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1.
Life (Basel) ; 12(4)2022 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-35455057

RESUMO

Brainstem tumors are heterogenous and cancerous glioma tumors arising from the midbrain, pons, and the medulla that are relatively common in children, accounting for 10% to 20% of all pediatric brain tumors. However, the prognosis of aggressive brainstem gliomas remains extremely poor despite aggressive treatment with chemotherapy and radiotherapy. That means there are many life-threatening patients who have exhausted all available treatment options and are beginning to face end-of-life stage. Therefore, the unique properties of highly selective heavy particle irradiation with boron neutron capture therapy (BNCT) may be well suited to prolong the lives of patients with end-stage brainstem gliomas. Herein, we report a case series of life-threatening patients with end-stage brainstem glioma who eligible for Emergency and Compassionate Use, in whom we performed a scheduled two fractions of salvage BNCT strategy with low treatment dosage each time. No patients experienced acute or late adverse events related to BNCT. There were 3 patients who relapsed after two fractionated BNCT treatment, characterized by younger age, lower T/N ratio, and receiving lower treatment dose. Therefore, two fractionated low-dose BNCT may be a promising treatment for end-stage brainstem tumors. For younger patients with low T/N ratios, more fractionated low-dose BNCT should be considered.

2.
PLoS One ; 17(3): e0264641, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35231071

RESUMO

Intracranial germinoma (IG) rarely occurs in adults. Its optimal treatment strategy is unclear. We evaluated the outcomes of radiotherapy in adults with intracranial germinoma. Data of 29 adult patients (age, 18-52 years; median age, 24.3 years) with IG treated with radiotherapy at Taipei Veterans General Hospital were retrospectively reviewed. They were followed up for a median time of 5.9 years (range, 1.0-12.8 years). We used the Kaplan-Meier method to estimate the progression-free survival (PFS) and overall survival (OS), and univariate and multivariate Cox proportional hazards regression models to identify the factors affecting PFS. PFS and OS were compared between adult and pediatric patients with IG. The 1-, 3-, and 5-year PFS rates were 96.6%, 85.8%, and 77.8%, respectively, in the adult patients, and the OS rate were all 100%. Seven patients (24.1%) experienced recurrence, and in six of them, salvage therapy successfully controlled the disease. Two patients (6.9%) died after 5 years of follow-up due to disease progression and central pontine myelinolysis. In the univariate and multivariate Cox analysis, bifocal lesions had a significantly lower PFS than those with single lesions (p = 0.008). Kaplan-Meier survival analysis showed that adult patients had a poorer PFS (p = 0.06) and OS (p = 0.025) than pediatric patients. Our study showed bifocal lesions were associated with lower PFS than a single lesion among adult IG patients, and adult IG patients tended to have poorer PFS and OS compared to pediatric IG patients. For adult patients with bifocal IG, we recommend treatment with craniospinal irradiation, whole ventricle irradiation (WVI) with chemotherapy, or frequent spine images follow-up for patients who received only WVI.


Assuntos
Neoplasias Encefálicas , Germinoma , Adolescente , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Criança , Irradiação Craniana/efeitos adversos , Intervalo Livre de Doença , Germinoma/radioterapia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
3.
Sci Rep ; 12(1): 1728, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110660

RESUMO

Spinal metastasis from malignant primary brain tumors (MPBTs) in pediatric patients is rare and often appears as enhancing lesions on MRI. However, some indolent enhancing spinal lesions (IESLs) resulting from previous treatment mimic metastasis on MRI, leading to unnecessary investigation and treatment. In 2005-2020, we retrospectively enrolled 12 pediatric/young patients with clinical impression of spinal metastasis and pathological diagnosis of their spinal lesions. Three patients had MPBT with IESL, and 9 patients had malignant tumors with metastases. The histopathologic diagnosis of IESL was unremarkable marrow change. We evaluated their MRI, CT, and bone scan findings. The following imaging findings of IESL vs. spinal metastasis were noted: (1) IESLs appeared round/ovoid (3/3, 100%), whereas spinal metastasis appeared irregular (9/9, 100%) (P = 0.005); (2) target-shaped enhancement was noted in (3/3, 100%) vs. (0/9, 0%) of cases, respectively (P = 0.005); (3) pathologic fracture of the vertebral body was noted in (1/3, 33.3%) vs. (9/9, 100%) of cases, respectively (P = 0.045); (4) expansile vertebral shape was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); (5) obliteration of the basivertebral vein was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); and (6) osteoblastic change on CT was noted in (3/3, 100%) vs. (2/9, 22.2%) of cases, respectively (P = 0.034). IESL in pediatric patients with MPBT can be differentiated from metastasis based on their imaging characteristics. We suggest close follow-up rather than aggressive investigation and treatment for IESL.


Assuntos
Doenças da Medula Óssea/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Adolescente , Adulto , Biópsia , Doenças da Medula Óssea/patologia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/secundário , Coluna Vertebral/patologia , Adulto Jovem
4.
J Chin Med Assoc ; 85(2): 204-211, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34698689

RESUMO

BACKGROUND: Uterine carcinosarcoma (UCS) is a rare but highly lethal disease. Adjuvant chemotherapy is highly recommended for advanced UCS. To date, the standard chemotherapy regimen is still uncertain, although two regimens as paclitaxel-platinum (PP) and ifosfamide-platinum (IP) regimens are most commonly used. The aims of the current study attempt to compare both regimens in the management of advanced UCS patients. METHODS: We evaluated advanced UCS patients who were treated either with PP or with IP after primary cytoreductive surgery in single institute retrospectively. The clinical-pathological parameters, recurrence, and survival were recorded. RESULTS: A total of 16 patients were analyzed. Twelve patients received adjuvant PP therapy, and the remaining four patients received IP therapy. The median follow-up time was 28 months, ranging from 3.8 months to 121 months. Disease-related death occurred in 10 patients (62.5%). The median progression-free survival was 4.9 months, ranging from 3.8 months to 36.5 months in IP, and 23.1 months, ranging from 9.3 months to 121 months in PP, with statistically significant difference (p = 0.04). The median overall survival was 9.5 months (ranging from 3.8 months to 36.5 months) and 28.7 months (ranging from 10.3 months to 121 months) in IP and PP, respectively, without statistically significant difference (p = 0.06). Presence of pelvic and para-aortic lymphadenopathy and deep myometrial invasion (>1/2) were associated with worse prognosis by univariate analysis. No prognostic factor could be identified using multivariate analysis model. CONCLUSION: In the current study, due to extremely little number of subjects enrolled, the advantage of using paclitaxel-platinum regimen in the management of advanced UCS was still unclear, although a certain trend of favoring was supposed. We are looking forward to seeing more studies to identify the approximate regimen in the management of this highly lethal disease.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Ifosfamida/administração & dosagem , Paclitaxel/administração & dosagem , Platina/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos
5.
J Mol Med (Berl) ; 100(1): 135-146, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34689211

RESUMO

Fluoroscopy-induced chronic radiation dermatitis (FICRD) is a complication of fluoroscopy-guided intervention. Unlike acute radiation dermatitis, FICRD is different as delayed onset and usually appears without preexisting acute dermatitis. Unfortunately, the chronic and progressive pathology of FICRD makes it difficult to treat, and some patients need to receive wide excision and reconstruction surgery. Due to lack of standard treatment, investigating underlying mechanism is needed in order to develop an effective therapy. Herein, the Hippo pathway is specifically identified using an RNA-seq analysis in mild damaged skin specimens of patients with FICRD. Furthermore, specific increase of the Yes-associated protein (YAP1), an effector of the Hippo pathway, in skin region with mild damage plays a protective role for keratinocytes via positively regulating the numerous downstream genes involved in different biological processes. Interestingly, irradiated-keratinocytes inhibit activation of fibroblasts under TGF-ß1 treatment via remote control by an exosome containing YAP1. More importantly, targeting one of YAP1 downstream genes, nuclear receptor subfamily 3 group C member 1 (NR3C1), which encodes glucocorticoid receptor, has revealed its therapeutic potential to treat FICRD by inhibiting fibroblasts activation in vitro and preventing formation of radiation ulcers in a mouse model and in patients with FICRD. Taken together, this translational research demonstrates the critical role of YAP1 in FICRD and identification of a feasible, effective therapy for patients with FICRD. KEY MESSAGES: • YAP1 overexpression in skin specimens of radiation dermatitis from FICRD patient. • Radiation-induced YAP1 expression plays protective roles by promoting DNA damage repair and inhibiting fibrosis via remote control of exosomal YAP1. • YAP1 positively regulates NR3C1 which encodes glucocorticoid receptor expression. • Targeting glucocorticoid receptor by prednisolone has therapeutic potential for FICRD patient.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fluoroscopia/efeitos adversos , Glucocorticoides/uso terapêutico , Prednisolona/uso terapêutico , Radiodermatite/metabolismo , Animais , Linhagem Celular , Humanos , Queratinócitos/metabolismo , Camundongos Endogâmicos C57BL , Radiodermatite/tratamento farmacológico , Radiodermatite/genética , Pele/efeitos dos fármacos , Pele/metabolismo , /metabolismo
6.
Front Med (Lausanne) ; 8: 726214, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660637

RESUMO

Urothelial carcinoma is a common urological cancer in chronic kidney disease patients. Cystoscopy and urine cytology are the clinical diagnostic tools for UC. However, cystoscopy is an invasive procedure, while urine cytology showed low sensitivity for low-grade urothelial tumors. High accuracy with non-invasive tools for UC is needed for CKD patients. Our study collected a total of 272 urine and 138 plasma samples to detect the miRNA expression levels for establishing UC signatures from CKD patients. Seventeen candidate miRNAs of biofluids were selected and confirmed by qRT-PCR. Our results showed that urinary miR-1274a and miR-30a-5p expression levels were significantly lower but miR-19a-5p expression levels were higher in UC when compared with CKD. In plasma samples, miR-155-5p, miR-19b-1-5p, miR-378, and miR-636 showed significantly lower expression in UC compared to those with CKD. The Kaplan-Meier curve showed that lower expression of miR-19a, miR-19b, miR-636 and miR-378, and higher expression of miR-708-5p were associated with poor prognosis in patients with bladder cancer. In addition, we produced classifiers for predicting UC by multiple logistic regression. The urine signature was developed with four miRNAs, and the AUC was 0.8211. Eight miRNA expression levels from both urine and plasma samples were examined, and the AUC was 0.8595. Two miRNA classifiers and the nomograms could improve the drawbacks of current UC biomarker screenings for patients with CKD.

7.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575972

RESUMO

Glutamine and lipids are two important components of proliferating cancer cells. Studies have demonstrated that glutamine synthetase (GS) boosts glutamine-dependent anabolic processes for nucleotide and protein synthesis, but the role of GS in regulating lipogenesis remains unclear. This study identified that insulin and glutamine deprivation activated the lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) that bound to the GS promoter and increased its transcription. Notably, GS enhanced the O-linked N-acetylglucosaminylation (O-GlcNAcylation) of the specificity protein 1 (Sp1) that induced SREBP1/acetyl-CoA carboxylase 1 (ACC1) expression resulting in lipid droplet (LD) accumulation upon insulin treatment. Moreover, glutamine deprivation induced LD formation through GS-mediated O-GlcNAc-Sp1/SREBP1/ACC1 signaling and supported cell survival. These findings demonstrate that insulin and glutamine deprivation induces SREBP1 that transcriptionally activates GS, resulting in Sp1 O-GlcNAcylation. Subsequently, O-GlcNAc-Sp1 transcriptionally upregulates the expression of SREBP1, resulting in a feedforward loop that increases lipogenesis and LD formation in liver and breast cancer cells.


Assuntos
Acetil-CoA Carboxilase/genética , Glutamato-Amônia Ligase/genética , Neoplasias Hepáticas/genética , Fator de Transcrição Sp1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Glutamina/metabolismo , Humanos , Insulina/metabolismo , Lipídeos/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metabolismo/genética , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas/genética , Transdução de Sinais , beta-N-Acetil-Hexosaminidases/genética
9.
Biology (Basel) ; 10(4)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920984

RESUMO

Although boron neutron capture therapy (BNCT) is a promising treatment option for malignant brain tumors, the optimal BNCT parameters for patients with immediately life-threatening, end-stage brain tumors remain unclear. We performed BNCT on 34 patients with life-threatening, end-stage brain tumors and analyzed the relationship between survival outcomes and BNCT parameters. Before BNCT, MRI and 18F-BPA-PET analyses were conducted to identify the tumor location/distribution and the tumor-to-normal tissue uptake ratio (T/N ratio) of 18F-BPA. No severe adverse events were observed (grade ≥ 3). The objective response rate and disease control rate were 50.0% and 85.3%, respectively. The mean overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) times were 7.25, 7.80, and 4.18 months, respectively. Remarkably, the mean OS, CSS, and RFS of patients who achieved a complete response were 17.66, 22.5, and 7.50 months, respectively. Kaplan-Meier analysis identified the optimal BNCT parameters and tumor characteristics of these patients, including a T/N ratio ≥ 4, tumor volume < 20 mL, mean tumor dose ≥ 25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. In conclusion, for malignant brain tumor patients who have exhausted all available treatment options and who are in an immediately life-threatening condition, BNCT may be considered as a therapeutic approach to prolong survival.

10.
Oncogene ; 40(13): 2407-2421, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664454

RESUMO

Metastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Benzamidas/administração & dosagem , Fator II de Transcrição COUP/genética , MicroRNAs/genética , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Fatores de Transcrição/genética , Idoso , Animais , Benzamidas/efeitos adversos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
11.
Reproduction ; 161(1): 11-19, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112285

RESUMO

Endometriosis is a common gynecological disease in reproductive-age women. Although the hormone-dependent therapy is the first line treatment for endometriosis, it is not a curative regimen and associated with severe side-effects, which significantly decrease the life quality of affected individuals. To seek a target for treatment of endometriosis, we focused on plasma membrane proteins that are elevated in ectopic cells and exert beneficial effects in cell growth and survival. We performed bioinformatics analysis and identified the neurotrophic receptor tyrosine kinase 2 (NTRK2) as a potential candidate for treatment. The expression levels of NTRK2 were markedly upregulated in the lesions of clinical specimen as well as in the mouse endometriotic-like lesion. Mechanistic investigation demonstrated that upregulation of NTRK2 is induced by hypoxia in a hypoxia-inducible factor 1 alpha-dependent manner. Knockdown of NTRK2 or administration of ANA-12, a selective antagonist of NTRK2, significantly induced endometriotic stromal cells death, suggesting it may be a potential therapeutic agent. In vivo study using surgery-induced endometriosis mice model showed ANA-12 (1.5 mg/kg body weight) treatment induced apoptosis of endometriotic cells and caused the regression of ectopic lesions. Taken together, our findings suggest a possible mechanism responsible for the aberrant expression of NTRK2 in endometriotic lesions and this may be involved in the pathogenesis of endometriosis.


Assuntos
Endometriose/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , RNA Interferente Pequeno/uso terapêutico , Receptor trkB/metabolismo , Animais , Coristoma/metabolismo , Avaliação Pré-Clínica de Medicamentos , Endometriose/metabolismo , Feminino , Humanos , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Cultura Primária de Células , RNA Interferente Pequeno/farmacologia , Receptor trkB/antagonistas & inibidores , Células Estromais/metabolismo
13.
Mol Ther Oncolytics ; 18: 282-294, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32728616

RESUMO

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity of cancer. Hyperinsulinemia secondary to T2DM promotes cancer progression, whereas antidiabetic agents, such as metformin, have anticancer effects. However, the detailed mechanism for insulin and metformin-regulated cancer cell proliferation remains unclear. This study identified a mechanism by which insulin upregulated the expression of c-Myc, sterol regulatory element-binding protein 1 (SREBP1), and acetyl-coenzyme A (CoA) carboxylase 1 (ACC1), which are important regulators of lipogenesis and cell proliferation. Thymine DNA glycosylase (TDG), a DNA demethylase, was transactivated by c-Myc upon insulin treatment, thereby decreasing 5-carboxylcytosine (5caC) abundance in the SREBP1 promoter. On the other hand, metformin-activated AMP-activated protein kinase (AMPK) increased DNA methyltransferase 3A (DNMT3A) activity to increase 5-methylcytosine (5mC) abundance in the TDG promoter. This resulted in decreased TDG expression and enhanced 5caC abundance in the SREBP1 promoter. These findings demonstrate that c-Myc activates, whereas AMPK inhibits, TDG-mediated DNA demethylation of the SREBP1 promoter in insulin-promoted and metformin-suppressed cancer progression, respectively. This study indicates that TDG is an epigenetic-based therapeutic target for cancers associated with T2DM.

14.
PLoS Genet ; 16(6): e1008868, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32579581

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.


Assuntos
Fator II de Transcrição COUP/metabolismo , Neurônios Dopaminérgicos/patologia , Mitocôndrias/patologia , Doença de Parkinson/genética , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aldeído Desidrogenase , Animais , Encéfalo/citologia , Encéfalo/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/citologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Doença de Parkinson/patologia , Cultura Primária de Células , RNA-Seq , Ratos , Regulação para Cima
15.
Taiwan J Obstet Gynecol ; 59(3): 460-463, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32416900

RESUMO

OBJECTIVE: Endometriosis-associated epithelial ovarian cancer (EOC) is a specific category of EOC, containing either endometrioid or clear cell carcinoma subtype. The characteristic of endometriosis-associated EOC includes an early stage at the diagnosis, presence of single histology type, and better prognosis. The synchronous two subtypes of endometriosis-associated EOC and presentation of far-advanced stage status at the initial diagnosis is rarely reported. CASE REPORT: We reported a 60-year-old postmenopausal woman with FIGO IA endometriosis-associated endometrioid carcinoma at right ovary and FIGO IVA endometriosis-associated clear cell carcinoma at left ovary, right tube, omentum, lymph node and cytology of pleural effusion and ascites treated with optimal debulking surgery and dose-intensity taxane/platinum based chemotherapy. CONCLUSION: This case report confirms the long-term concept that clear cell carcinoma has much more aggressive behavior than endometrioid cell carcinoma does, regardless of association of endometriosis or not.


Assuntos
Adenocarcinoma de Células Claras/patologia , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/etiologia , Carcinoma Endometrioide/etiologia , Carcinoma Epitelial do Ovário/etiologia , Endometriose/complicações , Endometriose/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/etiologia , Neoplasias Ovarianas/etiologia , Ovário/patologia
16.
J Biomed Sci ; 27(1): 63, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32389123

RESUMO

Oxygen is essentially required by most eukaryotic organisms as a scavenger to remove harmful electron and hydrogen ions or as a critical substrate to ensure the proper execution of enzymatic reactions. All nucleated cells can sense oxygen concentration and respond to reduced oxygen availability (hypoxia). When oxygen delivery is disrupted or reduced, the organisms will develop numerous adaptive mechanisms to facilitate cells survived in the hypoxic condition. Normally, such hypoxic response will cease when oxygen level is restored. However, the situation becomes complicated if hypoxic stress persists (chronic hypoxia) or cyclic normoxia-hypoxia phenomenon occurs (intermittent hypoxia). A series of chain reaction-like gene expression cascade, termed hypoxia-mediated gene regulatory network, will be initiated under such prolonged or intermittent hypoxic conditions and subsequently leads to alteration of cellular function and/or behaviors. As a result, irreversible processes occur that may cause physiological disorder or even pathological consequences. A growing body of evidence implicates that hypoxia plays critical roles in the pathogenesis of major causes of mortality including cancer, myocardial ischemia, metabolic diseases, and chronic heart and kidney diseases, and in reproductive diseases such as preeclampsia and endometriosis. This review article will summarize current understandings regarding the molecular mechanism of hypoxia in these common and important diseases.


Assuntos
Endometriose/fisiopatologia , Cardiopatias/fisiopatologia , Hipóxia/fisiopatologia , Nefropatias/fisiopatologia , Doenças Metabólicas/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Neoplasias/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Doença Crônica , Endometriose/etiologia , Feminino , Cardiopatias/etiologia , Humanos , Hipóxia/complicações , Nefropatias/etiologia , Masculino , Doenças Metabólicas/etiologia , Isquemia Miocárdica/etiologia , Neoplasias/etiologia , Pré-Eclâmpsia/etiologia , Gravidez
17.
Cancers (Basel) ; 12(3)2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32235770

RESUMO

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

18.
Cancers (Basel) ; 12(3)2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32168907

RESUMO

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

19.
J Neurooncol ; 147(3): 619-631, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32222933

RESUMO

PURPOSE: The optimal treatment strategy for pediatric atypical teratoid rhabdoid tumor (ATRT) is inconclusive. This study evaluated the prognostic value of early radiotherapy (RT) and high-dose chemotherapy with autologous stem cell rescue (HDC/ASCR) in pediatric ATRT. METHODS: This pooled analysis included ATRT patients treated at our institution and from other studies who were identified by a search of the PubMed electronic database. The effect of patient demographics and treatment profiles on progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression. RESULTS: Overall, 34 patients from our institution and 436 patients from 35 published studies were included. In multivariable analysis, patients with gross total resection (GTR), early RT (time to RT interval < 2 months), and HDC/ASCR had both better PFS [hazard ratio (HR) 0.46, p[Formula: see text] 0.001; HR 0.64, p = 0.011; and HR 0.51, p = 0.005, respectively] and OS (HR 0.55, p = 0.002; HR 0.48, p = 0.004; and HR 0.42, p < 0.001, respectively). For patients aged < 3 years, both RT and HDC/ASCR were significant favorable factors for PFS (HR 0.32 and 0.46, respectively) and OS (HR 0.40 and 0.36, respectively), while early RT was not prognostic. For patients aged ≥ 3 years, early RT was significantly associated with better PFS (HR 0.51) and HDC/ASCR did not affect PFS, and neither was related to OS. CONCLUSION: Both early RT initiation and HDC/ASCR were important components in the treatment of pediatric ATRT. However, the optimal treatment strategies might differ by age.


Assuntos
Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/radioterapia , Teratoma/tratamento farmacológico , Teratoma/radioterapia , Adolescente , Adulto , Criança , Terapia Combinada , Feminino , Humanos , Masculino , Prognóstico , Resultado do Tratamento , Adulto Jovem
20.
Childs Nerv Syst ; 36(8): 1745-1753, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32090282

RESUMO

PURPOSE: A basal ganglia (BG) germinoma is a rare tumor, and the optimal treatment remains unknown. We evaluated the clinical outcomes of treatment of BG germinoma in pediatric patients in Taiwan. METHODS: We retrospectively reviewed the medical records of 34 children with BG germinoma who were treated with radiotherapy (RT) at Taipei Veterans General Hospital between 1989 and 2016. The median follow-up time is 8.3 years (1.8-25.2 years). Survival was analyzed using the Kaplan-Meier estimate. Univariate Cox proportional-hazards models were used to identify the potential risk factors. RESULTS: Only four patients (11.8%) experienced recurrence and all successfully underwent salvage therapy. One patient (2.97%) died due to suspected radiotherapy (RT)-related sarcoma in the scalp. The 2-, 3-, and 5-year DFS rates were 91.2%, 88.2%, and 79.4%, respectively; the 2-, 3-, and 5-year OS rates were 97.1%, 94.1%, and 82.4%, respectively. Focal RT showed low DFS in the Kaplan-Meier survival curves (P = .028) compared with non-focal RT (whole ventricle, whole brain, or cranial spinal area). In the univariate Cox proportional-hazards model, there was a significant difference in DFS between focal and non-focal RT (P = .03). There is no difference in DFS and OS between BG germinoma patients and non-BG germinoma patients. CONCLUSIONS: We found an excellent DFS and OS in pediatric patients with BG germinoma treated with RT. Whole ventricle irradiation is recommended for good tumor control and low treatment-related toxicity. BG germinoma patients showed similar treatment results as germinoma patients in other common sites.


Assuntos
Neoplasias Encefálicas , Germinoma , Gânglios da Base , Neoplasias Encefálicas/radioterapia , Criança , Germinoma/radioterapia , Humanos , Recidiva Local de Neoplasia , Dosagem Radioterapêutica , Estudos Retrospectivos , Taiwan , Resultado do Tratamento
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