bluuebunny/crossref_metadata_2025 huggingface dataset:
Multinational, Multicenter Evaluation of Prostate Cancer Tissue in Sub-Saharan Africa: Challenges and Opportunities
Authors: van Wyk Abraham C. , Lal Priti , Ogunbiyi J. Olufemi , Kyokunda Lynnette , Hobenu Fred , Dial Cherif , Jalloh Mohamed , Gyasi Richard , Oluwole Olabode P. , Abrahams Afua D. , Botha Adam R. , Mtshali Nompumelelo Zamokuhle , Andrews Caroline , Mante Sunny , Adusei Ben , Gueye Serigne M. , Mensah James E. , Adjei Andrew Anthony , Tettey Yao , Adebiyi Akin , Aisuodionoe-Shadrach Oseremen , Eniola Sefiu Bolarinwa , Serna Amparo , Yamoah Kosj , Chen Wenlong Carl , Fernandez Pedro , Robinson Brian D. , Mosquera Juan Miguel , Hsing Ann W. , Agalliu Ilir , Rebbeck Timothy R.
Published: June 2024

PURPOSE

Prostate cancer disproportionately affects men of African descent, yet their representation in tissue-based studies is limited. This multinational, multicenter pilot study aims to establish the groundwork for collaborative research on prostate cancer in sub-Saharan Africa.

METHODS

The Men of African Descent and Carcinoma of the Prostate network formed a pathologist working group representing eight institutions in five African countries. Formalin-fixed paraffin-embedded prostate tissue specimens were collected from Senegal, Nigeria, and Ghana. Histology slides were produced and digitally scanned. A central genitourinary pathologist (P.L.) and eight African general pathologists reviewed anonymized digital whole-slide images for International Society of Urological Pathology grade groups and other pathologic parameters. Discrepancies were re-evaluated, and consensus grading was assigned. A virtual training seminar on prostate cancer grading was followed by a second assessment on a subcohort of the same tissue set.

RESULTS

Of 134 tissue blocks, 133 had evaluable tissue; 13 lacked cancer evidence, and four were of insufficient quality. Post-training, interobserver agreement for grade groups improved to 56%, with a median Cohen's quadratic weighted kappa of 0.83 (mean, 0.74), compared with an initial 46% agreement and a quadratic weighted kappa of 0.77. Interobserver agreement between African pathologist groups was 40%, with a quadratic weighted kappa of 0.66 (95% CI, 0.51 to 0.76). African pathologists tended to overgrade (36%) more frequently than undergrade (18%) compared with the reference genitourinary pathologist. Interobserver variability tended to worsen with a decrease in tissue quality.

CONCLUSION

Tissue-based studies on prostate cancer in men of African descent are essential for a better understanding of this common disease. Standardized tissue handling protocols are crucial to ensure good tissue quality and data. The use of digital slide imaging can enhance collaboration among pathologists in multinational, multicenter studies.
Prospective evaluation of pre-treatment ctDNA burden in localized osteosarcoma to identify patients with inferior outcomes: A report from the LEOPARD study.
Authors: Shulman David Stephen , Klega Kelly S. , Chen Nan , Gohn Elliot , Henry Donovan , Choy Edwin , Cash Thomas , Schultz Kris Ann Pinekenstein , Mascarenhas Leo , Bagatell Rochelle , Turpin Brian , Setty Bhuvana , DeNardo Bradley , Hawkins Douglas S. , Bishop Michael W. , Shah Avanthi T , Maese Luke Devon , London Wendy B , DuBois Steven G. , Crompton Brian D.
Published: June 2024

11510

Background: Prior retrospective analyses demonstrated that elevated pre-treatment ctDNA was associated with poor outcomes in newly diagnosed localized osteosarcoma. The primary objective of the LEOPARD study (Liquid biopsy in Ewing sarcoma and osteosarcoma as a prognostic and response diagnostic) was to determine whether patients with detectable pre-treatment ctDNA have an inferior event-free survival (EFS) compared to patients with undetectable ctDNA. Methods: The LEOPARD study is a prospective multicenter ctDNA study for patients with bone sarcomas. Patients enrolled through 12 primary study sites, or provided samples after enrolling on the Children’s Oncology Group Project EveryChild (ABTR18B1-Q). Eligible patients were 1-50 years of age at enrollment, had unresected, high-grade, localized, non-pelvic osteosarcoma and were to receive standard chemotherapy (primary centers only). We utilized a validated ctDNA assay, ultra-low pass whole genome sequencing (ULP-WGS), for ctDNA quantification based on tumor aneuploidy (limit of detection 3%). We compared EFS according to baseline ctDNA burden using two pre-specified cut points (detectable/undetectable [≥3%] and ~median [≥5%]. We planned 113 patients for 80% power to detect a difference in 2-year EFS of ~20% or greater for patients with detectable baseline ctDNA (2-year EFS: 68%) vs undetectable ctDNA (2-year EFS: 87%; one-sided log-rank test; ⍺ =0.05). Results: From 10/1/17 to 3/3/23, 138 patients with osteosarcoma met eligibility and enrolled (67 - primary study centers; 71 - ABTR18B1-Q). 133 patients had an evaluable pre-treatment ctDNA measurement. Median age was 14.2 years (range: 4.2-30.3) and 50% of patients were male. At diagnosis, 63% had detectable ctDNA [median: 5.3% (range: 0-43.1)]. Age, sex, race, ethnicity, and tumor size were not associated with a difference in ctDNA burden. Baseline detectable ctDNA burden (≥3%) was associated with an increased risk of EFS-event (relapse/progression, second malignant neoplasm, death) compared to undetectable ctDNA (2-year EFS: 56% [95% CI 45-68%] vs. 88% [95% CI 78-98%]; P< 0.0001; Table). A similar pattern was seen using a cut point of ≥5% (53% [95% CI 41-67%] vs. 83% [95% CI 74-94%], P< 0.0001). Conclusions: These findings validate prior data associating baseline ctDNA detection with inferior EFS in patients with localized osteosarcoma and identify the first prospectively validated molecular biomarker in this disease. Baseline ctDNA burden is now positioned for implementation into upcoming therapeutic trials of risk-stratified therapy in localized osteosarcoma. [Table: see text]
Predictive gene signature for trabectedin efficacy in advanced soft‐tissue sarcoma: A Spanish group for research in sarcoma (GEIS) study.
Authors: Moura David Silva , Cordero Varela Juan A. , Alvarez Ramiro , Agra Pujol Carolina , Izquierdo Francisco , Ramos Rafael , Ortega Luis , Martin-Davila Francisco , Hernandez Leon Nieves , Romagosa Cleofe , Vaz-Salgado Maria Ángeles , Lavernia Javier , Bague Silvia , Mayodormo-Aranda Empar , Mondaza-Hernandez Jose Lucinio , Renshaw-Calderon Marta , Hindi Nadia , Valverde Morales Claudia , Martínez-Trufero Javier , Martin Broto Javier
Published: June 2024

11543

Background: Predictive biomarkers of trabectedin represent a clinical unmet need to support the rational selection of this drug in the advanced soft‐tissue sarcomas (STS) setting. A few potential predictive biomarkers of trabectedin had been described in previous studies, including ERCC1, BRCA1, and HMGA1, among others; however, they are based mostly on the analysis of single selected molecular factors. We presented here a predictive transcriptomic-based signature for trabectedin efficacy in STS. Methods: A total of 140 patients with advanced STS (at diagnosis or at any time from then on), with paraffin tumor block available, with at least 2 lines of treatment in advanced disease (one of them trabectedin) were included in this study. Gene expression was evaluated by direct transcriptomics, using HTG EdgeSeq Oncology Biomarkers Panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Raw counts were normalized to transcripts per million (TPM). Univariate Cox regression analysis was performed to find genes significantly associated with PFS and only those genes with significantly different curves were further retained (P < 0.05). These remaining genes were used as input to build a gene expression signature, using a multivariate Cox regression applying a Lasso penalty. Risk scores were calculated by multiplying the expression of every gene with its corresponding Cox regression coefficient. Results: A series of 140 patients was studied, with a median age of 51, 54% males, and a median follow-up from diagnostics of 45 months. The most frequent subtypes were L-sarcomas (54%). A twenty-nine-gene predictive signature of trabectedin efficacy was built for advanced STS treatment. This signature included 13 and 16 genes associated with resistance or sensitivity to trabectedin, respectively. Genes associated with low efficacy of trabectedin included HMGA1, NES, FANCA, and FANCB, among others, whereas the high expression of genes such as NTRK2 or CDKN2Awere associated with higher activity of trabectedin. Patients in the high‐risk gene signature group showed a significantly worse PFS compared with patients in the low‐risk group: [2.0 months (95% CI 1.7-2.2) vs. 8.2 months (95% CI 5.1-11.3), p<0.001]. Conclusions: Our study identified a new 29-gene-based signature that significantly predicts trabectedin efficacy in STS patients. Prospective validation of this predictive gene signature is warranted.
Anlotinib versus placebo as adjuvant therapy for completely resected high-grade soft tissue sarcomas: Interim results of a phase 2, double-blinded, randomized controlled trial.
Authors: Wang Chun-Meng , Hu Xianglin , Yang Ling-ge , Xu Yu , Huang Wen-Ding , Zhang Jian-rong , Sun Zheng-Wang , Chen Mo , Zheng Bi-qiang , Zhang Sheng-jian , Yu Lin , Fujiwara Tomohiro , Chen Yong , Sun Yang-bai , Houdek Matthew T. , Yan Wangjun
Published: June 2024

11562

Background: High-grade soft tissue sarcomas (STS) pose a therapeutic challenge due to the high risk of recurrence, even following complete resection. Anlotinib is a multi-targeted tyrosine kinase inhibitor blocking angiogenesis pathways of VEGFR, FGFR, and PDGFR. Given a promising efficacy for treating patients with unresectable advanced STS in previous trials, we evaluated the role of anlotinib as adjuvant therapy for completely resected high-grade STS. Methods: In a single-center, double-blinded, randomized, controlled trial, eligible patients were those adults who had not received adjuvant chemotherapy regimens after complete resection of high-grade STS. Patients were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1-14 every 3 weeks as a cycle, with up to six cycles until disease recurrence, unmanageable toxicity or death. The primary endpoints included 1-year, 2-year disease-free survival (DFS). Results: Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n=44) or placebo (n=44). With a median follow-up of 25.99 months at data accrual cutoff on Jan 15, 2024, the 1-year and 2-year DFS rates were 88% and 77% in the anlotinib group, compared to 64% and 58% in the placebo group. Compared to patients in the placebo group, patients in the anlotinib group had a reduced risk of disease recurrence (HR 0.47 [95% CI 0.22~1.00, P= 0.0445]). The median DFS was not reached. Based on tumor histology, the greatest improvement in DFS with anlotinib versus placebo was observed in patients with myxofibrosarcoma (1-year DFS rate: 82% versus 61%; 2-year DFS rate: 64% versus 43%, HR 0.54 [95% CI 0.17~1.65], P= 0.2698) and undifferentiated pleomorphic sarcoma (1-year DFS rate: 86% versus 67%; 2-year DFS rate: 78% versus 67%, HR 0.58 [95% CI 0.12~2.87], P= 0.4971). Thirty-eight patients experienced adverse events (AEs; 34 with grade 1~2, 4 with grade 3): 28 patients (64%) in the anlotinib group versus 10 patients (23%) in the placebo group ( P<0.001). Three patients discontinued anlotinib, including two for proteinuria/hematuresis (2/44, 5%) and one for secondary poor surgical wound healing (1/44, 2%). Conclusions: Current results suggest anlotinib could lower disease recurrence risk in patients with completely resected high-grade STS, with an acceptable toxicity profile. Clinical trial information: NCT03951571 . [Table: see text]
Intimal sarcomas (ISarc) of the cardiac chambers (CC) of the heart and great vessels (GV): A comprehensive genomic profiling (CGP) study.
Authors: Bou Zerdan Maroun , Pavlick Dean , Ross Jeffrey S. , Graziano Stephen L. , Basnet Alina
Published: June 2024

11575

Background: ISarc of the CC and GV are extremely rare primary tumors of the cardiac chambers (CC), aortic root (AO) and pulmonary artery (PA). These tumors are rarely resectable and are associated with rapid progression and poor clinical outcome. We queried whether CGP could uncover new routes to targeted therapies for this aggressive form of malignancy. Methods: 27 cases of ISarc were centrally reviewed and required direct association with the intimal surfaces of the CC and GV with supporting routine histologic features and immunohistochemical staining patterns. DNA and RNA extracted from the ISarc cases were both sequenced using a hybrid-capture based CGP to study all classes of genomic alterations (GA) and determine MSI status, TMB level, HRD score, genomic ancestry, cosmic trinucleotide signature (Signature) and germline status. PD-L1 expression was measured by IHC (Dako 22C3 and TPS scoring). Results: The 27 ISarc cases included 15 CC and 12 GV (11 pulmonary artery ISarc and 1 aortic root Isarc). There were 24 (88.9%) histologic grade 3 and 3 (11.1%) grade 2 tumors. Median ages for all ISarc ranged from 45 to 46 years and were similar in both groups. The CC ISarc pts tended to be female when compared with the GV pts (73% vs 50%; P=.26). GA potentially impacting targeted therapy selection in clinical trials for rare tumors included amplifications of MDM2 in 66.7% of CC ISarc and 50% of GV ISarc, PDGFRA in 53.3% CC and 41.7% of GV; homozygous deletions in CDKN2A in 26.7% in CC vs 66.7% of GV was near significant (p=0.055) and significantly more frequent point mutations in PIK3CAin CC at 20% vs 0% in GV (p=.007) and ERBB3 in 13.3% of CV and 8.3% of GV which was not significant. EUR ancestry was present in slightly more than 50% of ISarc cases and similar in both sub-groups. Median TMB was similar and ranged from 4.3 to 4.7 mutations/Mb with 1 (6.7%) CC ISarc having a TMB of > 10 mut/Mb. 1/5 (20%) tested ISarc cases stained for low level PD-L1 expression. Conclusions: CGP of ISarc cases reveals that these tumors do feature a modest number of GA potentially associated with benefit for targeted therapies but low and absent biomarkers predictive of immunotherapy benefit. Further study of ISarc in a setting of rare tumor clinical trials appears warranted. [Table: see text]
Technology-enhanced palliative care for patients with advanced cancer undergoing phase I therapies: A pilot randomized clinical trial (RCT).
Authors: Hui David , Subbiah Ishwaria M. , Hong David S. , Ellefson Jennifer , Becerra Josue , De la Cruz Vera J , Urbauer Diana L. , Shete Sanjay , Bruera Eduardo
Published: June 2024

12017

Background: Outpatient palliative care (PC) has been found to improve quality of life (QOL). It is not known if more frequent symptom monitoring and PC nursing contacts between clinic visits would offer additional benefits. We conducted a pilot RCT to examine the effect of a specialist PC referral with and without technology-enhancement (TEC) on symptoms in patients undergoing Phase I cancer therapies. Methods: This single-center parallel group RCT enrolled adult patients with advanced solid tumors prior to starting Phase I therapies and at least 1 Edmonton Symptom Assessment Scale (ESAS) symptom ≥4/10 and ESAS Global Distress Score (GDS) ≥20/90. Patients were randomized to PC alone or PC + TEC in a 1:1 ratio. Over the 12 w period, the PC group had in person or virtual outpatient visits with a PC physician, nurse, and as needed psychotherapist every 4 weeks; the PC + TEC group also received weekly symptom monitoring with ESAS electronically and weekly nursing phone call. The primary outcome was within-group change of GDS from baseline to 2 w; secondary outcomes included change in GDS over 4, 8, and 12 w, and change in QOL (FACIT-Sp) over 2, 4, 8 and 12 w. We estimated that a sample size of 50 patients per group would provide 90% power to detect a within-group GDS difference of 6 units with a 2-sided α of 2.5% and 20% attrition. Results: Between 12/15/2020 and 12/21/2022, 115 patients were enrolled and 101 were randomized (PC + TEC n = 57, PC n = 44). By 2 w, PC + TEC showed a significant within-group improvement in GDS (mean change -5 [95% CI -8.9, -1.2]; P= 0.01) but not PC alone (Table). PC+TEC group also had a significant improvement in GDS at 8 w and 12 w and in FACIT-SP at 2 w, 8 w and 12 w. PC alone group had a significant within-group improvement in GDS at 4 w and 12 w but no significant differences in QOL were detected. This study was not powered for between group comparison; however, FACIT-SP at 12 w was significantly higher in PC+TEC vs. PC alone (Table; mean difference 13.9; P= 0.02). Conclusions: Higher intensity of PC with closer monitoring showed within-group improvement in symptoms and QOL, while PC alone had some symptom reduction but no QOL improvement. Further studies are needed to confirm the QOL benefit of PC + TEC over PC alone. Clinical trial information: NCT04989556 . [Table: see text]
The effect of sodium glucose cotransporter-2 inhibitors on mortality and cardiovascular outcomes of patients with prostate cancer receiving luteinizing hormone releasing hormone agonists.
Authors: Tang Zhiting , Chiang Cho Han , Chang Yu-Cheng , See Xin Ya , Wang Qian , Chi Kuan-Yu , Chiang Cho Hung
Published: June 2024

12025

Background: Luteinizing hormone releasing hormone agonists (LHRHa) are the standard of care treatment for prostate cancer but associated with an increased risk of cardiotoxicity. Recent studies suggest that sodium glucose cotransporter-2 inhibitors (SGLT2i), a class of antidiabetic drugs, reduce the risk of cardiovascular events compared to other glucose-lowering agents. We aim to investigate the potential cardioprotective effect of SGLT2i in prostate cancer patients with T2DM undergoing LHRHa therapy. Methods: We performed a retrospective, propensity score matched study using the TriNetX database, a network comprising deidentified data across more than 120 participating healthcare institutions. We included patients with prostate cancer and T2DM who were treated with LHRHa for prostate cancer and received either SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) for diabetes. The primary outcomes were all-cause mortality, incident hypertension, and incident major cardiovascular adverse events (MACE), which was defined as a composite of heart failure, myocardial infarction, and atrial fibrillation/flutter within 5 years of LHRHa initiation. Results: We matched 932 patients treated with an SGLT2i to patients treated with a DPP4i. The median age was 73 years for both cohorts. A total of 110 and 275 patients died in the SGLT2i and DPP4i cohorts, respectively. In Cox proportional hazard analyses, SGLT2i was associated with a reduction in the risk of all-cause mortality (Hazard ratio (HR), 0.65 [95% CI, 0.52 to 0.81]), hypertension (HR, 0.40 [95% CI: 0.22-0.70]) and major adverse cardiovascular events (HR, 0.70 [95% CI, 0.50 to 0.97]) compared to DPP4i. Similarly, SGLT2i was associated with a statistically significant reduction in heart failure and myocardial infarction. There appeared to be a tendency toward a lower risk of atrial fibrillation/flutter. Conclusions: The use of SGLT2i was associated with a lower risk of mortality, hypertension, and cardiovascular events in patients with prostate cancer and T2DM undergoing LHRHa therapy. [Table: see text]
Fasting mimicking diet reduces anti-OX40/anti PD-L1 and anti-PD-1/anti-CTLA-4 cardiovascular side effects in preclinical melanoma models.
Authors: Quagliariello Vincenzo , Cortellino Salvatore , Delfanti Gloria , Di Mauro Annabella , Tatangelo Fabiana , Spagnolo Vanessa , Visco Euplio , Casorati Giulia , Chiodoni Claudia , Della Bona Paolo , Blazevits Olga , Ascierto Paolo Antonio , Maurea Nicola , Longo Valter
Published: June 2024

12029

Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation as cancer therapeutics with the potential to increase survival. However, ICIs-induced side effects ranging from autoimmune endocrine disorders to mucositis and to a rare but clinically significant cardiotoxicity with high rate of mortality represent important limitations. Cardiovascular complications in ICIs-treated patients includes myocarditis, vasculitis, arrhythmia, fibrosis and heart failure. Moreover, both the limited efficacy in a large portion of patients and the acquisition of resistance represent additional limitations for ICIs, underlining the need for new immunotherapy strategies. Fasting mimicking diets (FMDs) applied for several days periodically are emerging as highly promising enhancers of a wide variety of cancer therapies including immunotherapy. Here, a preclinical study in melanoma-bearing mice treated with two combinatorial ICIs therapies (anti-OX-40/PDL-1 or antiCTLA-4/anti-PD-1) during a standard or FMD was performed. Methods: Melanoma or lung cancer-bearing mice ( C57BL/6J female mice, 6–8 weeks old) were treated with two combinatorial ICIs therapies (anti-OX-40/PDL-1 or antiCTLA-4/anti-PD-1) during a standard diet or FMD for 21 days. Tumors were measured every 3–4 days using a digital caliper. Mice were monitored for tumor growth and survival. Mice were killed when tumor volume reached 1.5 cm3. Flow cytometry analysis of tumor-infiltrating lymphocytes and apoptosis, collagen quantification in myocardial tissues, quantification of CD3+ and CD8+ cells in myocardial tissues, of plasma and myocardial cytokines, and several pro-inflammatory biomarkers were performed through selective ELISA methods and western blotting analysis. Results: FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity. Conclusions: This study sets the stage for clinical trials aimed at assessing the ability of FMD to increase the efficacy of immunotherapy while reducing its side effects. These results also indicate that the anti-inflammatory and protective effects of FMD cycles in combination with ICI could affect other organs and systems.
Effect of anti CTLA-4 and PD-1 monoclonal antibodies on systemic SDF-1 and galectin-3 levels through NLRP3 and MyD-88 pathways in preclinical models.
Authors: Iovine Martina , Quagliariello Vincenzo , Passariello Margherita , Bruzzese Francesca , Palma Giuseppe , Luciano Antonio , Maurea Carlo , Berretta Massimiliano , Giacobbe Ilaria , Barbato Matteo , Giordano Vienna , Arianna Raffaele , Izzo Francesca , Ascierto Paolo Antonio , Bisceglia Irma , Canale Maria Laura , De Lorenzo Claudia , Maurea Nicola
Published: June 2024

12032

Background: Immune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed. Methods: Firstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and ten days (T10), ejection fraction, radial/longitudinal strain were calculated by using echocardiography. Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β and IL-6 were analyzed before, during and after ICIs therapy. Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs. Conclusions: Short therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3 in preclinical models. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.
Predictive factors for cardiac events following concurrent chemotherapy and radiation with durvalumab consolidation for unresectable non-metastatic non-small cell lung cancer.
Authors: Patel Nikita Pankaj , Dressler Danielle , Zhu Mengou , Liu Yingzhe , Sun Zequn , Patel Jyoti D.
Published: June 2024

12033

Background: The PACIFIC trial was a randomized phase 3 study which evaluated the use of Durvalumab as consolidation therapy after definitive chemoradiation for patients with unresectable non-metastatic NSCLC. There was a significant improvement in progression free survival and overall survival. It was established as a standard approach for management. Due to nonspecific activation of the immune system, immune related adverse events are commonly associated with ICIs. Immune related cardiotoxicity is less common however may present as arrhythmia, pericarditis, valvular disease, cardiomyopathy, and there is more recent data to suggest an acceleration of atherosclerotic plaque burden likely due to inflammation that can result from immune activation. In this population, there are usually several other risk factors for cardiac disease including age, history of tobacco use, exposure to cardiotoxic chemotherapy and chest radiation. The objective of this study is to quantify, characterize, and identify potential risk factors for cardiac events (CEs) that occur after exposure to concurrent chemotherapy and radiation followed by Durvalumab in patients with unresectable non-metastatic NSCLC. Methods: Patients who received concurrent chemotherapy and radiation followed by Durvalumab for treatment of NSCLC at a large academic medical center between January 1, 2017 and April 1, 2021 were retrospectively identified. Demographics, treatment history, cardiovascular comorbidities (pre-existing arrhythmia, coronary artery disease, diabetes mellitus, heart failure, hypertension, hyperlipidemia, cerebral vascular accident, peripheral artery disease, tobacco use) and CEs occurring within 5 years of treatment were collected by chart review. Logistic regression analysis was used to identify potential risk factors for cardiac events in this patient population. Results: Among 115 patients, 29 (25%) experienced CEs including 15 new/worsening arrhythmia, 11 new/worsening cardiomyopathy, and 9 new/worsening coronary artery disease. There were no cardiac deaths identified. The most common arrhythmia was atrial fibrillation. Pre-existing arrhythmia, dyslipidemia, and number of pack years showed significant association with cardiac events (p<0.05). Cumulative dose of radiation was found to be marginally significant on logistic regression analysis (p=0.07). Patients on a statin had a slightly lower odds of cardiac event (OR 0.03, p=0.02). Conclusions: Cardiac events following exposure to concurrent chemotherapy and Durvalumab may occur in up to 25% of patients with unresectable non-metastatic NSCLC. Further retrospective analysis of changes in coronary atherosclerotic plaque burden across PET-CT with ICI exposure and correlation with cardiac events is underway.
Efficacy and safety of immune checkpoint inhibitors in advanced solid tumors with hepatitis B infection.
Authors: Niu Ruiqi , Du Yingying , Qian Hesheng , Pang Jingdan , Zeng Xinyan , Chen Sheng , Wang Jing , Wu Wentian , Shao Changchun
Published: June 2024

12037

Background: Hepatitis B virus (HBV) infection is related to cirrhosis and hepatocellular carcinoma (HCC). The breakthroughs of immunotherapy (IO) have dramatically changed treatment paradigms in malignancies based on considerable survival benefits. Advanced tumor patients are under risk of HBV reactivation after IO, and serum HBV DNA positive (HBV+) is regarded as the exclusion of clinical study. It is urgent to explore the impact of HBV infection on the efficacy and safety of IO. Methods: A retrospective review of advanced tumors patients with HBV infection who received IO was performed at the First Affiliated Hospital of Anhui Medical University and Fuyang Cancer Hospital between January 1, 2019, and August 31, 2023. 563 patients were included, of which 346 were HCC patients. The long-term efficacy is overall survival (OS). CTCAE 5.0 was used to evaluate the hepatic adverse event. Results: In advanced tumor, patients who have had HBV+ had higher incidence of hepatic adverse events (hAE) ( P<0.001) and severe hepatic adverse events (hSAE) ( P=0.001) than HBV negative (HBV-). Among HBeAg positive(HBeAg+) hepatitis patients, there was no difference in hAE ( P=0.131) and hSAE ( P=0.431) between HBV+ and HBV- patients. However, in HBeAg negative (HBeAg-) patients, HBV+ patients have a significantly higher incidence of hAE ( P=0.003) and hSAE ( P=0.001) than HBV-. In HCC, there was no statistical difference in OS between HBV+ and HBV- patients (P=0.132), with 91.0% patients received antiviral treatment. HBV+ patients had more hAE ( P=0.023) and hSAE ( P=0.020). HBV+ HBeAg- patients had more hSAE than HBV- ( P=0.022). In HBeAg+ patients, there was no difference in OS ( P=0.755), hAE ( P=0.199) and hSAE ( P=0.426) between HBV+ and HBV-. In non-HCC, antiviral treatment brought more hAE ( P=0.025), which existed in HBeAg- ( P=0.029) and HBV- ( P=0.047). Thirty HCC patients converted HBV- to HBV+ during IO (mOS: 527d, 95% CI: 266.22-787.78), of which 2 patients had an ALT flare, of which 28 patients had hAE and 10 patients had hSAE. Conclusions: HBV+ patients have higher incidence of hAE and hSAE. In HCC, HBV+ patients are more likely to occur hAE and hSAE. HBV+ HCC patients had worse OS than who remained HBV- during ICIs. For non-HCC patients with antiviral treatment, there was no difference in OS or AEs and SAEs, regardless of infection status and HBV status. In HBeAg+ HCC patients, there was no statistical difference in OS, hAE, and hSAE regardless of HBV activity. Antiviral treatment was associated with a higher incidence of hAE and hSAE irrespective of tumor, infection status, and HBV DNA status. In advanced HCC, 18.9% of HBV- patients turned HBV+, which not only have worse OS and greater hepatic toxicity. Dynamic monitoring of HBV-related serological indicators and liver enzymes is needed for hepatitis B patientsduring IO, and HBV reactivation is a sign of poor clinical prognosis.
Neurofilament light chains: A biomarker for vincristine-related neuropathy.
Authors: McNally Gretchen A , Xu Menglin , Voorhees Timothy , Baiocchi Robert A. , Bond David Alan , Epperla Naren , Maddocks Kami J. , Sawhala Yazeed , Ramaswamy Bhuvaneswari , Lustberg Maryam B.
Published: June 2024

12114

Background: Sensory vincristine-related neuropathy is a well-known toxicity of front-line lymphoma treatments, potentially negatively impacting both disease outcomes as well as the long-term quality of life of cancer survivors. Most aggressive non-Hodgkin lymphomas are curable with the multi-agent chemotherapy regimens CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or infusional dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). This pilot study aimed to characterize and describe chemotherapy-induced peripheral neuropathy (CIPN) outcomes, utilizing patient and clinician-reported outcome measures and neurofilament light chains (NF-L). Nf-L, released in response to axonal damage, is emerging as a sensitive blood-based biomarker for CIPN. Studies in rats have demonstrated repeated vincristine exposure correlated with increased serum NF-L light chains and progressive damage. This has not previously been reported in humans. Methods: A single-center prospective study assessed CIPN toxicity in people with aggressive non-Hodgkin’s lymphoma treated with CHOP and EPOCH. Patient-reported outcome (PRO) measures included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) questionnaire. Items 19 and 20 were excluded. The clinician-reported outcome measure was the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0). Outcomes were evaluated at three time points: (1) Baseline, (2) Immediately before cycle four, and (3) Immediately before cycle six. Blood samples were collected from participants and processed for plasma Nf-L chain analysis. Results: There were 26 participants at baseline (CHOP: n = 17, EPOCH: n = 9), 21 participants at time point 2 (CHOP: n = 17, EPOCH: n = 7), and 16 participants at time point 3 (CHOP: n = 10, EPOCH n = 6). The mean CIPN-18 scores increased at each time point and were not significantly different by chemotherapy type. Five of the 16 participants (31.3%) experienced CIPN ≥ grade 1 at time point 3. A significant relationship existed between the CIPN-18 and the CTCAE (r- 0.39, p =0.002) and between CIPN-18 and Nf-L levels (r= 0.42, p = 0.002). The mean Nf-L levels increased from the first time point (mean = 54.4 pg/mL, 16-187.9 pg/mL) to the second time point (mean = 108.7 pg/mL, 37-232.2 pg/mL) and remained significantly elevated at Time Point 3 (mean = 92pg/mL, 34-172.2 pg/mL). Conclusions: One-third of all participants were experiencing symptoms of CIPN by the third time point (cycle six of therapy), as measured by the CTCAE > 0 and the CIPN-18 > 20. Our study lays the groundwork for using Nf-L as a potential biomarker, in combination with PROs, to identify, recognize, and measure vincristine-induced neurotoxicity.
Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission
Authors: Christophers Briana , Leahy Shannon N. , Soffar David B. , von Saucken Victoria E. , Broadie Kendal , Baylies Mary K.
Published: June 2024

Cofilin, an actin-severing protein, plays key roles in muscle sarcomere addition and maintenance. Our previous work found that Drosophila cofilin (DmCFL) knockdown in muscle causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA-sequencing analysis that unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL muscle knockdown causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown resulted in mislocalization of GluRIIA class glutamate receptors in more deteriorated muscles and strongly impaired NMJ transmission strength. These findings expand our understanding of the roles of cofilin in muscle to include NMJ structural development and suggest that NMJ defects may contribute to the pathophysiology of nemaline myopathy.
Establishment of a Transplantation Model of PDAC-Derived Liver Metastases
Authors: Ferrara Benedetta , Dugnani Erica , Citro Antonio , Schiavo Lena Marco , Marra Paolo , Camisa Paolo Riccardo , Policardi Martina , Canu Tamara , Esposito Antonio , Doglioni Claudio , Piemonti Lorenzo
Published: June 2024

Background

The highly metastatic nature of pancreatic ductal adenocarcinoma (PDAC) and the difficulty to achieve favorable patient outcomes emphasize the need for novel therapeutic solutions. For preclinical evaluations, genetically engineered mouse models are often used to mimic human PDAC but frequently fail to replicate synchronous development and metastatic spread. This study aimed to develop a transplantation model to achieve synchronous and homogenous PDAC growth with controlled metastatic patterns in the liver.

Methods

To generate an orthotopic PDAC model, the DT6606 cell line was injected into the pancreas head of C57BL/6 mice, and their survival was monitored over time. To generate a heterotopic transplantation model, growing doses of three PDAC cell lines (DT6606, DT6606lm, and K8484) were injected into the portal vein of mice. Magnetic resonance imaging (MRI) was used to monitor metastatic progression, and histologic analysis was performed.

Results

Orthotopically injected mice succumbed to the tumor within an 11-week period (average survival time, 78.2 ± 4.45 days). Post-mortem examinations failed to identify liver metastasis. In the intraportal model, 2 × 105 DT6606 cells resulted in an absence of liver metastases by day 21, whereas 5 × 104 DT6606lm cells and 7 × 104 K8484 cells resulted in steady metastatic growth. Higher doses caused significant metastatic liver involvement. The use of K8484 cells ensured the growth of tumors closely resembling the histopathologic characteristics of human PDAC.

Conclusions

This report details the authors’ efforts to establish an “optimal” murine model for inducing metastatic PDAC, which is critical for advancing our understanding of the disease and developing more effective treatments.
Η επίδραση του άγχους και της κατάθλιψης στην έκβαση της κύησης σε έγκυες γυναίκες διαφορετικής εθνικής καταγωγής
Authors: Αρβανιτίδου Όλγα
Published: June 2024

Η προγεννητική κατάθλιψη και το άγχος αποτελούν κοινές ψυχικές διαταραχές της περιγεννητικής περιόδου με πιθανή επίπτωση στο μαιευτικό και νεογνικό αποτέλεσμα. Στόχος της παρούσας μελέτης είναι η καταγραφή των επιπέδων προγεννητικού άγχους και κατάθλιψης σε μια κοορτή εγκύων, η μελέτη της επίδρασης δημογραφικών παραγόντων και παραγόντων της κύησης στα επίπεδα άγχους και κατάθλιψης, καθώς και η διερεύνηση της ψυχικών αυτών διαταραχών στο μαιευτικό και νεογνικό αποτέλεσμα. Πρόκειται για αναδρομική μελέτη με δείγματα-ερωτηματολόγια που έχουν συλλεγεί, από το έτος 2018 έως και 2022, από έγκυες γυναίκες διαφορετικής εθνικής καταγωγής, μεταξύ της 25ης και 42ης εβδομάδας κύησης. 521 έγκυες συμμετείχαν, εκ των οποίων συμπληρώθηκαν 468 ερωτηματολόγια κατά Hamilton, για τη διερεύνηση του άγχους, και 521 ερωτηματολόγια κατά Beck για τη διερεύνηση της κατάθλιψης. Διαπιστώσαμε την ύπαρξη ήπιας προγεννητικής αγχώδους διαταραχής και κατάθλιψης στον πληθυσμό της μελέτης, με στατιστικά σημαντική (μέτριας ισχύος) συσχέτιση μεταξύ των δύο. Η επίδραση των δυσμενών δημογραφικών παραγόντων ήταν πιο εμφανής στην περίπτωση της κατάθλιψης. Διαπιστώσαμε περιορισμένες, αδύναμες (αρνητικές) συσχετίσεις, του μεν άγχους με την εβδομάδα τοκετού, το ύψος και το Apgar 5, της δε κατάθλιψης με το Apgar 1. Τα νεογνά των εγκύων με υψηλό Beck score είχαν σημαντικά χαμηλότερο Apgar 1 (αλλά όχι Apgar 5) σε σχέση με εκείνα με χαμηλό Beck score, ενώ δεν διαπιστώσαμε διαφορά στα νεογνικά αποτελέσματα μεταξύ εγκύων με χαμηλό και υψηλό Hamilton score προγεννητικά. Τα ευρήματα της μελέτης μας καταδεικνύουν επίπεδα ήπιας κατάθλιψης και αγχώδους διαταραχής στον πληθυσμό μας, καθώς και μια σχετικά περιορισμένη επίδραση των προγεννητικών ψυχικών διαταραχών στο μαιευτικό και νεογνικό αποτέλεσμα. Ωστόσο, τα συμπεράσματά μας πρέπει να επιβεβαιωθούν από περαιτέρω μελέτες, μεγαλύτερες σε μέγεθος δείγματος και προοπτικές σε σχεδίαση.
Анималистический лингвокультурный код в русских говорах Одесщины (на материале фразеологии)
Authors: Арефьева Наталья
Published: June 2024

In this paper animalistic code, one of the most important cultural codes, which occupies a special place in the picture of the world of dialect speakers, on the material of phraseology of Russian island dialects of Odessa region of Ukraine, within the framework of natural code space, is analyzed. The phraseological units of Odessa region, grouped around this code, are considered against the background of national and dialectal phraseology, as well as against the background of the phraseology of other dialects / languages functioning in the immediate environment – Ukrainian, Bulgarian, Moldavian, Romanian. This approach, reflecting the current state of the phraseological fund of the South of Ukraine, helps to “reveal” interdialectal, interlingual and intercultural connections, makes it possible to “see” this or that phraseological unit in the system of all-Russian and Slavic phraseology against the broad background of Slavic folk culture. A significant part of phraseological units, grouped within the animalistic code, is at the intersection with other codes – economical, astronomical, axiological, actional, spatial. In the conceptualization of the animalistic code, both regional phraseological models and national, as well as interethnic ones, developed under the influence of a multilingual and multicultural environment, primarily under the influence of the Ukrainian language and its dialects, are defined.
Porównania w opowiadaniach gwarowych Adama Wawrosza
Authors: Bogoczová Irena , Bortliczek Małgorzata
Published: June 2024

The article is material-based and it came into being on the basis of analysing the comparisons excerpted from the dialect stories by Adam Wawrosz: (1) Na śćmiywku (1959), (2) Z naszej nolepy (1969), (3) Z Adamowej dzichty. Z twórczości Adama Wawrosza (1977). The author comes from the so-called Zaolzie, i.e. the Czech part of Cieszyn Silesia, and the language variety he used in his stories is referred to as West Cieszyn or Zaolzie dialect. What is used in the region of Zaolzie apart from the West Cieszyn dialect is the Czech language (in public places) and Polish (in schools and institutions belonging to the Polish minority). In the article, comparisons are presented and analyzed that – according to expert literature – belong to the broadly understood phraseology. The analysis of authentic research material shows that the comparisons used by Wawrosz are an innovative and expressive component of the artistic text. The expressiveness of these poetic comparisons softens or sharpens the topics discussed by the author. They name the extra-linguistic reality clearly and unambiguously, in accordance with the trivial (simple) vision of the world contained in the dialectal linguistic code (the dialectal image of the world), and they harmonize with the difficult life of the story’s characters and the nature surrounding them. These comparisons can be ironic and sarcastic or gentle and empathetic. The analyzed comparisons are a result of Wawrosz’s unique creativity and innovation. Many of them entered the language of the local population.
Semantic Correlation and Disambiguation of Perun in West and East Slavic Languages and Phraseology
Authors: Gajetti Giuliano
Published: June 2024

The aim of this paper is to investigate the stages of development of lexical item Perun (the late Proto-Slavic Thunder god) in Western and Eastern Slavic languages, dialects and phraseological units. This will be done considering how during a specific time, the theonym and the thunderstorm phenomenon associated with him have been inseparable and thus semantically correlated. Subsequently changes in the theonym, and in the use of the theonym, provoked changes in the common noun, resulting in semantic disambiguation. Often these changes brought a contrastive stance towards the theonym (Perun as a swear word or as an evil entity) but they also retained some positive meanings typical of previous cultural phases (Perun as a hero or a strong person). Western and Eastern Slavic languages and dialects show different pattern of semantic disambiguation and correlation, as the total disambiguation of Russian and Czech or the total correlation in Belarusian and Polish. The dialects and the phraseological material sums in general the contrastive attitude and the positive meaning of Perun, maintaining in some cases a certain degree of ambiguity.
Фразеологізми у сімейному спілкуванні двомовних родин: кейси з України
Authors: Кузнєцова Тетяна
Published: June 2024

The article presents the results of a study of the peculiarities of the use of phraseological units in family communication of bilingual families residing in the Sumy region (north-eastern region of Ukraine). It has been established that family phraseology is embodied in a kind of «home» dictionary, which encompasses usual, transformed, occasional stable sayings and precedent phenomena. Typically, these expressions are in Ukrainian, Russian and Surzhyk, marked by an expressive conversational style and emotional content. The most «stable» in the temporal dimension are specific common and occasional phraseological units, as well as precedent «children’s» texts, which largely shape not only a shared family phraseological dictionary but also represent the characteristics of the linguistic and cultural space of the family as a whole. The precedent texts of the Soviet discourse turned out to be the most «movable» in the composition of family phraseology. Following the large-scale invasion, a discernible shift away from Russian-language phrases and quotes from Soviet films, pop songs, and works of Russian literature is evident. In their place, we observe the active incorporation of Ukrainian-language precedent units from works of Ukrainian literature, cartoons, and contemporary Ukrainian variety shows. There is also an intensification of Surzhik language expressions, primarily employed as a stylistic tool. The events in Ukraine after February 24, 2022 led to the active replenishment of the family dictionary and wartime phraseology – Ukrainian and Surzhik-language persistent sayings-memes, which, undergoing structural and semantic changes in casual speech, are primarily used to express the emotions and feelings of Ukrainians, their attitude towards enemies, motivation to action.
Фразеологія в українсько-російському змішаному мовленні (суржику)
Authors: Палінська Олеся
Published: June 2024

Based on the oral Oldenburg corpus of Ukrainian-Russian mixed speech (OC-URMS), this study examines the coexistence of stable expressions derived from distinct linguistic and cultural contexts (Ukrainian and Russian) within the mixed speech of individuals residing in the Center and South of Ukraine. The research explores the sources, deformation, and adaptation of these stable expressions in the bilingual / tricodal environment, establishing connections with sociobiographical parameters of the respondents. Analysis of the OC-URMS material elucidates key patterns in the utilization of phraseology by speakers of mixed speech. The study reveals the presence of idioms with origins in both Ukrainian and Russian, with the latter predominating. Additionally, a shared phraseological pool is identified. Structurally, the assimilation of phraseological units aligns with a hierarchy of borrowings: units with a more “lexical” nature are more likely to have Russian origins, while those with a more “grammatical” character tend to be utilized in a distinctively Ukrainian form.