Obesity as a risk factor of in-hospital outcomes in patients with endometrial cancer treated with laparoscopic surgical mode

Objectives: Obesity has been suggested to have a negative influence on procedural outcomes of endometrial cancer laparoscopic treatment. Obesity and other possible risk factors of laparoscopic endometrial cancer treatment has not been precisely described in the literature. The aim of the study is to determine the factors that have the greatest influence on the course of laparoscopic surgery for endometrial cancer, with particular emphasis on the influence of obesity. Material and methods: The study included 75 females who were treated for endometrial cancer by laparoscopic surgery. Preoperative body-mass index (BMI), waist circumference(WC), waist to hip ratio(WHR), and selected anatomical indices were measured. The duration of surgery and hospitalization stay, loss of hemoglobin, and procedural-related complications served as parameters of in-hospital outcomes. Results: Multiple linear regression analysis indicate the body mass as most sensitive parameter of obesity which influence in-hospital outcomes in patients treated with laparoscopic procedure. Procedural-related complications occurred in the group of patients with significantly greater WC and BMI. Multiple linear regression indicates also histological grading (G1–G3), external conjugate, intertrochanteric distance as significant risk factors. The multiple linear regression analysis confirmed also that implementation of sentinel lymph node procedure is related with decreased hemoglobin loss in patients with cancer of endometrium compare to lymphadenectomy without sentinel node biopsy(Est.: 0.488; 95% CI: 0.083–0.892, p = 0.018). Conclusions: The most sensitive risk factor of in-hospital outcomes in laparoscopic treatment of endometrial cancer is body mass. The implementation of the sentinel node procedure is associated with reduced surgery time and reduced hemoglobin loss

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

The prognosis for B-cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however, lack of sufficient responses in preclinical models and the possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in a patient-derived xenograft model leads to downregulation of several tumor protein 53 (TP53)-related genes. Interestingly, auranofin, a thioredoxin reductase inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently of the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of the NOXA-encoding gene Phorbol-12-Myristate-13-Acetate-Induced Protein 1 (PMAIP1) associated with chromatin remodeling and increased transcriptional accessibility. Altogether, these results present an efficacious drug combination that could be considered for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations

Obesity as a risk factor of in-hospital outcomes in patients with endometrial cancer treated with laparoscopic surgical mode

Objectives: Obesity has been suggested to have a negative influence on procedural outcomes of endometrial cancer laparoscopic treatment. Obesity and other possible risk factors of laparoscopic endometrial cancer treatment has not been precisely described in the literature. The aim of the study is to determine the factors that have the greatest influence on the course of laparoscopic surgery for endometrial cancer, with particular emphasis on the influence of obesity. Material and methods: The study included 75 females who were treated for endometrial cancer by laparoscopic surgery. Preoperative body-mass index (BMI), waist circumference(WC), waist to hip ratio(WHR), and selected anatomical indices were measured. The duration of surgery and hospitalization stay, loss of hemoglobin, and procedural-related complications served as parameters of in-hospital outcomes. Results: Multiple linear regression analysis indicate the body mass as most sensitive parameter of obesity which influence in-hospital outcomes in patients treated with laparoscopic procedure. Procedural-related complications occurred in the group of patients with significantly greater WC and BMI. Multiple linear regression indicates also histological grading (G1–G3), external conjugate, intertrochanteric distance as significant risk factors. The multiple linear regression analysis confirmed also that implementation of sentinel lymph node procedure is related with decreased hemoglobin loss in patients with cancer of endometrium compare to lymphadenectomy without sentinel node biopsy(Est.: 0.488; 95% CI: 0.083–0.892, p = 0.018). Conclusions: The most sensitive risk factor of in-hospital outcomes in laparoscopic treatment of endometrial cancer is body mass. The implementation of the sentinel node procedure is associated with reduced surgery time and reduced hemoglobin loss

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions

Tumor of the pharynx – an unexpected diagnosis

Introduction. Head and neck haemangiomas occur quite rarely. These are benign lesions, often involving the pharynx and larynx. They almost always pose a diagnostic and therapeutic problem. Case description. This paper describes the case of an asymptomatic internal carotid artery aneurysm manifested by a throat tumour. A 78-year old woman with sudden deafness and vertigo was additionally diagnosed with a throat tumour. After radiological diagnosis of a haemangioma, the patient refused surgery. This article presents diagnostic methods and various types of treatments for head and neck haemangiomas. Attention was paid to the possibility of serious complications when deciding on surgical intervention of haemangiomas without a confirmed diagnosis. Conclusion. Suspicion of head and neck haemangiomas necessitates using all available diagnostic methods. The treatment plan should take into account the pace of progression, the patient’s age and co-morbid conditions.