Therapeutic considerations for prevention and treatment of thrombotic events in COVID-19.

Thrombosis is a known complication of SARS-CoV-2 infection, particularly within a severely symptomatic subset of patients with COVID-19 disease, in whom an aggressive host immune response leads to cytokine storm syndrome (CSS). The incidence of thrombotic events coinciding with CSS may contribute to the severe morbidity and mortality observed in association with COVID-19. This review provides an overview of pharmacologic approaches based upon an emerging understanding of the mechanisms responsible for thrombosis across a spectrum of COVID-19 disease involving an interplay between immunologic and pro-thrombotic events, including endothelial injury, platelet activation, altered coagulation pathways, and impaired fibrinolysis.

The mechanistic basis linking cytokine storm to thrombosis in COVID-19.

It is now well established that infection with SARS-CoV-2 resulting in COVID-19 disease includes a severely symptomatic subset of patients in whom an aggressive and/or dysregulated host immune response leads to cytokine storm syndrome (CSS) that may be further complicated by thrombotic events, contributing to the severe morbidity and mortality observed in COVID-19. This review provides a brief overview of cytokine storm in COVID-19, and then presents a mechanistic discussion of how cytokine storm affects integrated pathways in thrombosis involving the endothelium, platelets, the coagulation cascade, eicosanoids, auto-antibody mediated thrombosis, and the fibrinolytic system.

Phoenix rises, with Tucson's help: establishing the first four-year allopathic program in the nation's fifth largest city.

The authors describe the expansion of The University of Arizona College of Medicine from Tucson, Arizona, into Phoenix. They explain how the new Phoenix program, in partnership with Arizona State University, is one college of medicine for the state of Arizona, governed by a single accreditation by the Liaison Committee for Medical Education (LCME). The authors present 21 lessons to be considered early in a medical school expansion process: clearly establish responsibility, authority, and accountability; define activities under university purview and those that require broader engagement; delineate college-wide versus campus-specific functions; clearly define the intent of the new initiative; get frequent input from the LCME; use LCME input to ensure a student focus; be cautious in using consultants; use respected local "brokers"; create a single locus for input and concerns; educate constituencies about medical school requirements; engage leadership to create linkages across sites; encourage communication between leaders in both sites; discriminate between shared and distinctive local curriculum elements; consider the effort and experience required to develop a full curriculum versus those required to develop specific local curricular areas; create simple, transparent admission processes; define faculty profiles for the new program; ensure sufficient resources for core faculty; budget based on national metrics; create core mission-based principles to frame discussions and decisions; segregate clinical affiliation discussions from curriculum and recruitment of basic science faculty; and ensure sufficient land. Although these observations are most relevant to institutions planning expansions of already accredited programs, they derive from principles and practical considerations with wider applicability.

Reliability of identification of 655 sentinel lymph nodes in 263 consecutive patients with malignant melanoma.

BACKGROUND: The purpose of this study of sentinel lymph node biopsies (SLN) was threefold: to compare the reliability of lymphazurin blue dye to radioactive technetium 99m sulfur colloid (TC); to evaluate the reliability of frozen section examinations of sentinel lymph nodes; and to determine how much SLN dissections prolonged operative time. STUDY DESIGN: We evaluated the records of 263 consecutive patients with intermediate and high-risk melanomas (1.0 mm or thicker, or Clark Level IV or greater), who were treated by a single surgeon at the Yale Melanoma Unit between October 1, 1997, and September 30, 2001, and followed for more than 18 months. RESULTS: A total of 655 SLN were identified and removed from these 263 consecutive patients. Radioactive colloid was found to be more reliable (100%) in identifying the SLN than lymphazurin blue dye (51%) in the nodes of the patients. Twenty-eight patients (11%) had positive sentinel lymph nodes, and 2 patients (7%) had false-negative frozen sections. Three patients (11%) had false-negative frozen sections; tumor was found subsequently on permanent sections only after special immunohistochemical stains were used. The location or removal of SLN did not prolong the operative procedure unreasonably, requiring an average of 7 to 20 minutes for removal of SLN, and 33 minutes for frozen section reports, during which time the primary tumor resection and wound coverage were performed. CONCLUSIONS: SLN were found in all 263 patients. All SLN were identified reliably with radioactive colloid. Because blue dye was found in only half of the radioactive nodes, it is not appropriate to use this as the only marker for locating the SLN. This large series of patients attests to the reliability of frozen sections in identifying SLN harboring metastases, with 82% of the patients with nodal metastases identified in this fashion.

Real-time quantitative RT-PCR of cyclin D1 mRNA in mantle cell lymphoma: comparison with FISH and immunohistochemistry.

Presence of the balanced translocation t(11;14)(q13;q32) and the consequent overexpression of cyclin D1 found in mantle cell lymphoma (MCL) has been shown to be of important diagnostic value. Although many molecular and immunohistochemical approaches have been applied to analyze cyclin D1 status, correlative studies to compare different methods for the diagnosis of MCL are lacking. In this study, we examined 39 archived paraffin specimens from patients diagnosed with a variety of lymphoproliferative diseases including nine cases meeting morphologic and immunophenotypic criteria for MCL by: (1) real-time quantitative RT-PCR to evaluate cyclin D1 mRNA expression; (2) dual fluorescence in situ hybridization (FISH) to evaluate the t(11;14) translocation in interphase nuclei; and (3) tissue array immunohistochemistry to evaluate the cyclin D1 protein level. Among the nine cases of possible MCL, seven cases showed overexpression of cyclin D1 mRNA (cyclin D1 positive MCL) and two cases showed no cyclin D1 mRNA increase (cyclin D1 negative "MCL-like"). In six of seven cyclin D1 positive cases, the t(11;14) translocation was demonstrated by FISH analysis; in one case FISH was unsuccessful. Six of the seven cyclin D1 mRNA overexpressing cases showed increased cyclin D1 protein on tissue array immunohistochemistry; one was technically suboptimal. Among the two cyclin D1 negative MCL-like cases, FISH confirmed the absence of the t(11;14) translocation in both cases. All other lymphoproliferative diseases studied were found to have low or no cyclin D1 mRNA expression and were easily distinguishable from the cyclin D1 overexpressing MCLs by all three techniques. In addition, to confirming the need to assess cyclin D1 status, as well as, morphology and immunophenotyping to establish the diagnosis of MCL, this study demonstrates good correlation and comparability between measure of cyclin D1 mRNA, the 11;14 translocation and cyclin D1 protein.