Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.

An unusual case of an extensive post-injection retroperitoneal abscess in an intravenous drug user.

Retroperitoneal abscesses constitute an uncommon, complex, and life-threatening intra-abdominal infection. The insidious nature of the presentation, coupled with the presence of non-specific clinical symptoms, might result in misdiagnosis or delayed diagnosis, ultimately contributing to substantial morbidity and mortality. Herein we report a case of a 32-year-old intravenous drug user who presented to the emergency department complaining of high-grade fever, intense hiccough, and back pain due to retroperitoneal abscess formation after intravenous injection in the left femoral vein.

BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it.

Targeted therapy for oncogenic genetic alterations has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Mutations in the BRAF gene are detected in approximately 4% of patients and result in hyper-activation of the MAPK pathway, leading to uncontrolled cellular proliferation. Inhibition of BRAF and its downstream effector MEK constitutes a therapeutic strategy for a subset of patients with NSCLC and is associated with clinical benefit. Unfortunately, the majority of patients will develop disease progression within 1 year. Preclinical and clinical evidence suggests that resistance mechanisms involve the restoration of MAPK signaling which becomes inhibition-independent due to upstream or downstream alterations, and the activation of bypass pathways, such as the PI3/AKT/mTOR pathway. Future research should be directed to deciphering the mechanisms of cancer cells' oncogenic dependence, understanding the tissue-specific mechanisms of BRAF-mutant tumors, and optimizing treatment strategies after progression on BRAF and MEK inhibition.

"You are my sunshine, my only sunshine": maternal vitamin D status and supplementation in pregnancy and their effect on neonatal and childhood outcomes.

Vitamin D (VD) plays a crucial role in regulating calcium homeostasis, while the wealth of its pleiotropic actions is gaining increasing research interest. Sufficient VD concentrations are of clinical relevance, particularly in the context of physiological alterations, such as those occurring during pregnancy when maternal VD is the sole source for the developing fetus. As a result, inadequate VD concentrations in pregnancy have been associated with perinatal complications and adverse neonatal outcomes, including preeclampsia, gestational diabetes mellitus, increased rates of cesarean section, low birth weight, small-for-gestational-age infants, poor immune and skeletal growth, allergies, and respiratory infections. Over the past few decades, several observational studies have underlined the important role of maternal VD in the neural, musculoskeletal, and psychomotor growth and bone health of the offspring. However, the complexity of the factors involved in regulating and assessing VD homeostasis, including race, sun exposure, dietary habits, and laboratory measurement techniques, makes the interpretation of relevant research findings challenging. The aim of this narrative review is to summarize the evidence on the importance of VD in maintaining optimal health during pregnancy, infancy, childhood, and adolescence.

Malignant Superior Vena Cava Syndrome: State of the Art.

Superior vena cava syndrome (SVCS) is a clinical entity characterized by signs and symptoms arising from the obstruction or occlusion of the thin-walled superior vena cava (SVC) and can result in significant morbidity and mortality. Despite the rise of benign cases of SVCS, as a thrombotic complication of intravascular devices, it is most commonly seen secondary to malignancy as a consequence of thrombosis, direct invasion of tumor cells inside the vessel, or external compression. SVCS can be the initial presentation of a previously undiagnosed tumor in up to 60% of cases. Lung cancer and non-Hodgkin lymphoma (NHL) are responsible for up to 85%-90% of malignancy-related SVCS, while metastatic cancers account for approximately 10%. Herein, we review the pathophysiology, etiology, clinical presentation, diagnosis, and management of malignancy-related SVCS.

Heparin-induced Thrombocytopenia: Pathophysiology, Diagnosis and Management.

Heparin-induced thrombocytopenia (HIT), even rare, is a life-threatening, immune-mediated complication of heparin exposure. It is considered the most severe non-bleeding adverse reaction of heparin treatment and one of the most important adverse drug reactions. The pathophysiological basis of HIT results from the formation of an immunocomplex consisting of an auto-antibody against platelet factor 4 (PF4) - heparin complex, which binds to the surface of platelets and monocytes, provoking their activation by cross-linking FcgIIA receptors. Platelets and monocyte activation, leads to the generation of catastrophic arterial and venous thrombosis, with a mortality rate of 20%, without early recognition. The definitive diagnosis of HIT i.e., clinical and laboratory evidence, can not be done at the onset of symptoms because laboratory results may not be available for several days. Thus, the initial approach is to predict the likelihood of HIT, because in highly suspected patients immediate heparin cessation and initiation of alternative anticoagulation treatment are crucial for the prevention of the devastating thrombotic sequelae. Herein, we describe the pathophysiology, the clinical manifestations, the diagnostic approach, and the management of patients with HIT.

Isolated pneumomediastinum following laparoscopic cholecystectomy: a rare complication.

Development of postoperative pneumomediastinum is one of the most infrequent complications of laparoscopic procedures. We report a case of a 47-year-old woman who developed pneumomediastinum consequently to laparoscopic cholecystectomy. The patient was treated conservatively and was discharged on the fifth postoperative day. Early detection of this condition, differential diagnosis and careful monitoring of the patient are important, as it may lead to severe consequences, including the life-threatening tension pneumomediastinum.

BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it

Targeted therapy for oncogenic genetic alterations has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Mutations in the BRAF gene are detected in approximately 4% of patients and result in hyper-activation of the MAPK pathway, leading to uncontrolled cellular proliferation. Inhibition of BRAF and its downstream effector MEK constitutes a therapeutic strategy for a subset of patients with NSCLC and is associated with clinical benefit. Unfortunately, the majority of patients will develop disease progression within 1 year. Preclinical and clinical evidence suggests that resistance mechanisms involve the restoration of MAPK signaling which becomes inhibition-independent due to upstream or downstream alterations, and the activation of bypass pathways, such as the PI3/AKT/mTOR pathway. Future research should be directed to deciphering the mechanisms of cancer cells’ oncogenic dependence, understanding the tissue-specific mechanisms of BRAF-mutant tumors, and optimizing treatment strategies after progression on BRAF and MEK inhibition (AU)