bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulatory effects of selenium nanoparticles against drought stress in some grapevine rootstock/scion combinations
Authors: Daler Selda , Korkmaz Nesrin , Kılıç Tuğba , Hatterman-Valenti Harlene , Karadağ Ahmet , Kaya Ozkan
Published: August 2024

Background

Drought is a significant abiotic stress that adversely affects plant growth, development, and metabolic processes, thereby reducing plant yield, quality, and production, and threatening global food security. In recent years, nanotechnology has emerged as a promising strategy to overcome the existing environmental challenges and has been tested on some plant species. But it is still awaiting investigation for grapevines. The aim of this study was to investigate the potential of selenium nanoparticles (Se-NPs) to modulate some morphological, physiological, and biochemical parameters in grapevine saplings (5 BB/Crimson Seedless, 41 B/Crimson Seedless, and 1103 P/Crimson Seedless) under drought stress conditions.

Results

In the study, Se-NP solutions at different concentrations (0 (control), 1, 10, and 100 ppm) were applied by the spray method to wet the entire green surface of grapevine saplings grown under well-irrigated (90–100% field capacity) and drought stress (40–50% field capacity) conditions. Our results showed that 10 ppm Se-NP concentration had the most positive effect, 1 ppm concentration showed limited effects, and 100 ppm concentration led to toxic effects, especially when combined with drought conditions. Se-NP applications at 10 ppm concentration improved the growth parameters (leaf number, leaf area, root fresh and dry weight, shoot fresh and dry weight, etc.) and increased the SPAD index of grapevine saplings under both normal and drought conditions. Additionally, 10 ppm Se-NP applications improved the relative water content (RWC) and stomatal conductance values, proportional to the increases in protein content. On the other hand, under drought conditions, the drought index, leaf temperature, membrane damage index, hydrogen peroxide (H2O2) content, and malondialdehyde (MDA) levels significantly decreased as a result of 10 ppm Se-NP applications, showing an opposite trend. Furthermore, the levels of proline, total phenolics, and antioxidant enzymes (CAT, SOD, and APX) that rose significantly due to drought stress were reduced by 10 ppm Se-NP applications, which also helped to lessen the oxidative stress caused by the drought.

Conclusion

The study concluded that foliar application of Se-NPs at 10 ppm significantly enhances drought tolerance in grapevine saplings by improving antioxidant defense, proline and protein accumulation, and overall growth, while lower concentrations are less effective and higher concentrations can cause phytotoxicity. These findings indicate that Se-NPs applications may hold promise not only for grapevines but also for mitigating drought stress effects and improving productivity in other economically important fruit species, warranting further exploration across diverse crop systems.

Graphical Abstract
Left ventricular thrombus routine screening with contrast echocardiography in patients with anterior ST-elevation myocardial infarction: is it worth it?
Authors: Correia Joana Laranjeira , Ferreira Gonçalo R. M. , Fiuza João Gouveia , Almeida Mariana Duarte , Coelho Joana , Correia Emanuel , Correia José Miguel , Moreira Davide , Craveiro Nuno , Gonçalves Maria Luísa , Neto Vanda Devesa
Published: August 2024

Background

Left ventricular (LV) thrombus has a higher incidence among patients with anterior ST-elevation myocardial infarction (STEMI) when compared to other types of acute myocardial infarction and is associated with worse prognosis. The management of LV thrombus diagnosis remains challenging. Contrast echocardiography (transthoracic echocardiography, TTE) has shown potential in improving the accuracy for its diagnosis, thereby influencing treatment strategies concerning antithrombotic/anticoagulation therapy. The aim of this study was to assess the effectiveness of contrast TTE as a routine screening method for detecting LV thrombus in the acute phase of anterior STEMI.

Methods

A prospective, single center, randomized controlled trial was conducted among patients with anterior STEMI. The study group underwent contrast TTE, while the control group received a conventional approach. Demographical, clinical, and diagnostic data were collected. Thrombus detection rates were compared between groups.

Results

A total of 68 patients were included (32 in the study group and 36 in the control group). No substantial baseline differences were observed between groups. Thrombus detection rate was 25.0% in the study group and 13.9% in the control group, however these results did not reach statistical significance (P = 0.24). The prevalence of anterior/apical aneurysm was higher in the study group (46.9% vs. 22.2%, P = 0.03).

Conclusions

Conventional TTE may be adequate for diagnosing LV thrombus in the acute phase of anterior STEMI; however, further larger-scale and multicenter studies are necessary to obtain more robust and conclusive results. Ultrasound contrast may play a significant role in the detection of anterior/apical aneurysms, which are known risk factors for the subsequent development of thrombus.

Trial registration

NCT06480929 (ClinicalTrials.gov, Retrospectively registered).
Testamentary capacity
Authors: Burns Alistair , Series Hugh , Warner James , Bishop Andrew , McKean James
Published: August 2024

To make a valid will, a person should be able to understand the nature and consequences of doing so, the extent of their estate and the claims others may have on it. No disorder of mind should be present that would affect their testamentary decisions, and clinicians are therefore often asked to give an opinion on whether a person has testamentary capacity. This article discusses the legal issues involved, with reference to UK case law (in particular, the legal test of Banks v Goodfellow (1870)), and outlines the requirements of testamentary capacity assessment (including retrospective assessments), the clinician's responsibilities when requested by a solicitor to make an assessment of capacity (‘the golden rule’) and what they might expect if appearing in court to give expert witness regarding testamentary capacity. Fictitious case studies are presented illustrating certain points in testamentary capacity assessment.
Effect of nature on the mental health and well-being of children and adolescents: meta-review
Authors: Lomax Tessa , Butler Joseph , Cipriani Andrea , Singh Ilina
Published: August 2024

Background

Urbanisation is taking place worldwide and rates of mental illness are rising. There has been increasing interest in ‘nature’ and how it may benefit mental health and well-being.

Aims

To understand how the literature defines nature; what the characteristics of the nature intervention are; what mental health and well-being outcomes are being measured; and what the evidence shows, in regard to how nature affects the mental health and well-being of children and adolescents.

Method

A meta-review was conducted, searching three databases for relevant primary and secondary studies, using key search terms including ‘nature’ and ‘mental health’ and ‘mental well-being’. Inclusion criteria included published English-language studies on the child and adolescent population. Authors identified the highest quality evidence from studies meeting the inclusion criteria. Data were extracted and analysed using descriptive content analysis.

Results

Sixteen systematic reviews, two scoping reviews and five good quality cohort studies were included. ‘Nature’ was conceptualised along a continuum (the ‘nature research framework’) into three categories: a human-designed environment with natural elements; a human-designed natural environment; and a natural environment. The nature ‘intervention’ falls into three areas (the ‘nature intervention framework’): access, exposure and engagement with nature, with quantity and quality of nature relevant to all areas. Mental health and well-being outcomes fit along a continuum, with ‘disorder’ at one end and ‘well-being’ at the other. Nature appears to have a beneficial effect, but we cannot be certain of this.

Conclusions

Nature appears to have a beneficial effect on mental health and well-being of children and adolescents. Evidence is lacking on clinical populations, ethnically diverse populations and populations in low- and middle-income countries. Our results should be interpreted considering the limitations of the included studies and confidence in findings.
Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03.
Authors: Saura Cristina , Cortés Javier , Modi Shanu , Kim Sung-Bae , Hamilton Erika P. , Hurvitz Sara A. , Krop Ian E. , Curigliano Giuseppe , Iwata Hiroji , Im Seock-Ah , Herbolsheimer Pia Maarit , Karnoub Maha , Gambhire Dhiraj , Egorov Anton , Andre Fabrice
Published: August 2024

1023

Background: DESTINY-Breast (DB)-01, -02, and -03 evaluated T-DXd in pts with HER2+ mBC who received ≥1 prior line of therapy. These studies showed confirmed objective response rates by independent central review (ICR; blinded for DB-02 and -03) of 62%, 70%, and 79% and complete response (CR) rates of 7%, 14%, and 21%, respectively, with T-DXd. We report a pooled analysis according to pts’ best confirmed response in DB-01, -02, or -03. Methods: Endpoints included best confirmed response per (blinded) ICR ([B]ICR) based on RECIST v1.1, duration of response (DoR), progression-free survival (PFS) by (B)ICR, overall survival (OS), and safety. Results: The median (range) duration of T-DXd treatment for pts with a CR, partial response (PR), or stable disease (SD)/progressive disease (PD) was 27.4 (4.5-45.1) mo, 14.0 (2.1-39.3) mo, or 6.2 (0.7-40.1) mo, respectively. Of 834 evaluable pts assigned to T-DXd in DB-01, -02, or -03, 125 (15.0%) had a CR, 477 (57.2%) had a PR, and 232 (27.8%) had SD/PD. Pts with CR had a median of 2 prior regimens (range, 1-11) in the metastatic setting, whereas pts with PR or SD/PD had a median of 3 prior regimens. As shown in the Table, pts with CR had more favorable PFS and OS outcomes vs pts with PR or SD/PD. The proportion of pts with drug-related, serious treatment-emergent adverse events (TEAEs) was numerically lower in pts with CR (8.0%) than those with PR (12.4%) or SD/PD (15.5%). Pts with CR also had numerically lower rates of drug-related TEAEs associated with T-DXd discontinuation (14.4% vs 17.8% or 16.8%) and adjudicated drug-related interstitial lung disease (ILD)/pneumonitis (8.8% [0 fatal] vs 15.1% [2 fatal] or 11.6% [5 fatal]) and longer median time to first ILD onset (461 days vs 211 or 125 days) vs pts with PR or SD/PD. Conclusions: Pts treated with T-DXd benefited from durable responses resulting in prolonged PFS and OS, especially those with a CR. Despite longer treatment duration in responders, safety remained generally manageable and did not result in a higher percentage of pts with TEAEs over time. These results further support the use of T-DXd across broad pt groups with HER2+ mBC. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]
Symptom management through electronic patient-reported outcome (ePRO)-based intervention in patients with breast cancer treated with abemaciclib: Primary results from the LIBRA study, a phase II randomized controlled trial.
Authors: Takano Toshimi , Hayashida Tetsu , Nagayama Aiko , Ozaki Yukinori , Takahashi Maiko , Seki Tomoko , Yokoe Takamichi , Aoyama Yosuke , Kizawa Rika , Nishimura Meiko , Hosonaga Mari , Hara Fumikata , Kobayashi Takayuki , Ueno Takayuki , Kitagawa Yuko
Published: August 2024

11110

Background: We have developed a system using LINE, a widely-used social network service in Japan, for rapid collection of ePROs based on the PRO-CTCAE criteria. To evaluate the effectiveness of intervention through this system in reducing diarrhea frequency and enhancing quality of life (QOL) in patients treated with abemaciclib, we conducted a randomized controlled trial. Methods: Patients with hormone receptor-positive advanced breast cancer scheduled to begin abemaciclib treatment were randomized to the intervention and control arms with 1:1 ratio. The LINE-ePRO system was used to monitor symptoms daily in both arms. In the intervention arm, expert medical staffs contacted patients via phone when symptoms met certain criteria, whereas patients in the control arm received standard care. The primary endpoint was the increase in the number of defecations from baseline during 28 days. The secondary endpoints included the increase in the number of defecations from baseline during 56 days, other symptoms monitored via the LINE-ePRO system, QOL evaluated by EORTC QLQ C-30 and EQ-5D-5L, relative dose intensity (RDI), treatment interruption rate, progression-free survival (PFS), and overall survival (OS). This study (LIBRA, UMIN000045432) is funded by Eli Lilly. Results: Between Jan 2022 and Apr 2023, 60 women were enrolled and 58 (29 in each arm) were analyzed in this study. Median age was 57.5 years (range 43-80), 93% of patients were post-menopausal, 71% received abemaciclib as first-line treatment, and 74% were treated in combination with aromatase inhibitors. The increase in the number of defecations from baseline was significantly lower in the intervention arm compared to the control arm both during 28 days (0.64 vs. 1.21 per day, p=0.003) and during 56 days (0.55 vs. 1.18 per day, p=0.0004). No significant difference was observed in other symptoms between the arms. In the EORTC QLQ C-30 scales, global health status/QOL (mean score change from baseline to after one cycle of abemaciclib treatment: 0 vs. -13.5, p=0.038) and diarrhea (20.7 vs. 32.2, p=0.049) were better in the intervention arm. The treatment interruption and dose reduction rates were 41.4 and 31.0% in the intervention arm, and 31.0 and 27.6% in the control arm, respectively. The mean RDI of abemaciclib was numerically lower in the intervention arm (73.5% vs. 84.8%). Conclusions: This study is the first randomized trial to demonstrate that the intervention based on daily ePROs reduces the frequency of diarrhea in patients with advanced breast cancer treated with abemaciclib. Clinical trial information: UMIN000045432.
Durvalumab and tremelimumab versus doxorubicin in previously untreated patients with advanced or metastatic soft tissue sarcoma: Patient-reported outcomes (PROs) of the randomized phase II MEDISARC study (AIO-STS-0415).
Authors: Grünwald Viktor , Hermes Barbara , Tuchscherer Armin , Bauer Sebastian , Hamacher Rainer , Pink Daniel , Lindner Lars H , Gröschel Stefan , Reichardt Peter , Richter Stephan , Oing Christoph , Augustin Marinela , Crysandt Martina Margrit , Kortüm Martin , Kasper Bernd , Fischer Marc , Ivanyi Philipp
Published: August 2024

11519

Background: The randomized phase II MEDISARC trial (NCT03317457) tested durvalumab (DUR) and tremelimumab (TRE) vs. doxorubicin (DOX) in soft tissue sarcoma (STS) patients in first-line therapy. The study showed no PFS benefit (HR 1.22; 95%CI 0,90-1.64; P = .4049), but a trend in prolonged OS (HR 0.73; 95%CI 0.54-0.99; P = .185) in favor of DUR-TRE (Grünwald et al. ESMO 2024: LBA90). The current analysis reports on patient reported outcomes (PROs) under treatment. Methods: We utilized EORTC QLQ-C30 printed questionnaires in randomized patients. PRO were assessed during screening and under treatment every 12 weeks until progression, and 4 weeks after last dose. Time to deterioration (TTD; decrease by 5 points) and mean change from baseline was measured for QLQ-C30 domains. Formal statistic testing was not performed. Results: The median follow-up for DUR-TREM vs. DOX were 34.0 mo. (25.6-42.2) and 37.9 mo. (31.5-37.9). The median duration of therapy was 2.8 (0-13) and 2.1 (0-4) mo., respectively. 86 of 92 (93.5%) patients had ≥1 PRO assessments and were included into the analyses. The completion rate at week 12 was 41.3%. Mean baseline global health status (GHS) was 54.1 (SD: 25.64) and 56.5 (SD: 28.47), respectively. GHS above the median was associated with improved OS and PFS in both arms, indicating a possible predictive biomarker. Under treatment, changes in PRO domains at 12 weeks were noted. TTD favored DUR-TRE in selected functional and symptom domains. Details will be shown at the meeting. Conclusions: MEDISARC is the first study to compare check-point inhibitor and doxorubicin treatment in sarcoma patients. PRO measures from baseline to week 12 favored DUR-TRE. Overall, results indicated better symptom and quality of life in patients treated with DUR-TRE. Clinical trial information: NCT03317457. [Table: see text]
A phase 2 trial of the CDK4 inhibitor dalpiciclib in well-differentiated or dedifferentiated liposarcoma.
Authors: Liu Zengjun , Liu Mengyao , Xu Jing , Hu Wenyu , Zhang Hui , Tao Rongjie , Li Xinyu , Cha Lichao , Cui Jinfang , Zhao Junkai , Fu Heng , Fan Chunxiang , Tian Lantian , Qiu Fabo , Zhu Dongyuan
Published: August 2024

11547

Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in > 90% of well-differentiated liposarcomas (WDLS) and dedifferentiated liposarcomas (DDLS). Previous studies have already demonstrated the clinical benefit of CDK4 inhibitors in the treatment of WDLS and DDLS. Dalpiciclib is a more potent and novel CDK4 inhibitor. We designed a multi-center phase 2 study to evaluate the safety and efficacy of dalpiciclib in patients with advanced WDLS/DDLS. Methods: Eligible patients were adults aged 18 years and older, with a confirmed diagnosis of advanced WDLS/DDLS, measurable lesions according to RECIST 1.1, any (or no) priory therapy, and a history of progression by RECIST 1.1 in the 6 months prior to enrollment. All patients were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma (RB) protein expression by immunohistochemistry. All patients were treated with dalpiciclib 150 mg orally once per day for 21 consecutive days within a 28-day treatment cycle. The primary endpoint was progression free survival (PFS) at 12 weeks. Secondary end points included objective response rate and adverse events. Results: From August 2022 to October 2023, a total of 32 patients were enrolled, and 30 were evaluable for the primary end point. Median (range) age was 59 (40-76) years; 22 patients (69%) were male. At 12 weeks, PFS was 61.3% (95% CI, 44-78.5%). The median PFS was 17.4 weeks (95% CI, 10.65-24.15 weeks). Only one patient had a partial response to the treatment. Grade 3 to 4 events included neutropenia (37.5%), anemia (6.25%), thrombocytopenia (6.25%), and nausea (3.13%). Conclusions: Treatment with the CDK4 inhibitor dalpiciclib was associated with a favorable PFS rate in patients with advanced CDK4-amplified and RB-expressing WDLS/DDLS. Clinical trial information: ChiCTR2200062868.
Safety and efficacy of eribulin plus anlotinib in patients with advanced soft tissue sarcoma (ERAS): A multi-center phase II study.
Authors: Liu Jie , Deng Yaotiao , Wang Ying , Zhang Jie , Li Mei , Jiang Yu
Published: August 2024

11561

Background: Both the microtubule-dynamics inhibitor eribulin and the multi-targeted tyrosine kinase inhibitor anlotinib exhibit single-agent anti-tumor activity in previously treated soft tissue sarcoma (STS). This study aimed to evaluate the efficacy and safety of the combination treatment of eribulin and anlotinib in patients with advanced STS. Methods: In this multi-center phase II study (ERAS), patients with advanced soft tissue sarcoma who relapsed/progressed after anthracycline chemotherapy or were not candidates for such treatment were included. Patients received eribulin (1.1 mg/m² intravenously on days 1 and 8) and anlotinib (12mg orally once daily on days 1-14) every 21 days for 6-8 cycles, followed by anlotinib maintenance. The primary endpoint was progression-free survival rate at 24 weeks (PFR24w). Secondary endpoints included median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Thirty-one patients were enrolled. Twenty-eight (90.3%) patients had received anthracycline chemotherapy, and the remaining 3 (9.7%) were chemotherapy-naïve. Pathological types included L-type sarcomas (10 leiomyosarcomas and 6 dedifferentiated liposarcomas) and non-L-type sarcomas (n =15, with 8 subtypes). As of the cut-off date of Jan 28, 2024, the median follow-up time was 30.4 weeks. Response evaluation was feasible in 29 patients. The ORR, DCR and predicted PFR24w were 20.7%, 82.8% and 65.5%, respectively. The mPFS was 30.1 weeks, with no significant difference observed between patients with L-type sarcomas and non-L-type sarcomas. The mOS was not reached. Nineteen (61.3%) patients experienced at least one grade 3/4 adverse event. The most common grade 3/4 adverse events included neutropenia (35.5%), leukopenia (25.8%), hypertension (16.1%), hypertriglyceridemia (16.1%) and increased gamma-glutamyl transpeptidase (16.1%). Conclusions: The combination of eribulin and anlotinib shows promising efficacy with an acceptable toxicity profile in patients with advanced STS, irrespective of pathological type. Clinical trial information: ChiCTR2300067650.
Improving chemotherapy-induced alopecia for women receiving anthracycline plus taxane chemotherapy using the Paxman scalp cooling system at lower temperatures.
Authors: Goldfarb Shari Beth , Jamner Alanna , Toumbacaris Nicolas , Gordon Allison , Chen Yuan , Abdo Nadia , Dacunto Analisa , Blinder Victoria Susana , Fornier Monica N. , Chang Cassandra , Lacouture Mario E.
Published: August 2024

12143

Background: Chemotherapy-induced alopecia (CIA) not only impacts physical appearance but may also be detrimental to patient’s psychological well-being. To address CIA, patients often use scalp cooling devices such as the FDA-approved Paxman Scalp Cooling System (PSCS), currently approved at -5°C. This study explores the potential benefits of lower temperatures, -7.5°C and -10°C, to improve the efficacy of PSCS in minimizing CIA. Methods: This prospective study analyzed data from 33 women with stage I-III breast cancer receiving anthracycline and taxane chemo at MSKCC from 12/2019–10/2022. Photography, trichoscopy, and toxicity checks were conducted at baseline, weeks 4, 8 (primary endpoint), end of treatment (EOT), and 24 weeks post-chemotherapy. 23 patients reached week 8, while 10 withdrew prior due to lack of efficacy (5/10), change in treatment (3/10), or anxiety (2/10). Successful hair preservation (HP) was defined as CTCAE v4 grade 0 or 1 alopecia. Results: At baseline, all patients had grade 0 alopecia. At week 4, 81% achieved successful HP (17/21), and at week 8, over half maintained it (53%; 9/17). The majority had HP at EOT (69%; 11/16). At 24 weeks post-chemotherapy, all patients demonstrated continued HP (100%; 11/11) and all evaluated patients at 18 months post-treatment had grade 0 alopecia (100%,4/4). Among women with baseline photographs and trichoscopy (n=25), median average hair count at baseline was 154.0 per cm² and width 70.2 per cm². By week 4 (n=21), the median average hair count decreased by 20.0%, and width decreased by 8.0% compared to baseline. By week 8 (n=17), average count improved by 15% compared to week 4 (-3% from baseline) and average width decreased by 6% (-7.5% baseline). At EOT hair count decreased 37.8% and width decreased by 11.6% compared to baseline (n=16). At 24 weeks post-EOT there was a 13% increase in median average hair count with no measurable change in width compared to baseline (n=12). No patients (0%; 0/33) reported dose-limiting toxicities (DLTs) at -7.5°C (n=7) or -10°C (n=26). Conclusions: Patients successfully tolerated scalp cooling at lower temperatures, with no reported dose-limiting toxicities and successful HP. This study indicates higher HP rate at EOT (69%; 11/16) compared to studies using PSCS at -5°C. Post-EOT data shows successful hair regrowth with a higher average hair count than pre-treatment. A larger sample size is needed to assess the additional benefit of lower temperatures on HP and regrowth. Clinical trial information: NCT.[Table: see text]
Evaluation of survival outcomes in patients with solid organ cancer with brain metastasis treated with exacta encylopedic tumor analysis based treatments.
Authors: Kurzrock Razelle , Limaye Sewanti , Massoudi Farzad , Datar Rajan , Srinivasan Ajay , Gosavi Rahul Ashok , Datta Vineet , Syed Nelofer , Crook Tim
Published: August 2024

2033

Background: Brain metastasis in solid organ cancers presents a challenging scenario with an adverse prognosis and limited systemic treatment options. Treatment of such patients becomes more challenging because most drugs can't cross the blood-brain barrier, besides the treatment being too harsh for sensitive brain parenchyma. Moreover, these patients are frequently excluded from clinical trials, reflecting concerns about their poor prognosis influencing trial outcomes and potentially distorting efficacy data. While almost all cancers metastasize to the brain, cancers of the breast, lungs, kidney and melanoma carry a higher risk. Methods: The Resilient Study, a Phase-II, single-arm, open-label interventional trial, focused on evaluating the efficacy of Exacta Encyclopedic Tumor Analysis (ETA)-guided treatment for a range of solid organ cancers in patients who had failed multiple lines of treatment and were broadly refractory. 143 patients were recruited out of whom 126 patients were evaluable. Prior to treatment initiation, all patients underwent PET-CT and MRI scans to assess the extent of the disease. 9 out of 126 patients (7.1%) were found to have metastatic deposits of the brain comprising 6/21 patients (29%) of breast cancer, 2/5 patients (40%) of lung cancer, and 1/15 patient (7%) of colorectal cancer. Utilizing freshly biopsied tumor tissue (primary/lymph node/liver) and peripheral blood, Exacta ETA was performed, encompassing gene mutations, gene expression, and in vitro chemosensitivity profiling of viable tumor cells. Exacta ETA-derived personalized therapy recommendations were administered to patients. Follow-up data for OS was collated. Results: Median overall survival (OS) was not reached at the time of analysis. By considering the OS values censored at the interim (most recent follow-up), the median OS was 9.7 months (95% CI 7.06 - 12.3 months; range: 1 month – not reached) among patients without brain metastases (n = 117, 92.8%) and 10 months (95% CI 2.6 - 15.9 months; range: 2.6 months – not reached) among patients with brain metastases. Conclusions: Our data shows that personalized Exacta ETA-guided treatments resulted in almost similar OS for patients with brain metastases as seen in patients or without brain metastases. These findings stand out as significant considering the poor outcomes with Standard of Care treatments in patients with brain metastases. Clinical trial information: CTRI/2018/02/011808.
Initial data from a phase 1, first-in-human clinical trial for T-Plex, a multiplexed, enhanced T cell receptor-engineered T cell therapy (TCR-T) for solid tumors.
Authors: Thomas Sajeve Samuel , Pico Brian , Henick Brian S. , Leidner Rom , Samhouri Yazan , Isaacs James , Weiss Jared , Hurwitz Michael E. , Grewal Jaspreet Singh , Luke Jason J. , Chattopadhyay Shrikanta , Wang Yun , Motta Marlyane , Murray Jim , Barton Debora , Pinchasik Dawn , MacBeath Gavin , Moser Justin C
Published: August 2024

2542

Background: Solid tumors are notoriously heterogenous with highly variable antigen expression and an immunosuppressive microenvironment. HLA loss of heterozygosity (LOH) has also been identified in up to 40% of solid tumors, allowing tumor cells to evade T cell attack. To overcome these issues and a lack of potent endogenous antitumor T cells in cancer patients, TScan has developed T-Plex, a multiplexed cell therapy comprising two to three different TCR-Ts, chosen from a collection of TCR-Ts called the ImmunoBank. Product and study design details were presented at ASCO 2023 (Abstract #2554). Methods: A screening protocol (NCT05812027) pre-identifies patients with solid tumors any time during clinical care, enabling rapid enrollment into the treatment protocol (NCT05973487) upon disease progression. TCR-Ts currently in the master protocol target PRAME on HLA-A*02:01; HPV16 on HLA-A*02:01; MAGE-A1 on HLA-A*02:01, HLA-A*01:01, or HLA-C*07:02; or MAGE-C2 on HLA-B*07:02. All TCR-Ts in the ImmunoBank and master protocol are first tested as single therapies in dose levels 1 and 2 before becoming available for multiplexing in dose levels 3 and 4. Results: From September 2023 to the time of abstract submission, 140 participants with a variety of solid tumors were enrolled in the screening protocol and are in different stages of screening. To date, 65% have ≥1 HLA match, and 20% and 6% have 2 and 3 HLA matches, respectively, highlighting the advantage of including TCR-Ts targeting multiple different HLA types within the same master protocol. Of those who have completed target screening, 92% express at least one target and 65% qualify for at least one TCR-T. Intratumoral heterogeneity of target expression was observed even with the most prevalently expressed target, PRAME, supporting the rationale for multiplexed TCR-T treatment. Although HLA-LOH affects only half of HLA genes and the remaining intact HLA alleles in tumors can still be recognized by TCR-Ts, about 13% of participants had LOH of the targeted HLA allele, excluding them from TCR-T treatment. Conclusions: Initial data indicate that the combination of HLAs and targets in the ImmunoBank results in ≥1 TCR-T match for the majority of solid tumor patients evaluated to date, and many patients qualify for multiplexed TCR-T treatment. LOH testing can prevent selection and treatment with a TCR-T that would not confer benefit. The proportion of patients eligible for multiplexing is expected to increase as the ImmunoBank grows. Updated data on screened and treated patients will be presented at the meeting. Clinical trial information: NCT05973487 ; NCT05812027 .
Phase 1 trial of TU2218, TGFβ-RI and VEGF-R2 dual inhibitor in monotherapy and combination with pembrolizumab in patients with advanced solid tumors.
Authors: Oh Do-Youn , Tolcher Anthony W. , Chaudhry Arvind , Lee Arielle Shebay , Chaney Marya F. , Kim Kyu-Pyo , Kim Hun-taek
Published: August 2024

2613

Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance may emerge in some of the patients treated. VEGF and TGF-β pathways play an important role in the development and function of the tumor-microenvironment (TME), contributing to be the immunosuppressive. TU2218 is a highly potent, orally available dual inhibitor against TGFβ type I receptor (ALK5) and VEGFR2. This was a first-in-human study to investigate the safety and tolerability of TU2218 monotherapy and combination therapy with pembrolizumab. Methods: This non-randomized, open-label, multinational, multicenter study evaluated the safety, tolerability, PK, and preliminary efficacy of TU2218 alone and combination with pembrolizumab to determine the Recommended Phase 2 Dose of the Combination (RP2DC) in advanced solid tumors. Eligible patients were ≥ 18 years of age, ECOG performance status of 0 or 1 and had measurable lesion per RECIST 1.1. Part A of monotherapy was sequentially escalated to 6 dose levels of TU2218 ranging from 30 to 270 mg/day on a 2 weeks-on/1 week-off regimen using a BOIN design. In part B, patients received TU2218 doses of 105, 150 and 195 mg/day on a 2 weeks-on/1 week-off cycle in combination with pembrolizumab 200mg once every 3 weeks. Dose escalation followed a 3+3 design with a DLT evaluation period. Results: In the TU2218 monotherapy dosed BID (n=22), no Grade 3 or higher treatment related AE was reported, while all Grade 2 TRAEs were tolerable. Systemic exposure to TU2218 increased in a dose dependent manner. Following seven days of administration, TU2218 demonstrated reductions in PD markers and a correlation was observed between TU2218 exposure and the decrease of PD markers, particularly TGF-β1 (-16.5%) and CTGF (-45.4%) blood levels in groups of TU2218 Cmax ≥ 1.0 μM. Patients (n=12) received TU2218 at doses levels of 105 to 195mg/day in combination with pembrolizumab 200mg once every 3 weeks. The most frequently observed TRAE was pruritus (25%, n=3) and one patient experienced Grade 3 TRAE with maculo-papular rash (8.3%, n=1). No DLT was observed during the dose escalation and the MTD was not identified. The best ORR in the combination cohort demonstrated PR at 8.3% (n=1), SD 50% (n=6) and PD at 33% (n=4). The dose level at 195mg/day of TU2218 in combination with pembrolizumab was safe and tolerable. Conclusions: TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2 was well-tolerated in the monotherapy and in the combination therapy with pembrolizumab. The RP2DC was established for subsequent trials in specific cancer types. Clinical trial information: Phase 1a: NCT05204862 / Phase 1b: NCT05784688 .
Stereotactic body radiotherapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) versus TACE and TKIs alone for unresectable hepatocellular carcinoma (uHCC) with portal vein tumor thrombus (PVTT): A randomized controlled trial.
Authors: Duan Jiayu , Zhou Jitao , Liu Chang , Jiang Hanyu , Zhou Jin , Xie Kunlin , Wu Hong , Zeng Yong , Wang Xin
Published: August 2024

4102

Background: TKIs-based systemic therapy is a primary treatment option for uHCC. Clinical studies have established the effectiveness and safety of radiotherapy (RT) in patients with PVTT, who typically have a poor prognosis. Previous research has shown that combining TACE and RT can extend survival in HCC patients with PVTT compared to sorafenib treatment. This study aimed to explore the efficacy and safety of combined local therapy (TACE plus SBRT) and TKIs in HCC patients with PVTT. Methods: This single-center, randomized controlled study enrolled patients aged ≥18 years with HCC and PVTT. Additional eligible criteria included ECOG PS 0-1, Child-Pugh score ≤B7, no extrahepatic metastasis on CT scan, and normal liver volume ≥700cc. Patients were randomly assigned to either the SBRT+TACE+TKIs group (Group A) or the TACE+TKIs group (Group B). SBRT was administered at 35-45 Gy in 5 fractions, 3 fractions per week. TKIs (sorafenib 0.4g bid; donafenib 0.2g bid; or lenvatinib 8mg/12mg qd, depending on body weight) were paused during the perioperative period of TACE (up to 4 times). The primary endpoint was the 6-month progression-free survival (PFS) rate, with secondary endpoints including objective response rate (ORR), overall survival (OS), disease control rate (DCR) and treatment-related adverse events (TRAEs). Treatment response was evaluated using mRECIST. Results: A total of 90 patients with uHCC were enrolled from June 2019 to October 2023 in this trial, with baseline characteristics presented in the Table. As of January 5th 2024, the median follow-up time was 14.5 months [IQR, 2.43-55]. The 6-month PFS rate was significantly higher in Group A (78%) compared to Group B (36%, P=0.0245). Group A also showed prolonged median PFS (9.75 vs. 4.89 months, HR=1.703 [95%CI, 1.045-2.777], P=0.0245) and OS (17.93 vs. 9.61 months, HR=1.869 [95%CI, 1.059-3.266], P=0.017). Improved ORR was observed in the SBRT group (74.4% vs. 40.5%, P=0.0015). DCR was 81.4% in Group A and 66.7% in Group B ( P=0.1211). The most common grade 3/4 TRAEs were hypertension (Group A: 17.8%, Group B: 13.3%, P=0.5608), ALT elevation (Group A: 26.7%, Group B: 22.2%, P=0.6237), and AST elevation (Group A: 22.2%, Group B: 15.6%, P=0.4191). There was one treatment-related death in Group B due to liver failure. Conclusions: In uHCC patients with PVTT, the combination of SBRT and TACE-TKIs showed significant survival benefit without the identification of any severe safety concerns. Clinical trial information: ChiCTR1900025300. [Table: see text]
Improving patient understanding of GEP test results (IMPARTER4): An RCT.
Authors: Fallowfield Lesley , Solis-Trapala Ivonne , Starkings Rachel , Matthews Lucy , May Shirley , Jenkins Valerie A
Published: August 2024

527

Background: We developed two 8 min films to aid patients’ understanding about gene expression profiling (GEP) tests (Oncotype DX or Prosigna) in breast cancer. A previous study of 120 women without breast cancer demonstrated significantly better knowledge after film viewing compared to that after reading written materials (1). We present results of an RCT testing the films’ utility when given in clinics to women with early HR+ breast cancer for whom the benefit of chemotherapy was uncertain. Methods: Standard information policies about GEP testing differ, some clinics may provide patients with leaflets, others only verbal information. Patients who had consented to a GEP test were invited to join IMPARTER4. At baseline they completed anxiety trait/state and intolerance of uncertainty (IoU) questionnaires and were then randomized to Gp A (hospitals’ standard information alone) or Gp B (standard information plus the relevant GEP patient film). Prior to learning their risk of recurrence scores, researchers interviewed patients and probed their understanding and knowledge about GEP testing together with the role risk scores had in helping determine management options (hormone therapy plus or minus chemotherapy). Following test result discussions with oncologists, patients completed two further questionnaires measuring anxiety and decisional conflict. Treating physicians all completed IoU questionnaires once at baseline, Satisfaction with their clinical interviews conducted with patients about risk scores and management decisions was measured using a study specific questionnaire. Results: To date 225/230 patients from 18 UK hospitals (Gp A (standard information alone) n=103; Gp B (standard plus information film) n=122) were seen by 79 physicians. Socio-demographics, anxiety trait/state and IoU did not differ between groups. Prior to the results discussion, written information was given to 128/225 (56.9%), (66 in Gp A, and 62 in Gp B). Linear regression analyses (adjusted for age and education) showed that mean knowledge scores were higher in those receiving standard information plus the film (Gp B), (2.5 points (95% C.I:1.7-3.4) p<0.001). There was a trend for longer consultations in those patients having standard information alone (Gp A) (12.6% v 8.2%), who also asked more difficult questions (9.7% v 2.5%). Conclusions: Patient information films significantly improved knowledge about GEP tests and recurrence risk results compared to standard verbal and written information alone. Furthermore, the films appeared to enable shorter, more informed discussions between patients and their oncologists about the addition of chemotherapy to hormone therapy alone. Versions in Spanish, Italian, French, Urdu, Hindi, Gujarati, Punjabi, and Bengali are freely available. 1. Fallowfield et al, Br Ca Res & Tmt. 2022. Clinical trial information: 28497350.
A prospective cohort study on rivaroxaban in the prevention of catheter-related thrombosis in breast cancer.
Authors: Sang Die , Zhang Yurong , Fan Shanmin , Li Shiyu , Su Yanfang , Yuan Peng
Published: August 2024

e12602

Background: Chemotherapy is an important treatment strategy for breast cancer. Catheter related thrombosis (CRT) is one of the most common complications of catheterization, affecting patients’ living quality and survival. It is thus of great practical significance for exploring how to prevent CRT. That’s why we carried out this study to provide evidence-based medical data for the prevention and treatment of thrombosis in breast cancer patients. Methods: A prospective cohort study approach was adopted. Breast cancer patients who received deep vein catheterization chemotherapy from July 2021 to July 2023 were selected. Cohort A included patients in the treatment group: they received prophylactic anticoagulation after catheterization: Rivaroxaban, 10 mg, orally once/d for 2 months; cohort B included patients in the control group, who did not receive prophylactic anticoagulation. The thrombosis was compared between the patients in the two groups within six months after catheterization. The comparison between groups was tested by X2 test, and logistic regression analysis was used to analyze the influencing factors of CRT. Results: A total of 402 breast cancer patients were enrolled. The incidence of CRT was 2.0% (4/201) in the treatment group of 201 cases and 12.4% (25/201) in the control group of 201 cases ( P=0.000). The thrombus was mainly located around the axillary vein, basilic vein and subclavian vein, the innominate vein, and the internal jugular vein. There were 44.8% (13/29) patients developed CRT within 30 days after catheterization, 20.7% (6/29) patients developed CRT within 30~<60days, and 34.5% (10/29) patients developed CRT within 60~<120 days. Patients diagnosed with CRT received anticoagulant therapy for 3 months. Within three months, the thrombus regression rate reached 100.0% (29/29). Univariate analysis showed that whether to receive prophylactic anticoagulation, whether hemoglobin is normal, patients whether to experience previous endocrine therapy, different Age group and chemotherapy regimens were actors for thrombosis, P<0.05 respectively. Multivariate analysis indicated that age and whether to receive prophylactic anticoagulation were independent factors for thrombosis ( P=0.019, P=0.006, respectively). Patients diagnosed with CRT received deep vein cannulation while anticoagulation therapy was administered, with smooth infusion. They all completed antitumor therapy as planned, and no abnormalities such as new thrombosis and pulmonary embolism were found. Conclusions: The prophylactic anticoagulation regimen with Rivaroxaban can reduce the incidence of CRT in breast cancer, showing good efficacy and safety. Therefore, medical staff should carry out early prevention, early detection and early treatment for CRT to improve the living quality of patients. Clinical trial information: ChiCTR2000031649.
Efficacy and safety of neoadjuvant trastuzumab, pyrotinib, and dalpiciclib without chemotherapy in early-stage HR-negative/HER2-positive breast cancer: An open-label, single-arm phase II trial.
Authors: Zhi Xiao , Chen Feiyu , Liao Liqiu , Luo Shayang , Liu Xuan , Liu Xiangyan , Xu Tao , Hu Yu , Luo Na , Wang Kuansong , Wang Shouman
Published: August 2024

e12613

Background: The chemotherapy-free neoadjuvant regimens of dual HER2 blockade has showed encouraging rates of pathological complete response (pCR) in patients with HER2-positive breast cancer. Additionally, combining cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with anti-HER2 therapy has shown synergistic effects in hormone receptor (HR)-positive and HER2-positive breast cancer. However, there is limited data regarding this combination strategy in HR-negative/HER2-positive settings. The objective of this study was to evaluate the efficacy and safety of a chemotherapy-free regimen consisting of the CDK4/6 inhibitor dalpiciclib, and dual anti-HER2 components of pyrotinib and trastuzumab in patients with HR-negative/HER2-positive early breast cancer (EBC). Methods: This open-label, single-arm, phase II study was designed using the Simon two-stage method (Registration number: Chi-CTR-2200060748). Patients with HR-negative/HER2-positive operable EBC (tumor stage T1-3 and nodal stage N0-2) were enrolled. Eligible patients received trastuzumab (HLX02, 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks intravenously) for 15 weeks, plus pyrotinib (240 mg daily orally) and dalpiciclib (125 mg daily orally for 3 weeks, followed by 1 week off) for 16 weeks. Surgery was performed 3-6 weeks after the completion of the last cycle of study treatment. The primary endpoint was pCR (ypT0/Tis ypN0) at surgery, and secondary endpoints included objective response rate (ORR), change of Ki-67 labeling index, biomarker analysis, survival and safety. Results: Between Jun 24, 2022, and Sept 14, 2023, a total of 30 patients with a median age of 54.5 years (range: 35-66) were enrolled and treated in this ongoing trial. As of the data cutoff date on Jan 20, 2024, 26 patients underwent surgery, and pCR was achieved in 18 (69.2%) cases. Out of the 29 patients with evaluable response, 26 achieved partial response and 3 achieved stable disease, resulting in an ORR of 89.7%. The most common grade 3 or more treatment-related adverse events (AEs) were diarrhea (66.7%), decreased neutrophil count (33.3%), and decreased white blood cell count (20.8%). Most AEs were tolerable, and no treatment-related deaths occur. Conclusions: In patients with HR-negative/HER2-positive EBC, a dual HER2-targeted combination of pyrotinib and trastuzumab, along with dalpiciclib in the absence of chemotherapy showed promising efficacy with encouraging pCR and ORR rates, as well as a favorable safety profile in the neoadjuvant setting. Clinical trial information: Chi-CTR-2200060748.
Results of a phase 1/2 study of MHB036C: A potential best-in-class TROP2 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in locally advanced or metastatic solid tumors.
Authors: Lu Shun , Zhang Qingyuan , Meng Xiangjiao , Sun Yuping , Xiong Hui Hua , Lv Dongqing , Wang Xiaojia , Wu Lin , Dong Xiaorong , Ji Yuanyuan , Ji Yinghua , Han Liang , Lei Kaijian , Jiang Ou , Zhao Yanqiu , Zhang Zhen , Shi Junwei , Cao Guoqing
Published: August 2024

e15007

Background: MHB036C, an investigational ADC, comprises a humanized anti-TROP2 monoclonal antibody engineered to minimize potential toxicities mediated by non-specific uptake, and a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd) conjugated via a stable cleavable linker. In preclinical studies, MHB036C demonstrated superior tumor killing activities (5~10 times more potent than the DS-1062a analog) and a favorable safety profile with no unique toxicities as compared to other TROP2 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB036C. Methods: Patients with locally advanced or metastatic solid tumors were enrolled in dose-escalation (D-Esc) and dose-expansion (D-Exp) segments. The D-esc study, utilizing an accelerated titration followed by the traditional 3+3 design, assessed MHB036C at doses ranging from 0.25-2.25 mg/kg administered intravenously (IV) every 3 weeks. Results: At data cutoff (Dec 31, 2023), 26 pts were enrolled and received at least one dose of MHB036C (D-Esc, n=11, D-Exp, n=15). Two pts experienced dose-limiting toxicities (Grade 3 stomatitis) at 2.25 mg/kg. The MTD was determined to be 1.5 mg/kg. The most common TRAEs overall in ≥25% of pts were stomatitis, anemia, decreased appetite, vomiting, white blood cell (WBC) count decreased, fatigue, nausea, and neutrophil count decreased. The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were stomatitis (34.6%), WBC count decreased (11.5%), neutrophil count decreased (7.7%), and anemia (7.7%). No ILD was reported. Of 21 response-evaluable pts, 7 experienced partial responses. In the subset of 12 NSCLC pts treated with doses ranging from 1.3 to 2.25 mg/kg, the ORR was 33.3% (4/12) and the DCR was 83.3%. In the subset of 5 HER2-negative breast cancer pts encompassing 4 TNBC pts and 1 HR+/HER2- breast cancer patient, the ORR was 60.0% (3/5). Conclusions: MHB036C demonstrated a manageable safety profile without either major hematologic side effects or ILDs and encouraging efficacy in NSCLC and HER2- breast cancer, representing a potential best-in-class TROP2 ADC. The dose optimization and expansion study is ongoing to establish the RP2D for MHB036C. Clinical trial information: CTR20231246.