Real-Life Experience With First-Line Therapy Bortezomib Plus Melphalan and Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma Ineligible for High Dose Chemotherapy With Autologous Stem-Cell Transplantation.

Introduction: Currently, the regimen with bortezomib plus melphalan and prednisone (VMP) is a standard treatment for multiple myeloma and it is recommended as the first-line therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy with autologous stem-cell transplantation. Objectives: Participants of the clinical trial are highly selected populations; therefore, the aim of this study was to present observations from real practice that can provide important information for practitioners and to investigate clinical outcomes of VMP regimen in elderly patients with newly diagnosed MM. Patients and Methods: We retrospectively analyzed the data on the efficacy and survival parameters, such as overall survival (OS) and event-free survival (EFS), with attention to the effect of gender, age and International Staging System (ISS) stage, of VMP regimen in 164 patients with newly diagnosed MM not eligible for high-dose chemotherapy with autologous stem-cell transplantation (median age, 75 years; range, 60-86 years). Results: Patients aged 75 years or older constituted 50.6% of the study cohort. Frail patients were 10.36%, according to the clinical frailty scale of geriatric assessment (GA). A total of 1203 courses of VMP regimen (mainly VMP 1-29, 99.16 %) were administered. The median cumulative delivered dose of bortezomib was 46.8 mg/m2. The overall response rate (ORR), including all patients with a partial response or better, was 81.7% and the complete response rate (CRR) was 10.36 %. After a median 38.51 months of follow-up, the median overall survival (OS) was 34.33 months; the median event-free survival (EFS) after VMP and second-line therapy (mainly Rd, 56.31%) were 18.51 and 10.75 months, respectively. In the subgroup of patients with 75 years or older the median OS was 29.76 months; the median EFS after first and second-line therapy were 17.76 and 8.93 months, respectively. The hazard ratio for OS was 2.276 (p-value 0.046) and for EFS was 1.507 (p-value 0.055) for the ISS stage II and III group. Age and gender were not negative predictors of survival. Conclusions: VMP treatment is highly effective in the first-line therapy of elderly patients with multiple myeloma ineligible for HDT with auto-SCT.

Early Diagnosis of Neutropenic Enterocolitis by Bedside Ultrasound in Hematological Malignancies: A Prospective Study.

(1) Background: Neutropenic enterocolitis (NEC) is a life-threatening complication following chemotherapy with high mortality rates. Early diagnosis is crucial to improve outcomes. We designed a large prospective study employing bedside ultrasonography (US) as a novel approach to allow early diagnosis and prompt treatment to reduce mortality. (2) Methods: NEC was defined as US or computed tomography (CT)-proven bowel wall thickness ≥ 4 mm at the onset of at least one of the following symptoms: fever and/or abdominal pain and/or diarrhea during neutropenia. From 2007 to 2018, 1754 consecutive patients underwent baseline bedside US that was invariably repeated within 12 h from the onset of symptom(s) suggestive of NEC. (3) Results: Overall, 117 episodes of NEC were observed, and overall mortality was 9.4%. Bowel wall thickening was invariably absent in the negative control group. Abdominal pain associated with one or more symptoms correlated with the highest relative risk (17.33), sensitivity (89.7%), specificity (100%), and accuracy (96.2%) for diagnosis. The combination of abdominal pain and fever at onset significantly correlated with worse survival (p < 0.0001, OR 13.85). BWT (p = 0.046), type of therapy (p = 0.049) and blood culture positivity (p = 0.003) correlated with worse survival. (4) Conclusions: Bedside ultrasound is a non-invasive and radiation free imaging technique for early diagnosis of NEC and its prompt treatment significantly reduced mortality.

Hemophagocytic syndrome secondary to SARS-Cov-2 infection: a case report.

BACKGROUND: Hemophagocytic syndrome (HPS) is a severe hyperinflammatory disease, whose diagnosis is based on the HLH-2004 criteria. In secondary forms of HLH (sHLH), the primary goal is treating the triggering factors such as COVID-19 (Coronavirus disease 2019). The link between the cytokine storm related to COVID-19 and development of sHLH has already been reported since the onset of pandemic, but little is known about clinical manifestations of HLH which develop after the patient's recovery from mild symptomatic or asymptomatic Sars-CoV-2 infection. CASE PRESENTATION: We describe the case of a woman diagnosed with sHLH related to previous Sars-CoV-2 infection and successfully treated with steroids, colchicine, etoposide and ruxolitinib. CONCLUSIONS: Our report suggests that HLH-like syndrome might be secondary to Sars-CoV-2 infection, even if the patient utterly recovered from the mildly symptomatic viral infection. In addition, we underline the treatment with low dose ruxolitinib plus etoposide as a potential choice for Sars-CoV-2 infection related HLH.

The stability of paintings and the molecular structure of the oil paint polymeric network.

A molecular-level understanding of the structure of the polymeric network formed upon the curing of air-drying artists' oil paints still represents a challenge. In this study we used a set of analytical methodologies classically employed for the characterisation of a paint film-based on infrared spectroscopy and mass spectrometry-in combination with solid state NMR (SSNMR), to characterise model paint layers which present different behaviours towards surface cleaning with water, a commonly applied procedure in art conservation. The study demonstrates, with the fundamental contribution of SSNMR, a relationship between the painting stability and the chemical structure of the polymeric network. In particular, it is demonstrated for the first time that a low degree of cross-linking in combination with a high degree of oxidation of the polymeric network render the oil paint layer sensitive to water.

On Cancer, COVID-19, and CT Scans: A Monocentric Retrospective Study.

Background The use of computed tomography (CT) for coronavirus disease 2019 (COVID-19) diagnosis in an area of northern Italy with a high incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have identified more patients with this disease than RT-PCR in the very early onset of the COVID-19 pandemic. Methods We retrospectively reviewed 148 chest CT scans of oncological patients who were referred to the Radiological Unit of Policlinico S. Marco from 1 February 2020 to 30 April 2020, during the COVID-19 outbreak in Bergamo area. In parallel, we analyzed RT-PCR tests of these 148 patients. Results Among 32 patients with a diagnosis of COVID-19, 17 patients were asymptomatic or had mild symptoms (53.1%), while 15 developed severe disease (46.8%). The incidence of SARS-CoV-2 infection was 22.9%, the mortality rate was 18.8%. We did not find any correlation between disease severity and age, sex, smoking, or cardiovascular comorbidities. Remarkably, patients who were on treatment for cancer developed a milder disease than patients who were not on treatment. Conclusions The acceptance of CT-defined diagnoses in COVID-19 high-incidence areas like Bergamo region highlighted a larger oncological population affected by COVID-19 than RT-PCR, in particular, asymptomatic and mildly symptomatic patients, because only symptomatic patients underwent nasopharyngeal swabbing at the onset of the COVID-19 pandemic. We observed that patients actively treated for their cancer had a milder disease, in agreement with previous studies that suggested a protective role of immunosuppression. Admittedly, the sample of patients in our study was heterogeneous regarding the oncological disease, their prognosis, and the type of treatment; therefore, other studies are needed to confirm our data.

Autologous stem cell transplantation is safe in selected elderly multiple myeloma patients.

OBJECTIVES: ASCT is currently the "gold standard" first-line treatment for multiple myeloma patients younger than 65 years old, and limited data on efficacy and safety in older patients are available. METHODS: We retrospectively analyzed a cohort of 83 newly diagnosed multiple myeloma patients aged 65 or older. All patients were evaluated for fitness at diagnosis and after bortezomib-based induction treatment. RESULTS AND CONCLUSIONS: All patients collected an adequate PBSC graft, mainly after G-CSF plus cyclophosphamide; a median of 6.47 × 106 /kg CD34 + cells was collected. The conditioning regimen consisted of melphalan 100, 140 and 200 mg/m2 in 40, 15 and 28 patients, respectively. Median time to neutrophils' and platelets' recovery was 11 and 12 days, respectively. Adverse events of any grade were referred by 40% of patients. The overall response rate was 93%, CR/sCR were 39%. Median PFS was 35 months; median OS was not reached. In our study cohort, the achievement of at least VGPR after induction therapy and the obtainment of CR/sCR after ASCT are the only parameters that were associated with an improved PFS. ASCT is an effective and safe first-line treatment approach, a careful patients selection reduce the toxicity of the procedure.

Proteasome inhibition in multiple myeloma: lessons for other cancers.

Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.

Different types of amyloid concomitantly present in the same patients.

Different types of amyloid concomitantly present in the same patient is believed to be improbable. We reported four cases of patients with plasma cell disorders who were found to have biopsy proven concomitant different types of amyloid fibrils deposition. We characterized amyloid fibrils using immunogold electron microscopy. There is lack of experience in the treatment of these frail and elderly patients, who are on the threshold between necessity of chemotherapy for AL amyloidosis and necessity to avoid harmful treatment related toxicity. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible Requirements for safe SCT include systolic blood pressure >90 mm Hg, troponin T <0.06 ng/mL, age <70 years, and serum creatinine ≤1.7 mg/dL Nontransplant candidates can be offered melphalandexamethasone or cyclophosphamide-bortezomibdexamethasone.

The assessment of minimal residual disease versus that of somatic mutations for predicting the outcome of acute myeloid leukemia patients.

BACKGROUND: In addition to morphological and cytogenetic features, acute myeloid leukemias are characterized by mutations that can be used for target-therapy; also the minimal/measurable residual disease (MRD) could be an important prognostic factor. The purpose of this retrospective study was to investigate if somatic mutations could represent an additional prognostic value in respect of MRD alone. METHOD: At baseline, 98 patients were tested for NPM1, FLT3, and for WT1 expression; 31 for ASXL1, TET2, IDH1, IDH2, N-RAS, WT1, c-KIT, RUNX1, and DNMT3A. The same genes have been also tested after induction and consolidation. RESULTS: Overall, 60.2% of our patients resulted mutated: 24.5% carried mutations of FLT3-ITD, 38.7% of NPM1, 48.4% of c-KIT, 25.8% of N-RAS and 19.3% of IDH2. The probability of achieving a complete response (CR) was higher for younger patients, with low ELN risk score, NPM1-mutated, with low WT1 levels, and without FLT3. The presence of additional mutations represented a poor predictive factor: only 19% of these cases achieved CR in comparison to 43% of subjects without any of it. Concerning survival, it was conditioned by a lower ELN risk score, younger age, reduction > 1 log of the NPM1 mutational burden, disappearance of FLT3 mutations and lower WT1 expression. Regarding the role of the additional mutations, they impaired the outcome of 20% of the already MRD-negative patients. Concerning the possibility of predicting relapse, we observed an increase of the NPM1 mutational burden at the time-point immediately preceding the relapse (about 2 months earlier) in 50% of subjects. Similarly concerning WT1, an increase of its expression anticipated disease recurrence in 64% of cases. CONCLUSIONS: We demonstrated that additional somatic mutations are able to impair outcome of the already MRD-negative subjects. About MRD, we suggest a prognostic role also for the WT1 expression. Finally, we considered as relevant the assessment of NPM1 quantity clearance instead of the presence/absence of mutations alone. Still remains in doubt the utility in terms of long-term prognosis of a baseline more complex mutational screening; we could hypothesize that it would be useful for those patients where other markers are not available or who reached the MRD negativity.

Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer.

PURPOSE: The purpose of this study was to investigate the possible association between tumor necrosis factor-α (TNF-α) levels and defects in the activated protein C (APC) system as a determinant of venous thromboembolism (VTE) in metastatic colorectal cancer patients (mCRC) undergoing chemotherapy. METHODS: TNF-α levels (measured by immunoassay) and abnormalities in the APC system [evaluated by an APC-dependent thrombin generation assay (ThromboPath-ThP)] were evaluated in 45 mCRC patients undergoing chemotherapy. VTE events were recorded during follow-up. RESULTS: TNF-α levels were increased (p < 0.01), and APC functionality was decreased (p < 0.0001) in mCRC patients compared to age- and sex-matched controls. An inverse correlation was observed between TNF-α and APC impairment in mCRC (p < 0.0001). TNF-α was confirmed as an independent predictor (p = 0.007) for APC abnormalities at multivariate regression analysis. Nine (20 %) of 45 mCRC patients experienced VTE during chemotherapy. Bayesian analysis of combined ThP/TNF-α showed a positive predictive value of 0.67 in predicting VTE (p = 0.01). Cox proportional hazards survival analysis confirmed the predictive value of combined ThP/TNF-α determination in VTE risk assessment of mCRC patients (either negative vs. both positive: HR = 0.02; p = 0.001), and Kaplan-Meier analysis demonstrated that mCRC patients with either negative TNF-α or ThP values prior to chemotherapy were less likely to experience VTE (13 %) than patients with abnormalities of both markers (67 %, p = 0.002). CONCLUSIONS: These results suggest that the host inflammatory response to cancer cells and/or tumor-derived cytokines could be responsible for an impairment of the APC system and a switch toward a pro-thrombotic state, which might predispose to the occurrence of VTE in mCRC patients undergoing chemotherapy.

Novel high-sensitive D-dimer determination predicts chemotherapy-associated venous thromboembolism in intermediate risk lung cancer patients.

INTRODUCTION: We hypothesized that the use of a novel high sensitivity (HS) assay for D-dimer determination might ameliorate venous thromboembolism (VTE) risk prediction in intermediate risk lung cancer patients in whom chemotherapy could act as a trigger for VTE onset. PATIENTS AND METHODS: Pretreatment HS D-dimer levels were retrospectively evaluated in 108 lung cancer outpatients using a novel automated latex enhanced turbidimetric immunoassay. All patients were at the start of a new platinum-based chemotherapy regimen and were classified as intermediate risk according to Khorana's assessment model. Patients were followed-up for a median period of 6.9 months. RESULTS: Receiver operating characteristic (ROC) curves and corresponding Bayesian analysis showed that the best performance was obtained at a cutoff level of 1500 ng/mL, which resulted in a sensitivity of 81%, a specificity of 69%, a positive predictive value (PPV) of 31%, a negative predictive value (NPV) of 96%, and an accuracy of 70%. Patients with HS D-dimer levels above the cutoff had a worse VTE-free survival (60%) compared with those with levels below the cutoff (95%; P = .0001). Multivariate Cox proportional hazards survival analysis confirmed that pretreatment HS D-dimer levels were able to significantly predict VTE with a hazard ratio of 11 (95% confidence interval, 2.62-46.2; P = .001), independently of classic VTE risk factors. CONCLUSIONS: The use of HS D-dimer determination prior to chemotherapy might allow for VTE risk stratification of intermediate risk cancer patients, helping in identifying those individuals who could benefit from thromboprophylaxis.

Prospective comparison of prognostic scores in palliative care cancer populations.

PURPOSE: Predicting prognosis in advanced cancer aids physicians in clinical decision making and can help patients and their families to prepare for the time ahead. MATERIALS AND METHODS: This multicenter, observational, prospective, nonrandomized population-based study evaluated life span prediction of four prognostic scores used in palliative care: the original palliative prognostic score (PaP Score), a variant of PaP Score including delirium (D-PaP Score), the Palliative Performance Scale, and the Palliative Prognostic Index. RESULTS: A total of 549 patients were enrolled onto the study. Median survival of the entire group was 22 days (95% confidence intervals [95% CI] = 19-24). All four prognostic models discriminated well between groups of patients with different survival probabilities. Log-rank tests were all highly significant (p < .0001). The PaP and D-PaP scores were the most accurate, with a C index of 0.72 (95% CI = 0.70-0.73) and 0.73 (95% CI = 0.71-0.74), respectively. CONCLUSION: It can be confirmed that all four prognostic scores used in palliative care studies accurately identify classes of patients with different survival probabilities. The PaP Score has been extensively validated and shows high accuracy and reproducibility in different settings.

Palliative sedation in end-of-life care and survival: a systematic review.

PURPOSE: Palliative sedation is a clinical procedure aimed at relieving refractory symptoms in patients with advanced cancer. It has been suggested that sedative drugs may shorten life, but few studies exist comparing the survival of sedated and nonsedated patients. We present a systematic review of literature on the clinical practice of palliative sedation to assess the effect, if any, on survival. METHODS: A systematic review of literature published between January 1980 and December 2010 was performed using MEDLINE and EMBASE databases. Search terms included palliative sedation, terminal sedation, refractory symptoms, cancer, neoplasm, palliative care, terminally ill, end-of-life care, and survival. A manual search of the bibliographies of electronically identified articles was also performed. RESULTS: Eleven published articles were identified describing 1,807 consecutive patients in 10 retrospective or prospective nonrandomized studies, 621 (34.4%) of whom were sedated. One case-control study was excluded from prevalence analysis. The most frequent reason for sedation was delirium in the terminal stages of illness (median, 57.1%; range, 13.8% to 91.3%). Benzodiazepines were the most common drug category prescribed. Comparing survival of sedated and nonsedated patients, the sedation approach was not shown to be associated with worse survival. CONCLUSION: Even if there is no direct evidence from randomized clinical trials, palliative sedation, when appropriately indicated and correctly used to relieve unbearable suffering, does not seem to have any detrimental effect on survival of patients with terminal cancer. In this setting, palliative sedation is a medical intervention that must be considered as part of a continuum of palliative care.

Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients--a pilot study.

PURPOSE: Identifying cancer patients who are most at risk for venous thromboembolism (VTE) is essential to improve timely delivery of chemotherapy. Several studies have been performed to identify novel candidate biomarkers, but no agreement has yet been reached. In this light, we sought to analyze whether a dynamic evaluation of early changes of activated protein C (APC) function during chemotherapy could be predictive of a first VTE episode in cancer outpatients, thus improving risk stratification. METHODS: A retrospective single-center pilot study was conducted to investigate the adequacy of a dynamic evaluation of a novel APC-dependent thrombin generation assay (HemosIL ThromboPath (ThP)) in predicting VTE in 208 ambulatory cancer patients, enrolled on the basis of tight inclusion criteria, prior to start and before the second cycle of a new chemotherapy regimen. RESULTS: Retrospective analysis of samples showed the occurrence of an acquired APC resistance during chemotherapy, which was predictive of VTE. Univariate Cox proportional hazards survival analysis showed that early ThP changes predicted VTE (stable vs. decreasing ThP: hazard ratio (HR) 0.21; 95% CI 0.10-0.19; p < 0.0001), which was confirmed in the multivariate model (HR 0.25; CI 0.12-0.52, p < 0.0001). Stratification of patients according to a risk assessment model showed a 0.18 HR for stable vs. decreasing ThP assay results in an intermediate risk group. CONCLUSIONS: We may thus conclude that early changes of ThP assay in patients on active chemotherapy enhance VTE risk stratification, helping in identifying a population of cancer patients who might benefit from thromboprophylaxis.

Prospective observational Italian study on palliative sedation in two hospice settings: differences in casemixes and clinical care.

PURPOSE: Palliative sedation (PS) has been defined as the use of sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness. It is sometimes necessary in end-of-life care when patients present refractory symptoms. We investigated PS for refractory symptoms in different hospice casemixes in order to (1) assess clinical decision-making, (2) monitor the practice of PS, and (3) examine the impact of PS on survival. METHODS: This observational longitudinal cohort study was conducted over a period of 9 months on 327 patients consecutively admitted to two 11-bed Italian hospices (A and B) with different casemixes in terms of median patient age (hospice A, 66 years vs. hospice B, 73 years; P = 0.005), mean duration of hospice stay (hospice A, 13.5 days vs. hospice B, 18.3 days; P = 0.005), and death rate (hospice A, 57.2% vs. hospice B, 89.9%; P < 0.0001). PS was monitored using the Richmond Agitation-Sedation Scale (RASS). Sedated patients constituted 22% of the total admissions and 31.9% of deceased patients, which did not prove to be significantly different in the two hospices after adjustment for casemix. RESULTS: Patient involvement in clinical decision-making about sedation was significantly higher in hospice B (59.3% vs. 24.4%; P = 0.007). Family involvement was 100% in both hospices. The maximum level of sedation (RASS, -5) was necessary in only 58.3% of sedated patients. Average duration of sedation was similar in the two hospices (32.2 h [range, 2.5-253.0]). Overall survival in sedated and nonsedated patients was superimposable, with a trend in favor of sedated patients. CONCLUSIONS: PS represents a highly reproducible clinical intervention with its own indications, assessment methodologies, procedures, and results. It does not have a detrimental effect on survival.

Functional impairment in video terminal operators is related to low-grade inflammation.

PURPOSE: Progressive functional impairments develop with chronic repetitive tasks possibly involving inflammatory mediators. Aim of this study was to analyze systemic inflammatory changes in relation to the possible occurrence of pain and/or disability in video terminal operators (VTOs) undergoing upper-extremity repetitive stress due to chronic overuse. METHODS: Pain assessments, classification, and grade of impairment relied on self-report questionnaires administered to 21 VTOs and to 21 matched controls. The inflammatory status of the enrolled subjects was analyzed by determination of serum high sensitive C-reactive protein (hs-CRP) as well as systemic levels or monocyte expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). RESULTS: Serum levels of both cytokines were increased in VTOs compared to controls (P = 0.005 for TNF-α and P = 0.004 for IL-6). TNF-α levels correlated to IL-6 (P = 0.019), which, in turn, was associated to increased hs-CRP (P = 0.012). DASH score allowed to categorize VTOs according to disability. VTOs with mild (DASH = 22) or moderate (DASH = 46) disability (n = 10) had higher serum hs-CRP (P = 0.001) and IL-6 (P = 0.035) levels than VTOs without disabilities (DASH < 17) (n = 11). Monocyte stimulatory TNF-α expression was increased in individuals with mild/moderate disability. Monocyte expression of TNF-α was independently associated to that of IL-6, which, in turn, was associated to increased systemic hs-CRP levels together with mild/moderate functional impairment and weekly commitment to the display screen. CONCLUSIONS: The results here reported indicate the occurrence of a low-grade inflammatory condition in VTOs with mild/moderate disability, which might allow the early recognition of arising musculoskeletal disorders induced by repetitive stress.

Platelet activation and vascular endothelial growth factor 165 release in hepatocellular cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF165) is stored, transported and released by platelets. Platelet functional abnormalities have been described in patients with hepatocellular carcinoma (HCC). Thus, this study was designed to investigate the behavior of VEGF165 with respect to platelet activation in HCC. METHODS: Plasma and serum VEGF165 and plasma sP-selectin levels were analyzed in patients with HCC (n=70) or cirrhosis (n=45) and control subjects (n=70). Given the thrombocytopenia that characterizes both HCC and cirrhotic patients, plasma VEGF165 and sP-selectin as well as serum VEGF (plt-VEGF165-load) levels were normalized by platelet counts. RESULTS: Median concentrations of plasma VEGF165/platelet (p=0.002) and sP-selectin/platelet (p<0.0001) were higher in HCC or cirrhotic patients compared to controls. Moreover, sP-selectin/platelet was the only independent variable predictive of plasma VEGF165/platelet at multivariate analysis (p<0.0001). Conversely, plt-VEGF165-load correlated with tumor diameter (p<0.05) but not with sP-selectin/platelet and was an independent predictor for 5year overall survival (p=0.012). CONCLUSIONS: The results obtained are suggestive for VEGF165 release by tumor in HCC. It is plt-VEGF165-load, but not plasma VEGF165 or serum VEGF165 that is an independent predictor for overall survival of HCC patients.

VEGF-A gene promoter polymorphisms and microvascular complications in patients with essential hypertension.

OBJECTIVES: We investigated the possible involvement of vascular endothelial growth factor (VEGF-A) gene promoter polymorphisms in essential hypertension (EH). DESIGN AND METHODS: 1225bp of the VEGF-A gene promoter were screened for polymorphisms using PCR amplification and direct DNA sequence analysis in 62 EH and 62 normotensive (HS) individuals. Circulating VEGF-A levels were determined by immunoassay. RESULTS: -152G/A (p=0.009) and -116G/A (p=0.016) polymorphisms were correlated to hypertension (p<0.05). Median platelet VEGF-A load in EH was 2.10fg/plt. Patients with microvascular complications (MC) had higher platelet VEGF-A load than those without (p=0.005). Multivariate analyses showed that -116 A allele was an independent predictor of microalbuminuria (p=0.014) and increased platelet VEGF-A load (p=0.009) in EH. Platelet VEGF-A load independently predicted MC (p=0.049) in addition to -116G/A polymorphism (p=0.035). CONCLUSIONS: Abnormal regulation of VEGF-A due to polymorphism at position -116 might represent a genetic factor for increased VEGF-A production and MC in EH.

Increased plasma levels of soluble CD40 ligand correlate with platelet activation markers and underline the need for standardized pre-analytical conditions.

OBJECTIVES: To investigate whether sCD40L dosage might represent a useful tool to explore in vivo platelet function. DESIGN AND METHODS: sCD40L and sP-selectin levels and light transmission aggregometry (LTA) were analyzed in 69 healthy donors. Immunoassays were performed on platelet-depleted citrate plasma samples. The effects of in vitro aspirin treatment on the release of sCD40L were investigated in 15 subjects following platelet stimulation. The effects of a 1-month therapeutic course of low-dose aspirin on sP-selectin and sCD40L levels were also investigated. RESULTS: A significant correlation was observed between sCD40L and sP-selectin (p<0.01). In vitro aspirin treatment remarkably decreased sCD40L levels following platelet activation by exogenous agonists. sCD40L directly correlated with LTA (Rho=0.62, p<0.0001). In vivo aspirin treatment significantly reduced both sP-selectin and sCD40L levels (both p<0.01) in a direct correlation (Rho=0.66, p<0.05). CONCLUSIONS: Citrated plasma samples reflect sCD40L released from platelets, thus yielding the most valid estimates of in vivo circulating levels of this platelet activation markers.