[Typical Carcinoid of the Lung with Abnormal Elevation of Serum Pro-gastrin-releasing Peptide (ProGRP)].

A 40-year-old male was referred to our hospital because of a nodular shadow detected in the left lower lobe with the tendency to increase gently. Because fluoro-2-deoxy-D-glucose (FDG) uptake was extremely low on a FDG positron emission tomography (PET-CT), the tumor was highly suspected of the benign tumor. Five years later, a follow-up computed tomography (CT) showed the shadow to be enlarged. FDG uptake was changed to be high, and serum level of pro-gastrin-releasing peptide (Pro-GRP) was extremely elevated. Surgical treatment was chosen under suspicious diagnosis of neuroendocrine tumor, such as small cell carcinoma, large cell neuroendocrine carcinoma, and carcinoid. By the intraoperative aspiration cytology, a small cell carcinoma or a carcinoid was suspected and left lower lobectomy with systemic lymph node dissection was performed. The final histological diagnosis was a typical carcinoid. The elevated serum ProGRP immediately decreased to normal postoperatively.

Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: a multicenter randomized controlled trial.

BACKGROUND: We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non-small cell lung cancer patients. METHODS: Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival. RESULTS: From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1-3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94). CONCLUSIONS: The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1-3 elevation of bilirubin. TRIAL REGISTRATION: This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

Prognostic factors after pulmonary metastasectomy for colorectal cancer and rationale for determining surgical indications: a retrospective analysis.

OBJECTIVE: We aimed to identify prognostic factors after pulmonary metastasectomy for colorectal cancer and propose the clinical application of them. Furthermore, we endeavored to provide a rationale for pulmonary metastasesectomy. BACKGROUND: Several prognostic factors have been proposed, but clinical application of them remains unclear. Moreover, there is no theoretical evidence that pulmonary metastasectomy is indicated for colorectal cancer. METHODS: We retrospectively analyzed 1030 patients who underwent pulmonary metastasectomy for colorectal cancer from 1990 to 2008. Prognostic factors were identified and the relationship of recurrent sites after pulmonary resection to pulmonary tumor size was assessed. RESULTS: Overall 5-year survival was 53.5%. Median survival time was 69.5 months. Univariate analysis showed tumor number (P < 0.0001), tumor size (P < 0.0001), prethoracotomy serum carcinoembryonic antigen (CEA) level (P < 0.0001), lymph node involvement (P < 0.0001), and completeness of resection (P < 0.0001) to significantly influence survival. In multivariate analysis, all remained independent predictors of outcome. In patients whose recurrent sites extended downstream from the lung via hematogenous colorectal cancer spread, pulmonary tumor size was significantly larger than in those with recurrent sites confined to the lung and regions upstream from the lung. CONCLUSIONS: We should utilize these prognostic factors to detect patients who might benefit from surgery. Therefore, we should periodically follow up advanced colorectal cancer patients by chest computed tomography to detect small pulmonary metastases before serum CEA elevation. Metastases to the lung or organs upstream from the lung are regarded as semi-local for colorectal cancer. This concept provides a rationale for validating surgical indications for pulmonary metastases from colorectal cancer.

Delivery system for autologous growth factors fabricated with low-molecular-weight heparin and protamine to attenuate ischemic hind-limb loss in a mouse model.

Frozen and thawed platelet-rich plasma (PRP) contains high concentrations of various growth factors, such as fibroblast growth factor (FGF)-2, vascular endothelial growth factor, and hepatocyte growth factor. We previously reported that low-molecular-weight heparin/protamine microparticles (LH/P MPs) are useful as biodegradable carriers for the controlled release of FGF-2. In this study, we examined the ability of PRP/LH/P MPs to prevent limb loss in an induced ischemic hind-limb model that used adult BALB/c-nu/nu male mice. One day after inducing ischemia, intramuscular injections of a PRP/LH/P MPs solution were administered into several sites of the ischemic hind limb. Seven days and onward after the injections, the PRP/LH/P MPs-treated and PRP-treated groups recovered from ischemia, as reflected by the improved oxygen saturation. In the PRP-treated group, however, the level of recovery of oxygen saturation after ischemia decreased after 14 days. From the 21st day onward, there was a significant difference between those two groups. In the LH/P MPs-treated group, a partial recovery occurred only in the early period. The saline-treated group (i.e., the control) and the noninjection group (i.e., ischemia only) exhibited no recovery. The limb survival rate at 1 year in the ischemia-induced mice injected with PRP/LH/P MPs was approximately 25 % (two of eight mice) but was absent in the other groups.

Successful salvage surgery followed by second ALK-TKI after alectinib failure in a patient with ALK-positive NSCLC.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) have been approved for the therapy of locally advanced non-small cell lung cancer (NSCLC) caused by ALK rearrangement. However, its treatment after failure of initial ALK-TKI therapy remains controversial. CASE PRESENTATION: A 47-year-old woman with a hemosputum was diagnosed with adenocarcinoma of the left lung (cT2bN3M0, stage IIIB). Gene mutation analysis indicated positive ALK translocation. Alectinib was selected as the first-line treatment. Although the treatment effect was determined as a partial response, the main tumor regrew. Alectinib was discontinued, and salvage surgery was performed without causing morbidity. The pathological diagnosis was pleomorphic carcinoma without lymph node metastasis (yp-T2bN0). After surgery, lorlatinib was administered as the second-line treatment for 8 months until the patient could not tolerate continuation. Computed tomography scan revealed no lung cancer recurrence 14 months after discontinuation. CONCLUSIONS: Our experience with this case suggests that salvage surgery after alectinib treatment followed by lorlatinib therapy may be effective for initially unresectable ALK-positive NSCLC.

Aberrant mediastinal mediobasal segmental pulmonary artery in a patient with lung cancer undergoing right lower lobectomy: a case report.

BACKGROUND: A mediastinal mediobasal segmental pulmonary artery (A7) from the right main pulmonary artery is extremely rare. CASE PRESENTATION: We report the case of a 71-year-old woman with an aberrant mediastinal A7 who underwent right lower lobectomy for lung cancer (cT1bN0M0, stage IA2). Preoperative three-dimensional computed tomography (CT) angiography revealed an aberrant mediastinal A7 in the right main pulmonary artery. Right lower lobectomy and mediastinal lymph node dissection were performed. Intraoperatively, A7 was observed between the superior and inferior pulmonary veins and in the front of the lower bronchus near the anterior hilum. The artery was carefully dissected from the caudal side after inferior pulmonary vein dissection. The lung parenchyma, which was within the fissure due to poor lobulation between the middle and lower lobes, was safely divided. CONCLUSIONS: Thoracic surgeons need to carefully evaluate CT angiography or enhanced multidetector CT findings at preoperative conferences and always keep this anomaly in mind.

Pleural defect repair with an overlapping method using fibrin glue-coated collagen fleece.

PURPOSE: Collagen fleece coated with fibrin glue (TachoComb; CSL Behring, Tokyo, Japan) is a tissue adhesive and sealant used to stop hemorrhage and air leakage. We assessed the efficacy of overlapping methods combined with the use of TachoComb to repair pleural defects. METHODS: Using a beagle animal model, circular and square defects were created on the pulmonary pleura and then repaired with TachoComb patches of varying minimum overlap widths (MOW). The airway pressure at which air leakage from the repaired region occurred (bursting pressure) was measured in a water sealing test. The ability of TachoComb to withstand temporal changes was assessed by repairing a 6-mm circular defect. The bursting pressure was measured at 5 min, 10 min, 3 h, and 24 h after the repair. RESULTS: TachoComb patches with an MOW ≥ 6 mm withstood significantly higher pressures than patches with an MOW ≤ 3 mm for both circular and square defects. The bursting pressure was found to increase over time for up to 3 h after being applied, indicating that adhesion of the TachoComb patch to the pleural tissue improved during the 3-h period. CONCLUSION: Pleural defects repaired using an overlapping method with an MOW of 6 mm were able to withstand airway pressures ≥ 40 cmH(2)O.

Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology.

In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing taste-masked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These findings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).

Efficacy of peritoneal oxygenation using a novel artificial oxygen carrier (TRM-645) in a rat respiratory insufficiency model.

PURPOSE: Supplemental oxygenation is essentially important in critically ill patients with potentially reversible pulmonary insufficiency. An extracorporeal membrane oxygenator and percutaneous cardiopulmonary support have been used for these patients. However, these techniques are associated with so many complications that an additional new therapeutic modality is required. The purpose is to investigate if the peritoneal cavity can be used as "extrapulmonary respiration" that is analogous to peritoneal dialysis and utilizes the efficacy of liposome-encapsulated hemoglobin (artificial oxygen carrier; TRM-645). METHODS: Rats weighing an average of 300 g (n = 18) received an incision in the right chest to generate pneumothorax, which resulted in severe and lethal hypoxia. Oxygenated TRM-645 and human red blood cells (MAP group) were administered into the peritoneum in the experimental rats' pneumothorax model. No treatment except the right pneumothorax was administered to the sham group. RESULTS: Survival times from the pneumothorax were significantly longer in the TRM-645 and MAP groups than in the sham group (32.0 +/- 6.9 and 22.0 +/- 4.9 min vs 9.2 +/- 1.9 min, P < 0.01). In addition, an arterial blood gas analysis showed that the oxygenation in levels significantly improved. CONCLUSIONS: The abdomen (peritoneum) can potentially become an "artificial lung" that can be employed in critical care settings. TRM-645 provides an alternative to the use of washed human red blood cells.

[Bronchial carcinoid discovered due to repeated pneumonia in the lingular division of the left lung; report of a case].

Bronchial carcinoids are relatively rare, low-grade malignancies. Here we report a case of a bronchial carcinoid found by repeated pneumonia in the lingular division of the left lung. A 34-year-old man was referred to our hospital because of an abnormal shadow detected in an annual checkup. A chest computed tomography (CT) showed an infiltrative shadow in the lingular division. Two months later, a follow-up CT showed the shadow had remarkably improved. Two years after the 1st detection, an annual checkup revealed an abnormal shadow in the same lesion again. A chest CT showed not only an infiltrative shadow in the lingular division, but also a solid mass with calcification in the lingular bronchus. A bronchoscopy revealed an obstruction of the left upper lobe bronchus by a vascularized polypoid tumor. A transbronchial biopsy indicated a presence of a carcinoid, and a resection of the left upper lobe was performed. A histopathological examination showed that it was a typical carcinoid. The patient has been free of recurrence for 2 years since surgery. This is a case with repeated pneumonia and atelectasis caused by a bronchial carcinoid.

[Bronchoscopic follow-up of secondary racemose hemangioma of the bronchial artery].

A 63-year-old woman with cystic bronchiectasis who had been treated in our institute was admitted for recurrent prolonged hemoptysis. Bronchoscopic examination showed bloody discharges in the left basal bronchus and a bulging polypoid lesion covered with intact bronchial mucosa in the left B8. In comparison with the bronchoscopic examination 6 years ago, the lesion was larger and the mucosal color changed more injected. A bronchial arteriogram revealed a convoluted and dilated left bronchial artery. Because bronchial artery embolization failed, a left lower lobectomy was performed. The diagnosis of secondary racemose hemangioma of the bronchial artery was pathologically established. A racemose hemangioma of the bronchial artery is characterized by an enlarged and convoluted bronchial artery. The bronchoscopic findings of this disorder have been rarely reported. This case may provide valuable information about serial bronchoscopic findings and the progression of secondary racemose hemangioma in the bronchial artery.

Amelioration of airway stenosis in rabbit models by photodynamic therapy with talaporfin sodium (NPe6).

It is difficult to treat patients with acquired airway stenosis, and the quality of life of such patients is therefore lowered. We have suggested the application of photodynamic therapy (PDT) as a new treatment for airway stenosis and have determined the efficacy of PDT in animal disease models using a second-generation photosensitizer with reduced photosensitivity. An airway stenosis rabbit model induced by scraping of the tracheal mucosa was administered NPe6 (5 mg kg(-1)), and the stenotic lesion was irradiated with 670 nm light emitted from a cylindrical diffuser tip at 60 J cm(-2) under bronchoscopic monitoring. PDT using NPe6 improved airway stenosis (P = 0.043) and respiratory stridor. A significant prolongation of survival time was seen in the PDT-treated animals compared to that in the untreated animals (P = 0.025) and 44% of the treated animals achieved long-term survival (>60 days). In conclusion, PDT using NPe6 is effective for improvement in airway stenosis.

[Analysis of endobronchial aspergillosis in patients without obvious systemic predisposing factors].

BACKGROUND: Endobronchial aspergillosis is still an insufficiently recognized concept. PATIENTS AND METHODS: Ten patients who did not have obvious predisposing factors and parenchymal fungal infection were analyzed. They were confirmed to have endobronchial Aspergillus by histology and culture, and were classified according to the presence of bronchiectasis, allergic reaction, and asthmatic symptom. RESULTS: Bronchiectasis was detected in all 10 patients, IgE elevation (>370 IU/ml) in 7, Aspergillus specific IgE-RAST in 8, eosinophilia in 7, and asthmatic symptom in 5. Cases were classified into allergic bronchopulmonary aspergillosis (ABPA) (5 cases), ABPA not fulfilling Rosenberg's criteria (2 cases), and endobronchial aspergilloma (3 cases). CONCLUSION: We proposed classifying endobronchial aspergillosis without obvious systemic predisposing factors into "ABPA", "ABPA without asthma", "ABPA-S (seropositive)", and "Endobronchial aspergilloma". A fifth subtype of endobronchial aspergillosis containing "saprophyte" is warranted.

Expressions of ATF6, XBP1, and GRP78 in normal tissue, atypical adenomatous hyperplasia, and adenocarcinoma of the lung.

Little is known about the association between the atypical adenomatous hyperplasia (AAH)-adenocarcinoma in situ sequence of the lung and endoplasmic reticulum-stress responders such as ATF6, XBP1, and GRP78. Using stored tissues, we examined (i) the percentage of a splicing form (active form) of XBP1 messenger RNA in normal lung tissue (NLT) and adenocarcinoma (ACA; using reverse-transcription polymerase chain reaction); (ii) ATF6 and GRP78 protein expressions in NLT and ACA (using Western blotting analysis); (iii) ATF6, XBP1, and GRP78 protein expressions in NLT, AAH, and ACA, including some adenocarcinoma in situ (using immunohistochemistry); and (iv) the incidence of nuclear translocation of the 3 proteins in these lesions. The percentage of the splicing form of XBP1 messenger RNA showed a borderline difference between NLT and ACA (P = .068). In the Western blotting analysis, the nuclear fractions of ATF6 (including the active form) and GRP78 proteins were higher in ACA than in NLT. In the immunohistochemistry, the values obtained for the incidence of the nuclear translocation of ATF6, XBP1, and GRP78 proteins were as follows, respectively: 13.3%, 2.2%, and 0.5% in low-grade AAH; 37.9%, 2.3%, and 2.2% in high-grade AAH; and 47.2%, 10.6%, and 4.4% in ACA. A significant difference was detected between low-grade AAH and ACA for ATF6. In terms of nuclear translocation, high-grade AAH seemed intermediate between low-grade AAH and ACA. These results support endoplasmic reticulum-stress responses, such as nuclear translocation of these 3 proteins (including their active forms), being in parallel with the progression of the adenoma-carcinoma sequence in the lung.

Photodynamic therapy for airway stenosis in rabbit models.

BACKGROUND: Acquired airway stenosis in childhood is resistant to conventional treatment. We examined whether endoscope-assisted photodynamic therapy (PDT) is effective for airway stenosis in animal models of which the pathophysiologic progressions are similar to those of clinical cases showing rapid deterioration. METHODS: Tracheal mucosa-scraped rabbits were administered IV porfimer sodium (Photofrin; Wyeth K.K., Tokyo, Japan) [2 mg/kg], and the tracheal lesions were irradiated with 630 nm of light emitted from a cylindrical diffuser tip via a transtracheal approach. RESULTS: Rabbits without PDT (untreated animals) showed dense granulation tissue in the scraped lesion, resulting in airway stenosis complicated with respiratory stridor. PDT ameliorated the degree of airway stenosis (p = 0.008) and reduced respiratory stridor; rabbits that received PDT showed patchy granulation tissue that was only 20 to 30% of the volume of that seen in the untreated animals. Survival time of rabbits that received PDT was significantly prolonged compared with that of untreated animals (p = 0.03). CONCLUSIONS: PDT was effective for airway stenosis in rabbit models. This suggests that PDT has the potential as a new therapeutic method for airway stenosis originating from granulation tissue.

18F-FDG-PET/CT as an indicator for resection of pulmonary epithelioid hemangioendothelioma.

A 60-year-old man with a 7-year history of multiple pulmonary nodules presented to our hospital because the nodules were seen to have increased in size on review of films on a regular medical checkup 1 week earlier. Computed tomography (CT) revealed multiple pulmonary nodules with calcification in the lungs. The largest nodule measuring 2.5 cm in the maximum dimension was lobulated and ill-defined. The patient underwent 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT) to evaluate the multiple nodules and to search for a primary lesion. 18F-FDG-PET/CT revealed increased uptake in only two nodules with a standardized uptake value of 4.61 and 2.10, respectively. The two foci with increased 18F-FDG uptake were resected and pathologically proven to be pulmonary epithelioid hemangioendothelioma (PEH). PEH can transform into malignancy with metastasis. An 18F-FDG-PET/CT finding may be an indicator to decide on PEH resection.

[Drug delivery to the colon using novel one-step, dry-coated tablets (OSDrC)].

One-step dry-coated tablets (OSDrC), which are useful as colon-targeting drugs, were prepared using Eudragit L 100-55 (Eud-L) and chitosan (Chit) as an outer layer. The lag time of OSDrC with an outer layer of Eud-L : Chit at a ratio of 3 : 1 in each test medium was greater than the gastric emptying time in the first fluid simulating the stomach and was greater than the small intestine transit time in phosphate buffer (pH 7.4) simulating the small intestine. Drug-release profiles of OSDrC were evaluated under test conditions considering the amount of gastric acid and bile acid, as well as the amount of fluid in the colon. The lag time of OSDrC was greater than the gastric emptying time in test medium simulating the stomach and greater than the small intestine transit time in test medium simulating the small intestine, although it was affected by the amount of gastric acid and bile acid. Drug release from OSDrC was completed within the colonic transit time in the test medium simulating the colon, although it was affected by the amount of fluid in the colon. Therefore the prepared OSDrC were found to permit drug delivery to the colon.

[Bird-related chronic hypersensitivity pneuminitis demonstrating the fluctuation of disease activity accompanied with environmental changes].

We report a case of bird-related chronic hypersensitivity pneuminitis exhibiting the fluctuation of serum markers for interstitial lung disease along with the changes in life environment. A 65-year-old man had had an abnormal chest radiograph for 2 years and had complained of a non-productive cough. He had had 30 parakeets 20 years previously and had used feather products for 15 years. In autumn and early winter wild birds had visited persimmons trees in the neighboring garden. Antibodies to bird-related antigens in the broncho-alveolar lavage fluids and sera were positive and the thoracoscopic lung biopsy specimens histologically revealed airway-centered fibrosis. We then determined he was having bird-related chronic hypersensitivity pneumonitis. After avoidance of feather products, all of serum SP-A, SP-D and KL-6 decreased. But three markers elevated and radiographic findings worsened accompanied with the increase of visiting wild birds in next autumn. After pruning persimmon trees and starting corticosteroid with cyclosporine, disease activity gradually improved.

[A case of HTLV-1 associated bronchiolo-alveolar disorder showing progressive air trapping].

A 65-year-old woman whose parents were from Okinawa Prefecture, had productive cough and bilateral diffuse nodular lesions on chest X-ray. She had been shown a human T-cell lymphotropic virus type-1 (HTLV-1) carrier. Video-assisted thoracoscopic lung biopsy showed marked peribronchiolar infiltration of lymphocytes and stenosis of bronchioles. HTLV-1 associated bronchiolo-alveolar disorder (HABA) was diagnosed. The symptoms, hypoxemia and chest X-ray findings improved with oral erythromycin. However, expiratory chest CT showing mosaic perfusion, pulmonary function test demonstrating increased thoracic gas volume, and ventilation scintigraphy resulting in decreased clearance during 8 years, all of those findings indicated progression of air trapping. Abnormalities on chest CT partially improved, but bronchiolar lesions have deteriorated. Expiratory chest CT, body phlethysmography and ventilation scintigraphy were recommended to clarify the course of HABA.

[A case of idiopathic bronchial artery aneurysm connecting to the pulmonary artery].

Case. A 54-year old woman was found to have an abnormal shadow in a regular checkup chest X-ray film. We suspected a bronchial artery aneurysm based on a contrast-enhanced chest CT. Aortography, bronchial arteriography and pulmonary arteriography showed a bronchial artery aneurysm, 2 cm in diameter, connecting the right bronchial artery, inferior phrenic artery, and pulmonary artery. Bronchoscopy revealed dilatation and hypervascularity of moniliform submucosal vessels below the right truncus intermedius. She underwent bronchial artery embolization several times, but new feeding vessels developed each time. We considered this case required surgical resection. Bronchoscopy after aneurysmectomy revealed decrease of moniliform submucosal vessels. Histological examination revealed a three-layer structure leading to both the pulmonary and bronchial arteries. Conclusion. We diagnosed idiopathic bronchial artery aneurysm connecting to a pulmonary artery.