Faculty Bibliography

Intravascular large B-cell lymphoma (IVLBCL) is a very rare extra nodal lymphoma that tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules while sparing the organ parenchyma. The cause of its affinity for the vascular bed remains unknown. Because of its rarity and unremarkable clinical presentation, a timely diagnosis of IVLBCL is very challenging. Here, we describe a case of IVLBCL presenting as pancreatic mass that was ultimately diagnosed at autopsy. A 71-year-old Caucasian female presented with a 3-month history of fatigue, abdominal pain, and weight loss. She was referred to the emergency room with a new diagnosis of portal vein thrombosis and lactic acidosis. During her hospital course she was found to have a 1.9 × 1.8 cm lesion in the pancreatic tail on imaging; The cytologic specimen on the mass showed a high-grade lymphoma. A bone marrow biopsy showed no involvement. The patient's condition rapidly deteriorated and she, later, died due to multi-organ failure. An autopsy revealed diffuse intravascular invasion in multiple organs by the lymphoma cells. Based on our literature review-and to the best of our knowledge-there are virtually no reports describing the presentation of this lymphoma with a discernible tissue mass and associated multi-organ failure. The immunophenotypic studies performed revealed de novo CD5+ intravascular large B-cell lymphoma, which is known to be aggressive with very poor prognosis. Although it is a very rare lymphoma, it should be considered as a potential cause of multi-organ failure when no other cause has been identified. A prompt tissue diagnosis, appropriate high-dose chemotherapy and stem cell transplantation remain the only viable alternative to achieve some kind of remission.

Mitochondria, known for more than a century as the energy powerhouse of a cell, represent key intracellular signaling hub that are emerging as important determinants of several aspects of cancer development and progression, including metabolic reprogramming, acquisition of metastatic capability, and response to chemotherapeutic drugs. The majority of cancer cells harbors somatic mutations in the mitochondrial genome (mtDNA) and/or alterations in the mtDNA content, leading to mitochondrial dysfunction. Decreased mtDNA content is also detected in tumor-initiating cells, a subpopulation of cancer cells that are believed to play an integral role in cancer recurrence following chemotherapy. Although mutations in mitochondrial genes are common in cancer cells, they do not shut down completely the mitochondrial energy metabolism and functionality. Instead, they promote rewiring of the bioenergetics and biosynthetic profile of a cancer cell through a mitochondria-to-nucleus signaling activated by "dysfunctional" mitochondria that results in changes in transcription and/or activity of cancer-related genes and signaling pathways. Different cancer cell types may undergo different bioenergetic changes, some to more glycolytic and some to more oxidative. These different metabolic signatures may coexist within the same tumor mass (intra-tumor heterogeneity). In this review we describe the current understanding of mitochondrial dysfunction in the context of cancer chemoresistance with special attention to the role of mtDNA alterations. We put emphasis on potential therapeutic strategies targeting different metabolic events specific to cancer cells, including glycolysis, glutaminolysis, oxidative phosphorylation, and the retrograde signaling, to prevent chemoresistance. We also highlight novel genome-editing strategies aimed at "correcting" mtDNA defects in cancer cells. We conclude on the importance of considering intratumor metabolic heterogeneity to develop effective metabolism-based cancer therapy that can overcome chemoresistance. This article is part of a Special Issue entitled Respiratory complex I, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Epithelial-to-mesenchymal transition (EMT) allows epithelial cancer cells to assume mesenchymal features, endowing them with enhanced motility and invasiveness, thus enabling cancer dissemination and metastatic spread. The induction of EMT is orchestrated by EMT-inducing transcription factors that switch on the expression of "mesenchymal" genes and switch off the expression of "epithelial" genes. Mitochondrial dysfunction is a hallmark of cancer and has been associated with progression to a metastatic and drug-resistant phenotype. The mechanistic link between metastasis and mitochondrial dysfunction is gradually emerging. The discovery that mitochondrial dysfunction owing to deregulated mitophagy, depletion of the mitochondrial genome (mitochondrial DNA) or mutations in Krebs' cycle enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, activate the EMT gene signature has provided evidence that mitochondrial dysfunction and EMT are interconnected. In this review, we provide an overview of the current knowledge on the role of different types of mitochondrial dysfunction in inducing EMT in cancer cells. We place emphasis on recent advances in the identification of signaling components in the mito-nuclear communication network initiated by dysfunctional mitochondria that promote cellular remodeling and EMT activation in cancer cells.

After the publication of the article the authors noted the following errors in the assembling of the figures. In Fig. 3A the tubulin panel for PC-3 cells is incorrect. The correct panel is reported below. In Figs. 3B and 5B the panels are incorrect. The correct panels are shown below. These changes do not affect the interpretation of the data or conclusions of this work [the original article was published in the International Journal of Oncology 30: 217-224, 2007; DOI: 10.3892/ijo.30.1.217].

Rapid remission of MDS/AML may be induced with Decitabine; however, significant megakaryocyte expansion and subsequent thrombocytosis may occur. Decitabine-mediated reversion of the MDS to benign ET via hypomethylation of JAK/STAT pathway repressors is one potential mechanism to explain this observed phenomenon.

PURPOSE: To characterize the uptake and elimination of ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) agent, in bone marrow of healthy human subjects. MATERIALS AND METHODS: Four men and two postmenopausal women, aged 22 to 57 years, were prospectively included. Simultaneous fat, water, and T2* mapping of the proximal femora was performed at 1.5 Tesla using a three-dimensional multiple gradient echo sequence. After baseline imaging, ferumoxytol (Feraheme/Rienso) was injected intravenously at a dose of 5 mg Fe/kg body weight. Imaging was repeated at 3 days, 1 month, 3 months, and 5 months after administration. RESULTS: Imaging at 3 days revealed large increases in R2* ( =1/T2*) in hematopoietic marrow and lower average responses in fatty marrow, consistent with macrophage-specific uptake. However, certain regions of the diaphysis exhibited substantial R2* enhancement despite having very high fat content. This suggests the persistence of residual marrow stroma following adipose conversion, and may reflect the ability of diaphyseal marrow to adapt dynamically to fluctuating demand for hematopoiesis. Follow-up imaging demonstrated almost complete R2* recovery within 3 months. CONCLUSION: The observed R2* enhancement characteristics support applications for ferumoxytol in distinguishing normal or hypercellular marrow from neoplasms, infection and inflammation. Further studies are warranted in specific patient populations.J. Magn. Reson. Imaging 2013. (c) 2013 Wiley Periodicals, Inc.