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Lung squamous cell carcinoma (LSCC) is associated with poor prognosis. Molecular targeting drugs have been demonstrated to be effective for lung adenocarcinoma; however, they are often not effective for LSCC. Kallikrein-related peptidase 13 (KLK13) expression enhances the malignancy of lung adenocarcinoma; however, its expression and crucial role in LSCC remain largely unknown. The present study examined the relationship between the KLK13 expression and clinicopathological features of LSCC. A total of 94 patients diagnosed with LSCC who underwent lobectomy, segmentectomy or wedge resection were selected. KLK13 expression was evaluated through immunostaining of formalin-fixed paraffin-embedded sections of surgical specimens. Of the 94 LSCC samples, 70 exhibited no KLK13 expression, while the remaining 24 exhibited ectopic expression. KLK13 expression in tumors was focal and restricted to the cytoplasm of keratinized cells. LSCC cases were classified into KLK13-negative and KLK13-positive groups, and KLK13 expression was positively associated with E-cadherin expression (P=0.0143). Associations between KLK13 expression and keratinization (P=0.0052) or absence of lymphatic vessel invasion (P=0.0603) were observed; however, these trends did not reach statistical significance. The present findings indicated that KLK13 expression in keratinized LSCC may have a protective role in lymphatic vessel invasion of LSCC, which suggests its significance for therapeutic applications against LSCC.
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A multilocular thymic cyst (MTC) is a rare mediastinal tumor with multiloculated cyst-like structures in the anterior mediastinum. This tumfor is associated with inflammatory diseases, including human immunodeficiency virus (HIV) infection. The present study reports a case of MTC detected during coronavirus disease 2019 (COVID-19) treatment in an adult who was tested HIV positive. An anterior mediastinal tumor was incidentally detected on computed tomography in a 52-year-old man with a 20-year history of HIV infection on the 9th day of COVID-19. The patient was asymptomatic with no notable physical findings. Magnetic resonance imaging revealed a 28-mm bilocular cyst. Robot-assisted thoracoscopic tumor resection was performed. Pathological examination showed that the cyst was lined with squamous or cuboidal epithelium, and the cystic lesion wall was mainly composed of thymic tissue with follicular hyperplasia. Based on these findings, the patient was diagnosed with MTC. To date, only 15 MTC cases have been reported in patients with HIV, and the majority of cases showed HIV infection-related symptoms such as lymphoid interstitial pneumonia and parotid gland enlargement. The present case was atypical for an HIV-related MTC because it did not involve HIV infection-related symptoms, suggesting the possibility for an alternative etiology such as COVID-19. Further reports on MTC development in patients with COVID-19 are required to elucidate the relationship between MTC and COVID-19.
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A 41-year-old man presented with chronic cough and chest pain. Laboratory tests revealed anemia, inflammation, hypoalbuminemia, polyclonal hypergammaglobulinemia, and elevated interleukin-6 levels. Computed tomography revealed diffuse bilateral pulmonary nodules and multicentric lymphadenopathy. Histopathology of the pulmonary nodule resembled pulmonary hyalinizing granuloma (PHG), whereas lymph node histopathology was consistent with idiopathic multicentric Castleman disease (iMCD). The patient was diagnosed with iMCD involving PHG-like pulmonary nodules. Little is known about the association between these two diseases, and the present case provides insights regarding the relationship between PHG and iMCD.
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Enfermedad de Castleman , Nódulos Pulmonares Múltiples , Neumonía , Fibrosis Pulmonar , Masculino , Humanos , Adulto , Enfermedad de Castleman/complicaciones , Enfermedad de Castleman/diagnóstico por imagen , Nódulos Pulmonares Múltiples/diagnóstico , Diagnóstico Diferencial , Granuloma/complicaciones , Granuloma/diagnóstico , Fibrosis Pulmonar/complicacionesRESUMEN
PURPOSE: Many patients with coronavirus disease 2019 require mechanical ventilation and tracheostomy. However, the timing and indications for tracheostomy are controversial. This study assessed 11 patients with coronavirus disease 2019 who underwent tracheostomy with clinical information and retrospective analyses. METHODS: A single-center retrospective observational study was performed on patients with coronavirus disease 2019 who underwent tracheostomy between 2020 and 2021. RESULTS: Failure to wean was the most common indication for tracheostomy, followed by extracorporeal membrane oxygenation decannulation and the need for secretion management. After tracheostomy, six patients (54.5%) were liberated from the ventilator. The time from intubation to tracheostomy (21.1 ± 9.14 days) was correlated with the duration of ventilator dependency (36.83 ± 20.45 days, r2 = 0.792, p = 0.018). The mean Acute Physiological and Chronic Health Evaluation II score was significantly lower in the ventilator-liberated group (23 ± 2.77) than in the non-ventilator-liberated group (31 ± 6.13, p = 0.0292). Furthermore, patients with Acute Physiological and Chronic Health Evaluation II scores of < 27 points achieved ventilator liberation and a long-term survival (p = 0.0006). CONCLUSIONS: This study describes the outcomes of a cohort of patients who underwent tracheostomy after intubation for coronavirus disease 2019. The Acute Physiological and Chronic Health Evaluation II score predicted whether or not the patient could achieve ventilator liberation.
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COVID-19 , Desconexión del Ventilador , Humanos , Traqueostomía , Estudios Retrospectivos , JapónRESUMEN
Pulmonary leiomyoma is a rare disease, accounting for ~2% of cases of benign lung tumors. Pulmonary leiomyomas can be classified as tracheobronchial or pulmonary parenchymal, or as having an iceberg growth pattern, wherein the tumor extends into both the bronchial and pulmonary cavities. In the present report, a 41-year-old man complaining of sputum and discomfort during swallowing was referred to the National Center for Global Health and Medicine, because of an abnormal shadow on chest radiography and computed tomography (CT). Since the follow-up CT showed that the tumor in the third right lung segment had increased and progressed along the intra-bronchus over time, thoracoscopic right upper lobectomy was performed and leiomyoma was pathologically diagnosed. After resection, the symptoms of airway irritation improved. Since respiratory symptoms and radiographical findings are nonspecific with tracheobronchial and pulmonary parenchymal types of pulmonary leiomyoma, the identification of symptoms and determination of the extent of the lesion are necessary for treatment. In cases of iceberg growth pattern, in which the tumor extends into both the bronchial and pulmonary cavities, surgical resection should be considered.
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A crucial issue in radical radiation therapy for non-small-cell lung cancer is how to define the clinical target volume (CTV). Although the scope of microscopic extension (ME) and microscopic proximal bronchial extension (PBE) from a primary tumor should be considered when defining the CTV, there has been limited research on ME and PBE. Therefore, we conducted this systematic review. The PubMed, ICHUSHI (Japanese database), and Cochrane Library databases were searched, and 816 articles were initially retrieved. After primary and secondary screenings, eight articles were ultimately selected. The results of this systematic review suggest the importance of a 0 mm margin in stereotactic radiotherapy for early-stage cancer and a 5-8 mm margin in curative irradiation for locally advanced cancer. Regarding PBE, this review yielded the conclusion that it is appropriate to consider the addition of an approximately 15 mm margin from the bronchial vasculature. Although there were few articles with a high level of evidence, this systematic review enabled us to collate results from previous studies and to provide recommendations, to some extent, regarding the CTV margin in the current clinical environment, where high-precision radiation therapy, such as image-guided radiotherapy and intensity-modulated radiotherapy, is predominant.
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Non-congenital, non-traumatic spontaneous diaphragmatic liver hernia in adults is extremely rare and sometimes misdiagnosed as a thoracic tumor. Almost all previous reports with a definitive diagnosis reported preservation; thus, differential diagnosis is extremely important for planning optimal management of such clinical conditions. An abnormal shadow in the right lower lung field was detected on chest radiography in a 61-year-old woman. Further imaging study revealed a 33-mm diameter mass adjacent to the right diaphragm. Thoracoscopic surgery was performed as diagnostic treatment. We found a pale hemispherical herniated liver on the central tendon of the diaphragm. After repositioning the herniated liver, the orifice was closed with a non-absorbable suture, and the surface of the liver returned to being a perfectly smooth surface. With this result, we believe that repair of diaphragmatic liver hernia through a minimally invasive procedure has great benefits for patients.
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Hernia Hiatal , Hernias Diafragmáticas Congénitas , Neoplasias Torácicas , Adulto , Diafragma/diagnóstico por imagen , Diafragma/cirugía , Femenino , Hernias Diafragmáticas Congénitas/diagnóstico por imagen , Hernias Diafragmáticas Congénitas/cirugía , Humanos , Hígado/cirugía , Persona de Mediana Edad , ToracoscopíaRESUMEN
Thymic mucoepidermoid carcinoma (MEC) is a rare tumor, and its characteristics remain to be clarified. Here we investigated 20 cases of thymic MEC to systematically characterize its clinical, histopathologic, and molecular features. The median age of the patients was 56 years (range, 19 to 80 y), there was a slight male predilection (3:2), and 44% of the patients were asymptomatic at diagnosis. The median tumor size was 6.8 cm in diameter, 55% were pT1 tumors, and 50% were TNM stage I tumors. When 4 tumor grading systems for salivary MEC (Armed Forces Institutes of Pathology, Brandwein, modified Healey, and the Memorial Sloan-Kettering) were employed, low-grade, intermediate-grade, and high-grade tumors accounted for 35% to 70%, 5% to 25%, and 25% to 50%, respectively. Many histologic variants were noted, and 70% of the cases were classified as nonclassic variants. MAML2 rearrangement was detected in 56% of cases, and the fusion partner was CRTC1 in all cases. CRTC1-MAML2 fusion was associated with lower pT classification and lower TNM stage. The overall survival rate of all patients was 69% and 43% at 5 and 10 years, respectively. Worse overall survival was associated with higher pT stage, higher TNM stage, residual tumors, greater tumor size, high-grade tumor histology (Armed Forces Institutes of Pathology and Memorial Sloan-Kettering, but not the other 2), and with the absence of CRTC1-MAML2 fusion. Of note, none of the patients with CRTC1-MAML2 fusion-positive tumors died during the follow-up. In conclusion, the clinicopathologic and molecular findings of thymic MEC presented here are expected to contribute to the management of this rare tumor.
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Carcinoma Mucoepidermoide , Neoplasias de las Glándulas Salivales , Timoma , Neoplasias del Timo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Mucoepidermoide/patología , Proteínas de Unión al ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares , Proteínas de Fusión Oncogénica , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/terapia , Neoplasias del Timo/genética , Neoplasias del Timo/terapia , Transactivadores , Factores de Transcripción , Adulto JovenRESUMEN
At the beginning of the COVID-19 pandemic in 2020, many hospitals around the world recommended stopping elective surgery as a precaution to stop the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The number of elective surgeries was reduced in Japan due to several waves of the pandemic. This work describes the management of COVID-19 and actual polymerase chain reaction (PCR) screening in operating theaters at the National Center for Global Health and Medicine (NCGM), a designated hospital for specified infectious diseases in Japan. The following three steps for COVID-19 infection control were taken to maintain the operating theater: i) Do not bring COVID-19 into the operating theater, ii) Infection control for all medical staff, and iii) Surgical management of surgical patients with COVID-19. We introduced checklists for surgical patients, simulations of surgery on infected patients, screening PCR tests for all surgical patients, and use of a negative pressure room for infective or suspected cases. We determined the flow and timing of surgery for patients with COVID-19. However, many aspects of COVID-19 infection control measures in the operating theater are still unclear. Therefore, infection control measures require further advances in the future to manage new infections.
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Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity, but it exhibits thioltransferase activity. The significance of GSTO2 in lung function has been reported; however, the precise expression and molecular function of GSTO2 in the lungs remain unclear. In the present study, we found that GSTO2 is expressed in airway basal cells, non-ciliated, columnar Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. Contrastingly, no GSTO2 expression was observed in 94 lung squamous cell carcinoma (LSCC) samples. When human LSCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant GSTO2 hypermethylation in LSCC is the cause of its downregulation. Forced GSTO2 expression in LSCC cell lines inhibited cell growth and colony formation in vitro. In a subcutaneous xenograft model, GSTO2-transfected cells formed smaller tumors in nude mice than mock-transfected cells. Upon intravenous injection into nude mice, the incidence of liver metastasis was lower in mice injected with GSTO2-transfected cells than in those injected with mock-transfected cells. In addition, GSTO2 induction suppressed the expression of ß-catenin and the oxygen consumption rate, but it did not affect the extracellular acidification rate. Furthermore, GSTO2-transfected cells displayed lower mitochondrial membrane potential than mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, ß-catenin expression and mitochondrial membrane potential were recovered. Our study indicated that the loss of GSTO2 via DNA hypermethylation contributes to the growth and progression of LSCC, probably by modulating cancer metabolism via the p38/ß-catenin signaling pathway.
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Carcinoma de Células Escamosas/patología , Regulación hacia Abajo , Glutatión Transferasa/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/patología , Animales , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Decitabina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucólisis , Humanos , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fosforilación OxidativaRESUMEN
Bronchial atresia is a rare congenital condition that may lead to infectious complications. Almost all patients with this condition are diagnosed early in life with normal lungs, making them particularly suitable candidates for thoracoscopic surgery. A 30-year-old man was referred to our hospital due to an abnormal shadow on chest radiography taken 7 years prior. Despite being diagnosed with B5 bronchial atresia, he refused to undergo surgical resection. Seven years later, he developed right chest pain. Computed tomography showed B5 bronchial occlusion, mucoid impaction and emphysematous changes. Treatment with thoracoscopic right middle lobectomy and S3 partial resection using four ports resulted in good lung expansion after discharge. This study highlights that thoracoscopic surgical resection should be considered in patients with bronchial atresia.
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Tuberculoma is a manifestation of pleural tuberculosis. Although the clinical manifestation of tuberculoma has been widely reported, the pathogenesis of this condition still remains unclear. An abnormal shadow was detected on the chest radiograph of a 44-year-old man with a history of pulmonary tuberculosis. Computed tomography revealed a well-defined, elliptical 44 mm nodule located in the right posterior thoracic cavity. Thoracoscopic surgery was performed to rule out malignant tumors. Although loose adhesions were observed throughout the thoracic cavity, a nodule was found between the visceral pleura and parietal pleura. En bloc resection was performed, and the patient was pathologically diagnosed with tuberculoma. An acid-fast bacterium culture was negative, and the patient's recovery was uneventful without chemotherapy. Surgical resection should be considered to rule out malignancy, because tuberculomas are difficult to distinguish from malignant pleural tumors.
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Ectopic intrapulmonary thyroid tissue is extremely rare and considerably difficult to diagnose without surgery. Ectopic thyroid tissue, described as a mediastinal tumor, and intrapulmonary lesions are infrequent. An abnormal shadow was detected upon chest X-ray in a 60-year old woman with a history of benign thyroid goiter. A computed tomography scan revealed a solitary nodule measuring 27 mm in diameter in the left lower lobe, the diameter of which had increased by 5 mm since initial observation eight years ago. A thoracoscopic wedge resection was performed and the lesion was determined to be a non-invasive, soft-tissue tumor. It was pathologically diagnosed as an ectopic thyroid follicular adenoma. The course of the tumor was uneventful. A diagnosis of ectopic intrapulmonary thyroid should be made cautiously and only after ruling out metastasis of a follicular adenoma or thyroid carcinoma. This diagnosis of ectopic thyroid tissue was made possible by the surgical approach.
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Adenoma , Neoplasias Pulmonares , Neoplasias de la Tiroides , Adenoma/diagnóstico por imagen , Adenoma/cirugía , Femenino , Humanos , Pulmón , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Persona de Mediana Edad , Neoplasias de la Tiroides/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Mycobacterium abscessus (M. abscessus) infection is resistant to multi-antibacterial treatment, and surgical resection is often recommended. We report a case of M. abscessus infection in a young patient suspected of having a GATA2 mutation. A 19-year-old woman with a medical history of severe sinusitis and a family history of non-tuberculous mycobacteriosis presented at our hospital. M. abscessus was confirmed by sputum culture. The patient received multidrug therapy, including clarithromycin. CT scan demonstrated bronchodilation and capacity decrease due to non-obstructive atelectasis in the middle lobe. We performed thoracoscopic resection without complications. Congenital immunodeficiency was suspected given the patient's past medical and family history. The result of lymphocyte subset analysis revealed a GATA2 mutation, but no genetic mutation was detected by a next-generation sequencer. The patient followed a good clinical course. This paper reports the successful treatment of an M. abscessus infection and the importance of checking the genetic background of young patients.
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Infecciones por Mycobacterium no Tuberculosas/cirugía , Mycobacterium abscessus , Neumonectomía/métodos , Antibacterianos/uso terapéutico , Claritromicina/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium abscessus/genética , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Toracoscopía , Adulto JovenRESUMEN
A 42-year-old man diagnosed with acute myeloid leukemia complained of progressive swelling of the right side of his face with pain 11 days after the third cycle of consolidation therapy with high-dose arabinosylcytosine-cytarabine. Head and neck magnetic resonance imaging showed a mass lesion in his right maxillary sinus with parapharyngeal involvement, which included the right masseter muscle, intraorbital involvement, and an abscess in his brain. Chest computed tomography revealed peribronchial small nodules in his right upper lobe and a necrotic tumor in his right lower lobe. Molds identified as Cunninghamella bertholletiae were isolated from the necrotic ulcer. According to these results, chemotherapy for leukemia was discontinued. High-dose liposomal amphotericin (10 mg/kg/day) was initiated. Because renal dysfunction occurred, the dosage was decreased to 6 mg/kg and combined with 150 mg/day micafungin. Debridement of necrotic tissue in the right maxillary sinus and establishment of the fenestration between the sinus and oral cavity were performed. Subsequently, brain and lung lesions were surgically removed. Rhinocerebral mucormycosis was successfully treated without relapse over 3 years by a 112-day course of intravenous anti-fungal therapy and 223-day course of terbinafine and partial surgical removal, respectively, to maintain masticatory and ocular functions. To our knowledge, there has been no other report of a long-term survival case of rhinocerebral mucormycosis due to C. bertholletiae.
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Infecciones Fúngicas del Sistema Nervioso Central , Cunninghamella , Leucemia Mieloide Aguda , Enfermedades Pulmonares Fúngicas , Mucormicosis , Adulto , Antifúngicos/uso terapéutico , Antineoplásicos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Pulmón/patología , MasculinoRESUMEN
Bronchial abnormalities are rare, and they are infrequently associated with pulmonary vascular abnormalities. It is important to identify such abnormal anatomical structures before lobectomy of the lung under thoracoscopy. There have been only three reports on video-assisted thoracoscopic lobectomy in patients with anomalous bronchi and vascular abnormalities to date. Here, we present a report of video-assisted thoracoscopic right upper lobectomy performed in a patient with bronchial and vascular abnormalities. Both preoperative imaging and intraoperative findings revealed a displaced anomalous B2 bronchus arising from the bronchus intermedius, as well as abnormal distribution of the aberrant vein V2 draining into vein V6 . It is critical to understand the precise anatomical structures preoperatively to perform video-assisted thoracoscopic pulmonary lobectomy safely.
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Adenocarcinoma del Pulmón/cirugía , Neoplasias Pulmonares/cirugía , Neumonectomía/métodos , Anomalías del Sistema Respiratorio/cirugía , Cirugía Torácica Asistida por Video , Malformaciones Vasculares/cirugía , Adenocarcinoma del Pulmón/diagnóstico por imagen , Anciano , Bronquios/anomalías , Bronquios/diagnóstico por imagen , Bronquios/cirugía , Femenino , Humanos , Pulmón/anomalías , Pulmón/irrigación sanguínea , Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Malformaciones Vasculares/diagnóstico por imagenRESUMEN
Diffuse pulmonary lymphangiomatosis (DPL) is a rare lymphatic disease that can cause diverse respiratory symptoms. A 22-year-old man, whose chest CT had shown an abnormality for years, presented with acute respiratory failure due to the abrupt onset of hemoptysis. The diagnosis of DPL was confirmed by surgical lung biopsy and lymphangiography. Histopathological investigation showed dilated vascular and lymphatic vessels. DPL can cause acute and life-threatening symptoms during its chronic clinical course. A coexisting anomaly in the venous system may be present in DPL patients with hemoptysis.
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Pulmonary pneumatocele that forms immediately after pulmonary resection is extremely rare. This report describes a case of pneumatocele that formed rapidly in the left lower lobe immediately after left upper lobectomy in a patient with lung cancer and emphysema. Massive and persistent air leakage through a chest tube was noted immediately after chest closure. Therefore, the chest was reopened, and the cyst wall was incised. The air leakage point was cauterized and covered with a polyglycolic acid sheet and fibrin glue. Herein, we report a rare case of newly developed pneumatocele immediately after lobectomy.
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Complicaciones Intraoperatorias/diagnóstico , Enfermedades Pulmonares/diagnóstico , Pulmón/diagnóstico por imagen , Neumonectomía/efectos adversos , Anciano de 80 o más Años , Progresión de la Enfermedad , Humanos , Complicaciones Intraoperatorias/etiología , Enfermedades Pulmonares/etiología , Masculino , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Maximum standard uptake value (SUVmax) of F-18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) is reportedly useful for evaluating regional lymph nodes (RLNs) of non-small-cell lung cancer (NSCLC) to predict malignancy. However, it is difficult for clinicians to measure SUVmax (mSUVmax) as calculated by a workstation.We assessed the utility of simplified SUVmax (sSUVmax) in screening RLNs for pathologic malignancy. The highest color was visually defined in the region of interest. The resulting color can be quantified using the color bar, and interpreted as sSUVmax. Patients in respiratory medicine and surgery who underwent both contrast-enhanced CT and FDG-PET/CT within 3 months before radical lobectomy were evaluated retrospectively. The correlation was examined by regression analysis and receiver operating characteristic (ROC) curve analyses.Participants comprised 69 patients with NSCLC treated between May 2009 and April 2016. Medical group comprised 22 patients from respiratory medicine. The prediction model could be written as a linear relationship (mSUVmaxâ=â1.019â×âsSUVmax; Râ=â0.930). A total of 316 RLNs resected by surgery in total cohort were pathologically determined. From ROC curves, area under curve for sSUVmax was 0.72 (95% confidence interval, 0.61-0.83; Pâ<â.0002). The cutoff sSUVmax was 2.42 (sensitivity, 52%; specificity, 88%; accuracy, 85%).The sSUVmax allows quantification of colors from FDG-PET/CT and shows a close correlation to mSUVmax. This value may have potential in screening for RLNs, and thoracic clinicians can readily determine the value. These findings may facilitate better planning of therapeutic strategy in the real world.