RESUMO
Therapeutic management and prognostication for patients with B-acute lymphoblastic leukaemia (B-ALL) require appropriate disease subclassification. BCR::ABL1-like B-ALL is unique in that it is defined by a gene expression profile similar to BCR::ABL1+ B-ALL rather than a unifying recurrent translocation. Current molecular/cytogenetic techniques to identify this subtype are expensive, not widely accessible, have long turnaround times and/or require an adequate liquid biopsy. We have studied a total of 118 B-ALL cases from three institutions in two laboratories to identify surrogates for BCR::ABL1+/like B-ALL. We report that immunoglobulin joining chain (IGJ) and spermatogenesis associated serine-rich 2-like (SPATS2L) immunohistochemistry (IHC) sensitively and specifically identify BCR::ABL1+/like B-ALL. IGJ IHC positivity has a sensitivity of 83%, a specificity of 95%, a positive predictive value (PPV) of 89% and a negative predictive value (NPV) of 90%. SPATS2L staining has similar sensitivity and NPV but lower specificity (85%) and PPV (70%). The presence of either IGJ or SPATS2L staining augments the sensitivity (93%) and NPV (95%). While these findings would need to be validated in larger studies, they suggest that IGJ and/or SPATS2L IHC may be utilized in identifying BCR::ABL1-like B-ALL or in selecting B-ALL cases for confirmatory molecular/genetic testing, particularly in resource-limited settings.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Humanos , Imuno-Histoquímica , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Translocação GenéticaRESUMO
Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.
Assuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Receptor alfa de Ácido Retinoico , Torque teno virus , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/diagnóstico , Receptor alfa de Ácido Retinoico/genética , Masculino , Torque teno virus/genética , Proteínas de Fusão Oncogênica/genética , Feminino , Adulto , Pessoa de Meia-Idade , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
IgG4-related lymphadenopathy is a nodal manifestation of IgG4-related disease (IgG4RD) which is characterized by increased polytypic IgG4+ plasma cells and IgG4+/IgG+ plasma cell ratio in lymph nodes and morphologically manifested as various patterns of reactive lymphadenopathy: Castleman disease-like, follicular hyperplasia, interfollicular expansion, progressive transformation of germinal centers and inflammatory pseudotumor-like. It typically presents with solitary or multiple, mild to moderate lymph node enlargement in otherwise asymptomatic patients. The serum IgG4 level is frequently elevated but C-reactive protein often remains normal. In patients not having a history of IgG4RD or manifestation of extranodal IgG4RD, a diagnosis of IgG4-lymphadenopathy should only be made with great caution given the non-specific morphologic features that can overlap with ANCA-associated vasculitis, interleukin-6 syndromes, Rosai-Dorfman disease, inflammatory myofibroblastic tumor, syphilis, lymphoma, and plasma cell neoplasia. Elevated IgG4 parameters, appropriate morphologies, and clinical correlation are essential to make the diagnosis of IgG4-lymphadenopathy more specific and clinically meaningful.
Assuntos
Hiperplasia do Linfonodo Gigante , Doença Relacionada a Imunoglobulina G4 , Linfadenopatia , Linfoma , Humanos , Imunoglobulina G , Linfadenopatia/patologia , Linfonodos/patologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Linfoma/patologia , Doença Relacionada a Imunoglobulina G4/patologiaRESUMO
BACKGROUND: The role of cytoreduction prior to hematopoietic cell transplant (HCT) for patients with pediatric myelodysplastic syndrome (MDS) and related disorders remains unclear. PROCEDURE: We performed a single-center retrospective analysis of pre-transplant disease management and subsequent HCT outcome for pediatric patients with MDS and related disorders who underwent HCT between 2010 and 2020. RESULTS: Total 62 patients (median age 11 years) with idiopathic MDS (n = 16), MDS secondary to an underlying germline condition (n = 11), secondary acute myeloid leukemia (n = 9), myeloproliferative neoplasms (n = 8), and treatment-related myeloid neoplasms (n = 18) received an allogeneic HCT. Cytoreduction prior to HCT was performed in 30/62 (48%) patients; this subset of patients had higher risk disease characteristics, including a higher blast count on presentation. In the overall cohort, use of cytoreduction before HCT was associated with higher rates of relapse (cumulative incidence of relapse 24 months post HCT: 48.1% [27.5%-66.1%]) for those who received cytoreduction versus 16.6% (5.9%-32.1%) for those who did not (p = .03). There was a trend toward decreased overall survival (OS) for those patients who received cytoreduction (24 months post HCT 57.1% vs. 75.3%, respectively; p = .06). OS for patients who received cytoreduction and attained measurable residual disease (MRD) negativity prior to HCT was superior compared to those with persistent disease (24 months post HCT 63.9% [36%-81.2%] vs. 33.3% [7.8%-62.3%], respectively; p = .04). CONCLUSION: Cytoreduction did not provide survival benefit in our overall cohort, but its increased use in children with higher risk disease impacted the analysis. Patients receiving cytoreduction and achieving MRD-negative status before HCT demonstrated improved OS compared to those with persistent disease.
RESUMO
The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Neoplasias , Humanos , Anemia Aplástica/genética , Anemia Aplástica/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico , Patologistas , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/complicações , Transtornos da Insuficiência da Medula Óssea/complicações , Células Germinativas , Neoplasias/complicações , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Utilizing RNA-seq, this study compared the transcriptomic responses of three improved strains (VSel, PSel, and CSel) of rainbow trout fry during acute stages of challenge with infectious hematopoietic necrosis virus (IHNV). The VSel strain has been selected for resistance against the specific strain of IHNV used in our challenge, PSel has undergone selection for utilization of plant-protein based feeds and previously has shown elevated non-specific disease resistance despite no disease related selection pressures, and the final strain, CSel, is a commercial strain that has been domesticated for several years but has not been selected for specific viral disease resistance. Following a 21-day IHNV challenge, Kaplan-Meier survival estimator curves and cumulative percent mortality (CPM) showed significant differences in IHNV resistance across strains: VSel - 19.3 ± 5.0%, PSel - 67. ± 3.03%, CSel - 94.6 ± 4.1% CPM. To evaluate acute responses to IHNV infection, whole blood, as well as samples from the kidney, liver, and intestine, were collected at 0, 4, 12, 24, and 48 h post infection (hpi). Serum lysozyme activity, a marker of non-specific innate immunity, showed strain and temporal effects during the acute infection phase with PSel showing the highest activity at 0 and 48 hpi. Differential gene expression responses were detected, with varying degrees, in all tissues, both between strains, as well as across acute timepoints within strains. The VSel strain showed upregulation for a particular subset of viral recognition genes during early infection timepoints and rather limited upregulation of immune genes later, while maintaining and reactivating metabolic pathways. The CSel strain showed a downregulation of metabolic related genes and a limited upregulation of immune genes, while the PSel strain showed similar downregulation of metabolic genes during acute infection, yet when compared to the CSel strain, showed a more robust innate immune response. Evaluation of upregulated immune response genes, as well as interferon-related genes showed the PSel strain to have the greatest number of uniquely upregulated immune genes in both the kidney and intestine, with CSel and PSel showing a similar number of such genes upregulated in liver. A moderate number of immune response genes were shared between PSel and CSel in all tissues, though both PSel and VSel showed a high number of uniquely overexpressed immune response genes in the kidney, and PSel showed the highest number of uniquely upregulated interferon related genes in the intestine. Overall, the VSel response was unique from the CSel with very little overlap in activated immune responses. Findings from this study highlight the disparity in IHNV resistance among genetic strains of rainbow trout, while identifying molecular mechanisms underlying differences in disease phenotypes. Furthermore, our results on trout strains with distinct selection backgrounds yields comparative insights into the adaptive gains brought about by selection programs for pathogen-specific disease resistance, as well as the non-specific immune enhancement associated with selection for utilization of plant-based diets.
Assuntos
Doenças dos Peixes , Vírus da Necrose Hematopoética Infecciosa , Oncorhynchus mykiss , Infecções por Rhabdoviridae , Animais , Resistência à Doença/genética , Vírus da Necrose Hematopoética Infecciosa/fisiologia , InterferonsRESUMO
Squamous cell carcinoma (SqCC) is the most common malignancy of the anal canal, where it is strongly associated with HPV infection. Characteristic genomic alterations have been identified in anal SqCC, but their clinical significance and correlation with HPV status, pathologic features, and immunohistochemical markers are not well established. We examined the molecular and clinicopathologic features of 96 HPV-positive and 20 HPV-negative anal SqCC. HPV types included 89 with HPV16, 2 combined HPV16/HPV18, and 5 HPV33. HPV-positive cases demonstrated frequent mutations or amplifications in PIK3CA (30%; p = 0.027) or FBXW7 mutations (10%). HPV-negativity was associated with frequent TP53 (53%; p = 0.00001) and CDKN2A (21%; p = 0.0045) mutations. P16 immunohistochemistry was positive in all HPV-positive cases and 3/20 HPV-negative cases (p < 0.0001; sensitivity: 100%; specificity: 85%) and was associated with basaloid morphology (p = 0.0031). Aberrant p53 immunohistochemical staining was 100% sensitive and specific for TP53 mutation (p < 0.0001). By the Kaplan-Meier method, HPV-negativity, aberrant p53 staining, and TP53 mutation were associated with inferior overall survival (OS) (p < 0.0001, p = 0.0103, p = 0.0103, respectively) and inferior recurrence-free survival (p = 0.133, p = 0.0064, and p = 0.0064, respectively). TP53/p53 status stratified survival probability by HPV status (p = 0.013), with HPV-negative/aberrant p53 staining associated with the worst OS, HPV-positive/wild-type p53 with best OS, and HPV-positive/aberrant p53 or HPV-negative/wild-type p53 with intermediate OS. On multivariate analysis HPV status (p = 0.0063), patient age (p = 0.0054), T stage (p = 0.039), and lymph node involvement (p = 0.044) were independently associated with OS. PD-L1 expression (CPS ≥ 1) was seen in 30% of HPV-positive and 40% of HPV-negative cases, and PD-L1 positivity was associated with a trend toward inferior OS within the HPV-negative group (p = 0.064). Our findings suggest that anal SqCC can be subclassified into clinically, pathologically, and molecularly distinct groups based on HPV and TP53 mutation status, and p16 and p53 immunohistochemistry represent a clinically useful method of predicting these prognostic groups.
Assuntos
Neoplasias do Ânus/genética , Carcinoma de Células Escamosas/genética , Mutação , Infecções por Papillomavirus/genética , Proteína Supressora de Tumor p53/genética , Adulto , Neoplasias do Ânus/patologia , Neoplasias do Ânus/virologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Análise Mutacional de DNA/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , PrognósticoRESUMO
Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p < 0.0001), KMT2D (1% vs. 16%, p < 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p < 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment.
Assuntos
Enzima Desubiquitinante CYLD/genética , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Adenoide Cístico/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Acute myeloid leukemia (AML) is a stem cell malignancy that originates in the bone marrow and involves the peripheral blood. Extramedullary AML is rarer, but it is most commonly associated with the former French-American-British (FAB) subtypes M4 or M5 of AML. AML cells may also home to the central nervous system and other solid organs such as cortical bone and skin. Such target sites of metastasis depend on microenvironmental niche interactions, which have not been fully elucidated to date. Visceral organs usually do not represent a favorable niche for AML stem cell occupancy. Herein, we describe the case of an 80-year-old man with extramedullary AML involvement of the renal pelvis. Hypercalcemia and obstructive uropathy were presenting features. The visceral niche is a rare site of involvement of myeloid malignancy, and hypercalcemia may reflect a mechanism of extramedullary involvement. We propose a treatment paradigm for this uncommon subset of AML based on advanced age and complex karyotype.
Assuntos
Pelve Renal/patologia , Leucemia Mieloide Aguda/diagnóstico , Abdome/diagnóstico por imagem , Idoso de 80 Anos ou mais , Humanos , Pelve Renal/diagnóstico por imagem , Terapia a Laser , Leucemia Mieloide Aguda/cirurgia , Masculino , Tomografia Computadorizada por Raios XRESUMO
Paired box protein 8 (PAX8) is a transcription factor that is considered a relatively specific marker of carcinomas of the thyroid, kidney, and Müllerian/Wolffian duct derivatives. Unexpected PAX8 immunoreactivity has occasionally been reported in other tumors. The frequency of PAX8 expression in carcinomas of the biliary tract is not well studied. We evaluated the immunohistochemical expression of PAX8 in 73 cases of biliary tract carcinoma. We found that 28 of 73 (38%) biliary tract carcinomas had variable immunoreactivity for PAX8, assessed by a widely used polyclonal antibody (ProteinTech Group, Chicago, IL). This included 3 (4%) of cases with strong diffuse, and 14 (19%) of cases with strong focal staining. Strong PAX8 expression was more frequent in distal bile duct carcinomas than other biliary sites (p = 0.015), and showed a weak association with advanced T stage (T3-T4 versus T1-T2; p = 0.09). No correlation was observed between PAX8 positivity and age at diagnosis, gender, or lymph node metastasis. The 28 polyclonal PAX8-positive cases were largely negative for monoclonal PAX8 and PAX6 immunostains, with only rare tumor cells with weak immunoreactivity being present in a subset of cases. We show that a substantial fraction of biliary tract carcinomas exhibit immunoreactivity with a widely used polyclonal PAX8 antibody. Pathologists should be aware of this potential pitfall during the diagnostic workup of hepatobiliary lesions to avoid misdiagnosis as a metastasis from a PAX8-positive tumor.
Assuntos
Sistema Biliar/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Fator de Transcrição PAX8/metabolismo , Coloração e Rotulagem/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/secundário , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Estadiamento de Neoplasias/métodos , Patologistas/educação , Neoplasias Pélvicas/secundário , Estudos Retrospectivos , Coloração e Rotulagem/métodosRESUMO
Anal squamous cell carcinoma (SqCC) is a morphologically heterogeneous entity. Basaloid and non-keratinizing anal SqCC may be confused with other tumors including neuroendocrine carcinoma due to morphologic overlap, and expression of neuroendocrine markers is not well-studied in anal SqCC. Prompted by a case of anal SqCC that was initially misdiagnosed as neuroendocrine carcinoma on the basis of morphology and CD56 expression, we retrospectively examined the expression of neuroendocrine markers CD56, synaptophysin, and chromogranin in 48 cases of basaloid anal SqCC, with clinicopathologic correlation. HPV16 was identified in 46 cases, HPV33 in one case, and one case was HPV-negative. Three (6.3%) cases demonstrated CD56 expression, including two with diffuse and one with focal expression. Two CD56-positive cases demonstrated basaloid morphology with peripheral palisading and the other demonstrated adenoid cystic/cylindroma-like morphology. None of the cases showed significant synaptophysin or chromogranin expression. The three cases expressing CD56 were HPV16-positive, and one demonstrated a CTNNB1 mutation. There was no difference in clinicopathologic features including stage, outcome, or HPV status, between CD56-positive and negative groups. Our findings support that CD56 expression is infrequently expressed in anal SqCC and is not indicative of neuroendocrine differentiation in the absence of expression of more specific neuroendocrine markers such as synaptophysin and chromogranin. Pathologists should be aware that CD56 expression may occur in basaloid anal SqCC and is a diagnostic pitfall due to morphologic overlap with neuroendocrine carcinoma and other tumors including basal cell carcinoma.
Assuntos
Canal Anal/patologia , Antígeno CD56/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Escamosas/patologia , Cromograninas/metabolismo , Erros de Diagnóstico/prevenção & controle , Erros de Diagnóstico/estatística & dados numéricos , Feminino , Seguimentos , Papillomavirus Humano 16/isolamento & purificação , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias/métodos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Estudos Retrospectivos , Sinaptofisina/metabolismo , beta Catenina/genéticaRESUMO
A novel third channel catfish growth hormone secretagogue (ghrelin) receptor, GHS-R3a, gene was characterized. Identification and analysis of the genomic organization of channel catfish GHS-R3a revealed differences in exon/intron structure relative to the previously published GHS-R1a and GHS-R2a sequences. Amino acid sequence alignment of catfish GHS-R3a with -R1a and -R2a revealed 48 and 52% sequence identity, respectively. Phylogenetic analysis predicted a new clade of GHS-R3a receptors found only in fish, with representation in the teleost infradivisions Osteoglossomorpha, Clupeomorpha, and Euteleostei. In functional analyses, homologous catfish ghrelin increased intracellular Ca2+ concentration in human embryonic kidney (HEK) 293 cells stably expressing catfish GHS-R3a. On the contrary, intracellular Ca2+ concentration was unaffected by treatment with the synthetic growth hormone secretagogues GHRP-6 and hexarelin. Realtime PCR results indicated high expression of GHS-R3a in the brain and gonads, demonstrating tissue specificity among the catfish GHS-Rs. The effects of fasting and refeeding on all three ghrelin receptors were evaluated in catfish brain, pituitary, stomach, and Brockmann bodies. Most notably, GHS-R3a was the only receptor observed to significantly increase (2.9-6.3-fold) in brain, pituitary, and stomach within 4â¯days of fasting (Pâ¯<â¯.05). Stomach GHS-R1a also increased (Pâ¯<â¯.05) after 4â¯days; however, GHS-R2a was only elevated in brain and pituitary after refeeding for 1â¯week. Expression of all three ghrelin receptors were elevated (Pâ¯<â¯.05) in the Brockmann bodies after 2â¯weeks of fasting and returned to prefasting levels following refeeding. Together with the previously published characterization of GHS-R1a and -R2a, these results establish three ghrelin receptors, each altered by energy state, in channel catfish and add to the growing body of information on GHS-R evolution and function.
Assuntos
Proteínas de Peixes/metabolismo , Ictaluridae/metabolismo , Receptores de Grelina/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar/genética , Relação Dose-Resposta a Droga , Jejum , Células HEK293 , Homeostase , Humanos , Ligantes , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , RNA Mensageiro/genética , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/genética , Homologia de Sequência de AminoácidosRESUMO
Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P=0.006) and female (P=0.035), with tumors exhibiting a larger size (P=0.013), but lower stage (P<0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (P<0.001 for each), and a lower frequency of KRAS mutation (P=0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma.
Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas B-raf/genética , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Modelos Logísticos , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Fatores de Risco , Linfócitos T Citotóxicos/patologia , Carga Tumoral , Evasão Tumoral , Microambiente Tumoral , Adulto JovemAssuntos
Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina , Linfoma Difuso de Grandes Células B/genética , Idoso , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Progressão da Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Difuso de Grandes Células B/patologiaRESUMO
Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) that shows overlap with classical Hodgkin lymphoma (CHL) and a favorable prognosis compared to mediastinal gray-zone lymphoma (MGZL). We performed immunohistochemistry on initial diagnostic specimens of 49 cases of uniformly treated PMBL to determine the frequency and clinical significance of expression of antigens commonly seen in CHL and MGZL, along with markers previously shown to be prognostic in DLBCL, not otherwise specified. The median age was 37 years with a female:male ratio of 2.3. After a median follow-up of 78 months, 24% of patients had relapsed or refractory disease and 22% had died; the 5-year PFS was 70%. Variable CD15 expression was seen in 31% of cases, but was not associated with adverse outcome. Hans cell-of-origin, proliferation index, and MYC/BCL2 coexpression were not associated with outcome, while low PDL1 (P = 0.011) and high MUM1 (P = 0.065) staining were each associated with shorter PFS. A biologic risk score (one point each for low PDL1 and high MUM1) stratified patients into three prognostic risk groups for PFS (P = 0.001) and OS (P = 0.032). On separate multivariate models, low PDL1 was independent of R-IPI risk group for PFS (HR 6.0, P = 0.023), as was a biologic risk score of 2 (HR 5.6, P = 0.011). Incorporation of the biologic risk score sub-stratified patients within R-IPI groups for both PFS (P < 0.001) and OS (P < 0.001). In summary, we characterize the immunophenotypic spectrum of PMBL and identify PDL1 and MUM1 as prognostic biomarkers for high-risk disease. Am. J. Hematol. 91:E436-E441, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Antígeno B7-H1/análise , Imunofenotipagem , Fatores Reguladores de Interferon/análise , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Feminino , Doença de Hodgkin/patologia , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/imunologia , Neoplasias do Mediastino/mortalidade , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Observations from the present study provide the first characterization of the GH-IGF axis in Shovelnose sturgeon Scaphirhynchus platorhynchus, an ancestral fish species. An initial characterization of steady-state IGF-I and IGF-II gene expression in multiple tissues was conducted using real-time RT-qPCR. Overall, the tissues had significantly different profiles of IGF-I gene expression, with the highest IGF-I expression observed in the liver. The highest IGF-II gene expression was also observed in the liver, with minimal or no detection in muscle. A comparison between IGF-I and IGF-II expression within individual tissues revealed higher levels of IGF-II than IGF-I mRNA in the spleen, stomach and trunk kidney, and higher levels of relative IGF-I mRNA expression in the intestine and muscle. The GH-IGF axis was further elucidated by observing the effects of exogenous GH on IGF-I and IGF-II expression in liver and muscle tissue. The results revealed a significant dose-dependent response of both hepatic IGF-I and IGF-II, and muscle IGF-I mRNA expression following rbGH administration. At the highest rbGH concentration (240µg/g BW), IGF-I mRNA levels in liver and muscle peaked significantly at 48h, indicating both hepatic and muscle IGF-I expression to be stimulated by GH. Hepatic IGF-II expression was also stimulated 48h following rbGH administration. Expression of IGF-II mRNA was not inducible in the muscle. Few studies have evaluated the effects of exogenous GH on IGF expression in ancestral vertebrate species, and as such, this research provides valuable insight into the evolution of the somatotropic axis in vertebrates.
Assuntos
Proteínas de Peixes/genética , Peixes/genética , Perfilação da Expressão Gênica/métodos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like I/genética , Animais , Relação Dose-Resposta a Droga , Hormônio do Crescimento/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genéticaRESUMO
Amyloidosis is extremely rare, with an estimated 2225 new US cases reported annually. Signs and symptoms of the disease are subtle and imaging findings are not pathognomonic. Currently, diagnosis requires biopsy to demonstrate the deposition of amyloid. Elastography is a new imaging modality that evaluates tissue elasticity. It has shown to have efficacy in characterizing thyroid nodules, detecting prostate cancer, and staging liver fibrosis. We present a case of hepatic amyloidosis in a 51-year-old male that demonstrates significantly increased stiffness with a median value of 99.1 kPa (range 25.7-188.9 kPa) on shear-wave elastography (SWE) imaging, which is significantly higher than the cut-off range reported for cirrhosis on SWE (10.4-11.5 kPa). This finding raises the possibility that elastographic imaging may be sensitive to tissue mechanical changes induced by amyloid deposition.