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1.
Medicine (Baltimore) ; 100(17): e25493, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907099

RESUMO

BACKGROUND: A combination of fluoropyrimidines and platinum is widely accepted as the standard first-line treatment for advanced gastric and gastroesophageal adenocarcinomas. However, the benefit compared with platinum-free chemotherapeutic regimens remains controversial. We compared the efficacy and safety of capecitabine with oxaliplatin or docetaxel, as first-line therapy in advanced gastric cancer. METHODS: Eligible patients were randomly assigned to receive either capecitabine and oxaliplatin (XELOX) (capecitabine 1,000 mg/m2; twice daily for 14 days with oxaliplatin 130 mg/m2 on day 1, every 21 days), or DX (capecitabine 1,000 mg/m2; twice daily for 14 days with docetaxel 75 mg/m2 on day 1, every 21 days). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival, overall survival, and prespecified safety endpoints. RESULTS: Ninety patients were enrolled in the West China Hospital from April 2012 to August 2016; a total of 83 and 66 patients were eligible for safety and efficacy analyses, respectively. Between the XELOX and DX groups, ORR (24.2% vs 24.2%, p = 1.000), DCR (90.9% vs 75.8%, p = 0.099), progression-free survival (6.1m vs 4.1m, p = 0.346), and overall survival (8.8m vs 9.0m, p = 0.973) were similar. There was no significant difference in toxicity between the two regimens. The frequent grade 3 or higher toxicities in the XELOX and DX groups were peripheral neuropathy and hematological toxicity, respectively. Toxicity was tolerable; no treatment-related deaths occurred in either group. CONCLUSIONS: The DX regimen was not superior to XELOX, but instead, similar. The platinum-containing regimen remains the preferred first-line option for advanced gastric and gastroesophageal adenocarcinomas, and DX might be considered as an alternative for patients unsuitable for platinum-containing chemotherapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaloacetatos/uso terapêutico , Intervalo Livre de Progressão , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida
2.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799513

RESUMO

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome's distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Ensaios Clínicos como Assunto , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Medicina de Precisão/métodos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Análise de Sobrevida , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade
3.
Gan To Kagaku Ryoho ; 48(3): 336-340, 2021 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-33790152

RESUMO

To the effect of chemotherapy in cancer patients, in addition to direct cytotoxicity against cancer cells, contribution of tumor immune-mediated mechanisms have been reported. To elucidate the immune environment involved in the response to chemotherapy in esophageal cancer, we collected pre-treatment biopsy tissues from 86 patients, performed multiple staining with fluorescein-labeled tyramide, and analyzed lymphocytes and macrophages using a variable-wavelength filter fluorescence microscope to compare the effects of chemotherapy. Although there was no correlation with various T-cell fractions, high levels of CD163- or CD206-positive M2 macrophages (TAM) were significantly associated with chemotherapy non-responders. The results suggest that the combination of TAM inhibitors may be useful in overcoming chemotherapy resistance in esophageal cancer.


Assuntos
Neoplasias Esofágicas , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Imuno-Histoquímica , Macrófagos
4.
Anticancer Res ; 41(4): 1771-1778, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813381

RESUMO

BACKGROUND/AIM: Eicosapentaenoic acid (EPA) is an unsaturated fatty acid with various bioactivities, including antitumor effects. We previously reported a synergistic antitumor effect of cisplatin (CDDP) and EPA. Here, we examined the underlying mechanism. MATERIALS AND METHODS: The human oesophageal cancer cell line TE-1 was treated with the combination of EPA and CDDP. Nuclear translocation of NF-κB, a transcription factor involved in cytokine production, was detected by immunohistochemistry. IL-6 levels were measured by ELISA. Apoptosis and cell cycle distribution were evaluated by flow cytometry. RESULTS: Nuclear translocation of NF-κB in TE-1 cells was synergistically decreased by CDDP and EPA. IL-6 production was increased following treatment with CDDP, but treatment with EPA decreased IL-6 levels. Apoptosis was synergistically induced by CDDP and EPA. A G2/M cell cycle arrest was observed with the combination of CDDP and 150 µM EPA, and S phase arrest with the combination of CDDP and 100 µM EPA. CONCLUSION: The combination of CDDP and EPA synergistically suppresses NF-κB nuclear translocation and increases apoptosis by inducing cell cycle arrest at the S or G2/M phase.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Ácido Eicosapentaenoico/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais
5.
Carbohydr Polym ; 261: 117846, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766342

RESUMO

In the clinical treatment of cancer, improving the effectiveness and targeting of drugs has always been a bottleneck problem that needs to be solved. In this contribution, inspired by the targeted inhibition on cancer from combination application of disulfiram and divalent copper ion (Cu2+), we optimized the concentration of disulfiram and Cu2+ ion for inhibiting esophageal cancer cells, and loaded them in hyaluronic acid (HA)/polyethyleneimine (PEI) nanoparticles with specific scales, in order to improve the effectiveness and targeting of drugs. The in vitro cell experiments demonstrated that more drug loaded HA/PEI nanoparticles accumulated to the esophageal squamous cell carcinoma (Eca109) and promoted higher apoptosis ratio of Eca109. Both in vitro and in vivo biological assessment verified that the disulfiram/Cu2+ loaded HA/PEI nanoparticles promoted the apoptosis of cancer cells and inhibited the tumor proliferation, but had no toxicity on other normal organs.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Cobre/administração & dosagem , Dissulfiram/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Ácido Hialurônico/química , Nanopartículas/química , Polietilenoimina/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Células Cultivadas , Cobre/farmacocinética , Dissulfiram/farmacocinética , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Íons Pesados , Humanos , Ácido Hialurônico/síntese química , Ácido Hialurônico/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/uso terapêutico , Polietilenoimina/síntese química , Polietilenoimina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Ann Oncol ; 32(5): 590-599, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33609722

RESUMO

Gastroesophageal adenocarcinoma (GEA) and squamous esophageal cancer (ESCC) are responsible for >1 million deaths annually globally. Until now, patients with metastatic GEA and ESCC could anticipate survival of <1 year. Anti- programmed cell death protein 1 (anti-PD-1) monotherapy has demonstrated modest efficacy in previously treated GEA and ESCC. In 2020, four pivotal trials have established anti-PD-1 therapy as a new standard of care for selected GEA and ESCC patients as first-line advanced and adjuvant therapy. In this review, we discuss the recent results of the CheckMate 649, ATTRACTION-4, KEYNOTE-590 and CheckMate 577 trials. We consider these results in the context of current standards of care and historical trials of immune checkpoint blockade in GEA and ESCC. We explore biomarker selection for anti-PD-1 therapy and appraise the future of combination therapies. In CheckMate 649, treatment with oxaliplatin-fluoropyrimidine chemotherapy plus nivolumab in patients with combined positive score ≥5 GEA tumors provided a clinically meaningful and statistically significant improvement in overall survival. The ATTRACTION-4 trial did not see a similar overall survival benefit, despite a clear improvement in progression-free survival. We review potential explanations for this result. KEYNOTE-590 showed profoundly improved survival when pembrolizumab was added to cisplatin-fluoropyrimidine chemotherapy in ESCC patients with combined positive score ≥10 tumors; this benefit was less convincing in unselected ESCC. Finally, CheckMate 577 provides proof-of-concept for the improvement in disease-free survival with adjuvant nivolumab in high-risk resected GEA and ESCC following trimodality therapy. Immune checkpoint blockade has come of age in GEA and ESCC, and will now be integrated into first-line and earlier lines of therapy, providing benefit for a larger proportion of patients. Biomarker standardization will be critical to select the patients most likely to benefit from treatment. For patients with immune evasive tumors, novel combinations under development show promise; however, global trials are needed.


Assuntos
Neoplasias Esofágicas , Neoplasias Gástricas , Anticorpos Monoclonais Humanizados , Terapia Combinada , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Nivolumabe/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico
8.
Ann Oncol ; 32(5): 609-619, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33610734

RESUMO

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Claudinas/genética , Claudinas/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica , Humanos , Neoplasias Gástricas/tratamento farmacológico
9.
Am J Clin Oncol ; 44(4): 158-161, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33625121

RESUMO

OBJECTIVE: The objective of this study was to review real-world patterns of chemotherapy utilization among patients with metastatic gastric/lower esophageal adenocarcinoma with particular focus on the use of ramucirumab plus paclitaxel in previously treated patients. METHODS: This is a retrospective, registry-based study using datasets from Alberta Cancer Registry and other provincial databases in Alberta, Canada. Multivariable logistic regression analysis was used to identify factors associated with palliative chemotherapy use. Among patients who received >1 line of chemotherapy, Kaplan-Meier survival estimates were used to compare outcomes according to ramucirumab plus paclitaxel use. Multivariable Cox regression analysis was then used to identify factors associated with overall survival (OS) in this cohort. RESULTS: A total of 1590 patients were included (including 1070 gastric patients and 520 lower esophageal patients). The following factors were associated with use of palliative chemotherapy: younger age (odds ratio with increasing age: 0.95; 95% confidence interval [CI]: 0.94-0.95), and lower Charlson Comorbidity Index (odds ratio with increasing index: 0.82; 95% CI: 0.74-0.91). Within the subcohort of patients who received >1 line of chemotherapy, use of ramucirumab/paclitaxel was associated with better OS (P=0.033). Multivariable Cox regression analysis suggested that the following factors are associated with better OS: use of ramucirumab/paclitaxel (hazard ratio [HR]: 1.56; 95% CI: 1.07-2.29) and living within urban zones including Calgary or Edmonton zones (vs. Northern zone) (HR for Calgary zone vs. Northern zone: 0.44; 95% CI: 0.23-0.85; HR for Edmonton zone vs. Northern zone: 0.41; 95% CI: 0.22-0.77). CONCLUSIONS: Use of paclitaxel/ramucirumab combination beyond first-line treatment is associated with improved OS among patients with metastatic gastric/lower esophageal adenocarcinoma in this real-world study. Further work is needed to reduce disparity in our health care system between individuals living in rural versus urban areas.


Assuntos
Adenocarcinoma/secundário , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Cuidados Paliativos , Estudos Retrospectivos
10.
Cell Prolif ; 54(3): e13004, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33543561

RESUMO

OBJECTIVES: Endoscopic submucosal dissection (ESD), a preferential approach for early oesophageal neoplasms, inevitably results in oesophageal strictures in patients. Clinical use of glucocorticoids through submucosal injection is beneficial for inhibiting oesophageal stricture following injury; however, it also has limitations, such as dose loss and perforation. Hence, alternatives to glucocorticoid therapy should be developed. METHODS: A novel porous composite scaffold, ChCo-TAMS, composed of chitosan, collagen-I and triamcinolone acetonide (TA) loaded into poly (lactic-co-glycolic) acid (PLGA) microspheres (TAMS), was successfully constructed and subjected to biological testing to ameliorate oesophageal ESD-related stenosis. RESULTS: The synthesized biomaterials displayed unique properties in inhibiting the activation of macrophages, chemokine-mediated cell recruitment and fibrogenesis of fibroblasts. Further application of the scaffolds in the rat dermal defect and porcine oesophageal ESD model showed that these novel scaffolds played a robust role in inhibiting wound contracture and oesophageal ESD strictures. CONCLUSIONS: The developed composite scaffolds provide a promising clinical medical device for the prevention of post-operative oesophageal stricture.


Assuntos
Quitosana/farmacologia , Colágeno/efeitos dos fármacos , Constrição Patológica/patologia , Neoplasias Esofágicas/tratamento farmacológico , Estenose Esofágica/tratamento farmacológico , Animais , Materiais Biocompatíveis/metabolismo , Quitosana/metabolismo , Colágeno/metabolismo , Constrição Patológica/etiologia , Neoplasias Esofágicas/patologia , Estenose Esofágica/prevenção & controle , Camundongos , Microesferas , Triancinolona/metabolismo , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/farmacologia
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(2): 250-255, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33624599

RESUMO

OBJECTIVE: To investigate the efficacy of anlotinib plus S-1 for treatment of patients with recurrent or metastatic esophageal squamous cell carcinoma with failed first-line chemotherapy. OBJECTIVE: Twenty-six patients with recurrent or metastatic esophageal squamous cell carcinoma patients who experienced progression after first-line paclitaxel plus platinum chemotherapy in our hospital between July, 2018 and February, 2020 were enrolled in this study. The patients received oral anlotinib along with S-1 treatment (anlotinib at 12 mg once daily and S-1 at 50 mg twice daily for two weeks; 3 weeks per cycle). The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse effects were evaluated for all the patients. OBJECTIVE: No complete remission (CR) was observed in the 26 patients. Partial remission (PR) was achieved in 6 cases, stable disease (SD) in 12 cases, and progressive disease (PD) occurred in 8 cases, with an ORR of 23.1% and a DCR of 69.2% in these patients. The median PFS was 4.5 months (95%CI: 2.7-6.4 months). Univariate analysis showed that the patients with moderate or high tumor differentiation had significantly longer PFS than those with low tumor differentiation (6.1 months vs 1.9 months, P < 0.05). Multivariate analysis suggested that pathological differentiation grade (HR=6.778, 95%CI: 1.997-23.012) was an independent factor for a prolonged PFS. The adverse effects in the patients included mainly fatigue, hypertension and hand-foot syndrome, mostly of grade 1 to 2. OBJECTIVE: Patients with recurrent or metastatic esophageal squamous cell carcinoma can benefit from a second-line anlotinib plus S-1 treatment, which has relatively mild adverse effects with a good safety profile.


Assuntos
Neoplasias Esofágicas , Quinolinas , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago , Humanos , Indóis , Resultado do Tratamento
12.
Gen Thorac Cardiovasc Surg ; 69(3): 525-533, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33449265

RESUMO

BACKGROUND: The prognosis of patients with esophageal squamous cell carcinoma (ESCC) has been improved by multidisciplinary therapy with chemoradiotherapy and surgery, but it remains poor. Advanced stage, malignant potential, and chemo-resistance contribute to the poor prognosis. Here, we attempted to identify predictive factors of the response to chemotherapy and the prognosis of ESCC patients. PATIENTS AND METHODS: We examined 51 ESCC patients who were treated with chemotherapy followed by radical surgery, and 23 patients who were treated with chemotherapy alone. We conducted quantitative reverse transcription-polymerase chain reaction gene expression analysis using RNA extracted from 74 tumor tissue samples collected before chemotherapy and 67 tumor tissue samples collected after chemotherapy, focusing on PIK3CA, AKT-1, mTOR, 4E-BP1, p70S6K, PD-L1, and PD-L2. RESULTS: The proportions of patients with high expressions of AKT-1 and PD-L1 before chemotherapy were significantly higher among the non-responders than among the responders (p = 0.034, p = 0.020, respectively). Multivariate analyses revealed that high PD-L1 expression before chemotherapy was associated with poor response to chemotherapy (odds ratio 2.998; 95% CI 1.043-8.619; p = 0.042) and high p70S6K expression before chemotherapy was a poor prognostic factor (hazard ratio 2.518; 95% CI 1.058-5.988; p = 0.037). In addition, the patients with high expression of PD-L1 and PD-L2 in the tumors after chemotherapy had significantly worse survival than those with low expression of these genes (p = 0.012, p = 0.007, respectively). CONCLUSION: These results demonstrated that PD-L1 and p70S6K in the primary ESCC tissues were related to a poor response to chemotherapy and poor prognosis, respectively.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Biomarcadores Tumorais/genética , Quimiorradioterapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Humanos , Prognóstico
13.
Lancet Gastroenterol Hepatol ; 6(3): 209-217, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33508242

RESUMO

BACKGROUND: Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer. METHODS: We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting. FINDINGS: Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort. INTERPRETATION: Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure. FUNDING: Taiho Pharmaceutical and Eli Lilly.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Pirrolidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Administração Intravenosa , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Combinação de Medicamentos , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Segurança , Timina/administração & dosagem , Timina/efeitos adversos , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos
14.
Radiat Res ; 195(3): 244-252, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33400798

RESUMO

In this work, individual radiosensitivity was evaluated using DNA damage response and chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) for the prediction of acute toxicities of chemoradiotherapy (CRT) in esophageal cancer patients. Eighteen patients with esophageal cancer were enrolled in this prospective study. Prescribed doses were 60 Gy in 11 patients and 50 Gy in seven patients. Patients received 2 Gy radiotherapy five days a week. PBLs were obtained during treatment just before and 15 min after 2 Gy radiation therapy on the days when the cumulative dose reached 2, 20, 40 Gy and 50 or 60 Gy. PBLs were also obtained four weeks and six months after radiotherapy in all and 13 patients, respectively. Dicentric and ring chromosomes in PBLs were counted to evaluate the number of CAs. Gamma-H2AX foci per cell were scored to assess DNA double-strand breaks. We analyzed the association between these factors and adverse events. The number of γ-H2AX foci before radiotherapy showed no significant increase during CRT, while their increment was significantly reduced with the accumulation of radiation dose. The mean number of CAs increased during CRT up to 1.04 per metaphase, and gradually decreased to approximately 60% six months after CRT. Five patients showed grade 3 toxicities during or after CRT (overreactors: OR), while 13 had grade 2 or less toxicities (non-overreactors: NOR). The number of CAs was significantly higher in the OR group than in the NOR group at a cumulative dose of 20 Gy (mean value: 0.63 vs. 0.34, P = 0.02), 40 Gy (mean value: 0.90 vs. 0.52, P = 0.04), and the final day of radiotherapy (mean value: 1.49 vs. 0.84, P = 0.005). These findings suggest that number of CAs could be an index for predicting acute toxicities of CRT for esophageal cancer.


Assuntos
Quimiorradioterapia/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Histonas/genética , Adulto , Idoso , Aberrações Cromossômicas/efeitos dos fármacos , Aberrações Cromossômicas/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tolerância a Radiação/genética , Dosagem Radioterapêutica
15.
BMC Surg ; 21(1): 35, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33435947

RESUMO

BACKGROUND: Guidelines do not recommend surgery for patients with oligometastatic disease from esophagogastric adenocarcinoma (EGAC), although some studies suggest a more favorable survival. We analyzed the outcome of oligometastatic EGAC receiving FLOT chemotherapy followed by surgery. METHODS: The data of patients with either pre-therapeutic, post-neoadjuvant or intraoperative clinical diagnosis of oligometastatic EGAC were extracted from a prospective database of the 2009-2018 treatment period. 48 consecutive patients were identified with oligometastatic disease, who underwent perioperative chemotherapy plus surgery. We retrospectively analyzed surgical outcome and overall survival. RESULTS: The overall 5-year survival was 18%. 12 patients (25%) with pre-therapeutic oligometastatic EGAC, who had no histologic vital tumor evidence of metastases after surgery had a survival rate of 48% compared to an 11% 5-year survival rate of 36 patients (75%), who had histologic vital tumor metastatic evidence after FLOT chemotherapy and surgical resection (p = 0.012). The survival rates after R0, R1 and R2 (non-resected metastases) resection were 21% (n = 33), 0% (n = 4) and 17% (n = 11), respectively (p = 0.273). CONCLUSION: Oligometastatic EGAC is associated with poor overall survival even after complete resection of all tumor manifestations. The subgroup of patients with a complete histologic response of metastatic lesions to neoadjuvant FLOT shows 5-year survival rates similar to non-metastatic EGAC. Trial registration Not applicable.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Terapia Neoadjuvante/métodos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento
16.
Life Sci ; 269: 119064, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33460665

RESUMO

AIMS: Previous studies have uncovered the function of receptor-interacting protein kinase 1 (RIPK1) to mediate both cell survival and death. Moreover, RIPK1 modulates apoptosis and necroptosis depending on its activity, phosphorylation or ubiquitylation status. Many studies have explained the role or mechanism of RIPK1 in necroptosis. However, the role of RIPK1 has not been elucidated fully in human esophageal squamous cell carcinoma (ESCC) cells. MATERIALS AND METHODS: The protein and mRNA expression levels of RIPK1 in a panel of ESCC cell lines by Western blot and real-time quantitative reverse transcription PCR (qRT-PCR) were analyzed. MTS assay was used to examine cellular proliferation, flow cytometric analysis to detect apoptosis, mitochondrial membrane potential and reactive oxygen species production. ESCC cells with either inhibitor or overexpressed RIPK1were analyzed to determine cell proliferation, colony formation and apoptosis. Flow cytometry and western blotting assays were used to explore the underlying mechanism. KEY FINDINGS: In our study, RIPK1 expression was found to contribute significantly to cisplatin-induced apoptosis in the human ESCC cells. The reduced RIPK1 expression promoted cells proliferation and overexpressed RIPK1 facilitated cell apoptosis. Mechanistic investigations have revealed that the inhibition of proliferation for RIPK1 in ESCC cells was regulated via activation of c-Jun NH2-terminal kinase signaling. Additionally, damages were observed in the mitochondrial membrane, depletion of ATP and increased generation in reactive oxygen species. SIGNIFICANCE: Our findings verified the evidence that RIPK1 can promote cell death in ESCC cells, with potential implications for activating c-Jun NH2-terminal kinase pathway as a novel approach to the disease.


Assuntos
Apoptose , Cisplatino/farmacologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Antineoplásicos/farmacologia , Proliferação de Células , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Humanos , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Células Tumorais Cultivadas
17.
Cancer Lett ; 496: 93-103, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038490

RESUMO

Oesophageal cancer is associated with high morbidity and mortality rates because it is highly invasive and prone to recurrence and metastasis, with a five-year survival rate of <20%. Therefore, there is an urgent need for new methods aimed at improving therapeutic intervention. Several studies have shown that targeted therapy may be effective for the treatment of oesophageal cancer. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase with kinase activity and scaffolding function, could be overexpressed in a variety of solid tumours, including oesophageal cancer. FAK participates in survival, proliferation, progression, adhesion, invasion, migration, epithelial-to-mesenchymal transition, angiogenesis, DNA damage repair, and other biological processes through multiple signalling pathways in cancer cells. It plays an important role in the occurrence and development of tumours and has been linked to the prognosis of oesophageal cancer. FAK has been suggested as a potential therapeutic target in oesophageal cancer; thus, the combination of FAK inhibitors with chemotherapy, radiotherapy, and immunotherapy is expected to prolong the survival of patients. This paper presents a brief overview of the structure of FAK and its potential role in oesophageal cancer, providing a rationale for the future application of FAK inhibitors in the treatment of the disease.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos
18.
J Infect Chemother ; 27(1): 99-102, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33023821

RESUMO

We present three patients affected by pulmonary squamous cell carcinoma, metastatic esophageal cancer and advanced non-Hodgkin lymphoma, who incurred in coronavirus 2019 (COVID-19) infection during the early phase of epidemic wave in Italy. All patients presented with fever. Social contact with subject positive for COVID-19 was declared in only one of the three cases. In all cases, laboratory findings showed lymphopenia and elevated C-reactive protein (CRP). Chest x-ray and computed tomography showed bilateral ground-glass opacities, shadowing, interstitial abnormalities, and "crazy paving" pattern which evolved with superimposition of consolidations in one patient. All patients received antiviral therapy based on ritonavir and lopinavir, associated with hydroxychloroquine. Despite treatment, two patients with advanced cancers died after 39 and 17 days of hospitalization, while the patient with lung cancer was dismissed at home, in good conditions.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Neoplasias/complicações , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Idoso , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Surtos de Doenças , Quimioterapia Combinada , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/tratamento farmacológico , Evolução Fatal , Humanos , Itália , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
19.
Medicine (Baltimore) ; 99(50): e23633, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327342

RESUMO

BACKGROUND: Transient receptor potential vanilloid 2 (TRPV2) was previously shown to play an important role in the maintenance of cancer stem cells, and its specific inhibitor, tranilast, also has potential as a targeted therapeutic agent for esophageal squamous cell carcinoma (ESCC). The present study is being conducted to confirm the safety and efficacy of the additional use of tranilast with conventional preoperative adjuvant chemotherapy for patients with advanced ESCC. PATIENTS AND METHODS: Between 56 and 59 patients aged between 20 and 74 years with clinically diagnosed Stage II or Stage III ESCC will be enrolled. Eligible patients will receive preoperative adjuvant chemotherapy, 2 cycles of combination therapy with cisplatin, 5-fluorouracil, and tranilast. Recruitment started in November 2019, with the final follow-up being planned for March 2029. One subject has been enrolled since October 21, 2020. The pathological therapeutic effect is the primary endpoint. The objective response rate, safety of preoperative adjuvant chemotherapy, recurrence-free survival (RFS), and overall survival (OS) are the secondary endpoints. RFS and OS will be calculated as the time from surgery to first recurrence and all-cause death, respectively. ETHICS AND DISSEMINATION: This protocol has been approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine and all participating hospitals in August 30, 2019 (Number: CRB5180001). Written informed consent will be obtained from all patients before their registration, which is in accordance with the Declaration of Helsinki. The results of the present study will be disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION: Trial registration number jRCTs051190076.


Assuntos
Quimioterapia Adjuvante/métodos , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , ortoaminobenzoatos/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/efeitos adversos , Cisplatino/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Análise de Sobrevida , Adulto Jovem , ortoaminobenzoatos/administração & dosagem , ortoaminobenzoatos/efeitos adversos
20.
Medicine (Baltimore) ; 99(51): e23537, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371077

RESUMO

BACKGROUND: Esophageal cancer is one of the most common malignant tumors, with early metastasis, highly malignant characteristics. Morbidity ranks 7th among all malignant tumors, and mortality ranks 6th. Esophageal adjuvant therapy can significantly improve overall survival in unresectable esophageal cancer patients. With the breakthrough and progress of immunotherapy, the possibility of curing esophageal cancer has greatly increased. Some clinical trials have reported that compared with traditional platinum-based chemotherapy, the use of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors alone can benefit patients and effectively prolong their overall survival. We compare the efficacy of single immunotherapy with traditional platinum-based chemotherapy in a systematic review and meta-analysis to provide a reliable basis for clinicians. METHODS: We will search PubMed, Medline, Embase, Web of Science, Cancerlit, Google Scholar, and the Cochrane Central Register of Controlled Trials for related studies published before December 1, 2019 without language restrictions. Two review authors will search and assess relevant studies independently. Randomized controlled trials (RCTs) or quasi-RCTs, and prospective cohort studies will be included. We will perform subgroup analysis in sex, age, ethnicity, and tumor stage of esophageal cancer patients. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: The results of this systematic review and meta-analysis will provide a basis for clinicians to formulate the best chemotherapy regimen for patients, as well as a research clue for clinical researchers in this field. The results of this study will expand the treatment options for esophageal patients, but due to the nature of the disease and intervention, large sample clinical trials are not abundant, so we will include some high-quality small sample trials, which may cause high heterogeneity. INPLASY REGISTRATION NUMBER: INPLASY2020110012.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Esofágicas/tratamento farmacológico , Imunoterapia/métodos , Compostos de Platina/uso terapêutico , Fatores Etários , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/mortalidade , Grupos Étnicos , Humanos , Imunoterapia/efeitos adversos , Estadiamento de Neoplasias , Compostos de Platina/administração & dosagem , Compostos de Platina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Fatores Sexuais
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