Mammary myofibroblastoma: a clinicopathological analysis of fifteen cases / 中华病理学杂志

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of breast myofibroblastoma. Methods: The clinicopathological data and prognostic information of 15 patients with breast myofibroblastoma diagnosed at the Department of Pathology of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China from 2014 to 2022 were collected. Their clinical characteristics, histological subtypes, immunophenotypes and molecular characteristics were analyzed. Results: There were 12 female and 3 male patients, ranging in age from 18 to 78 years, with a median and average age of 52 years. There were 6 cases in the left breast and 9 cases in the right breast, including 12 cases in outer upper quadrant, 2 cases in inner upper quadrant and 1 case in outer lower quadrant. Most of the cases showed a well-defined nodule grossly, including pushing growth under the microscope in 13 cases, being completely separated from the surrounding breast tissue in 1 case, and infiltrating growth in 1 case. Among them, 12 cases were classic subtype and composed of occasional spindle cells with varying intervals of collagen fiber bundles; eight cases had a small amount of fat; one case had focal cartilage differentiation; one case was epithelioid subtype, in which epithelioid tumor cells were scattered in single filing or small clusters; one case was schwannoma-like subtype, and the tumor cells were arranged in a significant palisade shape, resembling schwannoma, and one case was invasive leiomyoma-like subtype, in which the tumor cells had eosinophilic cytoplasm and were arranged in bundles, and infiltrating into the surrounding mammary lobules like leiomyoma. Immunohistochemical studies showed that the tumor cells expressed desmin (14/15) and CD34 (14/15), as well as ER (15/15) and PR (15/15). Three cases with histologic subtypes of epithelioid subtype, schwannoma-like subtype and infiltrating leiomyoma-like subtype showed RB1 negative immunohistochemistry. Then FISH was performed to detect RB1/13q14 gene deletion, and identified RB1 gene deletion in all three cases. Fifteen cases were followed up for 2-100 months, and no recurrence was noted. Conclusions: Myofibroblastoma is a rare benign mesenchymal tumor of the breast. In addition to the classic type, there are many histological variants, among which the epithelioid subtype is easily confused with invasive lobular carcinoma. The schwannoma-like subtype is similar to schwannoma, while the invasive subtype is easily misdiagnosed as fibromatosis-like or spindle cell metaplastic carcinoma. Therefore, it is important to recognize the various histological subtypes and clinicopathological features of the tumor for making correct pathological diagnosis and rational clinical treatment.

Clinicopathological features and prognosis of SMARCA4-deficient non-small cell lung carcinoma: an analysis of 127 cases / 中华病理学杂志

Objective: To investigate and elucidate the clinicopathological and prognostic characteristics of SMARCA4-deficient non-small cell lung cancer. Methods: The clinicopathological and prognostic data were collected in 127 patients with SMARCA4-deficient non-small cell lung cancer diagnosed in Shanghai Pulmonary Hospital, Shanghai, China from January 2020 to March 2022. The variation and expression of biomarkers related to treatment were retrospectively reviewed. Results: One hundred and twenty-seven patients were eligible for enrollment. Among them 120 patients (94.5%) were male and 7 cases (5.5%) were female, while the average age was 63 years (range 42-80 years). There were 41 cases (32.3%) of stage Ⅰ cancer, 23 cases (18.1%) of stage Ⅱ, 31 cases (24.4%) of stage Ⅲ and 32 cases (25.2%) of stage Ⅳ. SMARCA4 expression detected by immunohistochemistry was completely absent in 117 cases (92.1%) and partially absent in 10 cases (7.9%). PD-L1 immunohistochemical analyses were performed on 107 cases. PD-L1 was negative, weakly positive and strongly positive in 49.5% (53/107), 26.2% (28/107) and 24.3% (26/107) of the cases, respectively. Twenty-one cases showed gene alterations (21/104, 20.2%). The KRAS gene alternation (n=10) was most common. Mutant-type SMARCA4-deficient non-small cell lung cancer was more commonly detected in females, and was associated with positive lymph nodes and advanced clinical stage (P<0.01). Univariate survival analysis showed that advanced clinical stage was a poor prognosis factor, and vascular invasion was a poor predictor of progression-free survival in patients with surgical resection. Conclusions: SMARCA4-deficient non-small cell lung cancer is a rare tumor with poor prognosis, and often occurs in elderly male patients. However, SMARCA4-deficient non-small cell lung cancers with gene mutations are often seen in female patients. Vascular invasion is a prognostic factor for disease progression or recurrence in patients with resectable tumor. Early detection and access to treatment are important for improving patient survivals.

Primary cardiac angiosarcoma: a clinicopathological and molecular genetic analysis of thirteen cases / 中华病理学杂志

Objective: To investigate the clinicopathological and molecular features of primary cardiac angiosarcoma (PCAS), and to analyze the correlation between KDR mutation and the clinicopathological features of PCAS. Methods: Thirteen cases of PCAS were collected at Beijing Anzhen Hospital, Capital Medical University from January 2007 to December 2021. The clinicopathological features, diagnosis, differential diagnosis and outcome were retrospectively analyzed. KDR mutation was detected by next-generation sequencing (NGS) and then the expression of KDR (VEGFR2) was determined by immunohistochemistry (IHC), with review of relevant literatures. Results: There were eight males and five females with a mean age of 45 years. The primary tumor was in the right atrium in 10 cases, left atrium in two cases and right ventricle in one case. The histomorphology was mainly poorly differentiated angiosarcoma (11 cases), with highly pleomorphic spindle or round cells in solid sheets, brisk mitotic activity and extensive necrosis. Vascular lumen formation was observed in two cases of high to moderate differentiation, and biphenotypic differentiation was seen in five cases. IHC staining showed CD34, CD31, Fli1, ERG and vimentin were diffusely positive, pan-cytokeratin was positive, Ki-67 index ranged from 3% to 90%, which was positively correlated with the differentiation degree and grade of the PCASs (P<0.05). At the end of follow-up period, one patient was alive, two patients were lost to follow-up, and the remaining 10 patients had an average survival time of 4.6 months. Finally, NGS sequencing was performed on seven samples after screening, and the results showed that KDR and NF1 mutations were both present in three cases. VEGFR2 expression had no significant correlation with the differentiation degree and grade of PCAS (P>0.05), and it was not related to KDR mutation. Conclusions: PCASs mainly occur in the right atrium, and are mainly poorly differentiated. Ki-67 index is helpful to assess the degree and grade of tumor differentiation. The occurrence and development of PCAS may be related to the pathway involved in KDR mutation, but KDR mutation has no clear correlation with clinicopathological characteristics of PCAS, and immunohistochemical staining can not replace gene detection to determine whether the tumor had KDR mutation.

Clinicopathological analysis of primary gastric (gastrointestinal)-type mucoglandular lesion of endometrium / 中华病理学杂志

Objective: To investigate the clinical and pathological features of primary gastric (gastrointestinal)-type mucoglandular lesions of the endometrium. Methods: Eight cases of primary gastric (gastrointestinal)-type mucoglandular lesions of endometrium diagnosed between 2014 to 2022 were retrieved from pathology archives of the Obstetrics and Gynecology Hospital Affiliated to Fudan University, Shanghai, China. The clinical history, pathological sections and follow-ups were analyzed. Results: The eight patients ranged in age from 35 to 67 years, with an average age of 55.5 years. Seven patients were examined for high-risk human papillary virus (HPV) before operation. Only one of them was positive for high-risk HPV52. No cervical mucinous lesions were found in any of the patients. Two cases were invasive gastric (gastrointestinal)-type adenocarcinoma, 2 cases were benign gastric (gastrointestinal)-type mucinous metaplasia, and the other 4 cases were atypical gastric (gastrointestinal)-type mucinous gland hyperplasia. Microscopically, tumor cells showed mucous epithelium with gastrointestinal differentiation. Immunophenotyping showed that MUC6 was diffusely or focally positive in 5 cases, CK20 and CDX2 were positive in 3 cases. And p16 was negative or focally positive in 5 cases and strongly positive in 1 case. ER was expressed in both benign and atypical lesions, and weakly positive or negative in the invasive adenocarcinoma. p53 showed mutant expression in one case and wild-type expression in the rest. HPV in situ hybridization was negative. Conclusions: Primary gastric (gastrointestinal)-type mucoglandular lesions of the endometrium show various forms of gastrointestinal differentiation, which are high-risk HPV independent. Morphology combined with immunohistochemistry is helpful for the diagnosis, which can only be made on exclusion of cervical gastrointestinal glandular lesion, gastrointestinal metastatic carcinoma and the mucinous subtype of endometrioid carcinoma.

Expression of CD24 gene in human malignant pleural mesothelioma and its relationship with prognosis / 中华劳动卫生职业病杂志

Objective: To investigate the expression of CD24 gene in human malignant pleural mesothelioma (MPM) cells and tissues, and evaluate its relationship with clinicopathological characteristics and clinical prognosis of MPM patients. Methods: In February 2021, UALCAN database was used to analyze the correlation between CD24 gene expression and clinicopathological characteristics in 87 cases of MPM patients. The TIMER 2.0 platform was used to explore the relationship between the expression of CD24 in MPM and tumor immune infiltrating cells. cBioportal online tool was used to analyze the correlation between CD24 and MPM tumor marker gene expression. RT-qPCR was used to analyze the expressions of CD24 gene in human normal pleural mesothelial cell lines LP9 and MPM cell lines NCI-H28 (epithelial type), NCI-H2052 (sarcoma type), and NCI-H2452 (biphasic mixed type). RT-qPCR was performed to detect the expressions of CD24 gene in 18 cases of MPM tissues and matched normal pleural tissues. The expression difference of CD24 protein in normal mesothelial tissue and MPM tissue was analyzed by immunohistochemistry. A Kaplan-Meier model was constructed to explore the influence of CD24 gene expression on the prognosis of MPM patients, and Cox regression analysis of prognostic factors in MPM patients was performed. Results: The CD24 gene expression without TP53 mutation MPM patients was significantly higher than that of patients in TP53 mutation (P<0.05). The expression of CD24 gene in MPM was positively correlated with B cells (r(s)=0.37, P<0.001). The expression of CD24 gene had a positive correlation with the expressions of thrombospondin 2 (THBS2) (r(s)=0.26, P<0.05), and had a negative correlation with the expression of epidermal growth factor containing fibulin like extracellular matrix protein 1 (EFEMP1), mesothelin (MSLN) and calbindin 2 (CALB2) (r(s)=-0.31, -0.52, -0.43, P<0.05). RT-qPCR showed that the expression level of CD24 gene in MPM cells (NCI-H28, NCI-H2052 and NCI-H2452) was significantly higher than that in normal pleural mesothelial LP9 cells. The expression level of CD24 gene in MPM tissues was significantly higher than that in matched normal pleural tissues (P<0.05). Immunohistochemistry showed that the expressions of CD24 protein in epithelial and sarcoma MPM tissues were higher than those of matched normal pleural tissues. Compared with low expression of CD24 gene, MPM patients with high expression of CD24 gene had lower overall survival (HR=2.100, 95%CI: 1.336-3.424, P<0.05) and disease-free survival (HR=1.800, 95%CI: 1.026-2.625, P<0.05). Cox multivariate analysis showed that compared with the biphasic mixed type, the epithelial type was a protective factor for the prognosis of MPM patients (HR=0.321, 95%CI: 0.172-0.623, P<0.001). Compared with low expression of CD24 gene, high expression of CD24 gene was an independent risk factor for the prognosis of MPM patients (HR=2.412, 95%CI: 1.291-4.492, P=0.006) . Conclusion: CD24 gene and protein are highly expressed in MPM tissues, and the high expression of CD24 gene suggests poor prognosis in MPM patients.

EWSR1-SMAD3 positive fibroblastic tumor: a clinicopathological analysis / 中华病理学杂志

Objective: To investigate the clinicopathological features, immunophenotypes and molecular genetics of EWSR1-SMAD3 positive fibroblastic tumor (ESFT) with an emphasis on differential diagnosis. Methods: The clinicopathological data, immunohistochemical profiles and molecular profiles of 3 ESFT cases diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center from 2018 to 2021were analyzed. The related literature was also reviewed. Results: There were two males and one female. The patients were 24, 12 and 36 years old, respectively. All three tumors occurred in the subcutis of the foot with the disease duration of 6 months to 2 years. The tumors were presented with a slowly growing mass or nodule, accompanied with pain in 1 patient. The tumors ranged in size from 0.1 to 1.6 cm (mean, 1.0 cm). Microscopically, the tumors were located in the subcutaneous tissue with a nodular or plexiform growth pattern. They were composed of cellular fascicles of bland spindle cells with elongated nuclei and fine chromatin. One of the tumors infiltrated into adjacent adipose tissue. There was no nuclear atypia or mitotic activities. All three tumors showed prominent stromal hyalinization with zonal pattern present in one case. Focal punctate calcification was noted in two cases. The immunohistochemical studies showed that tumor cells were diffusely positive for ERG and negative for CD31 and CD34, with Ki-67 index less than 2%. Fluorescence in situ hybridization on the two tested cases identified EWSR1 gene rearrangement. The next generation sequencing analysis demonstrated EWSR1-SMAD3 fusion in all three cases. During the follow up, one patient developed local recurrence 24 months after the surgery. Conclusions: ESFT is a benign fibroblastic neoplasm and has a predilection for the foot, characterized by ERG immunoreactivity and EWSR1-SMAD3 fusion. Local recurrence might occur when incompletely excised. Familiarity with its clinicopathological features is helpful in distinguishing it from other spindle cell neoplasms that tend to occur at acral sites.

Histiocyte-rich rhabdomyoblastic tumor: a clinicopathological and molecular genetic analysis / 中华病理学杂志

Objective: To investigate the clinicopathologic and molecular genetic characteristics, diagnosis, differential diagnosis, treatment and prognosis of histiocyte-rich rhabdomyoblastic tumor (HRRMT). Methods: The clinical data of two cases of HRRMT diagnosed in Fujian Provincial Hospital and Fujian University of Traditional Chinese Medicine Affiliated People's Hospital from 2020 to 2021 were collected. Histopathology and immunohistochemical (IHC) staining were used to assess morphological changes; the genetic changes were analyzed with next-generation sequencing. The relevant literature was reviewed. Results: Both cases showed well-defined solid nodules and soft masses. Microscopically, the tumors had a fibrous pseudocapsule with lymphocytic aggregation, and locally invaded the surrounding skeletal muscle tissue, and the tumor cells were fusiform to epithelioid with an intensive foamy histiocytic infiltrate. No necrosis or mitosis was observed. Immunophenotyping showed the tumor cells were positive for desmin, either one or both skeletal muscle markers (myogenin or MyoD1), and negative for h-caldesmon, ALK and SMA. The Ki-67 index was<5%. Using next-generation sequencing, one case was found to harbour KRAS (G12D) and MSH3 (Q470*) mutations. Conclusions: HRRMT is a newly described skeletal muscle tumor with uncertain malignant potential. Its diagnosis and differential diagnosis depend on morphologic and IHC staining. No specific molecular genetics changes have been identified so far.

Primary lung salivary gland-type duct carcinoma: a clinicopathological analysis of two cases and review of literature / 中华病理学杂志

Objective: To investigate the clinicopathological features, diagnostic criteria and differential diagnosis of primary salivary gland-type duct carcinoma of lung(LSDC). Methods: Two patients with LSDC after surgical resection in Shanghai Pulmonary Hospital from 2020 to 2021 were included; their clinical parameters as well as pathological, immunohistochemical and molecular characteristics of the tumors were analyzed. The relevant literature was also reviewed. Results: Both patients were male, aged 49(case 1) and 64(case 2) years, respectively, and with a history of smoking. The chest computed tomography scan showed both lesions to be centrally located. Gross examination showed the maximum diameters were 16 mm and 35 mm, respectively. The histomorphology of LSDC resembled ductal carcinoma of breast, with intraductal islands of neoplastic cells, which also formed solid nests, papillary, micropapillary and cribriform structures. There was frequent accompanying comedo-like necrosis. The neoplasm cells were markedly heteromorphic, possessing large irregular nuclei with prominent nucleoli, abundant eosinophilic or clear cytoplasm, and mitotic figures were common. Both cases of LSDC were immunoreactive for CKpan, CK7, AR, HER2 staining was (2+) and were negative for TTF1, Napsin A, p40, GATA3, mammaglobin, GCDFP15, SOX10, PSA, P504S, ER, PR, vimentin, S-100, SMA, CK5/6 and p63. The tumor showed double-layer cell structure of the duct, and some basal cells/myoepithelial cells expressed p40 and CK5/6. Case 1 had no gene mutation while case 2 harbored TP53 and KMT2A gene mutation detected by next generation sequencing. Conclusions: LSDC is a very rare and highly aggressive salivary-type malignant tumor. The postoperative diagnosis mainly depends on histopathology and immunohistochemistry, attention should be paid to differential diagnosis to prevent missed diagnosis.

Caracterização funcional do gene codificador de proteína CD14 e do gene não codificador de proteína LINC01133 em linhagens celulares humanas de câncer de mama triplo negativo / Functional characterization of the CD14 protein-coding gene and the non-protein-coding LINC01133 gene in triple negative human breast cancer cell lines

Dentre os subtipos de câncer de mama, o triplo negativo (TNBC) é o que apresenta as maiores taxas de mortalidade, sendo, portanto, considerado um enorme desafio para a clínica. O uso de moléculas como marcadores tumorais vem auxiliando o clínico no diagnóstico, no prognóstico e, até mesmo, no tratamento do TNBC, sendo essenciais na redução de suas altas taxa de mortalidade. No entanto, um pequeno grupo de marcadores tumorais são validados na prática clínica, estimulando à busca por novos alvos, e sua caracterização funcional, como forma de se entender a Biologia desta doença. Assim, o objetivo deste trabalho é caracterizar funcionalmente o gene codificador de proteína CD14 e o gene não codificador de proteína LINC01133 em linhagens celulares humanas de TNBC, no intuito de descobrir o papel destas moléculas na progressão tumoral. Na primeira parte deste trabalho, analisou-se a expressão do CD14 frente à um painel de linhagens celulares que representam os diferentes subtipos dos tumores mamários. O CD14 exibiu elevados níveis de expressão nas linhagens nãotumorigênicas MCF10A e MCF12A e baixos níveis na linhagem triplo negativa Hs578T. A partir destes resultados, o CD14 foi superexpresso na linhagem Hs578T. Ensaios de caracterização funcional mostraram que a superexpressão do CD14 reduziu a capacidade migratória e invasiva das células, efeito que foi hipoteticamente relacionado ao aumento da expressão da E-caderina. No entanto, observou-se aumento no potencial tumorigênico, levando-nos a sugerir seu envolvimento num possível mecanismo utilizado pelas células para compensar a significativa redução do potencial migratório e invasivo. Os resultados obtidos indicam que o nível basal de expressão do CD14 observado na linhagem Hs578T é importante, podendo contribuir para a desenvolvimento primário do tumor, atuando como um oncogene. Na segunda parte deste trabalho, analisou-se a expressão de 10 RNAs longos não codificadores (lncRNAs), frente ao mesmo painel de linhagens descritoanteriormente. Dentre estes, o lncRNA LINC01133 exibiu baixos níveis de expressão nas linhagens não-tumorigênicas MCF10A e MCF12A e elevados níveis na linhagem triplo negativa Hs578T, sendo, então, escolhido como alvo de estudo. A partir destes resultados, decidimos superexpressar, de forma indutível, o LINC01133 na linhagem MCF10A e nocautear este gene, via sistema CRISPR/Cas9, na linhagem Hs578T. Ensaios de caracterização funcional mostraram que a superexpressão do LINC01133 na linhagem MCF10A reduziu a proliferação celular e inibiu o crescimento de colônias dependente de ancoragem, mas, em contrapartida, aumentou o crescimento de colônias independente de ancoragem e a capacidade migratória e invasiva destas células. No entanto, sugerimos que isto não seja suficiente para tornar estas células tumorigênicas e metastáticas. Por outro lado, o nocauteamento do LINC01133 na linhagem triplo negativa Hs578T aumentou de forma considerável todos os parâmetros de malignidade analisados. Baseado nos dados obtidos, sugerimos que o elevado nível de expressão do LINC01133 na linhagem Hs578T é importante na regulação negativa de processos relacionados com a progressão tumoral, atuando com um supressor tumoral. Os dados obtidos em nosso estudo contribuem para o enriquecimento de informações relacionadas à Biologia do TNBC, auxiliando, desta forma, no desenvolvimento de potenciais protocolos clínicos e terapêuticos utilizandos estes biomarcadores

Among the breast cancer subtypes, the triple negative (TNBC) displays the highest mortality rates, being, therefore, considered a major challenge for the clinic. The use of molecules as tumor markers has helped clinicians in the diagnosis, prognosis and even in treatment of TNBC, being essential in reducing its high mortality rate. However, a small group of tumor markers is validated in clinical practice, stimulating the search for new targets, and their functional characterization, as a way to understand the biology of this disease. Thus, the aim of this work is to functionally characterize the CD14 protein-coding gene and the non-protein-coding LINC01133 gene in human TNBC cell lines, in order to probe into the role of these molecules in tumor progression. In the first part of this work, the expression of CD14 was analyzed in a panel of cell lines that represent the different subtypes of breast tumors. High expression levels of CD14 were observed in the non-tumorigenic MCF10A and MCF12A lineages and low levels in the triple negative Hs578T lineage. Based on these results, CD14 was overexpressed in the Hs578T lineage. Functional characterization assays showed that CD14 overexpression reduced the migratory and invasive capacity of cells, an effect that was hypothetically related to increased E-cadherin expression. However, increased in the tumorigenic potential was observed, leading us to suggest its involvement in a possible mechanism used by cells to compensate for the significant reduction in the migratory and invasive potential. The results obtained indicate that CD14 expression basal level observed in the Hs578T lineage may be important to contribute to the primary development of tumor, thus acting as an oncogene. In the second part of this work, the expression of 10 long non-coding RNAs (lncRNAs) was analyzed against the same lineage panel described above. Among these, the LINC01133 lncRNA exhibited low expression levels in the non-tumorigenic MCF10A and MCF12A lineages and high levels in the triple negative Hs578T lineage, being, then, chosen as a target for this study. Based on these results, we decided toinducibly overexpress LINC01133 in the MCF10A lineage and knockout this gene, via the CRISPR/Cas9 system, in the Hs578T lineage. Functional characterization assays showed that overexpression of LINC01133 in the MCF10A lineage reduced cell proliferation and inhibited anchorage-dependent colony growth, but, on the other hand, increased anchorage-independent colony growth and the migratory and invasive capacity of these cells. However, we suggest that this is not sufficient to render these cells tumorigenic and metastatic. On the other hand, the knockout of LINC01133 in the triple negative Hs578T lineage considerably increased all the analyzed malignancy parameters. Based on the results obtained, we suggest that the high expression level of LINC01133 in the Hs578T lineage is important for down-regulation of processes related to tumor progression, acting as a tumor suppressor. The data obtained in our study contribute to the enrichment of information related to TNBC Biology, thus assisting in the development of potential clinical and therapeutic protocols using these biomarkers

Proteomics-based identification of cancer-associated proteins in chronic lymphocytic leukaemia

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is a neoplasm of B-cells characterized by variable prognosis. Exploring the proteome of CLL cells may provide insights into the disease. Therefore, eleven proteomics experiments were conducted on eleven primary CLL samples. RESULTS: We reported a CLL proteome consisting of 919 proteins (false discovery rate (FDR) 1%) whose identification was based on the sequencing of two or more distinct peptides (FDR of peptide sequencing 1%). Mass spectrometry-based protein identification was validated for four different proteins using Western blotting and specific antibodies in different CLL samples. Small sizes of nucleolin (~57 kDa and ~68 kDa) showed a potential association with good prognosis CLL cells (n = 8, p < 0.01). Compared with normal B-cells, CLL cells over-expressed thyroid hormone receptor-associated protein 3 (THRAP3; n = 9; p = 0.00007), which is implicated in cell proliferation; and heterochromatin protein 1-binding protein 3 (HP1BP3; n = 10; p = 0.0002), which promotes cell survival and tumourogenesis. A smaller form of HP1BP3, which may correspond to HP1BP3 isoform-2, was specifically identified in normal B-cells (n = 10; p = 0.0001). HP1BP3 and THRAP3 predicted poor prognosis of CLL (p 0.05). Consistently, THRAP3 and HP1BP3 were found to be associated with cancer-related pathways (p 0.05). CONCLUSIONS: Our findings add to the known proteome of CLL and confirm the prognostic importance of two novel cancer-associated proteins in this disease.

Perfil de citocinas Th1, Th2, Th17 y otras citocinas pro inflamatorias (IL-1ß, IL-6 y TNFα) en el plasma de pacientes con cáncer gástrico / Th1, Th2, Th17 cytokine profile and other pro-inflammatory cytokines (IL-1ß, IL-6 and TNFα) in the plasma of patients with gastric cancer

El cáncer gástrico (CG) es la neoplasia del tubo digestivo más prevalente en el mundo, asociada a factores genéticos del hospedero y externos, como infección por Helicobacter pylori. La patogénesis incluye inflamación crónica mediada por citocinas del microambiente tumoral, detectables sistémicamente. Estudios previos reportan niveles séricos de citocinas y su contribución al diagnóstico de CG. El presente estudio analiza el perfil de citocinas del tipo de Th1(IFNγ), Th2(IL-4 e IL-10), Th17(Th-17A) y otras pro inflamatorias: IL-1ß, IL-6 y TNF-α, en plasma de 70 casos de pacientes con CG comparándolos con 132 sujetos sanos equiparables en edad y sexo. Los casos provinieron del Hospital Roosevelt e Instituto Nacional de Cancerología de Guatemala (Incan) y formaron parte de un estudio previo. Se analizó la base de datos clínicos, patológicos y epidemiológicos. Se midieron los niveles de citocinas utilizando el sistema "MSD MULTI-SPOT Assay System". La edad promedio de los casos fue 59.5 años, (DE 13.0), 51%, eran positivos para IgG anti H. pylori. Un 71% presentó adenocarcinoma grado III (Borrman), según clasificación de Lauren 55% tenían tipo intestinal. Las siete citocinas cuantificadas se encontraron significativamente elevadas (p < .05) en el plasma de los casos respecto a sus controles. Los casos de CG tipo difuso presentaron niveles de IFNγ significativa-mente elevados. Por regresión logística, las citocinas IL-6 e IL-10, están asociadas significativamente a CG (p < .05) independientemente del estatus de infección por H. pylori. Se destacan la IL-6 e IL-10 como las principales citocinas asociadas a la presencia de CG.

Gastric cancer (GC) is the most prevalent gastrointestinal neoplasm in the world, associated with host and external genetic factors, such as Helicobacter pylori infection. The pathogenesis includes chronic inflammation mediated by cytokines of the tumor microenvironment, systemically detectable. Previous studies report serum levels of cyto-kines and their contribution to the diagnosis of GC. The present study analyzes the profile of cytokines of the type Th1 (IFNγ), Th2 (IL-4 and IL-10), Th17 (Th-17A) and other pro-inflammatory: IL-1ß, IL-6 and TNF-α, in plasma of 70 cases of patients with GC compared with 132 healthy subjects comparable in age and sex. The cases came from the Roosevelt Hospital and the National Cancer Institute of Guatemala -Incan- and were part of a previous study. The clinical, pathological and epidemiological databases were analyzed. Cytokine levels were measured using the "MSD MULTI-SPOT Assay System". The average age of the cases was 59.5 years, (SD 13.0), 51% were positive for IgG anti H. pylori, 71% had grade III adenocarcinoma (Borrman), according to Laurenís classification, 55% had intestinal type. The seven cytokines quantified were found to be significantly elevated (p < .05) in the plasma of the cases compared to their controls. The diffuse GC cases presented significantly elevated IFNγ levels. By logistic regression, the cytokines IL-6 and IL-10 are significantly associated with GC (p < .05) regardless of the H. pylori infection status. IL-6 and IL-10 stand out as the main cytokines associated with the presence of GC.

Prognostic and clinicopathological value of zwint expression levels in patients with lung adenocarcinoma: a systematic review and meta-analysis

The current study found that high Zeste White 10 interactor (ZWINT) expression is related to the poor prognosis of patients with a variety of cancers. This study mainly explored the relationship between the expression level of ZWINT and the prognosis of patients with lung adenocarcinoma (LUAD). Briefly, four English databases and two high-throughput sequencing databases were searched and relevant data for meta-analysis were extracted. Pooled mean difference and 95% confidence interval (CI) were used to assess the relationships between clinical features and the expression of ZWINT. Pooled hazard ratio and 95% CI were also used to assess the relationships between clinical features and the expression level of ZWINT. This meta-analysis was registered in PROSPERO (CRD42021249475). A total of 16 high-quality datasets comprising 2,847 LUAD patients were included in this study. Higher ZWINT expression levels were found in patients younger than 65 years, males, and smokers, and were correlated with advanced TNM stages and poor prognosis. Notably, there was no publication bias in this meta-analysis. Overall, our findings indicate that ZWINT is a potential biomarker for poor prognosis and clinicopathological outcomes of patients with LUAD.

Morphological changes of the cellularity in the prostatic gland from patients with confirmed cancer: Gleason level and presence of eosinophils and mast cells: cellular bioindicators / Cambios morfológicos de la celularidad en la glándula prostática de pacientes con cáncer confirmado: nivel de gleason y presencia de eosinófilos y mastocitos: bioindicadores celulares

The different pathologies of the prostate, involve the presence of a new microenvironment where inflammatory cells are actively recruited. This research explores the presence of mast cells and eosinophils associated with age and the evaluation of prostate cancer progress (Gleason Index). Forty two biopsies of anonymized patients, with confirmed prostate cancer, were used for histological analysis for eosinophils and mast cells and subsequent determination of Gleason index according to age. The results of the histological analyzes show the presence of eosinophils and mast cells in prostate biopsies with confirmed cancer. In the multiple correlation studies, a high correlation was observed between the presence of lymphocytes and the age of the patient diagnosed with prostate cancer, same correlation was observed between the patient's age and higher Gleason Index (Pearson and Spearman p< 0.05). It is concluded that in prostate biopsies from Chilean patients with confirmed cancer, eosinophilia and tissue mastocytosis were observed. Correlation analyzes show a direct correlation between older patients, higher Gleason index and presence of mast cell. Regarding eosinophilia, only a correlation between age and Gleason index was observed Further studies are suggested to determine that the presence of eosinophils and mast cells can be used as early bioindicators of prostate cancer.

Las diferentes patologías de próstata, involucran la presencia de un nuevo microambiente donde las células inflamatorias son activamente reclutadas. La presente investigación explora la presencia de mastocitos y eosinófilos asociadas a la edad y la evaluación del progreso del cáncer de próstata según índice de Gleason. Cuarenta y dos biopsias de pacientes anonimizados, con cáncer prostático confirmados, fueron utilizadas para su análisis histológico para eosinófilos y mastocitos y posterior determinación del índice de Gleason según edad. Los resultados de los análisis histológicos, muestran la presencia de eosinófilos y mastocitos en biopsias de próstata con cáncer confirmado. En los estudios de correlación múltiple, se observó una alta correlación entre la presencia de linfocitos, mastocitos y la edad del paciente diagnosticado con cáncer prostático, igual correlación se observó entre la edad del paciente y mayor índice de Gleason (Pearson y Spearman p<0,05). Se concluyó que en las biopsias de próstata de pacientes chilenos con cáncer confirmado, se observó eosinofilia y mastocitosis tisular. Los análisis de correlación muestran una correlación directa entre pacientes de mayor edad, índice de Gleason más alto y la presencia de mastocitos. Con respecto a la eosinofilia, solo se observó una correlación entre la edad y el índice de Gleason. Se sugieren estudios adicionales para determinar que la presencia de eosinófilos y mastocitos puede usarse como bioindicadores tempranos del cáncer de próstata.

Inmunocomplejos circulantes en el lupus eritematoso sistémico / Circulating immunocomplexes in systemic erythematous lupus

Introducción: Los biomarcadores son claves en el diagnóstico y pronóstico del lupus eritematoso sistémico en el cual las manifestaciones clínicas son extremadamente complejas y heterogéneas. Objetivo: Determinar el valor clínico de los inmunocomplejos circulantes en pacientes con lupus eritematosos sistémico. Métodos: Se determinaron los niveles séricos de inmunocomplejos fijadores del C1q y de los anticuerpos anti-ácido desoxirribonucleico de doble cadena (anti-ADNdc), anti-nucleosoma (anti-Nuc) y anti-proteínas ribosomales (anti-RibP) por el ensayo inmuno-adsorbente ligado a enzima (ELISA) en 93 pacientes con diagnóstico de lupus eritematosos sistémico. Se utilizaron exámenes no paramétricos para probar la asociación entre los inmunocomplejos y los auto-anticuerpos. La frecuencia de nefritis lupica en los grupos de pacientes positivos y negativos de inmunocomplejos circulantes se comparó mediante Chi cuadrado. Resultados: Los inmunocomplejos se encontraron en 24 (25,8 por ciento) pacientes con lupus eritematosos sistémico. Los pacientes que presentaron los títulos más altos de inmunocomplejos fueron los positivos a los tres auto-anticuerpos usados (p=0,044). Se encontró correlación directa entre los niveles de anti-RibP y los inmunocomplejos (Rho=0,303, p=0,003) y entre los anti-ADNdc y anti-Nuc (Rho=0,449, p=0,001). La nefritis lúpica se presentó en 58,3 por ciento de pacientes con inmunocomplejos, y 31,9 por ciento pacientes negativos de inmunocomplejos (p=0,213). Conclusiones: Los inmunocomplejos circulantes caracterizaron una fracción menor de pacientes con lupus eritematosos sistémico. La presencia de estos no se asoció a los anticuerpos anti-ADNdc ni a la nefritis lupica(AU)

Introduction: Biomarkers are essential in the diagnosis and prognosis of systemic erythematous lupus in which clinical manifestations are extremely complex and heterogeneous. Objective: To determine the clinical value of circulating immunocomplexes in patients with systemic erythematous lupus. Methods: Serum levels of C1q-binding immunocomplexes and anti-double-stranded deoxyribonucleic acid (anti-dsDNA), anti-nucleosome (anti-Nuc) and anti-ribosomal proteins (anti-RibP) were determined by enzyme-linked immunosorbent assay (ELISA) in 93 patients diagnosed with systemic lupus erythematosus. Nonparametric tests were used to test the association between immunocomplexes and auto-antibodies. The frequency of lupus nephritis in the circulating immunocomplex positive and negative patient groups was compared using Chi square. Results: Immunocomplexes were found in 24 (25.8 percent) patients with systemic lupus erythematosus. The patients with the highest immunocomplex titers were positive for the three autoantibodies used (p = 0.044). A direct correlation was found between the levels of anti-RibP and immunocomplexes (Rho = 0.303, p = 0.003) and between anti-dsDNA and anti-Nuc (Rho = 0.449, p = 0.001). Lupus nephritis occurred in 58.3 percent of immunocomplex patients, and 31.9 percent immunocomplex negative patients (p = 0.213). Conclusions: Circulating immunocomplexes characterized a smaller fraction of patients with systemic lupus erythematosus. Their presence was not associated with anti-dsDNA antibodies or lupus nephritis(AU)

Are stem cell marker expression and cd133 analysis relevant to differentiate colorectal cancer? / A expressão de marcadores de células-tronco e a análise do cd133 são relevantes na diferenciação do câncer colorretal?

ABSTRACT Background: CD133 and AXL have been described as cancer stem cell markers, and c-MYC as a key regulatory cellular mechanism in colorectal cancer (CRC). Aim: Evaluate the prognostic role of the biomarkers CD133, AXL and c-MYC and their association with clinicopathologic characteristics in colorectal adenocarcinomas and adenomas. Methods: A total of 156 patients with UICC stage I-IV adenocarcinomas (n=122) and adenomas (n=34) were analyzed. Tissue microarrays (TMA) from primary tumors and polyps for CD133, c-MYC and AXL expression were performed and analyzed for their significance with clinicopathologic characteristics. Results: Poorly differentiated adenocarcinomas and disease progression were independent risk factors for poor overall survival. The median overall survival time was 30 months. Positive CD133 expression (35.9% of all cases), particularly of right-sided CRCs (44.8% of the CD133+ cases), was negatively correlated with death in the univariate analysis, which did not reach significance in the multivariate analysis. c-MYC (15.4% of all cases) was predominantly expressed in advanced-stage patients with distant (non-pulmonary/non-hepatic) metastasis. AXL expression was found only occasionally, and predominantly dominated in adenomas, with less penetrance in high-grade dysplasia. Conclusions: CD133 expression was not associated with inferior overall survival in CRC. While AXL showed inconclusive results, c-MYC expression in primary CRCs was associated with distant metastasis.

RESUMO Racional: CD133 e AXL são descritos na literatura como marcadores de células-tronco tumorais, e c-MYC cumpre papel chave como mecanismo de regulação celular no câncer colorretal (CCR). Objetivo: Avaliar o papel prognóstico dos biomarcadores CD133, AXL e c-MYC e sua associação com características clinicopatológicas de adenocarcinomas e adenomas colorretais. Métodos: Um total de 156 pacientes com adenocarcinomas de estádio UICC I-IV (n=122) e adenomas (n=34) colorretais foram avaliados. Microarranjos teciduais (TMA) dos tumores primários e adenomas foram realizados em busca de expressão de CD133, c-MYC e AXL, com posterior análise de relação significativa com características clinicopatológicas. Resultados: Adenocarcinomas pobremente diferenciados e progressão de doença foram fatores de risco independentes para má sobrevida global. A taxa mediana de sobrevida global foi de 30 meses. Expressão positiva de CD133 (35,9% dos casos), particularmente em cânceres de cólon direito (44,8% dos casos CD133+), correlacionou-se negativamente com óbito na análise univariada, sem significância estatística na análise multivariada. c-MYC (15,4% dos casos) teve predomínio de expressão em pacientes com estádio avançado com metástases distantes (não-pulmonares/não-hepáticas). Expressão de AXL foi pouco encontrada, com predomínio em adenomas, com menor penetrância em displasia de alto grau. Conclusão: Expressão de CD133 não se associou com sobrevida global inferior em CCR. Enquanto AXL demonstrou resultados inconclusivos, expressão de c-MYC em tumores primários se associou-se à metástases à distância.

Expression profile of salivary micro RNA-21 and 31 in oral potentially malignant disorders

Abstract Oral potentially malignant disorders (OPMD) possess significant chances of malignancy conversion. In order to develop an early diagnostic tool, the present study evaluated the expression of miRNA-21 and 31 as salivary markers. The case-control study was carried out in 36 healthy participants as controls and in 36 patients who were newly diagnosed as OPMD having four different lesions including leucoplakia, oral sub mucous fibrosis (OSMF)궱, oral lichen planus, and (OSMF)궱 with leucoplakia. The samples were also classified as non-dysplastic, or with mild, moderate, and severe dysplasia according to their histopathological reports. The salivary miRNA-21 and 31 expressions were studied using real-time PCR. The statistical analysis was carried out using SPSS version 22. Salivary miRNA-21 (p-value = 0.02) and 31 (p-value = 0.01) were significantly upregulated in severe dysplasia compared with control. Among the different lesions, leucoplakia had significant upregulation of miRNA-21 and 31. miRNA-21 can be used as a diagnostic marker with specificity of 66% and sensitivity of 69%. The area under the ROC curve was 0.820 for miRNA-21 and 0.5 for miRNA-31, which proved that miRNA-21 is a better diagnostic marker than miRNA-31 for OPMD.

DEC1: a potential biomarker of malignant transformation in oral leukoplakia

Abstract The purpose of this study was to analyze the differential expression of DEC1 in oral normal mucosa (NM), oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC). Surgically excised specimens from patients with OLK (n = 47), OSCC (n = 30) and oral normal mucosa (n=11) were immunostained for DEC1. The expression of DEC1 protein was evaluated, and its association with the clinicopathological features was analyzed. The expression of DEC1 in NM, OLK and OSCC tissues increased in turn, and significant differences were observed among the groups (P < 0.0001). In terms of the association between DEC1 expression and epithelial dysplasia, DEC1 expression was lower in hyperkeratosis without dysplasia (H-OLK) than in OLK with moderate to severe dysplasia (S-OLK), and these differences were significant (p < 0.05). The expression of DEC1 in OSCC with OLK was significantly higher than that in OSCC without OLK (p < 0.01). Therefore, DEC1 could be a potential biomarker of malignant transformation in the carcinogenesis of OSCC, which may provide a new research direction for the transformation of oral potentially malignant disorders (OPMDs) into OSCC.

Intra-tumor genetic heterogeneity in Wilms tumor samples

SUMMARY Childhood renal tumors account for ~7% of all childhood cancers, and most cases are embryonic Wilms' tumors (WT). Children with WT are usually treated by either COG or SIOP. The later treats the children using preoperative chemotherapy, but both have around 90% of overall survival in five years. WT is a genetically heterogeneous group with a low prevalence of known somatic alterations. Only around 30% of the cases present mutation in known genes, and there is a relatively high degree of intra-tumor genetic heterogeneity (ITGH). Besides potentially having an impact on the clinical outcome of patients, ITGH may interfere with the search for molecular markers that are prospectively being tested by COG and SIOP. In this review, we present the proposal of the current UMBRELLA SIOP Study 2017/Brazilian Renal Tumor Group that requires the multi-sampling collection of each tumor to better evaluate possible molecular markers, as well as to understand WT biology

RESUMO Os tumores renais pediátricos correspondem a aproximadamente 7% de todos os tumores infantis, sendo o mais frequente o tumor de Wilms (TW). Crianças com TW são geralmente tratadas seguindo dois distintos protocolos terapêuticos (COG ou SIOP), sendo que no último, os pacientes recebem tratamento quimioterápico pré-operatório. Ambos apresentam sobrevida global em cinco anos em torno de 90%. TW é geneticamente heterogêneo, apresentando baixa prevalência de alterações somáticas conhecidas, com cerca de 30% dos casos apresentando mutações em genes conhecidos e um alto grau de heterogeneidade genética intratumoral (HGIT). Além de potencialmente ter um impacto sobre o desfecho clínico dos pacientes, a HGIT pode interferir na busca de marcadores moleculares que estão sendo testados prospectivamente pelos grupos COG e Siop. Nesta revisão, apresentamos a proposta do atual estudo Umbrella Siop 2017/Grupo de Tumores Renais Brasileiros (GTRB), que orienta a coleta de três diferentes regiões do tumor para melhor avaliar possíveis marcadores moleculares, bem como para compreender a biologia do TW.

Seminal citrate is superior to PSA for detecting clinically significant prostate cancer

ABSTRACT Purpose: To establish whether the citrate concentration in the seminal fluid ([CITRATE]) measured by means of high-resolution nuclear magnetic resonance spectroscopy (1HNMRS) is superior to the serum prostate-specific antigen (PSA) concentration in detecting of clinically significant prostate cancer (csPCa) in men with persistently elevated PSA. Materials and Methods: The group of patients consisted of 31 consecutively seen men with histological diagnosis of clinically localized csPCa. The control group consisted of 28 men under long-term follow-up (mean of 8.7 ± 3.0 years) for benign prostate hyperplasia (BPH), with persistently elevated PSA (above 4 ng/mL) and several prostate biopsies negative for cancer (mean of 2.7 ± 1.3 biopsies per control). Samples of blood and seminal fluid (by masturbation) for measurement of PSA and citrate concentration, respectively, were collected from patients and controls. Citrate concentration in the seminal fluid ([CITRATE]) was determined by means of 1HNMRS. The capacities of PSA and [CITRATE] to predict csPCa were compared by means of univariate analysis and receiver operating characteristic (ROC) curves. Results: Median [CITRATE] was significantly lower among patients with csPCa compared to controls (3.93 mM/l vs. 15.53 mM/l). There was no significant difference in mean PSA between patients and controls (9.42 ng/mL vs. 8.57 ng/mL). The accuracy of [CITRATE] for detecting csPCa was significantly superior compared to PSA (74.8% vs. 54.8%). Conclusion: Measurement of [CITRATE] by means of 1HNMRS is superior to PSA for early detection of csPCa in men with elevated PSA.

The role of Survivin as a biomarker and potential prognostic factor for breast cancer

SUMMARY Breast cancer (BC) is one of the primary health problems worldwide. As the most common cancer in women in the world and in Brasil, behind only non-melanoma skin cancer, this neoplasm corresponds to approximately 28% of new cases per year in the country. BC also affects men, although the incidence corresponds to only 1% of total cases. Currently, most of the chemotherapeutic agents used in BC treatment are extremely toxic and cause long-term side effects. There is also a need to obtain earlier diagnoses, more accurate prognoses and make new therapies available that are more selective and effective in order to improve the current scenario. Therefore, this work sought to evaluate the importance of the biomarker survivin (Sur) in relation to BC, through the detailing of the role of Sur as a biomarker, the correlation between this protein and the prognosis of BC patients, and a summary of therapeutic strategies that target Sur for the development of new anticancer therapies.

RESUMO O câncer de mama (CM) é um dos principais problemas de saúde em todo o mundo. Como o câncer mais comum em mulheres no mundo e no Brasil, precedido apenas pelo câncer de pele não melanoma, essa neoplasia corresponde a aproximadamente 28% dos novos casos por ano no país. O CM também afeta homens, embora a incidência corresponda a apenas 1% do total de casos. Atualmente, a maioria dos agentes quimioterápicos utilizados no tratamento do CM são extremamente tóxicos e causam efeitos colaterais a longo prazo. Há também a necessidade de se obterem diagnósticos mais precoces, prognósticos mais precisos e disponibilizar novas terapias seletivas e efetivas, a fim de melhorar o cenário atual. Portanto, este trabalho buscou avaliar a importância do biomarcador Survivina (Sur) em relação ao CM, por meio do detalhamento do papel do Sur como biomarcador, da correlação entre essa proteína com o prognóstico de pacientes com CM e de um resumo do tratamento terapêutico e das estratégias que visam utilizar a Sur para o desenvolvimento de novas terapias anticâncer.