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.

Differential expression of uridine phosphorylase in tumors contributes to an improved fluoropyrimidine therapeutic activity.

Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and antitumor efficacy of 5-FU and capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) in our UPase knockout (UPase(-/-)) model. Treatment with 5-FU (85 mg/kg) or capecitabine (1,000 mg/kg) five days a week for four weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase(-/-) animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase(-/-) mice. UPase expressing colon 38 tumors implanted in UPase(-/-) mice revealed an improved therapeutic efficacy when treated with 5-FU and capecitabine because of the higher maximum tolerated dose for fluoropyrimidines achievable in UPase(-/-) mice. (19)F-MRS evaluation of capecitabine metabolism in tumors revealed similar activation of the prodrug in UPase(-/-) mice compared with WT. In WT mice, approximately 60% of capecitabine was transformed over three hours into its active metabolites, whereas 80% was transformed in tumors implanted in UPase(-/-) mice. In UPase(-/-) mice, prolonged retention of 5'dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase(-/-) mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or capecitabine-based chemotherapy.

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.

Solitary fibrous tumor of the larynx: a case report and review of the literature.

Solitary fibrous tumors are relatively rare mesenchymal neoplasms that were originally described as pleural- or peritoneal-based lesions. Although they were considered a form of mesothelioma, subsequent investigation failed to reveal mesothelial differentiation. Characterization of their histologic and immunohistochemical features, as well as identification in a multitude of nonmesothelial-based locations has further served to distinguish these lesions from the more diffuse and aggressive mesothelioma. Reports of solitary fibrous tumor in the larynx are extremely rare. We report a case of solitary fibrous tumor of the larynx in a 38-year-old man.

Menstrual and reproductive factors and risk of non-Hodgkin's lymphoma among Connecticut women.

Several recent studies have suggested a potential role of menstrual and reproductive factors in the risk of non-Hodgkin's lymphoma. To further examine the relation, the authors analyzed data from a population-based case-control study of non-Hodgkin's lymphoma in Connecticut women between 1996 and 2000. A total of 601 histologically confirmed cases and 717 randomly selected population-based controls were included in this study. An in-person interview was conducted using a standardized and structured questionnaire to collect information on menstrual and reproductive factors and potential confounding factors. Compared with nulliparous women, women who had four or more pregnancies during their lifetime were found to have a significantly reduced risk of non-Hodgkin's lymphoma (odds ratio (OR) = 0.6, 95% confidence interval (CI): 0.4, 0.9). Risk appeared to decrease with increasing number of pregnancies (p(trend) = 0.03). The authors also observed an increased risk of non-Hodgkin's lymphoma overall (OR = 1.5, 95% CI: 1.0, 2.2) and of diffuse non-Hodgkin's lymphoma (OR = 1.7, 95% CI: 1.1, 2.7) for women who started their first menstrual period at age 15 or more years compared with those who started their first menstrual period before age 12 years. These findings support a reduced risk of non-Hodgkin's lymphoma associated with multiple pregnancies and an increased risk of non-Hodgkin's lymphoma associated with later age at menarche.

Blood transfusion and risk of non-Hodgkin's lymphoma in Connecticut women.

The incidence and mortality rates of non-Hodgkin's lymphoma have been increasing worldwide. Allogeneic blood transfusion has been suggested as a risk factor for non-Hodgkin's lymphoma, but the results from epidemiologic studies have been inconsistent. Data from a population-based case-control study of Connecticut women were analyzed to evaluate this relation. A total of 601 histologically confirmed, non-Hodgkin's lymphoma incident cases identified between 1996 and 2000 and 717 randomly selected controls were included in this study. Allogeneic blood transfusion was not associated with the increased risk of non-Hodgkin's lymphoma overall (odds ratio = 1.0, 95% confidence interval: 0.7, 1.3) or by subtype of the disease. The risk also did not vary by number of allogeneic blood transfusions, age at first transfusion, or time since first transfusion. When the reason for blood transfusion was considered, an increased risk of non-Hodgkin's lymphoma was found only for allogeneic blood transfusion for reason of anemia. In summary, the authors' findings do not support the hypothesis that allogeneic blood transfusion increases the risk of non-Hodgkin's lymphoma.

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.

Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut United States women.

OBJECTIVE: To further investigate the role of prior medical conditions and medication use in the etiology of non-Hodgkin lymphoma (NHL), we analyzed the data from a population-based case-control study of NHL in Connecticut women. METHODS: A total of 601 histologically confirmed incident cases of NHL and 717 population-based controls were included in this study. In-person interviews were administered using standardized, structured questionnaires to collect information on medical conditions and medication use. RESULTS: An increased risk was found among women who had a history of autoimmune disorders (such as rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, and multiple sclerosis), anemia, eczema, or psoriasis. An increased risk was also observed among women who had used steroidal anti-inflammatory drugs and tranquilizers. A reduced risk was found for women who had scarlet fever or who had used estrogen replacement therapy, aspirin, medications for non-insulin dependent diabetes, HMG-CoA reductase inhibitors, or beta-adrenergic blocking agents. Risk associated with past medical history appeared to vary based on NHL subtypes, but the results were based on small number of exposed subjects. CONCLUSION: A relationship between certain prior medical conditions and medication use and risk of NHL was observed in this study. Further studies are warranted to confirm our findings.

Hepatitis C virus and risk of non-Hodgkin lymphoma: a population-based case-control study among Connecticut women.

OBJECTIVES: Previous epidemiologic studies of hepatitis C virus (HCV) infection and B-cell non-Hodgkin lymphoma (B-NHL) have yielded conflicting results, perhaps due to differences in the classification of B-NHL and the choice of non-population-based control groups that may not reflect the background population prevalence of HCV. To further investigate the link between HCV and NHL, we conducted HCV testing on serum samples of 998 women (464 cases; 534 controls) from a population-based case-control study of women in Connecticut. METHODS: Serum samples were screened for HCV antibodies using an enzyme immunoassay; positive samples were confirmed by additional testing for HCV antibodies and for serum HCV RNA. RESULTS: Approximately 2% (8 of 464) of cases and 1% (5 of 534) of controls tested positive for HCV. The risk of NHL associated with HCV infection appeared to be concentrated among B-cell lymphomas [odds ratio (OR) 2.0; 95% confidence interval (CI) 0.6, 8.2], particularly among follicular lymphomas (OR 4.1, 95% CI 0.8, 19.4). CONCLUSIONS: The primary strength of this study is our use of a population-based study design, although the low prevalence of HCV among women in Connecticut resulted in wide CIs for the estimated association between HCV and B-NHL subtypes. Our study suggests that HCV may be associated with increased risk of development of B-NHL, and that this risk may vary by B-NHL subtype among women. Due to the relatively low prevalence of HCV in our study population and the scarcity of population-based epidemiological research on this subject, our study highlights the need for additional large, population-based studies of the role of HCV in the etiology of B-NHL.

Diet and nutrient intakes and risk of non-Hodgkin's lymphoma in Connecticut women.

A population-based case-control study (601 cases and 717 controls) was conducted in 1995-2001 among Connecticut women to evaluate the relation between diet and nutrient intakes and the risk of non-Hodgkin's lymphoma (NHL). When the highest quartile of intake was compared with the lowest, the authors found an increased risk of NHL associated with animal protein (odds ratio = 1.7, 95% confidence interval: 1.2, 2.4) and saturated fat (odds ratio = 1.9, 95% confidence interval: 1.1, 2.3) but a reduced risk for polyunsaturated fat (odds ratio = 0.6, 95% confidence interval: 0.4, 0.9) and no relation for vegetable protein and monounsaturated fat. An increased risk was also observed for higher intakes of retinol, eggs, and dairy products. On the other hand, a reduced risk was found for higher intakes of dietary fiber and for several fruit and vegetable items. Risk of NHL associated with diet and nutrient intakes appeared to vary based on NHL subtype. An association between dietary intake and NHL risk is biologically plausible because diets high in protein and fat may lead to altered immunocompetence, resulting in an increased risk of NHL. The antioxidant or inhibiting nitrosation reaction properties of vegetables and fruits may result in a reduced risk. Further investigation of the role of dietary intakes on the risk of NHL is warranted.

Hair-coloring product use and risk of non-Hodgkin's lymphoma: a population-based case-control study in Connecticut.

A population-based case-control study was conducted in Connecticut in 1996-2002 to test the hypothesis that lifetime hair-coloring product use increases non-Hodgkin's lymphoma risk. A total of 601 histologically confirmed incident female cases and 717 population-based controls were included in the study. An increased risk of non-Hodgkin's lymphoma was observed among women who reported use of hair-coloring products before 1980 (odds ratio = 1.3, 95% confidence interval (CI): 1.0, 1.8). The odds ratios were 2.1 (95% CI: 1.0, 4.0) for those using darker permanent hair-coloring products for more than 25 years and 1.7 (95% CI: 1.0, 2.8) for those who had more than 200 applications. Follicular type, B-cell, and low-grade lymphoma generally showed an increased risk. On the other hand, the authors found no increased risk of non-Hodgkin's lymphoma overall and by subtype of exposure and disease among women who started using hair-coloring products in 1980 or later. It is currently unknown why an increased risk of non-Hodgkin's lymphoma was found only among women who started using hair-coloring products before 1980. Further studies are warranted to show whether the observed association reflects the change in hair dye formula contents during the past two decades or indicates that recent users are still in their induction and latent periods.

Alcohol use and risk of non-Hodgkin's lymphoma among Connecticut women (United States).

OBJECTIVE: Incidence rates of non-Hodgkin's lymphoma (NHL) have risen dramatically over the past several decades; however, the etiology of NHL remains largely unknown. Previous studies of the relationship between alcohol consumption and NHL have yielded conflicting results. Data from a population-based case-control study among women in Connecticut were analyzed to determine the potential impact of alcohol consumption on risk of NHL. METHODS: The study included 601 histologically confirmed, incident cases of NHL and 718 population-based controls. In-person interviews were administered using standardized, structured questionnaires to collect data on history of consumption for beer, wine, and liquor. RESULTS: When compared to non-drinkers, women who reported consumption of at least 12 drinks per year of any type of alcohol experienced slightly reduced risk of NHL (OR: 0.82; 95% CI: 0.65-1.04). Further stratification by alcohol type revealed that the inverse association was mainly limited to wine consumption (OR: 0.75; 95% CI: 0.59-0.96), with no clear association for beer or liquor consumption. Risk of NHL was further reduced with increasing duration of wine consumption (p for linear trend = 0.02). Consumption of wine for greater than 40 years was associated with approximately 40% reduction in risk (OR: 0.63; 95% CI: 0.44-0.91). CONCLUSION: Our results are consistent with several recent epidemiologic studies that have also suggested an inverse association between wine consumption and risk of NHL. The reduction in risk of NHL associated with increased duration of wine consumption warrants further investigation in other populations.

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.