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Aim: Inherent variations in human leukocyte antigen (HLA) alleles have been revealed epidemiologically to influence the development of autoimmune diseases. HLA alleles may thus also be associated with the development of immune-related adverse events (irAEs), such as thyroid irAE. Materials & methods: In this case-control study, 71 cancer patients who received immune checkpoint inhibitors were enrolled and HLA-genotyped and the frequency of HLA alleles was compared. Results: A*26:01, DPA1*01:03 and DPB1*02:01 were significantly more frequent in patients with thyroid irAE than in patients without any irAEs (35.0 vs 3.2% [p = 0.004], 80.0 vs 45.2% [p = 0.020] and 55.0 vs 25.8% [p = 0.044], respectively). Conclusion: A*26:01, DPA1*01:03 and DPB1*02:01 appear to be associated with thyroid irAE.
Everyone has a unique combination of human leukocyte antigens (HLAs) in their body that help the immune system identify threats. HLAs were named from the fact that they were first identified on the surface of human leukocytes. Afterward, HLAs were also found on all human cells. HLAs present antigens to immune cells. These HLAs also influence how the immune system attacks cancer cells. Immune checkpoint inhibitors are drugs that can help the immune system fight cancer, but they sometimes cause severe adverse events. In this study, we investigated whether specific HLA genes are related to the development of an adverse event that affects the thyroid in cancer patients treated with immune checkpoint inhibitors. We found an association between three HLA genes (A*26:01, DPA1*01:03 and DPB1*02:01) and the development of the thyroid adverse event. However, larger studies are needed to confirm and generalize these initial exploratory findings.
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Introduction: Programmed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method. Methods: In total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression. Results: PD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group. Conclusion: Quantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/metabolismo , Reproducibilidad de los Resultados , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
In 2019, our facility introduced robot-assisted surgery for mediastinal tumors using da Vinci Si, which was upgrade to da Vinci X and Xi in 2021. Initially, the unilateral thoracic cavity approach was used for robot-assisted surgeries. The unilateral approach has the advantage of facilitating the anatomical recognition of either the left or right side, with the side used selected depending on the location of the lesion. Notably, challenges such as difficulty in recognizing objects were still encountered. To compensate for these shortcomings, our hospital introduced robotic subxiphoid-optical thymectomy, a subxiphoid approach, which has been used for all robot-assisted mediastinal tumor surgeries since its introduction under the guidance of Kyoto Prefectural University of Medicine. Additionally, extended thymectomy, which has been covered by insurance since 2020 and used as the standard surgical procedure for robot-assisted mediastinal tumor surgery at our department, can be performed using the same approach.
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Neoplasias del Mediastino , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Neoplasias del Mediastino/cirugía , Timectomía/métodos , Toracoscopía/métodosRESUMEN
Immune checkpoint inhibitors(ICIs)could cause immune-related adverse events(irAEs), of which endocrine disorders are relatively common. Symptoms include fatigue, anorexia, and shock, making diagnosis and treatment difficult. This study aimed to analyze the characteristics of patients with non-small cell lung cancer concomitant with endocrine disorders as irAEs. In total, 83 patients who were administered ICIs for advanced or postoperative recurrent non-small cell lung cancer between February 2016 and February 2021 were identified. We retrospectively studied the clinical course and findings of 7 patients who developed endocrine disorders after treatment. Four patients had hypopituitarism, and 3 patients had thyroid dysfunctions. There were 6 male patients and 1 female patient. Regarding anticancer agents, 5 patients received ICI alone, and 2 patients received ICI plus cytotoxic chemotherapies. The patients received treatment from the irAE treatment team in our hospital, and 5 of 7 patients could were able to be readministered ICIs. Endocrine disorders as irAEs require collaboration with specialized departments for early diagnosis and treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Enfermedades del Sistema Endocrino , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
Robot-assisted lung segmentectomy will be covered by insurance starting 2020. The results of the Japan Clinical Oncology Group( JCOG) 0802 trial have been reported, and the use of robot-assisted lung segmentectomy is expected to increase in the future. We present an introduction to robot-assisted lung segmentectomy at our institution using actual cases. Our facility constructs vascular three-dimensional (3D) images from computed tomography( CT) images as a preoperative simulation. Robot-assisted surgery is performed with the da Vinci Xi, using four arms with carbon dioxide insufflation through an assist hole in the anterior thoracic region of the fifth intercostal space, with a focus on the eighth intercostal space. The port placement and forceps used are the same as for lobectomy. Interdigitations are identified with intravenous indocyanine green after dissecting the pulmonary arteriovenous veins. After that, the da Vinci Xi firefly is activated, and the non-resected lungs are fluorescently stained to identify the inter-areas, and the inter-areas which are separated with an automatic suture device.
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Neoplasias Pulmonares , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Neumonectomía/métodos , Pulmón , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugíaRESUMEN
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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BACKGROUND: Carcinoid tumors can on rare occasions ectopically produce adrenocorticotropic hormone (ACTH), causing Cushing's syndrome, and patients could become immunocompromised. Care must therefore be taken regarding infectious complications. In particular, ACTH-producing pulmonary carcinoid is not easy to diagnose by itself, and when combined with pulmonary nodules as infectious foci, each is very difficult to diagnose. CASE: The patient was a 71-year-old woman with refractory diabetes. She showed clinical symptoms of Cushing's syndrome during treatment for diabetes and ectopic ACTH production was suspected based on biochemical and imaging tests. Nodules were identified in the left lung apex and lingual segment. Examination of resected nodules revealed that the nodule in the apex was pulmonary cryptococcosis, while the nodule in the lingual segment represented typical carcinoid. After surgery, clinical symptoms, laboratory findings, and diabetes all improved. CONCLUSION: We present this very instructive case in terms of the difficulty of diagnosing ACTH-producing tumors, the possibility of infection complicating the immunodeficiency caused by ACTH-producing tumors, and the surgical strategy.
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Síndrome de ACTH Ectópico , Tumor Carcinoide , Criptococosis , Síndrome de Cushing , Femenino , Humanos , Anciano , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/etiología , Síndrome de ACTH Ectópico/cirugía , Síndrome de Cushing/complicaciones , Tumor Carcinoide/complicaciones , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/cirugía , Hormona Adrenocorticotrópica , Pulmón/patología , Criptococosis/diagnóstico , Criptococosis/complicacionesRESUMEN
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a rare condition, is characterized by pathological proliferation of neuroendocrine cells. Some of them are localized to the airway mucosa, and others locally infiltrate to form tumorlets and nodules. Here, we present a patient with lung adenocarcinoma accompanied by DIPNECH, making the latter difficult to distinguish from multiple pulmonary metastases. The patient, a 72-year-old Japanese woman, was diagnosed as having stage IVA lung adenocarcinoma because she had multiple nodules in both lungs. Mutation of epidermal growth factor receptor gene having been found in the primary tumor, treatment with osimertinib was started. This resulted in shrinkage of the primary tumor, but not the multiple pulmonary nodules. To determine whether these lung nodules were indeed lung metastases, we performed right upper lobectomy with lymphadenectomy and wedge resection of the right lower lobe. On pathological examination, the primary tumor was diagnosed as invasive adenocarcinoma, whereas the multiple pulmonary nodules were diagnosed as DIPNECH manifesting as tumorlets. Therefore, the final diagnosis was stage IA1 lung adenocarcinoma accompanied by DINPECH. The patient had no recurrences 1 year after the operation without any additional treatment. This is a rare case of lung adenocarcinoma accompanied by DIPNECH presenting as multiple pulmonary nodules. DIPNECH should be included in the differential diagnosis of multiple pulmonary nodules.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Células Neuroendocrinas , Femenino , Humanos , Anciano , Células Neuroendocrinas/metabolismo , Células Neuroendocrinas/patología , Nódulos Pulmonares Múltiples/patología , Hiperplasia , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/patologíaRESUMEN
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
Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare and highly progressive tumor with a poor prognosis. Although immune checkpoint inhibitors have been approved for treatment of both small cell and non-small cell lung cancers, their role in the treatment of LCNEC is unclear. We describe a patient with postoperative recurrence of LCNEC who maintained complete remission for 4 years after a single administration of pembrolizumab. A 68-year-old Japanese man underwent thoracoscopic right lower lobectomy for LCNEC (pathological stage pT1bN0M0, stage IA2). Epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 expression rate in tumor cells was 5% (clone 22C3). Eight months later, the patient developed recurrence with mediastinal lymph node metastasis and pleural dissemination. Therefore, chemotherapy with cisplatin and etoposide was administered. However, relapse occurred 6 months later. Pembrolizumab was administered as second-line chemotherapy, which was discontinued after first dose because of interstitial pneumonia 1 month later. Thereafter, however, both the lymph node metastasis and pleural dissemination disappeared and did not relapse for 4 years. Pembrolizumab may be used as a treatment option for pulmonary LCNEC.
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Carcinoma de Células Grandes , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Anciano , Quinasa de Linfoma Anaplásico , Anticuerpos Monoclonales Humanizados , Antígeno B7-H1/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/patología , Carcinoma Neuroendocrino/patología , Cisplatino/uso terapéutico , Receptores ErbB/uso terapéutico , Etopósido/uso terapéutico , Humanos , Inhibidores de Puntos de Control Inmunológico , Pulmón/patología , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
Posterior mediastinal paraganglioma (PM-PGL) is a rare disease that is difficult to diagnose. If PM-PGL is misdiagnosed preoperatively, surgeons may encounter severe tachycardia and hypertension and easy bleeding from the tumor during the operation. Therefore, it is essential to include PGL as a differential diagnosis for mediastinal tumors. We herein describe a 73-year-old Japanese man with a PM-PGL that was diagnosed preoperatively and resected safely by video-assisted thoracic surgery. Preoperative management of hypertension with doxazosin mesylate, soft coagulation of the peritumor area, and careful clipping of feeding arteries were effective for hemostasis. The patient's vital signs were stable during and after the operation.
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Hipertensión , Neoplasias del Mediastino , Paraganglioma , Anciano , Humanos , Masculino , Neoplasias del Mediastino/diagnóstico , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/cirugía , Mediastino/patología , Mediastino/cirugía , Paraganglioma/diagnóstico , Paraganglioma/cirugía , Cirugía Torácica Asistida por VideoRESUMEN
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
An in vitro assay system using patient-derived tumor models represents a promising preclinical cancer model that replicates the disease better than traditional cell culture models. Patient-derived tumor organoid (PDO) and patient-derived tumor xenograft (PDX) models have been previously established from different types of human tumors to recapitulate accurately and efficiently their tissue architecture and function. However, these models have low throughput and are challenging to construct. Thus, the present study aimed to establish a simple in vitro high-throughput assay system using PDO and PDX models. Furthermore, the current study aimed to evaluate different classes of anticancer drugs, including chemotherapeutic, molecular targeted and antibody drugs, using PDO and PDX models. First, an in vitro high-throughput assay system was constructed using PDO and PDX established from solid and hematopoietic tumors cultured in 384-well plates to evaluate anticancer agents. In addition, an in vitro evaluation system of the immune response was developed using PDO and PDX. Novel cancer immunotherapeutic agents with marked efficacy have been used against various types of tumor. Thus, there is an urgent need for in vitro functional potency assays that can simulate the complex interaction of immune cells with tumor cells and can rapidly test the efficacy of different immunotherapies or antibody drugs. An evaluation system for the antibody-dependent cellular cytotoxic activity of anti-epidermal growth factor receptor antibody and the cytotoxic activity of activated lymphocytes, such as cytotoxic T lymphocytes and natural killer cells, was constructed. Moreover, immune response assay systems with bispecific T-cell engagers were developed using effector cells. The present results demonstrated that in vitro assay systems using PDO and PDX may be suitable for evaluating anticancer agents and immunotherapy potency with high reproducibility and simplicity.
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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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OBJECTIVE: Surgical treatment for patients who refuse blood transfusion due to religious beliefs is an important issue related to medical safety. Few reports have examined pulmonary surgery for these patients, and we analyzed clinical characteristics in such cases. METHODS: Ten Jehovah's Witness (JW) patients with lung tumor resection who declined blood transfusion for religious reasons between December 2013 and February 2020 at the Fukushima Medical University Hospital were included. Median total intraoperative blood loss was 17.5 mL (range 5-150 mL). Fibrin glue was used intraoperatively for 8 patients. Final pathological examination revealed pulmonary adenocarcinoma in 9 cases and metastasis of bladder cancer in 1 case. In 8 patients with pulmonary adenocarcinoma examined for epidermal growth factor receptor (EGFR) gene mutation, 6 cases showed mutation. No patients had serious complications, but 1 patient displayed temporary anemia due to postoperative hemorrhagic gastrointestinal ulcer. RESULT AND CONCLUSIONS: Our findings confirm that pulmonary resection is feasible and safe for JW patients if performed by experienced medical staff. However, awareness of complications associated with perioperative bleeding is important. Each JW patient should be interviewed individually and every available perioperative option aimed at blood-sparing management, including use of blood coagulation factors and fibrinogen concentrates, should be carefully discussed and clarified. In this study, the EGFR gene mutation rate was higher than usual for cases of lung adenocarcinoma. Further studies are necessary to assess clinical features in JW patients with lung cancer.