Novità nel mondo di Medicina di Laboratorio

A beloved physician and researcher who fought the status quo to foster antibiotic stewardship, Levy dedicated his life to warning the world about the dangers of misuse.
Medscape Medical News

Global commitments to fight antibiotic resistance have come from governments, pharmaceutical and health insurance companies, medical professionals, healthcare systems, and the food industry.
Medscape Medical News

The most common adult leukemia has seen a rush of new evidence in recent years. Here are some of the highlights.
Medscape Oncology

The IFCC Committee on Clinical Applications of Cardiac Bio-Markers (C-CB) has directives and initiatives focused on providing evidence-based educational resources to aid and improve understanding around key analytical and clinical aspects of cardiac biomarkers used in clinical practice and the research setting. As a task force, we have previously published position statements and recommendations focused on use and analytical aspects of high-sensitivity cardiac troponin assays. The current educational document is the first from the C-CB highlighting important biochemical, analytical, and clinical aspects as they relate to the natriuretic peptides (NPs), including B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP), with a focus on heart failure.

BACKGROUND:

Immunotherapy, especially the use of immune checkpoint inhibitors, has revolutionized the management of several different cancer types in recent years. However, for most types of cancer, only a minority of patients experience a durable response. Furthermore, administration of immunotherapy can result in serious adverse reactions. Thus, for the most efficient and effective use of immunotherapy, accurate predictive biomarkers that have undergone analytical and clinical validation are necessary.

CONTENT:

Among the most widely investigated predictive biomarkers for immunotherapy are programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden (TMB). MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types (e.g., for predicting response to first-line pembrolizumab monotherapy in non-small cell lung cancer). Although not yet approved for clinical use, TMB has been shown to predict response to several different forms of immunotherapy and across multiple cancer types. Less widely investigated predictive biomarkers for immunotherapy include tumor-infiltrating CD8+ lymphocytes and specific gene signatures. Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving. An urgent focus of future research should be the optimization and standardization of method for determining these biomarkers.

SUMMARY:

Biomarkers for predicting response to immunotherapy are paving the way for personalized treatment for patients with diverse cancer types. However, standardization of the available biomarker assays is an urgent requirement.

BACKGROUND:

Entresto™ is a new heart failure (HF) therapy that includes the neprilysin (NEP) inhibitor sacubitril. One of the NEP substrates is B-type natriuretic peptide (BNP); its augmentation by NEP inhibition is considered as a possible mechanism for the positive effects of Entresto. We hypothesized that the circulating products of BNP proteolysis by NEP might reflect NEP impact on the metabolism of active BNP. We suggest that NEP-based BNP cleavage at position 17–18 results in BNP ring opening and formation of a novel epitope with C-terminal Arg-17 (BNP-neo17 form). In this study, we use a specific immunoassay to explore BNP-neo17 in a rat model and HF patient plasma.

METHODS:

We injected BNP into rats, with or without NEP inhibition with sacubitril. BNP-neo17 in plasma samples at different time points was measured with a specific immunoassay with neglectable cross-reactivity to intact forms. BNP-neo17 and total BNP were measured in EDTA plasma samples of HF patients.

RESULTS:

BNP-neo17 generation in rat circulation was prevented by NEP inhibition. The maximum 13.2-fold difference in BNP-neo17 concentrations with and without sacubitril was observed at 2 min after injection. BNP-neo17 concentrations in 32 HF patient EDTA plasma samples ranged from 0 to 37 pg/mL (median, 5.4; interquartile range, 0–9.1). BNP-neo17/total BNP had no correlation with total BNP concentration (with r = –0.175, P = 0.680) and showed variability among individuals.

CONCLUSIONS:

BNP-neo17 formation is NEP dependent. Considering that BNP-neo17 is generated from the active form of BNP by NEP, we speculate that BNP-neo17 may reflect both the NEP activity and natriuretic potential and serve for HF therapy guidance.

BACKGROUND:

Chronic renal inflammation and fibrosis are common sequelae in diabetes mellitus (DM) and are major causes of premature mortality. Although upregulation of NPPC expression occurs in response to renal inflammation in experimental animals, nothing is known of the molecular forms of C-type natriuretic peptide (CNP) products in urine of people with DM or links with renal function.

METHODS:

ProCNP products in urine were characterized with HPLC and a range of antisera directed to specific epitopes of amino-terminal proCNP (NTproCNP). The 5-kDa intact peptide was quantified in spot urine samples from healthy adults and 202 participants with DM selected to provide a broad range of renal function.

RESULTS:

The predominant products of proCNP in urine were consistent with the 2-kDa fragment (proCNP 3–20) and a smaller peak of intact (5-kDa) fragment (proCNP 1–50, NTproCNP). No peaks consistent with bioactive forms (proCNP 82–103, 50–103) were identified. The urine NTproCNP to creatinine ratio (NCR) was more reproducible than the albumin to creatinine ratio (ACR) and strongly associated with the presence of chronic kidney disease. In models predicting independence, among 10 variables associated with renal function in DM, including plasma NTproCNP, only 3 (sex, ACR, and plasma creatinine) contributed to NCR.

CONCLUSIONS:

Characterization of the products of proCNP in urine confirmed the presence of NTproCNP. In spot random urine from study participants with DM, NCR is inversely associated with estimated glomerular filtration rate. In contrast to ACR, NCR reflects nonvascular factors that likely include renal inflammation and fibrosis.

BACKGROUND:

Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria.

METHODS:

A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30%) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared.

RESULTS:

Seventy-four patients defined by DLCN criteria (8.2%) and 207 patients defined by SB criteria (22.8%) were reclassified to "unlikely" FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L).

CONCLUSIONS:

Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol <251 mg/dL (<6.5 mmol/L). Lp(a) should be measured in all patients suspected of having FH.

BACKGROUND:

This prospective multicenter study evaluated the prognostic value of circulating tumor cells (CTCs) in relapsing nonoperable or metastatic head and neck squamous cell carcinoma (rHNSCC) treated by chemotherapy and cetuximab.

METHODS:

In 65 patients suitable for analyses, peripheral blood was taken at day 0 (D0) D7, and D21 of treatment for CTC detection by CellSearch®, EPISPOT, and flow cytometry (FCM). Progression-free survival (PFS) was assessed with the Kaplan–Meier method and compared with the log-rank test (P < 0.05).

RESULTS:

At D0, CTCs were detected with EPISPOT, CellSearch, and FCM in 69% (45/65), 21% (12/58), and 11% (7/61) of patients, respectively. In the patients tested with all 3 methods, EPISPOT identified 92% (36/39), 92% (35/38), and 90% (25/28) of all positive samples at D0, D7, and D21, respectively. Median PFS time was significantly lower in (a) patients with increasing or stable CTC counts (36/54) from D0 to D7 with EPISPOTEGFR (3.9 vs 6.2 months; 95% CI, 5.0–6.9; P = 0.0103) and (b) patients with ≥1 CTC detected with EPISPOT or CellSearch® (37/51) (P = 0.0311), EPISPOT or FCM (38/54) (P = 0.0480), and CellSearch or FCM (11/51) (P = 0.0005) at D7.

CONCLUSIONS:

CTCs can be detected before and during chemotherapy in patients with rHNSCC. D0–D7 CTC kinetics evaluated with EPISPOTEGFR are associated with the response to treatment. This study indicates that CTCs can be used as a real-time liquid biopsy to monitor the early response to chemotherapy in rHNSCC.

ClinicalTrials.gov Identifier:

NCT02119559

BACKGROUND:

Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping.

METHODS:

We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level.

RESULTS:

Tumoral steroid hormone metabolites—estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10–0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07–0.63; P = 0.003)—were significantly associated with prognosis in Kaplan–Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11–0.79; P = 0.015 and HR 0.30; 95% CI, 0.10–0.91; P = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17β 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying cluster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism.

CONCLUSIONS:

MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.