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OBJECTIVES: The relationship between cooling status during aortic surgery with hypothermic circulatory arrest and postoperative neurologic dysfunction remains unknown. In the present study, we evaluated the effect of cooling status on transient neurologic dysfunction after total arch replacement. METHODS: We studied patients who underwent elective total arch replacement with hypothermic circulatory arrest and antegrade selective cerebral perfusion from December 2011 to January 2021. Changes in tympanic temperature trends recorded during surgery were plotted. Several parameters, including the nadir temperature, cooling speed, and degree of cooling (cooling area, or the area under the curve of inverted temperature trends from cooling to rewarming as calculated by the integral method), were analyzed. The relationships between these variables and transient neurologic dysfunction were evaluated. RESULTS: Transient neurologic dysfunction was observed in 33 (14.5%) of the 228 included patients. In the transient neurologic dysfunction group, the cooling area was larger (2417.3 vs. 1920.8 °C min; P < 0.001) and the cooling speed was higher (0.68 vs. 0.51 °C/min; P < 0.001) than in the non-transient neurologic dysfunction group. A multivariate logistic model revealed that both the cooling area (odds ratio = 1.13 per 100 °C min; P < 0.001) and cooling speed (odds ratio = 3.69 per °C/min; P = 0.041) were independent risk factors for transient neurologic dysfunction. CONCLUSIONS: Both the cooling area, which indicates the degree of cooling, and cooling speed had significant relationships with transient neurologic dysfunction after total arch replacement. Together, these findings indicate that overcooling and rapid cooling may contribute to brain injury.
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Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.
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Diabetes Mellitus Tipo 1 , Glutamato Descarboxilasa , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Cadenas HLA-DRB1/genética , Glutamato Descarboxilasa/inmunología , Cadenas beta de HLA-DQ/genética , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Haplotipos , Japón , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Pueblos del Este de AsiaRESUMEN
OBJECTIVES: We analyzed the temperature in proximal aortic repair with moderate hypothermic circulatory arrest (HCA) and evaluated the effect of the cooling status on postoperative outcomes. METHODS: A total of 340 patients who underwent elective ascending aortic replacement or total arch replacement with moderate HCA from December 2006 to January 2021 were studied. The change in body temperature trends recorded during surgery was shown graphically. Several parameters, such as the nadir temperature, cooling speed and the degree of cooling (cooling area), which was the area under curve of inverted temperature trends from cooling to rewarming as calculated by the integral method, were analyzed. The relationships between these variables and a major adverse outcome (MAO) postoperatively defined as prolonged ventilation (>72 h), acute renal failure, stroke, reoperation for bleeding, deep sternal wound infection or in-hospital death were evaluated. RESULTS: An MAO was observed in 68 patients (20%). The cooling area was larger in the MAO group than in the non-MAO group (1668.7 vs 1383.2°C min; P < 0.0001). A multivariate logistic model showed that old myocardial infarction, peripheral vascular disease, chronic renal dysfunction, cardiopulmonary bypass time and the cooling area were independent risk factors for an MAO (odds ratio = 1.1 per 100°C min; P < 0.001). CONCLUSIONS: The cooling area, which indicates the degree of cooling, shows a significant relationship with an MAO after aortic repair. This finding indicates that the cooling status with HCA can affect clinical outcomes.
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Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/ß-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/ß-catenin signaling. First, we will review the molecular biology of Wnt/ß-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.
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Although the indications for immune checkpoint inhibitors are expanding rapidly, the disease will eventually progress in many patients. Elucidating and overcoming the resistant mechanisms to immune checkpoint inhibitors is a major challenge. WNT/ß-catenin pathway has long been known as one of the mechanisms involved in cell proliferation and epithelial-mesenchymal transition in cancer development. Recently, it has become clear that WNT/ß-catenin pathway also plays a role in cancer immune escape, as reported in melanoma. We have also studied WNT/ß-catenin pathway as a mechanism of immune escape in lung cancer. In this article, we review how WNT/ß-catenin pathway is involved in immune escape and resistance to immune checkpoint inhibitors, mainly in non-small cell lung cancer. In addition, we discuss how to overcome the tumor immune mechanism caused by WNT/ß-catenin pathway in the context of current combination therapies and therapies in development.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , beta Catenina/farmacologíaRESUMEN
Recently, ß-catenin mediated immune escape mechanism has been reported in several cancers. We investigated whether ß-catenin is associated with resistance to immune checkpoint inhibitor therapy in non-small cell lung cancer. Non-small cell lung cancer patients expressing high levels of ß-catenin showed poor progression-free survival and overall survival after single agent anti-PD-1 therapy. They had less infiltration of CD8-positive cells and antigen-presenting cells. Microarray analysis also showed low gene expression of CD8A and IFNG. siRNA knockdown of CTNNB1 in the ß-catenin-positive lung cancer cell line LK-2 tended to decrease CTNNB1 and ATF3 expression and increase CCL4 expression. The results suggest that ß- catenin suppresses tumor infiltration by antigen-presenting cells and confers resistance to immune checkpoint inhibitors in non-small cell lung cancer via downregulation of CCL4 production.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , ARN Interferente Pequeño/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Hematocrit (Hct) values after the initiation of cardiopulmonary bypass (CPB) must be maintained appropriately to avoid perioperative complications. Therefore, an accurate prediction is required. However, the standard prediction equation often results in actual values that are lower than the predicted values. This study aimed to clarify the limits of agreement (LOA) and bias of the prediction equations and investigate better the prediction equations. A retrospective study was performed on adult patients between April 2015 and December 2020. Study 1 included 158 patients, and Study 2 included 55 patients. The primary outcomes were the LOA and bias between the predicted and measured Hct values after the initiation of CPB, and two studies were conducted. In Study 1, total blood volume (TBV) was estimated, and the new blood volume index (BVI) was calculated. BVI was also evaluated for the overall value and gender differences. Therefore, the patient's background was compared by gender differences. In, Study 2 the conventional predicted equation (Eq. 1), the predicted equation using the new BVI (Eq. 2), and the predicted equation using the new BVI including physiological factors in the TBV equation (Eq. 3) were compared. In Study 1, BVI was 53 (44-67) mL/kg. In Study 2, bias ± LOA was - 2.5 ± 6.8% for Eq. 1, 0.1 ± 6.6% for Eq. 2, and 0.4 ± 6.2% for Eq. 3. The new equation is expected to predict the Hct value after the initiation of CPB with better LOA and bias than the conventional equation.
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Volumen Sanguíneo , Puente Cardiopulmonar , Adulto , Volumen Sanguíneo/fisiología , Puente Cardiopulmonar/efectos adversos , Hematócrito , Humanos , Estudios RetrospectivosRESUMEN
INTRODUCTION: The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers. However, the relationship between TLS formation and peripheral blood findings remains unclear. The purposes of the study were to evaluate the effect of the presence of TLS on survival and determine the peripheral blood characteristics associated with TLS formation in non-small cell lung cancer (NSCLC) patients. METHODS: A total of 147 consecutive NSCLC patients who underwent lung resection at Fukushima Medical University Hospital between 2013 and 2017 were enrolled. TLS expression was evaluated, and the relationships between clinical parameters and outcomes were analyzed. Peripheral blood mononuclear cells (PBMCs) were further analyzed by mass cytometry to characterize the TLS-positive microenvironment. RESULTS: Forty-six patients had high TLS expression, and the remaining 101 patients had low TLS expression. In stage II to IV patients (n = 35), disease-free survival was longer in the high TLS expression group (p = 0.027). A low neutrophil to lymphocyte ratio (NLR) < 2.75 in the peripheral blood was associated with high TLS expression (p = 0.003). Citrus analysis after mass cytometry assay showed that the number of cells expressing HLA-DR and CD9 in PBMCs was lower in the high TLS expression group. CONCLUSION: High TLS expression is associated with a good prognosis after surgery in stage II and III NSCLC patients. In the peripheral blood, a low NLR and few antigen-presenting cells indicate the presence of TLS in the tumor microenvironment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Estructuras Linfoides Terciarias , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/metabolismo , Pronóstico , Estudios Retrospectivos , Estructuras Linfoides Terciarias/patología , Microambiente TumoralRESUMEN
BACKGROUND/AIM: Treatments containing ipilimumab have shown a good outcome in patients with non-small cell lung cancer (NSCLC) regardless of the PD-L1 tumor proportion score (TPS). However, the association between PD-L1 TPS and the expression of CTLA-4 in tumor-infiltrating lymphocytes is unknown. PATIENTS AND METHODS: Fifty-five NSCLC patients who underwent surgery in our hospital were included in this study. We measured the proportions of CTLA-4+ regulatory T cells, and CTLA-4+ CD8 T cells, and statistically analyzed their correlations with the PD-L1 TPS. RESULTS: Statistical correlations were found neither between the proportion of CTLA-4+ regulatory T cells to CD8 T cells and the PD-L1 TPS (p=0.2859) nor between the proportion of CTLA-4+ cells in CD8 T cells and the PD-L1 TPS (p=0.1919). CONCLUSION: The proportions of CTLA-4+ regulatory T cells to CD8 T cells and CTLA-4+ cells in CD8 T cells were irrelevant to the PD-L1 TPS in NSCLC patients.
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Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Linfocitos Infiltrantes de Tumor/metabolismo , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , MasculinoRESUMEN
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.
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Adenocarcinoma del Pulmón/terapia , Carbazoles/administración & dosificación , Resistencia a Antineoplásicos , Neoplasias Pulmonares/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piperidinas/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonas/administración & dosificación , Adenocarcinoma del Pulmón/patología , Quinasa de Linfoma Anaplásico , Femenino , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Neumonectomía/métodos , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
Malignant mesothelioma is a cancer with a poor survival rate. It is difficult to diagnose mesotheliomas because they show a variety of histological patterns similar to those of various other cancers. However, since currently used positive markers for mesotheliomas may show false positives or false negatives, a novel mesothelial positive marker is required. In the present study, we screened 25 claudins and found that claudin-15 is expressed in the mesothelial cells. We made new rat anti-human claudin-15 (CLDN15) monoclonal antibodies that selectively recognize CLDN15, and investigated whether CLDN15 is a good positive marker for malignant pleural mesotheliomas (MPMs) using MPM tissue samples by immunohistochemistry and semi-quantification of the expression level using an immunoreactive score (IRS) method. Of 42 MPM samples, 83% were positive for CLDN15. The positive ratio was equal to or greater than other positive markers for MPMs including calretinin (81%), WT-1 (50%), and D2-40 (81%). In 50 lung adenocarcinoma sections, four cases were positive for CLDN15 and the specificity (92%) was comparable with other markers (90-100%). Notably, CLDN15 was rarely detected in 24 non-mesothelial tumors in the tissue microarray (12/327 cases). In conclusion, CLDN15 can be used in the clinical setting as a positive marker for MPM diagnosis.
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Adenocarcinoma del Pulmón/diagnóstico , Calbindina 2/genética , Claudinas/genética , Mesotelioma Maligno/diagnóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores de Tumor/genética , Diagnóstico Diferencial , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , Persona de Mediana Edad , Ratas , Proteínas WT1/genéticaRESUMEN
Although diffuse cysts in the lung can be found in many diseases, they are uncommon in metastatic lung adenocarcinoma. They are even more unusual after the administration of immune checkpoint inhibitors. A case of lung adenocarcinoma that developed diffuse cysts in the lungs during treatment with nivolumab is reported. The patient was a 60-year-old woman with postoperative recurrent lung adenocarcinoma in mediastinal lymph nodes and pleural dissemination. After first-line treatment with cisplatin, pemetrexed, and bevacizumab, computed tomography (CT) showed disease progression. Treatment was then switched to nivolumab. After 5 courses of nivolumab, CT showed multiple ground-glass nodules in her lungs. After 4 more courses of nivolumab, the ground-glass nodules increased in size, and cystic air spaces appeared in their centers. The patient did not have any symptoms. Laboratory tests showed no evidence of infection or nivolumab-induced pneumonitis. Sialyl Lewis X-i antigen increased, and positron emission tomography showed abnormal uptake of 18F-fluorodeoxyglucose in these lesions. Considering this evidence, the cystic lesions were diagnosed as multiple lung metastases. Various differential diagnoses should be considered when diffuse cystic lesions are found in the lungs after the administration of immune checkpoint inhibitors.
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ß-catenin expression by tumor cells suppressed dendritic cell recruitment to the tumor microenvironment in a melanoma model, resulting in fewer tumor-infiltrating lymphocytes. Immunohistochemistry was used in the present study to examine the association between the expression of ß-catenin and tumor infiltrating lymphocytes and CD11c+ cells in 122 patients with non-small cell lung cancer (NSCLC), who underwent radical surgery. ß-catenin was positive in 24% of NSCLC tumors compared with 59% of squamous cell carcinomas and 11% of adenocarcinomas. There was no significant association between the expression of ß-catenin and the frequency of CD8+ cell infiltration into tumor tissues, including the stroma. Conversely, the infiltration of CD8+ cells into tumor nests was significantly lower in ß-catenin-positive cases compared with that in negative ß-catenin cases. Similarly, CD11c+ cell infiltration was significantly lower in the ß-catenin-positive group. The ß-catenin-positive group had shorter overall survival and recurrence-free survival times compared with that in the negative group. Furthermore, ß-catenin-positive NSCLC had a high tumor mutation burden, but tended to have a low expression of programmed death-ligand 1. In conclusion, the expression of ß-catenin in NSCLC was negatively associated with CD11c+ cells and cytotoxic T cell infiltration at the tumor site and had a tendency towards a poor prognosis.
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OBJECTIVES: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (Pâ¯<â¯0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Proteínas de Unión al Calcio , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Humanos , Radioisótopos de Yodo , Neoplasias Pulmonares/radioterapia , Proteínas de la Membrana/metabolismo , Recurrencia Local de Neoplasia , Proyectos Piloto , Radioinmunoterapia , Estudios RetrospectivosRESUMEN
We treated 3,164 patients with advanced cancer with dendritic cell therapy between July 2005 and March 2020. The effective rate in patients treated with dendritic cell therapy more than 3 times was 19.0%. Among them, we treated 133 cancer patients with a combination of immune checkpoint inhibitors and dendritic cell therapy between June 2015 and March 2020. The effective rate in these patients was 54.1%. We treated 98 cancer patients with dendritic cell therapy with neoantigens between March 2018 and March 2020. The effective rate in these patients treated with neoantigens was 38.7%. The effective rate in patients treated without neoantigens was 18.3%. Dendritic cell therapy with neoantigens enhanced the effective rate. The effective rate of dendritic cell therapy with both immune checkpoint inhibitors and neoantigens was 60.7%.
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Antígenos de Neoplasias , Neoplasias , Células Dendríticas , Humanos , Inmunoterapia , Neoplasias/terapiaRESUMEN
There have been many reports on the association between tumor infiltrating lymphocytes and cancer prognosis. It is known that tumor infiltrating lymphocytes contain not only cytotoxic T lymphocytes but also bystander lymphocytes and immunosuppressive cells. In most of previous reports, tumor infiltrating lymphocytes were defined as CD3 or CD8 T cells. It is generally thought that patients with cancer rich in tumor infiltrating lymphocytes have a good prognosis. Most tumor infiltrating lymphocytes are thought to be cytotoxic T lymphocytes. It is also reported that cancer rich in tumor infiltrating lymphocytes is responsive to immune checkpoint inhibitors. In recent years, several reports revealed clonal replacement in tumor infiltrating lymphocytes after administration of immune checkpoint inhibitors. This change was also detectable in peripheral blood. From the viewpoint of lung cancer treatment, combination of immune checkpoint inhibitors and chemotherapy became the standard therapy. We need to understand the tumor immune microenvironment in order to select the best treatment regimen for each patient. However, it is often difficult to obtain an adequate amount of tissue biopsy sample in standard of care. It is hoped that we can understand the tumor immune microenvironment using the peripheral blood. Thus, studying the association between treatment response, tumor infiltrating lymphocytes, and peripheral blood is considered to be important to research and develop peripheral blood biomarkers in lung cancer.
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Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Biomarcadores de Tumor , Linfocitos T CD8-positivos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Pronóstico , Linfocitos T Citotóxicos , Microambiente TumoralRESUMEN
BACKGROUND: The standard adjuvant chemotherapy regimen for completely resected pathological stage II/IIIA non-small cell lung cancer (NSCLC) is four courses of cisplatin plus vinorelbine. However, the continuity and toxicity of cisplatin-based regimens remain problematic. Conversely, carboplatin-based chemotherapy is a less toxic and more tolerable regimen for various stages of NSCLC. In particular, the efficacy and tolerability of carboplatin plus S-1 in advanced NSCLC were confirmed by previous pivotal studies such as the LETS trail. Therefore, this phase II study assessed the feasibility, safety, and usefulness of carboplatin plus S-1 followed by maintenance S-1 as an adjuvant treatment. METHODS: In this single-arm, multicenter phase II study, 40 patients who previously underwent complete resection of NSCLC were enrolled from November 2013 to January 2015. The chemotherapy protocol was four cycles of carboplatin (AUC 5 on day 1) and oral S-1 (80 mg/m2 every other day from days 1 to 21) followed by oral S-1 (80 mg/m2 every other day for 48 weeks). The primary endpoint was the treatment completion rate, and the secondary endpoints were adverse events and 2-year recurrence-free survival. RESULTS: The treatment completion rate of the planned schedule was as low as 30.0% (90% confidence interval: 40.3-63.0%). The reasons for adjuvant chemotherapy discontinuation were adverse events, refusal, tumor recurrence, and other reasons in 13, 6, 10, and 2 patients, respectively. The 2-year progression-free survival rate was 66.7% among patients who completed maintenance chemotherapy. There were no treatment-related deaths, and most adverse events were less than grade 3. CONCLUSIONS: Carboplatin plus S-1 followed by S-1 maintenance for 1 year in the adjuvant treatment of NSCLC was not tolerable, although most adverse events were not severe. However, patients who can fully complete the regimen might experience clinical benefit.
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Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are an approved first-line therapy against unresectable or advanced non-small cell lung cancer (NSCLC) harboring EGFR gene activating mutations. However, the majority of tumors develop acquired resistance against EGFR-TKIs and some tumors exhibit natural resistance. A number of resistance mechanisms against the latest third-generation EGFR-TKIs have been reported, including tertiary EGFR C797S mutation and several gene alterations activating EGFR or other signaling pathways. The current study aimed to identify the frequency of natural EGFR-TKI resistance in pretreatment NSCLC and to predict the therapeutic effect of EGFR-TKIs. A total of 246 EGFR-TKI-naïve NSCLC patients harboring known EGFR gene mutations were identified. The presence of EGFR C797S and T790M mutations were determined using the peptide nucleic acid-locked nucleic acid PCR clamp method. ERBB2, MET, EGFR, ALK, BRAF, FGFR1, MYC, RET, CCND1, CCND2, CDK4, CDK6, MDM2 and MDM4 gene amplification, which can lead to resistance against any generation EGFR-TKIs, was determined using the multiplex ligation-dependent probe amplification assay. No concurrent C797S mutation with known EGFR mutations were identified. T790M mutation was identified in 12 patients (4.9%). ERBB2 or MET gene amplification was found in some patients (0.0-0.4%). MDM2 gene amplification was associated with tumor recurrence and shorter progression-free survival (PFS) for first- or second-generation EGFR-TKIs. De novo EGFR C797S mutation was not identified. Other resistance mechanisms against EGFR-TKIs were indicated in some patients with EGFR-TKI-naïve NSCLC. MDM2 gene amplification, which can lead to altered cell cycle, was associated with tumor recurrence and shorter PFS in EGFR-TKI therapy.
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Large cell neuroendocrine carcinoma (LCNEC) of the lung with epidermal growth factor receptor (EGFR) mutation is rare, and few cases have been treated with EGFR tyrosine kinase inhibitors (TKIs). We report the treatment of combined LCNEC with adenocarcinoma harboring an EGFR mutation with EGFR-TKIs and bevacizumab. Our patient was a 70-year-old asymptomatic woman who underwent surgical resection of the lung for combined LCNEC with adenocarcinoma harboring an activating EGFR mutation 11 months previously. Magnetic resonance imaging (MRI) and positron emission tomography revealed metastatic lesions in the brain and lung. The patient was diagnosed with recurrence of combined LCNEC with adenocarcinoma. The brain lesion was irradiated, followed by administration of afatinib. Eight months after irradiation, brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions. We switched treatment to erlotinib and bevacizumab, resulting in maintenance of stable disease for 10 months. Overall, the disease was controlled for 18 months with EGFR-TKIs and bevacizumab. Combination treatment with EGFR-TKIs and bevacizumab could be a treatment option for LCNEC of the lung harboring EGFR mutations, especially with brain metastasis.
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Cancer treatment using immune checkpoint inhibitors is widely used, although biomarkers predictive of response are not well established. However, both the expressions of programmed cell death ligand 1 (PD-L1) and the tumor mutation burden (TMB) hold promise as such biomarkers for immune checkpoint inhibitors; however, its characteristics and clinical and immunological impacts have not been fully analyzed. We, therefore, evaluated the clinical and immunological parameters related to TMB to identify potential new biomarkers. We enrolled 92 patients with non-small-cell lung cancer who underwent surgery at Fukushima Medical University Hospital from 2013 to 2016. TMB of individual tumors was calculated by whole-exome sequencing analysis. Major cancer-related gene mutations were evaluated using panel sequencing. Expression of PD-L1 and abundance of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry using surgical samples. The median TMB value was 60. TMB was significantly higher in men, current or former smokers, and in patients with squamous cell carcinoma, tumor size ≥ 2.8 cm, wild-type EGFR, TP53 gene mutation-positive status, and cyclin-dependent kinase-inhibitor gene 2A mutation-positive status. According to multivariate analysis, TMB was significantly associated with EGFR gene mutation-negative status (p = 0.0111) and TP53 gene mutation-positive status (p = 0.0425). If TMB is identified as a robust biomarker for immune checkpoint inhibitor administration, analysis of TP53 and EGFR mutations may provide a relatively rapid and easy proxy for predicting TMB.