Risk Factors for Superficial Thrombophlebitis: A Retrospective Case Control Study.

BACKGROUND: Data regarding risk factors for superficial thrombophlebitis (STP) cases presenting to a hospital is limited. OBJECTIVES: To investigate and stratify clinical and laboratory risk factors for STP. METHODS: We conducted a retrospective case control study comparing patients presenting to the emergency department with STP and age- and gender-matched controls. We collected data on multiple risk factors and five blood indices. RESULTS: The study comprised 151 patients and matched controls. Patients with STP were more likely to have varicose veins (43.7% vs. 5.3%, P < 0.001), recent immobilization (14.6% vs. 1.3%, P < 0.001), obesity (36.4% vs. 18.5%, P = 0.001), a history of venous thromboembolism (VTE) or STP (27.2% vs. 0.7%, P < 0.001), and inherited thrombophilia (9.3% vs. 1.3%, P = 0.002). Following multivariate analysis, all five risk factors remained significant, with a history of VTE or STP associated with the largest risk (odds ratio [OR] 35.7), followed by immobilization (OR 22.3), varicose veins (OR 12.1), inherited thrombophilia (OR 6.1), and obesity (OR 2.7). Mean platelet volume was higher (8.5 vs 7.9 fl, P = 0.003) in STP cases. CONCLUSIONS: A history of VTE or STP, immobilization, varicose veins, inherited thrombophilia, and obesity serve as independent clinical risk factors for STP presenting to hospital.

Chemical and thyroid hormone profile of the bone marrow interstitial fluid in hematologic disorders and patients without primary hematologic disorders.

Bone marrow interstitial fluid (BMIF) has not been well characterized. BMIF was isolated from 60 patients including plasma cell dyscrasias (PCD, n = 33), other primary hematologic disorders (OHD, n = 15), and patients with secondary or nonhemtologic disorders (NHD, n = 12) and analyzed for an array of chemical constituents. These included total cholesterol, glucose, phosphate, creatinine, urea, total protein, albumin, globulins, total bilirubin, aspartate aminotransferase, lactate dehydrogenase, sodium, osmolarity, free triiodothyronine (free T3), total triiodothyronine (total T3), and free tetraiodothyronine (free T4). Levels of BMIF components were compared between patient groups and to plasma levels. Compared with plasma, total cholesterol, total protein, total bilirubin, sodium, and calculated osmolarity were lower in BMIF in all groups (P < 0.05). Calculated globulins and aspartate aminotransferase were lower in BMIF of PCD patients and patients with NHD. Albumin was lower in BMIF of patients with PCD and patients with OHD. Lastly, free T4 was significantly higher in BMIF of patients with PCD and patients with OHD. Similar results were demonstrated in a separate analysis performed in patients with multiple myeloma. To conclude, the chemical and thyroid hormone composition of BMIF differs significantly from plasma in several key constituents.

Cytosine arabinoside and daunorubicin induction therapy in a patient with acute myeloid leukemia on chronic hemodialysis.

The combination of daunorubicin and cytarabine is the cornerstone of induction therapy for acute myeloid leukemia (AML). Little data are available on the optimal chemotherapy regimen for patients with AML and advanced renal failure, with some authors recommending administration of reduced daunorubicin doses. We report the case of a 54-year-old AML patient on chronic hemodialysis who was treated with a modified induction regimen with reduced-dose daunorubin. Daunorubicin levels were measured during the treatment schedule. Although daunorubicin terminal t1/2 appears to be unaffected in hemodialysis patients, the estimated 0-23 h area under the curve was comparable with that of patients receiving full-dose daunorubicin. Therefore, dose adjustment in this patient group may be prudent.

Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvß3 Integrin: In-Silico Based Study.

Background: Thyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvß3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvß3 integrin was published, a comprehensive analysis of additional TH metabolites is lacking. Methods: In-silico docking of 26 TH metabolites, including the biologically active thyroid hormones (T3 and T4) and an array of sulfated, deiodinated, deaminated or decarboxylated metabolites, to the αvß3 receptor binding pocket was performed using DOCK6, based on the three-dimensional representation of the crystallographic structure of the integrin. As the TH binding site upon the integrin is at close proximity to the well-defined RGD binding site, linear and cyclic RGD were included as a reference. Binding energy was calculated for each receptor-ligand complex using Grid score and Amber score with distance movable region protocol. Results: All TH molecules demonstrated negative free energy, suggesting affinity to the αvß3 integrin. Notably, based on both Grid and Amber scores sulfated forms of 3,3' T2 (3,3' T2S) and T4 (T4S) demonstrated the highest binding affinity to the integrin, compared to both cyclic RGD and an array of examined TH metabolites. The major thyroid hormones, T3 and T4, showed high affinity to the integrin, which was superior to that of linear RGD. For all hormone metabolites, decarboxylation led to decreased affinity. This corresponds with the observation that the carboxylic group mediates binding to the integrin pocket via divalent cations at the metal-ion-dependent adhesion (MIDAS) motif site. A similar reduced affinity was documented for deaminated forms of T3 (triac) and T4 (tetrac). Lastly, the reverse forms of T3, T3S, and T3AM showed higher Amber scores relative to their native form, indicating that iodination at position 5 is associated with increased binding affinity compared to position 5'. Summary: Three-dimensional docking of various TH metabolites uncovered a structural basis for a differential computational free energy to the αvß3 integrin. These findings may suggest that naturally occurring endogenous TH metabolites may impact integrin-mediate intracellular pathways in physiology and cancer.

Pre-diagnosis thyroid hormone dysfunction is associated with cancer mortality.

Research on the association between thyroid hormone levels and cancer mortality remains limited and inconclusive. We determined the relation of thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels with mortality in overall cancer and specific tumor types. Thyroid hormone levels 1-5 years prior to cancer diagnosis, as well as multiple clinical and demographic parameters, were retrospectively collected for 10,325 Israeli cancer patients, diagnosed between 2000 and 2016. Patients treated with thyroid altering medications were excluded. Cancer diagnosis was determined via the Israel National Cancer Registry. Multivariate-adjusted Cox proportional hazards model was used to assess the hazard ratios (HRs) based on thyroid hormone function for cancer mortality. A total of 5265 patients died during the follow-up period (median of 4.4 years). TSH, FT4, and FT3 levels in the hypothyroid range were associated with increase in overall mortality (adjusted HR 1.20, 1.74, 1.87, respectively). We further analyzed the association between TSH and mortality in 14 cancer subgroups. Specifically, TSH in both the hyperthyroid and hypothyroid range was associated with melanoma mortality (adjusted HR 2.20, 4.47, respectively). In conclusion, pre-diagnosis of thyroid dysfunction is associated with increased cancer mortality, a relation likely driven by specific cancer types. These findings suggest that thyroid hormones may potentially serve as prognostic markers in cancer.

Opposing effects of thyroid hormones on cancer risk: a population-based study.

OBJECTIVE: The association between dysregulated thyroid hormone function and cancer risk is inconclusive, especially among different age groups and uncommon malignancies. We sought to determine the relation of TSH and free T4 levels with overall cancer risk as well as risk of specific cancer types. DESIGN AND METHODS: Data on thyroid hormone profile was collected from 375 635 Israeli patients with no prior history of cancer. Cancer cases were identified via the Israel National Cancer Registry. Cox proportional hazards model was used to assess hazard ratios for overall cancer as well as 20 cancer subgroups. RESULTS: In this study, 23 808 cases of cancer were detected over median follow up of 10.9 years. Among patients younger than 50 at inclusion, TSH in the hyperthyroid range, elevated free T4 and subclinical hyperthyroidism were associated with increased cancer risk (HR: 1.3, 1.28 and 1.31, respectively). In contrast, patients 50 or older with clinical hyperthyroidism were at lower cancer risk (HR: 0.64). Elevated TSH was associated with decreased risk of prostate cancer (HR: 0.67). Log-TSH elevation was associated with decreased risk of thyroid cancer (HR: 0.82) and increased risk of melanoma (HR: 1.11) and uterine cancer (HR: 1.27). Elevated free T4 was associated with increased lung cancer risk (HR: 1.54), while free T4 levels above the normal range and clinical hyperthyroidism were related to lower colorectal cancer risk (HR: 0.59 and 0.08, respectively). CONCLUSIONS: Thyroid hormones display opposing effects on cancer risk, based on patient age and cancer type.

Anticoagulation in thrombocytopenic patients with hematological malignancy: A multinational clinical vignette-based experiment.

BACKGROUND: Thrombocytopenia in cancer patients with an indication for anticoagulation poses a unique clinical challenge. There are guidelines for the setting of venous thromboembolism but not atrial fibrillation (AF). Evidence is lacking and current practice is unclear. OBJECTIVE: To identify patient and physician characteristics associated with anticoagulation management in hematological malignancy and thrombocytopenia. METHODS: A clinical vignette-based experiment was designed. Eleven hematologists were interviewed, identifying 5 relevant variable categories with 2-5 options each. Thirty hypothetical vignettes were generated. Each physician received 5 vignettes and selected a management strategy (hold anticoagulation; no change; transfuse platelets; modify type/dose). The survey was distributed to hematologists and thrombosis specialists in 3 countries. Poisson regression models with cluster robust variance estimates were used to calculate relative risks for using one management option over the other, for each variable in comparison to a reference variable. RESULTS: 168 physicians answered 774 cases and reported continuing anticoagulation for venous thromboembolism or AF in 607 (78%) cases, usually with dose reduction or platelet transfusion support. Overall, management was affected by platelet count, anticoagulation indication, time since indication, type of hematological disease and treatment, and prior major bleeding, as well as physician demographics and practice setting. The CHA2DS2-VASc score and time since AF diagnosis affected anticoagulation management in AF. CONCLUSION: This study indicates what the widely accepted management strategies are. These strategies, and possibly others, should be assessed prospectively to ascertain effectiveness. The decision process is intricate and compatible with current venous thromboembolism guidelines.

Thyroid Hormones and Cancer: A Comprehensive Review of Preclinical and Clinical Studies.

Thyroid hormones take major part in normal growth, development and metabolism. Over a century of research has supported a relationship between thyroid hormones and the pathophysiology of various cancer types. In vitro studies as well as research in animal models demonstrated an effect of the thyroid hormones T3 and T4 on cancer proliferation, apoptosis, invasiveness and angiogenesis. Thyroid hormones mediate their effects on the cancer cell through several non-genomic pathways including activation of the plasma membrane receptor integrin αvß3. Furthermore, cancer development and progression are affected by dysregulation of local bioavailability of thyroid hormones. Case-control and population-based studies provide conflicting results regarding the association between thyroid hormones and cancer. However, a large body of evidence suggests that subclinical and clinical hyperthyroidism increase the risk of several solid malignancies while hypothyroidism may reduce aggressiveness or delay the onset of cancer. Additional support is provided from studies in which dysregulation of the thyroid hormone axis secondary to cancer treatment or thyroid hormone supplementation was shown to affect cancer outcomes. Recent preclinical and clinical studies in various cancer types have further shown promising outcomes following chemical reduction of thyroid hormones or inhibition or their binding to the integrin receptor. This review provides a comprehensive overview of the preclinical and clinical research conducted so far.

Synchronous airway lesions in laryngomalacia.

OBJECTIVE: Laryngomalacia is the most common cause of congenital stridor. Laryngomalacia may be associated with other structural and functional airway lesions. While previous studies suggested a 10-45% rate of synchronous airway lesions (SALs), the exact rate and it's clinical significance is unknown. The purpose of this study was to determine the prevalence of SALs below the glottic level in congenital laryngomalacia, and to investigate possible relations with other clinical findings. METHODS: A cohort of 228 infants with congenital stridor who underwent fiberoptic flexible bronchoscopy (FFB) was analyzed. Data was collected from the hospital records. All procedures were reevaluated from the video recordings. RESULTS: SALs below the vocal cords were observed in 7.5% of the case (17/228). The most common SAL was tracheal bronchus followed by tracheomalacia and stenosis of the left main bronchus. No correlation was found between the presence of a SAL below the vocal cords and any other medical condition except for neurodevelopmental disorders. Except for one patient, all cases with SAL did not have any clinical symptoms or signs that would have suggested an accompanying airway lesion. CONCLUSIONS: The rate of SALs in infants with congenital stridor due to laryngomalacia is low and most of the additional lesions are benign. The yield of discovering clinically significant SALs below the glottic level is low and the routine search for a synchronous lesion below the vocal cords should be questioned. Except for underlying neurodevelopmental problems, no clear risk factors for the existence of SALs were identified.

Mean platelet volume and risk of thrombotic and bleeding complications in patients with Philadelphia chromosome negative myeloproliferative neoplasms.

: Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are associated with increased thrombosis and bleeding risk. Mean platelet volume (MPV) is associated with thrombosis in nonmalignant settings. This study evaluates the association between MPV and thrombosis and bleeding in MPN. Patients with MPN without prior thrombosis, nonhematologic malignancy or anticoagulant use were included in this retrospective analysis. The primary endpoint was arterial or venous thrombosis. The secondary endpoints were any bleeding and major bleeding. MPV was measured at diagnosis and during the index episode. A total of 135 MPN patients met the inclusion criteria. Over a median follow-up of 6.6 years, 23 patients (15.6%) experienced thrombosis. There was no difference in MPV at diagnosis (8.47 vs. 8.73 fl, P = 0.4) or during the index event between patients with or without thrombosis. Twelve patients (8.9%) had a bleeding event, whereas seven (5.2%) had major bleeding. MPV was significantly higher among patients with major bleeding, both at diagnosis (10.04 vs. 8.61, P = 0.005) and during the bleeding episode. There was no association after regression analysis of variables associated with MPV at diagnosis. MPV is not associated with thrombotic events in MPN. The study generates the hypothesis that MPV may be an indirect marker of bleeding in MPN.

The anti-leukemic and lipid lowering effects of imatinib are not hindered by statins in CML: a retrospective clinical study and in vitro assessment of lipid-genes transcription.

Imatinib, which has revolutionized chronic myeloid leukemia (CML) treatment, was suggested to improve lipid profile. Statins, a dyslipidemia drug, were reported to potentiate imatinib's antileukemic effect. However, analysis of imatinib combined with statins is lacking. We have retrospectively analyzed the normalization period of bcr-abl, blood counts, and lipids in 40 CML patients, 19 of which co-treated with statins, during short (<12 months) and prolonged (>12 months) imatinib treatment. Prior statins treatment did not hinder nor sensitized imatinib's anti-leukemic and lipid-lowering effects. CML cells (K562) treated with 1µM imatinib (24-96 h) were further assessed for the expression of central lipid-related genes by real-time PCR. HMGCoAR, LDL-R, and apobec1 expressions were significantly increased while CETP declined after 48-96 h. To conclude, imatinib produces an independent favorable lipid profile, which is not hindered by statins and is partly mediated via transcription regulation of genes involved in the clearance of plasma lipids.

Temporal trends in management and outcomes of patients with acute coronary syndrome according to renal function.

INTRODUCTION: Recent new therapeutic options have improved outcomes of acute coronary syndrome (ACS) patients. However, data regarding the incremental effect of the improved treatment on patients with renal dysfunction are limited. We sought to evaluate temporal trends in management and outcome of ACS patients according to renal function. METHODS: The study population consisted of all ACS patients enrolled in the Acute Coronary Syndromes Israeli Survey (ACSIS) during 2002-2013. Patients were categorized as normal renal function, mild to moderate and severe renal insufficiency. Patient's characteristics, clinical data and outcomes were compared in each group between 2 time frames - early (2002-2006) vs. late (2008-2013). RESULTS: The study population included 11,234 patients. Regardless of renal function, patients enrolled in the recent surveys were more frequently selected for an invasive approach and were more commonly treated with guideline-based therapy. Among patients with normal renal function or mild to moderate renal dysfunction the improvement in treatment was associated with a significant reduction in 5-year mortality (10.1% vs. 12.6%, p=0.004, and 36% vs. 41.9%, p=0.01, respectively). On the other hand, outcomes of patients with severe renal insufficiency were unchanged. Multivariate analysis showed that reperfusion was associated with 41% mortality reduction in patients with mild to moderate renal insufficiency (HR=0.59 CI 95 0.48-0.72, p<0.01%). CONCLUSIONS: Treatment of ACS patients has improved over the past decade. Treatment improvement was associated with a significant mortality reduction in patients with normal renal function and mild to moderate renal dysfunction but not in patients with severe renal dysfunction.