RESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Doenças do Sistema Endócrino , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Estruturas Linfoides Terciárias , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Estudos Retrospectivos , Estruturas Linfoides Terciárias/patologia , Microambiente TumoralRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , beta Catenina/farmacologiaRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , RNA Interferente Pequeno/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMO
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.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Pneumonectomia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimioterapia Adjuvante , Receptores ErbB/genética , Feminino , Genômica , Humanos , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Mutação , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Sequenciamento do ExomaRESUMO
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.
Assuntos
Neoplasias Pulmonares , Linfócitos do Interstício Tumoral , Biomarcadores Tumorais , Linfócitos T CD8-Positivos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Linfócitos T Citotóxicos , Microambiente TumoralRESUMO
BACKGROUND: Garcin syndrome, which consists of unilateral palsies of almost all cranial nerves without either sensory or motor long-tract disturbances or intracranial hypertension, can be caused by malignant tumors at the skull base. The case of a patient with lung cancer that metastasized to the sphenoid bone and resulted in Garcin syndrome is presented. CASE PRESENTATION: A 76-year-old woman was diagnosed as having non-small cell lung cancer with pericardial and diaphragmatic infiltration, cT4N1M0, stage 3A. The left lower lobectomy with concomitant resection of the pericardium and diaphragm was performed. The pathological diagnosis was pleomorphic carcinoma, pT2bN0M0, stage 1B. She was then followed in the surgery clinic, and 2 months after surgery, she visited an emergency room complaining of headache and diplopia. Neurological examination showed the left IV, V1, and VI cranial nerve palsies. Metastatic tumor with bone destruction was found in the left sphenoid sinus on head computed tomography (CT) and contrast magnetic resonance imaging (MRI), and she was diagnosed with Garcin syndrome caused by sphenoid bone metastasis of lung cancer. Irradiation was performed as palliative treatment, but her neurological findings did not improve. Her general condition gradually worsened, and she died 5 months after surgery. CONCLUSIONS: Bone metastasis of lung cancer occurs frequently, but sphenoid bone metastasis is extremely rare. In this case report, Garcin syndrome caused by lung cancer is discussed in the context of the few previous reports.
Assuntos
Neoplasias Ósseas/complicações , Carcinoma Pulmonar de Células não Pequenas/complicações , Doenças dos Nervos Cranianos/etiologia , Neoplasias Pulmonares/complicações , Osso Esfenoide/patologia , Idoso , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Doenças dos Nervos Cranianos/patologia , Doenças dos Nervos Cranianos/radioterapia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Prognóstico , Osso Esfenoide/cirurgia , SíndromeRESUMO
A 63-year-old man visited our hospital with pain on micturition and was found to have a large rectal tumor with urinary bladder invasion on enhanced abdominal computed tomography (CT). The tumor appeared to be unresectable at presentation; thus, sigmoid colostomy was performed and chemotherapy was initiated. The tumor was found to be EGFR-positive and contained a wild-type KRAS. The mFOLFOX6 plus cetuximab (c-mab) regimen was initiated. The follow-up CT scan showed good tumor shrinkage after 4 courses of chemotherapy; 4 additional courses were administered. The tumor eventually regressed by more than 60% and was judged to be resectable. High anterior resection of the rectum with partial resection of the bladder was performed. Abdominal wall metastasis was detected 8 months after surgery, and additional resection was performed. The patient remained well with no other recurrence 8 months after the high anterior resection. Although chemoradiotherapy is the standard preoperative treatment of locally advanced rectal cancer, systemic therapy is effective in certain cases such as substantial tumor invasion of adjacent organs or metastasis. Here, we present a case of rectal cancer that became curatively resectable after preoperative chemotherapy with mFOLFOX6 plus c-mab.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Compostos Organoplatínicos/administração & dosagem , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Resultado do TratamentoRESUMO
A reactive oxygen species (ROS) assay was previously developed for photosafety evaluation of pharmaceuticals, and the present multi-center study aimed to establish and validate a standard protocol for ROS assay. In three participating laboratories, two standards and 42 coded chemicals, including 23 phototoxins and 19 nonphototoxic drugs/chemicals, were assessed by the ROS assay according to the standardized protocol. Most phototoxins tended to generate singlet oxygen and/or superoxide under UV-vis exposure, but nonphototoxic chemicals were less photoreactive. In the ROS assay on quinine (200 µm), a typical phototoxic drug, the intra- and inter-day precisions (coefficient of variation; CV) were found to be 1.5-7.4% and 1.7-9.3%, respectively. The inter-laboratory CV for quinine averaged 15.4% for singlet oxygen and 17.0% for superoxide. The ROS assay on 42 coded chemicals (200 µm) provided no false negative predictions upon previously defined criteria as compared with the in vitro/in vivo phototoxicity, although several false positives appeared. Outcomes from the validation study were indicative of satisfactory transferability, intra- and inter-laboratory variability, and predictive capacity of the ROS assay.
Assuntos
Laboratórios/normas , Preparações Farmacêuticas/efeitos da radiação , Espécies Reativas de Oxigênio/análise , Raios Ultravioleta , Estudos de Validação como Assunto , Benzofenonas/química , Benzofenonas/efeitos da radiação , Dermatite Fototóxica/etiologia , Dermatite Fototóxica/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Humanos , Preparações Farmacêuticas/química , Processos Fotoquímicos , Quinina/química , Quinina/efeitos da radiação , Padrões de Referência , Reprodutibilidade dos Testes , Raios Ultravioleta/efeitos adversosRESUMO
A patient presented with vomiting and gait disturbance. Investigation revealed a single cerebellar tumor and another tumor in the upper lobe of the left lung. Based on the severe vomiting and gait disturbance, we removed the cerebellar tumor first, achieving resolution of symptoms. The cerebellar tumor was pathologically diagnosed as metastatic lung adenocarcinoma. No other metastases were identified, including in the mediastinal lymph nodes. We therefore resected the primary lung tumor. On final pathological analysis, the tumor in the upper lobe of the left lung was diagnosed as adenosquamous carcinoma with no lymph node metastasis. PD-L1 expression was low in the primary lung adenosquamous carcinoma and high in the cerebellar metastasis. Furthermore, both tumors were KRASG12C -positive. Tumor PD-L1 expression is considered important for immune escape. In this case, adenocarcinoma cells in the primary adenosquamous carcinoma may have migrated to form a cerebellar metastasis. In advanced lung cancer, tumor growth may be observed in some lesions even when many other lesions are controlled by chemo- or immunotherapy. Biopsy to confirm histology and PD-L1 expression is worth considering, depending on the location of the metastases and the invasiveness of the biopsy procedure.
Assuntos
Neoplasias Encefálicas , Carcinoma Adenoescamoso , Neoplasias Cerebelares , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Carcinoma Adenoescamoso/patologia , Neoplasias Cerebelares/patologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Encefálicas/secundário , Biomarcadores Tumorais/metabolismoRESUMO
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.
RESUMO
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.
Assuntos
Hipertensão , Neoplasias do Mediastino , Paraganglioma , Idoso , Humanos , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/cirurgia , Mediastino/patologia , Mediastino/cirurgia , Paraganglioma/diagnóstico , Paraganglioma/cirurgia , Cirurgia Torácica VídeoassistidaRESUMO
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.
Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Idoso , Quinase do Linfoma Anaplásico , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Cisplatino/uso terapêutico , Receptores ErbB/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Pulmão/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
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.
Assuntos
Síndrome de ACTH Ectópico , Tumor Carcinoide , Criptococose , Síndrome de Cushing , Feminino , Humanos , Idoso , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/etiologia , Síndrome de ACTH Ectópico/cirurgia , Síndrome de Cushing/complicações , Tumor Carcinoide/complicações , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/cirurgia , Hormônio Adrenocorticotrópico , Pulmão/patologia , Criptococose/diagnóstico , Criptococose/complicaçõesRESUMO
Pulmonary large cell carcinoma (LCC) is classified as a poorly defined entity among non-small cell lung cancers (NSCLCs). At present, there are no effective anticancer drugs, such as molecular targeted drugs, for LCC, and it has been reported that patient prognosis is poor. Recently, the development of immune checkpoint inhibitors (ICIs) has changed the therapeutic strategies for patients with NSCLC. Here, we present a case of LCC successfully treated with pembrolizumab. A 58-year-old man who was a former smoker was diagnosed with LCC. The postoperative stage was T3N2M0. During postoperative adjuvant chemotherapy, swelling of the supraclavicular lymph node was observed and the patient was diagnosed with recurrence. The patient was treated with two regimens of conventional cytotoxic chemotherapy; however, he experienced some hoarseness. Imaging confirmed swelling of the hilar and mediastinal lymph nodes and the patient was subsequently diagnosed with disease progression. Previous surgical specimens when immunostained showed that a high proportion of the tumor cells were positive for expression of programmed death-ligand 1 (PD-L1), and it was decided to commence treatment with pembrolizumab. This treatment resulted in rapid regression of the hilar and mediastinal lymph nodes, and a progression-free period maintained for at least 24 treatment cycles. The patient's hoarseness improved, and the lymph nodes decreased in size. Immunotherapy targeting PD-1/PD-L1 may be an option for patients with PD-L1 positive LCC. This case report suggests that treatment with ICIs may be important in the selection of treatment for not only LCC but also relatively rare NSCLC with high PD-L1 expression.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma de Células Grandes/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Carcinoma de Células Grandes/patologia , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Testemunhas de Jeová , Perda Sanguínea Cirúrgica , Transfusão de Sangue , Humanos , Pulmão , Estudos RetrospectivosRESUMO
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.
Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Calbindina 2/genética , Claudinas/genética , Mesotelioma Maligno/diagnóstico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Ratos , Proteínas WT1/genéticaRESUMO
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.
Assuntos
Adenocarcinoma de Pulmão/terapia , Carbazóis/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonas/administração & dosagem , Adenocarcinoma de Pulmão/patologia , Quinase do Linfoma Anaplásico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Pneumonectomia/métodos , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
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.