bluuebunny/crossref_metadata_2025 huggingface dataset:
Psycho-emotional impact of the COVID-19 pandemic on nursing professionals in Ecuador: a cross-sectional study
Authors: Vaca-Auz Janet , Revelo-Villarreal Sonia , Anaya-González Jorge Luis , Vaca-Orellana Cristina , Castillo Rocío , Altamirano-Zavala Geovanna , Vicens-Blanes Francisco , Molina-Mula Jesús
Published: July 2024

Aim and objectives

To analyse the levels of anxiety, depression, post-traumatic stress, and burnout among nursing professionals working in the Imbabura region of Ecuador during the COVID-19 pandemic and identify the contributing socio-occupational factors.

Background

The high demand for care of COVID-19 patients led to increased work pressure on nurses, owing to increased demands for care and shortages of medical supplies and protective equipment.

Design

A cross-sectional study was conducted from September to December 2022 using a self-administered questionnaire addressed to nursing professionals who cared for COVID-19 patients.

Methods

The questionnaire included socio-demographic characteristics, the Spanish adaptation of Hospital Anxiety and Depression Scale (HADS-Spanish), Impact of Event Scale–Revised (IES-R) for the evaluation of post-traumatic stress disorder (PTSD), and the Spanish adaptation of the Maslach Burnout Inventory–Human Services Survey (MBI-HSS-Spanish) for burnout assessment. Univariate and multivariate analyses were performed.

Results

Of the 782 participants, 88.6% had a high level of burnout (MBI-HSS-Spanish scale score > 27). Female nurses, nurses with eight-hour work shifts, and older professionals exhibited high levels of anxiety and depression. Prolonged working hours in COVID-19 patient care services were found to be a risk factor for burnout and post-traumatic stress.

Conclusions

Participating nurses presented with a high level of chronic work stress and exhibited signs of anxiety and depression during the period under consideration. Providing nurses with psychological support measures and performing liaison consultations will alleviate the psychological burden on nurses.

Relevance to clinical practice

The study has shown that accounting for the environments where the emotional impact is greatest and how to reduce it would not only reduce anxiety, depression, and burnout in nurses but also improve the quality of care, not only in pandemic.

Patient or public contribution

Nurses contributed to the conduct of the study by participating in the data collection via questionaries.
Radiology of fibrosis part III: genitourinary system
Authors: Tarchi Sofia Maria , Salvatore Mary , Lichtenstein Philip , Sekar Thillai , Capaccione Kathleen , Luk Lyndon , Shaish Hiram , Makkar Jasnit , Desperito Elise , Leb Jay , Navot Benjamin , Goldstein Jonathan , Laifer Sherelle , Beylergil Volkan , Ma Hong , Jambawalikar Sachin , Aberle Dwight , D’Souza Belinda , Bentley-Hibbert Stuart , Marin Monica Pernia
Published: July 2024

Fibrosis is a pathological process involving the abnormal deposition of connective tissue, resulting from improper tissue repair in response to sustained injury caused by hypoxia, infection, or physical damage. It can impact any organ, leading to their dysfunction and eventual failure. Additionally, tissue fibrosis plays an important role in carcinogenesis and the progression of cancer.

Early and accurate diagnosis of organ fibrosis, coupled with regular surveillance, is essential for timely disease-modifying interventions, ultimately reducing mortality and enhancing quality of life. While extensive research has already been carried out on the topics of aberrant wound healing and fibrogenesis, we lack a thorough understanding of how their relationship reveals itself through modern imaging techniques.

This paper focuses on fibrosis of the genito-urinary system, detailing relevant imaging technologies used for its detection and exploring future directions.
Safety and efficacy of COVID-19 vaccination in the Chinese population with pulmonary lymphangioleiomyomatosis: a single-center retrospective study
Authors: Wang Weilin , Zhou Jingdong , Kong Xuetao , Wang Yixuan , Wu Qixian , Gong Xiaoqing , Tai Jingye , Pan Yingxin , Huang Hongyuan , Zhao Zhen , Jiang Mei , Liu Jie
Published: July 2024

Background

The safety and efficacy of vaccination against coronavirus disease 2019 (COVID-19) in patients with lymphangioleiomyomatosis (LAM) is still unclear. This study investigates COVID-19 vaccine hesitancy, vaccine safety and efficacy, and COVID-19 symptoms in LAM patients.

Results

In total, 181 LAM patients and 143 healthy individuals responded to the questionnaire. The vaccination rate of LAM patients was 77.34%, and 15.7% of vaccinated LAM patients experienced adverse events. Vaccination decreased the risk of LAM patients developing anorexia [OR: 0.17, 95% CI: (0.07, 0.43)], myalgia [OR: 0.34, 95% CI: (0.13, 0.84)], and ageusia [OR: 0.34, 95% CI: (0.14, 0.84)]. In LAM patients, a use of mTOR inhibitors reduced the risk of developing symptoms during COVID-19, including fatigue [OR: 0.18, 95% CI: (0.03, 0.95)], anorexia [OR: 0.30, 95% CI: (0.09, 0.96)], and ageusia [OR: 0.20, 95% CI: (0.06, 0.67)].

Conclusions

Vaccination rates in the LAM population were lower than those in the general population, as 22.7% (41/181) of LAM patients had hesitations regarding the COVID-19 vaccine. However, the safety of COVID-19 vaccination in the LAM cohort was comparable to the healthy population, and COVID-19 vaccination decreased the incidence of COVID-19 symptoms in LAM patients. In addition, mTOR inhibitors seem not to determine a greater risk of complications in patients with LAM during COVID-19.
Screening primary carnitine deficiency in 10 million Chinese newborns: a systematic review and meta-analysis
Authors: Zhou Jinfu , Li Guilin , Zeng Yinglin , Qiu Xiaolong , Zhao Peiran , Huang Ting , Wang Xi , Luo Jinying , Lin Na , Xu Liangpu
Published: July 2024

Background

Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. This study aimed to systematically analyze the incidence of PCD in China and delineate regional differences in the prevalence of PCD and SLC22A5 gene variants.

Methods

PubMed, Embase, Web of Science, and Chinese databases were searched up to November 2023. Following quality assessment and data extraction, a meta-analysis was performed on screening results for PCD among Chinese newborns.

Results

After reviewing 1,889 articles, 22 studies involving 9,958,380 newborns and 476 PCD cases were included. Of the 476 patients with PCD, 469 underwent genetic diagnosis, revealing 890 variants of 934 alleles of SLC22A5, among which 107 different variants were detected. The meta-analysis showed that the prevalence of PCD in China was 0.05‰ [95%CI, (0.04‰, 0.06‰)] or 1/20 000 [95%CI, (1/16 667, 1/25 000)]. Subgroup analyses revealed a higher incidence in southern China [0.07‰, 95%CI, (0.05‰, 0.08‰)] than in northern China [0.02‰, 95%CI, (0.02‰, 0.03‰)] (P < 0.001). Furthermore, the result of the meta-analysis showed that the frequency of the variant with c.1400C > G, c.51C > G, c.760C > T, c.338G > A, and c.428C > T were 45% [95%CI, (34%, 59%)], 26% [95%CI, (22%, 31%)], 14% [95%CI, (10%, 20%)], 6% [95%CI, (4%, 8%)], and 5% [95%CI, (4%, 8%)], respectively. Among the subgroup analyses, the variant frequency of c.1400C > G in southern China [39%, 95%CI, (29%, 53%)] was significantly lower than that in northern China [79‰, 95%CI, (47‰, 135‰)] (P < 0.05).

Conclusions

This study systematically analyzed PCD prevalence and identified common SLC22A5 gene variants in the Chinese population. The findings provide valuable epidemiological insights and guidance for future PCD screening effects in newborns.
App-based telerehabilitation program for older adults on waiting list for physiotherapy after hospital discharge: a feasibility pragmatic randomized trial
Authors: Borges Pollyana Ruggio Tristão , Sampaio Rosana Ferreira , Dias Jane Fonseca , Mancini Marisa Cotta , Ocarino Juliana Melo , Resende Renan Alves
Published: July 2024

Background

Inactivity while waiting for outpatient physiotherapy worsens the physical deconditioning of older adults after hospital discharge. Exercise programs can minimize the progression of deconditioning. In developing countries, telerehabilitation for older adults on the waiting list is still in the early stages. This study aimed to evaluate the feasibility of the study procedures of a telerehabilitation program for older adults waiting for outpatient physiotherapy after hospital discharge.

Methods

This pragmatic randomized controlled trial recruited older adults (≥ 60 years) with several clinical diagnoses on the waiting list for outpatient physiotherapy in the Brazilian public health system after hospital discharge. The telerehabilitation group (n = 17) received a personalized program of multicomponent remote exercises using a smartphone app. The control group (n = 17) followed the usual waiting list. We assessed recruitment and dropout rates, safety, adherence, and satisfaction. The preliminary effects were verified on clinical outcomes.

Results

We recruited 5.6 older adults monthly; dropouts were 12%. No serious adverse events were associated with the telerehabilitation program. The weekly adherence was 2.85 (1.43) days, and in 63.3% of the weeks the participants were enrolled, they performed the exercise program at least twice a week. Participants rated the telerehabilitation program as 9.71 (0.21), and the safety of remote exercises without professional supervision as 8.6 (2.2) on a 0–10 scale.

Conclusions

The telerehabilitation program using a smartphone app was safe and presented high participants’ satisfaction and adequate adherence, recruitment, and dropout rates. Therefore, the definitive study can be conducted with few modifications.

Trial registration

Brazilian Registry of Clinical Trials (ReBEC), RBR-9243v7. Registered on 24 August 2020. https://ensaiosclinicos.gov.br/rg/RBR-9243v7.
Rivaroxaban’s vascular dose for the neurovascular clinician
Authors: Chong Ji Y. , Jan Kalimullah
Published: July 2024

Rivaroxaban, a direct oral anticoagulant, has proven efficacy and safety at its standard dose in the treatment and prevention of various vascular conditions. These include the treatment of venous thromboembolism and stroke prevention in non-valvular atrial fibrillation. A “very low” vascular dose of rivaroxaban, when combined with low-dose aspirin, has been demonstrated to reduce major adverse cardiovascular events, including stroke, in both acute and chronic coronary syndrome. The combination of rivaroxaban and low-dose aspirin could potentially offer an additional strategy for stroke prevention in selected non-atrial fibrillation patients who are at a high risk of stroke.
A cost-efficient algorithm for diagnosing children with dysmorphic features
Authors: Levkova Mariya , Stoyanova Milena , Hachmeriyan Mari , Angelova Lyudmila
Published: July 2024

It is crucial to create a cost-effective work protocol that will guide everyone involved in diagnosing children with dysmorphic features step-by-step and ensure that testing costs are reduced without compromising care quality in light of the rising prevalence of rare diseases and congenital malformations. Based on our own experience, we offer an effective approach for identifying children with dysmorphic traits. Following a thorough medical history and physical examination utilizing the dysmorphology checklist we created, the patient should have their photographs taken. The second step involves using face recognition software and searching dysmorphology databases for a matching diagnosis. The final two steps of the suggested protocol are ordering the molecular-genetic analysis and providing genetic counseling. The suggested approach could help in everyday practice and reduce unnecessary testing. It takes significant clinical expertise and knowledge to correctly diagnose a syndrome, especially the capacity to recognize the particular dysmorphic symptoms that can be typical for a given genetic disorder. The suggested dysmorphology checklist could be extremely helpful for routine daily practice.
PAS-004: A novel macrocyclic MEK inhibitor to inhibit cancer cell growth in vitro and tumor growth in mouse xenograft studies.
Authors: Currie Graeme , Leviten Michael , Ryner Lisa , Khire Uday , Lazarus Mathew
Published: July 2024

3126

Background: Three MEK inhibitors have been approved to date to treat melanomas driven by RAS pathway mutations and a 4th compound (selumetinib) is approved to treat Neurofibromatosis type 1 (NF1) in pediatric patients. PAS-004 is the first macrocyclic MEK inhibitor in development for solid tumors and NF1. Methods: Ten NRAS mutant cancer cell lines were cultured for 48 hrs in the presence of the MEK inhibitor PAS-004, trametinib, binimetinib (bini) and selumetinib (selu) and cell proliferation was assayed using a Cell Titer Glo luminescence assay. The anti-tumor activity of PAS-004 was compared with selu and bini in two mouse xenograft studies using NRAS mutant human hepatocellular carcinoma (HCC) and lung carcinoma cell lines. Dose response was assessed with treatment initiated when the tumor reached a volume of 150 mm3 and mice treated for 20 days. Body weights and tumor volumes were measured twice weekly. Tumors were excised at the end of the study and pERK inhibition was assessed by Western blot. Terminal plasma was collected for PK analysis. Results: PAS-004 strongly inhibited 5/10 NRAS mutant cancer lines with IC50 values ranging from 0.024 to 0.306 µM. Maximal growth inhibition of >50% was achieved by PAS-004 in 8 cell lines and PAS-004 achieved greater maximal inhibition in 7/10 lines vs selu and bini. PAS-004 inhibition was comparable to trametinib in 5/10 cell lines tested. However, in contrast to trametinib PAS-004 did not reach a plateau at the highest dose tested in three of these lines. In the HCC xenograft study the highest dose of PAS-004 completely prevented tumor growth and the same dose caused a 69% reduction in tumor volume in the lung carcinoma xenograft study. The anti-tumor efficacy of PAS-004, when taken at equivalent doses, was shown to be superior to that of bini and selu. Specifically, PAS-004 at dose levels of 10 mg/kg and 5 mg/kg, once daily, exhibited higher efficacy compared to bini and selu at dose levels of 5 mg/kg and 2.5 mg/kg, when administered twice daily, respectively. No significant differences in body weight loss were seen between the compounds. Conclusions: The novel macrocyclic MEK inhibitorPAS-004 inhibited NRAS mutant tumor growth in mouse xenograft studies with similar activity as the approved MEK inhibitors selu and bini. In vitro, PAS-004 provided greater maximal growth inhibition of NRAS lines than selu and bini. These results support investigating PAS-004 further and a clinical trial in patients with advanced solid tumors carrying RAS pathway mutations, including NRAS variants, is ongoing.
The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in small-cell lung cancer (SCLC).
Authors: Kareff Samuel A. , Krause Harris Benjamin , Elliott Andrew , Lopes Gilberto , Lou Emil , Soares Heloisa P. , Oberley Matthew James , Chauhan Aman
Published: July 2024

3128

Background: The TEM8 receptor (coded by ANTXR1) plays several roles in oncogenesis. Novel oncolytic therapies, such as the SVV-01 virus, uniquely bind this protein in tumor histologies such as small-cell lung cancer (SCLC). Emerging pre-clinical data suggest that TEM8-targeting therapies may convert immunologically “cold” tumor microenvironments (TME) into “hot” milieu with greater responses to immune checkpoint inhibitors (ICIs). Methods: NextGen sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) was performed on SCLC ( N=1404) submitted to Caris Life Sciences (Phoenix, AZ). Mutations were defined as pathogenic SNVs/indels. ANTXR1H and ANTXR1L samples included those with >75th and <25th percentile expression, respectively. PD-L1 expression (22c3; Positive (+):TPS ³1%) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations per MB. Cell infiltration in the TME was estimated by QuantiSEQ. Gene expression profiles were analyzed for transcriptional signatures predictive of response to immunotherapy (T cell-inflamed) and MAPK pathway activation score (MPAS). Real-world median overall survival (mOS) was assessed from insurance claims data, and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( p<0.05). Results: No pathogenic mutations were significantly associated with ANTXR1H vs L tumors ( p>0.05 for all), along with no differences in the prevalence of TMB-H (28.6% vs 36.3%, p=1) or PDL1+ (45.0%: vs 35.0%, p=1). However, a greater proportion of B cells (6.53 % vs 5.12%, p<0.001), M1 (1.63% vs 0.37%, p<0.001) and M2 macrophages (3.40% vs 1.50%, p<0.001) were observed in ANTXR1H TME, which were more frequently classified as T cell-inflamed compared to ANTXR1L TME (23% vs 5%, p<0.001). ANTXR1H tumors also had higher MPAS compared to ANTXR1L (1.36 vs -1.86 arbitrary units, p<0.001). There was no significant difference in mOS between ANTXR1H vs L tumors (12.2 vs 10.5 months, HR: 0.95, p=0.678). Conclusions: Increased B cell, M1 and M2 macrophage infiltrates, and increased prevalence of T-cell inflamed tumors in ANTXR1H TME suggest that these patients with SCLC may respond preferentially to ICI. A Phase 1 trial incorporating SVV-01 along with ICI is underway. Prospective investigation of molecular associations and clinical outcomes related to ANTXR1 expression in SCLC is warranted.
Long-term follow up for adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma: Final results of the COMBI-AD study.
Authors: Hauschild Axel , Dummer Reinhard , Santinami Mario , Atkinson Victoria , Mandala Mario , Merelli Barbara , Chiarion-Sileni Vanna , Haydon Andrew Mark , Schachter Jacob , Schadendorf Dirk , Lesimple Thierry , Plummer Elizabeth Ruth , Larkin James , Tan Monique , Adnaik Sachin Bajirao , Burgess Paul , Jandoo Tarveen , Long Georgina V.
Published: July 2024

9500

Background: Dabrafenib plus trametinib, a standard-of care adjuvant treatment for patients with BRAF-mutated AJCC-stage III melanoma, has significantly improved the primary endpoint, relapse-free survival (RFS). Further to published interim assessments, we present updated and final results for RFS, distant-metastasis-free survival (DMFS) and overall survival (OS). Methods: In the COMBI-AD phase 3 study, patients received dabrafenib (150 mg BD) plus trametinib (2 mg OD; n=438) or matching placebos (n=432). Treatment continued for up to 12 months or until disease relapse, unacceptable toxicity, withdrawal of consent, or death. OS, RFS, and DMFS were summarized using Kaplan–Meier estimates. OS was compared between study arms using stratified log-rank test. Hazard ratio (HR) was calculated using Pike estimator. Safety data were summarized descriptively. Results: At final analysis, median duration of follow up was 100.0 months in the treatment arm and 82.5 months in the placebo arm. Median OS was not attained in the two arms (HR: 0.80; 95% CI: 0.62, 1.01; P=0.063). Consistent OS benefits were seen across most prespecified subgroups including patients with BRAFV600E mutation (n=397; HR: 0.75; 95% CI: 0.58, 0.96). Estimated RFS (HR: 0.52; 95% CI: 0.43, 0.63) and DMFS (HR: 0.56; 95% CI: 0.44, 0.71) favored the dabrafenib plus trametinib arm. In both arms, patients received salvage immunotherapies (29% each) and targeted therapy (21% vs. 37% for treatment and placebo arms, respectively). Safety profile was consistent with previous reports. Conclusions: COMBI-AD presents the longest follow-up data (over 10 years) in adjuvant treatment of stage III melanoma in the modern era. OS was improved with dabrafenib plus trametinib over placebo for adjuvant treatment of stage III melanoma with a 20% risk reduction for death. However, this difference was not statistically significant. Consistent with published results at 3 and 5 years, RFS and DMFS were more favorable in the treatment vs. placebo arm. Clinical trial information: NCT01682083 . [Table: see text]
FDG-PET associations with pathological response and survival with neoadjuvant immunotherapy for melanoma.
Authors: Zhou Li , Hsiao Edward , Lo Serigne N , Carlino Matteo S. , Au-Yeung George , Gonzalez Maria , Spillane Andrew John , Pennington Thomas , Howle Julie R. , Shannon Kerwin Frank , Kapoor Rony , Stretch Jonathan , Gyorki David E. , Saw Robyn P.M. , Ch'ng Sydney , Scolyer Richard A , Long Georgina V. , Menzies Alexander M.
Published: July 2024

9523

Background: This study sought to describe the changes seen with FDG-PET following neoadjuvant immunotherapy in melanoma patients (pts), and explore associations with pathological response and recurrence-free survival (RFS). Methods: Two prospective clinical trial cohorts of stage III pts with RECIST measurable nodal melanoma were included; 1) NeoTrio, 13 pts received 2 doses of preoperative pembrolizumab alone, and 2) NeoPele, 20 pts received 2 doses of pembrolizumab and 5 weeks of lenvatinib preoperatively. All pts underwent baseline and week 6 (preoperative) FDG-PET assessments and all had surgery. PET responses were evaluated based on the modified EORTC criteria. In addition to the standard categories Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), Stable Metabolic Disease (SMD), and Progressive Metabolic Disease (PMD), a novel category was established, near-CMR, where the maximum standardized uptake value (SUVmax) decreased by more than 90%. PET responses were determined while blinded to the outcome data. Pathological response was determined as per INMC criteria. Results: 33 pts were included, 67% male, median age 65 years, 48% BRAF mutant. Pathological response, PET response and correlations are shown in the Table. All 8 (24%) pts achieving CMR or near-CMR obtained major pathologic response (MPR), while the 14 pts (42%) with PMR had variable pathological outcomes (57% MPR, 21% pPR, 21% pNR). For the 6 pts with PMD, 5 (83%) had pNR and the one pts who achieved pCR recurred with brain metastases. After a median 29.9 mo follow-up (95% CI 27.0-33.1), PET response associated with RFS; those with CMR/near CMR had 100% 24mo RFS (nil recurrences to date) while those with PMR or SMD had inferior survival (79% and 80% 24mo RFS), and those with PMD the worst outcomes (17% 24mo RFS, all pts except one have recurred) (p=0.0029). The predictive value of PET and pathology for RFS was assessed using the Cox Proportional Hazards model. 12- and 24-month RFS AUCs of PET and pathology response were similar at 81.5% (95% CI: 67.7-95.3) vs. 80.9% (95% CI: 67.8-93.9), and 83.3% (95% CI: 69.1-97.5%) vs. 80.8% (95% CI: 66.6-94.9), respectively. Conclusions: FDG-PET demonstrates utility in predicting pathological response and survival with neoadjuvant immunotherapy in melanoma. PET may identify pts who are not going to be pathological responders and who have the worst survival outcomes, enabling a potential switch of neoadjuvant systemic therapy. [Table: see text]
Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years.
Authors: Tawbi Hussein A. , Hodi F. Stephen , Lipson Evan J. , Schadendorf Dirk , Ascierto Paolo Antonio , Matamala Luis , Gutiérrez Erika Castillo , Rutkowski Piotr , Gogas Helen , Lao Christopher D. , Menezes Juliana , Dalle Stéphane , Arance Ana Maria , Grob Jean-Jacques , Ratto Barbara , Rodriguez Saima , Mazzei Antonella , Dolfi Sonia , Long Georgina V.
Published: July 2024

9524

Background: NIVO + RELA as a fixed-dose combination (FDC) demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922), with a clinically meaningful, but not statistically significant, improvement in OS and a numerically higher objective response rate (ORR), resulting in regulatory approval of the FDC. Here we report updated descriptive analyses with 3 years of follow-up. Methods: Patients (pts) were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg Q4W. PFS per RECIST v1.1 was assessed by blinded independent central review (BICR); secondary endpoints included OS and ORR per BICR. Exploratory analyses included MSS (death due to melanoma, with censoring of deaths due to other causes), CNS metastasis-free survival in specified populations, and efficacy on subsequent systemic therapy. Results: At database lock (19 Oct 2023), median follow-up was 33.8 months (mo; range, 0.3–64.2). NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS (Table). NIVO + RELA was also favored over NIVO across the majority of key subgroups. Subsequent systemic therapy was received by 135 pts (38%) on NIVO + RELA and 141 pts (39%) on NIVO. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 78 pts (22%) on NIVO + RELA and 43 pts (12%) on NIVO; TRAEs (any grade) led to treatment discontinuation in 63 pts (18%) and 35 pts (10%), respectively. No new treatment-related deaths were reported since the last analysis. Conclusions: At 3 years of follow-up, NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS. OS and MSS demonstrated sustained improvement, with the OS HR 95% CI upper bound < 1. Efficacy results also continued to favor NIVO + RELA vs NIVO across the majority of prespecified subgroups. Safety of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. CNS metastasis-free survival and efficacy outcomes on subsequent systemic therapy will be presented. Clinical trial information: NCT03470922 . [Table: see text]
First-line treatment preferences for advanced melanoma among oncologists and patients in the US: A discrete choice experiment.
Authors: Postow Michael A. , Burgos Gabriela , DeCongelio Marc , Palaia Jennell , Ejzykowicz Flavia , Patel Divya , Rosenblatt Lisa , Modi Kushal , Pittman Zander , Honomichl Ryan , Paudel Neelanzana , Barnett Cody , Hay Jennifer L.
Published: July 2024

9539

Background: NCCN guidelines recommend nivolumab + ipilimumab, nivolumab + relatlimab, and anti-PD-1 monotherapy as category 1 preferred first-line (1L) treatments (txs) for advanced melanoma. These immunotherapies (IOs) however differ in administration, efficacy, and safety. Given these differences, this study examines oncologists (oncs) and patients (pts) preferences when choosing 1L tx. Methods: Pts with self-reported unresectable or metastatic melanoma and oncs completed an online cross-sectional survey. A discrete choice experiment assessed preferences for three efficacy attributes, three safety attributes, and dosing schedule. Attributes (shown in table) were identified via literature and qualitative research. Each attribute had two or three levels based on clinical trial data of recommended IOs. Participants completed 12 tasks; each task showed two tx options with varying levels for each attribute. Hierarchical Bayesian modeling was used to estimate preference weights for each level and relative importance estimates, based on the range between levels, were computed. Results: 75 oncs (male 76%; mean age 46 years; community-based 51%) and 62 pts (male 68%; mean age 43 years) were analyzed (pt recruitment ongoing; target n = 75). For both oncs and pts, improvements in safety attributes was more important than improvements in efficacy attributes (pts: 50.3 vs. 33.9; oncs: 48.6 vs. 40.9). For safety, a decrease in risk of discontinuation due to treatment-related adverse events (TRAEs) was most important in oncs (24.7); while for pts, lower risk of grade 3/4 TRAEs was most important (22.6). For efficacy, an increase in overall survival (OS) was most influential for oncs (21.0); pts had similar estimates within efficacy. Dosing schedule was third most important for pts (15.8), while it was among the least important for oncs. Conclusions: Oncs and pts prioritize minimizing the risk of serious AEs when efficacy differences are minimal in 1L advanced melanoma tx choice. These findings highlight that oncs and pts value an IO with an efficacy benefit while ensuring a favorable risk-benefit profile. This information can inform tx counseling and selection discussions among oncs and pts. [Table: see text]
Overall survival and efficacy subgroup analysis of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.
Authors: Wei Xiaoting , Zou Zhengyun , Zhang Weizhen , Fang Meiyu , Zhang Xiaoshi , Luo Zhiguo , Chen Jing , Huang Gang , Zhang Peng , Cheng Ying , Liu Jiwei , Liu Jiyan , Zhang Junping , Wu Di , Chen Yu , Ma Xiaobiao , Tian Hongqi , Jia Zhongwei , Guo Jun , Si Lu
Published: July 2024

9545

Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we report the updated efficacy results. Methods: This is a multicenter, single-arm, phase II, pivotal registrational study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors, version 1.1 assessed by independent radiology review committee (IRRC). Results: A total of 100 pts were enrolled and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (October 31, 2023), median follow-up was 24.4 months (95% CI: 21.9, 27.9). The confirmed ORR was 35.8% (95%CI: 26.3%, 46.3%). Median progression-free survival (mPFS) was 4.2 months (95%CI: 3.5, 5.6). The median overall survival (mOS) was immature during last year's ASCO annual meeting, and the present mOS was 13.7 months (95% CI of 10.3–18.0). The IRRC-assessed ORRs by melanoma subtype were 42.9% (95% CI of 29.7–56.8) in acral melanoma, 25.0% (95% CI of 7.3–52.4) in mucosal melanoma. ORRs by NRASmutation site were 41.3% (95% CI of 30.1–53.3), 13.3% (95% CI of 1.7–40.5) and 20.0% (95% CI of 0.5–71.6) for Q61, G12, and G13, respectively. ORR in patients who had been treated with immunotherapy was 40.6% (95% CI of 28.5–53.6), while in those without immunotherapy, ORR was 25.8% (95% CI of 11.9–44.6). The difference in PFS was not statistically significant across subgroups, regardless of melanoma type, NRAS mutation site, line of previous treatment, type of previous treatment and previous treatment with immunotherapy. The safety profile is similar with last year's ASCO annual meeting. The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, facial oedema, peripheral oedema, and increased aspartate aminotransferase. No treatment-related death was reported. Conclusions: Tunlametinib demonstrated an encouraging treatment response rate in patients with advanced NRAS-mutant melanoma with a manageable safety profile. These results suggest that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those who had previously received immunotherapy. Clinical trial information: NCT05217303 .
Immune phenotype profiling based on anatomic origin of melanoma and impact on clinical outcomes of immune checkpoint inhibitor treatment.
Authors: Hwang Soohyun , Ryu Hyang Joo , Kim Youhyun , Cho Soo Ick , Oum Chiyoon , Valero Puche Aaron , Lee Jinhee , Kim Kyoo Hyun , Chung Kee Yang , Shin Sang Joon , Ock Chan-Young , Jung Minkyu , Shen Jeanne
Published: July 2024

9569

Background: The inflamed immune phenotype is associated with a favorable response to immunotherapy in metastatic malignant melanoma. Although variations in molecular features across melanoma subtypes and differing ethnic distributions have been well reported, studies investigating immune phenotypes across multiple institutions within the context of different melanoma subtypes are scarce. We examined the association of immune phenotypes with outcomes after immunotherapy, based on subtypes of malignant melanoma. Methods: Two institutional advanced melanoma cohortsrepresenting Asian and Western populations (YUHS, n = 123; Stanford University, n = 102) were included. H&E-stained tumor slides were assessed using Lunit SCOPE IO, an AI-powered whole slide image analyzer, to define the inflamed score (IS, % of inflamed area) and the inflamed phenotype (>33.3% IS). Clinical outcomes after immune checkpoint inhibitor (anti-PD-1/PD-L1) treatment, including progression-free survival (PFS) and overall-survival (OS), were assessed. Results: In the overall cohort (n = 225), the inflamed phenotype was associated with prolonged PFS (HR = 0.634, 95% CI: 0.453 – 0.887, p = 0.007) and OS (HR = 0.655, 95% CI: 0.432 – 0.992, p = 0.044). On analysis of melanoma subtypes, we identified non-acral cutaneous melanomas (CM, n = 94), acral melanomas (AM, n = 52), mucosal melanomas (n = 43), uveal melanomas (n = 16), and melanomas of unknown primary site (n = 20), with a disproportionate enrichment of AM (37.4%) and mucosal (29.3%) melanoma cases in the YUHS cohort and CM cases (68.6%) in the Stanford cohort. The IS varied across different melanoma subtypes, with the highest IS observed in CM (median, [IQR]; 34.0, [5.8–52.2]), and significantly lower scores in AM (22.3, [7.7–36.9]), mucosal (13.6, [0–31.4]), and uveal melanoma (5.5, [0–13.6]). Among CM patients, the inflamed phenotype was significantly associated with better post-immunotherapy PFS (HR = 0.476, 95% CI: 0.274 – 0.826, p = 0.007). In contrast, the inflamed phenotype did not correlate with survival in AM patients (p = 0.58), who exhibited universally poorer PFS compared to non-AM patients (HR = 2.124, 95% CI: 1.486 - 3.005). Conclusions: AI-powered immune phenotype assessment highlights a heterogeneity of immune phenotypes across specific melanoma subtypes, as well as differential association with outcomes after immune checkpoint inhibitor treatment. While CM patients were well-stratified by immune phenotype, the predictive value of immune phenotyping was less pronounced in acral melanomas, which demonstrated poorer outcomes following immunotherapy.
Identifying the high risk group in stage pT1bN0 cutaneous melanoma.
Authors: Teterycz Pawel , Sryukina Tatsiana , Kluz Agnieszka , Ziobro Anna , Skoczylas Jacek , Zdzienicki Marcin , Rutkowski Piotr
Published: July 2024

9583

Background: In recent years, there has been a substantial improvement in prognosis for patients diagnosed with stage II or III melanoma due to the advent of adjuvant and neoadjuvant therapy. At the same time, significant percentage of melanoma deaths are caused by prevalent cases of thin melanoma. In this work, we aimed to identify the stage pT1bN0 melanoma subgroup with the worst prognosis. Methods: All cases of stage pT1b melanoma (with negative sentinel node biopsy) treated between 1998 and 2022 in high-throughput reference center were analyzed. Patients were followed for ten years or up to lost to follow-up or death. Patients alive at 10 year mark were censored. The patients were divided into groups with BOTH pT1b features (i.e., Breslow thickness > 0.8mm AND ulceration) vs those with just ONE of those features. Additionally, patients’ sex, the tumor’s pathological subtype, and mitotic index were analyzed. The Kaplan-Meier and the Cox proportional model were used in statistical analysis. Results: There were 665 cases identified. 63% of patients were female, median age was 49 (IQR: 38-60). 70% of patients were classified as pT1b due to Breslow thickness, 21% due to ulceration and 9% due to BOTH features. 48% of patients had superficially spreading melanoma, 3% - acral, 9% - nodular while other patients had other/unspecified subtype. The median mitotic index was 1/mm2, but this feature was missing in 46% of cases. Overall, 61 patients died during the follow-up. The 10-year overall survival (OS) rate for the whole group was 86% (95% CI: 83-90%). In a multivariable model, patients with BOTH IB features (HR 2.1, 95%CI:1.1-4.2), nodular or acral melanoma (HR 2.2, 95%CI:1.2-4.1) and males (HR 2.6, 95%CI:1.6-4.4) had worse prognosis; the mitotic index was not predictive for OS in this model. In patients with BOTH pT1b features the 10 year survival rate was 75% (95%CI: 62-89) and 87% (95%CI: 84-91%) in case of just one feature (log-rank p=0.008). Conclusions: There is a specific subgroup of patients diagnosed with stage IB who have a relatively bad prognosis. Focusing on perioperative treatment or on a more strict follow-up schedule in this group may prove beneficial.
Combined EORTC FDG-PET/CT and RECIST 1.1 response criteria and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.
Authors: De Barros E Silva Milton Jose , Tavares Monique Celeste , Lima Joao Paulo S. N. , Garcia Daniel , Rinck Jr Jose Augusto , Molina Andre , Lobo Matheus , Pinto Clovis Antonio Lopes , De Paula Rafaela Brito , van Akkooi Alexander Christopher Jonathan , Duprat Neto João Pedreira
Published: July 2024

9590

Background: Accurate identification of pathological response to neoadjuvant therapy for clinical stage III melanoma before surgery may allow us to better tailor the treatment. RECIST 1.1 has shown poor concordance rates with pathological responses and EORTC FDG-PET/CT response criteria using SUV max is susceptible to internal and external variables leading to difficulty in determining accuracy appropriately. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1mg/kg(N3+I1) for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. RECIST 1.1 and EORTC PETCT criteria were used to classify patients in terms of response. The pathological results were correlated to the image findings. Results: Between Jan 2019 and Jan 2024, 37 patients with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), positive nodes on baseline exam:1=30 (81%), 2=4(11%), and 3 or more =3(8%). Stage AJCC 8th edition: IIIB=23 (62%), IIIC=12 (32%), IIID=2(6%). Among them, 34 had baseline and post-neoadjuvant therapy PET-CT. Twenty-one (62%) had major pathological response (MPR) and 13(38%) had non-MPR. Using objective response and non-objective criteria to capture MPR and non-MPR, respectively, we found the following results: RECIST 1.1 (sensitivity= 48%, specificity=100%, accuracy=68%), EORTC-PET (sensitivity=90%, specificity=69%, accuracy=82%). Combining RECIST 1.1 and EORTC-PET/CT analysis, we found that: double objective responders (CR/PR and CMR/PMR, n=10) had 100% specificity to MPR and double progressors (PD/PMD, n=9) had 95% specificity to non-MPR. The only patient classified as double progressor that did not have non-MPR presented an intense inflammatory response with fever, pain and erythema leading to an increase in the size and number of lymph-nodes. No viable cells were found in the pathological report. Conclusions: Using combined RECIST 1.1 and EORTC-PET/CT response criteria may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.
Dynamics of circulating cytokines and chemokines during and after tumor-infiltrating lymphocyte cell therapy with lifileucel in advanced melanoma patients.
Authors: Qi Rongsu , Sarnaik Amod , Kirkwood John M. , Larkin James , Weber Jeffrey S. , Blaskovich Michelle , Kunkalla Kranthi , Fiaz Rana , Sulur Giri , Chou Jeffrey , Yin Hequn
Published: July 2024

9594

Background: Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, has demonstrated potentially clinically meaningful activity and durable responses in patients with advanced (unresectable or metastatic) melanoma. The regimen includes nonmyeloablative lymphodepletion (NMA-LD) prior to lifileucel infusion, and a short course of interleukin-2 (IL-2) post infusion. The safety profile of the regimen is consistent with the underlying disease and the known safety profiles of NMA-LD and IL-2. Cytokine release syndrome (CRS) is an acute and severe adverse event commonly associated with chimeric antigen receptor T-cell therapy. Here, we report circulating cytokine levels during and after the lifileucel treatment to monitor immune activation, and the dynamics of cytokines and chemokines to explore mechanism of action and potential predictive clinical biomarkers. Methods: The full analysis set of C-144-01 (NCT02360579) includes 153 patients with unresectable or metastatic melanoma who have progressed on checkpoint inhibitors and, if applicable, BRAF/MEK inhibitors. After tumor resection, patients received NMA-LD (cyclophosphamide on Days −7 to −6 and fludarabine on Days −5 to −1) followed by a single lifileucel infusion (Day 0) and up to 6 doses of IL-2 (Days 0-4). Peripheral blood samples were collected at baseline (pre-NMA-LD and pre-lifileucel infusion) and post-lifileucel infusion on Days 1, 4, 14, 42, and 84. Serum cytokine and chemokine levels were measured with BioPlex and included a multiplex panel for IL-6, IL-7, IL-9, IL-10, IL-12, CCL2, CXCL10, IFN-γ, and TNF-α. Plasma samples also were tested for IL-6, IL-15, and IL-7 levels by ELISA. Results: IL-15 levels following NMA-LD peaked at Day 1 and returned to baseline by Day 42. This is consistent with prior reports that NMA-LD increases circulating IL-15 levels, which may promote TIL expansion in the absence of competing endogenous lymphocytes. Similarly, IL-7 and CCL2 also peaked at Day 1. IL-6 did not increase during or after the lifileucel regimen, consistent with absence of severe systemic inflammation including higher grade CRS after lifileucel treatment. There was no difference in cytokine and chemokine levels between responders and nonresponders in the full analysis set. Conclusions: These data support the hypothesized mechanism of action of NMA-LD in the lifileucel regimen. Cytokine levels measured during treatment are consistent with lack of severe systemic inflammation observed in patients treated with lifileucel. Cytokine and chemokine dynamics did not predict for response to lifileucel. Clinical trial information: NCT02360579 .
Exploring factors impacting quality of life in patients with breast cancer undergoing adjuvant hormone therapy: Experience of the Medical Oncology Department-CHU Hassan II-FEZ University Hospital.
Authors: El Hilali Hafssa , Bahra Nassiba , Guennouni Sanae , Chbihi Chaymae , El Hakym Samia , Chouef Jihane , Talbi Oumaima , Medyouni Hajar , Amaadour Lamiae , Oualla Karima , Benbrahim Zineb , Bouhafa Touria , Mellas Nawfel , El Fakir Samira , Arifi Samia
Published: July 2024

e12507

Background: Considering that the recommended duration of adjuvant hormone therapy in localized breast cancer is at least 5 years, it becomes crucial to investigate the quality of life (QOL) of these patients and the factors influencing it. Objectives: To assess the quality of life (QOL) and identify factors impacting it in patients with localized hormone-sensitive breast cancer receiving adjuvant hormone therapy. Methods: We surveyed 335 patients with localized hormone-sensitive breast cancer undergoing adjuvant hormone therapy using the Moroccan Arabic dialect version of the EORTC QLQ-C30 questionnaire. Written informed consent was obtained from all participants. Confidentiality of participant data was maintained. The study was carried-out with respect to the Moroccan regulation in effect. Results: The overall quality of life (QOL) in our patient population was moderate, with positive scores for social functioning, followed by physical, cognitive, and emotional functioning. Financial difficulties emerged as the most influential factor affecting patients' QOL, followed by fatigue, pain, and other symptoms. Age-related declines in physical functioning were observed, with symptoms more prevalent, especially diarrhea, in patients aged 70 and above (p = 0.009). Urban patients faced a greater financial impact on QOL than rural patients (p = 0.025). Higher education correlated with improved QOL, particularly in physical functioning (p = 0.025). Married individuals demonstrated better overall QOL and fewer symptoms (p = 0.027). Menopausal patients exhibited lower ability and a higher loss of appetite (p = 0.027). No significant correlation was found between UICC stage and QOL. Patey-mastectomy was associated with more pain than tumorectomy (p = 0.024). Previous chemotherapy had no overall QOL impact, but users reported less diarrhea (p = 0.016). Hormone therapy type did not significantly affect overall health status, except for tamoxifen users who demonstrated improved functional roles (p = 0.008). The duration of adjuvant hormone therapy (<5 years or >5 years) showed no significant difference in patient QOL. Associated castration had a significant impact on overall health and role functioning, favoring non-castration (p = 0.034 and p = 0.011). Effective treatment tolerance positively influenced overall QOL, leading to better physical, emotional, and cognitive functioning (p < 0.0001), with fewer pronounced symptoms. Conclusions: Our study indicate that the overall QOL of patients with localized breast cancer under AET was moderate, and several factors were identified as major influences, each affecting the QOL in distinct ways.
De-escalation neoadjuvant chemotherapy in triple negative breast cancer.
Authors: Rodriguez Gonzalez Gara , Tuset Der-abrain Noemí , Prieto Garcia ANA , Gasol Cudos Ariadna , Morales Murillo Serafin
Published: July 2024

e12520

Background: Neoadjuvant chemotherapy (NAT) represents the predominant therapeutic approach in the early triple negative breast cancer. NAT has demonstrated high overall survival rates in patients that achieve a pathological complete response (pCR). In patients with a tumor size less than 5 cm and no involvement of axillary lymph nodes, it may be advisable to consider a shorter chemotherapy regimen to evaluate the achievement of pCR percentages compared to longer regimens. Methods: We conducted an analysis of a cohort comprising 62 patients with triple-negative breast cancer in stages I and II that received 4 cycles of NAT with paclitaxel 80 mg/m2 weekly for 12 weeks plus carboplatin in AUC 5 doses every three weeks. Results: The median age within the cohort was 61 years (32-83) with an initial tumor size of 22 mm (10-82) and Ki67 expression of 54% (13-90). Ten patients (16%) presented histologically confirmed initial axillary involvement. The group attained a pCR rate of 56% while only 21% exhibited a minor response with a residual tumor exceeding 10 mm. Over a median follow-up period of 34 months, the recurrence rate was only 5%. The distribution of pathological response across the different clinical variables is delineated in the Table. Conclusions: The NAT regimen with carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) for four cycles is safe for patients diagnosed with stage I and II, demonstrating a high pCR (56%) and a lower recurrence rate (5%). The pathological response observed across all clinical variable subgroups suggests that this regimen could be considered a potential standard for NAT in patients with stage I and II triple-negative breast cancer. [Table: see text]