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1.
Mol Ther ; 29(10): 2920-2930, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34023506

RESUMO

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.


Assuntos
Adenoviridae/genética , Neoplasias do Colo/terapia , Vesículas Extracelulares/transplante , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Vesículas Extracelulares/virologia , Células HCT116 , Humanos , Camundongos , Vírus Oncolíticos/genética , Tropismo Viral , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Surg ; 89: 105946, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33892160

RESUMO

BACKGROUND: Pharmacologic prophylaxis such as enoxaparin for venous thromboembolism (VTE) is rarely used in Japan, even following abdominal cancer surgery, for which it is recommended in relevant guidelines (at least 7 days of use) along with mechanical prophylaxis with intermittent pneumatic compression. Reasons for enoxaparin's unpopularity include concerns over postoperative bleeding and its inconvenience in clinical practice. Here, we conducted a prospective clinical study of short-term (3 days) use of enoxaparin, which is considered to minimally impact postoperative management without increasing bleeding risk. METHODS: Gastric cancer patients who underwent gastrectomy received enoxaparin for 3 days from postoperative day (POD) 1-4. The primary endpoint was the incidence of deep vein thrombosis (DVT), which was examined primarily via Doppler ultrasonography of the lower limbs between POD 8 and 14. The planned sample size was 70, which was calculated based on an estimated incidence rate of 9% and an upper limit of incidence rate of 20%, with alpha of 0.05 and beta of 0.2. RESULTS: A total of 70 gastric cancer patients were enrolled, and ultimately, 68 patients received the protocol intervention and DVT evaluation. Sixty-seven patients completed 6 enoxaparin injections, but 1 patient did not complete the course due to abdominal bleeding after initiation. The incidence of DVT was 4.4% (3/68), and the 95% upper confidence interval was 12.2%, lower than the 20% threshold we set as the upper limit of DVT incidence. DVT was detected only in the peripheral veins of the lower extremities in all 3 affected patients. The incidence of bleeding-related complications, which were not severe, was 1.5% (1/68). CONCLUSIONS: Short-term (3 days) use of enoxaparin was shown to be effective and safe for VTE prophylaxis, comparable to regular use (at least 7 days), in postoperative management of gastric cancer surgery.


Assuntos
Anticoagulantes/administração & dosagem , Enoxaparina/administração & dosagem , Gastrectomia/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/cirurgia , Resultado do Tratamento , Ultrassonografia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
3.
PLoS One ; 15(11): e0242223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33180871

RESUMO

BACKGROUND: Although proximal gastrectomy (PG) is a recognized surgical procedure for early proximal gastric cancer, total gastrectomy (TG) is sometimes selected due to concern about severe gastroesophageal reflux. Esophagogastrostomy by the double-flap technique (DFT) is an anti-reflux reconstruction after PG, and its short-term effectiveness has been reported. However, little is known about the long-term effects on nutritional status and quality of life (QOL). METHODS: Gastric cancer patients who underwent laparoscopy-assisted PG (LAPG) with DFT or laparoscopy-assisted TG (LATG) between April 2011 and March 2014 were retrospectively analyzed. Body weight (BW), body mass index (BMI), and prognostic nutritional index (PNI) were reviewed to assess nutritional status, and the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45 was used to assess QOL. RESULTS: A total of 36 patients (LATG: 17, LAPG: 19) were enrolled. Four of 17 LATG patients (24%) were diagnosed with Stage ≥II after surgery, and half received S-1 adjuvant chemotherapy. BW and PNI were better maintained in LAPG than in LATG patients until 1-year follow-up. Seven of 16 LATG patients (44%) were categorized as "underweight (BMI<18.5 kg/m2)" at 1-year follow-up, compared to three of 18 LAPG patients (17%; p = 0.0836). The PGSAS-45 showed no significant difference in all QOL categories except for decreased BW (p = 0.0132). Multivariate analysis showed that LATG was the only potential risk factor for severe BW loss (odds ratio: 3.03, p = 0.0722). CONCLUSIONS: LAPG with DFT was superior to LATG in postoperative nutritional maintenance, and can be the first option for early proximal gastric cancer.


Assuntos
Estado Nutricional , Qualidade de Vida , Neoplasias Gástricas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Índice de Massa Corporal , Esofagectomia , Feminino , Gastrectomia , Humanos , Estimativa de Kaplan-Meier , Laparoscopia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Retalhos Cirúrgicos
4.
Mol Ther ; 28(3): 794-804, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-31991110

RESUMO

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.


Assuntos
Adenoviridae/imunologia , Antineoplásicos Imunológicos/farmacologia , Terapia Genética , Imunomodulação , Terapia Viral Oncolítica , Vírus Oncolíticos/imunologia , Telomerase/imunologia , Adenoviridae/genética , Animais , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Terapia Combinada , Citotoxicidade Imunológica , Modelos Animais de Doenças , Sinergismo Farmacológico , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nihon Shokakibyo Gakkai Zasshi ; 117(1): 64-71, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31941858

RESUMO

A 45-year-old Japanese man presenting with leg purpura, abdominal pain, and arthralgia was diagnosed with IgA vasculitis. His symptoms resolved after the intravenous administration of prednisolone. However, on day 20 of admission, he experienced bloody discharge and hypovolemic shock. The bleeding point was not identified on contrast-enhanced computed tomography scanning. The blood loss was approximately 10800ml and the patient received transfusions of 48 units of concentrated red blood cells, 18 units of fresh frozen plasma, and 30 units of concentrated platelets. Laparotomy and enteroscopy were performed through the incision of the jejunum to detect the bleeding source. Spurting bleeding was observed during the enteroscopy and partial resection of the jejunum was performed. Histopathological examination of the resected specimen revealed large vessels beneath the jejunal ulcer scar, suggesting bleeding from a Dieulafoy's lesion. Leukocytoclastic vasculitis or cytomegalovirus infection was not observed in the resected specimen. Gastrointestinal symptoms in patients with IgA vasculitis usually improve with bowel rest and conservative treatment. Administration of steroids or factor XIII is recommended for patients with severe abdominal pain refractory to conservative management. Rarely, massive bleeding, perforation, intussusception, and/or intestinal obstruction occur in the gastrointestinal tract and these complications affect patients' prognoses. The clinical course in the present patient indicated that severe bleeding from the gastrointestinal tract can occur even after symptom remission in patients with IgA vasculitis. In such cases, prompt treatment, including laparotomy and/or enteroscopy, is essential.


Assuntos
Imunoglobulina A/metabolismo , Jejuno , Vasculite/diagnóstico , Anti-Inflamatórios/uso terapêutico , Hemorragia Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Vasculite Leucocitoclástica Cutânea
6.
Am J Ophthalmol ; 138(1): 6-17, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15234277

RESUMO

PURPOSE: Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by salivary and lacrimal glandular destruction leading to symptoms of dry mouth and dry eye. Dryness can also occur in the absence of glandular destruction. Patients with SS have autoantibodies that bind to muscarinic acetylcholine receptors in the exocrine glands. Recently, a muscarinic acetylcholine receptor agonist, cevimeline, has been approved for use against symptoms of dry mouth in patients with SS. In this study, the efficacy of cevimeline in improving symptoms of dry eye was examined. DESIGN: Prospective, randomized, double-blind, multi-center clinical study. METHODS: Sixty patients were randomly assigned to three groups-placebo; cevimeline, 20 mg three times daily; or cevimeline, 30 mg three times daily-and received treatment for 4 weeks. Patients were evaluated before treatment, at week 2, at the end of treatment, and at the end of a 2- to 4-week follow-up period. RESULTS: Compared with the placebo, statistically significant differences were seen with cevimeline, 20 mg three times daily, in subjective symptoms, tear dynamics, condition of the corneoconjunctival epithelium, and global improvement rating. No difference was found among the three groups regarding the safe use of the drug. CONCLUSIONS: These results indicate that cevimeline, 20 mg three times daily, is safe and effective in improving symptoms of dry eye in patients with SS. Additional studies, with larger patient populations, are needed to further assess the effectiveness of cevimeline for dry eye.


Assuntos
Agonistas Muscarínicos/uso terapêutico , Quinuclidinas/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Tiofenos , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/metabolismo , Método Duplo-Cego , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Feminino , Fluorofotometria , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/administração & dosagem , Agonistas Muscarínicos/efeitos adversos , Cooperação do Paciente , Estudos Prospectivos , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Rosa Bengala , Segurança , Síndrome de Sjogren/metabolismo , Lágrimas/metabolismo , Resultado do Tratamento
7.
J Cataract Refract Surg ; 28(11): 2050-3, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12457685

RESUMO

Gas-permeable hard contact lenses were prescribed to 2 patients with corneal microstriae 3 months and 9 months, respectively, after laser in situ keratomileusis. The uncorrected visual acuity (UCVA) in both patients when the hard contact lenses were prescribed was 20/30 with +2.25 -1.25 x 60 and +1.50 -2.25 x 150, respectively. At 6 months in Case 1 and 3 months in Case 2, the topographic change showed corneal remodeling, with the UCVA 20/20 in both cases.


Assuntos
Lentes de Contato , Doenças da Córnea/etiologia , Doenças da Córnea/terapia , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Adulto , Doenças da Córnea/patologia , Doenças da Córnea/fisiopatologia , Topografia da Córnea , Humanos , Masculino , Pessoa de Meia-Idade , Acuidade Visual
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