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OBJECTIVES: This study aimed to evaluate the clinical impact of preoperative endoscopic ultrasound-guided tissue acquisition (EUS-TA) on the prognosis and incidence of positive peritoneal lavage cytology (PLC) during laparotomy or staging laparoscopy in patients with resectable (R) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). METHODS: We retrospectively collected data from patients diagnosed with body and tail PDAC with/without EUS-TA at our hospital from January 2006 to December 2021. RESULTS: To examine the effect of EUS-TA on prognosis, 153 patients (122 in the EUS-TA group, 31 in the non-EUS-TA group) were analyzed. There was no significant difference in overall survival between the EUS-TA and non-EUS-TA groups after PDAC resection (P = 0.777). In univariate and multivariate analysis, preoperative EUS-TA was not identified as an independent factor related to overall survival after pancreatectomy [hazard ratio 0.96, 95 % confidence interval (CI) 0.54-1.70, P = 0.897]. Next, to examine the direct influence of EUS-TA on the results of PLC, 114 patients (83 in the EUS-TA group and 31 in the non-EUS-TA group) were analyzed. Preoperative EUS-TA was not statistically associated with positive PLC (odds ratio 0.73, 95 % CI 0.25-2.20, P = 0.583). After propensity score matching, overall survival and positive PLC were the same in both groups. CONCLUSIONS: EUS-TA had no negative impact on postoperative survival and PLC-positive rates in R/BR PDAC.
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Carcinoma Ductal Pancreático , Pancreatectomia , Neoplasias Pancreáticas , Lavagem Peritoneal , Humanos , Masculino , Feminino , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Idoso , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Estudos Retrospectivos , Prognóstico , Endossonografia , Idoso de 80 Anos ou mais , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , CitologiaRESUMO
BACKGROUND: In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy. METHODS: The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves. RESULTS: During January 2017-June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0-34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0-16.6) and 4.0 (95% CI, 2.6-5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22-0.67; p = 0.001). CONCLUSIONS: Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Idoso , Humanos , Masculino , Doença Crônica , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Recidiva Local de Neoplasia , Nivolumabe/uso terapêutico , Prognóstico , Estudos Retrospectivos , FemininoRESUMO
BACKGROUND: Buprenorphine is used for canine postoperative pain management. This study aimed to describe the pharmacokinetics and evaluate the analgesic efficacy of buprenorphine (Simbadol, 1.8 mg/mL) administered by different routes in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, masked, clinical trial. Buprenorphine (0.02 mg/kg) was administered intravenously (IV), intramuscularly (IM) or subcutaneously (SC) (n = 8/group) 0.5 h before general anesthesia with propofol-isoflurane. Carprofen (4.4 mg/kg SC) was administered after anesthetic induction and before ovariohysterectomy. Pain was scored using the short-form Glasgow composite pain scale for dogs (SF-GCPS). Dogs were administered morphine (0.25 mg/kg IV) when SF-GCPS scores were ≥ 5/20. Blood sampling was performed up to 720 min after drug administration. Plasma buprenorphine and norbuprenorphine concentrations were analyzed using liquid chromatography mass spectrometry. Pharmacokinetics of buprenorphine was described using a non-compartmental model (PK Solver 2.0). Statistical analysis was performed using linear mixed models and Fisher's exact test (p < 0.05). RESULTS: Pain scores were significantly higher than baseline after IV (0.5-2 h), IM (0.5-3 h) and SC (0.5-4 h) but not among groups. Prevalence of rescue analgesia was significantly higher in SC (7/8 dogs) than IV (2/8) but not different between IV and IM (3/8) or IM and SC. The frequency of rescue analgesia was not significantly different among groups (IV = 2, IM = 5 and SC = 9). Norbuprenorphine was not detected. For IV, IM and SC administration, clearance was 1.29, 1.65 and 1.40 L/hour/kg, volume of distribution was 6.8, 14.2 and 40.1 L/kg, the elimination half-life was 3.7, 5.7, 22 h, and the area under the plasma concentration-time curved extrapolated to infinity was 15.7, 12.4 and 16.4 ng/mL/hour, respectively. Bioavailability for IM and SC was 62.6 and 40%, respectively. Maximum plasma concentrations of buprenorphine were 6.2 and 1.3 ng/mL at 0.14 and 0.33 h after IM and SC administration, respectively. CONCLUSIONS: The route of administration influences the analgesic efficacy of buprenorphine in dogs. SC administration of buprenorphine failed to provide clinical analgesia due to erratic drug absorption. At the doses administered, the IV and IM routes are preferred for postoperative analgesia.
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Analgésicos Opioides/farmacocinética , Buprenorfina/farmacocinética , Cães/cirurgia , Dor Pós-Operatória/veterinária , Administração Intravenosa/veterinária , Analgesia/veterinária , Analgésicos Opioides/administração & dosagem , Animais , Buprenorfina/administração & dosagem , Feminino , Histerectomia/veterinária , Injeções Intramusculares/veterinária , Injeções Subcutâneas/veterinária , Ovariectomia/veterinária , Medição da Dor/veterinária , Dor Pós-Operatória/tratamento farmacológico , Estudos ProspectivosRESUMO
Preoperative or induction chemotherapy with docetaxel, cisplatin, plus 5-fluorouracil (DCF) is a promising regimen for advanced esophageal cancer. However, the DCF regimen is associated with a high risk of severe neutropenia or febrile neutropenia (FN). However, the current guidelines fail to recommend an optimal dosing schedule of pegfilgrastim along with the DCF regimen to prevent FN. In the present study, we assessed the efficacy and safety of giving pegfilgrastim early on day 3 during DCF therapy for esophageal cancer. In this single-arm phase II study, patients with squamous cell carcinoma of the esophagus were recruited. They were treated with the DCF therapy on days 1-5, with pegfilgrastim given on day 3. Primary endpoint was the occurrence of grade 4 neutropenia. Secondary endpoints included the incidence of FN, grade 3 neutropenia, dose delays/reductions, antitumor effect, and safety. Between July 2016 and December 2018, 23 patients were enrolled. The incidence of grade 4 neutropenia was 8.7% (95% confidence interval 1.1%-28.0%). No patient experienced FN. Of the 19 patients who received two cycles of DCF, one required a dose reduction/treatment delay due to hematological toxicity in the second treatment cycle. No serious adverse events, considered relevant to pegfilgrastim, were observed. This is the first prospective study that showed an efficacious dosing schedule of pegfilgrastim for preventing hematological toxicity during DCF therapy. The results might be generalized to other similar regimens where continuous infusions of 5-fluorouracil are used.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Filgrastim/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Filgrastim/efeitos adversos , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/prevenção & controle , Polietilenoglicóis/efeitos adversos , Estudos ProspectivosRESUMO
We treated 123cancer patients with a combination of immune checkpoint inhibitor and dendritic cell therapy between June 2015 and April 2019. The effective rate of cases administered for B3times was 51.5%. Hyperthermia was found to enhance the effects of radiotherapy, chemotherapy, and immunotherapy. In addition, hyperthermia enhanced the effects of combined immunotherapy. In clinical cases and animal models, immunohistochemical staining showed that the expression of PD-L1 and MHC classâ and invasion of CD8 cells were increased after hyperthermia.
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Imunoterapia , Animais , HumanosRESUMO
Intestinal fibrosis with stricture formation is a severe complication of Crohn's disease (CD). Though new therapeutic targets to enable the prevention or treatment of intestinal fibrosis are needed, markers of this condition and the basic mechanisms responsible have not been established. NADPH oxidase (NOX) 4 has already been reported to play a key role in models of fibrogenesis, including that of the lung. However, its importance in intestinal fibrogenesis remains unclear. In this study, we examined the role of NOX4 in collagen production by intestinal myofibroblasts stimulated with transforming growth factor (TGF)-ß1. Using LmcMF cells, an intestinal subepithelial myofibroblast (ISEMF) line, we first examined the induction of collagen production by TGF-ß1. Subsequently, we investigated the role of NOX4 in TGF-ß1-induced collagen I production in these cells using SB525334 (an SMAD2/3 inhibitor), diphenyleneiodonium (an NOX inhibitor), and Nox4 small interfering RNA (siRNA). Production of collagen was assessed with Sirius red staining, and Nox4 expression was measured by quantitative real-time PCR. Reactive oxygen species (ROS) production was determined using DCFDA and fluorescent microscopy. We observed that TGF-ß1 induced collagen production via NOX4 activation and ROS generation in LmcMF cells. Nox4 siRNA and inhibitors of TGF-ß1 receptor and NOX significantly reduced TGF-ß1-induced ROS and collagen production. Thus, in the present study, we revealed that collagen production in ISEMFs is induced via an NOX4-dependent pathway. This work supports a function for NOX4 in intestinal fibrogenesis and identifies it as a potential therapeutic target in recalcitrant fibrotic disorders of CD patients.
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Colágeno/biossíntese , Miofibroblastos/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Animais , Linhagem Celular , Camundongos , Miofibroblastos/efeitos dos fármacos , NADPH Oxidase 4/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
It has been reported that docetaxel, cisplatin, and 5-FU combination chemotherapy(DCF)is effective for advanced esophageal cancer. However, we often encounter severe hematotoxicity during DCF therapy. Here, we retrospectively analyzed the data of patients with advanced esophageal cancer treated with DCF at our department, and assessed the efficacy of pegfilgrastim and the issues associated with its use. According to the results, pegfilgrastim may reduce the severe hematotoxicity associated with DCF therapy and may contribute to the maintenance of the intensity of DCF. However, neutropenia had already occurred before pegfilgrastim administration on day 7 in most patients. Therefore, the appropriate timing of pegfilgrastim administration in DCF must be determined in a future prospective study.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Filgrastim , Neutropenia , Polietilenoglicóis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Filgrastim/uso terapêutico , Fluoruracila/administração & dosagem , Humanos , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , TaxoidesRESUMO
BACKGROUND AND OBJECTIVES: Several recent studies identified that postoperative infectious complications contribute to recurrence and poor outcome in patients with gastric cancer. This study was designed to investigate the prognostic impact of postoperative pneumonia, and to identify the putative risk factors for its occurrence. METHODS: We retrospectively analyzed 1,415 consecutive patients who underwent curative gastrectomy for gastric cancer between 1997 and 2013. RESULTS: A total of 31 (2.2 %) patients developed postoperative pneumonia (Clavien-Dindo classification ≥II). Patients with postoperative pneumonia showed a significantly poorer prognosis than patients without (P < 0.001). Concerning the occurrence of postoperative pneumonia, univariate and multivariate analyses identified older age (≥65 years; P = 0.010; odds ratio [OR] 3.59), lower nutritious status (albumin <3 0; P = 0.029; OR 4.51), advanced stage (pStage ≥II; P = 0.045; OR 2.35), concurrent hypertension (P = 0.042; OR 2.21) and total gastrectomy (P = 0.026; OR 2.42) as independent risk factors. CONCLUSIONS: Postoperative pneumonia was shown to be associated with long-term poor outcome in patients with gastric cancer. Care should be taken for patients with clinical factors such as older age, lower nutritional status, advanced stage, concurrent hypertension, and total gastrectomy.
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Gastrectomia/efeitos adversos , Pneumonia/etiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Fatores Etários , Idoso , Feminino , Gastrectomia/métodos , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estado Nutricional , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/complicaçõesRESUMO
Although nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) has been used to treat first-line resistant unresectable pancreatic cancer, the efficacy and safety data among the elderly remain limited. We retrospectively analyzed clinical outcomes among elderly patients. Patients treated with nal-IRI+5-FU/LV were assigned to the elderly (≥75 years) and non-elderly (<75 years) groups. Herein, 85 patients received nal-IRI+5-FU/LV, with 32 assigned to the elderly group. Patient characteristics in the elderly and non-elderly groups were as follows: age: 78.5 (75-88)/71 (48-74), male: 17/32 (53%/60%), performance status (ECOG) 0:9/20 (28%/38%), nal-IRI+5-FU/LV in second line: 23/24 (72%/45%), respectively. A significantly high number of elderly patients exhibited aggravated kidney and hepatic functions. Median overall survival (OS) and progression-free survival (PFS) in the elderly group vs. non-elderly group were 9.4 months vs. 9.9 months (hazard ratio (HR) 1.51, 95% confidence interval (CI) 0.85-2.67, p = 0.16) and 3.4 months vs. 3.7 months (HR 1.41, 95% CI 0.86-2.32, p = 0.17). Both groups exhibited a similar incidence of efficacy and adverse events. There were no significant differences in OS and PFS between groups. We analyzed the C-reactive protein/albumin ratio (CAR) and neutrophil/lymphocyte ratio (NLR) as indicators that could determine eligibility for nal-IRI+5-FU/LV. The median CAR and NLR scores in the ineligible group were 1.17 and 4.23 (p < 0.001 and p = 0.018, respectively). Elderly patients with worse CAR and NLR score could be deemed ineligible for nal-IRI+5-FU/LV.
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OBJECTIVES: Both pancreatic stenting and rectal nonsteroidal anti-inflammatory drugs (NSAIDs) prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. The aim of the study was to compare post-ERCP pancreatitis (PEP) prophylaxis using pancreatic stents and/or rectal NSAIDs prospectively. METHODS: A total of 321 patients undergoing ERCP were studied. Each patient was randomly allocated to receive pancreatic stent placement (PS), 50 mg of rectal diclofenac (NSAID), or both (PS + NSAID) for PEP prophylaxis. The primary outcome was the occurrence rate of PEP, and secondary outcomes included the severity of PEP and serum pancreatic amylase and lipase levels on the day after ERCP. RESULTS: Five patients (PS: 2/101, NSAID: 1/106, PS + NSAID: 2/102) developed PEP, and the overall occurrence rate of PEP was 1.6% (5/309). The occurrence rates of PEP in the PS, NSAID, and PS + NSAID groups were statistically equivalent with an equivalent margin of 10%. The severity of PEP was mild in all 5 patients. Median serum pancreatic amylase and lipase levels in the NSAID group were significantly lower than those in the PS and PS + NSAID groups. CONCLUSIONS: Rectal administration of 50 mg of diclofenac may become a first-line therapy for PEP prophylaxis in our country.
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Colangiopancreatografia Retrógrada Endoscópica , Pancreatite , Administração Retal , Amilases , Anti-Inflamatórios não Esteroides/uso terapêutico , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Diclofenaco/uso terapêutico , Humanos , Lipase , Pancreatite/tratamento farmacológico , Pancreatite/etiologia , Pancreatite/prevenção & controle , StentsRESUMO
Background: A trial with trifluridine/tipiracil (FTD/TPI) versus placebo in patients with heavily pretreated metastatic gastric cancer showed that FTD/TPI is effective with manageable toxicity in these patients. However, real-world data on the effects of FTD/TPI in patients with advanced gastric cancer (AGC) are limited. Methods: We retrospectively collected and analyzed the clinicopathological data of patients with AGC who received FTD/TPI monotherapy at our institutions (Kobe City Medical Center General Hospital, Osaka Red Cross Hospital, Himeji Red Cross Hospital, and Kansai Medical University Hospital) between September 2019 and July 2021. Tumor responses were evaluated based on the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 53 patients were included in the study. The median age was 70 (range, 37-85) years; 39 patients (74%) were men; the numbers of patients with Eastern Cooperative Oncology Group performance status scores of 0, 1, and 2 were 10 (19%), 39 (74%), and 4 (8%), respectively; and 27 patients (51%) had diffuse-type histology. A total of 29 patients (56%) had ascites. Prior nivolumab therapy was administered to 49 patients (92%). The response rate and disease control rate (DCR) were 2% and 35%, respectively. The median progression-free survival was 2.4 months, and OS was 5.8 months. Patients with ascites exhibited significantly shorter OS (8.6 vs 4.7 months, P = .0291) than those without ascites, and DCR (54% vs 18%, P = .0055) was significantly worse in patients with ascites. There was no significant difference in the frequency of adverse events of grade 3 or higher between patients with and without ascites. Conclusion: In a real-world setting, FTD/TPI has similar effectiveness as late-line chemotherapy for patients with AGC, including those who previously had received nivolumab.
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SMARCA4-deficient sarcoma was first reported in the chest and recently in the uterus, but not in the stomach. Here, we present a patient diagnosed with SMARCA4-deficient sarcoma of the stomach, using histochemistry. An emergency operation was performed due to perforation of the tumor. However, one month after the operation, two nodes recurred, and six cycles of combination chemotherapy consisting of adriamycin and ifosfamide were administered. The combination chemotherapy showed a remarkable effect, and complete remission was achieved. The patient was alive without recurrence after 48-month follow-up. SMARCA4-deficient sarcoma is an exceedingly rare tumor with an extremely poor therapeutic response to anticancer drugs. Herein, we present the first case of SMARCA4-deficient sarcoma of the stomach, where a complete response to chemotherapy was achieved.
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Antineoplásicos , Sarcoma , Neoplasias Gástricas , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , DNA Helicases , Feminino , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/uso terapêutico , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/genética , Estômago/patologia , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/uso terapêuticoRESUMO
Immune checkpoint molecules are expressed on cancer cells and regulate tumor immunity by binding to ligands on immune cells. Although soluble forms of immune checkpoint molecules have been detected in the blood of patients with some types of tumors, their roles have not been fully elucidated. Soluble PD-L1, PD-1, CD155, LAG3, and CD226 (sPD-L1, sPD-1, sCD155, sLAG3, and sCD226, respectively) were measured in the sera of 47 patients with advanced esophageal cancer and compared with those of 24 control subjects. Pretreatment levels of sPD-1 and sCD155 were significantly higher in the patients with cancer than in the control subjects (P = 0.023, P = 0.001). The sPD-1 levels tended to be higher in the patients with lymph node metastasis, a large tumor diameter, and higher levels of serum SCC antigen (P = 0.150, P = 0.189, and P = 0.078, respectively). However, higher levels of sCD155 were associated with a better response to chemotherapy and favorable overall survival (P = 0.111 and P = 0.068, respectively). After 2 courses of chemotherapy, the levels of sCD155 and sCD226 were significantly increased (P < 0.001 and P = 0.002, respectively). Moreover, the increase in sCD226 during chemotherapy was associated with poor treatment response (P = 0.019). sPD-1 levels are possibly dependent on the tumor aggressiveness of the esophageal cancer. Furthermore, the pretreatment levels of sCD155 and kinetic change of sCD226 after chemotherapy may be used as biomarkers of the treatment response and prognosis in patients with esophageal cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Antígenos CD/sangue , Antígenos de Diferenciação de Linfócitos T/sangue , Antígeno B7-H1/sangue , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/sangue , Receptores Virais/sangue , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Undernutrition and sarcopenia are associated with a higher incidence of chemotherapy-related toxicity and a poor prognosis in several kinds of cancer, but the impact of sarcopenia on the outcomes of chemotherapy for esophageal cancer remains unclear. Thus, the purpose of this retrospective study was to investigate whether sarcopenia affects the efficacy and toxicities of chemotherapy for advanced esophageal cancer patients. Data were collected from 31 esophageal cancer patients who underwent neo-adjuvant chemotherapy followed by surgery. Body composition was assessed at the start of chemotherapy by bioelectrical impedance analysis, and outcomes of chemotherapy were compared between sarcopenic and non-sarcopenic groups. Of the 31 patients, sarcopenia was observed in 16 (51.6%). The incidence of toxicities was not different between the two groups. However, as for pathologic response, a good therapeutic effect (Grade 2 or higher) was more common in the non-sarcopenic group than in the sarcopenic group (53.3% vs. 25.0%). Multivariate analysis showed that sarcopenia was an independent predictor of poor pathological response (odds ratio 8.02; P = 0.037). The results of this study suggest the potential utility of sarcopenia assessment in neoadjuvant patient selection strategies.
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Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Músculo Esquelético/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Quimioterapia Adjuvante , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Retrospectivos , Sarcopenia/patologiaRESUMO
Although improvements in the chemotherapy modalities for pancreatic cancer have been realized, pancreatic cancer remains one of the most lethal malignancies. New-generation cancer immunotherapy methods, such as blocking of the PD-1/PD-L1 pathway, are consistently being investigated to improve the survival of pancreatic cancer patients. In the present study, we evaluated the influence of anticancer agents 5-fluorouracil, gemcitabine and paclitaxel on PD-L1 expression in human pancreatic cancer cell lines MIA PaCa-2 and AsPC-1 and in murine pancreatic cancer cell line Pan02. Additionally, we analyzed the molecular mechanisms that facilitated the regulation of PD-L1 expression in these cell lines. We observed that when AsPC-1, MIA PaCa-2 and Pan02 cells were stimulated by 5-fluorouracil, gemcitabine or paclitaxel, PD-L1 surface protein expression was enhanced. Similarly, the mRNA level of PD-L1 was upregulated in the AsPC-1 and Pan02 cells when stimulated by each of the three anticancer agents. The phosphorylation of STAT1 and an increase in total STAT1 were also observed in the AsPC-1 cells when stimulated by each anticancer agent. In response to JAK2 inhibitor treatment, PD-L1 upregulation induced by the anticancer agents was reduced in a dose-dependent manner. These results suggest that i) the JAK2/STAT1 pathway is involved in the anticancer agent-mediated PD-L1 transcription; and ii) the anticancer agents altered the tumor immune response which may induce tumor immune escape. These findings can have an influence on the design of treatments that combine chemotherapy and immunotherapy.
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Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Janus Quinase 2/metabolismo , Neoplasias Pancreáticas/metabolismo , Fator de Transcrição STAT1/metabolismo , Apoptose/efeitos dos fármacos , Antígeno B7-H1/genética , Western Blotting , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Janus Quinase 2/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Although it is established that the composition of the human intestinal microbiota changes with age, transition of the intestinal microbiota of animals with age has not been well studied. In the present study, we collected fresh fecal samples from dogs of 5 different age groups (pre-weanling, weanling, young, aged, senile) and analyzed the compositions of their intestinal microbiota with a culture-based method. The results suggested that the composition of the canine intestinal microbiota also changes with age. Among intestinal bacteria predominant in dog intestines, lactobacilli appeared to change with age. Both the number and the prevalence of lactobacilli tended to decrease when dogs became older. Bifidobacteria, on the other hand, was not predominant in the intestine of the dogs. We also identified lactobacilli at the species level based on 16S rRNA gene sequences and found that the species composition of Lactobacillus also changed with age. It was further suggested that bacteria species beneficial to host animals may differ depending on the host species.
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The transition of intestinal microbiota with age has been well described in humans. However, the age-related changes in intestinal microbiota of cats have not been well studied. In the present study, we investigated the composition of intestinal microbiota of cats in 5 different age groups (pre-weanling, weanling, young, aged, senile) with a culture-based method. For lactobacilli and bifidobacteria, we also quantified with molecular-based method, real-time PCR. The results suggested that the composition of the feline intestinal microbiota changes with age, while the changes were different from those of humans and dogs. Bifidobacteria which are predominant in human intestine or lactobacilli which are predominant in dog intestine, did not appear to be important in cat intestines. Enterococci, instead, seem to be major lactic acid producing bacteria in cats. We also identified lactobacilli and bifidobacteria at the species level based on 16S rRNA gene sequences and found that the species composition of Lactobacillus also changed with age.
Assuntos
Biodiversidade , Microbioma Gastrointestinal , Fatores Etários , Animais , Bifidobacterium/classificação , Bifidobacterium/genética , Gatos , DNA Bacteriano/genética , Fezes/microbiologia , Lactobacillus/classificação , Lactobacillus/genética , Metagenoma , Metagenômica/métodosRESUMO
Mucin is produced and secreted by epithelial goblet cells and is a key component of the innate immune system, acting as a barrier in the intestinal tract. However, no studies have been conducted investigating the increase in mucin secretion to enhance the intestinal barrier function. The present study investigated whether rebamipide (Reb) acts as a secretagogue of intestinal mucin and the underlying mechanisms involved, thereby focusing on the effect on goblet cells. The LS174T cell line was used as goblet celllike cells. Using Rebtreated LS174T cells, the level of mucin content was assessed by periodic acidSchiff (PAS) staining, and mucin 2, oligomeric mucus/gelforming (MUC2) mRNA expression was assessed using quantitative polymerase chain reaction (PCR). Furthermore, MUC2 secretion in the supernatant was quantified by the dot blot method. The present study additionally investigated the involvement of the epidermal growth factor receptor/Akt serine/threonine kinase 1 (Akt) pathway in mucin secretion by western blotting. The results suggested that Reb strongly enhanced the positivity of PAS staining in LS174T cells, thereby suggesting increased intracellular mucin production. The PCR results indicated that Reb significantly increased MUC2 mRNA in whole cell lysate of LS174T cells. In order to assess the subsequent secretion of mucin by LS174T, MUC2 protein expression in the supernatant was assessed using the dot blot method and it was demonstrated that Reb significantly increased the secretion of MUC2 in a concentrationdependent manner. The pAkt was significantly increased by Reb treatment, and an Akt inhibitor specifically suppressed MUC2 secretion. Overall, Reb increased mucin secretion directly via pAkt. Rebincreased mucin may act as a strong nonspecific barrier against pathogenic stimulants in various intestinal diseases.
Assuntos
Alanina/análogos & derivados , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/metabolismo , Mucinas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolonas/farmacologia , Alanina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucinas/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Chemo (chemoradio) therapy can induce oral mucositis and change body composition in patients with esophageal cancer. The impact of the amino acid-rich elemental diet Elental® on oral mucositis and changes in body composition during chemo (chemoradio) therapy is unclear. Thus, the purpose of the present study was to examine the preventive effects of Elental on oral mucositis and sarcopenia progression during chemo (chemoradio) therapy for esophageal cancer. Patients were randomized to receive either azulene oral rinse (Arm 1) or Elental (Arm 2) during the treatment cycle (4 weeks). The incidence of oral mucositis and other adverse events was evaluated weekly. Body composition pre- and post-treatment cycle was measured by bioelectric impedance analysis. Thirtythree patients (17 azulene and 16 Elental) completed the study, and the groups were well matched. Elental tended to reduce the incidence of oral mucositis (Arm 1, 23.5% and Arm 2, 12.5%), but there was no statistically significant difference between the groups. The average body mass index (BMI) and body fat mass decreased significantly in both groups after the treatments. Lean body mass (LBM) was reduced in Arm 1, but was increased in Arm 2 after the treatment; the relative change of LBM after the treatment was significant between Arm 1 and Arm 2 (P=0.007). This study revealed that Elental nutrition could counteract sarcopenia development during chemoradiotherapy for esophageal cancer. These properties may lead to improvement of the quality of life and clinical outcome of esophageal cancer patients treated with chemo (chemoradio) therapy (Clinical Trial Registry ID: UMIN 000007960).