The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) ...gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection.
translocations, a hallmark of Burkitt lymphoma, occur in 5-15% of diffuse large B-cell lymphoma, and have a negative prognostic impact. Numerical aberrations of
have also been detected in these ...patients, but their incidence and prognostic role are still controversial. We analyzed the clinical impact of
increased copy number on 385 patients with diffuse large B-cell lymphoma screened at diagnosis for
,
, and
rearrangements. We enumerated the number of
copies, defining as amplified those cases with an uncountable number of extra-copies. The prevalence of
translocation, increased copy number and amplification was 8.8%, 15%, and 1%, respectively. Patients with 3 or 4 gene copies, accounting for more than 60% of patients with
copy number changes, had a more favorable outcome compared to patients with >4 copies or translocation of MYC, and were not influenced by the type of treatment received as first-line. Stratification according to the number of
extra-copies showed a negative correlation between an increasing number of copies and survival. Patients with >7 copies or the amplification of
had the poorest prognosis. Patients with >4 copies of MYC showed a similar, trending towards worse prognosis compared to patients with
translocation. The survival of patients with >4 copies, translocation or amplification of
seemed to be superior if intensive treatments were used. Our study underlines the importance of fluorescence
hybridization testing at diagnosis of diffuse large B-cell lymphoma to detect the rather frequent and clinically significant numerical aberrations of
.
Lack of robust predictive biomarkers, other than MGMT promoter methylation, makes temozolomide responsiveness in newly diagnosed glioblastoma (GBM) patients difficult to predict. However, we ...identified patients with long-term survival (≥35 months) within a group of newly diagnosed GBM patients treated with standard or metronomic adjuvant temozolomide schedules. We thus investigated possible molecular profiles associated with longer survival following temozolomide treatment.
We investigated the association of molecular features with progression-free (PFS) and overall survival (OS). Human-derived GBM cancer stem cells (CSCs) were used to investigate in vitro molecular mechanisms associated with temozolomide responsiveness. Surgically removed recurrences allowed investigation of molecular changes occurring during therapy in vivo. Statistical analyses included one- and two-way analysis of variance, Student's t test, Cox proportional hazards, and the Kaplan-Meier method. All statistical tests were two-sided.
No association was found between survival and gene classifiers associated with different molecular GBM subtypes in the standard-treated group, while in metronomic-treated patients robust association was found between EGFR amplification/overexpression and PFS and OS (OS, EGFR-high vs low: hazard ratiodeath = 0.22, 95% confidence interval = 0.09 to 0.55, P = .001). The result for OS remained statistically significant after Bonferroni correction (P interaction < .0005). Long-term survival following metronomic temozolomide was independent from MGMT and EGFRvIII status and was more pronounced in EGFR-overexpressing GBM patients with PTEN loss. In vitro findings confirmed a selective dose- and time-dependent decrease in survival of temozolomide-treated EGFR+ human-derived glioblastoma CSCs, which occurred through inhibition of NF-κB transcriptional activity. In addition, reduction in EGFR-amplified cells, along with a statistically significant decrease in NF-κB/p65 expression, were observed in specimens from recurrent metronomic-treated EGFR-overexpressing GBM patients.
EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies.
Inflammatory myofibroblastic tumor (IMT) is a locally aggressive neoplasm, most frequently occurring in the abdominal cavity as multiple recurrent nodules. We report a case of IMT in a 24-year-old ...male presenting as multiple nodules involving the omentum, the liver, and the colon. Spindle tumor cells expressed ALK with a cytoplasmic granular distribution, the CLTC-ALK fusion gene was demonstrated by reverse-transcriptase polymerase chain reaction analysis, and break-apart fluorescence in situ hybridization (FISH) probes for the ALK gene showed a pathological pattern (single red signal associated with 1/2 normal fused signals) highly suggestive for combined gene fusion and deletion. To reduce the surgically unresectable liver mass, the patient was treated with crizotinib, and after 4 months of treatment the disease was defined stable according to RECIST criteria. Interestingly, ALK and FISH/FICTION analysis revealed that tumor cells were widely dispersed as multiple microscopic foci or as single cells beneath the omental mesothelium. These findings indicate that IMT multifocality might result either from dissemination from the main tumor mass or development of multiple independent neoplastic foci; furthermore, they underline the need of omentectomy in abdominal IMT to obtain surgical radicality.
Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good ...clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and
IGH
rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of
BCL2
,
BCL6
,
MYC
, and
PAX5
genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals.
HPV DNA has never been investigated in nipple discharges (ND) and serum-derived extracellular vesicles, although its presence has been reported in ductal lavage fluids and blood specimens.
We ...analyzed 50 ND, 22 serum-derived extracellular vesicles as well as 51 pathologic breast tissues for the presence of 16 HPV DNA types.
We show that the presence of HPV DNA in the ND is predictive of HPV DNA-positive breast lesions and that HPV DNA is more represented in intraductal papillomas. We also show the presence of HPV DNA in the serum-derived extracellular vesicles.
Our data supports the use of liquid biopsy to detect HPV DNA in breast pathology.
El propósito del presente estudio consiste en identificar y relacionar los 17 objetivos del desarrollo sostenible en el proceso de planificación estratégica de la educación Superior. Se seleccionó ...como caso de estudio a la Universidad Simón Bolívar de Venezuela y su Plan Estratégico de Desarrollo. Como parte del proceso metodológico se diseñó una herramienta de evaluación que permitiera a partir de la recolección y categorización, reconstruir la información e interpretar la relación existente entre las variables y parámetros. La investigación responde al enfoque cuantitativo, utilizando la observación documental y el análisis de contenido para comprender el objeto de estudio. Se concluye poca presencia, visibilidad y disparidad de los ODS, además que la planificación institucional no responde a los compromisos con la Agenda 2030, ni son una respuesta para atender los lineamientos que representan los retos del milenio.
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