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Background and Objectives: Metastatic breast cancer (MBC), particularly the HER2-positive subtype, represents a significant clinical challenge, with approximately 20–25% of breast cancer cases demonstrating HER2 overexpression. Trastuzumab, a monoclonal antibody targeting HER2, has significantly improved outcomes in these patients. However, progression after second-line treatments such as trastuzumab emtansine (T-DM1) necessitates exploring subsequent therapeutic options. This study aims to compare the efficacy of trastuzumab plus gemcitabine (GT) with lapatinib plus capecitabine (LC) as third-line treatments in HER2-positive MBC post-T-DM1 failure. Materials and Methods: This retrospective study included 98 HER2-positive MBC patients treated between 2017 and 2023 who progressed after T-DM1. Patients were divided into two groups: 21 received GT, and 28 received LC. Key endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events. Statistical analyses were performed using SPSS 26.0, with Kaplan–Meier survival curves, log-rank tests, and Cox proportional hazards models. Results: Median PFS was significantly longer in the GT group (9.5 months) compared to the LC group (4.3 months, p = 0.02). OS was also higher for GT (22.1 months vs. 10.0 months, p = 0.02). ORR favored the GT group (33.3% vs. 10.7%, p = 0.046), and progressive disease was more common in the LC group (57.1% vs. 33.3%, p = 0.022). The safety profile showed higher rates of diarrhea in the LC group, but both regimens were generally well tolerated. Conclusions: Trastuzumab re-challenge with gemcitabine demonstrated superior PFS, OS, and ORR compared to lapatinib plus capecitabine, suggesting it may be a more effective third-line therapy in HER2-positive MBC patients who have progressed after T-DM1. Further prospective studies are needed to confirm these findings and optimize treatment sequencing. [ABSTRACT FROM AUTHOR]

Background: The treatment and escape for metastatic renal cell carcinoma (RCC) has rapidly evolved, particularly with the integration of immune therapies into first-line regimens. However, optimal strategies following progression in first-line immunotherapy remain uncertain. This study aims to evaluate the efficacy and safety of axitinib and cabozantinib as third-line therapies after progression on nivolumab following first-line VEGF-TKI therapy. Methods: Patients with metastatic RCC who progressed on prior nivolumab treatment after receiving first-line VEGF-TKI therapy were included. Data on patient characteristics, treatment regimens, response rates, progression-free survival (PFS), and overall survival (OS) were collected. Statistical analyses were conducted to assess the prognostic factors and treatment outcomes. Results: A total of 46 patients were included who were predominantly male (83%) with clear-cell histology (89%). The median PFS on first-line TKI therapy was 10.2 months. All the patients received nivolumab as a second-line therapy, with a median of 12 cycles. The median second-line PFS was seven months. Third-line therapies included axitinib (24 patients) and cabozantinib (20 patients). The median PFS for axitinib and cabozantinib was six months, with comparable survival outcomes. The IMDC risk group and treatment tolerability were significant predictors of survival in multivariate analysis. Adverse events were manageable, with hypertension, fatigue, and diarrhea being the most common. Conclusion: Axitinib and cabozantinib show promise as third-line therapies post-nivolumab progression in metastatic RCC, though prospective validation is warranted. This study underscores the need for further research to establish treatment standards in this evolving landscape. [ABSTRACT FROM AUTHOR]

Objective: Non-alcoholic steatohepatitis (NASH) is one of the most common metabolic diseases of the liver. In patients with NASH, progression to cirrhosis can be observed in approximately 25% over a decade following diagnosis, and it is considered the most frequent cause of cryptogenic cirrhosis. Fibrinogen-like protein-2 (FGL-2) is a sub-member of the fibrinogen superfamily secreted by regulatory T cells. It inhibits the maturation of dendritic cells and induces apoptosis in B cells, playing a role in innate and adaptive immunity regulation. Recent studies have shown high serum FGL-2 levels are a poor prognostic indicator in patients with viral hepatitis. Methods: The study included 30 NASH patients diagnosed by biopsy and a control group of 21 healthy individuals. Serum FGL-2 levels of individuals in both groups were compared. The relationship between the clinicopathological features of individuals in both groups and FGL-2 levels was also examined. Results: Serum FGL-2 levels in NASH patients were found to be 47±12 ng/ml, while in the control group, it was 37±10 ng/ml. Statistical evaluation was performed using the Mann- Whitney U test. A significant difference was found between patients classified by biopsy as simple steatosis, borderline NASH, definite NASH, and the control group (p=0.002). A significant difference was also observed when evaluating these four groups among themselves (Kruskal-Wallis test, p=0.012). Conclusion: Our study identified higher serum FGL-2 levels in patients diagnosed with NASH, consistent with steatohepatitis observed in biopsies. Elevated FGL-2 levels may indicate hepatic damage at the microinflammation level. Estimating disease severity, non-invasive monitoring and control of disease progression, selecting patients for aggressive treatment approaches, and intensifying monitoring intervals for cirrhosis and HCC could be crucial. However, more comprehensive studies on this topic are needed. [ABSTRACT FROM AUTHOR]

Introduction: Nivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits programmed cell death-1 activity by binding to the programmed cell death-1 receptors. Cancer cells express increased number of programmed cell death-1 ligands and this allows them to escape the cytotoxic effects of the T cells. Therefore, the negative programmed cell death-1 receptor signal regulates T-cell proliferation and activation is disrupted. However, this change in the activity of the T cells can cause them to lose their ability to recognize host cells. The immune response enabled by these agents has led to side effects, commonly known as "immune-related adverse events." Case report: We report a case of a 66-year-old male patient who was treated with nivolumab for recurrent renal cell carcinoma presented with hepatitis and adrenalitis. Three weeks after starting nivolumab, the patient had abdominal pain and weakness, and then aspartate and alanine transaminase levels were found to be elevated. Management and outcome: Hepatitis was predicted to be due to nivolumab, because other causes were excluded. He started using oral methylprednisolone and then, hepatitis improved. However, while receiving methylprednisolone treatment, fludrocortisone was started with the pre-diagnosis of adrenalitis due to the persistence of fatigue, weakness, and hyponatremia and hyperkalemia. With both treatments, the patient's symptoms and sodium and potassium level returned to normal. Discussion: This case emphasizes the need for patient's education and awareness of immune-related adverse events, and the importance of understanding the management of life-threatening complications of the checkpoint inhibitors, because these side effects require prompt recognition and treatment. [ABSTRACT FROM AUTHOR]

Background: Ado-trastuzumab emtansine is an antibody-drug conjugate that combines the cytotoxic activity of emtansine with human epidermal growth factor receptor 2-targeted antitumor features of trastuzumab. Objective: We conducted a study of metastatic breast cancer patients treated with trastuzumab emtansine. By evaluating progression-free survival, overall survival, and response rates, we aimed to find prognostic factors of trastuzumab emtansine treatment. Methods: Our study is a single-center, retrospective, observational study. We have clinical data from 78 patients treated with trastuzumab emtansine for metastatic breast cancer, from May 2016 through May 2019, at Kartal Dr Lutfi Kirdar Education and Research Hospital, Medical Oncology Department. Our objective is to assess the survival and response rates in trastuzumab emtansine-treated individuals and the factors associated with survival. The factors we analyzed were cancer antigen 15-3 sensitivity, Eastern Cooperative Oncology Group-Performance Status, presence or absence of visceral metastases, presence or absence of cranial metastases, and treatment-associated thrombocytopenia. Results: Among 78 patients, median progression-free survival was 7.8 months, and overall survival was 21.1 months. Twenty of the patients had an objective tumor response. The results showed that trastuzumab emtansine was tolerable with a manageable safety profile and consistent with the results of the previous literature. Mostly seen adverse events were anemia, thrombocytopenia, fatigue, and increased levels of alkaline phosphatase. Patients with Eastern Cooperative Oncology Group-Performance Status = 2 had worse progression-free survival and overall survival compared to ones with Eastern Cooperative Oncology Group-Performance Status < 2; progression-free survival and overall survival are worse in cancer antigen 15-3-sensitive breast cancer patients. According to our findings, treatment-associated thrombocytopenia was a significant prognostic factor for survival. Patients with thrombocytopenia had 12 months progression-free survival, whereas patients without thrombocytopenia had only 4.1 months progression-free survival. In like manner, overall survival was much better in the thrombocytopenia-experienced patients as 29.5 versus 11.8 months. Conclusions: Trastuzumab emtansine prolongs progression-free survival and overall survival with a manageable safety profile. Thrombocytopenia, Eastern Cooperative Oncology Group-Performance Status, and cancer antigen 15-3 are correlated with progression-free survival and/or overall survival. [ABSTRACT FROM AUTHOR]

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Background and Objective: Breast cancer (BC) remains a significant health concern, particularly in advanced stages where the prognosis is poor. The combination of endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has improved outcomes for advanced BC (aBC) patients. However, resistance to CDK4/6i remains a challenge, with no validated biomarkers to predict response. The receptor activator of the nuclear factor-kB (RANK) pathway has emerged as a key player in aBC, particularly in luminal BC. RANK overexpression has been associated with aggressive phenotypes and resistance to therapy. In view of these findings, we proceeded to investigate the potential involvement of the RANK pathway in luminal BC resistance to CDK4/6i. The objective was to evaluate the effectiveness of denosumab in increasing overall survival (OS) and progression-free survival (PFS)., Methods: In this retrospective analysis, 158 BC patients with bone metastases were included. Patients with human epidermal growth factor receptor-2 (HER2)-negative and hormone receptor-positive BC who received palbociclib or ribociclib in addition to antiresorptive medication were included. Patients received either denosumab or zoledronic acid (ZA) therapy. The primary endpoint was OS, with PFS as a secondary endpoint., Results: Although the PFS and OS of denosumab were better than ZA in this study, it did not show a significant difference between the two drugs. Meanwhile, mOS was not achievable in patients in the denosumab group, while it was 34.1 months in patients in the ZA group. The hazard ratio (HR) showed a significant improvement for the denosumab group in patients under 60 of age (HR: 0.33, p<0.01), patients with a score of 1 HER2 overexpression (HR: 0.09, p=0.01), and patients with resistant endocrine (HR: 0.42, p=0.02) compared to ZA., Conclusion: This study highlights the potential clinical relevance of the RANK pathway in BC treatment, and our findings suggest that denosumab may offer significant benefits in terms of PFS and OS for certain subgroups, particularly those with HER2 scores of 1, patients under 60, and those with endocrine-resistant BC. In conclusion, considering that RANK pathway status may be a predictive biomarker for CDK4/6i treatment and may cause treatment resistance, our results demonstrate the clinical relevance of the combination of CDK4/6i + ET with RANKL inhibition., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Kartal Dr. Lütfi Kirdar City Hospital issued approval 2023/514/250/2. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Akdag et al.)