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1.
Ann Surg Oncol ; 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39225857

RESUMO

BACKGROUND: There are few reports on conversion surgery (CS) after chemotherapy plus nivolumab as a first-line treatment in patients with unresectable advanced or recurrent gastric cancer (GC). This multicenter study was conducted to analyze real-world data on CS after chemotherapy plus nivolumab as a first-line treatment and to identify predictive biomarkers. METHODS: This multicenter study included 104 patients who received chemotherapy plus nivolumab as primary treatment for unresectable advanced recurrent GC from 12 institutes. We investigated and analyzed patient characteristics and blood test data in the presence or absence of CS, the relationship between the Gustave Roussy Immune Score (GRIm-s) and CS, and the characteristics of CS cases. RESULTS: CS was performed in 12 patients (11.5%). Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was significantly better in patients who underwent CS (p < 0.0001). There were no CS cases with high-risk GRIm-s (0%), however there were 22 non-CS cases (23.9%). No high-risk GRIm-s cases were converted to CS. Minimally invasive surgery was performed in 50.0% of the cases, with R0 resection in all cases and only one case of urinary retention (Grade II) as a postoperative complication, indicating a good postoperative short-term outcome. There were two cases of postoperative recurrence (16.7%), both of which were grade 1b. CONCLUSIONS: The short-term postoperative results of CS after chemotherapy plus nivolumab as the first-line treatment for GC were acceptable in this study. There were no high-risk GRIm-s cases among those who underwent CS, suggesting that the GRIm-s may be a predictor of CS.

2.
Oncology ; : 1-17, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39265540

RESUMO

INTRODUCTION: In this study, we aimed to identify biomarkers for predicting treatment outcomes and efficacy of chemotherapy plus nivolumab, as well as predict immune-related adverse events (irAEs) characteristics of immune checkpoint inhibitors. METHODS: This multicenter study included 104 patients who received chemotherapy plus nivolumab as the primary treatment for unresectable advanced recurrent gastric cancer. Blood test results were collected before the start and after two courses of treatment. The neutrophil-lymphocyte ratio, prognostic nutritional index (PNI), and lactate dehydrogenase/albumin ratio (LAR) were examined after treatment in each case to determine changes compared to values before the start of treatment. RESULTS: A total of 57 (54.8%) patients experienced a complete or partial response. The LAR of the stable disease (SD)/progressive disease (PD) group significantly increased (p=0.018). An examination of the presence of grade ≥3 irAEs and changes in related factors showed that the LAR of all patients increased. CONCLUSION: The LAR was correlated with the best therapeutic response; therefore, it may be a potential biomarker of treatment outcomes and efficacy.

3.
Cancer Rep (Hoboken) ; 7(7): e2145, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39051558

RESUMO

BACKGROUND: The expansion of preoperative immunochemotherapy has led to an increase in the number of patients with lung cancer receiving immune checkpoint inhibitors (ICIs). Therefore, oncologists should manage a variety of immune-related adverse events (irAEs). One of the rare, life-threatening, and recently proposed irAEs is cytokine release syndrome (CRS). Although the standard treatment of irAE is systemic administration of steroids, it has been suggested that tocilizumab may be an effective treatment option for CRS. CASE: This case describes a 69-year-old man with stage IIIA lung adenocarcinoma who received chemotherapy and nivolumab, which is an ICI, as neoadjuvant immunochemotherapy. After the first administration, the patient developed severe skin rash, fever, and arthralgia. We suspected irAEs and administered systemic steroids. However, fever and arthralgia did not improve, although the skin rash disappeared. These were also significant challenges for surgery. Noting the elevated levels of inflammatory cytokines, we consulted a rheumatologist. Finally, we decided to terminate neoadjuvant therapy after one cycle and administer tocilizumab. Tocilizumab dramatically improved the patient's symptoms and allowed him to undergo radical surgery. Pathological findings revealed that the patient achieved a major pathological response. CONCLUSION: This indicates the potential effectiveness of early tocilizumab administration for ICI-induced CRS, even in mild cases.


Assuntos
Anticorpos Monoclonais Humanizados , Síndrome da Liberação de Citocina , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Idoso , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/efeitos adversos , Síndrome da Liberação de Citocina/induzido quimicamente , Síndrome da Liberação de Citocina/etiologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Nivolumabe/efeitos adversos , Nivolumabe/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento
4.
Cancer Rep (Hoboken) ; 7(2): e1981, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38212894

RESUMO

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive lung cancer has a better long-term prognosis with ALK-inhibitor than other lung cancers. However, resistance to ALK-inhibitors and the control of metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK-positive lung cancer. CASE: We present the case of a 23-year-old man who developed multiple brain metastases while receiving alectinib treatment for ALK-positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained. CONCLUSION: While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK-inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.


Assuntos
Aminopiridinas , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Lactamas , Neoplasias Pulmonares , Pirazóis , Humanos , Masculino , Adulto Jovem , Quinase do Linfoma Anaplásico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico
5.
Clin J Gastroenterol ; 16(6): 854-858, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37733231

RESUMO

The metastasis of breast cancer to the gastrointestinal tract is rare. Herein, we presented the case of an 85-year-old woman who had a history of invasive lobular carcinoma and experienced complete colon rupture due to relatively low-energy trauma. The patient underwent bilateral total mastectomy and axillary dissection following preoperative chemotherapy 6 years ago. She had a local recurrence 2 years after the surgery and underwent chemotherapy. Subsequently, the cancer metastasized to the thoracolumbar area and retroperitoneum. In addition, the patient fell from a height of 30 cm while hanging laundry and her abdomen hit a hose reel. Emergency surgery was performed, and the entire circumference of the sigmoid colon was ruptured. The ruptured colon lesion was resected, and the stump was closed. A double-barrel transverse colostomy was created as it was impossible to lift the stump up to the abdominal wall. Histopathological examination revealed the invasive lobular carcinoma metastasis and a linitis plastica-like change of the colon wall, which probably consequently weakened. In addition, minimal trauma can damage the gastrointestinal tract that had invasive lobular carcinoma metastasis.


Assuntos
Neoplasias da Mama , Carcinoma Lobular , Segunda Neoplasia Primária , Feminino , Humanos , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Lobular/secundário , Colo Sigmoide/patologia , Mastectomia , Segunda Neoplasia Primária/cirurgia , Melanoma Maligno Cutâneo
6.
Lab Chip ; 23(4): 727-736, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36484269

RESUMO

There have been significant advances in the field of nanofluidics, and novel technologies such as single-cell analysis have been demonstrated. Despite the evident advantages of nanofluidics, fluid control in nanochannels for complicated analyses is extremely difficult because the fluids are currently manipulated by maintaining the balance of driving pressure. To address this issue, the use of valves will be essential. Our group previously developed a nanochannel open/close valve utilizing glass deformation, but this has not yet been integrated into nanofluidic devices for analytical applications. In the present study, a nanofluidic analytical system integrated with multiple nanochannel open/close valves was developed. This system consists of eight pneumatic pumps, seven nanochannel open/close valves combined with piezoelectric actuators, and an ultra-high sensitivity detector for non-fluorescent molecules. For simultaneous actuation of multiple valves, a device holder was designed that prevented deformation of the entire device caused by operating the valves. A system was subsequently devised to align each valve and actuator with a precision of better than 20 µm to permit the operation of valves. The developed analytical system was verified by analyzing IL-6 molecules using an enzyme-linked immunosorbent assay. Fluid operations such as sample injection, pL-level aliquot sampling and flow switching were accomplished in this device simply by opening/closing specific valves, and a sample consisting of approximately 1500 IL-6 molecules was successfully detected. This study is expected to significantly improve the usability of nanofluidic analytical devices and lead to the realization of sophisticated analytical techniques such as single-cell proteomics.


Assuntos
Ensaio de Imunoadsorção Enzimática , Técnicas Analíticas Microfluídicas , Ensaio de Imunoadsorção Enzimática/métodos , Interleucina-6/química , Técnicas Analíticas Microfluídicas/métodos , Nanotecnologia/métodos
7.
Surg Today ; 52(5): 832-843, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34734320

RESUMO

PURPOSE: This retrospective nationwide survey investigated the quality of life (QOL) of patients with esophagogastric junction cancer after gastrectomy using the Postgastrectomy Syndrome Assessment Scale-45. METHODS: The Postgastrectomy Syndrome Assessment Scale-45 comprises 45 questions classified into symptoms, living status, and QOL domains. A total of 1950 gastrectomized patients with upper-third gastric or esophagogastric junction cancer returned the completed forms. Among them, 224 eligible patients with esophagogastric junction cancer were selected, including 86, 120, and 18 patients who underwent total gastrectomy, proximal gastrectomy (reconstruction-esophagogastrostomy: 56; double-tract method: 51), and other procedures, respectively. RESULTS: The postoperative period was significantly shorter (47 ± 30 vs. 34 ± 30 months, p = 0.002), and the rates of early-stage disease and minimally invasive approaches significantly higher (both p < 0.001) in the proximal gastrectomy group than in the total gastrectomy group. Despite advantageous background factors for proximal gastrectomy, the postoperative QOL did not differ markedly between the groups. Compared to patients who underwent reconstruction with the double-tract method, patients who underwent esophagogastrostomy had significantly larger remnant stomachs but a similar QOL. CONCLUSION: Even with total gastrectomy, a postoperative QOL comparable to that with proximal gastrectomy can be maintained. Clarifying the optimal reconstruction methods for proximal gastrectomy for esophagogastric junction cancer is warranted. TRIAL REGISTRATION: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: 000032221).


Assuntos
Síndromes Pós-Gastrectomia , Neoplasias Gástricas , Junção Esofagogástrica/cirurgia , Gastrectomia/métodos , Humanos , Síndromes Pós-Gastrectomia/cirurgia , Período Pós-Operatório , Qualidade de Vida , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia
8.
PLoS One ; 16(11): e0260500, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34843570

RESUMO

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Transcriptoma/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade
9.
Cancer Med ; 10(14): 4796-4804, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34121358

RESUMO

BACKGROUND: The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti-programmed cell death-1 antibody in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time-to-treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). RESULTS: CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months-not reached] vs. 3.9 months [95% CI: 3.4-5.1 months, p < 0.01]) and longer OS (27.4 [95% CI: 20.7 months-not reached] vs. 14.8 months [95% CI: 11.2-17.9 months, p = 0.003]). Most patients discontinued the immune checkpoint inhibitor (ICI) treatment when they developed CIP. Seven patients (25%) lived for more than 300 days from treatment discontinuation and did not show any long-term tumor growth after treatment discontinuation. CONCLUSION: CIP was associated with prolonged PFS and OS. Additionally, 25% of CIP patients did not show any tumor growth for long periods after treatment discontinuation. Careful management of CIP can help in obtaining the best clinical efficacy from anti-PD-1 antibody.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalos de Confiança , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Pneumonia/mortalidade , Intervalo Livre de Progressão , Estudos Retrospectivos , Falha de Tratamento , Suspensão de Tratamento
10.
JMA J ; 3(1): 58-66, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33324776

RESUMO

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. METHODS: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. RESULTS: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). CONCLUSIONS: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

11.
Surg Case Rep ; 6(1): 186, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737607

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is a very rare disease, and its pathogenesis is unknown. There are few reports of MPNST of the oesophagus. We report a case of an MPNST that was diagnosed and resected. CASE PRESENTATION: A 30-year-old female presented with dysphagia. She had been aware of the dysphagia approximately 6 months before presentation. The chest X-ray showed shadows in the right mediastinum. Barium fluoroscopy revealed a semicircular raised lesion in the lower oesophagus. Upper gastrointestinal endoscopy revealed a type 1 oesophageal tumour centred on the posterior wall 26-35 cm from the incisors. The surface was ulcerated, and the tumour was exposed. The affected area showed no iodine uptake. The EUS showed an isoechoic mass. The CT scan showed a mass of 71 × 61 × 55 mm in the beginning of the lower oesophagus with low density mass and swelling of the right recurrent nerve lymph node to 12 mm. On FDG-PET, the tumour showed an SUVmax of 11.05, and no abnormal accumulation was found in lymph nodes or other organs. The MRI showed a hyperintense mass on the T2WI, which had prolonged contrast enhancement, and no findings of invasion into surrounding tissue were found. The patient underwent right thoracotomy and open thoracic oesophagectomy. The affected lymph node was tumour negative by rapid pathological diagnosis during the operation. Histologically, spindle cells with different-sized nuclei were mixed throughout the tissue. Some regions showed nuclear polymorphism or a storiform pattern, and locally, there were approximately 7 mitoses/10 HPFs. The margin was relatively clear, but spindle-shaped tumour cells infiltrated the surrounding interstitium and basal myoepithelium, and the patient was diagnosed with MPNST. In this case, the postoperative course was good, and 16 months after the operation, the patient is currently under observation at the outpatient stage without recurrence. CONCLUSIONS: MPNST in the oesophagus is a relatively rare disease. Diagnosis before treatment is sometimes difficult, but the prognosis is good if radical resection is possible.

12.
Oncologist ; 25(3): e536-e544, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32162801

RESUMO

BACKGROUND: Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. SUBJECTS, MATERIALS, AND METHODS: We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. RESULTS: Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. CONCLUSION: Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted. IMPLICATIONS FOR PRACTICE: This single-institutional medical record review that included 155 patients with advanced non-small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression-free survival were significantly better in patients with skin reactions. Pre-existing rheumatoid factor was an independent predictor of skin reactions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Estudos Retrospectivos
13.
Anal Chem ; 91(4): 3009-3014, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30661360

RESUMO

A gradient system was developed for the separation of proteins on a femtoliter scale utilizing nanofluidic channels. In the history of chromatography, miniaturization of the separation column has been important for efficient separation and downsizing of instruments. Previously, our group developed a small and highly efficient chromatography system utilizing nanofluidic channels, although a flexible design of the gradient was difficult and separation of proteins was not achieved. Here, we propose a flexible gradient system using standard HPLC pumps and an auxiliary mixer with a simple sample injection system. In contrast to our previous sample injection system using pressure balance, the system enables a femtoliter-scale sample injection which is compatible with gradient elution using HPLC pumps. The system was carefully designed, verified for sample injection and gradient elution, and finally applied to the separation of proteins from model and real samples. This femtoliter-scale, efficient separation system will contribute to omics studies at the single-cell level.


Assuntos
Proteínas/isolamento & purificação , Análise de Célula Única , Cromatografia Líquida de Alta Pressão/instrumentação , Células Hep G2 , Humanos , Tamanho da Partícula , Pressão , Proteínas/química , Análise de Célula Única/instrumentação , Propriedades de Superfície
14.
Artigo em Inglês | MEDLINE | ID: mdl-32476938

RESUMO

BACKGROUND: We have often encountered adverse events requiring dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis. OBJECTIVES: The objectives of this study were to clarify the incidence of dose reduction and/or discontinuation following the commercialization of nintedanib and to investigate predictors of dose reduction and/or discontinuation of nintedanib at our hospital. METHODS: We retrospectively identified 25 patients who had received nintedanib 150 mg twice daily at Sendai Kousei Hospital and categorized them into two groups according to whether they had or had not required dose reduction and/or discontinuation and sought to identify predictors of dose reduction and/or discontinuation. RESULTS: Seventeen patients developed adverse events, which included diarrhea (n=10, 44%), hepatotoxicity (n=7, 28%), and anorexia (n=2, 16%). No adverse event-related deaths occurred during the study period. Patients who required dose reduction and/or discontinuation were significantly older than those who did not (72 years vs 67 years; P=0.047). Body surface area (BSA) was significantly lower in the group that needed dose reduction and/or discontinuation than in the group that did not (1.63 m2 vs. 1.78 m2; P=0.028). Multivariate logistic regression revealed that the association of low BSA with dose reduction and/or discontinuation was statistically significant. CONCLUSIONS: A low BSA was associated with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis. Further studies in larger patient samples are needed to validate these findings.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Superfície Corporal , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Fatores de Risco
15.
JAMA Oncol ; 5(3): 376-383, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30589930

RESUMO

Importance: Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1. Objective: To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment. Design, Setting, and Participants: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. Exposures: Absence or presence of specific autoimmune markers and antibodies before treatment. Main Outcomes and Measures: Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. Results: Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001). Conclusions and Relevance: The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic benefits while minimizing irAEs.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Autoanticorpos/sangue , Autoimunidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Tempo
16.
Gan To Kagaku Ryoho ; 45(12): 1755-1758, 2018 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-30587735

RESUMO

A laparoscopy-assisted right hemicolectomy and D3 lymph node dissection were performed to treat a 60-year-old woman with ascending colon cancer. Microscopically, the resected specimen was diagnosed as adenocarcinoma(tub1>tub2, pSS, pN1, M0). Adjuvant chemotherapy using UFT/UZEL was administered for 6 months. Enlarged para-aortic lymph nodes were identified by follow-up CT 2 years post operation, and a para-aortic lymph node dissection was performed. Microscopic examination revealed that the #216 b1 int lymph node contained poorly differentiated metastatic adenocarcinoma. After 36 courses of FOLFOX as adjuvant chemotherapy, the chemotherapy was discontinued because of an adverse event. She has remained well without recurrence for 5 years after the second surgery. There have been reports of survival improvements by surgical resections in patients with solitary para-aorta lymph node metastases of colorectal cancer. These observations suggest that the surgical therapy may have contributed to the improved prognosis in the present case.


Assuntos
Quimioterapia Adjuvante , Colo Ascendente , Neoplasias do Colo/tratamento farmacológico , Recidiva Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Excisão de Linfonodo , Linfonodos , Metástase Linfática , Pessoa de Meia-Idade
17.
Oncologist ; 23(11): 1358-1365, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29934411

RESUMO

BACKGROUND: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non-irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined. RESULTS: The objective response rate was 57% in the irAE group versus 12% in the non-irAE group. Median progression-free survival was 12.0 months in the irAE versus 3.6 months in the non-irAE group. The incidence of both irAEs and pre-existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre-existing antithyroid antibody as an independent predictor of treatment response. CONCLUSION: Objective response rate and progression-free survival were significantly better in the irAE than in the non-irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre-existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy. IMPLICATIONS FOR PRACTICE: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Estudos Retrospectivos
18.
Arthritis Rheumatol ; 69(9): 1879-1890, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28556548

RESUMO

OBJECTIVE: To determine the function and serum levels of soluble forms of programmed death 1 (sPD-1) and one of its ligands, soluble PD ligand 2 (sPD-L2), in patients with systemic sclerosis (SSc) and in a mouse model of topoisomerase I (topo I)-induced SSc. METHODS: Serum levels of sPD-1 and sPD-L2 in 91 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). Expression of PD-1 and PD-L2 on T cells, B cells, and macrophages was quantified by flow cytometry. The effects of blockade of PD-1 and PD-L2 were analyzed by microfluidic ELISA (micro-ELISA), a technique that can measure very low amounts of cytokines. In addition, the effects of sPD-1 and sPD-L2 on disease progression were assessed in mice with topo I-induced SSc. RESULTS: Serum levels of sPD-1 and sPD-L2 were elevated in patients with SSc and correlated with the extent of fibrosis and immunologic abnormalities. Expression levels of PD-1 and PD-L2 were significantly elevated on SSc T cells, B cells, and macrophages. Micro-ELISA analysis of serum samples from patients with SSc showed that PD-L2high B cells had higher levels of interleukin-10 (IL-10) production compared with PD-L2low B cells, indicating that PD-L2 acts as a regulator of T cell cytokine production via cognate interactions with T cells and B cells. In mice with topo I-induced SSc, production of IL-10 by topo I-specific B cells in cultures with T cells and topo I protein was significantly higher than that by conventional B cells, and intraperitoneal injection of recombinant chimeric PD-1-Fc and PD-L2-Fc canceled these enhanced effects. CONCLUSION: These results suggest that sPD-1 and sPD-L2 contribute to disease development in SSc via the regulation of cognate interactions with T cells and B cells.


Assuntos
Proteína 2 Ligante de Morte Celular Programada 1/sangue , Receptor de Morte Celular Programada 1/sangue , Escleroderma Sistêmico/sangue , Adulto , Animais , Linfócitos B/metabolismo , DNA Topoisomerases Tipo I , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/patologia , Índice de Gravidade de Doença , Linfócitos T/metabolismo
19.
Gan To Kagaku Ryoho ; 43(8): 1009-13, 2016 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-27539046

RESUMO

A 6 2-year-old woman visited our hospital with a complaint of anal bleeding and was diagnosed with rectal cancer. She underwent low anterior resection and D3 lymphadenectomy. The pathological diagnosis was shown as follows: Ra, Circ, type 2, por1, pSS, ly3, v1, pN2, pStage III b, and KRAS wild type. UFT/UZEL with polysaccharide K(PSK)was initiated as adjuvant chemotherapy after the operation. However, multiple liver metastases were found on CT after 3 courses of UFT/UZEL with PSK, and pathological reexamination revealed that the primary tumor was a neuroendocrine carcinoma. She underwent chemotherapy with CBDCA combined with CPT-11, but bone marrow suppression was observed after 4 courses of the treatment. As second-line chemotherapy, FOLFOX4 plus panitumumab(Pmab)was administered. Although the disease remained stable through 10 courses of FOLFOX4 plus Pmab, Grade 3 peripheral neuropathy was observed. Hence, FOLFIRI plus bevacizumab(Bmab)was administered as third-line chemotherapy. Twenty-eight courses of FOLFIRI plus Bmab were administered, and transcatheter arterial chemoembolization(TACE)was performed during chemotherapy. However, her general condition worsened after the therapies, and she died 2 years 3 months after the initial chemotherapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Adenocarcinoma/cirurgia , Terapia Combinada , Evolução Fatal , Feminino , Humanos , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia
20.
World J Gastroenterol ; 13(25): 3487-92, 2007 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-17659696

RESUMO

AIM: To evaluate the effect of ANP on warm I/R injury in a porcine THVE model. METHODS: Miniature pigs (mini-pigs) weighing 16-24 kg were observed for 120 min after reperfusion following 120 min of THVE. The animals were divided into two groups. ANP (0.1 mug/kg per min) was administered to the ANP group (n = 7), and vehicle was administered to the control group (n = 7). Either vehicle or ANP was intravenously administered from 30 min before the THVE to the end of the experiment. Arterial blood was collected to measure AST, LDH, and TNF-alpha. Hepatic tissue blood flow (HTBF) was also measured. Liver specimens were harvested for p38 MAPK analysis and histological study. Those results were compared between the two groups. RESULTS: The AST and LDH levels were lower in the ANP group than in the control group; the AST levels were significantly different between the two groups (60 min: 568.7 +/- 113.3 vs 321.6 +/- 60.1, P = 0.038 < 0.05, 120 min: 673.6 +/- 148.2 vs 281.1 +/- 44.8, P = 0.004 < 0.01). No significant difference was observed in the TNF-alpha levels between the two groups. HTBF was higher in the ANP group, but the difference was not significant. A significantly higher level of phosphorylated p38 MAPK was observed in the ANP group compared to the control group (0 min: 2.92 +/- 1.1 vs 6.38 +/- 1.1, P = 0.011 < 0.05). Histological tissue damage was milder in the ANP group than in the control group. CONCLUSION: Our results show that ANP has a protective role in I/R injury with p38 MAPK activation in a porcine THVE model.


Assuntos
Fator Natriurético Atrial/uso terapêutico , Isquemia/tratamento farmacológico , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Feminino , Isquemia/metabolismo , Isquemia/patologia , L-Lactato Desidrogenase/sangue , Masculino , Suínos , Fator de Necrose Tumoral alfa/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/análise , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
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