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1.
Lab Invest ; 104(5): 102048, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38490470

RESUMO

Yes-associated protein (YAP), an effector molecule of the Hippo signaling pathway, is expressed at high levels in cutaneous melanoma. However, the role of YAP in melanoma progression according to cellular localization is poorly understood. Tissues from 140 patients with invasive melanoma were evaluated by immunohistochemistry. Flow cytometry, western blotting, viability assays, wound healing assays, verteporfin treatment, and xenograft assays were conducted using melanoma cell lines B16F1 and B16F10 subjected to YapS127A transfection and siYap knockdown. Nuclear YAP localization was identified in 63 tumors (45.0%) and was more frequent than cytoplasmic YAP in acral lentiginous and nodular subtypes (P = .007). Compared with cytoplasmic YAP melanomas, melanomas with nuclear YAP had higher mitotic activity (P = .016), deeper invasion (P < .001), and more frequently metastasized to lymph nodes (P < .001) and distant organs (P < .001). Patients with nuclear YAP melanomas had poorer disease-free survival (P < .001) and overall survival (P < .001). Nuclear YAP was an independent risk factor for distant metastasis (hazard ratio: 3.206; 95% CI, 1.032-9.961; P = .044). Proliferative ability was decreased in siYapB16F1 (P < .001) and siYapB16F10 (P = .001) cells and increased in YapS127AB16F1 (P = .003) and YapS127AB16F10 (P = .002) cells. Cell cycle analysis demonstrated relative G1 retention in siYapB16F1 (P < .001) and siYapB16F10 (P < .001) cells and S retention in YapS127AB16F1 cells (P = .008). Wound healing assays showed that Yap knockdown inhibited cell invasion (siYapB16F1, P = .001; siYapB16F10, P < .001), whereas nuclear YAP promoted it (YapS127AB16F, P < .001; YapS127AB16F1, P = .017). Verteporfin, a direct YAP inhibitor, reduced cellular proliferation in B16F1 (P = .003) and B16F10 (P < .001) cells. Proliferative effects of nuclear YAP were confirmed in xenograft mice (P < .001). In conclusion, nuclear YAP in human melanomas showed subtype specificity and correlated with proliferative activity and proinvasiveness. It is expected that YAP becomes a useful prognostic marker, and its inhibition may be a potential therapy for melanoma patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Núcleo Celular , Melanoma , Neoplasias Cutâneas , Fatores de Transcrição , Proteínas de Sinalização YAP , Animais , Feminino , Humanos , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Progressão da Doença , Melanoma/metabolismo , Melanoma/patologia , Melanoma Maligno Cutâneo , Camundongos Nus , Fosfoproteínas/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP/metabolismo
2.
Oncologist ; 29(6): e811-e821, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38470950

RESUMO

BACKGROUND: Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). PATIENTS AND METHODS: Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. RESULTS: Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. CONCLUSIONS: Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.


Assuntos
Melanoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Humanos , Melanoma/genética , Melanoma/tratamento farmacológico , Melanoma/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Proteínas Proto-Oncogênicas B-raf/genética , GTP Fosfo-Hidrolases/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-raf/genética , Idoso de 80 Anos ou mais , Inibidores de Proteínas Quinases/uso terapêutico
3.
Dermatol Surg ; 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39401451

RESUMO

BACKGROUND: Digital mucous cysts (DMCs) are benign cysts located in digital interphalangeal joints or the proximal nail fold. Despite various treatments, standardized guidelines are lacking, and recurrence rates remain high. OBJECTIVE: This study evaluates the efficacy and safety of a novel treatment combining surgical deroofing with trichloroacetic acid application. MATERIALS AND METHODS: This study was conducted on 27 patients with DMCs treated from 2019 to 2022. Clinical features and therapeutic responses were documented with photographic records at the initial presentation and follow-ups. Histopathological examinations confirmed diagnoses and classified histopathological types. RESULTS: Among 27 lesions, 20 were within the proximal nail fold, 7 were beneath the proximal nail fold; 26 were ganglionic, and 1 was myxomatous. Four patients required multiple treatments within 6 months due to recurrences. Long-term follow-up showed clinical improvement in all patients: 17 achieved complete remission, and 8 showed partial improvement. The treatment was effective regardless of cyst type, with minimal complications and mild postoperative pain resolving within days. CONCLUSION: The combination of surgical deroofing and trichloroacetic acid application minimizes complications and enhances efficacy. It allows for repetitive treatments in case of recurrence, making it a viable option for managing persistent DMCs, with favorable outcomes and minimal complications.

4.
Microvasc Res ; 142: 104357, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35283207

RESUMO

Blood vessels in lymph nodes (LNs) are unique in comprising both capillaries and high endothelial venules (HEVs). Hyaline vascular type Castleman's disease accompanies robust angiogenesis, but it is unclear how the capillaries and HEVs respond. We retrospectively examined surgical specimens of hyaline vascular type unicentric Castleman's disease patients (n = 24) and control LNs (n = 9). We performed immunohistochemistry of CD 31 for capillaries and MECA-79 for HEVs and calculated their microvascular density. We measured CT enhancement as the ratio of Hounsfield Units (HUs) of the target lesion against muscle compared with microvascular density. The microvascular density of Castleman's disease specimen were (CD 31+) 169.7 ± 77.6, (MECA-79+) 203.5 ± 96.7, and the microvascular density of control LNs were (CD 31+) 80.7 ± 20.1, (MECA-79+) 67.4 ± 23.7, respectively. The microvascular density of both CD 31+ (P < 0.001) and MECA-79+ (P < 0.001) was higher in Castleman's disease. A positive correlation existed between CT HU ratio and microvascular density for both markers (CD 31: r = 0.517, P = 0.002; MECA-79: r = 0.521, P = 0.002). Intra-nodal angiogenesis of Castleman's disease involves robust proliferation of not only CD 31+ capillaries, but also MECA-79+ HVEs, which each correlated with degree of CT enhancement.


Assuntos
Hiperplasia do Linfonodo Gigante , Hiperplasia do Linfonodo Gigante/diagnóstico por imagem , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/cirurgia , Humanos , Hialina , Imuno-Histoquímica , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
5.
Neoplasma ; 69(3): 630-639, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35263998

RESUMO

Glucose and glutamine metabolism is involved in important tumor mechanisms. Metabolism-related protein expression has been previously reported to predict tumor prognosis. We aimed to investigate glucose and glutamine metabolism-related protein expression and its implication in breast ductal carcinoma in situ (DCIS). A tissue microarray was prepared for 205 DCIS cases. Glucose and glutamine metabolism-related proteins were immunostained. Based on the results of estrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER)-2, and Ki-67, DCIS was classified into the luminal type, HER-2 type, and triple-negative breast cancer (TNBC). DCIS stroma was classified into non-inflammatory and inflammatory types per stromal histology. DCIS (N=205) was classified into luminal type (n=112), HER-2 type (n=81), and TNBC (n=12). Hexokinase II (p=0.044), GLS (p=0.003), and SLC7A5 (p<0.001) expression rates were the highest in TNBC. Inflammatory type stroma showed higher SLC7A5 (p<0.001) and SLC7A11 (p=0.008) expression rates than non-inflammatory type stroma. In summary, DCIS demonstrated differential expression of metabolism-related proteins according to the molecular subtype and stromal features. TNBC showed the highest glucose and glutamine metabolism-related protein expression, and inflammatory type stroma showed higher glutamine metabolism-related protein expression than non-inflammatory type stroma.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Glucose , Glutamina , Humanos , Transportador 1 de Aminoácidos Neutros Grandes , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
6.
Adv Anat Pathol ; 27(2): 75-86, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31913182

RESUMO

The gastrointestinal (GI) tract is a prevalent site for extranodal lymphomas. Some subtypes of GI tract lymphomas are aggressive and have dismal clinical outcomes. Therefore, prompt histopathologic detection of such types can be very important. We thus introduce a practical approach in the histopathologic diagnosis of GI lymphomas according to the revised World Health Organization (WHO) classification. When lymphocyte proliferation is found in the GI tract, a stepwise approach can help narrow down the differential diagnoses. When considering subtype incidence, macroscopic findings, and microscopic patterns, applying a first-line marker battery of CD20, CD3, CD30, and Epstein-Barr virus-encoded RNAs can effectively narrow down the top differential diagnoses at the initial step. Generally, the most common subtype among GI tract lymphomas is B-cell non-Hodgkin lymphoma identified by CD20 expression, followed by T-cell and NK-cell non-Hodgkin lymphomas identified by the CD3 expression, and some subtypes are defined by Epstein-Barr virus infection or CD30 expression. Macroscopically, lymphomas present as various gross types, such as large masses, small lesions, superficial and shallow lesions, polyp-like or polyposis-like features, or ulcer/necrosis/perforation. Microscopically, large pleomorphic cells or small to medium-sized tumor cells grow with various architectures and tumor microenvironments. Incorporation of macroscopic and microscopic features and the stepwise immunophenotyping may be a practical approach to the differential diagnosis of aggressive lymphoma, indolent/low-grade lymphoma, or benign to indolent lymphoproliferative disease. Exceptions always exist; this approach focuses on the relatively prevalent circumstances of lymphomatous lesions initially encountered in the GI tract.


Assuntos
Antígenos CD20 , Biomarcadores Tumorais , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/patologia , Herpesvirus Humano 4/genética , Antígeno Ki-1 , Linfoma/diagnóstico , Linfoma/patologia , Linfócitos B/patologia , Neoplasias Gastrointestinais/virologia , Humanos , Imunofenotipagem , Linfoma/virologia , RNA Viral , Linfócitos T/patologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-39069454

RESUMO

In this report, a tumor exhibited EWSR1::RORß gene fusion, to our knowledge, is the first such reported case. The Ewing sarcoma breakpoint region 1 gene (EWSR1) is known to be associated with several soft tissue tumors although its specific role remains unclear. Its fusion with a member of the ETS family, including FLI1 and ERG, results in Ewing sarcoma, and its fusion with other genes unrelated to the ETS family, including NFATC2 and PATZ1, results in round cell sarcoma with EWSR1-non-ETS fusions, previously referred to as Ewing-like sarcoma. RORß encodes retinoic acid-related orphan receptor ß, a nuclear receptor (NR), and is involved in circadian rhythm modulation and cancer regulation. The specific role of RORß in tumorigenesis remains unclear; however, this case report suggests that it may form part of a new tumorigenic entity.

9.
Yonsei Med J ; 65(2): 108-119, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38288651

RESUMO

PURPOSE: With the revision of the Organ and Transplantation Act in 2018, the hand has become legal as an area of transplantable organs in Korea. In January 2021, the first hand allotransplantation since legalization was successfully performed, and we have performed a total of three successful hand transplantation since then. By comparing and incorporating our experiences, this study aimed to provide a comprehensive reconstructive solution for hand amputation in Korea. MATERIALS AND METHODS: Recipients were selected through a structured preoperative evaluation, and hand transplantations were performed at the distal forearm level. Postoperatively, patients were treated with three-drug immunosuppressive regimen, and functional outcomes were monitored. RESULTS: The hand transplantations were performed without intraoperative complications. All patients had partial skin necrosis and underwent additional surgical procedures in 2 months after transplantation. After additional operations, no further severe complications were observed. Also, patients developed acute rejection within 3 months of surgery, but all resolved within 2 weeks after steroid pulse therapy. Motor and sensory function improved dramatically, and patients were very satisfied with the appearance and function of their transplanted hands. CONCLUSION: Hand transplantation is a viable reconstructive option, and patients have shown positive functional and psychological outcomes. Although this study has limitations, such as the small number of patients and short follow-up period, we should focus on continued recovery of hand function, and be careful not to develop side effects from immunosuppressive drugs. Through the present study, we will continue to strive for a bright future regarding hand transplantation in Korea.


Assuntos
Transplante de Mão , Humanos , Transplante de Mão/efeitos adversos , Transplante de Mão/métodos , Transplante Homólogo/efeitos adversos , Imunossupressores/uso terapêutico , Institucionalização , República da Coreia , Rejeição de Enxerto
10.
Clin Cancer Res ; 30(8): 1457-1465, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38363333

RESUMO

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.


Assuntos
Anemia , Fibromatose Agressiva , Triazóis , Humanos , Mesilato de Imatinib , Fibromatose Agressiva/tratamento farmacológico , Compostos de Anilina/uso terapêutico , Anemia/tratamento farmacológico , Anemia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
11.
Nat Commun ; 15(1): 685, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38263321

RESUMO

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10-4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.


Assuntos
Anticorpos Monoclonais , Indazóis , Pirimidinas , Sarcoma , Neoplasias de Tecidos Moles , Sulfonamidas , Humanos , Recidiva Local de Neoplasia
12.
In Vivo ; 37(2): 862-867, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36881068

RESUMO

BACKGROUND/AIM: Cutaneous melanoma, a melanocyte malignancy, can be divided into many clinical subtypes that differ in presentation, demographics, and genetic profile. In this study, we used next-generation sequencing (NGS) analysis to review genetic alterations in 47 primary cutaneous melanomas in the Korean population and compared them to alterations from melanomas in Western populations. PATIENTS AND METHODS: We retrospectively reviewed clinicopathologic and genetic features of 47 patients diagnosed with cutaneous melanomas between 2019-2021 at Severance Hospital, Yonsei University College of Medicine. NGS analysis was performed at diagnosis to evaluate single nucleotide variations (SNVs), copy number variations (CNVs), and genetic fusions. Genetic features in Western cohorts of melanoma were then compared with previous studies performed in the USA: Cohort 1 (n=556), Cohort 2 (n=79), and Cohort 3 (n=38). RESULTS: The most common histological classification of melanoma was the acral lentiginous type (23/47, 48.9%). BRAF V600 mutation was most frequent (11/47, 23.4%), but was significantly lower compared to Cohort 1 (240/556, 43.2%) and Cohort 2 (34/79, 43.0%) (p=0.0300). CNV analysis identified amplifications in chromosomes 12q14.1-12q15 (11/47, 23.4%) including CDK4 and MDM2 genes and 11q13.3 (9/47, 19.2%) including CND1, FGF19, FGF3, and FGF4 genes more frequently in the present study population than Cohort 1 (p<0.0001). CONCLUSION: These results clearly demonstrated differences in genetic alterations between melanomas in Asian and Western populations. Therefore, BRAF V600 mutation should be considered a significant signaling pathway explaining melanoma pathogenesis occurrence in both Asian and Western populations, whereas loss of chromosome 9p21.3 is unique to melanomas in Western populations.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Neoplasias Cutâneas/genética , Variações do Número de Cópias de DNA/genética , População do Leste Asiático , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Melanoma Maligno Cutâneo
13.
Hepatol Int ; 17(1): 77-85, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36253584

RESUMO

BACKGROUND: The differential diagnosis of intrahepatic cholangiocarcinomas (iCCAs) from metastatic adenocarcinomas from organs adjacent to the liver (gallbladder, pancreas, and stomach) is difficult due to histopathological similarity and a lack of specific markers. This study aimed to develop a method to differentiate iCCA and adenocarcinomas originated from extrahepatic organs adjacent to the liver. METHODS: We retrospectively enrolled surgically resected iCCA (n = 181) and adenocarcinomas from extrahepatic organs (n = 30, n = 28, and n = 38 from gallbladder, pancreas, and stomach, respectively) between 2007 and 2013. The albumin mRNA in situ hybridization (ISH) and immunohistochemistry (IHC) of filamin-A and cytokeratin 19 (CK19) were performed using tissue microarray. Using logistic regression analysis of three markers, iCCA-score was developed, and its diagnostic performance was evaluated. RESULTS: The iCCAs were more frequently positive for albumin ISH (23.2% vs. 0%), filamin-A IHC (47.5% vs. 12.5%) and CK19 (68.5% vs. 40.6%) than extrahepatic adenocarcinomas (p < 0.001 for all). The iCCA-score consisting of these three markers was developed, and it showed higher diagnostic performance (area under the curve [AUC], 0.798 vs. 0.616, p < 0.001). Taking an iCCA-score of 2 or higher as the threshold for iCCA, the sensitivity was substantially higher than albumin ISH alone (45.9% and 23.2%, respectively; p < 0.001), but maintained high specificity (94.8% and 100%, respectively). CONCLUSION: Albumin ISH and IHC staining for filamin-A and CK19 showed distinct expression patterns between iCCA and extrahepatic adenocarcinomas from gallbladder, pancreas, and stomach. We developed iCCA-score that consisted of those three markers, and it showed better diagnostic performance than albumin ISH alone.


Assuntos
Adenocarcinoma , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Queratina-19/genética , Filaminas/genética , Estudos Retrospectivos , Biomarcadores Tumorais , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Albuminas , Ductos Biliares Intra-Hepáticos/química , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/genética
14.
Cancers (Basel) ; 14(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36497457

RESUMO

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-ß signaling pathway. Moreover, we selected the combination treatment comprising TGF-ß inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-ß inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-ß inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

15.
Cells ; 10(10)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34685738

RESUMO

The International Society for Cutaneous Lymphoma (ISCL) proposes a diagnostic algorithm for early mycosis fungoides (MF) that includes clinical, histological, immunophenotypical, and molecular criteria. Here, we analyzed the immunologic markers and features of T-cell clonality in 38 early MF cases and 22 non-MF cases to validate the ISCL algorithm. We found that CD5 and CD7 expression differed significantly between early MF and non-MF cases, with epidermal discordance of CD7 expression more frequently identified in early MF. Notably, increasing the cut-off value for CD7 expression from 10% to 22.5% improved its sensitivity. Furthermore, TCR-γ and ß chain rearrangements were more frequently detected in early MF than in non-MF cases. Based on these findings, we propose CD5 and CD7 deficiency as mandatory immunopathologic criteria and PCR-based testing for TCR-γ and ß chains as required molecular/biologic criteria to improve the efficiency of early MF diagnosis using the ISCL algorithm.


Assuntos
Algoritmos , Internacionalidade , Linfoma/patologia , Micose Fungoide/diagnóstico , Sociedades Médicas , Adulto , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Feminino , Rearranjo Gênico do Linfócito T , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/genética , Micose Fungoide/imunologia , Micose Fungoide/patologia , Curva ROC , Receptores de Antígenos de Linfócitos T/genética
16.
Head Neck ; 41(1): 198-207, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30536665

RESUMO

BACKGROUND: The purpose of this study was to comprehensively characterize head and neck squamous cell carcinoma (HNSCC) arising in young patients (<45 years old). METHODS: We performed immunohistochemistry, silver, and fluorescence in situ hybridization using samples obtained from 396 radically resected cases among 1787 HNSCCs. RESULTS: Young age HNSCCs occurred in 10.9% (194/1787) and were most common in the oral tongue (50.5%). They revealed distinctively lower frequency of p16 positivity, high c-MET expression, MET copy number gain, and lower pan-Trk expression. PD-L1 positivity in tumor cells and ICOS+ tumor infiltrating lymphocytes (TILs) were higher in the young age. Perineural invasion, PD-L1 positivity, and higher ratio of CD163+ tumor infiltrating macrophages to CD8 + TILs were determined to be independent factors for poor progression-free survival. CONCLUSION: Characterizing these features of young age HNSCC may help to identify the underlying pathogenesis and to improve patient outcome through different treatment strategies.


Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Variações do Número de Cópias de DNA , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor trkA/metabolismo , Receptores de Superfície Celular/metabolismo
17.
Hum Pathol ; 81: 18-25, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29753009

RESUMO

Salivary duct carcinoma (SDC) is an aggressive carcinoma with poor prognosis. Although anti-HER2 therapy is a potential treatment option for HER2-positive SDC, other potential therapeutic targets are not known, in particular for HER2-negative cases. In this study, the recently identified receptors tyrosine kinases MET and tropomyosin-receptor kinase (Trk) were investigated as potential therapeutic targets. A total of 28 consecutive, surgically resected, de novo SDC cases were selected after evaluating histology and immunohistochemical expression of androgen receptor. Immunohistochemical expression of c-erb2, TrkA, TrkB, TrkC, and c-MET was analyzed, and the genetic status of the HER2 and MET genes was investigated through dual-color silver in situ hybridization. High expression of c-MET or Trk was defined as that above the median value. Among the 28 SDC cases, 64.3% (18/28) were HER2-positive. c-MET expression varied, with a median H-score of 65 (range, 0 to 200). Copy number gain and amplification of MET were noted in 57.1% (16/28) and 10.7% (3/28) of cases, respectively. TrkA was variably expressed, with a median H-score of 100 (range, 0 to250). High TrkA expression was significantly related to an inferior overall survival rate in HER2-negative SDC. High expression of TrkA and c-MET and MET copy number gain/amplification were frequent events in SDC, and high expression of TrkA revealed the tendency to be related to poor prognosis in HER2-negative SDC. TrkA and MET may be possible therapeutic targets in SDC, especially in HER2-negative SDC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/química , Proteínas Proto-Oncogênicas c-met/análise , Receptor trkA/análise , Ductos Salivares/química , Neoplasias das Glândulas Salivares/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma/genética , Carcinoma/mortalidade , Carcinoma/patologia , Feminino , Amplificação de Genes , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-met/genética , Receptor ErbB-2/análise , Fatores de Risco , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/mortalidade , Neoplasias das Glândulas Salivares/patologia , Fatores de Tempo , Regulação para Cima
18.
Brain Tumor Res Treat ; 6(2): 101-104, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30381926

RESUMO

Pheochromocytoma (PCC) is a neuroendocrine tumor that mainly arises from the medulla of the adrenal gland. Some PCCs become malignant and metastasize to other organs. For example, it typically involves skeletal system, liver, lung, and regional lymph nodes. However, only a few cases of PCC with brain metastasis have been reported worldwide. We report a case of metastatic brain tumor from PCC in South Korea in 2016. A 52-year-old man presented with headache, dizziness and motor aphasia. He had a medical history of PCC with multi-organ metastasis, previously underwent several operations, and was treated with chemotherapy and radiotherapy. Brain MRIs showed a brain tumor on the left parietal lobe. Postoperative pathology confirmed that the metastatic brain tumor derived from malignant PCC. This is the first report PCC with brain metastasis in South Korea.

19.
Korean J Thorac Cardiovasc Surg ; 51(2): 142-145, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29662814

RESUMO

Malignant gastrointestinal neuroectodermal tumor (GNET) is a very rare disease entity, especially in the esophagus. The diagnosis of GNET is based on histologic, immunohistochemical, and genetic findings. The choice of treatment is complete resection, and further treatment options can be considered. Herein, we describe a case of successful surgical treatment of a 23-year-old man with recurrent malignant esophageal GNET.

20.
APMIS ; 125(11): 974-984, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28975663

RESUMO

We evaluated the expression patterns of p16, which is used as a surrogate marker of HPV infection in head and neck squamous cell carcinoma (HNSCC), in regard to their biological and prognostic implications. p16 expression patterns and infiltrated immune cells were analyzed through immunohistochemistry of p16, CD3, CD8, PD-1, FOXP3, and CD163 on surgically resected HNSCCs (n = 393). Patterns of p16 immunoexpression were defined as STRONG (strong, diffuse expression in cytoplasm, and nucleus in >70% of tumor cells), MARGINAL (expression restricted to tumor margins), MOSAIC (ragged, discontinued expression), NUCLEAR (expression in nuclei only), and ABSENT (no expression). The STRONG pattern was more frequent in the oropharynx, and the MARGINAL pattern was noted only in the oral cavity. MOSAIC and NUCLEAR patterns were noted at variable sites. No two patterns of p16 expression showed the same immune cell composition of CD3+ T cells, CD8+ cytotoxic T cells, PD-1+ T cells, FOXP3+ regulatory T cells, and CD163+ macrophages. In overall and disease-free survival analyses, the STRONG pattern showed the most favorable prognosis, while the NUCLEAR pattern had the worst prognosis. HNSCC anatomical sites, tumor-related immune cell components, and patient outcomes were associated with p16 expression patterns. Each architectural pattern of p16 expression may be related to different biological and prognostic phenotypes.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Infecções por Papillomavirus/diagnóstico , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Biomarcadores Tumorais/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Antígenos CD8/genética , Antígenos CD8/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Papillomavirus Humano 16/crescimento & desenvolvimento , Papillomavirus Humano 16/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/patologia , Prognóstico , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de Sobrevida
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