Monitoring Humoral Response Following BNT162b2 mRNA Vaccination against SARS-CoV-2 in Hematopoietic Stem-Cell Transplantation Patients: A Single-Center Prospective Study along with a Brief Review of Current Literature.

Data on antibody response (AR) after vaccination against SARS-CoV2 in hematopoietic stem-cell transplantation setting (HSCT) were initially scarce, mainly due to the exclusion of such patients from approval studies. Shortly after the worldwide application of vaccination against SARS-CoV-2 in vulnerable populations such as patients with hematologic malignancies, limited single-center trials, including HSCT patients, were published. However, there was a great heterogeneity between them regarding the type of underlying malignancy, co-current treatment, type of vaccine, method of AR measurement, and time point of AR measurement. Herein, we present the results of a prospective study on AR after vaccination for SARS-CoV-2 using the BNT162b2 vaccine in a cohort of 54 HSCT recipients-mostly autologous from a single Unit-along with a broad review of the current literature. In our cohort, the AR positivity rate at 1 month was 80.8% and remained positive in 85.7% of patients at 3 months after vaccination. There were only nine non-responders, who were more heavily pretreated and more frequently hypogammaglobulinemic compared to responders. High antibody titers (AT), [AT ≥ 1000 U/mL], were detected in 38.5% and 30.6% of the patients at m1 and m3, respectively. A significant decline in AT between m1 and m3 was demonstrated-p < 0.0001; median AT1 and AT3 were 480.5 and 293 U/mL, respectively. A novel finding of our study was the negative impact of IgA hypogammaglobulinemia on response to vaccination. Other negative significant factors were treatment with anti-CD20 antibody at vaccination and vaccination within 18 months from HSCT. Our data indicate that HSCT recipients elicit a positive response to the BNT162b2 vaccine against SARS-CoV-2 when vaccinated at 6 months post-transplant, and vaccination should be offered to this patient population even within the post-pandemic COVID-19 era.

Prognostic Impact of Serum ß2-Microglobulin Levels in Hodgkin Lymphoma Treated with ABVD or Equivalent Regimens: A Comprehensive Analysis of 915 Patients.

The significance of serum beta-2 microglobulin (sß2m) in Hodgkin lymphoma (HL) is controversial. We analyzed 915 patients with HL, who were treated with ABVD or equivalent regimens with or without radiotherapy. Sß2m levels were measured by a radioimmunoassay (upper normal limit 2.4 mg/L). Sequential cutoffs (1.8-3.0 by 0.1 mg/L increments, 3.5 and 4.0 mg/L) were tested along with ROC analysis. The median sß2m levels were 2.20 mg/L and were elevated (>2.4 mg/L) in 383/915 patients (41.9%). Higher sß2m was associated with inferior freedom from progression (FFP) at all tested cutoffs. The best cutoff was 2.0 mg/L (10-year FFP 83% vs. 70%, p = 0.001), which performed better than the 2.4 mg/L cutoff ("normal versus high"). In multivariate analysis, sß2m > 2.0 mg/L was an independent adverse prognostic factor in the whole patient population. In multivariate overall survival analysis, sß2m levels were predictive at 2.0 mg/L cutoff in the whole patient population and in advanced stages. Similarly, sß2m > 2.0 mg/L independently predicted inferior HL-specific survival in the whole patient population. Our data suggest that higher sß2m is an independent predictor of outcome in HL but the optimal cutoff lies within the normal limits (i.e., at 2.0 mg/L) in this predominantly young patient population, performing much better than a "normal versus high" cutoff set at 2.4 mg/L.

The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects.

Non-Hodgkin lymphoma's (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. Its role in lymphomagenesis is confirmed in many different types of B cell lymphomas. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens.

Serum Procalcitonin Levels in Newly Diagnosed Hodgkin Lymphoma: Correlation with Other Inflammatory Biomarkers.

Background and Objectives: Procalcitonin (PCT) is a useful biomarker for the diagnosis of sepsis. Inflammatory markers are elevated in patients with Hodgkin lymphoma (HL), and yet ongoing infection rarely coexists at diagnosis. PCT levels might be helpful in differentiating bacterial from disease-related inflammation. Materials and Methods: We evaluated serum PCT levels and other inflammation markers in newly diagnosed HL patients. Values < 0.50 ng/mL were considered normal (0.10−0.50 ng/mL: detectable, <0.10 ng/mL: undetectable), while values ≥ 0.50 ng/L were considered elevated. Results: Among 137 patients, 55 had B symptoms (40%), 77/130 (59%) had elevated Erythrocyte Sedimentation Rate (ESR) and 116 (85%) had elevated C-Reactive Protein (CRP) (median 38.1 mg/L (range; 2.97−328)). PCT levels were normal in most patients (undetectable 94/137 (68.5%) and detectable 41/137(30%)) with median value < 0.10 ng/mL (range; <0.10−15.90). Elevated PCT was recorded in only two patients (1.5%). Patients with PCT < 0.10 ng/mL had significantly lower median CRP (25.75; range (2.97−203.0)) compared to patients with PCT ≥ 0.1 ng/mL (median CRP 92.50 mg/L; range (3.34−328.0)). Almost all patients (40/41, 97.6%) with detectable PCT had elevated CRP. Conclusions: This is the first study showing that the inflammation characterizing HL is not associated with PCT elevations, although CRP levels are elevated in 85% of the patients. Normal PCT levels may rule out the possibility of occult infection, thus preventing extensive evaluation, which may delay treatment initiation.

Symptomatic ovarian involvement as the initial presentation of primary mediastinal large b-cell lymphoma.

Primary mediastinal large B- cell lymphoma (PMLBCL) is a mature aggressive B-cell lymphoma which affects mainly young and middle-aged women. The majority of patients present with bulky mediastinal lymphadenopathy. Extranodal involvement is a rare phenomenon at disease presentation. Herein, we describe a case of a young female with PMLBCL presenting with symptomatic, bulky ovarian involvement. The 23-year old patient presented at the Emergency Department with abdominal pain. The chest X-ray film revealed a mediastinal mass and CT scan revealed a large pelvic mass, possibly involving the ovaries. Due to the development of signs of acute abdomen, she was urgently transferred to the operation room where surgical resection of the right ovary and the adjacent mass was performed. The histological examination of the resected material revealed proliferation of PMLBCL cells. This is the first report in the scientific literature describing symptomatic ovarian mass as the initial mode of presentation of PMLBCL.

SGLT-2 inhibitors and nephroprotection: current evidence and future perspectives.

Chronic kidney disease (CKD) is a major public health issue and an independent risk factor for cardiovascular and all-cause mortality. Diabetic kidney disease develops in 30-50% of diabetic patients and it is the leading cause of end-stage renal disease in the Western world. Strict blood pressure control and renin-angiotensin system (RAS) blocker use are the cornerstones of CKD treatment; however, their application in everyday clinical practice is not always ideal and in many patients CKD progression still occurs. Accumulated evidence in the past few years clearly suggests that sodium-glucose co-transporter-2 (SGLT-2) inhibitors present potent nephroprotective properties. In clinical trials in patients with type 2 diabetes mellitus, these agents were shown to reduce albuminuria and proteinuria by 30-50% and the incidence of composite hard renal outcomes by 40-50%. Furthermore, their mechanism of action appears rather solid, as they interfere with the major mechanism of proteinuric CKD progression, i.e., glomerular hypertension and hyperfiltration. The present review summarizes the current evidence from human trials on the effects of SGLT-2 inhibitors on nephroprotection and discusses their position in everyday clinical practice.

Renovascular Hypertension: Novel Insights.

Renovascular hypertension (RVH) remains among the most prevalent and important, but also potentially reversible, causes of secondary hypertension. The predominant causes of renal artery stenosis (RAS) are atherosclerotic renovascular arterial stenosis (ARAS) and renal fibromuscular dysplasia. This condition can lead to progressive renal injury, cardiovascular complications and 'flash pulmonary edema'. Duplex Doppler ultrasonography, computed tomographic angiography and magnetic resonance angiography are the most commonly used diagnostic methods. There are three therapeutic options available: medical therapy including renin-angiotensin-aldosterone system antagonists, lipid-lowering agents, and antiplatelet therapy, percutaneous angioplasty with or without stent placement and surgical revascularization. Three large trials failed to demonstrate the superiority of renal artery revascularization over pharmaceutical therapy in controlling blood pressure and preserving renal function. For this reason, today revascularization is only recommended for patients with progressive worsening of renal function, recurrent 'flash pulmonary edema' and rapid increase in antihypertensive requirement in patients with previously well-controlled hypertension. However, more properly designed trials are needed in order to identify which patient populations would probably benefit from renal revascularization.

The Growing Epidemic of Diabetes Mellitus.

BACKGROUND: During the past decades, the prevalence of diabetes (DM) has increased significantly, mainly as a result of continuous rise in the incidence of type 2 DM. According to World Health Organization statistics, >422 million adults globally were suffering from DM in 2014 and a continuous rise in DM prevalence is expected. OBJECTIVE: The present review considers recent epidemiological data providing worldwide estimates regarding the incidence of DM. METHODS: A comprehensive literature search was conducted to identify available data from epidemiological studies evaluating the current burden of DM. RESULTS: Over the past few decades the prevalence of DM has risen significantly in nearly all countries and may be considered as a growing epidemic. Urbanization and income status are major factors which influence current rates in the prevalence studies introducing interesting differences between several population groups. CONCLUSION: Having recognized the global burden of DM, we now realize the urgent need for effective interventions. In order to monitor the public-health strategies and design effective future interventions we need reliable global estimates regarding the prevalence of DM.

Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Reductions in albuminuria of more than 30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin-angiotensin system (RAS) blockade represents the cornerstone of CKD treatment. However, as CKD progression still occurs, other nephroprotective options were explored; mineralocorticoid receptor antagonists (MRA) were tested with generally positive results. METHODS: We conducted a systematic review and meta-analysis on the effects of MRAs on albuminuria/proteinuria, and adverse events, such as change in renal function and hyperkalemia incidence. A detailed search in electronic databases, clinical trial registries and grey literature was performed to retrieve randomized controlled trials (RCTs) in which administration of an MRA alone or on-top of ACEi/ARB was compared with placebo or active treatment. RESULTS: Of the 45 initially identified reports, 31, with 2767 participants, were included in analysis of the primary outcome. The use of MRAs (alone or on top of RAS blockade) compared with placebo decreased urine albumin-to-creatinine ratio (UACR) by -24.55% (95% CI -29.57 to -19.53%), urine protein-to-creatinine ratio (UPCR) by -53.93% (95% CI -79% to -28.86%) and 24 h albumin excretion by -32.47% (95% CI -41.1 to -23.85%). MRAs also reduced UACR by -22.48% (95% CI -24.51 to -20.44%) compared with calcium-channel-blockers (CCBs), whereas no differences were found compared with a second ACEi/ARB or nonpotassium-sparing diuretics. Addition of an MRA was associated with change in estimated glomerular filtration rate (eGFR) of -2.38 ml/min per 1.73 m (95% CI -3.51 to -1.25), rise in potassium by 0.22 mEq/l (95% CI 0.16-0.28 mEq/l) and a 2.6-fold increase in hyperkalemia risk (RR 2.63, 95% CI 1.69-4.08) compared with placebo/active control. CONCLUSION: Use of MRAs alone or on top of RAS blockade confers important antiproteinuric effects in patients with CKD, with a slight increase in mean potassium levels.

The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

: Diabetic kidney disease is a serious microvascular complication of diabetes mellitus and the leading cause of end-stage renal disease in western countries. New therapeutic agents are needed to delay its onset and progression. Recent literature suggests that sodium-glucose cotransporter 2 (SGLT-2) inhibitors may have renoprotective effects. Our aim was to systematically review the effect of SGLT-2 inhibitors on albuminuria and proteinuria in patients with diabetes mellitus. Studies were identified by search in major electronic databases, clinical trial registers, and sources of gray literature. We included randomized controlled trials of currently approved SGLT-2 inhibitors with a duration of at least 12 weeks. The primary outcome was the between-groups difference in the proportional (%) change of albuminuria or proteinuria between baseline and end of treatment. SGLT-2 inhibitors were associated with statistically significant reduction in albuminuria compared to placebo or active control [weighted mean difference (WMD) -25.39%, 95% confidence interval (CI) -34.17 to -16.62] (15 studies, N = 17 540 patients). When trials were stratified according to the level of baseline albuminuria, reduction in urine albumin-to-creatinine ratio was more prominent in randomized controlled trials in patients with moderately (WMD -40.78%, 95% CI -63.21 to -18.34) or severely increased albuminuria (WMD -36.40%, 95% CI -51.53 to -21.26). Only one study reported data for urine protein-to-creatinine ratio. Finally, SGLT-2 inhibitors reduced systolic and diastolic blood pressure by 4.43 mmHg (95% CI -5.24 to -3.63) and 1.81 mmHg (95% CI -2.38 to -1.23), respectively.

New Horizons in the Pathogenesis, Pathophysiology and Treatment of Familial Hypercholesterolaemia.

BACKGROUND: Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased incidence of premature atherosclerotic Cardiovascular Disease (CVD) or aortic stenosis. OBJECTIVE: The aim of the review was to investigate the pathogenesis and the pathophysiology of FH. RESULTS: The most common (60-80%) FH cause is mutations of the LDL Receptor (LDLR) protein (6 classes with a different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB) (<5%) and gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 genes (PCSK9) (<1%) contribute to its pathogenesis. An Autosomal Recessive Hypercholesterolaemia (ARH) is another cause, very rare (1/2.500 births), mainly in Sardinia. The remaining patients with a clinical diagnosis of monogenic hypercholesterolaemia do not present any known genetic cause. Since FH is a significant public health problem, early diagnosis and treatment are of utmost importance. Recent studies demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced CVD in patients with null mutation than those with receptor-defective mutations. This analysis completes the adequate clinical diagnosis. CONCLUSION: Both homozygous and heterozygous FH are related to mutations of LDLR (mainly), APOB, PCSK9, while other rare forms exist. All aberrations lead to the impaired removal of LDL-C from the blood leading to its accumulation and subsequent CVD earlier than in the general population.

Boosting the Limited Use of Mineralocorticoid Receptor Antagonists Through New Agents for Hyperkalemia.

BACKGROUND: Hyperkalemia is an important clinical problem that is associated with significant lifethreatening complications. Several conditions are associated with increased risk for hyperkalemia such as chronic kidney disease, diabetes mellitus, heart failure, and the use of renin-angiotensin-aldosterone system (RAAS) inhibitors. OBJECTIVE: The purpose of this review is to present and critically discuss treatment options for the management of hyperkalemia. METHOD: A comprehensive review of the literature was performed to identify studies assessing the drug-induced management of hyperkalemia. RESULTS: The management of chronic hyperkalemia seems to be challenging and includes a variety of traditional interventions, such as restriction in the intake of the dietary potassium, loop diuretics or sodium polystyrene sulfonate. In the last few years, several new agents have emerged as promising options to reduce potassium levels in hyperkalemic patients. Patiromer and sodium zirconium cyclosilicate 9 (ZS-9) have been examined in hyperkalemic patients and were found to be efficient and safe. Importantly, the efficacy of these novel drugs might allow the continuation of the use of RAAS inhibitors, morbidity- and mortality-wise beneficial class of drugs in the setting of chronic kidney disease and heart failure. CONCLUSION: Data support that the recently emerged patiromer and ZS-9 offer significant hyperkalemia-related benefits. Larger trials are needed to unveil the impact of these drugs in other patients' subpopulations, as well.

Ambulatory Pulse Wave Velocity Is a Stronger Predictor of Cardiovascular Events and All-Cause Mortality Than Office and Ambulatory Blood Pressure in Hemodialysis Patients.

Arterial stiffness and augmentation of aortic blood pressure (BP) measured in office are known cardiovascular risk factors in hemodialysis patients. This study examines the prognostic significance of ambulatory brachial BP, central BP, pulse wave velocity (PWV), and heart rate-adjusted augmentation index [AIx(75)] in this population. A total of 170 hemodialysis patients underwent 48-hour ambulatory monitoring with Mobil-O-Graph-NG during a standard interdialytic interval and followed-up for 28.1±11.2 months. The primary end point was a combination of all-cause death, nonfatal myocardial infarction, and nonfatal stroke. Secondary end points included: (1) all-cause mortality; (2) cardiovascular mortality; and (3) a combination of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, coronary revascularization, or hospitalization for heart failure. During follow-up, 37(21.8%) patients died and 46(27.1%) had cardiovascular events. Cumulative freedom from primary end point was similar for quartiles of predialysis-systolic BP (SBP), 48-hour peripheral-SBP, and central-SBP, but was progressively longer for increasing quartiles for 48-hour peripheral-diastolic BP and central-diastolic BP and shorter for increasing quartiles of 48-hour central pulse pressure (83.7%, 71.4%, 69.0%, 62.8% [log-rank P=0.024]), PWV (93.0%, 81.0%, 57.1%, 55.8% [log-rank P<0.001]), and AIx(75) (88.4%, 66.7%, 69.0%, 62.8% [log-rank P=0.014]). The hazard ratios for all-cause mortality, cardiovascular mortality, and the combined outcome were similar for quartiles of predialysis-SBP, 48-hour peripheral-SBP, and central-SBP, but were increasing with higher ambulatory PWV and AIx(75). In multivariate analysis, 48-hour PWV was the only vascular parameter independently associated with the primary end point (hazard ratios, 1.579; 95% confidence intervals, 1.187-2.102). Ambulatory PWV, AIx(75), and central pulse pressure are associated with increased risk of cardiovascular events and mortality, whereas office and ambulatory SBP are not. These findings further support that arterial stiffness is the prominent cardiovascular risk factor in hemodialysis.