A spatio-temporal image analysis for growth of indeterminate pulmonary nodules detected by CT scan.

The objective is to evaluate the performance of computational image classification for indeterminate pulmonary nodules (IPN) chronologically detected by CT scan. Total 483 patients with 670 abnormal pulmonary nodules, who were taken chest thin-section CT (TSCT) images at least twice and resected as suspicious nodules in our hospital, were enrolled in this study. Nodular regions from the initial and the latest TSCT images were cut manually for each case, and approached by Python development environment, using the open-source cv2 library, to measure the nodular change rate (NCR). These NCRs were statistically compared with clinico-pathological factors, and then, this discriminator was evaluated for clinical performance. NCR showed significant differences among the nodular consistencies. In terms of histological subtypes, NCR of invasive adenocarcinoma (ADC) were significantly distinguishable from other lesions, but not from minimally invasive ADC. Only for cancers, NCR was significantly associated with loco-regional invasivity, p53-immunoreactivity, and Ki67-immunoreactivity. Regarding Epidermal Growth Factor Receptor gene mutation of ADC-related nodules, NCR showed a significant negative correlation. On staging of lung cancer cases, NCR was significantly increased with progression from pTis-stage 0 up to pT1b-stage IA2. For clinical shared decision-making (SDM) whether urgent resection or watchful-waiting, receiver operating characteristic (ROC) analysis showed that area under the ROC curve was 0.686. For small-sized IPN detected by CT scan, this approach shows promise as a potential navigator to improve work-up for life-threatening cancer screening and assist SDM before surgery.

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.

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.

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.

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.

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.

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.

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.

Comparison of the amino acid profile between the nontumor and tumor regions in patients with lung cancer.

Energy metabolism in cancer cells is reprogrammed to meet the energy demands for cell proliferation under strict environments. In addition to the specifically activated metabolism of cancer, including the Warburg effect and glutaminolysis, most amino acids (AAs) are utilized for gluconeogenesis. Significant increases in AAs and energy metabolites in the tumor region occur in gastric and colon cancers. However, a different AA-related energy metabolism may exist in lung cancer because of the abundant blood supply to lung tissue. This study compared the profiles of AAs and their related metabolites in energy metabolism, analyzed by an HPLC-MS/MS system, between tissues from nontumor and tumor regions collected from 14 patients with non-small cell lung cancer (NSCLC). In the energic metabolism precursor categories, the glucogenic AAs, which included the pyruvate precursors (Ser, Gly, Thr, Ala, and Trp), the α-ketoglutarate precursors (Glu, Gln, and Pro) and the succinyl-CoA precursors (Val, Ile, and Met) were significantly increased in the tumor region compared to in the nontumor region. However, no significant differences existed between the two regions in the ketogenic AAs (Leu, Lys, and Tyr). These differences were not observed between the subgroups with and without diabetes mellitus in the two regions. The metabolites on the left-hand side of the TCA cycle were significantly higher in the tumor region, but no differences in metabolites in the right-hand side. The mRNA expressions of major AA transporters and cancer proliferation factors were also significantly increased in the tumor region, compared to these in their counterparts. In lung cancer, glucogenic AAs that are actively transported from circulating fluids would be predominantly utilized for gluconeogenesis, with and without diabetes mellitus. The characteristics of the AA-related metabolism would be associated with tissue-specific cell proliferation in patients with NSCLC.

A combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent.

The aim of this study was to evaluate the feasibility of a combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent (gold studded stent [GSS]). Laser irradiation (664 nm, continuous wave) was performed through the GSS using a straight and cylindrical fiber 1.0 cm away from a power meter. There are two types of GSS: the TD type for the trachea and the BD type for the bronchus. Laser outputs were set to 150 mW, 180 mW, 210 mW, 240 mW, 270 mW, and 300 mW. The laser powers passing through the both types of GSS were measured three times for each outputs and the averages were calculated. Based on the results, animal experiment was performed using two female pigs. Under general anesthesia, a GSS (BD type) was inserted into trachea of pigs, and PDT using NPe6 as a photosensitizer was performed by 100 J/cm2 laser irradiation on parts of the trachea with and without a GSS. Immediately after and 1 week after PDT, pig tracheas were harvested and histological analysis was performed. Histological analysis of areas with or without the stent showed edematous changes between the cartilage and submucosal layer immediately after PDT, and necrotic changes 1 week later. The effectiveness of NPe6-PDT for pigs' trachea covered by the stent was same as trachea without the stent. The use of a GSS may enable PDT to be effective even in the area covered by the stent.

Skin fluorescence following photodynamic therapy with NPe6 photosensitizer.

BACKGROUND: The second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patient's photosensitive period. METHODS: The NPe6 fluorescence measurements using a constructed fluorescence sensing system at the inside of the arm were acquired prior to and 5 and 10min after NPe6 administration as well as at the time of PDT (4-5h after administration), at discharge (2 or 3days after PDT), and at 1 or 2 weeks after PDT. Participants were interviewed as to whether they had any complications at 2 weeks after PDT. RESULTS: Nine male patients and one female patient entered this study. Nine patients were inpatients and one patient was an outpatient. All of the measurements of NPe6 fluorescence in the skin could be obtained without any complications. The spectral peak was detected at the time of discharge (2-3days after administration) in most cases and it decreased at 1 or 2 weeks after PDT. CONCLUSIONS: The fluorescence of NPe6 in the skin could be detected feasibly using the fluorescence sensing system in human patients. Measuring the relative concentration of NPe6 in the skin indirectly by measuring fluorescence intensity might be useful to predict the period of skin photosensitivity after PDT.

Low-fat diet management strategy for chylothorax after pulmonary resection and lymph node dissection for primary lung cancer.

OBJECTIVE: We reviewed our experience of iatrogenic chylothorax after pulmonary resection for primary lung cancer to evaluate a low-fat diet management strategy. METHODS: From October 2003 to March 2010, 1580 patients underwent lobectomy or greater resection and systematic mediastinal lymph node dissection for primary lung cancer at our institution. Chylothorax was diagnosed on the basis of chylous leakage from the chest tube and was confirmed by presence of triglycerides (>110 mg/dL) in the drainage fluid. We initially treated the patients with chylothorax conservatively with a low-fat diet (fat intake <10 g/day). If chest tube drainage produced >500 mL of chylous fluid during the first 24 hours after the initiation of the low-fat diet, surgical intervention was performed. If chest tube drainage produced >300 mL/day of chylous fluid after 3 days of a low-fat diet, we performed pleurodesis by injecting a preparation of OK-432, a penicillin-treated lyophilized preparation of a Streptococcus strain into the thoracic cavity through a chest tube. RESULTS: Postoperative chylothorax developed in 37 patients (2.3%), 33 men and 4 women, with a median age of 69 years (range, 44-84). The initial procedures were pneumonectomy in 1 patient and lobectomy in 36 patients. In 23 patients (62%), their condition resolved with the low-fat diet only. A total of 10 patients underwent OK-432 pleurodesis, and 8 of these were cured with continuation of the low-fat diet. These 31 patients who responded to conservative treatment (84%) resumed a normal diet at a median of 10 days (range, 5-27) after the chylothorax diagnosis. The remaining 6 patients (16%) underwent reoperation and were discharged at a median of 18 days (range, 14-33) after the initial surgery. CONCLUSIONS: A low-fat diet and OK-432 pleurodesis achieved positive results in >80% of patients with chylothorax after pulmonary resection with systematic mediastinal lymph node dissection within 4 weeks after the initial surgery. More than 500 mL of chylous fluid during the first 24 hours after the initiation of the low-fat diet was valid as an indication of the need for surgical intervention.

Clinicopathological characteristics of EGFR mutated adenosquamous carcinoma of the lung.

Adenosquamous carcinoma of the lung (Ad-Sq) is an uncommon subtype with poor prognosis. We analyzed the clinicopathological characteristics of Ad-Sq, focusing the correlation between Epidermal Growth Factor Receptor (EGFR) mutation and clinicopathological factors. A total of 67 cases were selected from September 1992 to May 2011. EGFR mutational analysis (n = 59) was performed by direct sequence. We also performed immunohistochemical staining for EGFR mutated cases using the two mutation-specific antibodies for deletion and L858R. Postoperative 3-year survival rate of Ad-Sq was 58.7%, statistically worse in comparison with adenocarcinoma (58.7% vs. 78.1%, P = 0.038). Twenty-four percent (14/59) were positive for EGFR mutations. Patients who had never been smokers and who were lymphatic permeation positive were seen more frequently in the mutation positive group (P = 0.035, 0.027, respectively). Moreover, the EGFR mutated group tended to have a more positive prognosis than negative. Focusing on the pathological features, the lepidic growth pattern was more frequently seen in the positive group (P = 0.018). Immunoreactivity for the DEL-specific and L858-specific antibody were observed in both adenocarcinoma and squamous cell carcinoma components. Our study demonstrated that EGFR mutated Ad-Sq had similar clinicopathological features as EGFR mutated adenocarcinoma.

Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype.

BACKGROUND: The prognostic significance of the tumor microenvironment, which is created by both cancer cells and cancer-associated fibroblasts (CAFs), has been increasingly recognized. The purpose of this study was to analyze the prognostic markers of stage I squamous cell carcinoma (SqCC), with special reference to the immunophenotypes of both cancer cells and CAFs. METHODS: A total of 142 patients with stage I SqCC were included in this study. We examined the expressions of E-cadherin, laminin-5, podoplanin, c-MET, carbonic anhydrase IX (CA-IX), CD10, and CD44 in the cancer cells and those of podoplanin, CA-IX, CD10, and CD44 in the CAFs to evaluate their prognostic value. RESULTS: Patients with low E-cadherin expression in the cancer cells showed a significantly poorer prognosis than those with high E-cadherin expression in the cancer cells ( P , .001). On the other hand, high podoplanin expression in the CAFs was also associated with a significantly poorer prognosis ( P , .001). A multivariate analysis identified low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs as significantly independent prognostic factors for overall survival ( P 5 .013 and P 5 .0011, respectively). According to subgroup analyses combining E-cadherin expression in cancer cells and podoplanin expression in CAFs, 5-year overall survival of patients with low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs was 7.0% and showed a significantly poorer prognosis as compared with other groups ( P , .001). CONCLUSIONS: The current study indicates that immunophenotypes of CAFs could have a prognostic value independent of those of the cancer cells in SqCC.

Prognostic impact of CD204-positive macrophages in lung squamous cell carcinoma: possible contribution of Cd204-positive macrophages to the tumor-promoting microenvironment.

INTRODUCTION: Tumor-associated macrophages (TAMs) are recruited into cancer-induced stroma and produce a specific microenvironment for cancer progression. CD204 (+) TAMs are reportedly related to tumor progression and clinical outcome in some tumors. The aim of this study was to clarify the correlation between CD204 (+) TAMs and the clinicopathological features of lung squamous cell carcinoma. METHODS: We investigated the relationships between the numbers of CD204 (+) TAMs and clinicopathological factors, microvessel density, and the numbers of Foxp3 (+) lymphocytes in 208 consecutively resected cases. We also examined the relationships between the numbers of CD204 (+) TAMs and the expression levels of cytokines involved in the migration and differentiation of CD204 (+) TAMs. RESULTS: A high number of CD204 (+) TAMs in the stroma was significantly correlated with an advanced p-stage, T factor, N factor, and the presence of vascular and pleural invasion. A high number of CD204 (+) TAMs in the stroma was also a significant prognostic factor for all p-stages and p-stage I. Moreover, the numbers of CD204 (+) TAMs were correlated with the microvessel density and the numbers of Foxp3 (+) lymphocytes. A high number of CD204 (+) TAMs was strongly correlated with the tissue expression level of monocyte chemoattractant protein-1. CD204 (+) TAMs were shown to be significant independent prognostic factors in a multivariate analysis. CONCLUSIONS: CD204 (+) TAMs were an independent prognostic factor in lung squamous cell carcinoma. CD204 (+) TAMs, along with other tumor-promoting stromal cells such as regulatory T cells and endothelial cells, may create tumor-promoting microenvironments.