Optimal Regimen Research Articles

Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.

Identifying effective treatment(s) for sarcopenia and sarcopenic obesity are of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (> 80%), very low carbohydrate (< 5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in pre-clinical and clinical research has escalated within the past 10-15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R, S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans.

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T<0.5ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360mg SC and 180mg IM with a maintenance dose of 360mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

Perioperative non-opioid analgesia strategies after high tibial osteotomy: a systematic review of prospective studies.

Little is known about the optimal analgesia regimen after HTO. Thus, this study systematically reviewed the literature on clinical and patient-reported outcomes of pain management strategies for patients after HTO. A comprehensive search of the PubMed, Cochrane CENTRAL, and CINAHL databases was conducted from inception through September 2023. Studies were included if they evaluated pain reduction with analgesia strategies after HTO and were excluded if they did not report pain control outcomes. Five studies with 217 patients were included. Patients with a multimodal intraoperative injection cocktail to the knee, femoral nerve block (FNB), or adductor canal block (ACB) for HTO had significant improvement in visual analog scale (VAS) and numerical rating scale (NRS) scores in the first 12h postoperatively compared to controls. Patients on duloxetine had significantly lower NRS scores at 1, 7, and 14 days postoperatively and significantly lower nonsteroidal anti-inflammatory drug (NSAID) usage throughout the two-week postoperative period than the control group. Patients receiving an ACB had significantly lower opioid consumption than controls at 12h postoperative. In patients with an FNB or ACB, no significant difference in quadriceps strength or time to straight leg raise postoperatively was observed compared to controls. A multimodal periarticular injection cocktail, FNB, or an ACB effectively reduces pain on the first day after HTO, with an ACB able to reduce opioid consumption on the first postoperative day. Duloxetine combined with an ACB effectively decreases pain for two weeks postoperatively while reducing NSAID consumption in patients after HTO. IV.

Targeting Therapeutic Windows for Rheumatoid Arthritis Prevention.

Rheumatoid arthritis (RA) is a worldwide public health problem. Interventions to delay or prevent the onset of RA have attracted much attention in recent years, and researchers are now exploring various prevention strategies. At present, there is still no unified consensus for RA prevention, but targeting therapeutic windows and implementing interventions for at-risk individuals are extremely important. Due to the limited number of clinical trials on pharmacologic interventions, further studies are needed to explore and establish optimal intervention regimens and effective measures to prevent progression to RA. In this review, we introduce the RA disease process and risk factors, and present research on the use of both Western and Chinese medicine from clinical perspectives regarding RA prevention. Furthermore, we describe several complete and ongoing clinical studies on the use of Chinese herbal formulae for the prevention of RA.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse

BackgroundWe sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid...

Construction and validation of clinical prediction model of acupuncture and moxibustion for Bell's palsy

To establish and validate a clinical prediction model of acupuncture and moxibustion for Bell's palsy so as to provide a tool for predicting the effect of acupuncture and moxibustion on Bell's palsy. A total of 269 patients with Bell's palsy were collected from department of acupuncture, moxibustion and tuina, Shengli Oilfield Central Hospital, neurology department, Shenxian County Central Hospital and department of rehabilitation medicine, Dongying Municipal Hospital of TCM from June 2018 to June 2023. All of these cases were treated with acupuncture and moxibustion. Of them, 182 cases, from department of acupuncture, moxibustion and tuina, Shengli Oilfield Central Hospital and neurology department, Shenxian County Central Hospital, were randomized into a training group (128 cases) and an internal validation group (54 cases); 87 cases from department of rehabilitation medicine, Dongying Municipal Hospital of TCM were assigned to an external validation group. The clinical data of all of the cases were extracted from the electronic medical record information platform. Using SPSS25.0 and R4.2.3, through univariate and multivariate Logistic regression analysis, the independent factors influencing the effects of acupuncture and moxibustion on Bell's palsy were identified. By means of internal and external validations, the receiver operating characteristic curve (ROC), the goodness-of-fit curve (GFC) and the decision curve analysis (DCA) were plotted. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the model were calculated; and its comprehensive performance was evaluated. The results of the multivariate Logistic regression analysis showed that the independent factors for the unsatisfactory effect on Bell's palsy were advanced age, severe symptoms before treatment, no use of steroids within 72 h of onset, and lack of acupuncture-moxibustion therapy during the acute phase or single acupuncture-moxibustion protocol (P<0.05, P<0.01). Based on these factors, nomogram model and online columnar plot prediction tool (https://bmuchen.shinyapps.io/dynnomapp/) were established. The area under the ROC curve of the model was 0.921 (95% CI: 0.877, 0.966), 0.876 (95% CI: 0.787, 0.966), and 0.846 (95% CI: 0.766, 0.926) in the training group, the internal validation group, and the external validation group, respectively, indicating good predictive value. The model showed a satisfactory calibration curve alignment. The decision threshold in the range of 0 to 0.8 provided clinical benefits for participants. The model exhibited the sensitivity from 65.9% to 88.0%, the specificity ranging from 77.3% to 90.7%, the accuracy from 77.8% to 85.9%, the positive predictive value from 83.3% to 90.1%, and the negative predictive value from 70.8% to 78.7%. The comprehensive evaluation indicated a satisfactory clinical application value of the model. The clinical prediction model of acupuncture and moxibustion for Bell's palsy is valuable in its practice and promotion to a certain extent. The predicted results are conductive to clinicians' judgement of the effect of acupuncture and moxibustion for this disease and making effective and high-quality clinical decisions, as well as formulating the optimal therapeutic regimen.

Current view of the management of patients with endometrial hyperplasia: A review

Endometrial hyperplasia (EH) is a spectrum of morphological changes in the endometrium characterized by the proliferation of glands and an increase in the gland-stromal ratio. The relevance of this disease is due to its high prevalence (10–55%). The clinical significance of EH is related to the increased risk of endometrioid cancer. One of the leading causes of EH is absolute or relative hyperestrogenism and progesterone deficiency that does not eliminate the proliferative effect of estrogens. The risk group for EH includes women with early menarche, late menopause, infertility, anovulation, polycystic ovary syndrome, obesity, type 2 diabetes mellitus, hypertension, Lynch syndrome, estrogen-producing ovarian tumors, as well as those receiving estrogen monotherapy or tamoxifen. Most leading experts believe that therapy should include surgery followed by drug therapy aimed at eliminating risk factors to reduce the risk of EH recurrence. Despite numerous research findings demonstrating the benefits of a particular treatment modality and the consequent presence of these modalities in clinical guidelines, the potential benefits of alternative therapies are still being discussed. This issue requires further study and the selection of optimal treatment regimens for patients with EH.

Effectiveness of dose-intensified salvage regimens versus standard-dose chemotherapy on progression-free survival in early progressed follicular lymphoma before autologous stem cell transplantation: a systematic review protocol.

This review will evaluate the effectiveness of dose-intensified versus standard-dose salvage regimens on progression-free survival in early progressed follicular lymphoma before high-dose chemotherapy and autologous stem cell transplantation. Despite the substantial advances in the management of follicular lymphoma, approximately 20% of patients experience progression of the disease within 2 years of induction therapy. These patients have worse outcomes, and autologous stem cell transplantation is deemed to improve outcomes in this context. Little is known about the optimal salvage regimen. Studies must include patients ≥18 years old with early progressed follicular lymphoma who were submitted to autologous stem cell transplantation in subsequent remission. Clinical trials and observational studies will be included. The search strategy will be carried out in MEDLINE (PubMed), Embase (Periódicos CAPES), Scopus, Web of Science, LiLACS, and the Cochrane Library. No date or language restrictions will be imposed. The recommended JBI approach to critical appraisal, study selection, data extraction, and data synthesis will be used. Studies should score at least 50% in accordance with the critical appraisal tool. Data will be pooled whenever possible using the random effects model. Heterogeneity will be assessed using the standard χ2 and I2 tests. A funnel plot will be generated to assess publication bias if there are 10 or more studies included in the meta-analysis. The GRADE approach will be used to rate certainty of evidence. PROSPERO CRD42022373345.

Systematic review and network meta-analysis on the efficacy and safety of parmacotherapy for hand osteoarthritis.

Hand osteoarthritis poses a significant health challenge globally due to its increasing prevalence and the substantial burden on individuals and the society. In current clinical practice, treatment options for hand osteoarthritis encompass a range of approaches, including biological agents, antimetabolic drugs, neuromuscular blockers, anti-inflammatory drugs, hormone medications, pain relievers, new synergistic drugs, and other medications. Despite the diverse array of treatments, determining the optimal regimen remains elusive. This study seeks to conduct a network meta-analysis to assess the effectiveness and safety of various drug intervention measures in the treatment of hand osteoarthritis. The findings aim to provide evidence-based support for the clinical management of hand osteoarthritis. We performed a comprehensive search across PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials was conducted until September 15th, 2022, to identify relevant randomized controlled trials. After meticulous screening and data extraction, the Cochrane Handbook's risk of bias assessment tool was applied to evaluate study quality. Data synthesis was carried out using Stata 15.1 software. 21 studies with data for 3965 patients were meta-analyzed, involving 20 distinct Western medicine agents. GCSB-5, a specific herbal complex that mainly regulate pain in hand osteoarthritis, showed the greatest reduction in pain [WMD = -13.00, 95% CI (-26.69, 0.69)]. CRx-102, s specific medication characterized by its significant effect for relieving joint stiffness symptoms, remarkably mitigated stiffness [WMD = -7.50, 95% CI (-8.90, -6.10)]. Chondroitin sulfate displayed the highest incidence of adverse events [RR = 0.26, 95% CI (0.06, 1.22)]. No substantial variation in functional index for hand osteoarthritis score improvement was identified between distinct agents and placebo. In summary, GCSB-5 and CRx-102 exhibit efficacy in alleviating pain and stiffness in HOA, respectively. However, cautious interpretation of the results is advised. Tailored treatment decisions based on individual contexts are imperative.

Fundamentals of rational antibiotic therapy in outpatient pediatrics

Antibiotics are one of the most prescribed groups of drugs in outpatient pediatric practice. To date, there are still disagreements about the need for the use of antibiotics and the optimal dosage regimen for many infections that pediatricians face daily. The authors conducted a search for publications in the PubMed, Google Scholar and eLibrary by the following keywords: «pediatric,» «antibiotics,» «antibiotic resistance,» «outpatient pediatrics» in English, and «педиатрия,» «антибиотики,» «антибиотикорезистентность,» «амбулаторная педиатрия» in Russian. Recent studies show that uncomplicated childhood infectious diseases in vaccinated children can be treated with shorter courses of antibiotics. The rational use of antibiotics in outpatient pediatric practice is of great importance for reducing resistance to them. Since the first step in choosing treatment tactics is to establish the etiology of the disease, future research should focus more on identifying potential biomarkers and diagnostic tests that allow rapid diagnosis of the etiology of an infectious disease, as well as optimizing the dosage and duration of antibiotic therapy courses.

Exercise adherence for patients with trismus after head and neck cancer treatment.

Head and neck cancer treatment often leads to trismus, a condition characterized by limited mouth opening. Exercise-based therapy is the most common intervention but there are no clear guidelines as to the optimal exercise regimen. Restorabite™ is a portable and force-regulated trismus device designed to enhance exercise adherence. This study explores the adherence to exercises using Restorabite™ in head and neck cancer patients with trismus and identifies facilitators and barriers to exercise therapy. Mixed-methods, prospective cohort study undertaken at a quaternary oncology hospital, in Sydney Australia involving participants diagnosed with head and neck cancer diagnosed with trismus (maximal incisal opening under 35 mm). Patients underwent a 10-week individualized trismus program using Restorabite™ with weekly speech pathology reviews. Exercise adherence was tracked through categorized descriptors. Data were collected prospectively at baseline, during 10 weeks of therapy with Restorabite™, and at 6- and 12-month post-trismus exercise. Participants described facilitators of trismus therapy, and barriers to completing the prescribed exercises. Clinical documentation of these responses was then analyzed using content analysis. One-hundred and thirty-five participants were recruited. During the intervention 69% (n = 93) exercised as recommended, 24% (n = 32) exercised less, and 7% (n = 10) exercised more than recommended. At 6 months post-intervention, 55.5% (n = 75) exercised as recommended, 38.5% (n = 52) exercised less, and 4% (n = 6) exercised more. At 12 months, 36% (n = 49) exercised as recommended, 48% (n = 62) exercised less, and 11% (n = 15) exercised more. MIO increased from a mean of 18.6 mm at baseline, to 30.1 mm at the end of the 10-week intervention. This was maintained at 6 and 12 months (31.7 and 32.1 mm, respectively). Adherence to the exercise program was associated with greater improvement in maximum interincisal opening (p < 0.001). Facilitators of adherence included intrinsic motivation, device portability, perceived functional change, and external support tools. Barriers included cancer treatment toxicities, competing priorities, and health challenges. Positive outcomes included functional improvements, while negative outcomes included increased pain. Seventy-six percent of patients prescribed Restorabite™ performed trismus exercises at or more than the recommended frequency. Facilitators and barriers identified provide insights into factors influencing adherence. Future research should involve comparative studies that compare the adherence and effectiveness of different exercise programs.

Integrated models of population pharmacokinetics and exposure response to optimize dosage regimen for anaprazole sodium in duodenal ulcer

Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. Inaddition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Abstract PO1-01-04: The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [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 PO1-01-04.

Abstract PO5-01-03: Neoadjuvant HER2-targeted regimens with or without anthracyclines for HER2-positive inflammatory breast cancer (IBC): a multicenter retrospective study

Abstract Background Previous randomized clinical trials have shown no significant benefit with the addition of anthracyclines to neoadjuvant treatment for HER2-positive breast cancer. However, these studies did not focus on inflammatory breast cancer (IBC), or a small minority of patients on these trials. The study aims to compare pathologic complete response rates with and without anthracyclines in HER2-positive IBC. Methods We reviewed patients diagnosed with Stage III HER2-positive IBC who underwent neoadjuvant therapy and modified radical mastectomy at MD Anderson Cancer Center and Dana-Farber Cancer Institute between 2014 and 2021. Patients received either docetaxel/trastuzumab/pertuzumab-doxorubicin/cyclophosphamide (THP-AC) or docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP). The primary outcome was pathologic complete response (pCR) rate, defined as ypTisT0/N0. Secondary outcomes included 2-year event-free survival (EFS) and overall survival (OS). Univariate and multivariable analyses were performed with adjustments for clinically relevant covariates. Results Ninety-nine patients were included in the analysis. Thirty-nine patients received TCHP and 60 received THP-AC. The median follow-up time was 3.02 years. Three patients had disease progression during neoadjuvant therapy. pCR rates did not differ between the two regimens (48.7% TCHP vs. 51.7% THP-AC; p = 0.774). Patient’s baseline characteristics did not significantly affect the pCR rate, except for age. A multivariable logistic regression model adjusted for age and estrogen receptor (ER) status did not show a significant association between pCR and regimen (odds ratio 1.232, 95% CI 0.537–2.829 for THP-AC vs. TCHP, p = 0.623). The 2-year EFS rates for TCHP and THP-AC were 57% and 74%, respectively. In univariate analysis, patients who received THP-AC had better EFS than patients who received TCHP (hazard ratio [HR] 0.423, 95% CI 0.214–0.835, p = 0.013). The EFS benefit of THP-AC remained statistically significant after adjusting for age and type of adjuvant therapy in the final reduced multivariable Cox model (HR 0.441, 95% CI 0.220–0.882, p = 0.021). Univariate analysis did not show a significant association between EFS and other baseline covariates (body mass index, race, N and M category, nuclear grade, ER status, and HER2-targeted therapy). OS did not differ between the THP-AC and TCHP groups (HR 0.419, 95% CI 0.122–1.440, p = 0.167). Conclusions The present analysis revealed that a non–anthracycline-containing regimen in HER2-positive IBC patients had no significant difference in pCR rates but was associated with lower 2-year EFS when compared to an anthracycline-containing regimen. However, OS was similar. Limitations of the study include a small sample size, lack of temporal analysis, and retrospective design with its possible selection bias. Further investigation of the optimal neoadjuvant regimen for patients with HER2-positive IBC is warranted. Citation Format: Toshiaki Iwase, Sridhar Nithya, Megumi Kai, Jie Willey, Wenli Dong, Yu Shen, Savitri Krishnamurthy, Anthony Lucci, H. T. Carisa Le-Petross, Azadeh Nasrazadani, Sadia Saleem, Rachel Layman, Vicente Valero, Debu Tripathy, Wendy Woodward, Yee Chung Cheng, Faina Nakhlis, Jennifer Bellon, Filipa Lynce, Naoto Ueno. Neoadjuvant HER2-targeted regimens with or without anthracyclines for HER2-positive inflammatory breast cancer (IBC): a multicenter retrospective 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 PO5-01-03.

The influence of oral antioxidants on men with infertility: a systemic review.

This study aims to investigate the current evidence regarding the impact of oral antioxidant supplementation on semen parameters of infertile men. We conducted a systematic search of PubMed, and Cochrane electronic databases, adhering to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The focus was on studies exploring the effects of antioxidant therapy on infertile men, with an examination of antioxidants in terms of types, doses, rationale for use, and their impact on semen parameters measures. A total of 18 studies that met the inclusion criteria were included in this study. Out of these, 14 studies reported a significantly positive influence of antioxidant therapy on basic semen parameters and advanced sperm function. These comprised 11 randomized clinical trials and 7 prospective studies. Commonly utilized antioxidants included Vitamin E, Vitamin C, carnitines, co-enzyme Q10, N-acetyl cysteine, zinc, selenium, folic acid, and lycopene. Overall, antioxidants generally demonstrate a favorable effect on semen parameters of infertile men. However, further research is necessary to pinpoint the optimal antioxidant regimen that can be applied safely and effectively in clinical practice.

Abstract PO1-01-02: Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study

Abstract Background: The optimal neoadjuvant treatment regimen for HER2-positive breast cancer remains unclear, especially regarding the use of anthracycline. We conducted a prospective phase II study to evaluate sequential neoadjuvant chemotherapy with pegylated liposomal doxorubicin (PLD)/cyclophosphamide followed by taxanes in the presence of full-course trastuzumab/pertuzumab in HER2-positive early breast cancer patients. Methods: In this single-arm, open-label, multicenter, phase II study, eligible patients with confirmed HER2-positive early breast cancer were recruited from four independent hospitals. Patients received four cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (ypT0/is ypN0, tpCR). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, the proportion of patients requiring breast-conserving surgery, and safety. For biomarkers analysis, tumor tissues were collected at baseline and evaluated for Topoisomerase 2 Alpha (TOP2A) expression assessed prospectively with immunohistochemistry (IHC) assay by independent pathologists. Results: Between May 27, 2020 and May 11, 2022, 78 eligible patients were treated and underwent surgery, of whom 42 (53.8%) patients underwent breast-conserving surgery. After neoadjuvant therapy, 47 (60.3%, 95% CI, 48.5%-71.2%) patients achieved a tpCR in the breast and axilla. The bpCR was observed in 49 (62.8%) patients. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. All (100%) patients achieved disease control since the end of the first cycle. No correlations between clinicopathological variables and pathological response were observed. Grade 3 or worse AEs occurred in 35 (44.9%) patients. Nine (11.5%) patients experienced asymptomatic LVEF reduction (≥10% from baseline), but all with a minimum value of &amp;gt;55%. No treatment-related surgical delay or death occurred. For biomarkers analysis, the status of TOP2A was not found to be associated with pCR or 4th-cycle ORR. Conclusions: This dual HER2-blockade plus polychemotherapy as sequential neoadjuvant regimen demonstrates promising anti-tumor activity and acceptable tolerability for patients with HER2-positive breast cancer. Citation Format: Yaping Yang, Liang Jin, Yudong li, Fengxia Gan, Nanyan Rao, Jun Zhang, Ruifa Feng, Zhenzhen Liu, Qiang Liu. Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II 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 PO1-01-02.

Abstract PS09-02: Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer

Abstract Background: Intratumor HER2 heterogeneity (ITH-HER2) predicates resistance to targeted anti-HER2-based therapy, and understanding its impact on response to HER2-directed therapies is particularly important with regimens that rely solely on targeted anti-HER2 therapies without chemotherapy. Methods: To determine the effect of ITH-HER2 on response to therapy, we conducted a single-arm phase II study in which patients (pts) with centrally confirmed HER2+ early-stage breast cancer received six cycles of preoperative T-DM1 plus pertuzumab. Baseline image-guided biopsies allowed central pathology evaluation of ITH HER2, defined as an area with HER2 amplification in &amp;gt;5% but &amp;lt; 50% of tumor cells or a HER2-negative area by FISH. The study met its primary endpoint by demonstrating inferior pathologic complete response (pCR) measured by Residual Cancer Burden (RCB) in the subset of ITH-HER2 pts. Single-cell ERBB2 FISH analysis identified the fraction of ERBB2 nonamplified cells as a factor associated with therapeutic resistance (Metzger et al. Cancer Discovery 2021). Secondary endpoints included event-free survival (EFS), invasive disease-free survival (iDFS), and breast cancer-specific survival (BCSS) by ITH-HER2 status and RCB scores. Results: 163 pts were enrolled and received treatment in the study from Jan 2015 to Jan 2018. Central pathology evaluation of HER2 heterogeneity was successful in 96% (157/163) of cases, with 16 classified as ITH-HER2. RCB-0 or -I rate in the ITH-HER2 vs. not was (25% v. 67%, OR = 5.6, p = 0.002). Median follow-up, including all treated pts (n =163), was 65.4 months (IQR, 60.3-76.6). The 5yr EFS, iDFS, and BCSS were 91% [86.5% - 95.6%], 89.4% [84.5% - 94.5%], and 96% [92.9% - 99.2%], respectively. ITH-HER2 was associated with numerically inferior outcomes for EFS, iDFS, and BCSS (Table 1). The subset of pts with non-ITH-HER2 at baseline (n= 141) and RCB-0 or -I (n = 95/141, 67%) had a 5-yr IDFS of 94.2% [89.3% - 99.3%]. A sensitivity analysis describing survival outcomes by chemotherapy use in the adjuvant setting will be presented at the meeting, along with translational research results evaluating the association of HER2DX assay with pCR and survival outcomes. Conclusions: The inferior pCR rates among cases classified as ITH-HER2 translated into numerically inferior outcomes for both EFS and iDFS. The number of events is small; therefore, our results are exploratory. Selecting pts whose tumors lack ITH-HER2 can increase the chances of achieving RCB 0/I with neoadjuvant TDM1 + pertuzumab. Neoadjuvant TDM1 + pertuzumab, followed by adjuvant HER2-directed therapy without classic chemotherapy agents, could represent an optimal regimen for non-ITH-HER2 pts experiencing RCB 0/I at the time of surgery and deserves further study. Table 1. 5-year survival estimates by ITH-HER2 Citation Format: Otto Metzger, Se Eun Kim, Nabihah Tayob, Giuseppe Viale, Denise Yardley, Aleix Prat, Vandana Abramson, Laura Spring, Adrienne Waks, Eileen Wrabel, Michelle DeMeo, Aditya Bardia, Patrizia Dell'Orto, Leila Russo, Tari King, Franziska Michor, Eric Winer, Kornelia Polyak, Sara Tolaney, Ian Krop. Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage 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 PS09-02.

The Impact of Spironolactone Co-administration on Cyclosporin Initial Dosage Optimization for Pediatric Refractory Nephrotic Syndrome.

Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration. Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen. In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively. The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time.

Factor Xa inhibitors vs. warfarin in patients with Hughes syndrome: a systematic review and meta-analysis of randomized controlled trials.

The optimal treatment regimen for patients with Hughes syndrome remains unclear. Therefore, the authors sought to compare the outcomes of warfarin vs. factor Xa inhibitors in patients with Hughes syndrome. MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) comparing 8 efficacy and safety of warfarin and factor Xa inhibitors in patients with Hughes syndrome. Recurrent thrombosis, all-cause mortality, stroke, adverse reactions, and bleeding were among 10 outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate 11 relative risks (RRs) with 95% CIs. The analysis included 625 patients from four RCTs and one post-hoc analysis. Meta-analysis showed a statistically non-significant difference between factor Xa inhibitors and warfarin in the recurrent thrombosis risk (arterial or venous) [RR 2.77 (95%, CI 0.79, 9.65); P=0.11, I2=50%]. Consistent results were revealed among patients with a previous history of arterial thrombosis [RR 2.76 (95% CI 0.93, 8.16); P=0.75, I2=0%], venous thrombosis [RR 1.71 (95% CI 0.60, 4.84); P=0.31, I2=15%] and patients who were triple antiphospholipid antibodies (aPL) positive [RR 4.12 (95% CI 0.46, 37.10); 21 P=0.21, I2=58%]. Factor Xa inhibitors were significantly associated with an increased risk of stroke [RR 8.51 (95% CI 2.35, 13.82); P=0.47, I2=0%]. Factor Xa inhibitors exhibited an increased risk of stroke among patients with Hughes syndrome. In addition, although not significant, the higher RRs among patients on factor Xa inhibitors may indicate a higher risk of thrombotic events associated with factor Xa inhibitors.