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1.
Anticancer Res ; 40(10): 5765-5776, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988904

RESUMO

BACKGROUND/AIM: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients. PATIENTS AND METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA. RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues. CONCLUSION: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Mucina-1/genética , Proteínas WT1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante/métodos , Células Dendríticas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mucina-1/uso terapêutico , Proteínas WT1/uso terapêutico
2.
Medicine (Baltimore) ; 99(35): e21922, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871929

RESUMO

RATIONALE: Cancer-related stroke has been regarded as an emerging subtype of ischemic event. Acute treatment for this subtype may include the antiplatelet agents, anticoagulants, or endovascular intervention. PATIENT CONCERNS: A 63-year-old woman with sudden-onset right hemiparesis and conscious change was sent to our emergency department. The patient had underlying sigmoid adenocarcinoma and received chemotherapy FOLFIRI (FOL, folinic acid; F, fluorouracil; and IRI, irinotecan) with targeted therapy cetuximab following lower anterior resection since the diagnosis was made. DIAGNOSES: Brain magnetic resonance angiography revealed a filling defect in left carotid bulb, and neurosonography showed a thick atherosclerotic plaque (size 4.9 mm) in the left internal carotid artery on day 5 after the onset of stroke. INTERVENTIONS: During the first three hours after onset, administration of IV tissue plasminogen activator did not resolve the thrombus. Dabigatran (110 mg bid) started on day 7. OUTCOMES: The atherosclerotic plaque dissolved on day 24. The patient recovered her muscle strength but still had nonfluent speech in mild extent. LESSONS: Thrombolytic and anticoagulant medications in this patient suggested the thrombus formation with fibrin-rich content which may be attributable to both cancer and chemotherapy. Dabigatran, an oral anticoagulant, had a benefit for this subtype of ischemic stroke among patients with cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antitrombinas/uso terapêutico , Trombose das Artérias Carótidas/terapia , Artéria Carótida Interna , Infarto da Artéria Cerebral Média/induzido quimicamente , Terapia Trombolítica , Adenocarcinoma/complicações , Adenocarcinoma/tratamento farmacológico , Administração Oral , Trombose das Artérias Carótidas/diagnóstico por imagem , Artéria Carótida Interna/diagnóstico por imagem , Dabigatrana/uso terapêutico , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Angiografia por Ressonância Magnética , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/terapia , Neoplasias do Colo Sigmoide/complicações , Neoplasias do Colo Sigmoide/tratamento farmacológico , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico
3.
Tokai J Exp Clin Med ; 45(3): 113-116, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32901897

RESUMO

Mutations in the gene encoding epidermal growth factor receptor (EGFR) are the most frequent driver mutations in lung adenocarcinoma in Japan. Exon 19 deletion and L858R mutation in exon 21 are the most common EGFR mutations. Uncommon mutations, such as G719X, S768I, and L861Q, and compound mutations, combinations of 2 common or uncommon mutations, have also been reported. EGFR tyrosine kinase inhibitors (TKIs) are effective against cancers harboring common mutations; however, their efficacy against cancers with uncommon or compound mutations remains unclear. We report the case of a 67-year-old man with lung adenocarcinoma (clinical stage IIIA [cT1N2M0]), harboring an uncommon compound mutation, G719X and S768I. The cancer progressed within 2 months of initial chemoradiotherapy. Treatment with afatinib (40 mg/day) produced a partial response, which was maintained for 17 months with continued treatment. A literature review revealed that lung cancer with G719X/S768I compound mutation exhibited good response to EGFR-TKIs, even better than that of lung cancers with single uncommon mutations.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Receptores ErbB/genética , Éxons/genética , Deleção de Genes , Humanos , Masculino , Resultado do Tratamento
4.
Lancet Oncol ; 21(8): 1066-1076, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32653053

RESUMO

BACKGROUND: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. METHODS: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients. INTERPRETATION: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). FUNDING: MacroGenics.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Eur J Endocrinol ; 183(4): 411-417, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32688334

RESUMO

Objective: At present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. The aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients. Design and methods: We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n = 43) or only endogenous TSH (n = 34). Results: As expected from the matching procedure, the clinical-pathological features and the cumulative 131-I activities administered to the two groups were very similar. After 4 years of follow-up, 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately, we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of the bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately. Conclusions: This study shows (i) an overall clinical benefit of the 131-I therapy, since the majority of patients remained affected but with a stable disease, and (ii) that the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tireotropina/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Quimioterapia Adjuvante , Criança , Terapia Combinada , Feminino , Seguimentos , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pontuação de Propensão , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Resultado do Tratamento , Adulto Jovem
6.
Anticancer Res ; 40(7): 3659-3667, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620605

RESUMO

BACKGROUND/AIM: FOLFIRINOX [fluorouracil (5-FU), irinotecan, oxaliplatin] and gemcitabine plus nab-paclitaxel are standard treatments for patients with pancreatic ductal adenocarcinoma (PDAC). Despite efficacy rates of less than 32%, evidence is lacking to guide the use of one drug over the other. Herein, we compared the sensitivity of patient-derived PDAC cell lines to each of these regimens. MATERIALS AND METHODS: Changes in the growth of 19 low-passage patient-derived PDAC cell lines were evaluated in response to treatment with FOLFIRINOX and gemcitabine plus paclitaxel (Gem-Pac). RESULTS: Six cell lines exhibited optimal sensitivity (high EMax and low GI50) to FOLFIRINOX and three cell lines exhibited optimal sensitivity to Gem-Pac. Several cell lines that were optimally sensitive to one drug regimen exhibited very poor response to the other. CONCLUSION: Further characterization of cancer cells exhibiting preferential sensitivity to each of these regimens may allow the identification of biomarkers to guide the selection of appropriate chemotherapy for a given patient.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico
7.
Anticancer Res ; 40(7): 4011-4015, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620645

RESUMO

BACKGROUND/AIM: The aim of this monocentric study was to evaluate the efficacy and tolerability of a polychemotherapy regimen based on gemcitabine, docetaxel, capecitabine, cisplatin (PDGX) as second-line for advanced pancreatic cancer after FOLFIRINOX. PATIENTS AND METHODS: Patients received FOLFIRINOX as first-line regimen were retrospectively identified between January 2016 and January 2019. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were treated in our center by PDGX. RESULTS: During this period, 18 patients received PDGX regimen as second-line therapy. Main grade 3 toxicities were hematologic, which required dose adaptation in 14/18 patients. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2,91 and 5,3 months, respectively. Total OS from the initiation of first-line was and 11,9 months. CONCLUSION: Second-line PDGX regimen after FOLFIRINOX failure is feasible, with notable toxicity profile and is associated with poor clinical outcomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Capecitabina/uso terapêutico , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Docetaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/efeitos adversos , Cisplatino/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Docetaxel/efeitos adversos , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Resultado do Tratamento
8.
PLoS One ; 15(7): e0236315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706791

RESUMO

The natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in cancer cell lines and tumors. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin's anti-oncogenic effects, such as prevention of cell migration and formation of anchorage independent colonies, are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cancer cell lines. In this study, we assessed nobiletin's circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also varied in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin's effects on cell proliferation and migration have been studied previously were evaluated: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that circadian, migration, and proliferative effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity and substantially reduced oncogenic features, specifically two-dimensional cell motility and anchorage-independent growth. Based on these results and those previously described, we posit that the effects of nobiletin are indeed cell-type dependent, and that a positive correlation may exist between nobiletin's circadian and therapeutic effects.


Assuntos
Antineoplásicos Fitogênicos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Flavonas , Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Flavonas/farmacologia , Flavonas/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico
9.
Lancet Oncol ; 21(8): 1045-1056, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32682457

RESUMO

BACKGROUND: S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. METHODS: We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. FINDINGS: Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). INTERPRETATION: TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. FUNDING: Taiho Pharmaceutical and Yakult Honsha.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Tegafur/administração & dosagem , Tegafur/efeitos adversos
10.
Lancet Oncol ; 21(8): 1057-1065, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32589866

RESUMO

BACKGROUND: Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study. METHODS: This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete. FINDINGS: Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12·6 months (IQR 10·5-14·3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred. INTERPRETATION: Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future. FUNDING: Merck Sharp & Dohme.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos
11.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(6): 605-609, 2020 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-32521984

RESUMO

Robotic-assisted transanal total mesorectal excision (R-TaTME) has unique advantage in low rectal cancer. Single incision plus oneport (SIPOP) laparoscopic operation can synchronously cooperate with robotic-assisted transanal operation, in order to the difficulty of operation, improve the quality of operation and shorten the time of operation. A retrospective analysis was conducted on the clinical and pathological data of one patient who underwent SIPOP synchronously combined with R-TaTME + sigmoid-anal anastomosis + ileostomy at the Department of General Surgery, Army Characteristic Medical Center on September 11, 2019. This 71-year-old patient was male with body mass index of 24.08 kg/m(2) and received preoperative chemotherapy. Rectal adenocarcinoma was confirmed by colonoscopy biopsy, and distance from tumor lower edge to anal verge was 3 cm. MRI indicated T2N1 stage. The operation was completed successfully, and the transabdominal and robotic transanal surgery totaled 117 minutes, with 15 minutes for the robotic transanal preparation step. There was about 20 ml of intraoperative blood loss and no blood transfusion was performed. The patient was discharged 6 days after operation. No intraoperative or postoperative complications occurred. The postoperative TNM staging was stage I (pyT2N0cM0). No recurrence or metastasis was found at postoperative 7 month. It is a safe, effective and feasible technique for patients with low rectal cancer.


Assuntos
Adenocarcinoma/cirurgia , Neoplasias Retais/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Cirurgia Endoscópica Transanal/métodos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Canal Anal/cirurgia , Anastomose Cirúrgica , Antineoplásicos/administração & dosagem , Colo Sigmoide/cirurgia , Humanos , Ileostomia , Laparoscopia/métodos , Masculino , Mesentério/cirurgia , Terapia Neoadjuvante , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Reto/cirurgia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/instrumentação , Cirurgia Endoscópica Transanal/instrumentação
13.
J Cancer Res Clin Oncol ; 146(9): 2219-2229, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32507974

RESUMO

PURPOSE: Pancreatic cancer is a lethal form of cancer that can be triggered by prolonged or acute inflammation of the pancreas. Inflammation have been shown to be regulated by a group of key protein molecules known as the inflammasomes. The NLRP3 inflammasome is the most studied inflammasome and have been strongly implicated to regulate cancer cell proliferation. Therefore, this study aimed to examine the regulation of NLRP3 inflammasome under LPS-induced inflammation and its role in modulating cell proliferation in a panel of pancreatic cancer cells. METHODS: The effects of LPS-induced NLRP3 activation in the presence or absence of MCC950, NLRP3-specific inhibitor, was tested on a panel of three pancreatic cancer cell lines (SW1990, PANC1 and Panc10.05). Western blotting, cell viability kits and ELISA kits were used to examine the effects of LPS-induced NLRP3 activation and inhibition by MCC950 on NLRP3 expression, cell viability, caspase-1 activity and cytokine IL-1ß, respectively. RESULTS: LPS-induced inflammation in the presence of ATP activates NLRP3 that subsequently increases pancreatic cancer cell proliferation by increasing caspase-1 activity leading to overall production of IL-1ß. The inhibition of the NLRP3 inflammasome activation via the specific NLRP3 antagonist MCC950 was able to reduce the cell viability of pancreatic cancer cells. However, the efficacy of MCC950 varies between cell types which is most probably due to the difference in ASC expressions which have a different role in inflammasome activation. CONCLUSION: There is a dynamic interaction between inflammasome that regulates inflammasome-mediated inflammation in pancreatic adenocarcinoma cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/metabolismo
14.
J Cancer Res Clin Oncol ; 146(9): 2231-2239, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32533405

RESUMO

BACKGROUND: Adjuvant chemotherapy could improve the prognosis of stage II-III non-small cell lung cancer (NSCLC). However, its influences on stage IB were controversial. The purpose of this study was to investigate whether patients with stage IB NSCLC could benefit from adjuvant chemotherapy. METHODS: Stage IB NSCLC in 2010-2015 was selected from the surveillance, epidemiology, and end result database. Chi square test was used to compare the clinical characteristics of patients with different adjuvant chemotherapy status. Kaplan-Meier survival curves were plotted by the log-rank test. Cox proportional hazard regression was used to perform multivariate analysis on overall survival (OS), and the life table method was employed to calculate 1-, 3-, and 5-year survival rates. RESULTS: A total of 2915 patients were included in this study, and the number of patients with visceral pleural invasion (VPI) was 1096 (37.6%), of which 145 (13.2%) received adjuvant chemotherapy. There was no statistical difference in OS among the total population with or without chemotherapy (p = 0.295), nor in patients with VPI (p = 0.216). In patients with VPI, the 1-, 3-, 5-year survival curves of patients who are receiving adjuvant chemotherapy showed an upward trend compared with patients who did not. Additionally, female, high differentiated, adenocarcinoma, and tumor size ≤ 3 cm were also independent prognostic factors for improving the prognosis of patients with VPI. CONCLUSION: In our study, stage IB NSCLC did not benefit from adjuvant chemotherapy, even in patients with VPI. However, the significance of adjuvant chemotherapy in patients with VPI is still worth further exploration.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Invasividade Neoplásica/patologia , Pleura/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
15.
Clin Nucl Med ; 45(7): e334-e335, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32404713

RESUMO

A 72-year-old man with a family history of prostate cancer and initial diagnosis of favorable intermediate risk prostate cancer via biopsy in 2017 elected for active surveillance. Two years later, he underwent prostate biopsy showing intermediate-risk cT1c Nx Mx lesion with Gleason score 3 + 4 = 7 (5 core positive). Transrectal ultrasound showed a prostate volume 28 mL, and the prostate-specific antigen was 8.1. Patient elected to proceed with combination radiation therapy and androgen deprivation therapy.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Radioisótopos de Flúor , Neoplasias da Próstata/diagnóstico por imagem , Fluoreto de Sódio , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Antagonistas de Androgênios/uso terapêutico , Biópsia , Humanos , Masculino , Gradação de Tumores , Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ultrassonografia
16.
Nature ; 581(7806): 100-105, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376951

RESUMO

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Assuntos
Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacos
17.
Nat Commun ; 11(1): 2176, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358491

RESUMO

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD40/agonistas , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Antígenos CD40/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética
18.
Gan To Kagaku Ryoho ; 47(4): 688-690, 2020 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-32389985

RESUMO

A 68-year-old man with jaundice was diagnosed with pancreatic cancer. The tumor seemed to invade the portal vein, the common hepatic artery, and the splenic artery plexus. The initial diagnosis was unresectable pancreatic cancer. The patient was treated with gemcitabine plus nab-paclitaxel therapy. The tumor reduced in size, and invasion of the main vessels was alleviated after 3 courses. Therefore, we performed total pancreatectomywith total gastrectomy. Histopathological findings showed pancreatic adenocarcinoma, T4(PV)N2M0, fStage Ⅳb, R0. There are reports of curative resection for unresectable pancreatic cancer after chemotherapy. However, the majorityof these reports were about pancreatoduodenectomyor distal pancreatectomy. We present a rare case of curative total pancreatectomy after chemotherapy.


Assuntos
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Idoso , Artéria Hepática , Humanos , Masculino , Terapia Neoadjuvante , Pâncreas , Pancreatectomia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia
19.
Int J Clin Oncol ; 25(8): 1441-1449, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32448950

RESUMO

BACKGROUND: There is no standard chemotherapy available for unresectable or metastatic small bowel adenocarcinoma (SBA) because of its rarity. This systematic review aims to assess the efficacy and safety of chemotherapy for patients with unresectable or metastatic SBA. METHODS: In accordance with the PRISMA statements, literature search was conducted using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The included studies were prospective randomized, nonrandomized, or observational studies. Risk of bias was assessed the ROBINS-I tool. RESULTS: Seven prospective single-arm Phase II studies were included in this review. Six of them were assessed as having a moderate risk of bias and one as having a serious risk of bias. A meta-analysis was not performed, because the studies were single-arm. Systemic chemotherapy based on fluoropyrimidine regimens achieved favorable outcomes with acceptable adverse effects as a first therapy; however, the regimens differed in each study. The object response rate was 18-50%, and the disease control rate was 29-87%. With 5-fluorouracil, adriamycin, and mitomycin-C regimen, one treatment-related death occurred. A second line of therapy including chemotherapy with nab-paclitaxel also showed favorable efficacy. The object response rate was 20%, and the disease control rate was 50%. CONCLUSIONS: Systemic chemotherapy based on fluoropyrimidine regimens was mainly used for unresectable or metastatic SBA. While it may achieve favorable outcomes with acceptable adverse effects, further evidence is needed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Intestino Delgado/patologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Albuminas/administração & dosagem , Doxorrubicina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Intestino Delgado/efeitos dos fármacos , Paclitaxel/administração & dosagem , Estudos Prospectivos , Resultado do Tratamento
20.
Oncology ; 98(8): 542-548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32434189

RESUMO

BACKGROUND: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized gastric adenocarcinoma (GAC). We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. METHODS: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). RESULTS: The median follow-up time was 3.5 years (range; 0.4-16.7). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75.3%) out of 97 patients underwent planned surgery. R0 resection and pCR rae were 93.2 and 20.6%, respectively. Pathologic partial response (<50% residual carcinoma) rate was 50.7%. The median OS was 6.4 years (95% Cl 3.3-12.4) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72.4% (95% CI 62.1-80.3) and 54.3% (95% CI 43.2-64.1) for the entire cohort and 83.2% (95% CI 72.3--90.1) and 66% (95% CI 52.3-75.8) for patients that underwent surgery. Pathologic lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.02) were independently associated with longer RFS in the multivariate analysis. CONCLUSION: Our data shows that three-drug combination is feasible without providing substantial advantage compared with two-drug combination in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Quimioterapia de Indução/métodos , Terapia Neoadjuvante/métodos , Cuidados Pré-Operatórios/métodos , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
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