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Clinical Cancer Research : An Official... Jun 2024Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients...
PURPOSE
Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer.
EXPERIMENTAL DESIGN
A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS).
RESULTS
The model showed significant association with patient´s outcomes in all five cohorts. The model predicted high Ki67 (area under the curve; AUC (95% confidence interval) of 0.80 (0.64 - 0.92), 0.81 (0.60 - 1.00) and 0.80 (0.65 - 0.93)) and high PAM50 ROR (AUC of 0.78 (0.64 - 0.89)). This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS (hazard ratio=2.92 (95% CI 1.08 - 7.86), p=0.034 and HR=2.16 (1.02 4.55), p=0.043).
CONCLUSION
A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy, which marks a step towards more personalized treatments in patients with Luminal B breast cancer.
PubMed: 38922642
DOI: 10.1158/1078-0432.CCR-24-0244 -
Breast Cancer Research and Treatment Jun 2024This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone...
Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).
PURPOSE
This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial).
METHODS
Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV).
RESULTS
In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B.
CONCLUSION
We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.
PubMed: 38922548
DOI: 10.1007/s10549-024-07414-7 -
Breast Cancer Research and Treatment Jun 2024In Ireland, over 3000 patients are diagnosed with breast cancer annually, and 1 in 9 Irish women will be diagnosed with breast cancer in their lifetime. There is...
PURPOSE
In Ireland, over 3000 patients are diagnosed with breast cancer annually, and 1 in 9 Irish women will be diagnosed with breast cancer in their lifetime. There is evidence that female breast cancer survivors are more likely to die of cardiovascular disease than their age-matched counterparts. Specific services for cancer patients suffering from cancer therapy related cardiovascular toxicity have led to a higher incidence of safe anti-cancer treatment completion. Such services are not widely available in our jurisdiction, and the purpose of this trial is to remedy this situation.
METHODS
This protocol describes a prospective, single arm, pilot feasibility study implementing a dedicated Cardio-Oncology assessment and surveillance pathway for patients receiving multimodal breast cancer treatment. It incorporates novel biomarker and radiomic surveillance and monitoring approaches for cancer-therapy related cardiac dysfunction into routine care for breast cancer patients undergoing adjuvant systemic chemotherapy.
RESULTS
Declaration of results will via peer reviewed academic journals, and communicated directly to key knowledge users both nationally and internationally. This engagement will be critical to enable to healthcare services and policy sector make informed decisions or valuable changes to clinical practice, expenditure and/or systems development to support specialized Cardio-Oncology clinical pathways. All data is to be made available upon request.
CONCLUSION
Dedicated cardio-oncology services have been recommended in recent literature to improve patient outcomes. Our protocol describes a feasibility study into the provision of such services for breast cancer.
PubMed: 38922547
DOI: 10.1007/s10549-024-07322-w -
Journal of Patient-reported Outcomes Jun 2024Breast cancer-related lymphedema (BRCL) is one of the most common causes of upper extremity (UE) lymphedema in developed nations and substantially impacts health-related...
BACKGROUND
Breast cancer-related lymphedema (BRCL) is one of the most common causes of upper extremity (UE) lymphedema in developed nations and substantially impacts health-related quality of life. To advance our understanding of the epidemiology and treatment of BRCL, rigorously developed and validated patient-reported outcome measures (PROMs) are needed. This study aimed to demonstrate the iterative content validity of a modular UE lymphedema-specific PROM called the LYMPH-Q UE module.
METHODS
A multi-step iterative qualitative approach was used. Semi-structured interview data from in-depth qualitative interviews with adult women (18 years and older) with BCRL were used to develop the first set of the LYMPH-Q UE scales. The content validity of these scales was demonstrated with patient and clinician feedback. Over the course of cognitive debriefing interviews, additional concepts of lymphedema worry and impact on work were identified as missing from the LYMPH-Q UE module. Subsequently, two new qualitative studies (a focus group and in-depth concept elicitation interviews with patients) were conducted, and two new scales were developed to measure lymphedema worry and impact on work life and their content validity was demonstrated.
RESULTS
Qualitative data from in-depth and cognitive interviews with 15 (age 40-74 years) and 16 (age 38-74 years) women with BRCL, respectively, and feedback from 12 clinical experts, were used to develop and demonstrate the content validity of six LYMPH-Q UE scales measuring symptoms, function, appearance, psychological, information, and arm sleeve. Additionally, data from in-depth interviews with 12 (age 35-72 years) women with UE lymphedema and four focus groups (n = 16 women; age 35-74 years) was used to develop and assess the content validity of two new LYMPH-Q UE scales measuring lymphedema worry and impact on work life. The content validity of the previously established six scales was also demonstrated in these subsequent qualitative studies.
CONCLUSION
The LYMPH-Q UE is a modular PROM developed using international guidelines for PROM development and can be used in clinical practice, research, and quality improvement to enhance patient-centered shared decision-making. This study's innovative and iterative approach to content validation demonstrates that the LYMPH-Q UE is a comprehensive measure that includes important concepts relevant to patients with UE lymphedema.
Topics: Humans; Female; Patient Reported Outcome Measures; Middle Aged; Quality of Life; Qualitative Research; Upper Extremity; Aged; Interviews as Topic; Adult; Reproducibility of Results; Lymphedema; Breast Cancer Lymphedema; Focus Groups; Breast Neoplasms; Psychometrics
PubMed: 38922461
DOI: 10.1186/s41687-024-00701-3 -
Insights Into Imaging Jun 2024To construct and validate multiparametric MR-based radiomic models based on primary tumors for predicting lymph node metastasis (LNM) following neoadjuvant...
OBJECTIVES
To construct and validate multiparametric MR-based radiomic models based on primary tumors for predicting lymph node metastasis (LNM) following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients.
METHODS
A total of 150 LARC patients from two independent centers were enrolled. The training cohort comprised 100 patients from center A. Fifty patients from center B were included in the external validation cohort. Radiomic features were extracted from the manually segmented volume of interests of the primary tumor before and after nCRT. Feature selection was performed using multivariate logistic regression analysis. The clinical risk factors were selected via the least absolute shrinkage and selection operator method. The radiologist's assessment of LNM was performed. Eight models were constructed using random forest classifiers, including four single-sequence models, three combined-sequence models, and a clinical model. The models' discriminative performance was assessed via receiver operating characteristic curve analysis quantified by the area under the curve (AUC).
RESULTS
The AUCs of the radiologist's assessment, the clinical model, and the single-sequence models ranged from 0.556 to 0.756 in the external validation cohort. Among the single-sequence models, model exhibited superior predictive power, with an AUC of 0.756 in the external validation set. In combined-sequence models, model had the best diagnostic performance in predicting LNM after nCRT, with a significantly higher AUC (0.831) than those of the clinical model, model, and the single-sequence models (all p < 0.05).
CONCLUSIONS
A multiparametric model that incorporates MR radiomic features before and after nCRT is optimal for predicting LNM after nCRT in LARC.
CRITICAL RELEVANCE STATEMENT
This study enrolled 150 LARC patients from two independent centers and constructed multiparametric MR-based radiomic models based on primary tumors for predicting LNM following nCRT, which aims to guide therapeutic decisions and predict prognosis for LARC patients.
KEY POINTS
The biological characteristics of primary tumors and metastatic LNs are similar in rectal cancer. Radiomics features and clinical data before and after nCRT provide complementary tumor information. Preoperative prediction of LN status after nCRT contributes to clinical decision-making.
PubMed: 38922456
DOI: 10.1186/s13244-024-01726-4 -
Journal of Robotic Surgery Jun 2024Robotic-assisted surgery emerged as a technological advancement in the twentieth century, with gynaecology being a key adopter of this approach. The Senhance Surgical...
Robotic-assisted surgery emerged as a technological advancement in the twentieth century, with gynaecology being a key adopter of this approach. The Senhance Surgical System has gained prominence for total hysterectomies from single-site experiences, but multi-site reporting are still lacking in present literature. This multi-site study, conducted at Klaipeda University Hospital and Academic Teaching Hospital Feldkirch, aimed to explore the safety and feasibility of total hysterectomies with the Senhance Surgical System. The study involved 295 cases, showcasing a well-established routine with minimal procedure times. The average age of the patients was 53.5 years (SD: 10.3 years), ranging from 18 to 80 years. The patients' BMI averaged 25.6 kg/m (SD: 6.2 kg/m), ranging from a minimum of 17.7 kg/m to a maximum of 69.5 kg/m. The duration of surgery varied between 30 and 215 min, with a median of 95 min (IQR: 81-116). The docking time was a median of 3 (IQR: 2-5) min and varied between 1.0 and 30.0 min, with a minimum to a maximum range of 1.0 to 122 min. Conversion (3 cases, 1%) and adverse events (6 cases, 2%) were infrequent. Additionally, robotic malfunctions were recorded minimally in 4,1% (12 cases) of the procedures, and pain on a 0-10 visual pain scale was reduced from mild [2.7 (± 1.2)] one day postoperative to minimal [0.9 (± 0.5)] at discharge. Overall, a great routine with the Senhance Surgical System proves good control and, thus, feasibility and safety. Therefore, the Senhance Surgical System is a viable option for total hysterectomy.
Topics: Humans; Robotic Surgical Procedures; Female; Middle Aged; Hysterectomy; Adult; Aged; Operative Time; Aged, 80 and over; Adolescent; Feasibility Studies; Young Adult
PubMed: 38922454
DOI: 10.1007/s11701-024-01944-4 -
Analytical and Bioanalytical Chemistry Jun 2024Glycation is a non-enzymatic posttranslational modification coming from the reaction between reducing sugars and free amino groups in proteins, where early glycation...
Glycation is a non-enzymatic posttranslational modification coming from the reaction between reducing sugars and free amino groups in proteins, where early glycation products (fructosyl-lysine, FL) and advanced glycation end products (AGEs) are formed. The occurrence of glycation and accumulation of AGEs have been closely associated with hepatocellular carcinoma (HCC). Here, we reported the characterization of differential glycation in HCC using tissue proteomics with stable isotopic labeling; early glycation-modified peptides were enriched with boronate affinity chromatography (BAC), and AGEs-modified peptides were fractionated with basic reversed-phase separation. By this integrated approach, 3717 and 1137 early and advanced glycated peptides corresponding to 4007 sites on 1484 proteins were identified with a false discovery rate (FDR) of no more than 1%. One hundred fifty-five sites were modified with both early and advanced end glycation products. Five early and 7 advanced glycated peptides were quantified to be differentially expressed in HCC tissues relative to paired adjacent tissues. Most (8 out of 10) of the proteins corresponding to the differential glycated peptides have previously been reported with dysregulation in HCC. The results together may deepen our knowledge of glycation as well as provide insights for therapeutics.
PubMed: 38922433
DOI: 10.1007/s00216-024-05392-9 -
Nanoscale Jun 2024Targeted drug delivery using metal-organic frameworks (MOFs) has shown significant progress. However, the tumor microenvironment (TME) impedes efficient MOF particle...
Targeted drug delivery using metal-organic frameworks (MOFs) has shown significant progress. However, the tumor microenvironment (TME) impedes efficient MOF particle transfer into tumor cells. To tackle this issue, we pre-coated nano-sized MOF-808 particles with multifunctional proteins: glutathione S-transferase (GST)-affibody (Afb) and collagenase, aiming to navigate the TME more effectively. The surface of MOF-808 particles is coated with GST-Afb-a fusion protein of GST and human epidermal growth factor receptor 2 (HER2) Afb or epidermal growth factor receptor (EGFR) Afb which has target affinity. We also added collagenase enzymes capable of breaking down collagen in the extracellular matrix (ECM) through supramolecular conjugation, all without chemical modification. By stabilizing these proteins on the surface, GST-Afb mitigate biomolecule absorption, facilitating specific tumor cell targeting. Simultaneously, collagenase degrades the ECM in the TME, enabling deep tissue penetration of MOF particles. Our resulting system, termed collagenase-GST-Afb-MOF-808 (Col-Afb-M808), minimizes undesired interactions between MOF particles and external biological proteins. It not only induces cell death through Afb-mediated cell-specific targeting, but also showcases advanced cellular internalization in 3D multicellular spheroid cancer models, with effective deep tissue penetration. The therapeutic efficacy of Col-Afb-M808 was further assessed imaging and evaluation of tumor inhibition following injection of IR-780 loaded Col-Afb-M808 in 4T1tumor-bearing nude mice. This study offers key insights into the regulation of the multifunctional protein-adhesive surface of MOF particles, paving the way for the designing even more effective targeted drug delivery systems with nano-sized MOF particles.
PubMed: 38921728
DOI: 10.1039/d4nr02345e -
Pathophysiology : the Official Journal... Jun 2024This narrative review delves into the evolving landscape of fertility preservation techniques, with a particular focus on their use in patients undergoing oncology... (Review)
Review
Fertility Preservation and Ovarian Hyperstimulation Syndrome Management in Cancer Care: A Pathophysiological Perspective on Gonadotropin-Releasing Hormone Agonists and Antagonists.
This narrative review delves into the evolving landscape of fertility preservation techniques, with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted, and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and the management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.
PubMed: 38921726
DOI: 10.3390/pathophysiology31020021 -
Marine Drugs Jun 2024SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this...
SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.
Topics: Animals; Mice; Macrophages; RAW 264.7 Cells; Lectins; Bivalvia; Cell Proliferation; Humans; Cytokines; Phenotype; Signal Transduction
PubMed: 38921580
DOI: 10.3390/md22060269