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2.
Gut ; 69(1): 122-132, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076405

RESUMO

OBJECTIVE: We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time. DESIGN: Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice. RESULTS: In KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-ß)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-ß production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-ß on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models. CONCLUSION: Stromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Colágeno/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Fibroblastos/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Camundongos Endogâmicos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Gut ; 69(1): 18-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171626

RESUMO

OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-ß as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.


Assuntos
Adenocarcinoma/secundário , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Instabilidade Cromossômica , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/imunologia , Ploidias , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Sequenciamento Completo do Exoma/métodos
4.
Biochem Med (Zagreb) ; 30(1): 010801, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839726

RESUMO

This is a case report of a challenging diagnosis of IgE monoclonal gammopathy of undetermined significance, which transformed into myeloma, then transformed into IgE-producing plasma cell leukaemia in a 71-year-old male who was followed in Brest, France, from 2015 to 2019. The IgE-producing variant is the rarest sub-type of multiple myeloma, and plasma cell leukaemia is considered to be the rarest and the most aggressive of human monoclonal gammopathies. In November 2015, hypogammaglobulinemia was detected during a systematic check-up. A kappa light chain monoclonal gammopathy was first diagnosed due to an increase of the free kappa/lambda light chains ratio. No monoclonal immunoglobulin was detected by either serum protein electrophoresis (Capillarys 2, Sebia, Issy-les-Moulineaux, France) or immunofixation (Hydrasys 2, Sebia, Issy-les-Moulineaux, France). In June 2018, a blood smear led to the diagnosis of plasma cell leukaemia. A monoclonal peak was detected and identified as IgE-kappa. Analysis of an archival sample taken three years earlier, revealed the presence of a monoclonal IgE, which had been missed at diagnosis. Chemotherapy with bortezomib and dexamethasone was introduced. The patient survived 10 months after the diagnosis of leukaemia. This case shows that an abnormal free light chain ratio should be considered as a possible marker of IgE monoclonal gammopathy even in the absence of a solitary light chain revealed by immunofixation. In addition, the use of an undiluted serum may increase the sensitivity of the immunofixation for the detection of IgE monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer.


Assuntos
Imunoglobulina E/metabolismo , Leucemia Plasmocitária/diagnóstico , Idoso , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Leucemia Plasmocitária/tratamento farmacológico , Masculino , Paraproteinemias/diagnóstico , Plasmócitos/patologia
5.
Bioelectrochemistry ; 131: 107350, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31518962

RESUMO

Curcumin (Cur), the yellow pigment of well-known turmeric (Curcuma longa L.) is effective in multiple cancers including triple negative breast cancer (TNBC). In combination with electrical pulses (EP), enhanced effects of curcumin (Cur + EP) are observed in TNBC cells. To gain insights into the mechanisms of enhanced anticancer effects of Cur + EP, we studied the proteins involved in the anticancer activity of Cur + EP in MDA-MB-231, human TNBC cells using high-throughput global proteomics. A curcumin dose of 50 µM was applied with eight, 1200 V/cm, 100 µs pulses, the most commonly used electrochemotherapy (ECT) parameter in clinics. Results show that the Cur + EP treatment reduced the clonogenic ability in MDA-MB-231 cells, with the induction of apoptosis. Proteomic analysis identified a total of 1456 proteins, of which 453 proteins were differentially regulated, including kinases, heat shock proteins, transcription factors, structural proteins, and metabolic enzymes. Eight key glycolysis proteins (ALDOA, ENO2, LDHA, LDHB, PFKP, PGM1, PGAM1 and PGK1) were downregulated in Cur + EP from Cur. There was a switch in the metabolism with upregulation of 10 oxidative phosphorylation pathway proteins and 8 tricarboxylic acid (TCA) cycle proteins in the Cur + EP sample, compared to curcumin. These results provide novel systematic insights into the mechanisms of ECT with curcumin.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Eletroquimioterapia/métodos , Proteínas de Neoplasias/metabolismo , Proteômica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Curcumina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Glicólise , Humanos , Fosforilação Oxidativa , Via de Pentose Fosfato/efeitos dos fármacos , Reprodutibilidade dos Testes , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
6.
J Urol ; 203(1): 57-61, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600114

RESUMO

PURPOSE: We sought to determine the trend of neoadjuvant chemotherapy use for nonmetastatic muscle invasive urothelial bladder cancer and whether it is associated with adverse perioperative morbidity after robot-assisted radical cystectomy. MATERIALS AND METHODS: We retrospectively reviewed the IRCC (International Robotic Cystectomy Consortium) database between 2006 and 2017. After excluding patients with nonmuscle invasive bladder cancer the patients were divided into 2 groups, including those who did vs did not receive neoadjuvant chemotherapy. Data were reviewed for demographics, preoperative, operative and 90-day perioperative outcomes. We used the Cochran-Armitage trend test to assess trends of neoadjuvant chemotherapy associations with high grade and overall complications with time. Multivariate stepwise regression analyses were done to determine whether neoadjuvant chemotherapy was associated with prolonged operative time, 90-day postoperative complications, readmissions, reoperations and mortality after robot-assisted radical cystectomy. RESULTS: A total of 298 patients (26%) received neoadjuvant chemotherapy. These patients were younger (age 67 vs 69 years, p=0.01) and more frequently had an ASA™ (American Society of Anesthesiologists™) score of 3 or greater (62% vs 55%, p=0.02) and pathological T3 stage or greater disease (28% vs 22%, p=0.04). The use of neoadjuvant chemotherapy increased significantly from 10% in 2006 to 2007 to 42% in 2016 to 2017 (p <0.01). On multivariate analysis neoadjuvant chemotherapy was not significantly associated with prolonged operative time, hospital stay, 90-day postoperative complications, reoperation or mortality. Neoadjuvant chemotherapy was associated with 90-day readmissions after robot-assisted radical cystectomy (OR 5.90, 95% CI 3.30-10.90, p <0.01). CONCLUSIONS: Neoadjuvant chemotherapy utilization has significantly increased in the last decade. It was not associated with perioperative surgical morbidity after robot-assisted radical cystectomy.


Assuntos
Quimioterapia Adjuvante , Cistectomia , Terapia Neoadjuvante , Procedimentos Cirúrgicos Robóticos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Antineoplásicos/uso terapêutico , Humanos , Masculino , Duração da Cirurgia , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
7.
J Clin Pathol ; 73(1): 17-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31300530

RESUMO

OBJECTIVE: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management. METHODS: Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed. RESULTS: High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20-89) with the two patients <45 years of age showing highest intratumour heterogeneity. TP53 was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance (KIT S821F, KIT T670I, RAS mutations at codons 12 and 13). CONCLUSION: We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.


Assuntos
Biomarcadores Tumorais/genética , Heterogeneidade Genética , Neoplasias de Cabeça e Pescoço/genética , Mutação , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Tomada de Decisão Clínica , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Seleção de Pacientes , Fenótipo , Medicina de Precisão , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma
8.
APMIS ; 128(1): 3-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31628675

RESUMO

Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here, we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer. A total of 56 patients were included in a one-armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin, and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes. ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS were in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis. Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR fusions, ERBB3, and BRCA1/2.


Assuntos
Neoplasias dos Ductos Biliares/genética , Exoma , Mutação , Adulto , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Inclusão em Parafina , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , beta Catenina/genética
10.
Tech Vasc Interv Radiol ; 22(4): 100629, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31864536

RESUMO

Vascular anomalies are classified as either tumors or malformations based on clinical findings rendered through radiologic evaluation, physical exam, and histologic interpretation. These findings comprise the phenotype of the disorder. Recently, advances in the molecular genetics of vascular anomalies have shed light on the genotype of these disorders. These phenotype/genotype characterizations will provide a more precise classification of vascular anomalies and identify potential therapeutic targets for expanded treatment options in the future. In this chapter, we will review the phenotype/genotype characterizations and the possible therapeutic pathways for targeted pharmacologic therapy.


Assuntos
Técnicas de Diagnóstico Molecular , Neoplasias de Tecido Vascular/genética , Malformações Vasculares/genética , Antineoplásicos/uso terapêutico , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular , Neoplasias de Tecido Vascular/diagnóstico por imagem , Neoplasias de Tecido Vascular/tratamento farmacológico , Fenótipo , Medicina de Precisão , Valor Preditivo dos Testes , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/tratamento farmacológico
11.
Medicine (Baltimore) ; 98(52): e18552, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876753

RESUMO

BACKGROUND: Compound Kushen injection (CKI) is a commonly used anti-tumor Chinese patent medicine, which is extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae) and has been widely prescribed as an add-on therapy to platinum-based chemotherapy (PBC) for advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain controversial. METHODS AND ANALYSIS: A systematic review and meta-analysis will be performed following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. All randomized controlled trials (RCTs) comparing CKI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. The disease control rate (DCR) will be defined as the primary outcome, and the objective response rate (ORR), quality of life (QOL), survival rate, and toxicities will be the secondary outcomes. RESULTS: This study will systematically evaluate the efficacy and safety of Compound Kushen injection combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results of this study will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review and meta-analysis of eligible randomized controlled trials will evaluate the effects of Compound Kushen injection as adjunctive therapy to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical use of this combination therapy for the specific subsets of patients. PROSPERO REGISTRATION NUMBER: CRD42019134892.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/uso terapêutico , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/uso terapêutico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Compostos de Platina/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Medicine (Baltimore) ; 98(52): e18435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876723

RESUMO

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) accounts for 10% to 15% of all primary hepatic carcinomas. However, there are no effective drug treatment strategies against ICC, and surgery is currently the only curative treatment. Here, we present a case of ICC successfully treated with anlotinib, a novel oral agent. PATIENT CONCERNS: The patient was a 66-year-old Han Chinese woman, and she was a retired worker. The patient had no history of hepatitis B infection or hypertension. Physical examination showed no abnormalities, and the patient showed no conscious discomfort. However, ultrasound revealed liver occupation. DIAGNOSIS: Liver ultrasound and enhanced computed tomography (CT) indicated liver cancer with intrahepatic metastasis. Serum carbohydrate antigen 199 and alpha fetoprotein levels were high at 4270 and 1561 ng/mL, respectively. Pathologic findings of CT-guided liver biopsy revealed an adenocarcinoma. Owing to further immunohistochemical staining and clinical results, a diagnosis of ICC was made. INTERVENTIONS: The patient had received 5 cycles of transhepatic arterial chemotherapy and embolization and 1 cycle of microwave ablation. Due to rapid tumor progression and loss of liver function, systemic chemotherapy was contraindicated. As second-line therapy, she received anlotinib, a novel tyrosine kinase inhibitor that inhibits tumor angiogenesis and proliferative signaling and has been used to treat refractory advanced non-small-cell lung cancer that shows progression despite treatment with ≥2 chemotherapy regimens. OUTCOMES: This patient showed a partial response after 2 cycles of treatment with anlotinib (12 mg daily, days 1-14 of a 21-day cycle). Drug-related side effects, such as hypertension and hand foot skin reaction, were observed. After 4 cycles of anlotinib, the efficacy appeared to be stable, and the patient showed a progression-free survival period of almost 4 months. However, the patient's condition worsened and she died of liver failure 6 months after treatment (overall survival, almost 6 months). CONCLUSION: Some cases of ICC may be responsive to the antiangiogenic drug, anlotinib, when combined with microwave ablation. Randomized clinical studies are required to further confirm the efficacy and safety of anlotinib in the clinical treatment of ICC.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/terapia , Indóis/uso terapêutico , Micro-Ondas/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/diagnóstico por imagem , Terapia Combinada , Feminino , Humanos , Tomografia Computadorizada por Raios X , Ultrassonografia
13.
Medicine (Baltimore) ; 98(51): e18210, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860968

RESUMO

BACKGROUND: Cisplatin is often used for the treatment of oral cancer (OC). However, there are inconsistent results. Thus, this study plans to systematically assess the clinical efficacy and safety of cisplatin for adult patients with OC. METHODS: We will search for PUBMED, EMBASE, Cochrane Library, AMED, Cumulative Index to Nursing and Allied Health Literature, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All of them will be searched from the construction of each database up to the present with no restrictions of language and publication status. The data analysis will be conducted using RevMan 5.3 software to assess the efficacy and safety of cisplatin for adult patients with OC. RESULTS: This study will summarize the most recent high-quality evidence and will provide helpful information about the efficacy and safety of cisplatin for adult patients with OC. CONCLUSION: The findings of this study will provide convinced evidence of cisplatin for adult patients with OC, and provide recommendations for clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019156558.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Humanos , Resultado do Tratamento
14.
Zhonghua Zhong Liu Za Zhi ; 41(12): 949-952, 2019 Dec 23.
Artigo em Chinês | MEDLINE | ID: mdl-31874554

RESUMO

Lung cancer is the most frequently diagnosed cancer and the most common cause of cancer mortality in China. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers. The mutation rate of epidermal growth factor receptor (EGFR) gene is relatively high, accounts for 32%~38% of all NSCLC. During the last decade, the application of EGFR specific tyrosine kinase inhibitors (TKI) significantly improved prognosis of NSCLC patients with sensitive EGFR mutations. Thus, the research and development of third generation EGFR-TKI have entered the period of rapid development. The fourth generation EGFR-TKI which targeting EGFR C797S has even begun clinical development in China. This review will discuss the clinical research and drug review of EGFR-TKI from the perspective of drug review.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , China , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Mutação
15.
Medicine (Baltimore) ; 98(52): e18414, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876714

RESUMO

RATIONALE: Primary pulmonary inflammatory myofibroblastic tumor (IMT) with distant metastasis is extremely rare. Moreover, metastasis of pulmonary IMT to bone marrow has never been reported in previous studies. Therapeutic approaches for anaplastic lymphoma kinase (ALK)-negative pulmonary IMT with metastasis are limited. Yet there is no report on the treatment of advanced IMT cases with anti-angiogenesis drugs. PATIENT CONCERNS: We described a patient with a complaint of fatigue, with the chest computed tomography (CT) scan revealing 2 masses in bilateral lung. DIAGNOSES: The CT-guided lung biopsy examined 1 lesion in the right lung, and the post-operative pathological diagnosis of ALK-negative pulmonary IMT was recommended. However, the lung lesions were found significantly enlarged during the subsequent visit 8 months later, along with multiple metastases to the bone and abdominal cavity. A bone marrow biopsy revealed bone marrow infiltration by spindle cells. INTERVENTIONS: The patient began to take Celecoxib due to the rapid progression of IMT, however, resulting in the aggravated gastric ulcer. He stopped taking the medicine 1 month later, with no remarkable change in the lesions by CT. Apatinib was administrated instead of Celecoxib. OUTCOMES: After the 5-month treatment of Apatinib, the mass in the abdominal cavity significantly shrank and the lung lesions slightly decreased in size. With the 9-month administration of Apatinib, the lung lesions and the abdominal mass kept stable, compared with the situation in the 5-month follow-up. LESSONS: Although pulmonary IMT shows the potential of metastasis, its metastasizing to bone marrow is a highly unusual event. Apatinib is effective for pulmonary IMT, and should be taken into consideration for the treatment of inoperable pulmonary IMT patients who lack ALK rearrangement.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias de Tecido Muscular/tratamento farmacológico , Piridinas/uso terapêutico , Quinase do Linfoma Anaplásico , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/patologia , Neoplasias de Tecido Muscular/diagnóstico , Neoplasias de Tecido Muscular/patologia , Tomografia Computadorizada por Raios X
16.
Autops. Case Rep ; 9(4): e2019116, Oct.-Dec. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-1024253

RESUMO

Basal cell carcinoma (BCC) is the most common skin cancer. It generally has an indolent course with low rates of metastasis and mortality. However, BCC is locally invasive and can cause significant morbidity due to destructive local spread. We report our experience with a patient who was referred to our skin cancer unit due to a previously neglected lesion on the parietal region of the scalp, which had developed for 7 years. The patient was prescribed vismodegib on the basis that surgery could cause excessive functional and aesthetic damage. The patient had an objective partial response after 20 months of treatment. He was then submitted to radical skin excision, leaving a large defect that was reconstructed using a free latissimus dorsi muscle flap. The patient recovered well, and at the 1-year follow-up there were no signs of local recurrence. Our case demonstrates the value of vismodegib treatment prior to surgery in a locally advanced, high-risk scalp BCC and highlights the importance of an individualized and specialized approach with these patients, within a multidisciplinary team.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Basocelular/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Equipe de Assistência ao Paciente , Procedimentos Cirúrgicos Reconstrutivos , Terapia Neoadjuvante , Antineoplásicos/uso terapêutico
17.
Bull Cancer ; 106(11): 946-958, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711572

RESUMO

AIM: A HER2-specific second-generation chimeric antigen receptor (5.137.z) was introduced into NK-92 cells, designated as NK-92/5.137.z cells. To evaluate the function and effectiveness of NK-92/5.137.z cells against gastric cancer cells and further determined whether combination with apatinib can synergize with this NK cell-based practice to better suppress gastric cancer. METHODS: The expression of HER2 was examined in gastric cancer. The in vitro and in vivo cytotoxic activities of NK-92/5.137.z cells with or without apatinib were evaluated against gastric cancer cell lines. RESULTS: HER2 proteins were over-expressed in a considerable proportion of gastric cancer cells. NK-92/5.137.z cells specifically lysed gastric cancer cells expressing HER2 and had higher levels of cytokine production. In vivo, NK-92/5.137.z cells were particularly efficient at eliminating small tumor xenografts, whereas larger solid tumors were not effectively controlled with NK-92/5.137.z cells. Treatment with apatinib increased NK cell infiltration into large tumor xenografts and improved the therapeutic efficacy of NK-92/5.137.z cells. CONCLUSION: NK-92/5.137.z cells could represent a novel treatment option for patients with gastric cancer, either used alone or combined with apatinib.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Piridinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Neoplasias Gástricas/terapia , Animais , Antígeno CD56/metabolismo , Degranulação Celular , Linhagem Celular Tumoral , Terapia Combinada/métodos , Xenoenxertos , Humanos , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Lentivirus , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Cancer Immunol Immunother ; 68(12): 2005-2014, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701161

RESUMO

Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class  (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Ácidos Graxos/metabolismo , Imunoterapia/métodos , Linfócitos T/imunologia , Neoplasias Urológicas/terapia , Adulto , Idoso , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Feminino , Humanos , Imunização , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Peroxissomos/metabolismo , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Transdução de Sinais , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/mortalidade
19.
Zhonghua Er Ke Za Zhi ; 57(11): 852-856, 2019 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-31665839

RESUMO

Objective: To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease. Methods: A prospective self-control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People's Liberation Army General Hospital from January 2011 to January 2019 were collected. The long-term rapamycin treatment for all patients initiated at 1 mg/(m(2)·d), which was gradually adjusted to reach a blood concentration of 5-10 µg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test. Results: Ninety-two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow-up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0,7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750,P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and ≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102,P=0.393,0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and ≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0,18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm)(Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214,P=0.345,0.225,0.301,0.058,0.109,0.225, respectively).Twenty-nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed. Conclusions: Rapamycin could decrease the diameter of TSC-related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.


Assuntos
Angiomiolipoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Sirolimo/uso terapêutico , Esclerose Tuberosa/complicações , Angiomiolipoma/etiologia , Criança , China , Feminino , Humanos , Recém-Nascido , Neoplasias Renais/etiologia , Masculino , Estudos Prospectivos , Sirolimo/administração & dosagem
20.
Nihon Shokakibyo Gakkai Zasshi ; 116(11): 952-959, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31708508

RESUMO

According to the 2017 WHO classification (4th version), PanNEC G3 was subdivided into two groups:well-differentiated PanNET G3 and poorly differentiated PanNEC. Considering the insufficient number of case reports, appropriate chemotherapy for the new category PanNET G3 remains unknown. Here, we report a case of PanNET G3 that responded to platinum-based chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Platina , Humanos , Gradação de Tumores , Tumores Neuroendócrinos , Neoplasias Pancreáticas
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