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BACKGROUND: We investigated the unknown mechanisms of osimertinib-resistant EGFR-mutant lung cancer. METHODS: An osimertinib-resistant cell line (PC-9/OsmR2) was established through continuous exposure to osimertinib using an EGFR exon 19 deletion (19Del) lung adenocarcinoma cell line (PC-9). EGFR 19Del (M1), L858R/T790M/C797S (M6), and L858R/C797S (M8) expression vectors were introduced into Ba/F3 cells. A second osimertinib-resistant line (M1/OsmR) was established through continuous exposure to osimertinib using M1 cells. RESULTS: SLC1A3 had the highest mRNA expression level in PC-9/OsmR2 compared to PC-9 cells by microarray analysis and SLC1A3 was increased by flow cytometry. In PC-9/OsmR2 cells, osimertinib sensitivity was significantly increased in combination with siSLC1A3. Because SLC1A3 functions in glutamic acid transport, osimertinib with a glutaminase inhibitor (CB-839) or an SLC1A3 inhibitor (TFB-TBOA) increased the sensitivity. Also, CB-839 plus TFB-TBOA without osimertinib resulted in greater susceptibility than did CB-839 or TFB-TBOA plus osimertinib. Comprehensive metabolome analysis showed that the M1/OsmR cells had significantly more glutamine and glutamic acid than M1 cells. CB-839 plus osimertinib exerted a synergistic effect on M6 cells and an additive effect on M8 cells. CONCLUSION: Targeting glutaminase and glutamic acid may overcome the osimertinib-resistant EGFR-mutant lung cancer.
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Acrilamidas , Compostos de Anilina , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Glutaminase , Neoplasias Pulmonares , Mutação , Humanos , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Glutaminase/genética , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 1 de Aminoácido Excitatório/antagonistas & inibidores , Benzenoacetamidas/farmacologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Indóis , Pirimidinas , TiadiazóisRESUMO
Background: In Japan, the number of patients with aggressive hematological malignancies (PHMs) admitted at the palliative care unit (PCU) in their end-of-life (EOL) stage was fewer than that of patients with solid tumors due to several reasons. The assessment of patient characteristics and the methods of survival prediction among PHMs in the EOL stage are warranted. Objectives: This study aimed to identify the current medical status and the method of survival prediction among PHMs treated at the PCU. Setting/Subjects/Measurements: We retrospectively analyzed the clinical data of 25 PHMs treated at our PCU between January 2017 and December 2020. The association between survival time and the palliative prognostic score (PAP) and palliative prognostic index (PPI) was analyzed. Results: The average age of the PHMs was higher than that of patients with lung cancer as a control. The median survival time of the PHMs was shorter than the control group. Most PHMs could not receive standard chemotherapy, and the most common cause of death was disease-related organ failure. Significant associations were observed between the survival time and each PAP/PPI value in patients with malignant lymphoma, but not in those with leukemia. Conclusion: The PHMs in the PCU had a lower median survival time than the control group. These results were induced by the result of patient selection to avoid treatment-related severe toxicity. The survival prediction using the PAP and PPI was less accurate in patients with leukemia.
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Most lung adenocarcinoma-associated EGFR tyrosine kinase mutations are either an exon 19 deletion (19Del) or L858R point mutation in exon 21. Although patients whose tumors contain either of these mutations exhibit increased sensitivity to tyrosine kinase inhibitors, progression-free and overall survival appear to be longer in patients with 19Del than in those with L858R. In mutant-transfected Ba/F3 cells, 19Del and L858R were compared by multi-omics analyses including proteomics, transcriptomics, and metabolomics. Proteome analysis identified increased plastin-2, TKT, PDIA5, and ENO1 expression in L858R cells, and increased EEF1G expression in 19Del cells. RNA sequencing showed significant differences between 19Del and L858R cells in 112 genes. Metabolome analysis showed that amino acids, adenylate, guanylate, NADPH, lactic acid, pyruvic acid glucose 6-phosphate, and ribose 5-phosphate were significantly different between the two mutant cells. Because GSH was increased with L858R, we combined osimertinib with the GSH inhibitor buthionine sulfoximine in L858R cells and observed synergistic effects. The complexity of EGFR 19Del and L858R mutant cells was demonstrated by proteomics, transcriptomics, and metabolomics analyses. Therapeutic strategies for lung cancer with different EGFR mutations could be considered because of their different metabolic phenotypes.
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Neoplasias Pulmonares , Proteômica , Humanos , Transcriptoma , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação/genética , Éxons , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Background: Herpes zoster (HZ) occurs mostly in elderly and immunocompromised individuals. Immune reconstitution may be associated with the pathogenesis of HZ. As immune checkpoint inhibitor (ICI) treatment amplifies the immune response, use of ICI may increase the incidence of HZ. There have been few studies of HZ in lung cancer patients treated with ICI. This study was performed to investigate the frequency of HZ in lung cancer patients who received ICI or cytotoxic chemotherapeutic agents. Methods: We searched the electronic medical records for lung cancer patients receiving anticancer drug therapy at our hospital, who developed HZ between April 2011 and June 2020. Results: The review identified 80 patients with a history of ICI treatment (ICI group) and 356 who had been treated with cytotoxic chemotherapeutic agents alone (non-ICI group). Among the 20 patients who developed HZ, 4 (5.0%) belonged to the ICI group and 16 (4.5%) to the non-ICI group (P=0.782). After exclusion of patients aged 65 years and older, to avoid effects of advanced age on the results, the ICI and non-ICI groups consisted of 24 and 81 patients, respectively. In total, 3 of the 24 patients (12.5%) in the ICI group and 1 of the 81 (1.2%) patients in the non-ICI group developed HZ (P=0.0365). Conclusions: There was no significant difference in the rate of HZ between lung cancer patients treated with ICI and those treated with cytotoxic chemotherapy alone. However, patients younger than 65 years treated with ICI might be at increased risk of HZ. Because this is a retrospective small study, further prospective observational studies are needed.
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Lung cancer that exhibits epidermal growth factor receptor (EGFR) gene mutation is sensitive to EGFR-tyrosine kinase inhibitors (TKIs), such as osimertinib. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) may be involved in overcoming EGFR-TKI resistance. Growth inhibition, colony formation, apoptosis, and mRNA/protein levels in four osimertinib-sensitive and resistant cell lines transfected with small interfering RNA (siRNA) targeting ROR1 (siROR1) were evaluated. Cell growth and colony formation were suppressed and apoptosis was increased in all cell lines treated with siROR1. Although EGFR, AKT, and ERK phosphorylation were not suppressed in all cell lines, TGF-ß2, AXL, CDH2, PARP1, PEG10, and TYMS mRNA expression levels were reduced. The combination of osimertinib with siROR1 was effective for the four cell lines, particularly in the two osimertinib-sensitive lines. In conclusion, targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer may be a novel therapeutic option.
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Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Resistencia a Medicamentos Antineoplásicos , Mutação , RNA Interferente Pequeno/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Terapia Combinada , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A 72-year-old man with locally advanced lung squamous cell carcinoma experienced red purpura on the lower legs and hematuria when the disease progressed during definitive chemoradiotherapy. He had renal dysfunction and proteinuria. Biopsy specimens of the skin lesion and kidney revealed immunoglobulin A vasculitis. Potential causes such as paraneoplastic syndrome and cancer treatment have been proposed. The administration of steroids rapidly improved the symptoms. The presentation of immunoglobulin A vasculitis is accompanied by malignancies. Clinicians should keep this syndrome in mind, even during curative-intent treatment.
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The unique radiological manifestation mimicking autoimmune pancreatitis caused by lung cancer metastasis to the pancreas has not previously been reported. The incidence of pancreatic secondary tumors has previously been reported to be approximately 15% in autopsy cases of malignant tumors, and it is unusual for thoracic oncologists to find that the second common primary tumor site of metastatic pancreas tumor is the lung.
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Pancreatite Autoimune/etiologia , Neoplasias Pulmonares/complicações , Neoplasias Pancreáticas/secundário , Idoso , Pancreatite Autoimune/patologia , Feminino , Humanos , Metástase NeoplásicaRESUMO
Lung cancer patients ≥75 years represent nearly 40% of all lung cancer patients and continue to increase. If elderly patients have a good performance status and adequate organ function, they can be treated the same as non-elderly patients. However, few comparative studies limited to elderly patients (≥75 years) have been conducted. We review the evidence on using immune check inhibitors for the treatment of elderly patients (≥75 years old) with advanced non-small cell lung cancer. Prospective randomized or non-randomized, retrospective, registrational, insurance-based, and community-based studies have shown that elderly (≥75 years) and non-elderly patients are similarly treated with immune check inhibitors effectively and safely. However, such analyses have not shown that immune check inhibitors are significantly more effective than chemotherapy alone. In addition, patient selection might be critically performed to administer immune check inhibitors in the elderly because they are more likely to have a poor performance status with comorbidities, which lead to little benefit, even in non-elderly patients. There is a need for more evidence showing the benefit of immune check inhibitors in non-small cell lung cancer patients ≥75 years.
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OBJECTIVE: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells. MATERIALS AND METHODS: Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed. RESULTS: Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the three MM cell lines we studied. CONCLUSION: Our findings may provide novel therapeutic insight into the treatment of advanced MM.
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Apoptose , Mesotelioma Maligno/patologia , Pemetrexede/farmacologia , Neoplasias Pleurais/patologia , RNA Interferente Pequeno/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Antineoplásicos/farmacologia , Proliferação de Células , Terapia Combinada , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/terapia , Neoplasias Pleurais/genética , Neoplasias Pleurais/terapia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Autoimmune hemolytic anemia (AIHA) is secondary to underlying diseases, such as autoimmune diseases and lymphoid malignancies. Recently, solid cancers have also been reported to be associated with AIHA, although there is not much information available. In this study, we retrospectively examined the correlation between AIHA and onset of malignancy in 100 patients diagnosed with AIHA based on the broad definition of AIHA at our hospital and cooperating institutions from January 1, 1995 to May 31, 2016. Malignancies were detected in 52 of the 100 patients (hematological malignancies: 39 patients; solid cancers: 22 patients; total malignancies including multiple primary malignancies: 67 patients). Of the 67 patients with malignancies, 28 were diagnosed with malignancies within 6 months of AIHA diagnosis. All patients with cold agglutinin disease (CAD) were associated with malignancies. Compared with warm AIHA, solid cancers were significantly more common among the patients with CAD. These findings emphasize the importance of investigating the malignancies upon diagnosis of AIHA.
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Anemia Hemolítica Autoimune/complicações , Neoplasias/complicações , Humanos , Estudos Retrospectivos , Fatores de RiscoAssuntos
Derrame Pleural/diagnóstico por imagem , Pneumonia/diagnóstico por imagem , Estenose de Veia Pulmonar/complicações , Estenose de Veia Pulmonar/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/etiologia , Pneumonia/etiologia , Radiografia Torácica , Estenose de Veia Pulmonar/patologia , Estenose de Veia Pulmonar/cirurgia , Tomografia Computadorizada por Raios XRESUMO
A 26-year-old man with right lower mandibular and chest pain, fever, and respiratory distress was urgently transported to our hospital. CT images revealed gas collection and an abscess from the neck to the mediastinum with bilateral pleural effusion. Descending necrotizing mediastinitis (DNM) induced by an odontogenic infection of a right mandibular molar abscess was diagnosed. The cervical and mediastinal areas were drained, extensive debridement was performed, necrotic tissue was excised, and broad-spectrum antibiotics were administered immediately. Prompt diagnosis and intensive care were necessary for managing the DNM, and the patient was discharged with no comorbidities.
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INTRODUCTION: Since June 2005, the University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR) has been an International Committee of Medical Journal Editors (ICMJE)-approved clinical trial registry in Japan. The number of clinical trials registered in the UMIN-CTR has increased annually. To date, no report exists regarding the publishing of clinical trials registered in the UMIN-CTR. Therefore, we evaluated the publication frequency of clinical trials registered in the UMIN-CTR in Japan. METHODS: We targeted trials that assessed the treatment effect of chemotherapy or molecular targeting drugs for lung cancer. We included trials registered between June 2005 and January 2010, and identified published trials through a computer-based search of MEDLINE and Google Scholar. The cumulative publication rate of the trials was calculated using Kaplan-Meier analysis. RESULTS: In our study, 179 trials met the inclusion criteria. Of these, 46.4% (83/179) trials were published by the end of the cut-off period. With regard to publication, differences existed between the information recorded in the UMIN-CTR database and the actual searched results. The publication rate between groups was insignificantly different; however, whether a clinical study group did or did not conduct a trial differed significantly (53.3% vs. 36.1%; P = 0.024). Phase II studies with positive results were more likely to be published (84.4%); however, the overall publication rate was low (41.8%), which may reflect publication bias. CONCLUSIONS: The UMIN-CTR fundamentally functions as the unique ICMJE-approved clinical trial registry in Japan. However, it seems insufficient to require it as the official clinical database.
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Ensaios Clínicos como Assunto , Neoplasias Pulmonares/terapia , Publicações , Sistema de Registros , Bases de Dados Factuais , Humanos , JapãoRESUMO
PURPOSE: Cure-oriented treatment of malignant lymphoma (ML) is possible even in an advanced stage; however, the progression of drug-induced interstitial lung disease (DILD) sometimes accounts for poor clinical outcomes. This study aims to assess the incidence and clinical characteristics of DILD among patients with ML and compares the serum level of Krebs von den Lungen-6 (KL-6) with that of circulating thymus and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17) as a diagnostic biomarker for DILD. PATIENTS AND METHODS: Between July 2011 and August 2016, we enrolled 36 patients with ML who were undergoing systemic chemotherapy at our hospital. Then, we evaluated the serum concentration of KL-6 and TARC/CCL17 by a sandwich-type electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: DILD developed in 22.2% of patients with ML. All patients recovered immediately after the discontinuation of causative drug and/or glucocorticoid therapy. Although the sensitivity of both TARC/CCL17 and KL-6 was almost equal, the mean concentration of serum KL-6 after the progression of interstitial lung disease was significantly higher than that before progression. CONCLUSION: DILD developed in patients who were treated with first-line rituximab combined regimen. Remarkably, TARC/CCL17 and KL-6 seemed approximately equal as a predictive biomarkers for DILD; however, KL-6 was more specific than TARC/CCL17.
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Neoplasias Ósseas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Japão/epidemiologiaRESUMO
A 74-year-old man was treated with ceftriaxone for 5 days and subsequently experienced epigastric pain. Computed tomography (CT) was performed 7 and 3 days before epigastralgia. Although the first CT image revealed no radiographic signs in his biliary system, the second CT image revealed dense radiopaque material in the gallbladder lumen. The third CT image, taken at symptom onset, showed high density in the common bile duct and enlargement of the pancreatic head. This is a very rare case of pseudolithiasis involving the common bile duct, as captured on a series of CT images.
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PURPOSE: "Rare cancer" is defined as malignancy with a disease prevalence (age-adjusted incidence rate) of less than six per 100,000 population. Proper treatments which these patients need cannot always be performed unless they find dedicated facilities. Patients tend to be desperate, searching for advice and care. Thus, they are called "cancer refugees". Osteosarcoma and soft tissue sarcoma (OS/STS) are representative rare cancers in Japan. We conducted a retrospective analysis of patients with OS/STS to improve the current treatment modalities in a Japanese regional city. PATIENTS AND METHODS: Twenty-one patients with OS/STS who were hospitalized to receive standard chemotherapy or palliative treatment were enrolled between October 2011 and January 2017. Patients with non-Hodgkin's lymphoma (NHL) and advanced cancer who were treated in the palliative care unit (PCU) of the Kawasaki Medical School General Medical Center were recruited as the control groups. We analyzed the difference in residential area between patients with OS/STS and the control groups. RESULTS: Approximately one-third of patients with OS/STS were referred from hospitals outside of Okayama prefecture. The ratio of patients with OS/STS referred from Okayama city and/or the same medical administration area of Okayama prefecture was lower than that of patients with NHL and advanced cancer who were treated in the PCU. CONCLUSION: Because the medical environment of patients with OS/STS in Japanese local cities has not been consolidated, completing medical care within the patient's own medical administration area is difficult. Thus, some patients with OS/STS may become "cancer refugees" who are unable to receive standard therapy near their residence.
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Calreticulin (CALR) and JAK2-V617F gene mutations, which are major genetic mutations in patients with primary myelofibrosis (PMF) and essential thrombocythemia (ET), exert different effects on the clinical features and outcomes of these diseases. We analyzed 88 and 9 patients with ET and PMF, respectively, and determined the differences in the clinical characteristics of ET patients with JAK2-V617F compared with CALR mutations. The frequency of the JAK2-V617F and CALR mutations were 64 and 22 %, respectively. Patients with CALR mutations were younger, had a lower white blood cell count, and had a lower rate of thrombotic events than patients with the JAK2 mutation. The neutrophil alkaline phosphatase (NAP) score of 16 patients with CALR mutations was significantly lower than the normal controls, which was mainly due to the high proportion of NAP-negative neutrophils. This is the first report to show an association between CALR mutations in patients with myeloproliferative neoplasms (MPN) and the NAP score. Although the mechanism is unclear, the NAP score could be a useful and reliable biochemical marker to discriminate the mutational status of MPN patients. Further investigation is warranted to determine whether these characteristics contribute to the pathogenesis of MPN and the NAP score.