Clinical Safety Research Articles

Efficacy and Safety of Monopolar Radiofrequency for Tightening the Skin of Aged Faces

Background: Monopolar radiofrequency (RF) has emerged as a promising modality for tightening the skin of aged faces. Although many studies have assessed the efficacy of monopolar RF via the clinical evaluation of photographs, few have examined the long-term effectiveness and safety of this therapy using various skin testing devices. Methods: Twenty women with aged faces participated in this study. After a single monopolar RF treatment, three blinded dermatologists who were not involved in the treatment evaluated its clinical efficacy and safety after 4, 12, and 24 weeks. Skin firmness, fine wrinkles, skin pores, and skin tone were also measured using an indentometer (Courage+Khazaka Electronic GmbH, Köln, Germany) and a facial aging measurement device (Mark-Vu; PSI Plus, Suwon-si, Republic of Korea). Results: Skin laxity in the jowls and nasolabial folds showed significant improvement 12 weeks after the single monopolar RF treatment when evaluated by dermatologists, and this improvement lasted 24 weeks (p < 0.05). Moreover, the participants reported improvement at 4 weeks compared to baseline which lasted 24 weeks (p < 0.05). Skin firmness measured in the cheek increased 4 weeks after treatment and continued to improve during 24 weeks of follow-up (p < 0.01). Although there was a gradual increase in improvement in skin pores, fine wrinkles, and skin tones, there were no statistical differences compared to the baseline. No patients experienced pain during the treatment, and no burns, skin breakdown, or scarring occurred after treatment. Conclusions: A single monopolar RF treatment is effective for females with aged face. A significant improvement in the jowls and nasolabial folds and facial skin firmness was observed between the 4- and 24-week follow-ups without adverse effects.

The clinical effectiveness and safety of Zone III REBOA for resection of sacropelvic tumors in patients older than 70 years

BackgroundREBOA is a method used to manage bleeding during surgery involving sacropelvic tumors. Nevertheless, studies on the use of REBOA among elderly people are lacking. The aim of this research was to investigate the efficacy and safety of Zone III REBOA in patients aged more than 70 years.MethodsA comparative study was conducted using case-control methods. A group of patients, referred to as Group A, who were younger than 70 years was identified and paired with a comparable group of patients, known as Group B, who were older than 70 years. Continuous monitoring of physiological parameters was conducted, and blood samples were collected at consistent intervals.ResultsTotally, 188 participants were enrolled and received REBOA. Among the 188 patients, seventeen were aged more than 70 years. By implementing REBOA, the average amount of blood loss was only 1427 ml. Experiments were also conducted to compare Group A and Group B. No notable differences were observed in terms of demographic variables, systolic blood pressure (SBP), arterial pH, lactate levels, blood creatinine levels, potassium levels, or calcium levels at baseline. Additionally, after the deflation of the REBOA, laboratory test results, which included arterial pH, lactate, potassium concentration, calcium concentration, and blood creatinine concentration, were not significantly different (P > 0.05).ConclusionThis study indicated that in selected patients aged more than 70 years can achieve satisfactory hemodynamic and metabolic stability with Zone III REBOA.Level of evidenceTherapeutic study, Level III.

Cardiovascular adverse events associated with antibody-drug conjugates (ADCs): a pharmacovigilance study based on the FAERS database.

As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD produced by them, as well as a lack of research on the real-world situation. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to ensure its clinical safety application, we analyzed post-marketing data on antitumor ADCs to identify risk factors and drugs associated with the risk of cardiovascular events. We used OpenVigil 2.1 to conduct a database query for adverse events (AEs) reported to the FAERS database between the time the drug was launched and the second quarter of 2023. Cardiovascular adverse events (AEs) were grouped into fourteen narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), and the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and cardiovascular disease (CVD) risk were calculated. In the FAERS database, 1863 AEs associated with CVD we studied were identified in patients receiving ADC therapy. Most reports came from people aged ≥65, but a significant number of cases were found to be unknown. The number of patients with antibody-drug conjugates (ADCs)-related CVD cases aged <18years, 18-64years, and≥ 65years was 52 (2.79%), 586 (31.45%), and 613 (32.90%), respectively. The proportion of female patients (834, 44.77%) was higher than that of male patients (752, 40.37%). Death (770 reports), disability (9 reports), Hospitalization initial or prolonged (407 reports), and life-threatening reactions (187 reports). Of the 770 deaths reported, 103 (31.7%) were associated with brentuximab vedotin, 10 (24.4%) with sacituzumab govitecan, 22 (19.3%) with enfortumab vedotin, and 35 (34.7%) with trastuzumab emtansine.49 (41.2%) cases were associated with polatuzumab vedotin, 62 (29%) with trastuzumab deruxtecan, 423 (54.3%) with gemtuzumab ozogamicin, and 66 (38.8%) with inotuzumab ozogamicin. In a disproportionate number of SMQS, cardiac failure (n = 277) and embolic and thrombotic events, venous (n = 446) were the most frequently reported CVD-related AEs in ADCs. By mining the FAERS database, we provided relevant information on the association between ADC use and cardiovascular-associated AEs. ADCs were associated with increased cardiovascular toxicity, deserving distinct monitoring and appropriate management. Further research is needed to confirm these findings and assess causality.

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

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

Abstract PO1-06-02: Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC)

Abstract Background Within HR+/HER2-negative breast cancer, PAM50 non-luminal tumors (HER2-enriched [HER2-E] and Basal-like) have higher expression of proliferation and immune-related genes and tumor infiltrating lymphocytes and might benefit from immunotherapy. Here, we report the efficacy, safety, and correlative analysis data of the TATEN trial, the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, ABC. Methods TATEN trial (NCT04251169) is a single-arm, multicenter, phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal ABC. Key inclusion criteria include progression to prior CDK4/6 inhibitors (CDK4/6i), presence of measurable disease, no prior chemotherapy for ABC, ECOG 0-1, and non-luminal metastatic disease by PAM50. Included patients received pembrolizumab at 200 mg every 3 weeks (beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2 beginning at cycle 2. The primary endpoint was overall response rate (ORR) according to RECIST V1.1. in patients who received at least one dose of combination treatment and had a first, post-baseline tumor assessment (evaluable population). Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), safety, and predictive biomarkers. The study was based on a Simon two-stage design. Stage I of the trial would be considered successful if at least 6 of 15 patients achieved a partial response and/or complete response. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41%. Metastatic biopsies from patients enrolled in pre-screening were also evaluated for tumor infiltrating lymphocytes (TILs) and were further analyzed with an expression panel of 192 genes, including PDL1 and PD1. Results From July 2020 to December 2021, 132 tumors were screened, and 27 PAM50 non-luminal tumors were identified (20%). Non-luminal tumors trended to have higher PDL1 expression (p=0.090) and TILs (p=0.084) compared to luminal tumors, while no difference was observed for PD1 (p=0.850). Of 20 recruited patients in the study (stage I+II), 18 were evaluable for the primary endpoint. Baseline characteristics were as follows: median age 55 years, ECOG 0 55%, de novo MBC 22%, and visceral disease 72.2%. Eleven patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 subtype, 2 patients had basal-like and 16 HER2-E tumors. At the time of data cut-off (June 2023), 13 patients (72.2%) had stopped their treatment because of progressive disease and 3 (16.6%) due to toxicity. Two patients (11.1%) were still on treatment. The ORR was 61.1 % (11 of 18, 95% CI 35.7-82.7). CBR was 88.9% (16 of 18, 95% CI 65.3-98.6), and median PFS was 8.3 months (95% CI 7.3 – 14.1). Treatment-related adverse events (TRAEs) of any grade (G) occurred in 19 patients (95%), while 45% of patients experienced G3 TRAEs. No G4 or G5 TRAEs were reported in the evaluable population. Gene expression analysis was successful for all recruited patients (n=20). High expression of the PAM50 luminal A signature (p=0.049), and the luminal genes PGR (p=0.028) and RRAGA (p=0.038) were associated with worse PFS (univariate analyses). The pan-leucocyte receptor CD84 (p=0.028) was associated with better PFS (univariate analysis). Conclusions Pembrolizumab in combination with paclitaxel is safe and exhibits promising efficacy outcomes in patients with CDK4/6i resistant HR+/HER2- ABC with a PAM50 non-luminal subtype. Although meeting the criteria for stage II, the enrollment was stopped prematurely due to the lack of funding and pembrolizumab supply. More correlative analyses will be presented at the conference. This study was funded in part by MSD. Citation Format: Aleix Prat, Benedetta Conte, Fara Brasó-Maristany, Nuria Chic, Montserrat Muñoz, Cristina Hernando, Manuel Alva, Silvia Vazquez, Salvador Blanch, Mafalda Oliveira, Esther Fernández, Oleguer Castillo, Patricia Galván, Ángela Aguirre, Esther Sanfeliu, Lorea Villanueva, Tomás Pascual, Eva Ciruelos. Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC) [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 PO1-06-02.

Abstract PO1-24-04: Gedatolisib, a pan-PI3K/mTOR inhibitor, shows superior potency and efficacy relative to other PI3K/AKT/mTOR pathway inhibitors in breast cancer models

Abstract Background: The PI3K, AKT, and mTOR (PAM) pathway is frequently activated in breast cancer (BC). Current standard-of-care therapy options for patients with advanced BC (ABC) include PAM inhibitors (PAMi), such as everolimus and alpelisib, and hormonal therapy, such as letrozole and fulvestrant. Most PAMi selectively inhibit one or only a few PAM pathway components, which can lead to drug resistance. To minimize drug resistance, a more comprehensive inhibition of the multiple PI3K isoforms and downstream mTOR complexes may be required. We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, as well as mTORC1 and mTORC2, can be more effective in BC cells than a PAMi targeting single PAM pathway components. Methods: A panel of BC cell lines with mutated or non-mutated PAM pathway genes (PIK3CA, PTEN, AKT) were evaluated for their sensitivity to gedatolisib and other PAMi (PI3K-α: alpelisib; AKT: capivasertib; mTORC1: everolimus; pan-PI3K/mTOR: gedatolisib). Cell viability, growth rate inhibition, and cell death were evaluated by luciferase- and fluorescence-based assays, both in monolayer cultures and three-dimensional (3D) cultures on reconstituted basement membrane. Flow cytometry analytical assays were conducted to assess DNA synthesis (EdU incorporation), protein synthesis (OPP incorporation), and PAM pathway activity (RPS6 and 4EBP1 phosphorylation). BC xenograft studies evaluating gedatolisib in vivo were also performed. Results: Gedatolisib strongly inhibited PAM pathway activity and reduced cell viability and growth rate in the cell lines tested. Compared to the other PAMi, gedatolisib exhibited more potent and efficacious anti-proliferative and cytotoxic effects, regardless of the cell lines’ PI3K pathway mutational status. Gedatolisib effects were confirmed in 3D culture on reconstituted basement membrane, where gedatolisib inhibited tumor cell spheroid growth and induced regression. Mechanistically, gedatolisib decreased both DNA and protein synthesis more effectively than the other PAMi tested. Gedatolisib also exerted superior anti-proliferative and cytotoxic effects relative to the other PAMi tested in estrogen receptor-positive BC cell lines concomitantly treated with fulvestrant. BC xenografts confirmed growth inhibitory effects of gedatolisib in vivo. Conclusions: The pan-PI3K/mTOR inhibitor, gedatolisib, may more effectively address potential drug resistance mechanisms associated with narrowly targeted PAM inhibitors. Gedatolisib has previously demonstrated promising preliminary clinical efficacy and safety data in ABC in combination with hormonal therapy. A Phase 3 study (VIKTORIA-1) evaluating gedatolisib plus fulvestrant with and without palbociclib is underway in patients with ABC. Citation Format: Stefano Rossetti, Aaron Broege, Adrish Sen, Salmaan Khan, Ian MacNeil, Jhomary Molden, Igor Gorbatchevsky, Brian F. Sullivan, Lance Laing. Gedatolisib, a pan-PI3K/mTOR inhibitor, shows superior potency and efficacy relative to other PI3K/AKT/mTOR pathway inhibitors in breast cancer models [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 PO1-24-04.

Intense pulsed light treatment for the management of meibomian gland dysfunction

Purpose of review Meibomian gland dysfunction (MGD) is one of the most common disorders encountered by ophthalmologists, and its management can prove challenging for both clinicians and patients. Intense pulsed light (IPL), which has been historically used in the field of dermatology, has emerged as a tool to help improve meibomian gland function. The goal of this review is to assess the clinical efficacy, utility, and safety of IPL for the treatment of MGD. Recent findings In recent randomized controlled trials, IPL has been shown to improve meibomian gland function, and subsequently tear film quality and dry eye symptoms. The mechanism of action still remains unclear. Recent literature suggests that IPL may also be used in conjunction with other therapies, such as meibomian gland expression, low-level light therapy, and thermal pulsation. Careful attention should be placed on each patient's Fitzpatrick skin type, as well as protecting the ocular structures to reduce the risk of adverse effects. Cost, accessibility, as well as a limited duration of efficacy may be drawbacks. Summary There is significant evidence supporting that IPL may be used as a potential well tolerated and effective treatment for MGD, though there are certain caveats regarding its long-term efficacy, accessibility, and cost.

Abstract PS02-02: Patient-reported outcomes from the Phase 3 CAPItello-291 trial investigating capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR-positive/HER2-negative advanced breast cancer

Abstract Background: In the Phase 3 CAPItello-291 trial, adding capivasertib (C), a pan-AKT inhibitor, to fulvestrant (F) in patients (pts) with aromatase inhibitor-resistant, HR+/HER2− (HER2− defined as IHC 0, or 1+ or IHC2+/ISH–) advanced breast cancer significantly improved PFS vs placebo (P) + F in the overall (HR 0.60, 95% CI 0.51, 0.71, p&amp;lt; 0.001) and AKT pathway-altered populations (HR 0.50, 95% CI 0.38, 0.65, p&amp;lt; 0.001). The safety profile of C-F was manageable; diarrhea (mostly grade 1) was the most frequent adverse event. Global health status (GHS)/health-related quality of life (HRQoL) was maintained from baseline in both arms; time to deterioration (TTD) favored C-F. We report results from additional patient-reported outcomes (PRO). Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). PRO measures assessed HRQoL, disease-related symptoms, functioning, and patient-reported treatment tolerability using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC QLQ Breast Cancer 23 items (EORTC QLQ-BR23), PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT). PROs were assessed at pre-specified timepoints. Change from baseline was assessed using Mixed Model Repeat Measures (on-treatment scores) for EORTC QLQ-C30 and summarized for EORTC QLQ-BR23; TTD was assessed using the stratified log-rank test for both. Results: Overall, 708 pts were randomized to C-F (n=355) or P-F (n=353). Overall compliance rates with EORTC QLQ-C30 and PGI-TT were 84.5% and 80.6% with C-F and 81.8% and 81.7% with P-F, respectively. Baseline compliance rates with the EORTC QLQ-C30 and PGI-TT were 88.2% and 82.8% with C-F and 87.3% and 83.1% with P-F, respectively. Mean changes from baseline in EORTC QLQ-C30 functional and symptom domain scores were maintained with C-F and P-F, except for diarrhea in the C-F arm, where scores worsened by &amp;gt;10 points (table). TTD analysis showed that HRs favored C-F vs P-F for all functional and symptom domains, except diarrhea (HR 2.75; 95% CI 2.01, 3.81), which favored P-F (table). Median TTD of diarrhea was shorter with C-F vs P-F in line with the C-F safety profile. Diarrhea with C-F was generally manageable, and discontinuations due to diarrhea were low (2.0%; n=7/355). For PGI-TT, most pts reported that they were ‘not at all’ or ‘a little bit’ bothered by the side effects of cancer therapy. Over the first 6 months, the proportion of pts reporting to be ‘somewhat’, ‘quite a bit’, or ‘very much’ bothered by side effects was higher for C-F vs P-F, with between-arm differences being highest in the first 2 cycles. Results from EORTC QLQ-BR23 domains will be presented at the meeting. Conclusions: Pts treated with C-F maintained HRQoL for longer than pts treated with P-F on all EORTC QLQ-C30 functional and symptom domain scores, except diarrhea. Worsening of diarrhea was observed with C-F, consistent with the safety profile of C, but events appeared tolerable and did not negatively impact GHS/HRQoL. Together with the clinical efficacy and manageable safety profile of C-F, the PRO results from the CAPItello-291 trial further support a positive benefit–risk profile of the combination in this population. https://clinicaltrials.gov/: NCT04305496. Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Citation Format: Hope Rugo, Mafalda Oliveira, Sacha Howell, Florence Dalenc, Javier Cortés, Henry Gómez, Xichun Hu, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Park, Joo Hyuk Sohn, Eriko Tokunaga, Masakazu Toi, Samih Yousef, Lyudmila Zhukova, Marta Fulford, Haylee Andrews, Ian Wadsworth, Celina D’Cruz, Nicholas Turner. Patient-reported outcomes from the Phase 3 CAPItello-291 trial investigating capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR-positive/HER2-negative advanced 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 PS02-02.

Abstract PS12-06: A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy as treatment for hormone receptor-positive metastatic breast cancer. Preclinical studies suggest CDK4/6 inhibitor monotherapy might also be effective in a subset of triple-negative breast cancers (TNBCs), including those that express a functional retinoblastoma (RB) protein and/or those of the Luminal Androgen Receptor (LAR) subtype. Currently, the clinical activity of CDK4/6 inhibitor therapy in TNBC has not been reported. Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with locally advanced or metastatic TNBC. Key eligibility criteria included: (i) Measurable disease by RECIST 1.1; (ii) Between 1-3 prior lines of systemic therapy for advanced TNBC; (iii) RB-positive tumor (defined as ≥ 50% of tumor cells staining positive for RB by immunohistochemistry [archival or fresh sample] on central testing); (iv) ECOG PS 0/1. Patients were treated with abemaciclib 200 mg orally (28-day cycles) twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or death. Tumor biopsies were mandatory at baseline and C2D1 if tumor tissue was safely accessible. The primary outcome was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR: CR + PR + SD ≥ 24 weeks), and safety and tolerability. The study had a two-stage design. Thirteen patients were enrolled in the first stage, with the plan to enrol a further 25 patients if at least one objective response was observed. Results: One unconfirmed partial response was observed in stage 1, and a total of 27 patients were enrolled before the trial was closed early due to slow accrual. The median age was 61 years and patients had received a median of 2 prior lines of systemic therapy for metastatic disease. Twelve patients had received prior immunotherapy. After a median follow-up of 28.5 months, the confirmed ORR was 0% and the CBR was 15%, with 4 of 27 patients experiencing stable disease for ≥ 24 weeks. The median PFS was 1.94 months (95% CI: 1.8 – 11.5 months), and the median OS was 8.44 months (95% CI: 4.6 – 15.6 months). There was no significant difference in PFS or OS between patients with PD-L1-positive versus PD-L1-negative disease, or Androgen Receptor (AR) positive versus negative tumors by immunohistochemistry. The most common adverse events of grade 2 or higher were diarrhea (41%), neutropenia (41%), anemia (30%), and nausea (30%). RNA-sequencing of baseline biopsies has been performed to identify biomarkers associated with clinical benefit, and results will be presented at the meeting. Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with Rb+ metastatic TNBC. This finding suggests that future trials of CDK4/6 inhibition as monotherapy in TNBC are not warranted. Citation Format: Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Ayesha Mohammed-Abreu, Julie Kasparian, Timothy Erick, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nabihah Tayob, Stuart Schnitt, Nancy Lin, Sara Tolaney. A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic 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 PS12-06.

Abstract PO3-20-06: TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer

Abstract Background: Despite being a rare presentation of breast cancer, inflammatory breast cancer (IBC) is responsible for up to 10% of all breast cancer-related deaths. Most IBCs express HER2, with up to 40% of all IBCs being HER2-positive and 40% being HER2-low. Additionally, IBC more often exhibits PD-L1 expression compared to non-IBC, suggesting a preeminent role for immune evasion in the development and progression of IBC. No systemic treatment approaches have been yet developed specifically for IBC, and standard treatments commonly lead to poor outcomes. Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate currently approved for patients with pretreated HER2-positive and HER2-low metastatic breast cancer. Early-phase data highlighted the safety and potential synergy of combining T-DXd with the immune checkpoint inhibitor durvalumab. The aim of TRUDI is to evaluate the clinical activity and safety of neoadjuvant T-DXd with durvalumab among patients with HER2-expressing IBC. Trial Design: TRUDI is an ongoing, open label, multicenter, two cohort investigator-initiated phase II neoadjuvant trial for patients with stage III HER2-expressing IBC. The trial was activated in May 2023, with enrollment ongoing. Eligible participants are women and men with previously untreated, stage III (T4d, any N) breast cancer, clinically determined to be IBC. Patients will be included in two cohorts, depending on the locally determined HER2 status (with any hormone receptor [HR] status): Cohort 1 (n=36) for patients with HER2-positive disease (HER2 IHC 3+ or 2+/ISH amplified); Cohort 2 (n=27) for patients with HER2-low disease (HER2 IHC 1+ or 2+/ISH not amplified). Patients will receive eight cycles of T-DXd (5.4 mg/kg IV every 21 days) combined with durvalumab (1125 mg IV every 21 days), followed by modified radical mastectomy and post-mastectomy radiation. Post-surgical systemic treatment will follow local standards. Tumor tissue will be collected at baseline, cycle 1 day 8, and at surgery; blood will be collected at baseline, cycle 4 day 1, cycle 7 day 1 and at surgery; stool will be collected at baseline, after 3-6 weeks of treatment and surgery. The primary endpoint is pathologic complete response (pCR; ypT0/Tis ypN0). Patients in each cohort will be enrolled based upon Simon two-stage designs: in Cohort 1, if ≥8/20 patients with HER2-positive IBC experience pCR then a total of 36 patients will be enrolled. In Cohort 2, if ≥1/18 patients with HER2-low IBC experience pCR then a total of 27 patients will be enrolled. Secondary endpoints include the residual cancer burden at surgery, event free survival, distant progression or distant disease-free survival, as well as safety of the regimen. Exploratory objectives will investigate biomarker analyses on tissue, blood, and microbiome to explore the association of HER2 expression, immune variables, and stool composition on the efficacy of T-DXd with durvalumab among patient with HER2-expressing IBC. To our knowledge, this is the first and only ongoing study testing the combination of an anti-HER2 antibody-drug conjugate with immunotherapy for the neoadjuvant treatment of patients with IBC. Clinical trial information: NCT05795101. Citation Format: Paolo Tarantino, Samuel Niman, Antonio Giordano, Faina Nakhlis, Jennifer Bellon, Wendy Woodward, Azadeh Nasrazadani, Sadia Saleem, Anthony Lucci, Michelle DeMeo, Naoto Ueno, Sara Tolaney, Vicente Valero, Meredith Regan, Rachel Layman, Filipa Lynce. TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory 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 PO3-20-06.

Abstract PS15-07: Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic Study

Abstract Abstract Background: Resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a major obstacle to the management of hormone-receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (mBC). Targeting the AR signaling pathway has been demonstrated with promising results in this population. This phase Ic study aimed to assess the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) characteristics of the combination of proxalutamide, a high-affinity AR antagonist, with ETs in androgen receptor (AR)+/HR+/HER2- mBC. Methods: Patients in part 1 regimen-finding phase received proxalutamide plus specific ETs (letrozole [cohort A], exemestane [cohort B], or fulvestrant [cohort C]) and were assessed for dose-limiting toxicity (DLT), PK, PD, and anti-tumor activity. Part 2 expansion phase evaluated the safety and efficacy of proxalutamide plus fulvestrant. The primary endpoint was safety and tolerability. Results: Between June 18, 2019, and Sep 15, 2022, 38 (18 in part 1 and 20 in part 2) patients were treated. Efficacy analysis indicated that the ORR was 16.7% (2/12, 95% CI, 2.1%-48.4%) for cohort C and 15.0% (3/20; 95% CI, 3.2%-37.9%) for part 2. Patients achieved a median progression-free survival (PFS) of 6.4 months (95% CI, 2.7-19.3) in cohort C while an mPFS of 11.0 months (95% CI, 5.5- not estimable) in part 2. In part 1, no DLTs were reported. Grade 3 or more treatment-emergent adverse events (TEAEs) were observed in 11 (29.7%) patients (7 [18.9%] in part 1 and 4 [10.8%] in part 2) and mainly included neutrophil count decreased (8.1%) and platelet count decreased (5.4%). Seven (18.9%) had serious AEs (4 [10.8%] in part 1 and 3 [8.1%] in part 2)[1]. PD results showed a greater reduction of estradiol in cohort C compared with that in cohort B. In addition, proxalutamide was absorbed rapidly into the body with the plasma concentrations of proxalutamide and metabolites reaching a nearly steady state on day 29. Patients with AR/ER of ≤1 seemed to achieve longer PFS over those of &amp;gt;1 (8.4 months vs. 4.1 months). Conclusions: These findings suggested favorable clinical outcomes and safety profiles of the combination of proxalutamide and fulvestrant in AR+/HR+/HER2- mBC patients who have progressed on the first-line therapy, and maybe with better efficacy in patients with lower AR/ER ratio. Trial registration: NCT20191063 Citation Format: Hui-Ping Li, Guohong Song, Hanfang Jiang, Xu Liang, Xiaojia Wang, Hua Yang, Lili Zhang, Youzhi Tong. Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic 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 PS15-07.

Clinical efficacy of Dermatophagoides farina drops on allergic rhinitis in children sensitized by dust mites combined with different allergens

ObjectiveThis study aimed to investigate the clinical efficacy and safety of sublingual immunotherapy (SLIT) using standardized dermatophagoides farina drops for the treatment of allergic rhinitis (AR) in children sensitized to dust mites combined with different allergens. The findings contribute to establishing a preliminary foundation for future in-depth studies on AR treatment. MethodsA total of 152 AR children undergoing SLIT were categorized into two groups based on serological test results: the inhalation group (dust mite combined with inhalation allergy) and the ingestion group (dust mite combined with ingestion allergy). The clinical efficacy and safety were evaluated by assessing the total nasal symptoms score (TNSS), total medication scores (TMS), visual analog scale scores (VAS scores), and the incidence of adverse reactions before treatment and after two years of treatment. ResultsAfter two years of treatment, TNSS, TMS, and VAS scores significantly improved compared to pre-treatment values in both the inhalation and ingestion groups (p < 0.05). However, there were no significant differences in efficacy between the two groups after two years of treatment (p > 0.05). During the treatment period, only 15 cases (10.9%, 9 cases in the inhalation group and 6 cases in the ingestion group) experienced mild adverse reactions. There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). ConclusionSLIT using standardized dermatophagoides farina drops demonstrates long-term efficacy in children with AR, regardless of whether they belong to the inhalation or ingestion group, without significant differences in treatment outcomes.

The safety and feasibility Assessment of Overlap Esophagojejunostomy with Self-pulling and Latter Transection Technique in Totally Laparoscopic Total Gastrectomy

BackgroundThis study presents an innovative technique in totally laparoscopic total gastrectomy (TLTG) for Overlap esophagojejunostomy, termed self-pulling and latter transection (Overlap SPLT). It evaluates the effectiveness and short-term outcomes of this novel method through a comparative analysis with the established functional end-to-end esophagojejunostomy incorporating self-pulling and latter transection (FETE SPLT). MethodsFrom September 2018 to September 2023, this study enrolled 68 gastric cancer patients who underwent totally laparoscopic total gastrectomy (TLTG) with Overlap SPLT anastomosis and 120 patients who underwent TLTG with FETE SPLT anastomosis. Clinicopathological characteristics, surgical and postoperative outcomes data for Overlap SPLT cases were gathered and retrospectively compared with those from FETE SPLT TLTG to evaluate the effectiveness and clinical safety. ResultsThe duration of anastomosis for Overlap SPLT was 25.3 ± 7.4minutes, significantly longer than that for the FETE SPLT (18.1 ± 4.0minutes, P = 0.031). Perioperatively, one anastomosis-related complication occurred in each group, but this did not constitute a statistically significant difference (P = 0.682). No statistically significant differences were found between the two groups in terms of operative time, postoperative hospital stay, operative cost, surgical margins, or number of lymph nodes removed. Postoperative morbidity rates were similar between the groups (4.4% vs. 5.8%, P = 0.676). ConclusionThe Overlap SPLT technique is regarded as a safe and feasible method for anastomosis. There were no apparent differences in complications between Overlap SPLT and FETE SPLT, but Overlap SPLT costed one additional stapler cartridge and required a longer duration.

Experience of using drospirenone/ethinyl estradiol combination in women of reproductive age

Introduction. A woman’s unwillingness to enter pregnancy due to social and somatic factors is associated with a high risk of its termination and concomitant complications. A personalized selection of a method of contraception is necessary, which best meets the needs of a woman, including in achieving non-contraceptive effects.Aim. To evaluate the effectiveness, safety and compliance indicators when using a combined drug (3 mg of drospirenone + 20 mcg of ethinyl estradiol) in women in the early and mature reproductive period.Materials and methods. A study involving 68 women (polycystic ovary syndrome (PCOS), n = 31, adenomyosis, n = 20, uterine fibroids, n = 7, a combination of 2 or more diagnoses) was conducted on the basis of the Scientific polyclinic Department of the V.I. Kulakov National Research Medical Center of the Ministry of Health of the Russian Federation) of reproductive age (18–34 years) who took a combined contraceptive drug for 6 months or more. The control of the results was carried out on the basis of monitoring in the form of a survey.Results. The average time of use of the drug was 9 (Q₁–Q₃: 8–11) months. After 3 and 6 months, 77.8% (21/27) and 100% of the observed patients, respectively, noted a decrease in the severity of PMS symptoms. 91.7% (n = 11/12) of patients noted a subjective decrease in the severity of acne and/or hirsutism after 6 months. 91.3% (n = 21/23) of women with copious painful menstruation noted normalization of the bleeding profile (volume of menstrual blood loss). 95.6% (65 patients out of 68) noted 100% compliance in the use of the drug.Conclusions. The drug Dimia has a favorable profile of clinical and pharmacological safety and efficacy, along with the complete reversibility of contraceptive action when actualizing the issue of the realization of reproductive function. The advantages of the drug are to achieve well-studied non-contraceptive effects, in which patients with PCOS, internal endometriosis and uterine fibroids are interested, in the form of relieving manifestations of PMS and reducing the severity of dysmenorrhea, as well as cosmetic skin imperfections (acne-type rashes, hirsutism). Thus, the drug can be recommended to women of reproductive age as a reliable contraceptive, as well as to achieve non-contraceptive effects.

Assessment of peripheral blood toll-like receptor 2 expression and vitamin D serum level as predictors of response to intralesional vitamin D in the treatment of warts

Background Warts are common dermatological conditions caused by human papilloma virus. Most treatments for human papilloma virus rely on the destruction of involved tissue. The role of vitamin D injection in treating warts is thought to be via regulating cell proliferation and differentiation through the upregulation of vitamin D receptors and the induction of antimicrobial peptides. Objective To assess the clinical efficacy and safety of intralesional vitamin D in the treatment of cutaneous warts and also the significance of peripheral blood toll-like receptors 2 (TLR2) expression and serum levels of 25-hydroxyvitamin D in predicting the therapeutic success. Patients and methods In this prospective interventional study, 50 patients of cutaneous warts were subjected to history taking, proper dermatological examination, and peripheral venous blood collection for detection of TLR2 mRNA expression and a serum level of 25 (OH) D. Vitamin D3 was slowly injected into the base of the largest or the oldest wart at 2-week intervals. Results A total of 34 (69.4%) patients showed response to intralesional Vitamin D [21 (42.9%) showed complete resolution of all lesions, 13 (26.5%) showed partial clearing] and 15 (30.6%) patients showed poor or no response after four sessions. Serum level of vitamin D did not show a significant relation with treatment response. TLR2 expression was higher in the group showing complete response. Conclusion Intralesional vitamin D injection offers a safe and cost-effective therapy for different types of cutaneous warts. TLR2 expression in patients’ serum can be used to predict response to treatment by intralesional vitamin D, with better response in patients with higher expression.

Immediate Sequential Bilateral Implantable Collamer Lens Surgery Is Safe and Effective.

To assess the clinical outcomes and safety profiles of patients who underwent immediate sequential bilateral phakic lens surgery. This retrospective multicenter study included 254 consecutive patients (508 eyes) who underwent bilateral same-day Implantable Collamer Lens (ICL) (STAAR Surgical) surgery. The authors focused on 1-year postoperative clinical outcomes and adverse events. In the initial cohort, 176 patients (352 eyes) met inclusion criteria. Of these, 335 eyes underwent myopic ICL placement, and 17 eyes received a hyperopic ICL. Notably, 87% of eyes achieved ±0.50 diopters (D) and 95% achieved ±1.00 D of the intended refraction. One year postoperatively, 78% of eyes demonstrated optimal vaulting (250 to 750 µm), with a significant 19% reduction in vaulting observed over the 12 months (P < .001). Only minor adverse events, including early cataract formation (1 case), secondary toric ICL rotation (3 cases), and ICL exchange due to inappropriate vaulting (6 cases), were noted. The findings corroborate the safety and efficacy of immediate sequential bilateral phakic lens surgery and indicate its potential as a treatment option. The low incidence of minor adverse events further reinforces its favorable safety profile. [J Refract Surg. 2024;40(5):e313-e320.].

Real-time regurgitation estimation in percutaneous left ventricular assist device fully supported condition using an unscented Kalman filter

Objective. Significant aortic regurgitation is a common complication following left ventricular assist device (LVAD) intervention, and existing studies have not attempted to monitor regurgitation signals and undertake preventive measures during full support. Regurgitation is an adverse event that can lead to inadequate left ventricular unloading, insufficient peripheral perfusion, and repeated episodes of heart failure. Moreover, regurgitation occurring during full support due to pump position offset cannot be directly controlled through control algorithms. Therefore, accurate estimation of regurgitation during percutaneous left ventricular assist device (PLVAD) full support is critical for clinical management and patient safety. Approach. An estimation system based on the regurgitation model is built in this paper, and the unscented Kalman filter estimator (UKF) is introduced as an estimation approach. Three offset degrees and three heart failure states are considered in the investigation. Using the mock circulatory loop experimental platform, compare the regurgitation estimated by the UKF algorithm with the actual measured regurgitation; the errors are analyzed using standard confidence intervals of ±2 SDs, and the effectiveness of the mentioned algorithms is thus assessed. The generalization ability of the proposed algorithm is verified by setting different heart failure conditions and different rotational speeds. The root mean square error and correlation coefficient between the estimated and actual values are quantified and the statistical significance of accuracy differences in estimation is illustrated using one-way analysis of variance (One-Way ANOVA), which in turn assessed the accuracy and stability of the UKF algorithm. Main results. The research findings demonstrate that the regurgitation estimation system based on the regurgitation model and UKF can relatively accurately estimate the regurgitation status of patients during PLVAD full support, but the effect of myocardial contractility on the estimation accuracy still needs to be taken into account. Significance. The proposed estimation method in this study provides essential reference information for clinical practitioners, enabling them to promptly manage potential complications arising from regurgitation. By sensitively detecting LVAD adverse events, valuable insights into the performance and reliability of the LVAD device can be obtained, offering crucial feedback and data support for device improvement and optimization.

Review of Evidence Supporting the Arista™ Absorbable Powder Hemostat.

Uncontrolled and diffuse bleeding is a dreaded event during open and laparoscopic surgery that may lead to postoperative complications, obstruction of the surgical field that reduces visualization, and prolonged operating times. Powder hemostats can be used to control bleeding and are easy to use, have a safe profile, and can achieve broad coverage area at a low cost. A strategic literature search of peer-reviewed, English language studies was conducted to capture evidence on the clinical efficacy and safety of a Microporous Polysaccharide Hemosphere (MPH) based Hemostat (Arista™ Absorbable Hemostat (Arista™ AH)). Six preclinical studies were found which supported the use of MPH in various animal models of laparoscopic and open surgery, all of which demonstrated its safety and efficacy. Five single-arm and 11 comparative clinical studies similarly supported the efficacy and safety of MPH in various surgery types, including cardiac, renal, and dermatologic surgery. Published evidence supports the safe and effective use of MPH across a variety of surgical settings.

Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial

Dysregulation of the gut microbiome has been implicated in Parkinson's disease (PD). This study aimed to evaluate the clinical effects and safety of a single faecal microbiota transplantation (FMT) in patients with early-stage PD. The GUT-PARFECT trial, a single-centre randomised, double-blind, placebo-controlled trial was conducted at Ghent University Hospital between December 01, 2020 and December 12, 2022. Participants (aged 50-65 years, Hoehn and Yahr stage 2) were randomly assigned to receive nasojejunal FMT with either healthy donor stool or their own stool. Computer-generated randomisation was done in a 1:1 ratio through permutated-block scheduling. Treatment allocation was concealed for participants and investigators. The primary outcome measure at 12 months was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score obtained during off-medication evaluations. Intention-to-treat analysis was performed using a mixed model for repeated measures analysis. This completed trial is registered on ClinicalTrials.gov (NCT03808389). Between December 2020 and December 2021, FMT procedures were conducted on 46 patients with PD: 22 in the healthy donor group and 24 in the placebo group. Clinical evaluations were performed at baseline, 3, 6, and 12 months post-FMT. Full data analysis was possible for 21 participants in the healthy donor group and 22 in the placebo group. After 12 months, the MDS-UPDRS motor score significantly improved by a mean of 5.8 points (95% CI-11.4 to-0.2) in the healthy donor group and by 2.7 points (-8.3 to 2.9) in the placebo group (p=0.0235). Adverse events were limited to temporary abdominal discomfort. Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages. Flemish PD patient organizations (VPL and Parkili), Research Foundation Flanders (FWO), Biocodex Microbiota Foundation.

Hypercholesterolemia: a literature review on management using tafolecimab: a novel member of PCSK9 monoclonal antibodies.

Cardiovascular diseases (CVD) persist as the leading cause of mortality globally, with atherosclerotic cardiovascular disease (ASCVD), including hypercholesterolaemia, being a significant contributor. Hyperlipidemia management includes various lipid-lowering drugs, including statins, Bempedoic acid, inclisiran, Lomitapide, ANGPTL3 inhibitors, and PCSK9 inhibitors. Statins have traditionally dominated lipid management therapies; however, a subset of patients remains unresponsive or intolerant to this therapy, necessitating novel therapeutic approaches. Tafolecimab, a promising and novel PCSK9 monoclonal antibody, demonstrated significant LDL-C reduction and a favourable safety profile in clinical trials. This review aimed to discuss the role and efficacy of Tafolecimab in the management of hypercholesterolaemia. The authors searched online databases, including PubMed, Scopus, and Embase, for articles related to talofecimab. The efficacy of Tafolecimab in diverse patient populations, including those with comorbid conditions and various lipid disorders, has been explored. Ongoing trials, such as CREDIT-1, CREDIT-2, and CREDIT-4, have provided valuable insights into Tafolecimab's potential as a lipid-lowering agent. Moreover, the drug's extended dosing interval may enhance patient compliance and reduce treatment costs. It has also been found that Tafolecimab has more affinity for PCSK9 and a longer duration of LDL-C reduction than other monoclonal antibody drugs such as evolocumab. Thus, this review focuses on Tafolecimab, a novel PCSK9 monoclonal antibody, its mechanism of action, clinical trial outcomes, safety profile, and potential role in hypercholesterolaemia management. Despite its assuring potential, the long-term impact of Tafolecimab on cardiovascular outcomes remains to be fully elucidated, necessitating further research. Regulatory authorities like the FDA and EMA should also evaluate Tafolecimab's risks and benefits. In conclusion, Tafolecimab shows potential as an innovative therapeutic option for hypercholesterolaemia, particularly in patients with specific risk factors, but warrants additional research.