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1.
Diagnostics (Basel) ; 11(10)2021 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-34679524

RESUMEN

Small cell neuroendocrine carcinoma (SNEC) is a rare subset of tumors in the sinonasal sinus. Combined tumors are exceedingly rare. Here, we describe a 65-year-old male with a mixed tumor of SNEC and sarcomatoid carcinoma arising in an inverted papilloma, containing squamous cell carcinoma in situ (SqCCis) in the sinonasal sinus. We evaluated the molecular characteristics of the two separate carcinoma components using next-generation sequencing. The patient presented with a nasal obstruction. Computed tomography showed a mass infiltrating the right ethmoid and maxillary sinuses. An excisional biopsy was performed. The tumor was found to have three morphologically distinct components. The first was SqCCis arising in an inverted papilloma, which was positive for cytokeratin and P40. The second consisted of nests of densely packed small round cells representing SNEC-positive neuroendocrine markers. The third was a solid sheet of anaplastic spindle cell proliferation, which was negative for the above markers. Oncogenic mutations such as FBXW7, TP53, and EGFR were detected in both SNEC and sarcomatoid carcinoma, and MYCL amplification was observed only in the SNEC component. This case highlights an extremely rare presentation of combined SNEC and sarcomatoid carcinoma arising from an inverted papilloma in the sinonasal sinus.

2.
Cancer Genomics Proteomics ; 18(5): 685-698, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34479920

RESUMEN

BACKGROUND/AIM: Invasive stratified mucin-producing carcinoma (ISMC) of the uterine cervix has been reported to be more aggressive than other subtypes of endocervical adenocarcinoma. We investigated the clinicopathological and molecular characteristics of eight ISMCs. PATIENTS AND METHODS: We reviewed the electronic medical records and pathology slides of eight patients with ISMC and conducted programmed death-ligand 1 (PD-L1) immunostaining and targeted sequencing. RESULTS: The patients were between 31 and 54 years. Six tumors were pure ISMCs, and two showed co-existing squamous cell carcinoma and usual-type endocervical adenocarcinoma. Lymph node metastases were detected in three cases. Three patients developed distant metastases to the adnexa, lungs, inguinal lymph nodes, and small intestine. Two patients experienced disease progression, and three developed postoperative local recurrences. All tumors showed PD-L1 over-expression, with a mean combined positive score of 73.8 (range=30-100). One tumor harbored erb-b2 receptor tyrosine kinase 2 amplification. CONCLUSION: ISMC of the uterine cervix exhibits a high risk of recurrence, metastasis, and resistance to chemoradiation therapy. PD-L1 over-expression was consistently observed in all ISMCs. This finding raises the possibility that patients with ISMC may benefit from PD-L1 immunotherapy.

3.
Anticancer Res ; 41(9): 4609-4617, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34475089

RESUMEN

BACKGROUND/AIM: This study aimed to assess the yield of an Oncomine comprehensive assay v3 (OCAv3)-based next-generation sequencing (NGS) analysis for detecting anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusions in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: NGS data from 85 NSCLC cases were reviewed. ALK and ROS1 fusion status was compared to conventional tests. RESULTS: ALK or ROS1 fusion reads were detected in 17 NSCLC cases. Results in 10 NSCLC cases showed concordance with conventional tests, high-count fusion reads, a lack of mutually exclusive mutations of ALK or ROS1, and frequent signet-ring cell component. Seven NSCLC cases showing discordant results exhibited low to intermediate fusion read counts and mutations mutually exclusive from ALK or ROS1. CONCLUSION: Cases showing high-count fusion reads in OCAv3-based NGS have a strong possibility of carrying ALK or ROS1 fusion. Cases with low- to intermediate-count fusion reads should be interpreted with caution and may require additional confirmative tests.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Análisis de Secuencia de ARN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Análisis Citogenético , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
Elife ; 102021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34409942

RESUMEN

Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold slow depolarization underlies autonomous pacemaking and determines its rate. However, the ion channels that determine slow depolarization are unknown. Here we show that TRPC3 and NALCN channels together form sustained inward currents responsible for the slow depolarization of nigral DA neurons. Specific TRPC3 channel blockade completely blocked DA neuron pacemaking, but the pacemaking activity in TRPC3 knock-out (KO) mice was perfectly normal, suggesting the presence of compensating ion channels. Blocking NALCN channels abolished pacemaking in both TRPC3 KO and wild-type mice. The NALCN current and mRNA and protein expression are increased in TRPC3 KO mice, indicating that NALCN compensates for TRPC3 currents. In normal conditions, TRPC3 and NALCN contribute equally to slow depolarization. Therefore, we conclude that TRPC3 and NALCN are two major leak channels that drive robust pacemaking in nigral DA neurons.


Asunto(s)
Relojes Biológicos/fisiología , Neuronas Dopaminérgicas/fisiología , Canales Iónicos/genética , Proteínas de la Membrana/genética , Neuronas/fisiología , Sustancia Negra/fisiología , Canales Catiónicos TRPC/genética , Potenciales de Acción , Animales , Relojes Biológicos/genética , Neuronas Dopaminérgicas/citología , Femenino , Masculino , Ratones , Ratones Noqueados , Sustancia Negra/citología
5.
Medicina (Kaunas) ; 57(8)2021 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-34441043

RESUMEN

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015-2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542-10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Pronóstico , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genética
6.
Anticancer Res ; 41(5): 2719-2726, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33952503

RESUMEN

BACKGROUND/AIM: We present a case of uterine dedifferentiated mesonephric-like adenocarcinoma (MLA). CASE REPORT: A 54-year-old woman underwent total hysterectomy for a uterine mass under the impression of a uterine sarcoma. Histologically, MLA exhibited various growth patterns including tubular and glandular architecture. Undifferentiated carcinoma (UC) displayed discohesive tumor cells without any obvious architecture. Immunohistochemically, UC was positive for epithelial markers in very few scattered tumor cells. MLA exhibited the wild-type p53 expression pattern, whereas UC showed a uniform and strong p53 immunoreactivity. Targeted sequencing analysis revealed an identical Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in both components. A pathogenic missense tumor protein 53 (TP53) mutation was detected in UC, but not in MLA. CONCLUSION: The mutant p53 expression pattern exclusively detected in UC was concordant with the presence of missense TP53 mutation. Our observations suggested that TP53 mutation is associated with the possible transformation from MLA to UC.


Asunto(s)
Adenocarcinoma/diagnóstico , Carcinoma/diagnóstico , Sarcoma/diagnóstico , Enfermedades Uterinas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Carcinoma/genética , Carcinoma/patología , Carcinoma/cirugía , Desdiferenciación Celular/genética , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Sarcoma/genética , Sarcoma/patología , Sarcoma/cirugía , Enfermedades Uterinas/patología , Enfermedades Uterinas/cirugía , Conductos Mesonéfricos/diagnóstico por imagen , Conductos Mesonéfricos/patología , Conductos Mesonéfricos/cirugía
7.
Int J Clin Exp Pathol ; 14(4): 545-550, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33936380

RESUMEN

A 42-year-old male presented with a history of headaches for the previous 2 weeks. Magnetic resonance imaging of the brain showed a 3 cm-sized well-defined, enhancing mass in the atrium of the right lateral ventricle. The tumor comprised two heterogeneous components: approximately one-third of the tumor exhibited complex and delicate papillary fibrovascular cores lined with uniform cuboidal-to-columnar epithelial cells, whereas the remaining part was seen as a solid sheet comprising ovoid-to-spindle cells with plump cytoplasm, which occasionally had a whorling pattern. Further, immunohistochemical staining with cytokeratin 7 (CK7) and epithelial membrane antigen (EMA) clearly demarcated each component: the CK7+/EMA- choroid plexus papilloma and CK7-/EMA+ meningioma. This report provides a description of an unusual case of concomitant choroid plexus papilloma and ventricular meningioma presenting as a single mass, along with a review of relevant literature.

8.
J Obstet Gynaecol Res ; 47(5): 1917-1921, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33650156

RESUMEN

A 78-year-old woman with the chief complaint of vaginal bleeding was referred to our institution. Pelvic magnetic resonance imaging showed a 2.1 cm × 2.0 cm soft tissue mass in the left vaginal area with left inguinal lymph node enlargement. A positron emission tomography/computer tomography scan showed a focal hypermetabolic lesion in the left vaginal area with involvement of vulvar area. Pelvic examination showed a vaginal wall mass and the patient underwent surgical excision of the mass. The results of pathology indicated lymphoepithelioma-like carcinoma (LELC) in the vagina. The patient was admitted subsequently in the oncological department for additional chemoradiation treatment. LELC is extremely rare in the vagina, and only three cases have been reported in the literature. Here we report an extremely rare case of this tumor and review of the previous literature.


Asunto(s)
Carcinoma de Células Escamosas , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Vagina/cirugía
9.
Pathology ; 53(5): 586-594, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33546812

RESUMEN

Immunohistochemical (IHC) assays for programmed death ligand 1 (PD-L1) expression are crucial for guiding immune checkpoint inhibitor therapies in advanced gastric adenocarcinoma (AGC). The results from clinical trials of various PD-L1 antibody clones are variable and the exchangeability of these assays is a highly sought goal. The aim of this study was to determine whether three different PD-L1 assays (SP263 and 22C3 on the Dako and Ventana platforms) are interchangeable through analysis of their concordance rate within samples between biopsy and paired resected specimens. One hundred pairs of biopsied and resected AGC specimens were collected and stained for PD-L1. The combined positive score (CPS) was used for the IHC analysis and a four tiered system was applied, i.e., <1, 1 to < 5, 5 to 50, and >50. The agreement for the different IHC assays was low across all cut-offs with the biopsied or resected specimens (biopsy, κ=0.17-0.453; resection, κ=0.02-0.311). The overall positive agreement (OPA) for the PD-L1 results from the biopsy and resection tissues was 100% (SP263, κ=1), 86% (22C3 on the Dako platform, κ=0.693) and 93% (22C3 on the Ventana platform, κ=0.82) at the CPS1 cut-off. The low concordances among the three PD-L1 IHC assays indicated that they cannot be used interchangeably in clinical practice. The results of the SP263 assay using CPS1 showed the highest agreement between the biopsy and resection specimens, suggesting SP263 may provide the most representative approach for the evaluation of PD-L1 status in gastric cancer.

10.
In Vivo ; 35(2): 921-927, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33622884

RESUMEN

BACKGROUND/AIM: The application of Oncomine Comprehensive Assay v3 (OCAv3) panel in diffuse gliomas (DGs) remains unknown. We investigated the utility of OCAv3-based next-generation sequencing (NGS) in isocitrate dehydrogenase (IDH)-mutated grade II-III DGs. PATIENTS AND METHODS: We collected 20 tissue samples obtained from IDH-mutated grade II-III DG patients and performed OCAv3-based NGS. RESULTS: By conventional molecular methods, the 20 DGs were classified into seven astrocytomas and 13 oligodendrogliomas. OCAv3 detected all mutations identified in these samples using the conventional methods. The results were highly corroborated by the known mutations in each group. Clustered copy number loss of genes located at the 1p and 19q loci was detected in all 13 oligodendroglioma cases, which harbor the 1p/19q codeletion. CONCLUSION: The application of OCAv3-based NGS will improve diagnostic accuracy in DG, with the most beneficial aspects expected in detecting copy number alterations to identify the 1p/19q codeletion correctly.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Cromosomas Humanos Par 1/genética , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética
11.
Mod Pathol ; 34(1): 141-160, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32709987

RESUMEN

Anorectal malignant melanoma (ARMM) is a rare disease with poor prognosis. Determining ARMM prognosis precisely is difficult due to the lack of proper assessment techniques. Immunotherapy has proven effective against cutaneous malignant melanoma and may show efficacy in ARMM. Herein, we assessed the immune profile of ARMM to identify possible prognostic biomarkers. Twenty-two ARMM formalin-fixed and paraffin-embedded samples were evaluated using an nCounter® PanCancer Immune Profiling Panel. Validation was performed through immunohistochemical staining for CD3, CD8, Foxp3, CD68, CD163, and PD-L1. RNA analysis revealed significantly decreased scores for pathways involved in cell regulation and function, as well as chemokines, in recurrent patients compared to nonrecurrent patients. In cell-type profiling, the recurrent cases displayed significantly low tumor infiltrating lymphocyte (TIL) scores. Recurrence/death prediction models were defined using logistic regression and showed significantly lower scores in recurrent and deceased patients (all, P < 0.001) compared to those in nonrecurrent and surviving patients. The high total TIL and tumor-associated macrophage (TAM) groups had significantly better overall survival outcomes compared to the low total TIL and TAM groups (P = 0.007 and P = 0.035, respectively). In addition, the presence of CD3 + TILs in the invasion front was an independent favorable prognostic indicator (P = 0.003, hazard ratio = 0.21, 95% confidential interval, 0.01-0.41). Patients with inflamed or brisk-infiltration type tumors also had a significantly better overall survival than that of patients with immune-desert/excluded and absent/non-brisk type tumors (P = 0.03 and P = 0.0023, respectively). In conclusion, TILs have a strong prognostic value in ARMM, and the quantification of TILs and an analysis of the TIL phenotype and infiltration pattern during pathological diagnosis are essential to guide treatment strategies and accurate prognosis in ARMM.

12.
Gastric Cancer ; 24(2): 327-340, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32924090

RESUMEN

BACKGROUND: Recent clinical studies on immune checkpoint (IC) inhibitors in the context of advanced gastric cancer (AGC) have failed to show significant survival benefits but have suggested the possible role of IC inhibitors in anti-AGC immunity. Considering the low efficacy of targeted drugs in AGC, there is an urgent need for the discovery of new targets for the development of immunotherapeutics and prognostic markers for patient selection. This study aimed to investigate the expression of a new IC molecule, V-set Ig domain-containing 4 (VSIG4), and its clinical significance in AGC and other major cancers. METHODS: We analyzed the expression of VSIG4 and its correlation with survival in various carcinomas, including 882 surgically resected samples from patients with stage II-III AGC (two academic hospitals). RESULTS: VSIG4 positivity in AGC was significantly associated with overall survival (OS; Hazard ratio (HR) = 2.661, 95% confidence interval [CI] = 2.012-3.519, P < 0.001) and event-free survival (HR = 2.8, 95% CI = 2.18-3.72, P < 0.001). These findings were successfully validated in independent cohorts. VSIG4 expression was also significantly correlated with low intratumoral CD8 + T-cell infiltration (CD8i) (P = 0.029) and high Foxp3 + /CD8i ratio (P = 0.026), which is consistent with the previously reported immunological function of VSIG4. However, VSIG4 expression was not associated with survival in other cancers (colon, P = 0.459; lung, P = 0.275; kidney, P = 0.121; breast, P = 0.147). CONCLUSION: Our results suggest that VSIG4 is an independent prognostic factor in AGC and also implies that VSIG4 is a second-tier IC molecule in AGC, thus, providing an important basis for the development of gastric cancer-specific immunotherapeutics.

13.
In Vivo ; 34(6): 3619-3626, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33144476

RESUMEN

BACKGROUND/AIM: Histone modification is associated with tumorigenesis and cancer progression. Recent studies have revealed the prognostic value of histone modification; however, its prognostic role in distal bile duct cancer remains unclear. PATIENTS AND METHODS: We analyzed the expression of H3K9me3, H4K20me3, and H3K36me3 and its correlation with survival outcomes in resected samples from 88 patients with distal bile duct cancer. RESULTS: Low expression rates of H3K9me3, H4K20me3, and H3K36me3 were significantly associated with poor overall survival (p=0.003, 0.008, and 0.047, respectively) and event-free survival (p=0.03 for H3K9m3). Additionally, low-expression of H3K9me3 was an independent poor prognostic indicator (p<0.001; HR=7.85; 95% CI=2.693-22.883). CONCLUSION: H3K9me3 was an independent poor prognostic factor in distal common bile duct cancer. Our results suggest that histone markers are potential prognostic markers and provide better management for patients at risk for an aggressive course of disease.


Asunto(s)
Neoplasias de los Conductos Biliares , Histonas , Neoplasias de los Conductos Biliares/genética , Conducto Colédoco , Histonas/genética , Histonas/metabolismo , Humanos , Pronóstico , Procesamiento Proteico-Postraduccional
14.
World J Clin Cases ; 8(20): 4708-4718, 2020 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-33195638

RESUMEN

BACKGROUND: Gastric heterotopic pancreas (GHP) is generally asymptomatic and rarely features complications such as pancreatitis, pseudocysts, gastric outlet obstruction, bleeding, obstructive jaundice, or intussusception. However, the treatment of complicated GHP is challenging and often requires surgical resection. AIM: To investigate the clinical outcomes of endoscopic submucosal dissection (ESD) as alternative to surgical resection for complicated GHP. METHODS: This is a single-center, retrospective study. Between January 2013 and December 2017, a total of 5 patients underwent ESD for complicated GHP at Asan Medical Center. Patients who were diagnosed with complicated GHP were treated conservatively as with general practice for acute pancreatitis. After conservative management for resolving the acute phase of pancreatitis, ESD was performed as definitive treatment for complicated GHP. ESD was performed using the conventional method under conscious sedation. The clinical features of patients and tumors, procedure-related characteristics, and long-term outcomes were investigated. RESULTS: The age of the 5 patients ranged from 28-43 years. Two of the patients were males. All lesions were located in the greater curvature of the antrum. On endoscopic ultrasonography during the pain episode, all lesions were located across the muscularis mucosa, submucosa, and proper muscle layers. The median lesion size was 20 [interquartile range (IQR), 18-35] during the pain episode at the time of the diagnosis of complicated GHP, and 15 mm (IQR, 9-33) at the time of ESD after conservative treatment. The procedure time ranged from 15-120 min. There were no procedure-related adverse events such as perforation or bleeding. The length of hospital stay after the procedure ranged from 2-4 d. All patients were symptom free during the median follow-up period of 46.0 mo (IQR, 39-60). CONCLUSION: ESD appears to be a feasible and effective treatment option for complicated GHP based on the favorable clinical outcomes.

15.
Anticancer Res ; 40(10): 5777-5785, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988905

RESUMEN

BACKGROUND/AIM: Emerging evidence suggests that Insulin-like growth factor II mRNA-binding protein 3 (IMP3) promotes tumor progression in several human malignancies. We investigated whether IMP3 expression has clinicopathological and prognostic significance in gallbladder adenocarcinoma (GBAC). PATIENTS AND METHODS: We examined immunohistochemical IMP3 expression in 204 GBACs and its associations with clinicopathological parameters and patient outcomes. RESULTS: The majority (87.7%) of GBACs exhibited at least focal cytoplasmic and membranous IMP3 immunoreactivity. Tumor-specific IMP3 expression highlighted proper muscle invasion, which was not detected in the corresponding hematoxylin and eosin-stained slides. This finding upgraded pathological tumor stage (pT) from pT1a to pT1b in four well-differentiated GBACs. High IMP3 expression was associated with high histological grade, advanced stage, and lymphatic invasion, as well as worse overall survival. CONCLUSION: Tumor-specific IMP3 expression in GBAC is helpful in determining the tumor extent, especially in well-differentiated tumors. High IMP3 expression reflects aggressive oncogenic behavior of GBAC. IMP3 expression may be used as a diagnostic and prognostic marker in GBAC.


Asunto(s)
Carcinoma/genética , Neoplasias de la Vesícula Biliar/genética , Pronóstico , Proteínas de Unión al ARN , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma/patología , Femenino , Neoplasias de la Vesícula Biliar/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Proteínas de Unión al ARN/genética
16.
Anticancer Res ; 40(10): 5925-5932, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988924

RESUMEN

BACKGROUND/AIM: Paired box 8 (PAX8) is an organ-specific marker discriminating Müllerian and breast carcinomas. Recent studies have described PAX8 expression in a small subset of breast carcinomas, which may cause a diagnostic pitfall in the determination of cancer origin. The aim of this study was to investigate characteristics of PAX8-expressing metastatic breast carcinomas (MBCs) to help elucidate the primary site of occurrence. PATIENTS AND METHODS: Using immunohistochemistry, we examined PAX8 status in 80 MBCs and 52 matched primary breast carcinomas (PBCs). RESULTS: A total of 20% of MBCs displayed PAX8 expression and the concordance rate of PAX8 expression between MBCs and PBCs was 92.3%. In MBCs, PAX8 expression was significantly associated with high-grade features (p=0.042), estrogen and progesterone receptor negativities (p=0.005 and p=0.017, respectively). CONCLUSION: PAX8 may be identified in MBCs with high-grade and non-luminal molecular subtypes. Careful assessment is needed when designating a primary site relying principally on PAX8 positivity.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Inmunohistoquímica , Factor de Transcripción PAX8/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Persona de Mediana Edad
17.
Sci Rep ; 10(1): 10680, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32606309

RESUMEN

BCL2 overexpression has been reported to be associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL). However, currently there is no consensus on the evaluation of BCL2 expression and only the proportion of BCL2 positive cells are evaluated for the determination of BCL2 positivity. This study aimed to define BCL2 positivity by quantitative analysis integrating both the intensity and proportion of BCL2 expression. BCL2 expression of 332 patients (221 patients for the training set and 111 patients for the validation set) with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were analyzed using the tumor-specific automated quantitative analysis (AQUA) scoring method based on multiplex immunofluorescence. In the training set, high BCL2 AQUA score (N = 86, 38.9%) was significantly associated with poor prognosis (p = 0.01, HR 2.00; 95% CI [1.15-3.49]) independent of international prognostic index, cell of origin, and MYC expression. The poor prognostic impact of the high BCL2 AQUA score was validated in the validation set. AQUA scoring of BCL2 expression incorporating both the intensity and proportion of BCL2 positive cells was independently associated with survival outcomes of patients with primary DLBCL treated with R-CHOP.


Asunto(s)
Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Estudios de Evaluación como Asunto , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Proteínas Proto-Oncogénicas c-myc/metabolismo , Rituximab/uso terapéutico , Vincristina/uso terapéutico
18.
Br J Pharmacol ; 177(16): 3795-3810, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32436268

RESUMEN

BACKGROUND AND PURPOSE: NALCN is a Na+ leak, GPCR-activated channel that regulates the resting membrane potential and neuronal excitability. Despite numerous possible roles for NALCN in both normal physiology and disease processes, lack of specific blockers hampers further investigation. EXPERIMENTAL APPROACH: The effect of N-benzhydryl quinuclidine compounds on NALCN channels was demonstrated using whole-cell patch-clamp recordings in HEK293T cells overexpressing NALCN and acutely isolated nigral dopaminergic neurons that express NALCN endogenously. Src kinase activity was measured using a Src kinase assay kit, and voltage and current-clamp recordings from nigral dopaminergic neurons were used to measure NALCN currents and membrane potentials. KEY RESULTS: N-benzhydryl quinuclidine compounds inhibited NALCN channels without affecting TRPC channels, another important route for Na+ leak. In HEK293T cells overexpressing NALCN, N-benzhydryl quinuclidine compounds potently suppressed muscarinic M3 receptor-activated NALCN currents. Structure-function relationship studies suggest that the quinuclidine ring with a benzhydryl group imparts the ability to inhibit NALCN currents regardless of Src family kinases. Moreover, N-benzhydryl quinuclidine compounds inhibited not only GPCR-activated NALCN currents but also background Na+ leak currents and hyperpolarized the membrane potential in native midbrain dopaminergic neurons that express NALCN endogenously. CONCLUSION AND IMPLICATIONS: These findings suggest that N-benzhydryl quinuclidine compounds have a pharmacological potential to directly inhibit NALCN channels and could be a useful tool to investigate functions of NALCN channels.


Asunto(s)
Canales Iónicos , Proteínas de la Membrana , Compuestos de Bencidrilo , Células HEK293 , Humanos , Quinuclidinas , Familia-src Quinasas
19.
Front Oncol ; 10: 329, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32219067

RESUMEN

The risk stratification of diffuse large B-cell lymphoma (DLBCL) is crucial. The International Prognostic Index, the most commonly used and the traditional risk stratification system, is composed of fixed and artificially dichotomized attributes. We aimed to develop a novel prognostic model that allows the incorporation of up-to-date attributes comprehensively without information loss. We analyzed 204 patients with primary DLBCL who were uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) from 2007 to 2012 at Asan Medical Center. Using the multivariable fractional polynomial (MFP) method and bootstrap resampling, we selected the variables of significance and the best fitted functional form in fractional polynomials. Age, serum ß2-microglobulin, serum lactate dehydrogenase, and BCL2 expression were selected as significant variables in predicting overall survival (OS), while age was excluded in predicting 2-years event-free survival. The prognostic score calculated by the MFP model effectively classifies patients into four risk groups with 5-years OS of 89.91% (low risk), 81.21% (low-intermediate risk), 66.40% (high-intermediate risk), and 37.89% (high risk). We suggest a new prognostic model that is simple and flexible. By using the MFP method, we can incorporate various clinicopathologic factors into a risk stratification system without arbitrary dichotomization.

20.
Histopathology ; 74(6): 883-891, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30609091

RESUMEN

AIMS: Pathological staging of colorectal cancers (CRCs) that involve adhesion to adjacent organs (clinical stages T4b, cT4b) is sometimes difficult because the morphology of the invasive front varies. To resolve this issue, we reviewed 492 surgically resected CRC samples, comprising 96 cT4b tumours and, for comparison, 335 typical pathological stages (p) T3 and 61 pT4a tumours. METHODS AND RESULTS: Cases were subdivided into four groups according to the presence or absence of microscopic tumour invasion into the muscular wall of the adjacent organs and peritumoral abscess along invasive front. Those that directly invaded the wall of the adjacent organs without peritumoral abscess were associated with a significantly worse overall (OS) and recurrence-free survival (RFS) than the other three types of cT4b tumours. Those with peritumoral abscess showed similar prognosis to typical pT3 tumours, even when the advancing edge of the tumour invaded the wall of adjacent organs (staged as pT4b). Tumours showing fibrous adhesions without tumour cell invasion into the muscular wall of the adjacent organs showed a similar prognosis to typical pT3 tumours and showed a better prognosis than pT4a tumours. CONCLUSION: Only CRCs with tumour cell invasion into the muscular wall of the adjacent organs should be classified as pT4b, and it might be better to avoid 'the presence of tumour cells in fibrous adhesion' to define pathological T4b CRCs. In addition, the presence of a peritumoral abscess should be recorded as a predictor of better prognosis.


Asunto(s)
Neoplasias Colorrectales/patología , Invasividad Neoplásica/patología , Estadificación de Neoplasias/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico
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