ABSTRACT
Blood vessels in tumors are often dysfunctional. This impairs the delivery of therapeutic agents to and distribution among the cancer cells. Subsequently, treatment efficacy is reduced, and dose escalation can increase adverse effects on non-malignant tissues. The dysfunctional vessel phenotypes are attributed to aberrant pro-angiogenic signaling, and anti-angiogenic agents can ameliorate traits of vessel dysfunctionality. However, they simultaneously reduce vessel density and thereby impede drug delivery and distribution. Exploring possibilities to improve vessel functionality without compromising vessel density in the tumor microenvironment, we evaluated transcription factors (TFs) involved in epithelial-mesenchymal transition (EMT) as potential targets. Based on similarities between EMT and angiogenic activation of endothelial cells, we hypothesized that these TFs, Snai1 in particular, might serve as key regulators of vessel dysfunctionality. In vitro, experiments demonstrated that Snai1 (similarly Slug and Twist1) regulates endothelial permeability, permissiveness for tumor cell transmigration, and tip/stalk cell formation. Endothelial-specific, heterozygous knock-down of Snai1 in mice improved vascular quality in implanted tumors. This resulted in better oxygenation and reduced metastasis. Notably, the tumors in Snai1KD mice responded significantly better to chemotherapeutics as drugs were transported into the tumors at strongly increased rates and more homogeneously distributed. Thus, we demonstrate that restoring vessel homeostasis without affecting vessel density is feasible in malignant tumors. Combining such vessel re-engineering with anti-cancer drugs allows for strategic treatment approaches that reduce treatment toxicity on non-malignant tissues.
ABSTRACT
Introduction: Rhino-orbital-cerebral mucormycosis (ROCM) is a rare angioinvasive fungal infection known to be associated with high morbidity and over 50% mortality. ROCM is becoming more common due to an increase in predisposing immunocompromising comorbidities as well as COVID-19. Case Presentations: We report 2 cases - a 75-year-old woman with diabetes and a 39-year-old man with recurrent diabetic ketoacidosis. Both presented initially with acute sinonasal symptoms, were positive for SARS-CoV-2, and diagnosed with acute ROCM. Both underwent mutilating surgical therapy as well as high-dose amphotericin B treatment. With continued oral antifungal treatment, patient 1 showed stable symptoms despite radiographically increasing disease and died of urosepsis 5 months after first surgery. With posaconazole treatment, patient 2 recovered from the disease and showed no clinical sign of disease progression after 1 year. Conclusion: Despite the rarity of the disease, ROCM should be considered if the findings of clinical and radiological examination fit, so that a delay in treatment initiation can be avoided. As our both cases show, survival from ROCM is possible - albeit at a high cost.
ABSTRACT
We describe a case of rhino-orbital-cerebral mucormycosis (ROCM) in a diabetic patient. She presented with cavernous sinus syndrome and ischemia of the optic nerve. Initially unremarkable findings in the nasal cavity and paranasal sinus delayed early diagnosis. Within two weeks, a follow-up MRI showing progressive orbital inflammation, thrombosis of the cavernous sinus and erosive destruction of the left middle nasal concha together with necrotic black tissue in the left nasal cavity and destruction of the maxillary sinus demonstrated in a consecutively performed ethmoidectomy, finally gave way to diagnosis. Definite diagnosis was established by histopathology and culture. Treatment consisted of a combination of liposomal Amphotericin B, partial surgical resection and improved diabetes control. Despite insufficient surgical treatment, the progression of the disease was remarkably slow - a typical hallmark of chronic ROCM. With this case report we aim to underline the difficulties in establishing a prompt diagnosis of ROCM and to remind readers of its chronic form. 2012 Elsevier Ltd. All rights reserved.
Subject(s)
Humans , Male , Female , Diastole , Hypertension , Hypertension/complications , Hypertension/physiopathology , Hypertension/therapyABSTRACT
Un paciente con diagnostico de linfoma de Hodgkin estadio IV-B recibio terapia radioactiva (4000 rads.). Despues de haber permanecido diez anos completamente asintomatico consulto por el primer episodio sincopal y bloqueo auriculo ventricular completo. Se hace una revision de la literatura sobre el tema