Publications by authors named "Manuela Mollejo"

97 Publications

Mastocytosis in the skin accompanied by pseudo-Kaposi's sarcoma.

J Dermatol 2021 May 8;48(5):657-660. Epub 2021 Mar 8.

Spanish Reference Center of Mastocytosis, Instituto de Estudios de Mastocitosis de Castilla-La Mancha (CLMast), Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain.

Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of neoplastic mast cells in the skin and/or other extracutaneous tissues. Most patients with skin involvement can be subclassified into one of the three subtypes of cutaneous mastocytosis currently recognized by the World Health Organization (i.e., mastocytoma, maculopapular cutaneous mastocytosis and diffuse cutaneous mastocytosis); however, some patients may occasionally present with atypical skin lesions that cannot be ascribed to any of these disease subtypes. Here, we report three patients diagnosed with mastocytosis and an unusual cutaneous involvement mimicking Kaposi's sarcoma. Skin biopsies showed neoplastic mast cell infiltrates together with features commonly seen in acroangiodermatitis, and immunohistochemistry for human herpesvirus 8 was negative. One patient fulfilled the criteria for aggressive systemic mastocytosis, showed no response to cytoreductive therapy, and died because of disease progression. The remaining two patients had indolent and smoldering systemic mastocytosis, respectively, but they showed several features associated with an unfavorable prognosis such as extensive involvement of the hematopoiesis by the KIT D816V mutation, increased serum β2-microglobulin, and decreased serum lactate dehydrogenase. The presence of pseudo-Kaposi's sarcoma skin lesions is an uncommon finding in mastocytosis which may alert physicians to the possible existence of underlying features indicative of a poor prognosis.
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http://dx.doi.org/10.1111/1346-8138.15734DOI Listing
May 2021

Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma.

Sci Rep 2021 Jan 21;11(1):1886. Epub 2021 Jan 21.

Lymphoma Research Group, Medical Oncology Department, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Majadahonda, Madrid, Spain.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N1, EZB, MCD, BN2, and ST2 groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST2 is the group with the best clinical outcome and N1, the more aggressive one. EZB identified a subgroup with a worse prognosis among GCB-DLBLC cases.
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http://dx.doi.org/10.1038/s41598-020-80376-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820010PMC
January 2021

Craniopharyngiomas: A clinicopathological and molecular study of 52 cases - Experience in the Complejo Hospitalario de Toledo and Hospital Universitario 12 de Octubre (Madrid).

Clin Neuropathol 2021 Jan-Feb;40(1):26-35

Craniopharyngiomas (CPs) are histologically benign tumors that are associated with high levels of morbidity. Two clinicopathological variants - adamantinomatous (ACP) and papillary (PCP) - have been described. They differ in their molecular features, whereby activating mutations in (V600E) and genes characterize PCP and ACP, respectively. Recently, both variants have been shown to express elevated PD-L1 protein expression, but ACP also exhibited tumor cell-intrinsic PD-1 expression. In this study we analyze these molecular alterations in 52 cases with a long follow-up and examine their associations with immunohistochemical and clinical characteristics. ACPs comprise 73.1% of cases, while 21.2% are PCPs. Aberrant nuclear immunoreactivity for β-catenin was observed in all ACPs. p.V600E mutations were observed in 90.9% of PCPs. Only one ACP case featured both alterations. Both types of CP exhibited strong nuclear staining for p63 with diffuse and basal distribution. ACP and PCP consistently expressed PD-L1, most in a substantial percentage of tumor cells, with a distinctive spatial distribution of expression in each subtype; only ACP demonstrated PD-1 expression. There was no evidence of differences in clinical prognosis between ACPs and PCPs. The identification of hallmark molecular signatures in the two CP variants is useful for sub-categorization in routine histopathology reporting. It is also pertinent to personalized therapy and for the development of improved non-invasive therapeutic strategies in this disease.
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http://dx.doi.org/10.5414/NP301268DOI Listing
December 2020

TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors.

Neurooncol Adv 2020 Jan-Dec;2(1):vdz059. Epub 2020 Jan 24.

Department of Pathology (Neuropathology) and Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.

Background: Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than "classic" IDHwt GBM.

Methods: We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data.

Results: p53 was altered by gene mutation or protein overexpression in all cases, while driver , , , or mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of , , , and mutations, while lower frequency of amplification, deletion, and promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with and mutations. In the histopathological review of TCGA IDHwt, -mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with -mutant gcGBMs had better overall survival than those with GBMs (log-rank test,  < .002).

Conclusions: gcGBMs have molecular features that contrast to "classic" IDHwt GBMs: unusually frequent mutations and few amplifications and deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine.
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http://dx.doi.org/10.1093/noajnl/vdz059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212869PMC
January 2020

Simultaneous occurrence of cutaneous mastocytosis and juvenile xanthogranuloma in a child: Random or true association?

Pediatr Dermatol 2020 Jul 5;37(4):716-720. Epub 2020 May 5.

Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Spanish Network on Mastocytosis (REMA), Toledo, Spain.

Juvenile xanthogranuloma (JXG) and cutaneous mastocytosis (CM) are two distinct conditions that have rarely been reported in association. We report a child with CM and disseminated JXG, who showed a significant decrease in serum tryptase levels and regression of JXG lesions over time. Due to the paucity of reports, a true association between these two conditions has not been validated, although a potential induction of histiocytic lesions by mast cell degranulation has been proposed.
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http://dx.doi.org/10.1111/pde.14185DOI Listing
July 2020

Spatio-temporal and Cellular Expression Patterns of PTK7 in the Healthy and Traumatically Injured Rat and Human Spinal Cord.

Cell Mol Neurobiol 2020 Oct 23;40(7):1087-1103. Epub 2020 Jan 23.

Laboratory of Molecular Neurology, Hospital Nacional de Parapléjicos, Toledo, Spain.

Despite the emerging role of protein tyrosine kinase 7 (PTK7) as a Wnt co-receptor and the relevant functions of the Wnt family of proteins in spinal cord injury (SCI), the potential involvement of PTK7 in SCI is currently unknown. As a first essential step to shed light on this issue, we evaluated the spatio-temporal and cellular expression patterns of PTK7 in healthy and traumatically injured rat and human spinal cords. In the uninjured rats, PTK7 expression was observed in the ependymal epithelium, endothelial cells, meningeal fibronectin-expressing cells, and specific axonal tracts, but not in microglia, astrocytes, neurons, oligodendrocytes, or NG2+ cells. After rat SCI, the mRNA expression of PTK7 was significantly increased, while its spatio-temporal and cellular protein expression patterns also suffered evident changes in the injured region. Briefly, the expression of PTK7 in the affected areas was observed in axons, reactive astrocytes, NG2+ and fibronectin-expressing cells, and in a subpopulation of reactive microglia/macrophages and blood vessels. Finally, in both healthy and traumatically injured human spinal cords, PTK7 expression pattern was similar to that observed in the rat, although some specific differences were found. In conclusion, we demonstrate for the first time that PTK7 is constitutively expressed in the healthy adult rat and human spinal cord and that its expression pattern clearly varied after rat and human SCI which, to our knowledge, constitutes the first experimental evidence pointing to the potential involvement of this co-receptor in physiological and pathological spinal cord functioning.
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http://dx.doi.org/10.1007/s10571-020-00794-6DOI Listing
October 2020

Frizzled 1 and Wnt1 as new potential therapeutic targets in the traumatically injured spinal cord.

Cell Mol Life Sci 2020 Nov 3;77(22):4631-4662. Epub 2020 Jan 3.

Laboratory of Molecular Neurology, Hospital Nacional de Parapléjicos, Toledo, Spain.

Despite the experimental evidence pointing to a significant role of the Wnt family of proteins in physiological and pathological rodent spinal cord functioning, its potential relevance in the healthy and traumatically injured human spinal cord as well as its therapeutic potential in spinal cord injury (SCI) are still poorly understood. To get further insight into these interesting issues, we first demonstrated by quantitative Real-Time PCR and simple immunohistochemistry that detectable mRNA expression of most Wnt components, as well as protein expression of all known Wnt receptors, can be found in the healthy human spinal cord, supporting its potential involvement in human spinal cord physiology. Moreover, evaluation of Frizzled (Fz) 1 expression by double immunohistochemistry showed that its spatio-temporal and cellular expression pattern in the traumatically injured human spinal cord is equivalent to that observed in a clinically relevant model of rat SCI and suggests its potential involvement in SCI progression/outcome. Accordingly, we found that long-term lentiviral-mediated overexpression of the Fz1 ligand Wnt1 after rat SCI improves motor functional recovery, increases myelin preservation and neuronal survival, and reduces early astroglial reactivity and NG2+ cell accumulation, highlighting the therapeutic potential of Wnt1 in this neuropathological situation.
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http://dx.doi.org/10.1007/s00018-019-03427-4DOI Listing
November 2020

Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis.

Int J Cancer 2020 01 1;146(2):373-387. Epub 2019 Jul 1.

Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, Oviedo, Spain.

Loss of 5-hydroxymethylcytosine (5hmC) has been associated with mutations of the ten-eleven translocation (TET) enzymes in several types of cancer. However, tumors with wild-type TET genes can also display low 5hmC levels, suggesting that other mechanisms involved in gene regulation might be implicated in the decline of this epigenetic mark. Here we show that DNA hypermethylation and loss of DNA hydroxymethylation, as well as a marked reduction of activating histone marks in the TET3 gene, impair TET3 expression and lead to a genome-wide reduction in 5hmC levels in glioma samples and cancer cell lines. Epigenetic drugs increased expression of TET3 in glioblastoma cells and ectopic overexpression of TET3 impaired in vitro cell growth and markedly reduced tumor formation in immunodeficient mice models. TET3 overexpression partially restored the genome-wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines, while elevated TET3 mRNA levels were correlated with better prognosis in glioma samples. Our results suggest that epigenetic repression of TET3 might promote glioblastoma tumorigenesis through the genome-wide alteration of 5hmC.
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http://dx.doi.org/10.1002/ijc.32520DOI Listing
January 2020

Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma.

PLoS One 2019 25;14(2):e0212813. Epub 2019 Feb 25.

Lymphoma Research Group, Medical Oncology Department, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Madrid, Spain.

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388933PMC
November 2019

Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing.

J Neuropathol Exp Neurol 2018 08;77(8):710-716

Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain.

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.
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http://dx.doi.org/10.1093/jnen/nly048DOI Listing
August 2018

Spontaneously Ruptured Spleen Samples in Patients With Infectious Mononucleosis: Analysis of Histology and Lymphoid Subpopulations.

Am J Clin Pathol 2018 Aug;150(4):310-317

Pathology Service, Fundación Jiménez Díaz, CIBERONC, Madrid, Spain.

Objectives: Spontaneous rupture of the spleen is occasionally seen as the presenting event in infectious mononucleosis (IM). Diagnosis of these cases can be very challenging.

Methods: We describe the morphologic and immunohistochemical findings in a series of seven splenectomy specimens removed after spontaneous rupture in patients with IM. Most cases were submitted for a second opinion since the histology of the cases suggested malignant lymphoma.

Results: All the cases showed similar findings, with red pulp expansion occupied by activated T and B cells, including scattered large lymphocytes with both T- and B-cell markers, together with a polymorphic background rich in cytotoxic T cells. Clonality analysis revealed T-cell receptor clonal patterns in four of the six cases evaluated.

Conclusions: IM should be considered a possible diagnosis in any case of splenic rupture whose histology suggests possible aggressive lymphoma.
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http://dx.doi.org/10.1093/ajcp/aqy056DOI Listing
August 2018

Loss of 5hmC identifies a new type of aberrant DNA hypermethylation in glioma.

Hum Mol Genet 2018 09;27(17):3046-3059

Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, Principado de Asturias, Oviedo, Spain.

Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC and 5-methylcytosine (5mC) in human primary samples from 12 non-tumoral brains and 53 gliomas. We found that the levels of 5hmC identified in non-tumoral samples were significantly reduced in gliomas. Strikingly, hypo-hydroxymethylation at 4627 (9.3%) CpG sites was associated with aberrant DNA hypermethylation and was strongly enriched in CpG island shores. The DNA regions containing these CpG sites were enriched in H3K4me2 and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. As this 5mC gain is inversely correlated with loss of 5hmC and has not been identified with classical sodium bisulfite-based technologies, we conclude that our data identifies a novel 5hmC-dependent type of aberrant DNA hypermethylation in glioma.
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http://dx.doi.org/10.1093/hmg/ddy214DOI Listing
September 2018

Splenic marginal zone lymphoma.

Best Pract Res Clin Haematol 2017 Mar - Jun;30(1-2):56-64. Epub 2016 Nov 5.

Servicio de Anatomía Patológica, Hospital Virgen de la Salud, Toledo, Spain.

Splenic marginal zone lymphoma (SMZL) is an indolent small B-cell lymphoma involving the spleen and bone marrow characterized by a micronodular tumoral infiltration that replaces the preexisting lymphoid follicles and shows marginal zone differentiation as a distinctive finding. SMZL cases are characterized by prominent splenomegaly and bone marrow and peripheral blood infiltration. Cells in peripheral blood show a villous cytology. Bone marrow and peripheral blood characteristic features usually allow a diagnosis of SMZL to be performed. Mutational spectrum of SMZL identifies specific findings, such as 7q loss and NOTCH2 and KLF2 mutations, both genes related with marginal zone differentiation. There is a striking clinical variability in SMZL cases, dependent of the tumoral load and performance status. Specific molecular markers such as 7q loss, p53 loss/mutation, NOTCH2 and KLF2 mutations have been found to be associated with the clinical variability. Distinction from Monoclonal B-cell lymphocytosis with marginal zone phenotype is still an open issue that requires identification of precise and specific thresholds with clinical meaning.
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http://dx.doi.org/10.1016/j.beha.2016.09.005DOI Listing
October 2017

Intravascular large B-cell lymphoma in a kidney biopsy.

Blood 2016 06 9;127(23):2939. Epub 2016 Jun 9.

Hospital Virgen de la Salud de Toledo.

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http://dx.doi.org/10.1182/blood-2016-02-697490DOI Listing
June 2016

Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas.

J Invest Dermatol 2017 01 1;137(1):197-206. Epub 2016 Sep 1.

Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain; IBBTEC-UC-CSIC-SODERCAN Instituto de Biomedicina y Biotecnología de Cantabria, Santander, Spain. Electronic address:

Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multivariable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.
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http://dx.doi.org/10.1016/j.jid.2016.08.015DOI Listing
January 2017

Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 mutations and review of the literature.

Oncotarget 2017 Sep 19;8(40):68950-68963. Epub 2016 Jul 19.

Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría, University of Salamanca, Salamanca, Spain.

Resistance to imatinib has been recurrently reported in systemic mastocytosis (SM) carrying exon 17 mutations. We evaluated the efficacy and safety of imatinib therapy in 10 adult SM patients lacking exon 17 mutations, 9 of which fulfilled criteria for well-differentiated SM (WDSM). The World Health Organization 2008 disease categories among WDSM patients were mast cell (MC) leukemia ( = 3), indolent SM ( = 3) and cutaneous mastocytosis ( = 3); the remainder case had SM associated with a clonal haematological non-MC disease. Patients were given imatinib for 12 months -400 or 300 mg daily depending on the presence vs. absence of > 30% bone marrow (BM) MCs and/or signs of advanced disease-. Absence of exon 17 mutations was confirmed in highly-purified BM MCs by peptide nucleic acid-mediated PCR, while mutations involving other exons were investigated by direct sequencing of purified BM MC DNA. Complete response (CR) was defined as resolution of BM MC infiltration, skin lesions, organomegalies and MC-mediator release-associated symptoms, plus normalization of serum tryptase. Criteria for partial response (PR) included ≥ 50% reduction in BM MC infiltration and improvement of skin lesions and/or organomegalies. Treatment was well-tolerated with an overall response rate of 50%, including early and sustained CR in four patients, three of whom had extracellular mutations of , and PR in one case. This later patient and all non-responders ( = 5) showed wild-type . These results together with previous data from the literature support the relevance of the mutational status in selecting SM patients who are candidates for imatinib therapy.
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http://dx.doi.org/10.18632/oncotarget.10711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620310PMC
September 2017

Glomerular C3d as a novel prognostic marker for renal vasculitis.

Hum Pathol 2016 10 30;56:31-9. Epub 2016 May 30.

Nephrology Department, Hospital Universitario Fundacion Alcorcón, Alcorcón 28922, Spain.

Pauci-immune necrotizing crescentic glomerulonephritis is the histologic substrate of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Several studies in animal models have demonstrated the crucial role of complement activation in the pathogenesis of ANCA-associated vasculitis, but only small series have analyzed the prognostic implications of complement glomerular deposits. This study aimed to assess the clinical and prognostic implications of C3d- and C4d-positive glomerular staining in renal vasculitis. Eighty-five patients with a diagnosis of pauci-immune necrotizing crescentic glomerulonephritis were included in the study. C3d and C4d were analyzed by immunohistochemical staining using a polyclonal antibody. The primary predictors were glomerular C3d- and C4d-positive staining. The primary end point was the cumulative percentage of patients who developed end-stage renal disease. Glomerular staining for C3d and C4d was observed in 42 (49.4%) of 85 biopsies and 38 (44.7%) of 85 biopsies, respectively. C3d-positive staining was associated with the severity of renal impairment and with a lower response rate to treatment (P=.003 and P=.04, respectively). Renal survival at 2 and 5 years was 60.9% and 51.8% in C3d-positive patients compared with 87.7% and 78.9% in C3d-negative patients (P=.04). C4d-positive staining did not show any impact in renal outcome. When adjusted by renal function and other histologic parameters, C3d staining remained as an independent predictor for renal survival (hazard ratio, 2.5; 95% confidence interval, 1.1-5.7; P=.03). Therefore, this study demonstrates that C3d-positive glomerular staining is an independent risk factor for the development of end-stage renal disease in ANCA-associated renal vasculitis.
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http://dx.doi.org/10.1016/j.humpath.2016.05.015DOI Listing
October 2016

Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker.

Oncotarget 2016 Apr;7(14):18036-49

Departments of Haematology and Pathology, Hospital Marques de Valdecilla, and IDIVAL, Santander, Spain.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches.
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http://dx.doi.org/10.18632/oncotarget.7495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951269PMC
April 2016

An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

Clin Cancer Res 2016 Apr 8;22(8):2032-40. Epub 2015 Dec 8.

Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.

Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).

Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).

Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1170DOI Listing
April 2016

Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients.

Br J Haematol 2016 Jan 12;172(1):56-63. Epub 2015 Oct 12.

Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain.

The diagnosis of 'rare diseases', such as mastocytosis, remains a challenge. Despite this, the precise benefits of referral of mastocytosis patients to highly specialized reference centres are poorly defined and whether patients should be managed at non-specialized versus reference centres remains a matter of debate. To evaluate the quality and efficiency of diagnostic procedures performed at the reference centres for mastocytosis in Spain (REMA) versus other non-reference centres, we retrospectively analysed a series of 122 patients, for the overall degree of agreement obtained for the World Health Organization (WHO) diagnostic and classification criteria betwen the referring and REMA centres. Our results showed that not all WHO diagnostic criteria were frequently investigated at the referring centres. Among the five WHO diagnostic criteria, the highest degree of agreement was obtained for serum tryptase levels [median 90% (95% confidence interval 84-96%)]; in turn, the overall agreement was significantly lower for the major histopathological criterion [80% (72-89%)], and the other three minor criteria: cytomorphology [68% (56-80%)] immunophenotyping of BM mast cells [75% (62-87%)] and detection of the KIT mutation [34% (8-60%)]. Referral of patients with diagnostic suspicion of mastocytosis to a multidisciplinary reference centre improves diagnostic efficiency and quality.
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http://dx.doi.org/10.1111/bjh.13789DOI Listing
January 2016

Antineutrophil cytoplasmic antibody negative pauci-immune extracapillary glomerulonephritis.

Nephrology (Carlton) 2016 Apr;21(4):301-7

Nephrology, Toledo, Spain.

Aim: Pauci-immune extracapillary glomerulonephritis (PEGN) is one of the most common causes of rapidly progressive glomerulonephritis and is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). However, a significant number of individuals with PEGN test negative for ANCA and this study aimed to analyze the characteristics of this subgroup of patients.

Methods: Patients from two centres who were diagnosed with PEGN between 1997 and 2014 were studied retrospectively. Clinicopathological characteristics and renal outcome were compared between patients presenting with pauci-immune necrotizing extracapillary glomerulonephritis associated or not with the presence of circulating ANCA.

Results: Among the 114 patients with PEGN, 29 (25.4%) were ANCA negative. Compared with the 85 ANCA-positive patients, ANCA-negative patients were younger at the onset (54.8 ± 17.2 vs. 62 ± 14.0 years; P < 0.05). The median level of urinary protein excretion was significantly higher among ANCA-negative patients (3.1 vs. 1 g/24 h; P < 0.001), whereas no differences were found in renal function and need for dialysis between ANCA-negative and positive groups. Extrarenal involvement was present independently of ANCA status. Histological analysis showed that ANCA-negative patients were more likely to have mesangial proliferation (P < 0.05). Renal and global survival were similar between ANCA-negative and positive patients, and treatment response and relapse rates were comparable in both groups.

Conclusions: ANCA-negative pauci-immune extracapillary glomerulonephritis is not a rare condition and is part of a systemic vasculitis disease. Although ANCA-negative patients have renal and histological characteristics that differ from ANCA-positive patients, renal survival and treatment response in PEGN are independent of ANCA status.
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http://dx.doi.org/10.1111/nep.12608DOI Listing
April 2016

Secretory meningioma with KLF4 K409Q mutation in collision with glioma.

Clin Neuropathol 2015 Nov-Dec;34(6):322-9

Aims: The simultaneous occurrence of two primary intracranial tumors is a rare event, especially if unrelated to radiotherapy or genetic disorders. We present two patients, both with two primary intracranial tumors simultaneously present at adjacent sites, in order to explore a possible mechanism of synchronous tumor formation.

Methods: We performed a molecular analysis of the K409Q mutation of the KLF4 gene, in addition to conventional immunohistochemistry.

Results: Preoperative gadolinium-enhanced magnetic resonance imaging revealed a necrotic mass with an irregular ring-like enhancement adjacent to a frontal meningioma in patient 1, and an infiltrative non-enhancing glial tumor with no evidence of another tumor in patient 2. Postoperative histological examination revealed the presence of two distinct tumors in both cases: secretory meningioma and glioblastoma in patient 1 and secretory meningioma and anaplastic astrocytoma in patient 2. Secretory meningiomas both showed the KLF4 K409Q mutation, while none of the glial tumors had it.

Conclusions: To our knowledge, these are the first two cases reported of the simultaneous occurrence of secretory meningiomas with mutation of KLF4 in collision with a glioblastoma and an anaplastic astrocytoma, respectively. These collision tumors presumably have different molecular origins.
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http://dx.doi.org/10.5414/NP300860DOI Listing
September 2016

Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis.

J Allergy Clin Immunol 2016 Jan 19;137(1):168-178.e1. Epub 2015 Jun 19.

Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain.

Background: Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined.

Objective: We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM.

Methods: Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied.

Results: Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM.

Conclusions: WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.
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http://dx.doi.org/10.1016/j.jaci.2015.05.008DOI Listing
January 2016