Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
BMC Cancer ; 23(1): 1046, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37904096

RESUMO

BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable for surgery due to the anatomic reason. PM-HNRMS has a poor prognosis in children. However, its clinical outcomes remain unclear in adults due to the rarity. Further, there is almost no detailed data about salvage therapy. METHODS: We retrospectively examined the adult patients with PM-HNRMS treated at institutions belonging to the Kyushu Medical Oncology Group from 2009 to 2022. We evaluated the overall survival (OS) and progression-free survival (PFS) of the patients who received a first-line therapy. We also reviewed the clinical outcomes of patients who progressed against a first-line therapy and received salvage therapy. RESULTS: Total 11 patients of PM-HNRMS received a first-line therapy. The characteristics were as follows: median age: 38 years (range 25 - 63 years), histology (alveolar/spindle): 10/1, and risk group (intermediate/high): 7/4. As a first-line therapy, VAC and ARST0431-based regimen was performed in 10 and 1 patients, respectively. During a first-line therapy, definitive radiation for all lesions were performed in seven patients. The median PFS was 14.2 months (95%CI: 6.0 - 25.8 months): 17.1 months (95%CI: 6.0 - not reached (NR)) for patients with stage I-III and 8.5 months (95%CI: 5.2 - 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5% and 11.3% for all patients. Median OS in all patients was 40.8 months (95%CI: 12.1 months-NR): 40.8 months (95%CI: 12.1 - NR) for patients with stage I-III and NR for patients with stage IV. The 5-year OS rate was 48.5% for all patients. Among seven patients who received salvage therapy, three are still alive, two of whom remain disease-free for over 4 years after completion of the last therapy. Those two patients received multi-modal therapy including local therapy for all detected lesions. CONCLUSION: The cure rate of adult PM-HNRMS is low in spite of a first-line therapy in this study. Salvage therapy might prolong the survival in patients who received the multi-modal therapy including local therapy for all detected lesions.


Assuntos
Neoplasias de Cabeça e Pescoço , Rabdomiossarcoma , Adulto , Humanos , Pessoa de Meia-Idade , Neoplasias de Cabeça e Pescoço/terapia , Japão , Recidiva Local de Neoplasia/terapia , Estudos Retrospectivos , Rabdomiossarcoma/patologia , Terapia de Salvação
2.
Invest New Drugs ; 40(2): 420-429, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34792690

RESUMO

PURPOSE: Docetaxel, cisplatin, and 5-fluorouracil (DCF) have high response rates, but severe neutropenia is frequently observed. The occurrence of neutropenia is associated with high histological response in solid tumors, and it might be associated with tumor shrinkage after DCF therapy. This study aimed to determine the genetic polymorphisms involved in the clinical response to preoperative DCF therapy in esophageal cancer patients. METHODS: We included 56 patients with measurable lesions who received preoperative DCF therapy for esophageal cancer. Twenty-one genetic polymorphisms were analyzed, and univariate logistic regression analysis was used to evaluate the association between genetic polymorphisms and tumor shrinkage. A multivariate logistic regression analysis adjusted for T category and tumor location and a univariate analysis for potential genetic factors with P values < 0.05 were performed to explore the predictive factors and to estimate odds ratios and their 95% confidence intervals. RESULTS: No patient achieved a complete response, whereas 20 patients achieved a partial response, 31 patients had stable disease, and 5 patients had progressive disease. Although no association was found between pharmacokinetic-related gene polymorphisms, XRCC3 rs17997944 was extracted as the only genetic factor that affected tumor shrinkage (P = 0.033) by univariate analysis. The multivariate analysis adjusted for T category and tumor site also showed that XRCC3 rs1799794: AA was a predictive factor that affected tumor shrinkage (odds ratio, 0.243; 95% confidence interval, 0.065-0.914; P = 0.036). CONLUSIONS: XRCC3 rs1799794, which is involved in homologous recombination, is a genetic factor that affects clinical responses to DCF therapy.


Assuntos
Neoplasias Esofágicas , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Fluoruracila/uso terapêutico , Humanos , Polimorfismo Genético/genética , Estudos Retrospectivos
3.
Gastric Cancer ; 25(5): 862-878, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35661943

RESUMO

BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.


Assuntos
Carcinoma de Células em Anel de Sinete , Neoplasias Gástricas , Caderinas/genética , Caderinas/metabolismo , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Perfilação da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
4.
BMC Surg ; 22(1): 174, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35549907

RESUMO

BACKGROUND: In gastrectomies, especially subtotal gastrectomies and operations on the gastroesophageal junction, identifying the exact location of the tumor and establishing the appropriate resection line is very important. Accurate resection lines have a major impact on the preservation of organ function and curability. Preservation of as much as possible of the remaining stomach, including the fornix, may be an important surgical goal for maintaining an adequate postoperative quality of life. In adenocarcinoma of the gastroesophageal junction, the height of the esophageal dissection may affect reconstruction of the transhiatal approach. METHODS: We perform a new technique, near infrared ray-guided surgery, for the accurate localization of a tumor using the Firefly technology of the daVinci Xi system and intra-operative upper gastrointestinal endoscopy. We used this new technique for cases of upper gastric cancer or adenocarcinoma of the gastroesophageal junction. In this retrospective study, we examined to determine the extent (mm) of the tumor invasion of the esophagus, visualization of near infrared ray contained within endoscopic light, and distance from the proximal margin of the tumor to the surgical cut line on rapid histopathology and in the permanent preparation, including the operative videos and extracted specimens. RESULTS: We performed near infrared ray-guided surgery for 12 patients with gastric cancer or adenocarcinoma of the gastroesophageal junction, and the near infrared ray was clearly seen as green light with Firefly mode in all the patients. Near infrared ray-guided surgery was useful for obtaining localization of the tumor. In addition, it was possible to resect organ with adequate margins from tumor. Rapid intraoperative histopathological examinations confirmed that the resected specimens had negative margins. None of the patients required additional resection. CONCLUSIONS: We believe that because near infrared ray-guided surgery can provide an accurate resection line, it will be useful for the resection of upper gastric cancer and adenocarcinoma of the gastroesophageal junction. It will also provide patients with a good postoperative quality of life after surgery.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Animais , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Vaga-Lumes , Gastrectomia/métodos , Gastroscopia , Humanos , Raios Infravermelhos , Margens de Excisão , Qualidade de Vida , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tecnologia
5.
Int J Clin Oncol ; 26(2): 345-354, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33085058

RESUMO

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Junção Esofagogástrica , Recidiva Local de Neoplasia , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Combinação de Medicamentos , Junção Esofagogástrica/patologia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Ácido Oxônico/efeitos adversos , Ácido Oxônico/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Tegafur/efeitos adversos , Tegafur/uso terapêutico
6.
JCO Precis Oncol ; 8: e2300681, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38748981

RESUMO

PURPOSE: The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer. METHODS: We conducted a retrospective study using real-world clinical data and next-generation sequencing-based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment. RESULTS: In 114 patients with human epidermal growth factor receptor-2 (HER2)-positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P = .044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1/ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2-nonamplified tumors; P < .0001). ERBB2-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2-mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P = .046). CONCLUSION: CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.


Assuntos
Receptor ErbB-2 , Neoplasias Gástricas , Trastuzumab , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapêutico , Receptor ErbB-2/genética , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Idoso de 80 Anos ou mais
7.
Anticancer Res ; 43(4): 1817-1826, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36974805

RESUMO

BACKGROUND/AIM: Recent advances in chemotherapy have made significant progress in conversion surgery (CS) for unresectable pancreatic cancer (uPC). However, the success rate and efficacy of CS have not been fully demonstrated in patients with uPC treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP). PATIENTS AND METHODS: We retrospectively reviewed the records of 318 patients with uPC who received FFX or GnP as first-line chemotherapy. The efficacy in the CS group, defined as undergoing complete resection after chemotherapy, was analyzed, and compared with the non-CS group; then, contributing factors to achieving CS were extracted. We also analyzed differences in the efficacy of CS between locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). RESULTS: Overall, CS was achieved in 4.3% of cases, eight patients (13.3%) with LAPC and five (2.1%) with MPC. Contributing factors to CS were LAPC, no liver metastasis, CA19-9 ≤37, and chemotherapy response. After adjusting for these, overall survival was significantly better in the CS group than in the non-CS group [median of 32.9 vs. 11.3 months; adjusted hazard ratio (HR)=0.32; 95% confidence interval (CI)=0.14-0.70; p<0.01]. Median relapse-free survival duration after CS was 19.1 and 18.1 months in the LAPC-CS and MPC-CS group, respectively (p=0.84). The median post-conversion survival was 27.6 months in the entire CS group, 43.8 months in the LAPC-CS group and 21.3 months in the MPC-CS group. CONCLUSION: CS was achieved in 13.3% of LAPC and 2.1% of MPC cases. If possible, CS can markedly improve prognosis, even in MPC.


Assuntos
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Gencitabina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Retrospectivos , Desoxicitidina , Recidiva Local de Neoplasia/tratamento farmacológico , Fluoruracila , Paclitaxel/uso terapêutico , Albuminas/uso terapêutico , Leucovorina , Neoplasias Pancreáticas
8.
Sci Rep ; 12(1): 19984, 2022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411324

RESUMO

A new class of deformation is presented for a planar loop structure made up of slender elastic bodies and joints. In demonstrating the circumferential shortening of the multi-jointed elastic loop, diverse three-dimensional (3D) deformations emerge through piecewise deflections and discrete rotations. These 3D morphologies correspond to conformations of molecular ring systems. Through image processing, the 3D reconstructions of the deformed structures are characterized by number, geometry, and initial imperfections of the body segments. We elucidate from measurements that the conformational deformation without self-stress results from a cyclical assembly of compressive bending of elastic bodies with high shear rigidity. The mechanical insights gained may apply in controlling the polymorphism exhibited by the cyclical structures across scales.


Assuntos
Processamento de Imagem Assistida por Computador , Conformação Molecular , Pressão
9.
Front Cardiovasc Med ; 9: 848091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35387436

RESUMO

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy. Case Summary: A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion. Conclusion: Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

10.
Cancer Lett ; 532: 215597, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35150810

RESUMO

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFß signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFß and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Peritoneais , Derrame Pleural , Animais , Ascite/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fibroblastos/metabolismo , Humanos , Macrófagos , Camundongos , Neoplasias Peritoneais/metabolismo , Derrame Pleural/metabolismo , Derrame Pleural/patologia , Antígenos Thy-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
11.
Mol Clin Oncol ; 15(4): 221, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34476105

RESUMO

Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.

12.
Biocontrol Sci ; 24(1): 57-65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880314

RESUMO

 Effective spatial disinfection systems are required for human health care, public hygiene, and food and medicine manufacturing. Although some aerosolized disinfectants were already applied to its purpose, accurate evaluation systems were under constructed. In this study, the spatial sporicidal activity of aerosolized hypochlorite solution (AHS) to dormant cells, Bacillus subtilis spores, was evaluated by an originally designed chamber system. In the test-chamber, AHS was supplied and existed as micro-droplets, and environmental relative humidity (RH) could be controlled. Available chlorine (AC) exposure was also controlled with appropriate AC loading but was influenced by the acidity of AHS. Our results indicated that inactivation of spore was depend on AC exposure amount and time. On the other hand, unsaturated environmental RH markedly decreased spore inactivation. This study indicated that our test-chamber system can provide reproducible test data under a homogeneous air condition, and, thereby, that the data obtained by the chamber system should contribute to predicting the AC-required dose to disinfect a whole building.


Assuntos
Bacillus subtilis/efeitos dos fármacos , Desinfetantes/farmacologia , Desinfecção/métodos , Ácido Hipocloroso/farmacologia , Esporos Bacterianos/efeitos dos fármacos , Aerossóis , Bacillus subtilis/fisiologia , Desinfetantes/química , Desinfecção/instrumentação , Ácido Hipocloroso/química , Viabilidade Microbiana/efeitos dos fármacos , Soluções
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA