RESUMO
PURPOSE: Bioelectrical impedance analysis (BIA) has been used recently to measure the body water of patients with acute heart failure. We used BIA in this study to better understand, and possibly identify a predictive marker for, perioperative water behavior in cardiac surgery patients. METHODS: We measured body water and studied its behavior in 44 patients undergoing surgery for cardiac valvular disease at our hospital. Measurements included the levels of extracellular water (ECW), intracellular water (ICW), and total body water, the edema index (EI), and the ratio of ECW to total body water. The first measured EI was defined as the "preoperative EI" and the maximum as the "peak EI". RESULTS: A negative correlation was found between the preoperative EI and the preoperative estimated glomerular filtration rate (eGFR) (R = 0.644, p < 0.001). Positive correlations were found between the peak EI and the ICU stay (R = 0.625, p < 0.001), the peak EI and the ventilation time (R = 0.366, p < 0.01), and the preoperative EI and the ICU stay (R = 0.464, p = 0.026). CONCLUSION: The EI is possibly a predictive marker for perioperative water management in cardiac surgery.
Assuntos
Água Corporal/metabolismo , Impedância Elétrica , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/cirurgia , Assistência Perioperatória , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Edema/diagnóstico , Edema/etiologia , Edema/prevenção & controle , Espaço Extracelular/metabolismo , Feminino , Taxa de Filtração Glomerular , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Espaço Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Valor Preditivo dos Testes , Estudos Retrospectivos , RiscoRESUMO
MHC class I chain-related molecule A and B (MICA/B) are NK group 2 member D (NKG2D) ligands, which are broadly expressed in transformed cells. Both DNA damage-induced ataxia-telangiectasia-mutated (ATM)- and ATM and Rad3-related protein kinases (ATM-ATR) signaling and oncogene-induced PI3K-AKT signaling regulate the expression of NKG2D ligands, which promote NK cell-mediated cytotoxicity via NKG2D-NKG2D ligand interactions. NKG2D ligand overexpression was recently reported to be correlated with good prognosis in several types of cancer. However, the prognostic significance of NKG2D ligands in non-small cell lung cancer (NSCLC) remains unclear. Here, MICA/B expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical surgery. In addition, expression of MICA/B was assessed in NSCLC cell lines treated with cisplatin in order to evaluate the regulatory mechanisms of MICA/B expression. Overall, 28 out of 91 (30.8%) specimens showed high expression level of MICA/B, which was associated with low (18)F-fluorodeoxyglucose uptake and manifestation of adenocarcinoma. After a median follow-up of 48.2 months, high MICA/B expression was associated with good recurrence-free survival (p = 0.037). In vitro assays using cell lines revealed that MICA/B expression was upregulated by cisplatin via ATM-ATR signaling, resulting in enhanced NK cell-mediated cytotoxicity. Upregulated MICA/B expressions in patients with radically resected NSCLC are predictive of good disease prognosis. Cisplatin-induced MICA/B upregulation is possibly an indirect mechanism by which the innate immune system eliminates tumor cells. NKG2D-NKG2D ligand-targeting therapy is a promising avenue for future immune-chemotherapy development.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/farmacologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Neoplasias Pulmonares/metabolismo , Regulação para Cima/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Pneumatosis intestinalis (PI) is defined as the presence of gas in the bowel wall and is a relatively rare finding. PI has been associated with various pathological conditions and medications. Although several chemotherapeutic agents and molecular targeted therapy agents are reported to be associated with PI, there have been few reports describing the association between the anti-epidermal growth factor receptor agent gefitinib, a tyrosine kinase inhibitor (TKI), and PI. The present report describes a case of PI secondary to gefitinib therapy. CASE PRESENTATION: An 80-year-old woman who had been diagnosed with recurrent lung adenocarcinoma presented with remarkable appetite loss, abdominal distension, and constipation after starting gefitinib therapy. A computed tomography (CT) scan of the abdomen revealed PI extending from the small intestine to the rectum. The patient was managed conservatively, and gefitinib therapy was discontinued. Subsequently, the symptoms improved and a follow-up abdominal X-ray showed a reduction in intramural air. After gefitinib was restarted, PI occurred three more times. CONCLUSIONS: Although PI is extremely rare, physicians should be aware of the risk of PI in patients undergoing gefitinib therapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Pneumatose Cistoide Intestinal/induzido quimicamente , Quinazolinas/efeitos adversos , Adenocarcinoma de Pulmão , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Gefitinibe , Humanos , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Quinazolinas/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Adjuvant chemotherapy after the resection of stage IB-IIIA non-small cell lung cancer (NSCLC) is now the standard of care based on large-scale phase III trials and a meta-analysis. However, chemotherapy has plateaued in terms of its efficacy, and the search for treatment prediction biomarkers is imperative for the further identification of treatable subgroups. Therefore, we investigated the significance of cyclooxygenase-2 (Cox-2) expression and the applicability of a Cox-2 inhibitor in patients who had received adjuvant chemotherapy. METHODS: We conducted a retrospective review of data from 97 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The criteria for regimen selection were based on a discussion among the cancer board and enrollment in a clinical trial. Immunohistochemical staining (IHC) for Cox-2 was performed, and the correlation between Cox-2 expression and disease-free survival (DFS) was evaluated. RESULTS: IHC showed that 56 cases (57.7%) were positive for Cox-2. The rate of Cox-2 expression was similar for the PB and OT groups. Among the patients who received PB, the DFS of the patients with Cox-2 expression was significantly poorer than that of the patients without Cox-2 expression (P = 0.017), but there was no significant difference among the patients who received OT (P = 0.617). In a multivariate analysis, Cox-2 expression and lymph node metastasis were independent predictors of DFS among patients who received PB. CONCLUSIONS: Cox-2 expression was a powerful predictor of DFS among patients who received PB as an adjuvant chemotherapy. Further study investigating the use of a Cox-2 inhibitor for adjuvant chemotherapy is needed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ciclo-Oxigenase 2/metabolismo , Neoplasias Pulmonares/enzimologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/enzimologia , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Platina/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tegafur/administração & dosagemRESUMO
BACKGROUND: The maximal standardized uptake value (SUVmax) on fluorodeoxyglucose-positron emission tomography (FDG-PET) for primary tumors is correlated with clinicopathological and prognostic factors in patients with non-small cell lung cancer. However, previous investigations have discussed the role of SUVmax without distinguishing among the histological subtypes of lung cancer. Herein, we investigated the correlations among the SUVmax on FDG-PET, clinicopathological or prognostic factors, and the expression of tumor angiogenic biomarkers according to histological subtypes. METHODS: We conducted a retrospective review of data from 52 patients with invasive adenocarcinoma (ADC) and 32 patients with squamous cell carcinoma (SQC) measuring less than 3 cm in diameter. Immunohistochemical staining for cyclooxygenase-2 (Cox-2), Ki-67, and vascular endothelial growth factor, which might influence cancer progression, was performed and the correlations between the expressions of these biomarkers and the SUVmax were evaluated. RESULTS: Among ADC patients, a statistically significant correlation was observed between the SUVmax and the major clinicopathological factors; among SQC patients, however, no statistically significant association was observed. The disease-free survival (DFS) period of the ADC patients with a high SUVmax was significantly poorer than that of the patients with a low SUVmax, but the DFS of the SQC patients with a high SUVmax was not significantly poorer. In a multivariate analysis, the pathological stage and the SUVmax were independent prognostic factors of the DFS among the ADC patients. Among the SQC patients, however, only Cox-2 expression was an independent prognostic factor of DFS. CONCLUSIONS: Some clear differences in prognostic values of the SUVmax on FDG-PET and Cox-2 expression exist between patients with ADC and those with SQC. Based on these relationships between the SUVmax and clinicopathological or biological factors that influence cancer progression, the importance of the SUVmax appears to be quite different for patients with ADC and those with SQC.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Ciclo-Oxigenase 2/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Adenocarcinoma/enzimologia , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/mortalidade , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Approximately 3-5% of non-small cell lung cancers (NSCLC) harbor ALK fusion genes and may be responsive to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. There are only a few reports on cell lines with EML4-ALK variant 3 (v3) and tumoroids that can be subject to long-term culture (> 3 months). In this study, we established tumoroids (PDT-LUAD#119) from a patient with lung cancer harboring EML4-ALK that could be cultured for 12 months. Whole-exome sequencing and RNA sequencing analyses revealed TP53 mutations and an EML4-ALK v3 mutation. PDT-LUAD#119 lung tumoroids were sensitive to the ALK tyrosine kinase inhibitors (ALK TKIs) crizotinib, alectinib, entrectinib, and lorlatinib, similar to NCI-H3122 cells harboring EML4-ALK variant 1 (v1). Unexpectedly, clear squamous cell carcinoma and solid adenocarcinoma were observed in xenografts from PDT-LUAD#119 lung tumoroids, indicating adenosquamous carcinoma. Immunostaining revealed that the squamous cell carcinoma was ALK positive, suggesting a squamous transformation of the adenocarcinoma. Besides providing a novel cancer model to support basic research on ALK-positive lung cancer, PDT-LUAD#119 lung tumoroids will help elucidate the pathogenesis of adenosquamous carcinoma.
Assuntos
Quinase do Linfoma Anaplásico , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Proteínas de Fusão Oncogênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Transformação Celular Neoplásica/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Crizotinibe/farmacologia , Linhagem Celular Tumoral , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
Among mucus-producing lung cancers, invasive mucinous adenocarcinoma of the lung is a rare and unique subtype of pulmonary adenocarcinoma. Notably, mucus production may also be observed in the five subtypes of adenocarcinoma grouped under the higher-level diagnosis of Invasive Non-mucinous Adenocarcinomas (NMA). Overlapping pathologic features in mucus-producing tumors can cause diagnostic confusion with significant clinical consequences. In this study, we established lung tumoroids, PDT-LUAD#99, from a patient with NMA and mucus production. The tumoroids were derived from the malignant pleural effusion of a patient with lung cancer and have been successfully developed for long-term culture (> 11 months). Karyotyping by fluorescence in situ hybridization using an alpha-satellite probe showed that tumoroids harbored aneuploid karyotypes. Subcutaneous inoculation of PDT-LUAD#99 lung tumoroids into immunodeficient mice resulted in tumor formation, suggesting that the tumoroids were derived from cancer. Xenografts from PDT-LUAD#99 lung tumoroids reproduced the solid adenocarcinoma with mucin production that was observed in the patient's metastatic lymph nodes. Immunoblot analysis showed MUC5AC secretion into the culture supernatant of PDT-LUAD#99 lung tumoroids, which in contradistinction was barely detected in the culture supernatants of NCI-A549 and NCI-H2122 pulmonary adenocarcinoma cells known for their mucin-producing abilities. Here, we established a novel high-mucus-producing lung tumoroids from a solid adenocarcinoma. This preclinical model may be useful for elucidating the pathogenesis of mucus-producing lung cancer.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Mucina-5AC , Muco , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Muco/metabolismo , Animais , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Mucina-5AC/metabolismo , Mucina-5AC/genética , Camundongos , Linhagem Celular Tumoral , Células Tumorais Cultivadas , Masculino , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/metabolismoRESUMO
Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.
Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Animais , Camundongos , Medicina de Precisão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologiaRESUMO
A 52-year-old female never-smoker with an abnormal shadow in the right lung detected on radiography was referred to our institution. Contrast-enhanced computed tomography revealed an irregular nodule in the upper lobe of the right lung, suggestive of a pulmonary vascular abnormality. Angiography revealed a direct communication between the right internal mammary artery (IMA) and the right upper lobe pulmonary artery branches, with dilated and tortuous vascular proliferation. As multiple branch arteries were seen flowing into the upper lobe from the IMA, transcatheter selective embolization of these vessels and right upper lobectomy by video-assisted thoracoscopic surgery were performed. Contrary to the clinical diagnosis, the pathological finding was a pulmonary adenocarcinoma of the right upper lobe. Additional lymph node dissection was performed later. We report an extremely rare and unprecedented case of pulmonary adenocarcinoma fed by the right IMA, with a literature review.
Assuntos
Adenocarcinoma de Pulmão , Fístula , Pneumopatias , Neoplasias Pulmonares , Feminino , Humanos , Pessoa de Meia-Idade , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Artéria Pulmonar/patologia , Pneumonectomia/métodos , Pulmão/patologia , Adenocarcinoma de Pulmão/patologia , Pneumopatias/cirurgia , Neoplasias Pulmonares/patologia , Fístula/patologiaRESUMO
BACKGROUND: The purpose of this study is to clarify the correlations between the expression of membrane-bound estrogen receptor-α (mERα) and epidermal growth factor receptor (EGFR) mutation and clinicopathological factors, especially in relation to the prognosis, in patients with lung adenocarcinoma. METHODS: We conducted a retrospective review of the data of 51 lung adenocarcinoma patients with tumors measuring less than 3 cm in diameter. Immunohistochemical staining for mERα expression and detection of the EGFR mutation status were performed. RESULTS: Among the 51 patients, the tumors in 15 showed both mERα expression and EGFR mutation. ("double positive") Significant associations between "double positive" and vascular invasion, vascular endothelial growth factor expression, and Ki-67 expression were observed. A multivariate analysis revealed that only "double positive" was an independent risk factor influencing the recurrence-free survival. CONCLUSIONS: Presence of mERα expression together with EGFR mutation was found to be an independent prognostic factor for survival in patients with lung adenocarcinoma, suggesting cross-talk between mERα and EGFR mutation.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Receptores ErbB/genética , Receptor alfa de Estrogênio/metabolismo , Neoplasias Pulmonares/metabolismo , Mutação , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Feminino , Seguimentos , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Pulmonary hypoplasia is diagnosed during the perinatal period and is a cause of death in newborns. However, these developmental abnormalities are diagnosed in adulthood in some cases. A 70-year-old male smoker was diagnosed with stage IIIA pulmonary adenocarcinoma in the right upper lobe with right middle lobe hypoplasia. He subsequently underwent right upper and middle lobectomy with lymph node dissection by video-assisted thoracoscopic surgery. In addition to an invasive adenocarcinoma in the right upper lobe, pathological examination of the hypoplastic lobe revealed neuroendocrine hyperplasia, as well as tumorlets and a typical carcinoid. Eight cases of pulmonary neuroendocrine tumors that developed from pulmonary hypoplasia have been reported to date. Interestingly, all but one case occurred in the right middle lobe. Neuroendocrine cell hyperplasia has been reported to develop in hypoplastic lungs postnatally; therefore, we speculated that the lesion was the origin of these neuroendocrine tumors. Moreover, the pathological findings suggested that atelectasis was involved in the pathogenesis of this rare condition. In adults, when lobar hypoplasia is diagnosed, neuroendocrine tumors should be anticipated.
Assuntos
Adenocarcinoma , Tumor Carcinoide , Neoplasias Pulmonares , Tumores Neuroendócrinos , Adenocarcinoma/complicações , Adulto , Idoso , Tumor Carcinoide/patologia , Humanos , Hiperplasia , Recém-Nascido , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Masculino , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/cirurgiaRESUMO
Despite high expectations for lung tumoroids, they have not been applied in the clinic due to the difficulty of their long-term culture. Here, however, using AO (airway organoid) media developed by the Clevers laboratory, we succeeded in generating 3 lung tumoroid lines for long-term culture (>13 months) from 41 lung cancer cases (primary or metastatic). Use of nutlin-3a was key to selecting lung tumoroids that harbor mutant p53 in order to eliminate normal lung epithelial organoids. Next-generation sequencing (NGS) analysis indicated that each lung tumoroid carried BRAFG469A, TPM3-ROS1 or EGFRL858R/RB1E737*, respectively. Targeted therapies using small molecule drugs (trametinib/erlotinib for BRAFG469A, crizotinib/entrectinib for TPM3-ROS1 and ABT-263/YM-155 for EGFRL858R/RB1E737*) significantly suppressed the growth of each lung tumoroid line. AO media was superior to 3 different media developed by other laboratories. Our experience indicates that long-term lung tumoroid culture is feasible, allowing us to identify NGS-based therapeutic targets and determine the responsiveness to corresponding small molecule drugs.
RESUMO
BACKGROUND: The principle treatment for retroperitoneal liposarcoma is surgical resection, however there are many cases of recurrence. In addition to local recurrence, retroperitoneal liposarcoma, particularly dedifferentiated liposarcoma is known to occasionally cause lung metastases. CASE REPORT: A 72-year-old woman with a diagnosis of retroperitoneal liposarcoma and probable right upper lobe early pulmonary adenocarcinoma underwent sequential local tumor resection and right upper lobectomy. Twenty months after liposarcoma resection, a computed tomography (CT) scan of the chest revealed a nodule located in the left lower lobe. A CT-guided biopsy was performed and she was subsequently diagnosed with pulmonary metastasis from retroperitoneal liposarcoma. The nodule enlarged chronologically, however a left lower lobectomy could not be performed because respiratory function after the right upper lobectomy was not sufficient. Therefore, in order to preserve the left superior segment (S6), the basal segments (S8+S9+S10) were resected. Seven months after the surgery, she is living a self-reliant life without recurrence of liposarcoma. CONCLUSION: Here we have reported a case of pulmonary metastasis from retroperitoneal liposarcoma following limited surgery. In cases where respiratory function is limited, lower lobe segmentectomy can be an effective treatment. For the treatment of a single pulmonary metastasis from retroperitoneal liposarcoma, metastasectomy was considered to be effective as long as no local recurrence was seen after initial primary tumor resection.
RESUMO
BACKGROUND Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder clinically characterized by pulmonary cysts, spontaneous pneumothorax, renal cell cancer, and skin fibrofolliculomas. The disorder is caused by germline mutations in the FLCN gene. CASE REPORT A 56-year-old female was admitted to our hospital with a diagnosis of bilateral spontaneous pneumothorax. A computed tomography (CT) scan of the chest revealed bilateral multiple bullae predominantly located in the subpleural and mediastinal areas in the bilateral upper and lower lobes. Although she was cured by thoracic cavity drainage, she underwent resection of bilateral lung bullae because she had a prior history of right pneumothorax at 37- and 45-years of age. She had no signs of renal tumor but had fibrofolliculoma in her face and a family history of pneumothorax, we therefore suspected BHD syndrome. DNA sequence analyses determined that there was a two base pair deletion in exon 4 of the FLCN gene, confirming the diagnosis of BHD syndrome. CONCLUSIONS Here we report a case of BHD syndrome with a previously unreported FLCN mutation.
Assuntos
Síndrome de Birt-Hogg-Dubé/genética , DNA/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: The maximal standardized uptake value (SUVmax) of pulmonary lesions on dual-time-point (DTP) fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be useful for differentiation between malignant and non-malignant pulmonary lesions, and also to be of value for intrathoracic nodal staging of non-small cell lung cancer (NSCLC). However, a few NSCLC lesions have been found to show decreased FDG uptake on delayed images, and the significance of this finding remains unknown. PATIENTS AND METHODS: We conducted a retrospective review of the data of 284 patients with NSCLC who underwent DTP FDG-PET before surgery. Cases of adenocarcinoma in situ and minimally invasive adenocarcinoma were excluded, because these lesions show little FDG uptake. Each patient was scanned at 60 min (early acquisition; SUV-E) and 115 min (delayed acquisition; SUV-D) after the radiopharmaceutical injection. The intratumoral retention index (RI) of 18F-FDG was measured for each examination by the DTP method. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared in relation to the SUV-E, SUV-D, and RI by univariate and multivariate analysis using models including the clinico-pathological prognostic factors. RESULTS: Of the 284 cases, the RI ≤ 0 was in 49 cases (17.3%). This group of patients showed lower values of SUV-E and SUV-D, a smaller tumor size, and a lower rate of lymphatic invasion or vascular invasion. It was particularly noteworthy that lymph node metastasis was not histopathologically confirmed in any of these patients. Univariate analysis identified the RI, SUV-E and SUV-D, besides age, tumor size, lymph node metastasis, and tumor differentiation grade as predictors of the RFS. On the other hand, multivariate analysis identified the RI and lymph node metastasis, but not the SUV-E and SUV-D, as independent predictors of the RFS. CONCLUSIONS: This study demonstrated that DTP FDG-PET of the primary tumor in NSCLC can be useful to predict the RFS of the patients. In addition, this method may also be useful to predict the presence/absence of intrathoracic lymph node metastasis in these patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de TempoRESUMO
The immune microenvironment of primary tumors has been reported to be a prognostic factor. We previously reported that the tumor-infiltrating regulatory T cell (Treg) count was positively correlated with the intratumoral cyclooxygenase-2 (COX-2) expression level and was associated with a poor survival among patients with non-small cell lung cancer (NSCLC). Recently, numerous single nucleotide polymorphisms (SNPs) in the COX-2 gene have been identified, and these SNPs may contribute to differential gene expression and enzyme activity levels. However, whether COX-2 genetic variants influence the functions of COX-2 in NSCLC remains unclear. Eighty NSCLC patients who underwent a complete resection at our institute were enrolled. We extracted DNA from the peripheral blood and identified five different COX-2 SNPs. The correlations between the COX-2 SNPs and the expression levels of COX-2, Tregs and Ki-67 were studied. The prognostic significance of the COX-2 SNPs was also evaluated. COX-2 SNPs were not correlated with the expression of COX-2. However, for the COX-2 -1195G/A polymorphism, the AA genotype group had a significantly higher Treg score. Furthermore, the AA group had a significantly higher Treg score regardless of the COX-2 expression level. The COX-2 -1195AA genotype group tended to have a shorter disease-free survival period than the GA/GG group. In conclusion, the COX-2 -1195G/A polymorphism influences the infiltration of Tregs into NSCLC, and the COX-2 SNP factor may be a prognostic factor reflecting Treg infiltration in NSCLC.
Assuntos
Adenocarcinoma/enzimologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ciclo-Oxigenase 2/genética , Neoplasias Pulmonares/enzimologia , Linfócitos T Reguladores/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Expressão Gênica , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximabmediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Quinazolinas/administração & dosagem , Receptor ErbB-2/biossíntese , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab/administração & dosagem , Cetuximab/imunologia , Receptores ErbB/biossíntese , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Lapatinib , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Mesotelioma/imunologia , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/imunologia , Trastuzumab/administração & dosagem , Trastuzumab/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Adjuvant chemotherapy after the complete resection of non-small-cell lung cancer (NSCLC) is now the standard of care. To improve survival, it is important to identify risk factors for the continuation of adjuvant chemotherapy. In this study, we analyzed chemotherapy compliance and magnitude of the prognostic impact of the prognostic nutritional index (PNI) before adjuvant chemotherapy. METHODS: We conducted a retrospective review of data from 106 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The correlations between the PNI values and recurrence-free survival (RFS) were then evaluated. RESULTS: In the PB group, the percentage of patients who completed the four planned cycles of chemotherapy was not correlated with the PNI. In the OT group, however, a significant difference was observed in the percentage of patients who completed the planned chemotherapy according to the PNI before adjuvant chemotherapy. The RFS of patients with a PNI <50 before adjuvant chemotherapy was significantly poorer than that of the patients with a PNI ≥50. A multivariate analysis showed that nodal metastasis and PNI before chemotherapy were independent predictors of the RFS. However, PNI before surgery was not a predictor of the RFS. In the subgroup analysis, PNI before chemotherapy was independent predictor of the RFS in the OT group (P=0.019), but not in the PB group (P=0.095). CONCLUSION: The PNI before adjuvant chemotherapy influenced the treatment compliance with the planned chemotherapy in the OT group, but not the PB group. In addition, a low PNI before adjuvant chemotherapy was associated with a poor RFS in a multivariate analysis, especially in the OT group.
RESUMO
INTRODUCTION: Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown. METHODS: This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. RESULTS: We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. CONCLUSION: In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Células Matadoras Naturais/metabolismo , Neoplasias Pulmonares/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Receptores ErbB/antagonistas & inibidores , Gefitinibe , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , GencitabinaRESUMO
A 38-year-old man without any symptoms was admitted to our institution because of an abnormal shadow found incidentally on a chest X-ray. Chest computed tomography showed a round mass in the lingular segment of the left upper lobe. Lingular segmentectomy was performed, and the histopathological diagnosis was intrapulmonary schwannoma. Immunohistochemical staining revealed a positive result for S-100 protein and negative results for CD34 and desmin. We report this case of intrapulmonary schwannoma, which is extremely rare.