Hypercapnia Accelerates Adipogenesis: A Novel Role of High CO2 in Exacerbating Obesity.

Obesity is a major risk factor for the development of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS), which manifest as intermittent hypercapnia and sustained plus intermittent hypercapnia, respectively. In this study, we investigated whether CO2 affects adipocyte differentiation (adipogenesis) and maturation (hypertrophy). Human visceral or subcutaneous preadipocytes were grown to confluence and then induced to differentiate to adipocytes under hypocapnia, normocapnia, and hypercapnia with or without hypoxia. Adipogenesis was also induced under intermittent or sustained hypercapnia. Differentiated adipocytes were maintained to maturity under normocapnia or hypercapnia. Our main findings are as follows: (1) hypercapnia accelerated adipogenesis in visceral and subcutaneous preadipocytes, whereas hypocapnia inhibited adipogenesis; (2) hypercapnia did not affect adipocyte hypertrophy; (3) hypercapnia-accelerated adipogenesis was independent of extracellular acidosis, oxygen concentration, or either intermittent or sustained exposure to high CO2; and (4) the mechanisms underlying hypercapnia-accelerated adipogenesis involved increased production of cyclic adenosine monophosphate (cAMP) via soluble adenylyl cyclase, leading to the activation of protein kinase A and exchanger protein directly activated by cAMP, which, in turn, activated proadipogenic transcription factors, such as cAMP response element binding protein, CCAAT/enhancer binding protein ß, and peroxisome proliferator-activated receptor γ. This study reveals a novel role of high CO2 in promoting adipogenesis, which provides mechanistic clues to a pathoetiological interaction between OSA/OHS and obesity. Our data suggest a vicious cycle of disease progression via the following mechanism: OSA/OHS → hypoventilation → hypercapnia → increased adipogenesis → increased fat mass → exacerbated OSA/OHS.

Rapid growth of primary pulmonary meningioma with hemoptysis.

While lung cancer is the predominant neoplasm causing hemoptysis, rare benign neoplasms can also be associated with hemoptysis. A 60-year-old woman presented with cough and hemoptysis. Chest computed tomography revealed an oval-shaped, well-circumscribed solitary mass (10 cm in size) in the right lower lobe, which had grown rapidly over the past year. The presence of intramass air bubbles and a surrounding halo of ground-glass opacities suggested the hemorrhagic rupture of a circumscribed hematoma into the surrounding lung tissue. Subsequent right lower lobectomy revealed a well-demarcated hematoma; its wall consisted of nonatypical spindle tumor cells, which were histologically diagnosed as meningioma. No meningioma was observed in the central nervous system, leading to the diagnosis of primary pulmonary meningioma. This case highlights PPM as a rare benign tumor (World Health Organization grade 1) capable of rapid development due to intratumoral hemorrhage, presenting with hemoptysis.

Anesthetic management of airway stent placement by rigid bronchoscopy with superior laryngeal nerve block while preserving spontaneous breathing: A case report.

Key Clinical Message: The combination of superior laryngeal nerve block can reduce the respiratory depression that occurs during management under total intravenous anesthesia. Abstract: Anesthetic management of endobronchial stent placement by rigid bronchoscopy requires the maintenance of spontaneous breathing while suppressing upper airway reflexes. The combination of superior laryngeal nerve block (SLNB) can reduce the respiratory depression that occurs during management under total intravenous anesthesia. The patient was diagnosed as having lung cancer with invasion into the right middle bronchus and stenosis of the right main bronchus on chest computed tomography, and emergency airway stent placement was performed. Sedation was initiated with propofol and dexmedetomidine, and ultrasound-guided SLNB was performed after local anesthetic spraying into the oral cavity and trachea. Bucking was minimally controlled during insertion of the rigid bronchoscope. The patient's intraoperative hemodynamics remained stable, and there were no hypoxic events. SLNB can provide the suppression of the upper airway reflex while minimizing effects on spontaneous breathing, and may be useful for achieving balanced anesthesia during rigid bronchoscopy.

Temporary Stenting for Anastomotic Stenosis after Tracheal Resection of Adenoid Cystic Carcinoma: A Case Report.

A 51-year-old man who noticed discomfort in the pharynx was found to have a tracheal tumor on physical examination. He was diagnosed as having adenoid cystic carcinoma by a transbronchial biopsy and underwent tracheal segmental resection via a collar incision. He was additionally treated with radiation therapy owing to a positive surgical margin, and he subsequently developed anastomotic tracheal stenosis. Silicon stent placement to open the airway was performed for the tracheal stenosis. One year after stent placement, the trachea was dilated, so the stent was removed, and he is still under follow-up without recurrence free 1.5 years after stent replacement.

Efficacy of vinorelbine and zoledronate combination therapy against postoperative recurrence of lung cancer.

UNLABELLED: We report a case of a response to long-term treatment with vinorelbine and zoledronate in a patient with lymph node and multiple bone metastases after lung cancer surgery. CASE: The patient was a 70-year-old male initially examined by a local physician for an abnormal shadow that had been detected on a chest X-ray during a screening examination. CT revealed a mass shadow measuring 28 mm in diameter in the left S10, and because lung cancer was suspected, the patient was admitted to our hospital for the first time and examined. Lung cancer was diagnosed intraoperatively, and left lower lobectomy was performed. The pathological stage was III a, and postoperative adjuvant chemotherapy was performed, but recurrences in the form of lymph node and multiple bone metastases were detected. After diagnosis of the recurrence, the patient was treated with long-term vinorelbine (VNR)biweekly and zoledronate (ZOL) monthly, and a response was obtained. CONCLUSIONS: A patient with postoperative recurrence of lung cancer associated with multiple bone metastases responded to combination chemotherapy with VNR and ZOL. VNR was effective against postoperative recurrence in an elderly lung cancer patient with complications, and could be administered safely long-term. ZOL also had a favorable protective effect against skeletal-related events (SREs) in lung cancer, and the results suggested that it also had an antitumor effect in this patient.

Myasthenia gravis that has developed long after radical resection of lung cancer: A case report.

Myasthenia gravis (MG) is the most common disorder of neuromuscular transmission and is a heterogeneous disorder generally caused by auto-antibody to the nicotinic acetylcholine receptor. The current study presented a rare case of MG that occurred a long time after surgical resection of lung cancer. A 58-year-old man with lung adenocarcinoma underwent upper lobectomy and mediastinal lymph node dissection. Severe myasthenic symptoms began 7 years after the operation, and emergent mechanical ventilation was needed because of myasthenic crises. Levels of serum anti-acetylcholine receptor antibody were high and typical decremental responses to repetitive stimulation on electromyography were observed. Appropriate therapies for a severe acute condition were performed, and MG has been controlled for 6 years since then. There is no recurrence of lung cancer or appearance of thymoma. In conclusion, although very rare, physicians should be aware of MG as a potential comorbidity developing in patients with a history of lung cancer.

A Rare Case of Chest Wall Castleman's Disease with Calcification.

Castleman's disease with calcification of the chest wall is very rare, and there have been few reports of such cases to date. A 57-year-old woman was referred to our hospital for a tumor with calcification on her left lateral chest wall, which was detected on chest computed tomography. Findings of her chest magnetic resonance imaging suggested schwannoma or a solitary fibrous tumor, and therefore, we performed surgery for diagnostic and therapeutic purposes. Pathologically, the tumor with calcification was diagnosed as Castleman's disease of the hyaline-vascular type. After the surgery, the patient has had no obvious symptoms and continues to undergo regular follow-up examinations.

Metachronous Primary Lung Cancer Occurring during the Spontaneous Regression of Locally Advanced Lung Cancer: A Rare Case Report.

A 71-year-old man was diagnosed as having right primary lung squamous cell carcinoma, clinical stage IIIA, but he refused treatment. However, the right upper lobe nodule and lymph node (LN) #4R showed gradual shrinking without treatment. Four years after the diagnosis, a new nodule was detected in the left lung field. We considered that this new nodule might be metachronous primary lung cancer, and hence resected it for diagnosis and treatment. The tumor in the left lung was diagnosed as basaloid squamous cell carcinoma, and that in LN #4R was diagnosed as squamous cell carcinoma with keratinization. Therefore, the patient was diagnosed as having metachronous primary lung cancer that developed during the spontaneous regression of locally advanced lung cancer.

Subcutaneous abscess due to empyema necessitans caused by Porphyromonas gingivalis in a patient with periodontitis.

Empyema necessitans is a rare empyema complication characterized by an extension of empyema out of the pleural space into the subcutaneous tissues of the chest wall. We herein report a case of empyema necessitans that presented as a subcutaneous chest wall abscess caused by Porphyromonas gingivalis (P. gingivalis), an important anaerobic periodontal pathogen, in a 74-year-old woman with periodontitis. The patient was admitted to our hospital with a painful soft tissue mass in the chest wall extending from a subpleural lung abscess associated with empyema. Exploratory percutaneous puncture and aspiration of the chest wall mass yielded foul-smelling chocolate-colored pus, which was found to be caused due to infection with P. gingivalis. Treatment with antibacterials resulted in a relapse of empyema necessitans requiring a second admission 1 month later. An additive treatment with surgical open drainage and decortication of the subcutaneous abscess successfully cured the abscess. Physicians must be aware of emphysema necessitans as an etiology of a chest wall mass and should consider periodontitis as a source of infection.

Investigation of EGFR mutations in non-small cell lung cancer usually undetectable by PCR methods.

Epidermal growth factor receptor (EGFR) mutations are the most significant genomic drivers of non-small cell lung cancer (NSCLC) and determine the efficacy of EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. PCR methods are used clinically for the detection of EGFR mutations. The Scorpion Amplification Refractory Mutation System (Scorpion-ARMS) and the cobas® EGFR Mutation Test v2 (cobas v2) are widely used PCR methods. However, those PCR methods only selectively detect the common EGFR mutations. The aim of the present study was to reveal the true frequency of EGFR mutations in NSCLC by investigating EGFR mutations usually undetectable by PCR methods by using direct sequencing. A total of 70 Japanese patients who underwent lung resection for NSCLC between September 2016 and March 2019 were included in the present study. Subsequently, PCR methods and direct sequencing were performed. In total, 29 mutations were detected by cobas v2. In total, 41 patients were identified as EGFR wild-type by cobas v2, among whom direct sequencing detected mutations in 3 patients. Subsequent Scorpion-ARMS was performed in the 3 patients in whom direct sequencing detected mutations. In total, one exon 21 L858R + G863D compound mutation was identified as a L858R single mutation, and two other mutations were undetectable. Moreover, 1 patient who was 'wild-type' on cobas v2 but 'EGFR mutation' on direct sequencing developed recurrence after surgery and responded to EGFR-TKI treatment. In present study, the percentage of undetectable EGFR mutations by cobas v2 was 9.4% in 32 mutations. It was inferred that the cause of the discrepancy in the mutation type (L858R + G863D in exon 21, and L858R in exon 21) between cobas v2 and Scorpion ARMS was due to the different limit of detection between these two PCR methods. In conclusion, the findings of the present study suggested that a selective mutation detection method may decrease the opportunity of patients with NSCLC to receive EGFR-TKI therapy. Thus, the development of a screening test to determine the EGFR status as wild-type or mutant is required for EGFR-TKI therapy.

Involvement of 27-hydroxycholesterol on the progression of non-small cell lung cancer via the estrogen receptor.

The oxysterol 27-hydroxycholesterol (27HC) promotes the proliferation of breast cancer cells as a selective estrogen receptor modulator (SERM), but it is mostly produced by alveolar macrophages in vivo. The present study evaluated hypothesis that 27HC may also promote the proliferation of lung cancer cells. In the tumor and nontumor regions of lung tissue from 23 patients with non-small cell lung cancer (NSCLC) who underwent lung cancer surgery, we compared the 27HC content and its synthetic and catabolic enzyme expressions (CYP27A1 and CYP7B1), the expressions of the estrogen receptor (ER) gene and its target gene cMYC by using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), real-time RT-PCR, and immunohistochemical staining. In addition, we evaluated the effects of 27HC and ß-estradiol (E2) treatments on the proliferation of a cultured lung cancer cell line (H23 cells) expressing ERß. In squamous cell carcinoma and in adenocarcinoma, the 27HC content was significantly higher in the tumor region than in the nontumor region, and in cancer grade III than in the other cancer grades. CYP27A1-positive macrophages were histologically detected in the nontumor regions of both cancer types, whereas the gene and protein expressions of ERß, as well as the CYP7B1 and cMYC genes, were significantly increased in the tumor tissues. In cultured H23 cells, proliferation was significantly increased by 27HC and E2 treatments for 48 h. Similar to breast cancer, the present results supported idea that the 27HC produced from alveolar macrophages promotes the proliferation of lung cancer cells highly expressing ER through the SERM action. Therefore, 27HC should be an important target for cancer therapy of NSCLC.

Prognostic Implication of PD-L1 Expression on Osimertinib Treatment for EGFR-mutated Non-small Cell Lung Cancer.

BACKGROUND/AIM: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to reveal the treatment outcomes and prognostic factors of osimertinib as first-line therapy in clinical practice settings. PATIENTS AND METHODS: We retrospectively evaluated clinical outcomes of patients with EGFR-mutated NSCLC treated with osimertinib as first-line therapy across 12 institutions in Japan between August 2018 and March 2020. RESULTS: Among 158 enrolled patients, the objective response rate (ORR) was 68%, and the estimated median progression-free survival (PFS) was 17.1 months [95% confidence interval (CI)=14.5-19.7]. Subgroup analysis showed that PFS in the group with high programmed death-ligand 1 (PD-L1) expression was significantly shorter than that in groups with low or no PD-L1 expression (10.1 vs. 16.1 vs. 19.0 months; p=0.03). Univariate and multivariate analyses demonstrated that high PD-L1 expression was the only independent adverse prognostic factor of osimertinib outcome related to PFS (hazard ratio=2.71; 95%CI=1.26-5.84; p=0.01). In terms of anti-tumor response, there was no statistically significant correlation between PD-L1 expression and the ORR (67% vs. 76% vs. 65%; p=0.51). No significant correlation was also found between PD-L1 and the incidence of de novo resistance to osimertinib (p=0.39). CONCLUSION: Although PD-L1 expression was not associated with either the ORR or frequency of de novo resistance, high PD-L1 expression could be an independent adverse prognostic factor related to PFS in osimertinib treatment.

New aspects of photodynamic therapy for central type early stage lung cancer.

BACKGROUND: and Objective Photodynamic therapy (PDT) has come to be considered as the first choice of treatment for central type early stage lung cancer (CELC). Recent advances in the ability to diagnose CELC, and in photosensitizers, as well as sophisticated clinical management, may improve the therapeutic outcome and expand the indications of PDT. MATERIALS AND METHODS: We made the search for papers on PDT for lung cancer to select the most relevant articles. Based on this review and our recent data, we discussed the best available evidence for the diagnosis, the definition of indications, photosensitizers, and clinical management with regard to PDT. RESULTS: To obtain complete response (CR) by PDT, the selection of the indications is extremely important, including the extent of the tumor on the bronchial surface and the depth of invasion in the bronchial wall. The development of autofluorescence bronchoscopy (AFB) and endobronchial ultrasonography (EBUS) have had a large impact on diagnostic bronchoscopy for CELC. CELCs less than 1 cm in diameter showed a favorable cure rate by PDT, thus this is a good indication for PDT. The relatively newer photosensitizer NPe6, which has a stronger antitumor effect than Photofrin, showed similar treatment outcome even for large tumors >1.0 cm in diameter. Furthermore, comprehensive management including photodynamic diagnosis before and after PDT should be effective to minimize the possibility of local recurrence after PDT. CONCLUSION: The present guidelines of PDT for CELC were established based on the data obtained from studies in the 1980's. We postulate that comprehensive diagnosis and the new generation of photosensitizers may increase the CR rate and expand the indications of PDT for larger tumors.

Glomus Tumor in a Segmental Bronchus: A Case Report.

Glomus tumors originate from a neuroarterial structure called the glomus body, and grow mostly in soft tissue. It is rare for glomus tumors to develop in the respiratory system. The patient of the present case had an abnormal shadow in the right lung on chest X-ray, and computed tomography (CT) findings displayed a lung tumor in the right S6. Bronchoscopy was performed for the diagnosis of the lung tumor, and a polypoid bronchial tumor was unexpectedly found to occupy the right B3. The bronchial tumor was diagnosed as a glomus tumor, and the lung tumor was diagnosed as an adenocarcinoma. The bronchial glomus tumor was cauterized by argon plasma coagulation (APC). Three weeks after the cauterization by APC, the right lower lobectomy was performed for the treatment of the lung adenocarcinoma. The patient has remained disease free for 2 years.

A tracheobronchial adenoid cystic carcinoma incidentally detected by chest radiography and pulmonary function test.

Tracheobronchial adenoid cystic carcinomas are rare tumors that progress slowly.　Diagnosis by chest plain radiography is difficult, and suspecting the existence of a disease that causes stenosis in the airways is an important key for diagnosis. A 51-year-old woman referred to our hospital because of dyspnea on exertion. Chest plain radiograph showed a slight widening of the mediastinum. The flow-volume curve of respiratory function test revealed flat portions of the curve suggesting the central airway obstruction pattern. Chest CT confirmed the existence of tracheobronchial tumor, which was pathologically diagnosed as adenoid cystic carcinoma. Chest physicians and thoracic surgeons should be careful not to miss these trivial findings in the first inspections.

Digital Breast Tomosynthesis Complements Two-Dimensional Synthetic Mammography for Secondary Examination of Breast Cancer.

OBJECTIVE: To compare the performance of two-dimensional synthetic mammography (SM) combined with digital breast tomosynthesis (DBT) (SM/DBT) and full-field digital mammography (FFDM) including women with DBT (FFDM/DBT) undergoing secondary examination for breast cancer. MATERIAL AND METHODS: Out of 186 breasts, including 52 with breast cancers; FFDM/DBT and SM/DBT findings were interpreted by four expert clinicians. Radiation doses of FFDM, SM/DBT, and FFDM/DBT were determined. Inter-rater reliabilities were analyzed between readers and between FFDM/DBT and SM/DBT by Cohen's Kappa coefficients. Diagnostic accuracy was compared between SM/DBT and FFDM/DBT by Fisher's exact tests. Two representative cancer cases were examined for differences in the interpretation between FFDM and SM. RESULTS: A higher radiation dose was required in FFDM/DBT than in SM/DBT (median: 1.50 mGy vs. 2.95 mGy). Inter-rater reliabilities were similar between both readers and modalities. Both sensitivity and specificity were equivalent in FFDM/DBT and SM/DBT (p = 0.874-1.00). Compared with FFDM, SM did not clearly show abnormalities with subtle margins in the two representative cancer cases. CONCLUSION: SM/DBT had a similar performance to FFDM/DBT in detecting breast abnormalities but requires less radiation. DBT complements SM to improve accuracy to a level equivalent to that of FFDM. Taken together, SM/DBT may be a good substitute for FFDM/DBT for the secondary examination of breast cancer.

Atypical carcinoid with multiple central airway metastases: A case report.

A 51-year-old man was found to have multiple polypoid tracheal and bilateral main bronchial tumors during postoperative follow-up of atypical carcinoid. He underwent transtracheal biopsy, and was diagnosed as having central airway metastases of the atypical carcinoid. He underwent chemotherapy, but the effects were unfavorable. Owing to the risk of airway obstruction, he was referred to our hospital for interventional bronchoscopy. Carcinoid tumors usually present as peripheral lung lesions or solitary endobronchial abnormalities, but rarely appear as multiple central airway lesions. We present a very rare case of multiple central airway metastases of atypical carcinoid, controlled by bronchoscopic treatment.

Intrathoracic lipoma in the horizontal fissure of the right lung: a case report.

Lipomas are benign tumors that originate from mesenchymal tissue, such as subcutaneous tissue. Intrathoracic lipomas are rare, and they can occur in the chest wall, mediastinum and bronchi. In the present case, the patient had an intrathoracic lipoma that was located in the horizontal fissure of the right lung. Retrospective review of chest radiographs taken at a previous health checkup confirmed that the tumor was growing. The patient had no symptoms, and computed tomography and magnetic resonance imaging suggested that the tumor was a hamartoma. The tumor was resected by video-assisted thoracic surgery, and was diagnosed by pathological analysis as an intrathoracic lipoma consisting of no atypical fats.

A population-based study of outcomes in patients with surgically resected non-small cell lung cancer with anaplastic lymphoma kinase-rearranged mutations: A matched-pair study.

The present study aimed to evaluate clinical outcomes in patients with surgically resected non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK)-rearranged mutations. A matched-pair analysis in completely resected ALK-rearranged NSLC patients and those with neither ALK nor epidermal growth factor receptor (EGFR) mutations diagnosed at 11 institutes was performed between April 2008 and March 2019. A total of 51 patients with surgically resected ALK-rearranged NSCLC were included. Women constituted 68.6%, and smokers 29.4%. The median age was 65 years. In matched-pair analysis, disease-free survival and overall survival did not differ between patients with ALK-rearranged mutations and those without mutations. Post-recurrence survival in patients with ALK mutations was longer than that of patients with neither ALK nor epidermal growth factor receptor mutations. ALK genetic testing should be performed, even in elderly patients with NSCLC. Favorable prognosis might be expected after appropriate treatment for patients with recurrent ALK-mutated disease.

The role of airway stent placement in the management of tracheobronchial stenosis caused by inoperable advanced lung cancer.

PURPOSE: To our knowledge there is no in-depth report on the benefits of airway stenting, which focuses specifically on patients with inoperable advanced lung cancer causing severe central airway obstruction. We evaluated the role of airway stenting as one aspect of the multidisciplinary management of advanced lung cancer. METHODS: We performed airway stenting in 40 lung cancer patients, placing a total of 58 stents. Stenting was done as a final modality in 22 patients with terminal-stage lung cancer (group A). The other 18 patients received additional therapy after stenting (group B), 12 (66.7%) of whom were treatment-naïve on admission. RESULTS: The performance status (PS) and Hugh-Jones classification (H-J) scores improved in both groups after stenting: from 3.56 to 2.48 (P = 0.001) and 4.29 to 3.20 (P = 0.004) in group A, and from 3.15 to 1.25 (P < 0.001) and 4.10 to 2.10 (P < 0.001) in group B, respectively. The median survival time and 1-year survival rate after stenting were 1.6 months and 5.1%, respectively, in group A, and 5.6 months and 25.0%, respectively, in group B. CONCLUSIONS: Airway stenting followed by adjuvant therapy may improve the survival of treatment-naïve patients with severe symptomatic airway obstruction caused by advanced lung cancer.