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BACKGROUND & AIMS: Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and its relationship to AIH. Therefore, we compared VILI with AIH. METHODS: Formalin-fixed and paraffin-embedded liver biopsy samples from patients with VILI (n = 6) and from patients with an initial diagnosis of AIH (n = 9) were included. Both cohorts were compared by histomorphological evaluation, whole-transcriptome and spatial transcriptome sequencing, multiplex immunofluorescence, and immune repertoire sequencing. RESULTS: Histomorphology was similar in both cohorts but showed more pronounced centrilobular necrosis in VILI. Gene expression profiling showed that mitochondrial metabolism and oxidative stress-related pathways were more and interferon response pathways were less enriched in VILI. Multiplex analysis revealed that inflammation in VILI was dominated by CD8+ effector T cells, similar to drug-induced autoimmune-like hepatitis. In contrast, AIH showed a dominance of CD4+ effector T cells and CD79a+ B and plasma cells. T-cell receptor (TCR) and B-cell receptor sequencing showed that T and B cell clones were more dominant in VILI than in AIH. In addition, many T cell clones detected in the liver were also found in the blood. Interestingly, analysis of TCR beta chain and Ig heavy chain variable-joining gene usage further showed that TRBV6-1, TRBV5-1, TRBV7-6, and IgHV1-24 genes are used differently in VILI than in AIH. CONCLUSIONS: Our analyses support that SARS-CoV-2 VILI is related to AIH but also shows distinct differences from AIH in histomorphology, pathway activation, cellular immune infiltrates, and TCR usage. Therefore, VILI may be a separate entity, which is distinct from AIH and more closely related to drug-induced autoimmune-like hepatitis. IMPACT AND IMPLICATIONS: Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI). Our analysis shows that COVID-19 VILI shares some similarities with autoimmune hepatitis, but also has distinct differences such as increased activation of metabolic pathways, a more prominent CD8+ T cell infiltrate, and an oligoclonal T and B cell response. Our findings suggest that VILI is a distinct disease entity. Therefore, there is a good chance that many patients with COVID-19 VILI will recover completely and will not develop long-term autoimmune hepatitis.
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COVID-19 , Doença Hepática Crônica Induzida por Substâncias e Drogas , Hepatite Autoimune , Humanos , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , COVID-19/prevenção & controle , Fígado/patologia , Receptores de Antígenos de Linfócitos T , VacinaçãoRESUMO
BACKGROUND: Hepatocellular adenoma (HCA) is a rare liver tumour, which can have atypical morphological features such as cytological atypia, pseudoglandular architecture, and altered reticulin framework. Little is known about the genetic and epigenetic alterations of such HCAs and whether they show the alterations classically found in hepatocellular carcinoma (HCC) or in HCA without atypical morphology. METHODS: We analysed five HCAs with atypical morphological features and one HCA with transition to HCC. Every tumour was subtyped by immunohistochemistry, sequenced by a targeted NGS panel, and analysed on a DNA methylation microarray. RESULTS: Subtyping of the five HCAs with atypical features revealed two ß-catenin mutated HCA (b-HCA), two ß-catenin mutated inflammatory HCA (b-IHCA), and one sonic hedgehog activated HCA (shHCA). None of them showed mutations typically found in HCC, such as, e.g. TERT or TP53 mutations. The epigenomic pattern of HCAs with atypical morphological features clustered with reference data for HCAs without atypical morphological features but not with HCC. Similarly, phyloepigenetic trees using the DNA methylation data reproducibly showed that HCAs with morphological atypia are much more similar to nonmalignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV). CONCLUSION: In our series, mutational, DNA methylation, as well as CNV analyses, supported a relationship of atypical HCAs with nonatypical HCAs rather than with HCC. Therefore, in cases with difficult differential diagnosis between HCC and HCA, it might be advisable to perform targeted sequencing and/or combined methylation/copy number profiling.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , beta Catenina/genética , Variações do Número de Cópias de DNA , Proteínas Hedgehog , Epigênese GenéticaRESUMO
BACKGROUND & AIM: The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA. METHODS: We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA. RESULTS: 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed. CONCLUSIONS: In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.
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Fosfatase Alcalina/sangue , Autoanticorpos/sangue , Colangite/tratamento farmacológico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Idoso , Fosfatase Alcalina/imunologia , Fosfatase Alcalina/metabolismo , Autoanticorpos/imunologia , Colangite/imunologia , Colangite/metabolismo , Estudos de Coortes , Feminino , Humanos , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/metabolismo , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prognóstico , Resultado do Tratamento , Ácido Ursodesoxicólico/imunologia , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/imunologia , gama-Glutamiltransferase/metabolismoRESUMO
Pilocytic astrocytoma is a WHO grade I tumor usually diagnosed in pediatric patients, and rarely encountered in the adult population. Therefore, available information about the magnetic resonance imaging characteristics of adult pilocytic astrocytoma is scarce. We report on the MRI features and corresponding histopathologic findings of six consecutive aPA cases diagnosed. The tumors were encountered in both infra- and supratentorial compartments, and their MRI characteristics were quite heterogeneous. Features included the typical solid-cystic appearance located in the cerebellum as well as the relatively unusual multifocal and/or hemorrhagic features located intra-ventricularly. The aPA MRI characteristics are remarkably variable, and might mimic those of higher grade tumors in adult patients.
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Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Adulto , Idoso , Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1+ tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version].
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Imunomodulação/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Microambiente TumoralRESUMO
BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is normally detectable in embryonic tissues and absent in adult tissues. ROR1 was shown to inhibit apoptosis, potentiate EGFR signaling and reported to be overexpressed and associated with poor prognosis in several tumor models. This study aimed to assess the expression of ROR1 in lung adenocarcinoma (AC) patients. METHODS: We analyzed ROR1 expression by quantitative real-time PCR (qRT-PCR) in 56 histologically confirmed lung AC, stage I to IV, in addition we evaluated its association with TTF-1 (thyroid transcription factor-1) expression and the main molecular alterations involved in lung cancerogenesis. RESULTS: ROR1 overexpression was observed in 28.6% of the entire cohort, using a cut-off of 1, or in 51.8% of the cases using the median value as threshold. Among patients without any genetic alteration, ROR1 overexpression was observed in 34.8% considering a cut-off of 1 and 52.2% considering the median value. The distribution of ROR1 was homogeneous among the different molecular categories: we found no association of ROR1 expression and the presence of gene mutations/rearrangements or the expression of TTF-1. CONCLUSIONS: ROR1 overexpression could constitute a potential therapeutic target because altered in a consistent number of lung AC, especially in cases without druggable genetic alterations. ROR1 expression is independent of classical lung cancer molecular alterations and not correlated, in a Caucasian cohort, to TTF-1 expression.
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Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Neoplasias Pulmonares/patologia , Mutação , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Taxa de Sobrevida , Adulto JovemRESUMO
An amendment to this paper has been published and can be accessed via the original article.
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PURPOSE: The aim of this study is to analyse the results of revision surgery for failed adult spinal deformity patients and to describe the surgical strategy selection process, based on the identification of the main clinical diagnosis responsible for failure. METHODS: We retrospectively reviewed the clinical and radiological data of 77 consecutive patients treated in a 3-year time (2016-2019) for surgical revision of long fusion (more than five levels fused) for adult spinal deformity in a high-volume spine centre, divided into four groups based on the diagnosis: rod breakage (RB) group, proximal junctional failure (PJF) group, distal junctional failure (DJF) group and loss of correction (LOC) group with symptomatic sagittal or coronal malalignment (including iatrogenic flatback). RESULTS: Seventy-seven patients met our inclusion criteria, with a female prevalence (66 F vs. 11 M). The mean age at revision surgery was 63. Fused levels before surgery were averagely 12, and revision added averagely two levels to the preexisting fusion area. Clinical status was apparently improved in ODI scores and VAS scores, while it was slightly worsened in SF36 scores. Different diagnosis groups have been addressed with different surgical strategies, according to the different surgical goals: interbody cages and multi-rod construct to improve stiffness and favour bony fusion, "kickstand" rod and "tie" rod to correct coronal and sagittal malalignment, specific rod contouring and proximal hooks in "claw" configuration to reduce mechanical stress at the proximal junctional area. Intraoperative complications occurred in 18% of patients and perioperative complications in 39%. CONCLUSION: Revision surgery in long fusions for adult spinal deformity is a challenging field. Surgical strategy should always be planned carefully. A successful treatment is a direct consequence of a correct preoperative diagnosis, and surgery should address the primary cause of failure. All the above-mentioned surgical techniques and clinical skills should be part of surgeon's expertise when managing these patients. These slides can be retrieved under Electronic Supplementary Material.
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Reoperação , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/efeitos adversos , Coluna Vertebral/cirurgia , Feminino , Humanos , Complicações Intraoperatórias , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Falha de TratamentoRESUMO
Programmed cell death ligand-1 immunohistochemical detection (PD-L1 IHC) is a putative predictor of response to PD-1/PD-L1-targeted checkpoint inhibitors. However, there is no gold standard assay in hepatocellular carcinoma (HCC). We evaluated 5 PD-L1 IHC assay platforms (E1LN3, 28-8, 22c3, SP263 and SP142) in 100 HCCs reporting PD-L1 expression in malignant (M) and tumour-infiltrating immune cells (TICs) and non-tumorous cirrhotic tissues (NTICs). We found substantial inter-assay heterogeneity in detecting PD-L1 expression in M (R2 = 0.080-0.921), TICs (Cohen's κ = 0.175-0.396) and NTICs (κ = 0.004-0.505). Such diversity may impact on the reliability and reproducibility of PD-L1 IHC assays as a predictor of response to immune checkpoint inhibitors.
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Antígeno B7-H1/análise , Carcinoma Hepatocelular/química , Neoplasias Hepáticas/química , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/químicaRESUMO
Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3'UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.
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Regulação Neoplásica da Expressão Gênica , Melanoma/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Neoplasias Cutâneas/genética , Regiões 3' não Traduzidas , Antineoplásicos/uso terapêutico , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , MicroRNAs/metabolismo , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Sulfonamidas/uso terapêutico , Análise de Sobrevida , VemurafenibRESUMO
BACKGROUND: Quality of cancer care (QoCC) has become an important item for providers, regulators and purchasers of care worldwide. Aim of this study is to present the results of some evidence-based quality indicators (QI) for prostate cancer (PC) at the population-based level and to compare the outcomes with data available in the literature. METHODS: The study included all PC diagnosed on a three years period analysis (01.01.2011-31.12.2013) in the population of Canton Ticino (Southern Switzerland) extracted from the Ticino Cancer Registry database. 13 QI, approved through the validated Delphi methodology, were calculated using the "available case" approach: 2 for diagnosis, 4 for pathology, 6 for treatment and 1 for outcome. The selection of the computed QI was based on the availability of medical documentation. QI are presented as proportion (%) with the corresponding 95% confidence interval. RESULTS: 700 PC were detected during the three-year period 2011-2013: 78.3% of them were diagnosed through a prostatic biopsy and for 72.5% 8 or more biopsy cores were taken. 46.5% of the low risk PC patients underwent active surveillance, while 69.2% of high risk PC underwent a radical treatment (radical prostatectomy, radiotherapy or brachytherapy) and 73.5% of patients with metastatic PC were treated with hormonal therapy. The overall 30-day postoperative mortality was 0.5%. CONCLUSIONS: Results emerging from this study on the QoCC for PC in Canton Ticino are encouraging: the choice of treatment modalities seems to respect the international guidelines and our results are comparable to the scarce number of available international studies. Additional national and international standardisation of the QI and further QI population-based studies are needed in order to get a real picture of the PC diagnostic-therapeutic process progress through the definition of thresholds of minimal standard of care.
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Neoplasias da Próstata/terapia , Indicadores de Qualidade em Assistência à Saúde , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Neoplasias da Próstata/mortalidade , Qualidade da Assistência à Saúde , SuíçaRESUMO
MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression.
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Biomarcadores Tumorais/genética , Cromossomos Humanos Par 8 , Rearranjo Gênico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-myc/análise , Espanha , SuíçaRESUMO
Several studies performed over the last decade have focused on the role of sialylation in the progression of cancer and, in particular, on the association between deregulation of sialidases and tumorigenic transformation. The plasma membrane-associated sialidase NEU3 is often deregulated in colorectal cancer (CRC), and it was shown that this enzyme co-immunoprecipitates in HeLa cells with epidermal growth factor receptor (EGFR), the molecular target of most recent monoclonal antibody-based therapies against CRC. To investigate the role of NEU3 sialidase on EGFR deregulation in CRC, we first collected data on NEU3 gene expression levels from a library of commercial colon cell lines, demonstrating that NEU3 transcription is upregulated in these cell lines. We also found EGFR to be hyperphosphorylated in all cell lines, with the exception of SW620 cells and the CCD841 normal intestinal cell line. By comparing the effects induced by overexpression of either the wild-type or the inactive mutant form of NEU3 on EGFR, we demonstrated that the active form of NEU3 enhanced receptor activation without affecting EGFR mRNA or protein expression. Moreover, through western blots and mass spectrometry analysis, we found that EGFR immunoprecipitated from cells overexpressing active NEU3, unlike the receptor from mock cells and cells overexpressing inactive NEU3, is desialylated. On the whole, our data demonstrate that, besides the already reported indirect EGFR activation through GM3, sialidase NEU3 could also play a role on EGFR activation through its desialylation.
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Células Epiteliais/metabolismo , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neuraminidase/genética , Processamento de Proteína Pós-Traducional , Linhagem Celular Tumoral , Membrana Celular , Colo/metabolismo , Colo/patologia , Células Epiteliais/patologia , Receptores ErbB/metabolismo , Gangliosídeo G(M3)/metabolismo , Humanos , Modelos Moleculares , Proteínas de Neoplasias/metabolismo , Neuraminidase/metabolismo , Fosforilação , Ácidos Siálicos/metabolismo , Transdução de Sinais , Transcrição GênicaRESUMO
BACKGROUND: The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. METHODS: Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. RESULTS: A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. CONCLUSION: Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy.
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Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/terapia , Neoplasias das Glândulas Salivares/mortalidade , Neoplasias das Glândulas Salivares/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Rituximab/uso terapêutico , Neoplasias das Glândulas Salivares/patologia , Síndrome de Sjogren/complicações , Resultado do Tratamento , Adulto JovemRESUMO
HER2 is a well-recognized mediator of the cancerogenic process. It is dysregulated in a wide range of solid tumors, mainly via protein overexpression and/or gene amplification, thus making HER2 an attractive target for tailored treatment. The anti-HER2 therapy trastuzumab was approved for the treatment of HER2-positive metastatic breast cancer patients more than 10 years ago. Since then, trastuzumab and other HER2-inhibitors have been entered into clinical practice for the treatment of breast cancer and, more recently, have been approved to treat HER2-positive metastatic gastric cancers. Currently, HER2-targeted therapies are under evaluation in other tumor types. Due to the relevance of proper patient selection, the accurate assessment of HER2 status is fundamental. This review will discuss the established knowledge and novel insights into the HER2 story, mainly focusing on breast, gastric and colorectal cancers, as well as providing a brief overview of salivary gland, bladder, ovarian and lung tumors.
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Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genéticaRESUMO
Glioblastoma multiforme (GBM) is usually treated with surgery followed by adjuvant partial radiotherapy combined with temozolomide (TMZ) chemotherapy. Recent studies demonstrated a better survival and good response to TMZ in methylguanine-DNA methyltransferase (MGMT)-methylated GBM cases. However, approximately 20% of patients with MGMT-unmethylated GBM display an unexpectedly favorable outcome. Therefore, additional mechanisms related to the TMZ response need to be investigated. As such, we decided to investigate the clinical relevance of six miRNAs involved in brain tumorigenesis (miR-181c, miR-181d, miR-21, miR-195, miR-196b, miR-648) as additional markers of response and survival in patients receiving TMZ for GBM. We evaluated miRNA expression and the interplay between miRNAs in 112 IDH wt GBMs by applying commercial assays. Then, we correlated the miRNA expression with patients' clinical outcomes. Upon bivariate analyses, we found a significant association between the expression levels of the miRNAs analyzed, but, more interestingly, the OS curves show that the combination of low miR-648 and miR-181c or miR-181d expressions is associated with a worse prognosis than cases with other low-expression miRNA pairs. To conclude, we found how specific miRNA pairs can influence survival in GBM cases treated with TMZ.
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Glioblastoma , MicroRNAs , Humanos , Glioblastoma/metabolismo , MicroRNAs/metabolismo , Dacarbazina/uso terapêutico , Relevância Clínica , Temozolomida/farmacologia , Temozolomida/uso terapêuticoRESUMO
Integration of digital pathology (DP) into clinical diagnostic workflows is increasingly receiving attention as new hardware and software become available. To facilitate the adoption of DP, the Swiss Digital Pathology Consortium (SDiPath) organized a Delphi process to produce a series of recommendations for DP integration within Swiss clinical environments. This process saw the creation of 4 working groups, focusing on the various components of a DP system (1) scanners, quality assurance and validation of scans, (2) integration of Whole Slide Image (WSI)-scanners and DP systems into the Pathology Laboratory Information System, (3) digital workflow-compliance with general quality guidelines, and (4) image analysis (IA)/artificial intelligence (AI), with topic experts for each recruited for discussion and statement generation. The work product of the Delphi process is 83 consensus statements presented here, forming the basis for "SDiPath Recommendations for Digital Pathology". They represent an up-to-date resource for national and international hospitals, researchers, device manufacturers, algorithm developers, and all supporting fields, with the intent of providing expectations and best practices to help ensure safe and efficient DP usage.
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Técnica Delphi , Humanos , Suíça , Inteligência Artificial , Patologia Clínica/métodos , Patologia Clínica/normas , Consenso , Fluxo de Trabalho , Interpretação de Imagem Assistida por Computador/métodos , Sociedades MédicasRESUMO
Glioblastoma multiforme (GBM) remains one of the tumors with the worst prognosis. In recent years, a better overall survival (OS) has been described in cases subjected to Gross Total Resection (GTR) that were presenting hypermethylation of Methylguanine-DNA methyltransferase (MGMT) promoter. Recently, also the expression of specific miRNAs involved in MGMT silencing has been related to survival. In this study, we evaluate MGMT expression by immunohistochemistry (IHC), MGMT promoter methylation and miRNA expression in 112 GBMs and correlate the data to patients' clinical outcomes. Statistical analyses demonstrate a significant association between positive MGMT IHC and the expression of miR-181c, miR-195, miR-648 and miR-767.3p between unmethylated cases and the low expression of miR-181d and miR-648 and between methylated cases and the low expression of miR-196b. Addressing the concerns of clinical associations, a better OS has been described in presence of negative MGMT IHC, in methylated patients and in the cases with miR-21, miR-196b overexpression or miR-767.3 downregulation. In addition, a better progression-free survival (PFS) is associated with MGMT methylation and GTR but not with MGMT IHC and miRNA expression. In conclusion, our data reinforce the clinical relevance of miRNA expression as an additional marker to predict efficacy of chemoradiation in GBM.
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PURPOSE: Dedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases. PATIENTS AND METHODS: A retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out. RESULTS: Most patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome. CONCLUSIONS: Our study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications.
Assuntos
Melanoma , Sarcoma , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Humanos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Melanoma/patologia , Estudos Retrospectivos , Sarcoma/diagnósticoRESUMO
Histological transformation (HT) into diffuse large B-cell lymphoma (DLBCL) was documented in 37 of the 281 (13%; 95% CI, 9-18) follicular lymphoma (FL) patients treated at our institute from 1979 to 2007. HT occurred at a median of 2·75 years from initial FL diagnosis and HT rate was 15% at 10 years and 26% at 14 years, with a plateau from that point onward. Patients with bulky or extranodal disease, or those diagnosed before 1990 had a significantly higher risk of HT. When initial treatment strategies were taken into account, a reduced HT risk was seen in the patients initially managed with a 'watch and wait' policy, while the risk appeared significantly increased in the small subset of 18 patients initially managed with rituximab plus chemotherapy (P = 0·0005). HT was associated with a significantly shorter cause-specific survival (P = 0·0002). Predictors of survival after HT were the Follicular Lymphoma International Prognostic Index at diagnosis, as well as age and performance status at the time of HT. Our data confirm the adverse clinical outcome of FL after HT. In keeping with previous isolated reports, our findings suggest that there is a subgroup of patients in whom HT may not occur.