the schedules varied substantially in different patients. In particular, 8 patients who had non-pCR responses to their actual treatment were predicted to achieve pCR with the dense-dose Taxol (i.e., 4 cycles Taxol, 2 weeks per cycle), indicating a 21.62% improvement of pCR rate in the cohort. Discussion and conclusion: The preliminary results with our digital twin approach provided a unique opportunity of improving TNBC response to NAT through patient-specific optimization of therapeutic schedules. The ongoing effort focuses on accounting for toxicity and investigating the effects of altering therapy types and doses in combination with the schedules on the patient response. [1] Spring et al., Clin Cancer Res, 2020. [2] Schmid et al., NEJM, 2022. [3] Shah et al., Clin Cancer Res, 2022. [4] Yam et al., Clin Cancer Res, 2021. [5] Wu et al., Cancer Res, 2022. Table 1. Candidate therapeutic schedules Citation Format: Chengyue Wu, Ernesto Lima, Casey Stowers, Zhan Xu, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane Rauch, Thomas Yankeelov. Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy [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 PO5-03-06.

Abstract PO3-04-07: Characterization of response to first-line chemotherapy, trastuzumab, and pertuzumab among patients with de novo metastatic HER2-positive breast cancer

Abstract Background: With optimization of treatment for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer, the proportion of patients diagnosed with HER2+ metastatic breast cancer (MBC) who have de novo disease is expected to increase. The standard first-line treatment for HER2+ metastatic breast cancer (MBC) is the combination of a taxane, trastuzumab (H), and pertuzumab (P) based on the CLEOPATRA trial. Complete response (CR) rates with this regimen range from 13-18%; previous exposure to anti-HER2 therapies is associated with worse outcomes. However, rates of CR, clinicopathologic characteristics associated with CR, duration of response, and most common sites of relapse among patients with de novo HER2+ MBC are not well described. Methods: Patients with de novo HER2+ MBC who received first line HP-based therapy between 5/2011 and 2/2023 with genomic sequencing data available were included in this retrospective study. Clinicopathologic characteristics were abstracted from medical records. The primary objectives were to define CR rate and progression-free survival (PFS). For response assessment, radiology reports from imaging studies (PET or CT) following initiation of therapy were utilized and response was categorized as CR, defined as interpretation of “no evidence of disease,” or non-CR. Progression of disease (PD) was defined as increase in disease burden that led to treatment change. Factors associated with CR were examined using Wilcoxon rank sum test, Pearson’s Chi-squared test, and multivariable logistic regression. PFS was defined as time from first dose of therapy to PD or death and was calculated and compared using Kaplan Meier estimate and log-rank test. Results: We identified 705 patients with HER2+ MBC treated with first-line chemotherapy and HP, of whom 212 had de novo presentation. After exclusion of 40 patients due to incomplete treatment information, 172 patients were included in this analysis. Median age was 49. 108 patients (62.8%) had hormone receptor-positive disease. 149 (86.6%) patients were treated with paclitaxel or nab-paclitaxel, 20 (11.6%) patients were treated with docetaxel, and 3 patients (1.7%) were treated with vinorelbine. Response assessment was based on PET scans in 144/172 patients (83.7%) and CT scans in 28/172 patients (16.3%). 79 patients (45.9%) had CR while 93 patients (54.1%) had non-CR. Factors associated with CR included younger age at diagnosis (median age 42 among CR vs. 53 among non-CR, p=0.01) and HER2 3+ immunohistochemistry (p=0.007); hormone receptor-positivity was not associated with CR (65% CR rate among hormone receptor-positive, 63% among hormone receptor-negative, p=0.9). Among patients with CR, median time to CR was 5.5 months (interquartile range 3.6-10.2 months). In the total cohort, median follow-up was 50.9 months. 117 patients (68.0%) have progressed or died; 55 patients remain on first-line treatment. 37/79 (46.8%) of patients with CR have progressed or died and 80/93 (86.0%) of patients with non-CR have progressed or died (p<0.001). Median PFS was 21.6 months (95% CI 17.9-29.9) but differed by response; median PFS was 67.2 months (95% CI 49.1-not reached) for patients with CR vs.12.9 months (95% CI 10.2-18.9) for patients with non-CR (p< 0.0001). PD by site was as follows: breast/axillary nodes (34.2%), bone only or non-visceral site (25.4%), central nervous system (21.9%), and visceral site (18.4%). Conclusions: Nearly half of patients with de novo HER2+ MBC have CR on first-line chemotherapy and HP; patients with CR have significantly longer PFS compared to patients with non-CR. Future studies evaluating treatment discontinuation following durable CR and the utility of circulating tumor DNA in this setting are needed. Citation Format: Emanuela Ferraro, Atif Khan, George Plitas, Yuan Chen, Mehnaj Ahmed, Julia An, Chau Dang, Mark Robson, Sarat Chandarlapaty, Shanu Modi, Pedram Razavi, Sherry Shen. Characterization of response to first-line chemotherapy, trastuzumab, and pertuzumab among patients with de novo metastatic HER2-positive breast cancer [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 PO3-04-07.

Abstract PO3-19-01: A Randomized Controlled Trial of Metastasis-directed Therapy for Oligometastases in Breast Cancer (OLIGAMI trial; JCOG2110)

Abstract Background: Oligometastases were initially described as a concept bridging localized disease with widespread distant metastases, but a consensus on its definition has yet to be reached. Recently, the term "metastasis-directed therapy" (MDT) was coined to encompass local therapy for distant metastases, including surgery and radiation therapy (RT), especially stereotactic body radiation therapy (SBRT). Though OLIGO-BC1 and SABR-COMET have indicated the potential benefits of MDT for oligometastases, NRG-BR002 revealed no significant difference in progression-free survival (PFS). As a definitive conclusion to this clinical question has not been reached, there is an increasing demand for phase III trials focusing on breast cancer (BC). We planned the JCOG2110, also called as OLIGAMI trial . Design: OLIGAMI trial is a multi-institutional, two-arm, open-label, randomized controlled phase III trial being conducted with the participation of 50 hospitals belonging to Japan Clinical Oncology Group. After the first registration, all patients will be performed in a 12-week, subtype-specific, systemic therapy consisting of CDK4/6 inhibitors with hormonal therapy for luminal BC, docetaxel with trastuzumab and pertuzumab for HER2-positive BC, chemotherapy with immune checkpoint inhibitors for triple-negative BC expressing PD-L1, and olaparib for cases harboring BRCA mutations. For other triple-negative BC, chemotherapy will be administered. If this 12-week systemic therapy dose not cause any progression or complete response, patients proceed to second registration for randomization; arm A continues same systemic therapy alone, and arm B performs MDT followed by same systemic therapy. The MDT will involve either RT or surgery, and RT will involve mainly SBRT and partly conventional RT. Eligibility criteria: OLIGAMI trial will encompass all subtypes of advanced BC. The key criteria of the first registration are as follows: 1) Histologically diagnosed as invasive BC. Biopsy from oligometastases is desirable but not required. 2) Diagnosed with advanced BC with oligometastases by neck to pelvis enhanced CT, FDG-PET, and brain enhanced MRI. 3) Oligometastases defined as: (i) Maximum diameter of each tumor is 3 cm or less. (ii) Total number of 3 or less. (iii) In case of brain metastasis, maximum diameter is 2 cm or less and asymptomatic. 4) The patient with local recurrence is included. 5) De novo stage IV BC is included. The criteria of secondary registration are as follows: 1) The planned number of courses of systemic therapy has been performed. 2) No progression or new distant metastasis by response evaluation. 3) At least one oligometastaseis remains. Specific Aims: OLIGAMI trial aims to confirm the superiority of MDT to systemic therapy for oligometastases of BC. The primary endpoint is overall survival (OS) after randomization, while the secondary endpoints include OS after first registration, PFS, progression site (oligometastases vs. non-oligometastases), PFS specifically related to MDT (restricted arm B), proportion of adverse events and serious adverse events, and the non-progression proportion of health-related quality of life. Statistical methods: The sample size was calculated as 268 to detect 12% of 5-year OS difference with one-sided alpha of 0.05, power of 70%, 3 years of accrual, and 5 years of follow up. Therefore, we assumed the planned sample size for second registration for randomization as 270. We set the number of first registration as 340, assuming that there may be some patients with progression or complete response after the systemic therapy for 12 weeks. Present accrual and target accrual: The patient accrual will start in August 2023. Enrolment of 340 patients for first registration is planned over a 3-year accrual period. Contact information: Principal investigator, Toshiyuki Ishiba, MD. Ph.D. ishiba0313@gmail.com Citation Format: Toshiyuki Ishiba, Ikuno Nishibuchi, Fumitaka Hara, Keita Sasaki, Ryo Sadate, Yuta Sekino, Ryunosuke Machida, Haruhiko Fukuda, Takahiro Kogawa, Tomomi Fujisawa, Yasuaki Sagara, Yoichi Naito, Kaori Terata, Yukinori Ozaki, Akihiko Shimomura, Takehiko Sakai, Chizuko Kanbayashi, Tsuguo Iwatani, Hideo Shigematsu, Kenji Tamura, Takashi Mizowaki, Michio Yoshimura, Naoto Shikama, Tadahiko Shien, Hiroji Iwata. A Randomized Controlled Trial of Metastasis-directed Therapy for Oligometastases in Breast Cancer (OLIGAMI trial; JCOG2110) [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 PO3-19-01.

Relationships between bronchiectasis and time to achieving target trough immunoglobulin G levels in patients with common variable immunodeficiency.

Background: The main treatment of common variable immunodeficiency (CVID) is to maintain immunoglobulin G (IgG) levels within the target range. However, trough IgG levels differ among patients with similar body mass index (BMI) and those receiving the same dose of immunoglobulin replacement therapy (IGRT). A crucial factor that underlies these differences is the presence of extensive bronchiectasis, which is associated with the immunoglobulin salvage pathway. Objective: We compared trough IgG levels in patients with CVID and with and in those without bronchiectasis who had received the same dose of IGRT for 2 years to determine the association of IgG level with infection frequency. Method: This retrospective cohort study included 61 patients with CVID, of whom 21 had bronchiectasis. We reviewed the electronic records for demographic variables, baseline immunoglobulin levels, mean trough IgG levels over 2 years, efficacy levels (trough IgG level - baseline IgG level), the time interval from treatment initiation to achieving the target trough IgG level (700 mg/dL), and the number of infections. Results: The median age of the patients was 39 years (IQR, 27-51), and 29 were women (47.5%). There were no significant differences between the groups in terms of age, age at diagnosis, delay in diagnosis, sex, BMI, IGRT type (subcutaneous or intravenous), and baseline immunoglobulin levels. Trough IgG and efficacy levels were lower (P < 0.001 and P = 0.016, respectively), the time required to achieve the target IgG level was longer in patients with bronchiectasis than in those without bronchiectasis, and this time interval was significantly associated with the infection frequency. Trough IgG and albumin levels were correlated (p = 0.007), with minor differences between the groups (p = 0.04). Conclusion: Bronchiectasis was significantly associated with a longer time to achieve the target IgG levels. These long-term differences between the patients with and those without bronchiectasis have significant clinical implications.

Changes in Serum Interleukin-8 Levels Predict Response to Immune Checkpoint Inhibitors Immunotherapy in Unresectable Hepatocellular Carcinoma Patients.

Effective biomarkers are needed to predict the efficacy of immune checkpoint inhibitors (ICIs) therapy in hepatocellular carcinoma (HCC). We evaluated the early changes in serum interleukin-8 (IL-8) levels as a biomarker of response to ICIs in patients with unresectable HCC. Eighty patients who received ICIs therapy alone or in combination with other treatments for unresectable HCC were included. Serum was collected at baseline and 2-4 weeks after the first dose. Serum IL-8 levels were measured using by ELISA. In the progressive disease (PD) group, serum IL-8 levels increased significantly before the second dose of ICIs therapy compared with baseline levels (P < 0.001). Early changes in serum IL-8 levels were significantly associated with the response to ICIs therapy (P < 0.001). A cutoff value of 8.1% increase over the baseline most effectively predicted the response to ICIs. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy in patients with unresectable HCC. Patients with increases in serum IL-8 levels > 8.1% had significantly shorter overall survival (OS) and progression-free survival (PFS) than those with increases in serum IL-8 levels ≤ 8.1% (P < 0.001). Increases in serum IL-8 levels > 8.1% were independent prognosticators of worse OS (P = 0.003) and PFS (P < 0.001). Early changes in serum IL-8 levels, measured only 2-4 weeks after starting therapy, could predict the response to ICIs therapy, as well as OS and PFS of patients with unresectable HCC. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy and predicted worse OS and PFS.

Efficacy of single-dose versus triple-doses perioperative antimicrobial prophylaxis in patients undergoing laparoscopic cholecystectomy

Introduction: Although debatable, prophylactic antibiotics may be required for patients undergoing cholecystectomy for symptomatic gallstone disease with certain associated risk factors. Our study aimed to perform a non-randomised prospective comparative trial evaluating a single-dose pre-operative antibiotic versus a triple-dose prophylactic post-operative antibiotic in patients with symptomatic uncomplicated cholelithiasis undergoing laparoscopic cholecystectomy. Methodology: This study was a non-randomised prospective comparative study in a single institution. Two hundred patients were enrolled and allocated to two groups. Group A patients were given a single dose of pre-operative prophylactic antibiotic, and Group B patients received a triple dose of prophylactic antibiotic therapy. We also studied the bacteriological profile of bile in all the patients using bile culture and antibiotic sensitivity, and we analysed their association with post-operative surgical site infection (SSI). Results: All the patients were followed up on post-operative days 7 and 30. On post-operative day 7, 2% of patients in Group A and 1% of patients in Group B were found to have SSI, and no statistically significant difference in SSI between the two groups was noted (P = 0.558). On post-operative day 30, no patient was found to have a SSI in either of the two groups. Moreover, post-operative bile culture was obtained in all the cases, and 6% of patients had a positive bile culture. However, none of them developed SSIs on post-operative day 7. Conclusion: A single-dose pre-operative antibiotic is as effective as three perioperative doses in preventing SSI in laparoscopic cholecystectomy for symptomatic, uncomplicated gallstone disease. Our study did not associate port-site SSI with a positive bile culture.

CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone.

Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs. Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism. The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05). The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.

2463: Low-Dose Contribution from Imaging and out-of-field doses in Radiation Therapy for Lymphoma patients

2463: Low-Dose Contribution from Imaging and out-of-field doses in Radiation Therapy for Lymphoma patients

Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community

IntroductionAlthough short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral...

Vonoprazan-based therapies versus PPI-based therapies in patients with H. pylori infection: Systematic review and meta-analyses of randomized controlled trials.

This study aims to evaluate the efficacy and safety of vonoprazan-amoxicillin (VA), vonoprazan-amoxicillin-clarithromycin (VAC), vonoprazan-based bismuth-containing quadruple therapy (VBQT), and PPI-based triple (PAC) or quadruple therapy (PBQT) for H. pylori infection with the consideration of duration of therapy and amoxicillin dose (H: high; L: low). PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for eligible randomized controlled trials (RCTs) up to December 15, 2023. The efficacy outcome was eradication rate, and safety outcomes included the rates of adverse events and treatment discontinuation. Twenty-seven RCTs were included. The pooled eradication rates were 82.8% for VA, 89.1% for VAC, and 91.8% for VBQT, which increased with the higher amoxicillin frequency of administration and extended duration of therapy within each regimen. There were no significant differences in eradication rate when comparing 7-VA versus 7-VAC and 14-VA versus 14-VAC. VA was at least comparable to PAC. The eradication rate did not differ significantly between 10-H-VA or 14-H-VA versus 14-PBQT. 7-L-VAC demonstrated higher eradication rate versus 7-PAC and comparable rate to 14-PAC. 14-VBQT showed higher eradication rates versus 14-PBQT. The adverse events rate was 19.3% for VA, 30.6% for VAC, and 38.4% for VBQT. VA had similar risk of adverse events versus VAC and significantly fewer adverse events compared to PBQT. The treatment discontinuation rate did not differ significantly between treatments. The eradication rate of VBQT was the highest at above 90% followed by VAC and VA. VA was as effective as VAC and superior to PPI-based therapies with favorable safety, highlighting the potential of VA therapy as a promising alternative to traditional PPI-based therapies. VPZ-based triple or quadruple therapies was more effective than PPI-based therapies. Further studies are needed to establish the optimal treatment regimen especially in the western countries.

Stereotactic Body Radiation Therapy for Oligoprogressive Pleural Mesothelioma: Fine-Tuning the Optimal Doses

There is growing evidence of a role of stereotactic body radiation therapy (SBRT) in the treatment of patients with oligoprogressive pleural mesothelioma (PM). The objective of this study was to investigate the optimal radiation therapy doses and schedules in this setting. The records of patients treated with SBRT (>5 Gy per fraction) for oligoprogression of PM at 2 institutions from June 2014 to September 2022 were reviewed. Patients were divided into 2 groups: “intermediate-dose” SBRT (i-SBRT; total dose, 30-36 Gy in 5-6 fractions) and “high-dose” SBRT (h-SBRT; total dose, 45-50 Gy in 4-8 fractions). The comparison between the 2 groups in terms of local control (LC) and toxicity was the primary endpoint of the study. Overall, 23 patients were treated for 25 pleural lesions. All had received upfront chemotherapy with platinum/pemetrexed. Fifteen patients were treated with i-SBRT and 8 patients with h-SBRT. The median equivalent dose was 40 Gy (range, 40-49.6) in the i-SBRT group and 74.46 Gy (range, 64-88) in the h-SBRT group. Six-month, 1-year, and 2-year LC were 100%, 100%, and 80% in the i-SBRT group and 100%, 100%, and 67% in the h-SBRT group, respectively (p =.94). Only 2 patients (1 for each dose group) had a recurrence in the radiation therapy field, both after experiencing a distant relapse. No severe acute and late toxicities were observed in the i-SBRT group, whereas in the h-SBRT group, 2 patients experienced G2 acute and late thoracic pain and 1 patient experienced G2 acute and G3 chronic thoracic pain. In our experience, SBRT is a safe and effective option for selected patients with oligoprogressive PM. Use of intermediate total doses keeping the dose per fraction high seems to offer an excellent LC, avoiding the risk of severe toxicity.

Long-Term Effects of 0.1 mg Recombinant-Human-Thyrotropin-Stimulated Fixed-Dose Radioiodine Therapy in Patients with Recurrent Multinodular Goiter after Surgery.

(1) Background: After thyroid malignancy is ruled out, treatment options for multinodular goiter patients include surgery, levothyroxine suppressive therapy, and 131-I therapy. Surgery effectively reduces goiter size but carries risks of surgical and anesthetic complications. 131-I therapy is the only nonsurgical alternative, but its effectiveness diminishes with goiter size and depends on iodine sufficiency. This study aimed to assess the efficacy and safety of 0.1 mg rhTSH as an adjuvant to a fixed dose of 131-I therapy in patients with a recurrence of large multinodular goiter, several years after the initial thyroidectomy. (2) Methods: 14 patients (13 females and 1 male), aged 59.14 ± 15.44 (range, 35-78 years) received 11mciu of 131-I, 24 h after the administration of 0.1 mg rhTSH. The primary endpoint was the change in thyroid volume (by ultrasound measurements) as well as in the diameter of the predominant nodule during a follow-up period of 10 years. Secondary endpoints were the alterations in thyroid function and potential adverse effects. (3) Results: A significant decrease in the volume of initial thyroid remnants (32.16 ± 16.66 mL) was observed from the first reevaluation (at 4 months, 23.12 ± 11.59 mL) as well as at the end of the follow-up period (10 years, 12.62 ± 8.76 mL), p < 0.01. A significant reduction in the dominant nodule was also observed (from 31.71 ± 10.46 mm in the beginning to 26.67 ± 11.05 mm). (4) Conclusions: Further investigation is needed since this approach could be attractive in terms of minimizing the potential risks of reoperation in these patients.

Effects of Short-, Medium-, and Long-Term Treatment Using Photobiomodulation Therapy Combined with Static Magnetic Field in Aging Rats.

(1) Background: We investigated the detrimental and protective effects of short-, medium, and long-term treatment with different doses of photobiomodulation therapy combined with static magnetic field (PBMT-sMF) during the aging process. (2) Methods: Rats were treated for 15, 30, and 60 weeks with 1, 3, 10, and 30 J of PBMT-sMF or a placebo control. In addition, eight young rats were not subjected to any procedure or treatment and were euthanized at six weeks old. Skin, muscle, bone, kidney, liver, and blood samples were analyzed. (3) Results: No differences between the groups in the morphology of the skin, muscle, and bone was observed. Glutamic pyruvic transaminase levels were increased in the placebo group after 30 and 60 weeks. Glutamic oxaloacetic transaminase levels were also increased in the placebo group after 30 weeks. An increase in creatinine in the PBMT-sMF 3, 10, and 30 J groups compared with that in the young control group was observed. No significant difference in urea levels between the groups was noted. Vascular endothelial growth factor increased in the PBMT-sMF 10 and 30 J groups after 15 weeks of treatment and in the PBMT-sMF 3 J after 60 weeks. Finally, vascular endothelial growth factor decreased in the PBMT-sMF 30 J group after 30 weeks of treatment. (4) Conclusions: PBMT-sMF did not have detrimental effects on the skin, muscle, bone, kidney, or liver after short-, medium-, and long-term treatments in aging rats. In addition, PBMT-sMF may have protective effects on the muscle tissue in aging rats after short- and long-term treatment.

Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Association of Use and Dose of Lipid-Lowering Therapy Post Acute Myocardial Infarction With 5-Year Survival in Older Adults.

Older people are underrepresented in randomized trials. The association between lipid-lowering therapy (LLT) and its intensity after acute myocardial infarction and long-term mortality in this population deserves to be assessed. The FAST-MI (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) program consists of nationwide French surveys including all patients admitted for acute myocardial infarction ≤48 hours from onset over a 1- to 2-month period in 2005, 2010, and 2015, with long-term follow-up. Numerous data were collected and a centralized 10-year follow-up was organized. The present analysis focused on the association between prescription of LLT (atorvastatin ≥40 mg or equivalent, or any combination of statin and ezetimibe) and 5-year mortality in patients aged ≥80 years discharged alive. Cox multivariable analysis and propensity score matching were used to adjust for baseline differences. Among the 2258 patients aged ≥80 years (mean age, 85±4 years; 51% women; 39% ST-segment elevation myocardial infarction; 58% with percutaneous coronary intervention), 415 were discharged without LLT (18%), 866 with conventional doses (38%), and 977 with high-dose LLT (43%). Five-year survival was 36%, 47.5%, and 58%, respectively. Compared with patients without LLT, high-dose LLT was significantly associated with lower 5-year mortality (adjusted hazard ratio, 0.78 [95% CI, 0.66-0.92]), whereas conventional-intensity LLT was not (adjusted hazard ratio, 0.93 [95% CI, 0.80-1.09]). In propensity score-matched cohorts (n=278 receiving high-intensity LLT and n=278 receiving no statins), 5-year survival was 52% with high-intensity LLT at discharge and 42% without statins (hazard ratio, 0.78 [95% CI, 0.62-0.98]). In these observational cohorts, high-intensity LLT at discharge after acute myocardial infarction was associated with reduced all-cause mortality at 5 years in an older adult population. These results suggest that high-intensity LLT should not be denied to patients on the basis of old age. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00673036, NCT01237418, and NCT02566200.

Time-gated single-pixel imaging of Cherenkov emission from a medical linear accelerator.

Cherenkov imaging is an ideal tool for real-time in vivo verification of a radiation therapy dose. Given that radiation is pulsed from a medical linear accelerator (LINAC) together with weak Cherenkov emissions, time-gated high-sensitivity imaging is required for robust measurements. Instead of using an expensive camera system with limited efficiency of detection in each pixel, a single-pixel imaging (SPI) approach that maintains promising sensitivity over the entire spectral band could be used to provide a low-cost and viable alternative. A prototype SPI system was developed and demonstrated here in Cherenkov imaging of LINAC dose delivery to a water tank. Validation experiments were performed using four regular fields and an intensity-modulated radiotherapy (IMRT) delivery plan. The Cherenkov image-based projection percent depth dose curves (pPDDs) were compared to pPDDs simulated by the treatment planning system (TPS), with an overall average error of 0.48, 0.42, 0.65, and 1.08% for the 3, 5, 7, and 9 cm square beams, respectively. The composite image of the IMRT plan achieved a 85.9% pass rate using 3%/3 mm gamma index criteria, in comparing Cherenkov intensity and TPS dose. This study validates the feasibility of applying SPI to the Cherenkov imaging of radiotherapy dose for the first time to our knowledge.

Complete Versus Incomplete Antenatal Corticosteroid Therapy and Number of Doses of Surfactant Used Posnatally: A Single-Center Study

Introduction: Antenatal corticosteroid therapy reduces the risk of developing RDS in premature infants. A single complete course of two doses of betamethasone is recommended between 24 weeks and 34 weeks. There are few data on the neonatal effects of an incomplete course of antenatal corticosteroid therapy. The main objective of our study is to evaluate the effectiveness of a complete versus incomplete course of antenatal corticosteroid therapy on the number of doses of surfactant received postnatally. Methods: This is a single-center retrospective study, including 145 newborns with RDS, divided into 2 groups according to the number of doses of antenatal corticosteroid therapy (1 dose; n = 23 and 2 doses; n = 95). Results: The clinical characteristics of the newborns were similar in the 2 groups. The number of doses of surfactants received postnatally and the severity of RDS are not influenced by the number of doses of antenatal corticosteroid therapy. On the other hand, the number of doses of surfactants received is influenced by the term of birth, the presence of an neonatal sepsis and by resuscitation in the delivery room. The severity of RDS is not influenced either by the interval between the last dose of antenatal corticosteroid therapy and delivery, nor by the cause of prematurity. We did not note any statistically significant difference in clinical improvement (duration of intubation, duration of non-invasive ventilation), the need for postnatal corticosteroid therapy and the risk of occurrence of morbidity and mortality (mortality rate, occurrence of BPD, IVH, severe NEC) between the two groups. Conclusion: just like a complete course, an incomplete course of antenatal corticosteroid therapy can also act on the severity of RDS. Prospective randomized studies should be considered for a formal determination of the neonatal effects of a complete versus incomplete course of antenatal corticosteroid therapy, including the trial BETADOSE.