bluuebunny/crossref_metadata_2025 huggingface dataset:
Profile of breast cancer in patients with Li-Fraumeni syndrome: An institutional experience.
Authors: S G Nithin , Gogia Ajay , Pramanik Raja , Deo S.V.S , Sharma Daya Nand , Batra Atul , Mathur Sandeep , Prasad Chandra Prakash
Published: June 2024

e13042

Background: Li Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome, associated with multisystem cancer predisposition. Considering the rarity of this syndrome, studies are very sparse on survival outcomes of breast cancer with germline TP53 mutation and there exists discrepancy amongst the results. Methods: This retrospective observational study included 17 patients with germline TP53 mutated breast cancer registered at All India Institute of Medical Sciences (AIIMS), New Delhi, India between the period of 1st April 2016 to 31st Dec 2023. Among the 577 high-risk breast cancer patients, who underwent germline mutation testing, 231 (40.03%) cases had pathogenic mutation [145(25.12%) were BRCA mutated,15 (2.59%) were TP53 mutated, and the rest were others pathogenic variant]. All the TP53 mutations were crosschecked via the ClinVar mutation database to be classified as pathogenic. Results: The median age of 15 patients was 31 years (23-55) and 12 (80%) cases were premenopausal. All the patients had breast cancer as the index malignancy. The Stage distribution (AJCC-7th edition) Stage I, 1(6.6%); Stage II, 7 (46.6 %); Stage III, 4 (26.6 %); and Stage IV, 3 (20 %). Eight cases (53.3%) were HER2 positive, 4 (26.6%) were hormone receptor-positive, and 3 (20%) were Triple-negative breast carcinoma (TNBC). Ten (10) patients received neoadjuvant chemotherapy and 6 (60%) had a complete pathological response. Eight cases (53.3%) cases had a significant family history with 9 (60%) of them having at least one first-degree relative with cancer and two had more than one first-degree relative with cancer. One patient had a family history of LFS. The most common familial cancer was breast, followed by lung, GI malignancies, brain tumor, and sarcoma. Synchronous breast cancer was seen in 2 patients, synchronous malignancies were seen in 4 cases (one patient: each with lung adenocarcinoma, periampullary carcinoma, carcinoma colon, and synovial sarcoma, along with breast cancer), Four patients (26.6%) had metachronous cancers: lung cancer, ovarian carcinoma, contralateral breast cancer, and high-grade sarcoma respectively. The most common mutations were point mutations ( n = 11, 73.3%) followed by frameshift mutations ( n = 4, 26.6%). The subtypes of point mutations included missense mutations ( n = 9) and nonsense mutations ( n = 2) with the most common aberration being a replacement of arginine with glycine (c.743G>A, p. Arg248Gln) and locus being exon 7. The median disease-free survival was 41 months and progression-free survival was 15 months. Conclusions: The prevalence of TP53 mutation in our breast cancer patients is 2.5%. With standard treatment protocols, the overall survival of LFS-associated breast cancer is similar to the historic cohort of patients without any germline mutation. Active surveillance of the patient and family screening is imperative, for all positive cases.
Genomic testing and uptake of alteration-targeted therapies among patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).
Authors: Mahadevia Himil , Chandra Simran , Gosch Kensey , Khamees Ibrahim , Sharma Parth , Gast Kelly C. , Pluard Timothy J. , Hensing Whitney L.
Published: June 2024

e13084

Background: There is no recognized standard of care treatment after progression on first-line endocrine therapy plus CDK4/6 inhibitor in HR+ / HER2 negative MBC. Alteration-targeted therapies (ATT) have the potential to delay initiation of chemotherapy with more favorable toxicity, and perhaps improved efficacy. Next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) can identify actionable mutations for targeted therapy. In this study, we sought to assess the results of genomic testing and uptake of ATT among patients with HR+ / HER2-negative MBC. Methods: We studied a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based health system in the Kansas City metro area. The analytic cohort included 125 patients with HR+ / HER2-negative MBC who received treatment after progression on first-line therapy. Genomic testing was performed as a standard of care from ctDNA or tumor-tissue using commercially available NGS assays. Targetable alterations were defined as those with FDA-approved or routinely used off-label treatment regimens in MBC ( PIK3CA, PTEN, AKT, ESR1, ERBB2, BRCA1, BRCA2, PALB2 mutations; TMB >10 or PDL1+). We identified patients who received any ATT and compared them with those who did not. Overall survival (OS) and time to initiation of chemotherapy (TTC) were compared between the two groups using Kaplan-Meier analyses and the log-rank test. Results: Ninety-nine patients (79.2%) had genomic testing and 49 (39.2%) were tested prior to second-line therapy. Of those tested, 84% had at least one targetable alteration. ESR1 mutations were most common, detected in 36% of patients, followed by PIK3CA (31.2%), PTEN (12%), BRCA1/2 (7.2%) and ERBB2 (5.6%). A total of 35 patients received ATT, and around half of those (17 patients) received ATT in the second line. Alpelisib was the most common ATT (62.9%), followed by elacestrant (20%) and neratinib (14.3%). There was no significant difference in OS or TTC between the two groups. Conclusions: Approximately 80% of patients with HR+ / HER2-negative MBC in our cohort underwent genomic testing after progression on first-line therapy, and the vast majority had at least one targetable alteration identified. However, only 35 patients received ATT with most receiving alpelisib. We observed no significant improvement in OS or TTC among those who received ATT, although the numbers were small. There have been two new targeted therapies approved in the past year and many novel agents are currently under investigation in clinical trials. Newer therapies with distinct targets, improved tolerability and efficacy have the potential to improve the uptake and clinical benefit of targeted therapy in MBC.
Efficacy and safety of sacituzumab govitecan in HR+/HER2– advanced breast cancer: A comprehensive systematic review and meta-analysis.
Authors: Qureshi Zaheer , Jamil Abdur , Altaf Faryal , Siddique Rimsha
Published: June 2024

e13085

Background: Breast cancer is the most commonly diagnosed cancer in women, with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) being the predominant subtype. Sacituzumab govitecan, a novel antibody-drug conjugate, has emerged as a promising treatment for metastatic HR+/HER2– breast cancer. The aim of this systematic review and meta-analysis was to evaluate its efficacy and safety. Methods: Adhering to PRISMA guidelines, a comprehensive search was conducted in PubMed, Scopus, and Cochrane databases up to December 2023. We included clinical trials and observational studies evaluating sacituzumab govitecan in patients with HR +/HER2–advanced breast cancer. The primary outcome was progression-free survival (PFS), while the secondary outcomes included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and adverse event profiles. Various statistical models were used for the analysis. Results: Nine studies met the inclusion criteria, and three were suitable for meta-analysis. The pooled analysis showed a Hazard Ratio (HR) of 0.57 for PFS, indicating a significant reduction in disease progression, and an HR of 0.68 for OS, suggesting improved survival. The treatment also significantly increased the likelihood of tumor response and clinical benefit but was associated with a higher occurrence of adverse events. Conclusions: Sacituzumab govitecan demonstrated significant efficacy in treating HR+/HER2– advanced breast cancer, reducing disease progression and mortality. However, its use is associated with a high rate of adverse events. These findings highlight the potential of Sacituzumab govitecan as a valuable addition to breast cancer treatment regimens, warranting further investigation and long-term studies.
A novel B7-H3 x CD3 bispecific T-cell engager for the treatment of B7-H3+ tumors.
Authors: Li Feng , Liu Ming , Hua Yanan , Wei Xuemei , Qin Luying , Cao Guangcan , Yang Daniel Chunxu , Zhang Wenjun
Published: June 2024

e14509

Background: B7-H3 (CD276) is a transmembrane protein highly expressed in solid tumors but with limited expression in normal tissues. Its presence is strongly associated with the inhibition of T-cell activity, cancer progression, and invasion. Furthermore, B7-H3 is strongly associated with poor prognosis and reduced patient survival. Given its crucial role in tumor biology, B7-H3 has emerged as an attractive therapeutic target for drug development. We utilized ExMab heterodimer platform and common light chain technology to develop EX105, a next-generation B7-H3×CD3 bispecific antibody. This innovative T-cell engager exhibits excellent anti-tumor activity in mouse models and good safety profile in NHP tox study. Methods: EX105 was generated using ExMab heterodimer platform and common light chain technology to form a heterodimeric IgG1 structure. Preclinical pharmacology studies, efficacy, and safety were evaluated. Anti-tumor activity study of EX105 includes in vitro T-cell cytotoxicity assays and in vivo PBMC reconstituted xenograft mice models. Preclinical safety evaluation of EX105 was performed through GLP single-dose and repeat-dose tox studies in non-human primates (NHPs). Results: Based on ELISA and FACS analyses, EX105 can bind to both human and cynomolgus monkey B7-H3 and CD3 antigens. Furthermore, SPR data suggest that EX105 exhibits a high affinity to B7-H3 and a much lower affinity to CD3. In consistent with that, EX105 only induced relatively low cytokine release. Nevertheless, EX105 showed a potent in vitro T cell cytotoxicity against B7-H3+ tumor cell lines. The in vivo anti-tumor activity of EX105 was further determined in several tumor xenograft models. Treatment with EX105 resulted in remarkable tumor regression in both “hot” tumor model and “cold” tumor model, indicating its effectiveness across a range of tumor types. Tox study in NHPs showed minimal adverse effects and no liver impairment after EX105 administration, even at high doses. The cytokine release data observed in this study suggests a good safety profile of EX105, with much lower cytokine release compared to other T cell engagers. Conclusions: These findings collectively indicate that EX105 has the potential to become a promising therapeutic agent for the treatment of various B7-H3 positive cancers. The first-in-human clinical trial for patients with advanced B7-H3 positive cancers is due to start.
The effect of resting dendritic cells on overall survival in the hepatocellular carcinoma tumor microenvironment.
Authors: Hanona Paul , Jairath Neil , Farha Mark , Yohanathan Lavanya , Ezekwudo Daniel , Jaiyesimi Ishmael A.
Published: June 2024

e14559

Background: Hepatocellular carcinoma (HCC) continues to have a poor prognosis even in the advent of new immunotherapy regimens. An area of growing interest in HCC is its tumor immune microenvironment. Classifying the immune microenvironment based on available genomics can lead to insights on prognosis and treatment, especially regarding the role of immunotherapy. Methods: RNA sequencing data was extracted from The Cancer Genome Atlas (TCGA), specifically from the hepatocellular carcinoma section (n = 366). CIBERSORT was utilized to organize the immune cell fractions present for each patient sample. Radiant by Shiny was used to perform a linear regression elucidating the relationship between overall survival and several other variables including: age, gender, tumor stage, race, ethnicity, B-cells naïve, B-cells memory, plasma cells, CD8 T-cells, CD4 T-cells, T-cells follicular, T-cells regulatory, natural killer activated and resting cells, monocytes, macrophages (M0, M1, M2), dendritic cells activated and resting, mast cells activated and resting, eosinophils, and neutrophils. Subgroup analyses were also performed via radiant regarding gender, race, and resting dendritic counts. Results: Resting dendritic cells were independently prognostic of overall survival on multivariable analysis (p = 0.041). The coefficient of correlation was +164.53 showing a positive association between the number of resting dendritic cells and the overall survival. Subgroup analysis showed no difference in resting dendritic counts between males and females (p = 0.526). Also, there was no difference seen in resting dendritic counts between populations of Asians and African Americans (p = 0.873), Asians and Whites (p = 0.223), and between Whites and African Americans (p = 0.811). Conclusions: Patients with a higher number of resting dendritic cells in their tumor immune microenvironment had a better overall survival. There was no difference between males and females in the resting dendritic counts. Likewise, there was no difference in the resting dendritic counts between Asian, African American, and white populations. Resting dendritic cells have been shown to be enriched in hepatocellular carcinomas with a low tumor mutational burden. This is a paradigm that should be explored further in the context of immunotherapy. Resting dendritic cells are also in a state of plasticity as they go from resting to active. Future genomic analysis of the tumor microenvironment regarding this plasticity could also lead to enhancing treatment options.
YF550-C1, an E3 ligase inhibitor of CBL-B, to demonstrate T cell and NK cell activation and anti-tumor activities in syngeneic and PDX tumor model.
Authors: Ye Jie , Liu Tengfei , Liu Yahui , Liu Xueqiang , Wu Fan , Lu Tingting , An Na , Chai Yushuang , Lin Xingyu , Liao Xuebin
Published: June 2024

e14570

Background: Casitas B-lineage lymphoma b (CBL-B) is one of ligase in E3 ubiquitin family, which mainly expressed in matured hematopoietic cells, including T and NK cells. Study showed that CBL-B deficiency upregulated interleukin-2 and interferon-gamma secretion during anti-CD3 and anti-CD28 stimulated TCR activation, even without co-stimulator anti-CD28[3]. Except T cells, CBL-B plays important role in NK cells as well. CBL-B was upregulated during NK cell activation. While downregulation of CBL-B enhanced the cytotoxicity of primary human NK cells against hematological cancer cell lines. In vivo studies proved that CBL-B deficiency protected mice from tumor growth by inducing antitumor immunity. Thus, CBL-B shows a promising target for cancer therapy. Methods: We developed a small molecule YF550-C1 that targeted CBL-B, and evaluated the activation on T cell and NK cell function, and the therapeutical effect on syngeneic tumor models. The T cell activation was indicated by levels of IL-2 and IFN-γ from CBL-B knockout or WT CD8+ T cells since stimulated with anti-CD3 or anti-CD3/28 for 48 hours. The resistance of PGE2-induced immunosuppressive was evaluated by measuring IL-2 and IFN-γ since human T cells treated with PGE2 and followed by series diluted YF550-C1 or comparable inhibitor cpd23. OVA specific antigen stimulated CD8+ T activation assay was conducted by coculture OT-1 CD8+ T cells and WT DC cells with 50:1 for 72 hours in the present of 5ug/ml OVA peptide and series diluted YF550-C1. The NK cell cytotoxicity was evaluated by co-culture human NK cells and K562-luc cells with 1.25:1 ratio in the present of 1000nM or 333nM YF550-C1, which indicated by luminance. Syngeneic mouse model that inoculated with different types of murine cancer cell lines was used to evaluate tumor growth. Results: CBL-B deficiency suppressed tumor growth in mouse tumor models and enhanced cytokines release in T cells upon TCR engagement. CBL-B inhibitor, YF550-C1, alleviated PGE2-mediated immunosuppression of human T cell activation. CBL-B inhibitor, YF550-C1, enhanced OVA-specific antigen stimulated CD8+ T cell activation. CBL-B inhibitor, YF550-C1, enhanced cytotoxicity of human NK cell against K562-luc cells. CBL-B inhibitor, YF550-C1, or in combinate with anti-PD-L1 suppressed tumor growth in syngeneic tumor models. Single-agent of CBL-B inhibitor YF550-C1 treatment was sufficient to suppress PD1/PD-L1 resistant NSCLC patient-derived tumor growth. Conclusions: These studies provided insight into the activity of the inhibitor of CBL-B, demonstrating that YF550-C1 displays excellently T cell activation, T cell immunosuppression alleviation, NK cell activation and antitumor activity in multiple preclinical tumor models. Our data showed that YF550-C1 is a promising candidate for cancer treatment as monotherapy or in combination with PD-L1 blockade.
PD-1 inhibitor combined with ablation in liver metastasis: A retrospective, multicenter study.
Authors: Liu Dengyao , Huang Tao , Sun Zhanguo , Hu Pan , Zhu Tao , Huang Dongcun , Xu Bingchen , Jiao Dechao , Zhang Fujun , Lin Letao
Published: June 2024

e14644

Background: This study aimed to retrospectively evaluate the efficacy of ablation combined with programmed cell death protein 1 (PD-1) inhibitor versus PD-1 inhibitor monotherapy in patients with liver metastasis. Methods: We retrospectively enrolled patients with liver metastasis who received PD-1 inhibitor therapy with or without ablation at three medical institutions between January 2017 and September 2022. Progression-free survival (PFS) and 1-year survival rates were compared after propensity score matching. Additionally, intrahepatic and extrahepatic lesion progression and treatment-related adverse events were recorded during follow-up. Finally, prognostic factors for the combined therapy group were analyzed. Results: We included 172 patients and classified them into the combined therapy and PD-1 inhibitor monotherapy (n = 86 each) groups. Patients in the combined therapy group had better median PFS and 1-year survival rates than those in the PD-1 inhibitor monotherapy group. Combined therapy was an independent prognostic factor for PFS in the univariate and multivariate analyses. New lesions constituted the main pattern of progression, with combined therapy showing significantly lower intrahepatic progression, but similar extrahepatic progression rates. Adverse events associated with PD-1 inhibitors were comparable between the two groups. Additionally, 8 (9.3%) patients experienced ablation-related complications. However, neither univariate, nor multivariate analyses revealed the predictive factors for PFS in the combined therapy group. Conclusions: Ablation combined with a PD-1 inhibitor was superior to PD-1 inhibitor monotherapy in improving the survival of patients with liver metastasis.
Unraveling the role of CTLA-4 variants in acute kidney injury after ICI treatments.
Authors: Wang Yanfei , Xiong Chenxi , Bian Jiang , Song Qianqian , Su Jing
Published: June 2024

e14682

Background: Immune checkpoint inhibitors (ICIs) often result in various immune-related adverse events (irAEs), which limit their therapeutic application and pose challenges to clinical decision-making. Among these irAEs, the incidence rate of ICI-related acute kidney injury (ICI-AKI) is on the rise. Understanding the genetic predisposition to ICI-AKI can inform personalized treatment plans, thereby minimizing risks and optimizing outcomes. This study aims to interrogate risk loci for AKI patients to gain insights into ICI-related AKI in cancer patients and to support the design of more personalized cancer therapies. Methods: This study comprehensively integrates meta-analysis, replication genome-wide association study (GWAS), fine-mapping, and mendelian randomization (MR) to explore potential genetic variants related with ICI-AKI. We first conducted a meta-analysis of 6 ICI pharmacogenomics studies, aggregating effect sizes from these studies using both fixed-effect and random-effects models to address heterogeneity and identified 186 significant genotypes. Subsequently, a GWAS was carried out over the 186 candidate genotypes in an independent cohort from the NIH All of Us program (N = 230,013) using logistic regression, identifying14,773 patients who developed AKI. To identify causal variants, we implemented fine-mapping techniques to further refine our genotype selection. Results: Our study identified genetic variants associated with an increased risk of AKI. Among these, the variant with the strongest association was located at the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene locus, rs3087243 (chr2: 203874196, G>A,T). This genotype exhibited a significant inverse relationship with AKI risk (beta = -8.19e-2, P = 2e-11), suggesting that reduced activity of the CTLA-4 gene may be linked to an elevated risk of developing AKI. Our findings indicate that cancer patients with this genotype may have a lower risk of ICI-related AKI after immunotherapy. In our future study, we will continue investigating significant SNPs including rs3087243 in cancer patients for their ICI-AKI risk. Conclusions: We identified an AKI-tolerant genotype, rs3087243. Patients with this genotype may be safter from developing ICI-related AKI after immunotherapy treatment. This work also highlights the research potential of All of Us clinicogenomics data.
Comparison of efficacy of antibody drug conjugate (ADCs) between younger and older patients: A meta-analysis of phase 3 studies.
Authors: Landre Thierry , Baldini Capucine , Bringuier Michael , Frelaut Maxime , Zelek Laurent H. , Taleb Cherifa
Published: June 2024

e15002

Background: Antibody-Drug-Conjugates (ADCs) are one of the new cornerstone of cancer treatments. New approvals are coming every year in various tumor types and settings. However, older adults remain underrepresented in clinical trials and consequently, few data is available for this population. Therefore, we performed a meta-analysis to compare the efficacy of ADCs between younger and older patients. Methods: PubMed and the ASCO or ESMO databases were searched up to December 2023. We included randomized controlled trials (RCTs) of ADCs (datopotamab deruxtecan, Enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan and trastuzumab deruxtecan) reporting subgroup comparison of overall survival (OS) and/or progression-free survival (PFS) based on age cutoffs. The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results: A total of 4654 patients from nine RCTs (ASCENT; DESTINY-Breast02, -Breast04, -Gastric01; EV-301, EV-302/KEYNOTE-A39; MIRASOL; TROPiCS-02 and TROPION-Lung01) were included. When patients are dichotomized into younger (N=2796) and older (N=1858) groups with an age cut-off of 65 years, ADCs improved OS in both younger (HR, 0.64; 95% CI, 0.52-0.80) and older (HR, 0.56; 95% CI, 0.44-0.71) groups. An improvement in PFS was observed in younger (HR, 0.55; 95% CI, 0.46-0.66) and older (HR, 0.52; 95% CI, 0.41-0.67) patients. Subgroup analyses according to ADCs and tumor type showed a consistent survival benefit in both younger and older groups. Conclusions: A benefit in OS with ADCs was significant in both younger and older patients with a cut-off age of 65 years. Prospective real life cohort study would be of interest to confirm those results with a description of geriatric parameters to better define the population.
Advancing cancer MRD monitoring through tumor whole-genome informed, duplex ctDNA sequencing.
Authors: Lee Won-Chul , Shin Jong-Yeon , Kim Chang Woo , Kwon Minsuk , Lee Sangmoon , Connolly-Strong Erin , Oh Brian Baek-Lok , Ju Young Seok
Published: June 2024

e15044

Background: Circulating tumor DNA (ctDNA), a cell-free DNA (cfDNA) present in the plasma of cancer patients, originates from cancer cells and serves as a crucial biomarker during cancer treatment. Despite its importance, the current limit of detection (LoD) of conventional ctDNA assays is suboptimal (0.01%; 10-4) for detecting ctDNA from microscopic residual and recurrent cancer tissues. To address this, we integrated two cutting-edge techniques: whole-genome sequencing (WGS) of primary cancer tissue (a mutation capture step) and duplex DNA sequencing-based cfDNA sequencing (mutation recapture steps). Methods: Thirteen colorectal cancer patients participated in this study. Primary tumor tissues and matched normal blood tissues were collected for WGS in the mutation capture step, while plasma samples for cfDNA sequencing in the mutation recapture steps were obtained just prior to colorectal cancer surgery and 1-month post-surgery follow-up. Tumor DNA and germline DNA were analyzed using CancerVision, a CLIA-certified clinical-grade cancer WGS platform, in the mutation capture step. In the mutation recapture steps, somatically acquired mutations from the previous step were tracked in cfDNA samples using the Concatenating Original Duplex for Error Correction (CODEC) technique, a duplex DNA sequencing technique that examines both Watson and Crick strands of double-stranded DNA molecules to discern true mutations from sequencing noise. Results: The median WGS depth of tumor and germline tissues was 40x and 20x, respectively. The mean depth of cfDNA WGS with CODEC was 25x, with a median duplex sequencing rate of 70%. Overall, 4,828-301,434 somatic base substitutions (SBSs) per sample were discovered in the capture step. Four of the thirteen tumors exhibited hypermutator characteristics with microsatellite instability features. The CODEC technique demonstrated excellent capability in tracing cancer-specific mutations in cfDNA sequencing with a technical sequencing error rate of 4 x 10-7, defining the maximum technical LoD, which is 250-fold lower errors than conventional sequencing. In our sample cohort, tumor fractions in cfDNA sequencing were robustly estimated from 0.001% (10-5), below the LoD of conventional MRD methods. Conclusions: Our integration of tumor-WGS-informed duplex cfDNA sequencing methods significantly enhances the sensitivity of sequencing-based MRD assays, achieving a technical LoD limit of 10-7 for detecting ctDNA in cancer patients. These approaches represent a breakthrough in monitoring MRD in real-world cancer patients.
Disease monitoring using plasma-based circulating tumor DNA (ctDNA) assays in rare malignancies.
Authors: Li Shenduo , Connor Dana , Fournier Lyndsey Lane , Rao Sarika , Manochakian Rami , Lou Yanyan , Zhao Yujie
Published: June 2024

e15046

Background: ctDNA assays can be used to assess molecular residual disease, and the value of ctDNA monitoring in disease surveillance and treatment response assessment has been demonstrated in colon, breast, lung, and bladder cancers. However, the data of ctDNA in rare cancers has been lacking. We conducted this retrospective study to investigate the potential roles of ctDNA monitoring in rare tumors in both surveillance and response evaluation. Methods: ctDNA assay results of 12 patients (pts) with rare cancers including adrenocortical carcinoma (ACC) (4 pts), salivary gland cancers (3 pts), pleural or peritoneal malignant mesothelioma (4 pts), and anaplastic thyroid cancer (ATC) (1pt) undergoing treatment or surveillance in 2023 at Mayo Clinic Florida were analyzed. The trends of ctDNA levels were correlated with radiographic images findings. Results: Among the 12 patients, ctDNA was detected in at least one time point in 9 (75%) pts, including 1 (100%) ATC pt, 2 (66%) salivary gland pts, 3 (75%) malignant mesothelioma pts, and 3 (75%) ACC pts. Among these 9 pts, 5 pts had ctDNA collected at more than one timepoints, and the trends of ctDNA levels were consistent with image findings in all 5 pts. Among these 5 pts, one pt received definitive surgery for ACC with clearance of ctDNA after the surgery and one salivary gland cancer pt was undergoing surveillance and later developed disease progression. The other 3 pts were undergoing palliative systemic therapy and had responded to treatments. Conclusions: ctDNA was detectable in majority of the patients with rare malignancies reviewed in this study, including ACC, ATC, pleural or peritoneal malignant mesothelioma, and salivary gland cancers. Further study is warranted to investigate the role of ctDNA monitoring in surveillance and treatment response evaluation in rare malignancies.
Multi-omics study on the molecular mechanism of anlotinib in regulating tumor metabolism.
Authors: Lu Yu , Han Xuedan , Zheng Lufeng , Zhang Hongwei , Li Xiaoman
Published: June 2024

e15121

Background: Anlotinib, an orally administered small molecule inhibitor of receptor tyrosine kinases (RTKs), exerts significant anti-angiogenic and vascular normalization effects. However, the mechanisms underlying its involvement in tumor metabolic reprogramming are still unclear. This study aims to investigate the distribution and expression levels of metabolites within tumors after anlotinib treatment using spatial metabolomics analysis. Methods: This study involves spatially analyzing the distribution differences of metabolites post-anlotinib administration and integrating transcriptomics and proteomics to explore the internal mechanisms of anlotinib action at a molecular level. Results: By integrating the transcriptomics and proteomics analyses, we identified that anlotinib treatment primarily modulated four metabolic pathways, including taurine and hypotaurine metabolism, steroid synthesis, pentose phosphate pathway, and lipid biosynthesis. This regulation significantly influenced the metabolic levels of compounds such as sulfonic acids, cholesterol, inositol phosphate pyrophosphate, and palmitoyl-CoA in the tumor, thereby impacting tumor initiation and progression. Conclusions: This study provides potential metabolic biomarkers for anlotinib treatment in tumors, and may identify potential biomarkers and pathways associated with the therapeutic efficacy of anlotinib treatment.
Concurrent hyperthermic intraperitoneal chemotherapy and intraoperative radiotherapy with cytoreductive surgery in patients with rectal cancer with peritoneal carcinomatosis.
Authors: Arabi Tarek , Alaswad Marwan , Sabbah Belal Nedal , Al Otry Abdullah , Hejazi Alwalid , Ismail Aya , Jaamour Heba , Alhosainy Ziad , Al Homoud Samar , Azzam Ayman , Amin Tarek
Published: June 2024

e15571

Background: Rectal cancer (RC) is often associated with peritoneal carcinomatosis (PC). Hyperthermic intraperitoneal chemotherapy (HIPEC) and intraoperative radiotherapy (IORT) have been shows to reduce recurrence and effectively treat PC across several cancers. However, little evidence is available regarding the concurrent use of HIPEC and IORT alongside cytoreductive surgery (CRS) in the literature. Methods: We retrospectively reviewed the medical records of RC patients with PC who received HIPEC plus IORT during CRS at the King Faisal Specialist Hospital and Research Centre. Demographic data, PC index (PCI), completeness of cytoreduction (CC), and tumor staging were collected. Overall survival (OS) was calculated from the time of surgery until death or last follow-up. Recurrence-free survival (RFS) was calculated from the time of surgery until recurrence or last follow-up. Unadjusted hazard ratios (HR) were used to determine the impact of parameters on OS or RFS. Results: 17 patients were included in our analysis. Basic demographic data can be found in Table 1. The most common operation performed was rectosigmoid resection in 7 (41.2%) patients, followed by low anterior resection in 6 (35.3%). The pT stage was T0 in 1 (5.9%), T4a in 7 (41.2%), and T4b in 9 (52.9%). The pN stage was N0 in 11 (64.7%), N1a in 1 (5.9%), N1b in 2 (11.8%), N1c in 2 (11.8%), and N2b in 1 (5.9%). There was positive resection margin in 2 patients. The PCI was ≤6 in 15 (88.2%), and the CC score was 0-1 in all patients. No patients had intraoperative complications. 12 (70.6%) received mitomycin C, 4 (23.5%) received cisplatin and mitomycin C, and one patient received a reduced dose of mitomycin C due to old age. 2 (11.8%) patients received two doses of IORT. 11 (64.7%) patients had postoperative complications, of which all were Clavein-Dindo grades 1-3b. Recurrence occurred in 11 (64.7%). The median OS was not reached, and the median RFS was 12 months. There were no parameters associated with OS. Male gender (HR: 7.7, 95% CI: 1.4-57.3), pM1 (HR: 4.5, 95% CI; 1.2-18.1), and perineural invasion (HR: 6.5, 95% CI: 1.2-49.3) were associated with poor RFS in univariate analysis. Conclusions: Incorporating HIPEC and IORT into CRS may be an effective treatment strategy for RC patients. Presence of distant metastasis and perineural invasion can be predictors of rapid recurrence. [Table: see text]
Systemic assessment of manual circular stapler versus powered circular stapler for anastomosis in rectal cancer: A multicenter prospective cohort study.
Authors: Li Xinxiang , Chen Yikuan , Zhang Ruijia , Luo Dakui , Liu Fangqi
Published: June 2024

e15614

Background: Mechanical anastomosis offers several advantages over traditional hand-sutured anastomosis. However, complications such as anastomotic leaks, strictures, and bleeding persist due to factors like interactions between staples and tissue. Powered circular anastomosis is an effective method to address these issues. Currently, there are no domestic studies on the application of powered-anastomosis technology in colorectal anastomosis. Methods: The study adopted a multicenter, randomized, parallel-controlled, non-inferiority study design, with a 1:1 random allocation ratio. The study involved 187 patients with rectal cancer who underwent Dixon surgery using IntoCare™ disposable powered circular stapler (ICS), and 195 patients who received similar process with manual circular stapler (MCS). The efficacy of stapler was evaluated by anastomosis success rate, anastomosis-related adverse events, anastomosis device performance assessment, operation time, anastomosis time, and postoperative recovery. Safety evaluation indicators included adverse events, vital signs, and laboratory tests. Results: Baseline demographic characteristics showed no notable disparities between two groups (Table 1). A high proportion of patients, 99.47% in the MCS group and 99.49% in the ICS group, successfully completed anastomosis. In the MCS group, the average anastomosis duration was clocked at 2.84 minutes (min) (±2.3), with a median time of 2.0 min (ranging from 1.0 to 22.0 min). In contrast, the ICS group exhibited a slightly quicker average anastomosis duration of 2.40 min (±1.7), and a comparable median time of 2.0 min (but with a narrower range from 1.0 to 15.0 min). Adverse events did not differ significantly between two groups. Conclusions: The results uncovered the powered stapler could considerably reduce stapling time while maintaining a safety profile. Notably, the incidence of patients with anastomotic leakage one month post-surgery, and anastomotic stricture six months post-surgery in the powered stapler group, was lower than those in the manual stapler group. This suggests that the anastomosis created by the powered stapler is more stable and promotes more effective postoperative anastomotic healing. Clinical trial information: NCT05879172 . [Table: see text]
Prevalence and predictors of coronary artery stent re-stenosis in patients with cancer with prior history of percutaneous coronary intervention: A nationwide analysis.
Authors: Aryal Badri , Sueldo Alexandra , Turk Ekrem , Quevedo Andres
Published: June 2024

e24018

Background: Data regarding the prevalence, and predictors of development of in-stent restenosis (ISR) in cancer patients undergoing percutaneous coronary intervention (PCI) are scarce. This study aimed to identify factors associated with the development of ISR following PCI in cancer patients. Methods: This is a retrospective cohort study using the National Inpatient Sample(NIS) from 2016 to 2020. Discharges with ICD-10 CM code indicating stenosis of coronary artery stent, and secondary ICD-10 CM code indicating cancer, and prior history of PCI were included. Primary outcome was development of ISR. Multivariate logistic regression model was used to identify predictors of ISR development, and p value of less than 0.05 was considered significant. Results: There were 873,320 patients who met inclusion criteria, among which 4060 patients were admitted for coronary stent re-stenosis. Mean age of included patients was 73, and 31% were females. The prevalence rate of in-stent restenosis was 0.46%. Factors associated with increased odds of development of ISR included diabetes (OR 1.31, 95% CI 1.13-1.51, p < 0.001), dyslipidemia (OR 1.92, 95% CI 1.60-2.31, p < 0.001), congestive heart failure (OR 1.78, 95% CI 1.52-2.06, p < 0.01), carotid disease (OR 1.99, 95% CI 1.43-2.78, p < 0.001), and aortic disease (OR 1.83, 95% CI 1.12-2.98, p 0.01). Age, gender, race, median household income, hospital location and hospital teaching status didn’t exhibit statistically significant increased risk. Conclusions: The prevalence of in-stent restenosis was 0.46%. Appropriate management of risk factors such as diabetes, dyslipidaemia, congestive heart failure is prudent to prevent development of ISR in cancer patients, underscoring the importance of regular cardiology follow up, along with routine cancer care.
Effect of fructose on anthracycline and HER-2 blocking agent mediated cardiotoxicity through NLRP3 and MyD88 mediated pathways: New roles of sweeteners in cardio-oncology.
Authors: Paccone Andrea , Quagliariello Vincenzo , D'Aiuto Giuseppe , Iovine Martina , Giacobbe Ilaria , Arianna Raffaele , Izzo Francesca , Maurea Fabrizio , Barbato Matteo , Inno Alessandro , Giordano Vienna , Maurea Nicola
Published: June 2024

e24020

Background: Combinatorial therapy based on anthracyclines and HER-2 blocking agents increases the risk of cardiomyopathy in women with breast cancer. Fructose is a monosaccharide associated with high risk of diabetes, non-alcoholic fatty liver disease, atherosclerosis and visceral obesity. A high fructose diet is a potential cardiometabolic risk factor and may increase cardiac risk in women with breast cancer treated with cardiotoxic drugs. In this study, we highlighted the role of sweeteners fructose in the worsening of cardiotoxicity induced by combinatorial therapy anthracycline-HER2-blocking agents. Methods: Human cardiomyocytes were pre-exposed with doxorubicin combined to trastuzumab (at 300 and 1000 nM) for 48 and 72h alone or combined to fructose at 0.25, 1 and 2.5 mM. After the incubation period, we performed the following tests: determination of cell viability, through mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6, CXCL-12). Results: High fructose increases significantly cell mortality of cardiomyocytes exposed to doxorubicin and trastuzumab through the activation of NLRP-3 and Myd-88 expression. Intracellular Ca++ levels were also increased of 4 times compared to non-fructose exposed cardiomyocytes; MDA and 4-HNA levels were increased of 48,3 and 51,2 % compared to non-fructose exposed cells (p<0.001). Fructose increases IL-1, IL-6 and CXCL-12 expression in cardiomyocytes in a concentration dependent manner, compared to doxorubicin-trastuzumab group (p<0.05). Conclusions: Data of the present study indicate that fructose induces a pro-inflammatory phenotype in human cardiac cells exposed to anticancer cardiotoxic drugs, providing even more data on the harmful role of fructose as a key player of cardiotoxic phenomena.
Beyond the pain: Decoding opioid use in advanced cancer ED visits.
Authors: Nortey Joel , Lynch Andrew , Lyon Liisa , Ramalingam Nirmala D. , Liu Raymond
Published: June 2024

e24034

Background: Patients with advanced cancer often turn to the emergency department (ED) for pain treatment, impacting their quality of life and escalating healthcare costs. A crucial step in reducing avoidable ED visits is to identify the characteristics of this patient group and explore potential intervention points. This study aims to characterize the use of narcotics in the ED among patients with advanced cancer. Methods: This retrospective cross-sectional study involved adults aged 18 and older diagnosed with Stage IV solid cancers who passed away within one year of diagnosis (excluding those who died within 30 days). Participants had at least one ED visit within that year at one of 21 cancer centers within Kaiser Permanente Northern California from 2018 to 2020. Demographics, clinical variables, frequencies, and trends in ED visits were collected and compared based on opioid utilization. Pain management details for those receiving opioids during ED visits were also recorded. Results: The study encompassed 2,554 patients with 6,406 ED visits in their final year of life. Sixty-one percent of these patients received opioids during their ED visits, with a median of three visits per patient. In 56% of visits, patients had filled an opioid prescription within the last 30 days. Morphine (39%) and hydromorphone (29%) were the most commonly administered opioids, primarily intravenously (66%). The prevalent cancer subtypes receiving opioids during ED visits were breast, head and neck, and upper GI. Among patients in treatment with chemo, radiation, or both, 65% received opioids during ED visits, a higher rate compared to the 55% of patients not in treatment. For treated patients, chemotherapy was associated with increased ED visits requiring opioid pain management. Median survival did not differ significantly between those who received opioids during ED visits (130 days) and those who did not (123 days). Conclusions: This study emphasizes the dynamic pain needs of this patient population throughout their final year, leading them to seek pain management from the ED when their pain exceeds their home regimen. Factors influencing these needs include cancer subtype and current treatment status, particularly chemotherapy. Further studies are essential to understanding the variations in pain needs over the final year, enabling providers to better recognize and address changes in patients' pain requirements outside the ED.
Correlation between Palliative Performance Scale results and observed survival among Mexican patients with advanced cancer.
Authors: Cruz-Zermeño Mayte , Covarrubias-Gómez Alfredo , Lagunas-Medina Alex , Esparza-Orozco María Fernanda , Esparza-Orozco Raúl Emiliano , Ramos-Lopez Wendy Alicia , Soto Pérez de Celis Enrique , Chavarri Guerra Yanin
Published: June 2024

e24040

Background: Cancer is a common cause of death among Hispanics. Estimating patient survival is critical in cancer care since it allows better shared decision-making and avoids use of futile therapy. Palliative Performance Scale (PPS) has been widely used for survival prediction among patients with cancer. However, its performance has not been validated across populations in Latin America, which could have different outcomes. The aim of this study was to analyze the correlation between PPS score and observed survival among patients with advanced cancer to facilitate physician and patient decision-making near the end of life. Methods: We conducted a retrospective observational analysis of patients with advanced cancer included in “ Te Acompañamos” cohort, a multidisciplinary patient navigator-led supportive care program in a single center in Mexico City. We used descriptive statistics to analyze clinico-demographic variables, PPS score, observed survival in days (from recruitment to death). Pearson correlation coefficients were used for correlating observed survival in days and predicted survival using PPS. U de Mann Whitney was used for comparing survival days between PPS groups. Results: We analyzed 246 patients with advanced cancer included in “Te Acompañamos” who died between August 2017-January 2024. Among these patients, 143 (58%) were women. Mean age was 64 years (SD 13). 153 patients (62%) had gastrointestinal (GI), 43 (17%) gynecologic, 19 (7%) genitourinary, 5 (2%) lung, 5 (2%) thyroid, and 21 (8%) other solid malignancies. Pancreatic cancer was the most common cancer (n = 60, 24%). Patients with GI cancer more frequently reported pain (59%) and had an average PPS of 67.7%. Mean survival was 233 days (SD 247) and mean predicted survival in days according to PPS was 68 days (SD 20). Correlation between observed survival days and PPS-predicted survival was low (R = 0.29). Patients with PPS < 50% had mean survival of 74.6 days while patients with PPS > 50% of 243.2 days (p < 0.05). Patients aged < 60 years with GI tumors had a higher PPS score, while older patients had a lower score (74.6% vs 65%; p < 0.05). No other significant differences were found in other subgroups. Conclusions: Our results show weak correlation between observed and predicted survival in days using PPS. However, lower PPS was associated with decreased survival. Among patients with GI cancers we observed that older patients had the lowest PPS scores. This study emphasizes the need to develop and validate more precise tools for survival prediction across patient populations, including minorities such as the Hispanics. Our study suggests that strategies to diagnose and alleviate pain promptly in patients with advanced cancer near the end of life are urgently required.
Relationship between hope and quality of life in patients with advanced cancer in Uruguay: An observational analysis.
Authors: Camejo Natalia , Amarillo Dahiana , Nantes Florencia , Castillo Cecilia , Krygier Gabriel David
Published: June 2024

e24055

Background: International research suggests a beneficial effect of hope on quality of life in advanced-stage cancer patients. Specific evidence for Latin America and Uruguay is limited, highlighting the need to explore this relationship for regional clinical strategies. Objective: To evaluate the correlation between hope and quality of life in Uruguayan patients with advanced cancer. Methods: This observational, analytical-descriptive, and cross-sectional study used the Herth Hope Index (HHI) and the Functional Assessment of Cancer Therapy - General (FACT-G) Quality of Life questionnaire. It included 59 patients aged 18 or older, diagnosed with advanced, non-curable cancer. Results: There was a positive but non-significant correlation between HHI and FACT-G scores (Pearson coefficient of 0.05). Hope significantly correlated with support from oncology services (p = 0.044), family support (p = 0.003), and spiritual beliefs (p = 0.029). Factors like bone metastases, diagnostic delay, and being accompanied at consultations significantly impacted quality of life (p = 0.041, p = 0.035, p = 0.012). Conclusions: The study observed a positive association between hope and quality of life, but the lack of statistical significance indicates the need for more research. Clinically, results highlight the importance of comprehensive care addressing spiritual and emotional needs, in addition to medical treatment. It also underscores the potential impact of supportive services on patient well-being. Future research should include larger sample sizes and consider longitudinal designs to better understand hope's effects over time in advanced cancer patients.