Search Results (152)

In this article, we provide a review of large B-cell lymphomas (LBCLs), comparing the recently published fifth edition of the WHO classification and the International Consensus Classification (ICC) on hematolymphoid tumors. We focus on updates in the classification of LBCL, an heterogeneous group of malignancies with varying clinical behaviors and different pathological and molecular features, providing a comparison between the two classifications. Besides the well-recognized diagnostic role of clinical, morphological and immunohistochemical data, both classifications recognize the ever-growing impact of molecular data in the diagnostic work-up of some entities. The main aim is to offer a guide for clinicians and pathologists on how the new classifications can be applied to LBCL diagnosis in routine practice. In the first part of the paper, we review the following categories: LBLs transformed from indolent B-cell lymphomas, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), double-hit/triple-hit lymphomas (DH/TH), high-grade large B-cell lymphoma, not otherwise specified (HGBCL, NOS), LBCL with IRF4 rearrangement, Burkitt lymphoma (BL) and HGBCL/LBCL with 11q aberration, focusing on the differences between the two classifications. In the second part of the paper, we provide a practical diagnostic algorithm when facing LBCLs in routine daily practice. Full article

Background/Objectives: The tumour microenvironment (TME) plays an important role in the development and progression of cancer and it differs among lymphomas, both with respect to the composition and quantity of specific tumour-infiltrating immune cells (TICs), such as FoxP3⁺ regulatory T cells (Tregs). The role of FoxP3⁺ Tregs in the TME of peripheral T-cell lymphomas (PTCLs) is complex, and their impact on overall survival (OS) remains unclear. Consequently, we aim to evaluate and compare the FoxP3⁺ cell quantity in nodal PTCLs and reactive lymph nodes (LNs), with a focus on investigating their impact on OS. Methods: excisional lymph node (LN) biopsies from 105 nodal PTCLs and 17 reactive LNs are immunohistochemically stained for FoxP3. Visual scoring of FoxP3⁺ cells is performed, and different cut-off values are used to evaluate the impact of FoxP3⁺ cell quantity on OS. Results: FoxP3⁺ cells are present in the TME of all cases, except for four cases where FoxP3⁺ is expressed in lymphoma cells. Lower FoxP3⁺ cell quantities are observed in certain nodal PTCL subtypes compared to reactive LNs. Patients with high FoxP3⁺ cell quantities show improved OS. However, the FoxP3⁺ cell quantity is not confirmed as an independent prognostic biomarker. Conclusions: these findings underscore the promise of FoxP3⁺ cell quantities as added value in prognosis and highlight the potential benefits of Treg-stimulating therapies in PTCLs. Full article

Orbit and retrial queues have been studied extensively in the literature. A key assumption in most of these works is that customers “go to orbit” when they are blocked upon arrival. However, real-life situations exist in which customers opt to go to orbit to efficiently use their orbit time rather than residing dormant at the service station while waiting for their service to be completed. This paper studies such a system, extending the scope of traditional orbit and retrial queues. We consider an M/G/1 queue where customers repeatedly go to orbit while their service remains in progress. That is, if a customer’s service is not completed by within a specified “patience time”, the customer goes to orbit for a random “orbit time”. When the customer orbits, the server continues rendering her/his service. If, on return, the service is already completed, the customer leaves the system. Otherwise, s/he waits for another patience time. This policy is repeated until service completion. We analyze such an intricate system by applying the supplementary variable technique and using Laplace–Stieltjes transforms. Performance measures are derived, and a comparison analysis is provided between various service time distributions. Full article

Background: Primary aldosteronism (PA) is a common cause of endocrine hypertension, characterized by excessive aldosterone secretion leading to hypertension, hypokalemia, and metabolic alkalosis. While historically diagnosed based on this classic triad of symptoms, current understanding reveals a more nuanced presentation. This study aimed to investigate the prevalence of PA-associated diseases in a large German population. Methods: Medical records from the IQVIA^TM Disease Analyzer database were analyzed retrospectively. PA patients (n = 860) were matched with non-PA individuals (n = 4300) by age and sex. Associations between PA and predefined chronic diseases were examined using multivariable logistic regression. Results: PA was significantly associated with hypokalemia (7.8% vs. 1.6%, odds ratio (OR): 3.45; 95% confidence intervals (CIs): 2.41–4.96), hypertension (56.1% vs. 28.5%; OR: 2.37; 95% CIs: 2.00–2.81), hepatic steatosis (11.3% vs. 3.0%; OR: 1.85; 95% CIs: 1.34–2.57), gout (8.3% vs. 2.2%; OR: 1.64; 95% CIs: 1.15–2.35), chronic kidney disease (6.3% vs. 2.2%; OR: 1.59; 95% CIs: 1.10–2.31), diabetes mellitus not otherwise specified (7.9% vs. 2.9%; OR: 1.49; 95% CIs: 1.06–2.09), obesity (13.5% vs. 5.1%; OR: 1.38; 95% CIs: 1.05–1.82), and depression (14.8% vs. 6.2%; OR: 1.37; 95% CIs: 1.07–1.77). Conclusions: While the study design had limitations, including reliance on ICD codes for diagnosis, these findings underscore the critical need for early detection and personalized management strategies for PA to reduce associated risks and improve patient outcomes. Full article

Molecular testing is recommended in patients with metastatic non-small cell lung cancer (NSCLC), but the extent of its use in Poland is unknown. The aim of the POL-MOL study was to investigate the frequency of using molecular testing in Polish patients with NSCLC. The invited Polish oncologists completed two questionnaires, and data for 1001 patients undergoing systemic treatment for NSCLC were collected. The use of molecular tests for the following genetic mutations was recorded: EGFR (del19, sub21), EGFR (other than del19/sub21), EGFR T790M, ALK (expression and rearrangement), RET, NTRK, ROS1, BRAF, HER2, and MET, as well as for immunochemical assessment of programmed cell death ligand 1 (PD-L1). Thanks to the weighting procedure, the results are representative of the population of Polish patients treated for NSCLC. Molecular tests were applied in 78% of patients with NSCL, 70% of patients with NSCLC not otherwise specified, and in 12% of patients with squamous cell carcinoma of the lung. The frequency of application increased with disease stage in all groups. In patients with squamous cell carcinoma, approximately 30% of tests for EGFR, ALK, and RET mutations were positive, which confirms the importance of testing at least a preselected subgroup of patients. Full article

Aggressive B-cell lymphoma encompasses Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and, as per the 2016 WHO classification, high-grade B-cell lymphoma (HGBL) not otherwise specified (NOS) and HGBL double/triple hit (DH/TH). However, the diagnostic distinction of HGBL from BL and DLBCL is difficult by means of histology/immunostaining in a substantial number of patients. This study aimed to improve subtyping by the identification of molecular features of aggressive B-cell lymphomas, with a specific focus on HGBL. To this end, we performed a comprehensive gene expression and mutational pattern analysis as well as the detection of B-cell clonality of 34 cases diagnosed with BL (n = 4), DLBCL (n = 16), HGBL DH (n = 8), and HGBL NOS (n = 6). Three distinct molecular subgroups were identified based on gene expression, primarily influenced by MYC expression/translocation and cell proliferation. In HGBL, compared to BL, there was an upregulation of PRKAR2B and TERT. HGBL DH exhibited elevated expression of GAMT and SMIM14, while HGBL NOS showed increased expression of MIR155HG and LZTS1. Our gene mutation analysis revealed MYC, ARID1A, BCL2, KMT2D, and PIM1 as the most affected genes in B-cell lymphoma, with BCL2 and CREBBP predominant in HGBL DH, and MYC and PIM1 in HGBL NOS. Clonality analysis of immunoglobulin heavy and light chain rearrangements did not show distinguishable V- or J-usage between the diagnostic subgroups. Full article

Background: Children and adolescents with subthreshold manic symptoms not meeting full DSM criteria for bipolar I or II disorder (BP-I or BP-II) are classified as unspecified bipolar disorder (formerly bipolar not otherwise specified: BP-NOS). Factors associated with transition from BP-II or NOS to BP-I may predict the progression of the disorder. Our objective is to analyze factors associated with transition to BP-I in a Spanish sample of youth with BP-NOS or BP-II. Methods: We included all youth diagnosed with BP before 18 years of age presenting to our clinic (October 1999–December 2014). We assessed clinical factors that may predict transition to BP I with a logistic regression and a multivariable model for data analysis. Results: A total of 72 patients with BP, mean (SD) age 14.5 (10.5–16.0) years, were followed for a median period of 3.9 years. In total, 95.8% of patients retained the BP diagnosis, but they changed type. Baseline BP-I % was 37.5%, and 62.5% at endpoint. BP-NOS decreased from baseline 54.2% to 25% at endpoint. The % of BP-II was 8.3% in both time points, but they were not the same individual patients, as some transitioned from BP-II to BP-I and some BP-NOS changed to BP-II. BP-NOS was stable in 46.1% of patients, but 38.5% transitioned to BP-I over time. Psychotic symptoms during prior depressive episodes (MDD) increased the risk of transition to BP-I by 11-fold. Each individual symptom of mania increased the risk of transition to BP-I by 1.41. Conclusions: BP-NOS was stable in 46.1% of patients, but 38.5% transitioned to BP-I over time. Psychotic symptoms during prior MDD episodes increased the risk of transition from BP-NOS to BP-I. Full article

Diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type of non-Hodgkin lymphoma (NHL). Significant efforts have been focused on utilizing advanced genomic technologies to further subclassify DLBCL, NOS into clinically relevant subtypes. These efforts have led to the implementation of novel algorithms to support optimal risk-oriented therapy and improvement in the overall survival of DLBCL patients. The pathogenesis of DLBCL at the molecular level indicates copy number variation (CNV) as one of the major forms of genetic alterations in the somatic mutational landscape. Random deregulation that results in complex breaks of chromosomes and restructuring of shattered chromosomal segments is called chromothripsis. Gene expression changes influenced by chromothripsis have been reported in cancer and congenital diseases. This chaotic phenomenon results in complex CNV, gene fusions, and amplification and loss of tumor suppressor genes. We present herein a summary of the most clinically relevant genomic aberrations, with particular focus on copy number aberrations in a case that highlights DLBCL, NOS arising from relapsed Hodgkin lymphoma. The focus of our study was to understand the relationship between the clinical, morphological, and genomic abnormalities in DLBCL, NOS through multiple techniques for therapeutic considerations. Full article

Two new diagnostic classifications of acute myeloid leukemia (AML) were published in 2022 to update current knowledge on disease biology. In previous 2017-edition categories of AML with myelodysplasia-related changes, AML was not otherwise specified, but AML with mutated RUNX1 experienced profound changes. We performed whole exome sequencing on a cohort of 69 patients with cytogenetic intermediate-risk AML that belonged to these diagnostic categories to correlate their mutational pattern and copy-number alterations with their new diagnostic distribution. Our results show that 45% of patients changed their diagnostic category, being AML myelodysplasia-related the most enlarged, mainly due to a high frequency of myelodysplasia-related mutations (58% of patients). These showed a good correlation with multilineage dysplasia and/or myelodysplastic syndrome history, but at the same time, 21% of de novo patients without dysplasia also presented them. RUNX1 was the most frequently mutated gene, with a high co-occurrence rate with other myelodysplasia-related mutations. We found a high prevalence of copy-neutral loss of heterozygosity, frequently inducing a homozygous state in particular mutated genes. Mild differences in current classifications explain the diagnostic disparity in 10% of patients, claiming a forthcoming unified classification. Full article

Breast cancer is a complex disease that includes entities with different characteristics, behaviors, and responses to treatment. Breast cancers are categorized into subgroups based on histological type and grade, and these subgroups affect clinical presentation and oncological outcomes. The subgroup of “special types” encompasses all those breast cancers with insufficient features to belong to the subgroup “invasive ductal carcinoma not otherwise specified”. These cancers account for around 25% of all cases, some of them having a relatively good prognosis despite high histological grade. The purpose of this paper is to review and illustrate the radiological appearance of each special type, highlighting insights and pitfalls to guide breast radiologists in their routine work. Full article

Diagnosis of myeloid neoplasm is currently performed according to the presence of a predetermined set of clinical, morphological, and molecular diagnostic criteria agreed upon by a consensus of experts. Even strictly adhering to these criteria, it is possible to encounter patients who present features that are not easily ascribable to a single disease category. This is the case, e.g., of patients with de novo myeloid neoplasms with features intermediate between primary myelofibrosis (PMF) and chronic myelomonocytic leukemia (CMML). In this study, we retrospectively searched the pathological database of IRCCS Humanitas Research Hospital to identify cases of chronic myeloid neoplasm with monocytosis with a driver mutation of classic myeloproliferative neoplasms (MPN) and showing morphological MPN features. For each case, we assessed all epidemiological, clinical, histopathological, and molecular data. Then, we carried out a literature review, searching for cases with features similar to those of our patients. We retrieved a total of 13 cases presenting such criteria (9 from the literature review and 4 from our institution); in all of them, there was a coexistence of clinical, histopathological, and molecular myelodysplastic and myeloproliferative features. To date, according to current classifications (World Health Organization and International Consensus Classification), given the presence/absence of essential features for PMF or CMML, these patients should be formally diagnosed as myelodysplastic/myeloproliferative neoplasm unclassified/not otherwise specified (U/NOS). This review aims to summarize the features of these difficult cases and discuss their differential diagnosis and their classification according to the novel classifications and the existing literature on overlapping myeloid neoplasms. Full article

Reports on neoplasms in bears are scarce, especially concerning ovarian tumors. A large primary ovarian neoplasm with multiple metastasis was found during the necropsy of a 14-year-old free-ranging Eurasian brown bear (Ursus arctos) from Northwestern Spain. Histopathology and immunohistochemistry allowed for the diagnosis of a sex cord stromal tumor. This is a complex group of neoplasms which differ in the predominant cell morphology and immunohistochemical features. The microscopic examination revealed two types of cells, one with eosinophilic cytoplasm, intermingled with larger vacuolated cells rich in lipids. The evaluation of the immunoreactivity to different markers, frequently used in the characterization of gonadal tumors (INHA, inhibin-alpha; PLAP, placental alkaline phosphatase; Ki-67; α-SMA, actin alpha-smooth muscle) and inflammation patterns (IBA1, ionized calcium-binding adapter molecule for macrophages; CD3 for T lymphocytes; CD20 for B lymphocytes), displayed significant INHA positive immunostaining of neoplastic cells, as well as inflammatory cell infiltration, mainly composed of macrophages and B lymphocytes. These findings were consistent with a malignant ovarian steroid cell tumor, not otherwise specified. The present study characterizes an unusual type of neoplasm, and also represents the first report of an ovarian sex cord stromal tumor in Ursidae. Full article

Background/Objectives: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity. This study’s objectives are to obtain updated epidemiological data that will help identify the specific types and subtypes of EB, determine the case distribution in Romania, and establish the incidence and prevalence of the condition. Methods: This population-based observational study included Romanian patients and collected data from 2012 to 2024. The following information was recorded: date of birth, status (deceased or alive), date of death (if applicable/available), sex, county, and city of residence, EB type and subtype if available, diagnosis (clinical and/or immunofluorescence mapping, transmission electron microscopy, genetic molecular analysis), affected genes, inheritance, and affected family members. Results: The study included a total of 152 patients. The point prevalence (the proportion of the population with a condition at a specific point in time) and the incidence of EB in Romania were 6.77 per million population and 24.23 per million live births, respectively. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB (KEB), and not otherwise specified EB, as well as EB (NOS), were the main types of the condition identified in 21%, 3%, 63%, 2%, and 11% of the total cases. The point prevalence and incidence for the same time intervals were 1.58 and 5.28 in EBS, 0.10 and 1.76 in JEB, 4.72 and 12.34 in DEB, 0.16 and 0 in KEB, and 0.21 and 4.85 in EB (NOS). Conclusions: The study provides updated epidemiological data for Romania and underlines the necessity for accurate diagnosis, facilitated by access to genetic molecular testing and better reporting systems. Full article

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. Full article

Consider a collection of entities moving continuously with bounded speed, but otherwise unpredictably, in some low-dimensional space. Two such entities encroach upon one another at a fixed time if their separation is less than some specified threshold. Encroachment, of concern in many settings such as collision avoidance, may be unavoidable. However, the associated difficulties are compounded if there is uncertainty about the precise location of entities, giving rise to potential encroachment and, more generally, potential congestion within the full collection. We adopt a model in which entities can be queried for their current location (at some cost) and the uncertainty region associated with an entity grows in proportion to the time since that entity was last queried. The goal is to maintain low potential congestion, measured in terms of the (dynamic) intersection graph of uncertainty regions, at specified (possibly all) times, using the lowest possible query cost. Previous work in the same uncertainty model addressed the problem of minimizing the congestion potential of point entities using location queries of some bounded frequency. It was shown that it is possible to design query schemes that are $O\left(1\right)$-competitive, in terms of worst-case congestion potential, with other, even clairvoyant query schemes (that exploit knowledge of the trajectories of all entities), subject to the same bound on query frequency. In this paper, we initiate the treatment of a more general problem with the complementary optimization objective: minimizing the query frequency, measured as the reciprocal of the minimum time between queries (granularity), while guaranteeing a fixed bound on congestion potential of entities with positive extent at one specified target time. This complementary objective necessitates quite different schemes and analyses. Nevertheless, our results parallel those of the earlier papers, specifically tight competitive bounds on required query frequency. Full article