Search

Background: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DL CO ), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment., Results: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DL CO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DL CO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event., Conclusion: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691., (© 2023. The Author(s).)

Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard of care for muscle-invasive bladder cancer (MIBC). However, less than half of patients are candidates for this treatment, and 50% will develop metastatic disease. Adjuvant chemotherapy could be offered if neoadjuvant treatment has not been administered for suitable patients. It is important to reduce the risk of systemic recurrence and improve the prognosis of localized MIBC. Systemic therapy for metastatic urothelial carcinoma has evolved in recent years. Immune checkpoint inhibitors and targeted agents, such as antibody-drug conjugates or FGFR inhibitors, are new therapeutic alternatives and have shown their benefit in advanced disease. Currently, several clinical trials are investigating the role of these drugs, as monotherapy and in combination with chemotherapy, in the neoadjuvant and adjuvant settings with promising outcomes. In addition, the development of predictive biomarkers could predict responses to neoadjuvant therapies.

Colorectal cancer (CRC) is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. The treatment of metastatic CRC (mCRC) is based on the use of chemotherapy, anti-vascular endothelial growth factor (VEGF), and anti-epidermal growth factor receptor (EGFR) for RAS wild-type tumors. Precision medicine tries to identify molecular alterations that could be treated with targeted therapies. ERBB2 amplification (also known as HER-2) has been identified in 2-3% of patients with mCRC, but there are currently no approved ERBB2-targeted therapies for mCRC. The purpose of this review is to describe the molecular structure of ERBB2, clinical features of these patients, diagnosis of ERBB2 alterations, and the most relevant clinical trials with ERBB2-targeted therapies in mCRC.

Purpose: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults., Methods: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics., Results: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild., Conclusion: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD., Competing Interests: Conflict of Interest M.W.: has received travel reimbursement and consulting fees from Sanofi Genzyme. A.B.: received honoraria for lectures, advisory boards, meetings, and travel support from Sanofi Genzyme and Takeda Shire. R.G.: has received honoraria, consulting fees, speaker fees, and travel reimbursement from Sanofi Genzyme. R.L.: has received consulting fees and travel reimbursement from Sanofi Genzyme. P.M.: has received consulting fees, speaker fees, and travel reimbursement from Sanofi Genzyme. E.M.: has received consulting fees and honoraria from Sanofi Genzyme. Employees of Sanofi Genzyme (or were at the time of the study) and own stock in the company: Y.C., S.F., B.L.T., A.Z., M.K., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

For patients with isolated liver metastases from colorectal cancer who are not candidates for potentially curative resections, non-surgical local treatments may be useful. Non-surgical local treatments are classified according to how the treatment is administered. Local treatments are applied directly on hepatic parenchyma, such as radiofrequency, microwave hyperthermia and cryotherapy. Locoregional therapies are delivered through the hepatic artery, such as chemoinfusion, chemoembolization or selective internal radiation with Yttrium 90 radioembolization. The purpose of this review is to describe the different interventional therapies that are available for these patients in routine clinical practice, the most important clinical trials that have tried to demonstrate the effectiveness of each therapy and recommendations from principal medical oncologic societies.

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.

In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing.

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders (combined incidence 1:5000) in which diverse lysosomal functions are impaired, impacting multiple organs and systems. The first clinical signs and symptoms are usually unspecific and shared by hundreds of other disorders. Diagnosis of LD traditionally relies on performing specific enzymatic assays, if available, upon clinical suspicion of the disorder. However, the combination of the insidious onset of LD and the lack of awareness on these rare diseases among medical personnel results in undesirable diagnostic delays, with unchecked disease progression, appearance of complications and a worsened prognosis. We tested the usefulness of a next-generation sequencing-based gene panel for quick, early detection of LD among cases of idiopathic splenomegaly and/or thrombocytopenia, two of the earliest clinical signs observed in most LD. Our 73-gene panel interrogated 28 genes for LD, 1 biomarker and 44 genes underlying non-LD differential diagnoses. Among 38 unrelated patients, we elucidated eight cases (21%), five with LD (GM1 gangliosidosis, Sanfilippo disease A and B, Niemann-Pick disease B, Gaucher disease) and three with non-LD conditions. Interestingly, we identified three LD patients harboring pathogenic mutations in two LD genes each, which may result in unusual disease presentations and impact treatment. Turnaround time for panel screening and genetic validation was 1 month. Our results underline the usefulness of resequencing gene panels for quick and cost-effective screening of LDs and disorders sharing with them early clinical signs., Competing Interests: G.M. received grants and honoraria from Sanofi Genzyme. L.G.G.‐S. received consulting fees from Biomarin, Sanofi Genzyme, Shire Takeda and Ultragenyx. M.M. received grants and honoraria from Sanofi Genzyme. J.V. received grants and honoraria from Sanofi Genzyme and consulting fees from Shire Takeda. F.J.dC. received grants and honoraria from Sanofi Genzyme. All the other authors have no conflict of interest to declare., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

The magnitudes of the challenges facing electron-based metrology for post-CMOS technology are reviewed. Directed selfassembly, nanophotonics/plasmonics, and resistive switches and selectors, are examined as exemplars of important post-CMOS technologies. Materials, devices, and architectures emerging from these technologies pose new metrology requirements: defect detection, possibly subsurface, in soft materials, accurate measurement of size, shape, and roughness of structures for nanophotonic devices, contamination-free measurement of surface-sensitive structures, and identification of subtle structural, chemical, or electronic changes of state associated with switching in non-volatile memory elements. Electron-beam techniques are examined in the light of these emerging requirements. The strong electron-matter interaction provides measurable signal from small sample features, rendering electron-beam methods more suitable than most for nanometer-scale metrology, but as is to be expected, solutions to many of the measurement challenges are yet to be demonstrated. The seeds of possible solutions are identified when they are available.

Type 1 (non-neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of Type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and nonspecific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease.

Bcl-2 protein plays a major role in the prevention of programmed cell death of differentiating cells. In the present study, the expression of cytoplasmic bcl-2 by human Bone Marrow Mast Cells (BMMC) from both normal and pathological bone marrow samples was examined. A total of 35 subjects corresponding to 9 healthy volunteers, 8 cases of adult indolent systemic mast cell disease (SMCD), 4 cases of pediatric mastocytosis (PM), 11 cases of hematological malignancies (HM), 2 cases of reactive bone marrow, and 1 case of mast cell leukemia (MCL) were analyzed. The expression of bcl-2 was studied using quantitative three-color flow cytometry. We also studied the molecular configuration of the bcl-2 gene and other relatives by Southern blot and polymerase chain reaction (PCR) in the MCL case. Bcl-2 expression was detected in BMMC from all samples analyzed. No significant differences on the expression of bcl-2 were detected between BMMC from healthy subjects and patients with SMCD, PM, HM, and reactive bone marrow. By contrast, bcl-2 protein was overexpressed in BMMC from MCL patient without gene rearrangement. Our results show that bcl-2 protein was constitutively expressed by BMMC. BMMC from MCL display overexpression of bcl-2, which could not be related to molecular rearrangements involving the bcl-2 gene. The expression of this protein by mature MC may play a role in the prevention of MC apoptosis and thus help to explain the long survival of these cells. The overexpression of bcl-2 by BMMC in MCL may help to explain their resistance to chemotherapy-induced apoptosis.

The aim of the present study was to explore the diagnostic value of the immunophenotypic analysis of bone marrow mast cells (BMMC) in indolent systemic mast cell disease (SMCD) patients. For that purpose, a total of 10 SMCD patients and 19 healthy controls were analyzed. Our results show that BMMC from SMCD are different from normal BMMC with regard to both their light scatter and immunophenotypic characteristics. Accordingly, forward light scatter (FSC), side (90 degrees) light scatter (SSC), and baseline autofluorescence levels were higher in BMMC from indolent SMCD patients than they were in control subjects. From the immunophenotypic point of view, the most striking findings were the constant expression of CD2 (P = .0001), CD25 (P = .0001), and CD35 (P = .06) molecules by BMMC from SMCD patients, markers that were absent from all normal controls. In contrast, CD71, absent in BMMC from indolent SMCD, was positive in BMMC from normal subjects. Although, slight differences between BMMC from SMCD patients and normal controls were found in several other markers, they did not reach statistical significance. In conclusion, our results show that simultaneous assessment of FSC/SSC and reactivity for the CD117, CD2, CD25, CD33, and CD35 forms the basis for the immunophenotypic characterization of BMMC from SMCD in adults and should be integrated with clinical and morphologic studies for the diagnosis of the disease.

The goal of the present paper was to define the immunophenotype of bone marrow mast cells (BMMC) from healthy controls and patients with hematologic malignancies (HM) based on the use of multiple stainings with monoclonal antibodies analyzed by flow cytometry. Our results show that BMMC from both groups of individuals display a similar but heterogeneous immunophenotype. The overall numbers of BMMC are higher in the HM group of individuals (p = 0.08). Three patterns of antigen expression were detected: (1) markers constantly positive in all cases analyzed (CD9, CD29, CD33, CD43, CD44, CD49d, CD49e, CD51, CD71, CD117, and Fc(epsilon)RI), (2) antigens that were constantly negative (CD1a, CD2, CD3, CD5, CD6, CD11a, CD14, CD15, CD16, CD19, CD20, CD21, CD23, CD25, CD30, CD34, CD38, CD41a, CD42b, CD65, CD66b, HLA-DR, and CD138), and (3) markers that were positive in a variable proportion of cases--CD11b (50%), CD11c (77%), CD13 (40%), CD18 (20%), CD22 (68%), CD35 (27%), CD40 (67%), CD54 (88%) and CD61 (40%). In addition, BMMC from all cases explored were CD45+, and this antigen was expressed at an intensity similar to that of mature granulocytes. In summary, our results show that BMMC from both healthy controls and HM patients display a relatively heterogeneous immunophenotype. Interestingly, we have observed clear differences between the immunophenotype of BMMC and MC from other tissues. This could be due either to the heterogeneity of human MC according to their tissue localization or to the sensitivity of the method used for antigen detection.

To the extent that tips are not perfectly sharp, images produced by scanned probe microscopies (SPM) such as atomic force microscopy and scanning tunneling microscopy are only approximations of the specimen surface. Tip-induced distortions are significant whenever the specimen contains features with aspect ratios comparable to the tip's. Treatment of the tip-surface interaction as a simple geometrical exclusion allows calculation of many quantities important for SPM dimensional metrology. Algorithms for many of these are provided here, including the following: (1) calculating an image given a specimen and a tip (dilation), (2) reconstructing the specimen surface given its image and the tip (erosion), (3) reconstructing the tip shape from the image of a known "tip characterizer" (erosion again), and (4) estimating the tip shape from an image of an unknown tip characterizer (blind reconstruction). Blind reconstruction, previously demonstrated only for simulated noiseless images, is here extended to images with noise or other experimental artifacts. The main body of the paper serves as a programmer's and user's guide. It includes theoretical background for all of the algorithms, detailed discussion of some algorithmic problems of interest to programmers, and practical recommendations for users.

In the present paper we have used a three-color immunofluorescence procedure combined with flow cytometry cell analysis and sorting for the identification and enumeration of human mast cells in both normal and pathological bone marrow samples. Our results show that bone marrow mast cells are clearly identifiable on the basis of their light-scatter properties and strong CD117 expression. These cells were negative for the CD34, CD38, and BB4 antigens. In addition, they were CD33+ and displayed a high reactivity for the anti-IgE monoclonal antibody. The identity of the CD117-strong+ cells (mast cells) was confirmed by both microscopic examination and flow cytometry analysis. The overall frequency of mast cells in the bone marrow samples analyzed in the present study was constantly lower than 1%. The lowest frequencies corresponded to normal human bone marrow samples (0.0080 +/- 0.0082%) and the highest to those patients suffering from indolent systemic mast cell disease (0.40 +/- 0.13%). In summary, our results show that the identification and enumeration of bone marrow mast cells can be achieved using multiparametric flow cytometry. Moreover, once identified, mast cells are suitable for being characterized from the phenotypic and the functional point of view, facilitating the comparison between normal and abnormal mast cells.