Sustained-Release Tacrolimus Stabilizes Decline of Forced Expiratory Volume in 1 Second Through Decreasing Fluctuation of Its Trough Blood Level.

BACKGROUND: Calcineurin inhibitors are a commonly used immunosuppressive drug and over 80% of lung transplant (LTx) recipients use tacrolimus. Sustained-release tacrolimus (SRT) was developed as a once-daily formulation, resulting in slower release and reduction in peak concentration compared with twice-daily immediate-release tacrolimus (IRT). Previous reports indicate that SRT may carry fewer side effects than IRT; however, the impact of SRT in bronchiolitis obliterans syndrome (BOS) after LTx is unclear. OBJECTIVE: Our study objective was to evaluate the effect of SRT in BOS after LTx. MATERIALS AND METHODS: We investigated the effect of SRT for BOS among 75 LTx recipients who were alive in 2017 in our LTx program. All analyses were carried out using student t test or F test. RESULTS: Thirty-five recipients took IRT, 32 recipients used SRT, 7 recipients used cyclosporine, and 1 patient who received bone marrow and a lung graft from the same donor did not use a calcineurin inhibitor. The most frequent reason for conversion of IRT to SRT was kidney dysfunction, followed by other IRT complications. Five recipients underwent conversion of IRT to SRT because of decline of forced expiratory volume in 1 second (FEV1) with fluctuation of the tacrolimus trough level. After induction of SRT, the fluctuation of the tacrolimus trough level was significantly reduced in 4 of 5 patients (P < .05). Before drug form conversion, the FEV1 in these 5 patients was significantly decreased; however, this exacerbation of FEV1 was attenuated after SRT induction (P < .05). CONCLUSION: SRT appeared to stabilize decline of FEV1 in patients with BOS possibly due to reducing the fluctuation of tacrolimus trough blood concentration.

Endobronchial Topical Amphotericin B Instillation for Pulmonary Chromomycosis After Lung Transplantation: A Case Report.

We report a very rare case of pulmonary chromomycosis caused by Scedosporium prolificans that developed after lung transplantation and was successfully treated with endobronchial topical amphotericin B instillation. The subject was a woman in her 50s with a history of bilateral lobar lung transplantation from living donors for idiopathic pulmonary hypertension. Eight years after the lung transplantation, chest radiography X-ray and computed tomography showed an abnormal shadow in the right lung. Bronchoscopic findings showed obstruction by a fungal component at the laterobasal bronchus B9. She was diagnosed with pulmonary chromomycosis after S. prolificans was detected in the bronchial aspirate. Systemic antifungal treatment with itraconazole was ineffective. Therefore, we administered topical amphotericin B weekly via endobronchial instillation and replaced oral itraconazole with voriconazole. The endobronchial procedure was safe and tolerable. Bronchial obstruction improved after three 3 instillations. We continued topical amphotericin B instillation once every 3 months for 2 years, and the abnormal shadow nearly disappeared. This case report describes infection by S. prolificans, which rarely becomes an etiologic agent in lung transplant patients, and shows that endobronchial topical amphotericin B instillation is a therapeutic option when systemic antifungal treatment is ineffective.

Cytotoxicity of Natural Killer Cells Activated Through NKG2D Contributes to the Development of Bronchiolitis Obliterans in a Murine Heterotopic Tracheal Transplant Model.

Bronchiolitis obliterans after lung transplantation is a major cause of postoperative mortality in which T cell-mediated immunity is known to play an important role. However, the exact contribution of natural killer (NK) cells, which have functions similar to CD8+ T cells, has not been defined. Here, we assessed the role of NK cells in murine bronchiolitis obliterans through heterotopic tracheal transplantations and found a greater percentage of NK cells in allografts than in isografts. Depletion of NK cells using an anti-NK1.1 antibody attenuated bronchiolitis obliterans in transplant recipients compared with controls. In terms of NK cell effector functions, an improvement in bronchiolitis obliterans was observed in perforin-KO recipient mice compared to wild type (WT). Furthermore, we found upregulation of NKG2D-ligand in allografts and demonstrated the significance of this using grafts expressing Rae-1, a murine NKG2D-ligand, which induced severe bronchiolitis obliterans in WT and Rag-1 KO recipients. This effect was ameliorated by injection of anti-NKG2D blocking antibody. Together, these results suggest that cytotoxicity resulting from activation of NK cells through NKG2D leads to the development of murine bronchiolitis obliterans.

Prolonged Negative Pressure Wound Therapy Followed by Split-Thickness Skin Graft Placement for Wide Dehiscence of Clamshell Incision After Bilateral Lung Transplantation: A Case Report.

Clamshell incision is a standard approach for bilateral lung transplantation, providing a good operative field; however, once wide dehiscence occurs, its management is sometimes difficult because of intense immunosuppression and malnutrition of the recipient. A 22-year-old man with idiopathic pulmonary arterial hypertension underwent cadaveric bilateral lung transplantation through a clamshell incision using standard cardiopulmonary bypass. He developed wound dehiscence on postoperative day (POD) 20 that resulted in exposure of the bilateral fifth ribs and open pneumothorax. Considering the extreme malnutrition and emaciation of the recipient, we avoided initial closure of the dehiscence. After the debridement of necrotic tissue, negative pressure wound therapy was initiated on POD 25 and was continued for approximately 6 months with trafermin spray application. Eventually, the wound, including the fifth ribs, was completely covered with granulation tissue except for the wire tying the sternum. On POD 217, the patient underwent removal of the sternal wire followed by split-thickness skin grafting. His wound was successfully closed and he was discharged without activity limitation on POD 265.

[Emergency anterior approach for decortication with right pneumonectomy in a patient with chronic expanding hematoma].

The patient was a 68 year-old woman who had a history of treatment of pulmonary tuberculosis 35 years ago. She has experienced dyspnea and hemosputa since several years ago and has been followed up as having chronic empyema. She was admitted to our hospital due to recent exacerbation of symptoms. X-ray films and computed tomography scans of the chest showed the right thoracic cavity to be totally filled with a mass and the shift of mediastinum to the left side. After several days from admission, she needed mechanical ventilation support due to dyspnea exacerbation. Emergency decortication with right pneumonectomy through median sternotomy with anterolateral incision was performed. Postoperative course was uneventful. Pathlogical diagnosis was chronic expanding hematoma.

[Management of surgical approach for intractable secondary spontaneous pneumothorax].

Secondary spontaneous pneumothorax (SSP) such as lymphangioleiomyomatosis (LAM), bronchiolitis obliterans (BO) is intractable or repeated the recurrence of pneumothorax. The most effective chemical pleurodesis for intractable pneumothorax is talc poudrage and so on that is associated with a reduction in the rate of pneumothorax recurrence. However, severe and broad pleural adhesion due to the pleural interventional procedures sometimes cause serious bleeding when the patients undergo lung transplantation. We must be considered for new approaches to these intractable secondary pneumothoraces which replaced traditional conservative and surgical approaches. We had proposed new 2 approaches of total pleural covering (TPC) and awake surgical intervention (ASI) for intractable pneumothorax. We applied the TPC modified with coverage of air leak points with polyglycolic acid (PGA) sheet to 5 patients with intractable bilateral pneumothorax to reduce the risk of excessive bleeding by chemical pleurodesis in lung transplantation. The bilateral pneumothorax was well controlled, and no recurrence has been observed. TPC is reliable procedure for management intractable bilateral SSP. For 12 high-risk patients with other underling pulmonary diseases on general poor conditions, a surgical intervention was performed in awake condition. The air leaks were stopped in 11 cases except for 1 case. The recurrence of pneumothorax after surgery was 2 cases. ASI for intractable secondary pneumothorax can be applicable to selected patients with deteriorated general condition.

[Surgical approaches for superior sulcus tumor].

Surgical approach is one of the most crucial aspects in the treatment of superior sulcus tumor (SST). Posterior approach as described by Paulson and coworkers is appropriate for the resection of SST invading posterior part of the 1st rib and the vertebrae, whereas anterior approaches as described by Masaoka, Dartevelle, Grunenwald, or Rusca are suitable for resection of SST involving subclavian vessels. We present 2 cases of SST who underwent complete resection through the posterior approach and a modified hemi-clamshell approach, respectively. We also discuss the surgical approaches for SST with referring to literatures.

[Experience of postoperative adjuvant chemotherapy of lung cancer at outpatient department].

In late years the cancer adjuvant chemotherapy shifts from an inpatient care to an outpatient treatment. For operated lung cancer patients, outpatient chemotherapy center has been working since October 2005 in our hospital. Chemotherapy regimens were carboplatin (CBDCA) + paclitaxel (PTX), CBDCA + gemcitabine (GEM), docetaxel (DTX) + tegaful-gimeracil-oteracil potassium (S-1), and GEM + vinorel bine (VRE). CBDCA was chosen instead of cisplatin (CDDP) and non-platinum doublets are also used because of less toxicity and more time saving. Adjuvant chemotherapy has been performed for a total of 25 outpatients. Twenty-two out of 25 completed chemotherapy. Neutrophilopenia was the most common toxicity and grade 3 or 4 neutrophilopenia was seen in 6 patients. Adjuvant chemotherapy of outpatients can be completed safely by the choice of a safe regimen, supportive therapy for the toxicity, and cooperation with the community medicine organization. Our chemotherapy regimen are thought to be feasible for postoperative lung cancer outpatients.

[Video recording system of endoscopic procedures for digital forensics].

Recently, endoscopic procedures including surgery, intervention, and examination have been widely performed. Medical practitioners are required to record the procedures precisely in order to check the procedures retrospectively and to get the legally reliable record. Medical Forensic System made by KS Olympus Japan offers 2 kinds of movie and patient's data, such as heart rate, blood pressure, and Spo, which are simultaneously recorded. We installed this system into the bronchoscopy room and have experienced its benefit. Under this system, we can get bronchoscopic image, bronchoscopy room view, and patient's data simultaneously. We can check the quality of the bronchoscopic procedures retrospectively, which is useful for bronchoscopy staff training. Medical Forensic System should be installed in any kind of endoscopic procedures.

[Clinical analysis of bronchoplastic surgery for lung cancer after 2000].

We investigated surgical complications and prognosis of bronchoplasty and bronchoplasty with pulmonary angioplasty (broncho-angioplasty) for lung cancer. Between October 2000 and October 2007, 37 bronchoplastic procedures were done in 572 patients who underwent lung resections for lung cancer. Eleven (29.7%) bronchoplasties were done with pulmonary angioplasty. There was no operative mortality and 1 hospital mortality (2.7%) causing by myocardial infarction. Six of 11 postoperative complications were bronchial complications and 2 additional lung resections were needed. The 5-year survival for all patients was 55.2% and for bronchoplasty was 57.8%. Though the 5-year survival of broncho-angioplasty was not able to calculate at present, the 3-year survival of which was 72.9%. There was no death of patients with adenocarcinoma after introduction of pre-operative assessment by FDG-PET for lymph node metastasis. These data suggest that bronchoplasty and broncho-angioplasty are safe operative procedures and could provide acceptable intermediate survivals with modern multimodality diagnostic and therapeutic tools.

Genome-wide profiling of promoter methylation in human.

DNA methylation in the promoter region of a gene is associated with a loss of that gene's expression and plays an important role in gene silencing. The inactivation of tumor-suppressor genes by aberrant methylation in the promoter region is well recognized in carcinogenesis. However, there has been little study in this area when it comes to genome-wide profiling of the promoter methylation. Here, we developed a genome-wide profiling method called Microarray-based Integrated Analysis of Methylation by Isoschizomers to analyse the DNA methylation of promoter regions of 8091 human genes. With this method, resistance to both the methylation-sensitive restriction enzyme HpaII and the methylation-insensitive isoschizomer MspI was compared between samples by using a microarray with promoter regions of the 8091 genes. The reliability of the difference in HpaII resistance was judged using the difference in MspI resistance. We demonstrated the utility of this method by finding epigenetic mutations in cancer. Aberrant hypermethylation is known to inactivate tumour suppressor genes. Using this method, we found that frequency of the aberrant promoter hypermethylation in cancer is higher than previously hypothesized. Aberrant hypomethylation is known to induce activation of oncogenes in cancer. Genome-wide analysis of hypomethylated promoter sequences in cancer demonstrated low CG/GC ratio of these sequences, suggesting that CpG-poor genes are sensitive to demethylation activity in cancer.

[New surgical technique of pulmonary segmentectomy by ultrasonic scalpel and absorbable sealing materials].

We developed new surgical technique of pulmonary segmentectomy by ultrasonic scalpel to sever intersegmental pulmonary tissue and absorbable sealing materials to cover the cut surface of lung. This method is expected to preserve more anatomical lung volume than the segmentectomy with surgical stapler. Two cases of post surgical recurrent lung cancer, 3 cases of pulmonary metastasis and 4 cases of primary lung cancer were applied this technique to preserve function. Among 3 materials examined, best result was obtained with polyglycolic acid felt (PGAF:Neoveil). PGAF is a very soft and thin (0.15 mm depth) new absorbable material that is able to closely adhere to irregular sections of the lung with fibrin glue and effectively seals air leakage. Mean chest drainage period after surgery in 6 cases with PGAF was 3.3 days. Excellent lung expansion was obtained immediately after the surgery and PGAF was disappeared completely on chest CT within 1 year. Although the possible superiority of this method is suggested in the present study, further comparative study is necessary to clarify the advantage of this new technique.

[Ultrasonographical approach for the diagnosis on the depth of invasion in early bronchogenic squamous cell carcinoma].

It is important to evaluate the depth of invasion to determine the appropriate treatment for roentgenographically occult bronchogenic squamous cell carcinoma (ROSCC). In order to evaluate the actual significance of TUS as a diagnostic tool of intraluminal carcinoma invasion, we have conducted a prospective trial. TUS was performed on 29 lesions of ROSCCs. We ultrasonographically classified the degree of the depth of intraluminal invasion into 2 groups; A: "inside of cartilaginous layer" and B: "cartilaginous layer or over". The patients were treated by irradiation, photodynamic therapy (PDT) or surgical resection. Clinicopathological findings and response to the treatment were compared with this ultrasonographical classification. In the evaluation of invasion within cartilage, the sensitivity was 88.2%, the specificity was 77.8%, the accuracy was 84.6%, and the positive predictive value was 88.2%. With TUS, the decision of treatment modality would be more appropriate.

Diagnostic results before and after introduction of autofluorescence bronchoscopy in patients suspected of having lung cancer detected by sputum cytology in lung cancer mass screening.

For the purpose of early detection, we have conducted population-based mass screening for lung cancer by sputum cytology since 1982. Although detection of lung cancer in its early stage is important for a good prognosis, it is often difficult to localize lesions in roentgenographically occult cancer. To clarify the role of autofluorescence bronchoscopy in localizing tumors in patients with roentgenographically occult cancer, we analyzed our diagnostic results. Fifty patients who had been detected by sputum cytology were screened by the light-induced fluorescence endoscope (LIFE)-Lung System from November 1997 to April 1999. We compared the results according to the screening methods: conventional bronchoscopy alone versus LIFE with conventional white-light bronchoscopy (November 1997 to April 1999). Twenty-eight cancerous lesions and 39 borderline lesions were detected by LIFE. Of the 39 borderline lesions, nine were detected only by LIFE. Multicentric lesions including cancer or dysplasia were also detected in 21 of the 50 patients by LIFE. The sensitivity by white-light bronchoscopy alone was 85.3%, whereas that of the LIFE-Lung System with white-light bronchoscopy was 94.1% (P=0.078). There were no cancerous lesions in the area observed as normal by LIFE. We also compared the diagnostic results of two localization methods: brushing of all bronchi (September 1986 to December 1990) and the LIFE-Lung System (November 1997 to April 1999). Although this was a historical comparison, the number of detected borderline lesions increased, which led to a high detection rate in patients with suspected-positive sputum (P=0.0006) by the LIFE-Lung System. In conclusion, the LIFE-Lung System is a safe and non-invasive system for detecting small intraepithelial lesions of the tracheobronchial tree. Autofluorescence bronchoscopy is more efficacious for localizing intraepithelial lesions and places fewer burdens on the patient than brushing of all bronchi.

[New approaches for excellent operative field during tracheobronchial anastomoses in sleeve pneumonectomy: cardiopulmonary bypass and diseased lung ventilation].

Cardiopulmonary bypass (CPB) and diseased lung ventilation were presented as new methods of oxygenation during carinal reconstruction. Two cases of left sleeve pneumonectomy (SP) were performed for bronchial gland carcinoma through clamshell incisions. Adequate oxygenation and excellent operative fields were provided by CPB in both patients. The postoperative courses of these patients were uneventful, although they developed temporary pulmonary edema that needed mechanical ventilation and appropriate diuretics for several days. One case of patient with squamous cell carcinoma after chemotherapy was successfully treated by right SP through midline sternotomy. Adequate oxygenation and excellent operative fields was obtained by diseased right lung ventilation in this patient. The postoperative course of the patient was uneventful without mechanical ventilation support. These procedures of oxygenation in this paper are considered to be safe and effective methods for carinal reconstruction.

[The application of poly (L-lactide) sternal coaptation pins for median sternotomy].

Poly (L-lactide) sternal coaptation pin has been developed as an assistant material for the fixation of sternum. We used the novel material to a patient who underwent median sternotomy. A 21-year-old male was suspected to have invasive thymoma in the anterior mediastinum. The median sternotomy was indicated as an approach for the resection of tumor. Tumor was completely resected and there was no invasion to sternum. For the fixation of sternum, three poly (L-lactide) sternal coaptation pins were inserted in the bone marrow of sternum and five stainless steel wires were used as conventional procedure. Sternum was adapted without slippage and no complication from the material was observed in the post-surgical period. The application of poly (L-lactide) sternal coaptation pin is a good option for ensuring the fixation of sternum.

Allelic loss on 17p13 (TP53) and allelic loss on 3p21 in early squamous cell carcinoma of the lung.

Roentgenographically occult bronchogenic squamous cell carcinomas are early lung cancers that localize in the bronchial wall, and are thought to be a good model to elucidate the carcinogenesis of lung cancer. In the present study, we analyzed the incidence of allelic losses on chromosome regions 3p21 and 17p13 in 40 cases of roentgenographically occult bronchogenic squamous cell carcinomas, using three microsatellite dinucleotide polymorphic markers. We also investigated the relationship between such allelic loss and the clinicopathological findings of those cases. These chromosome regions showed frequent losses. Moreover, the incidence of loss on 17p13 increased gradually along with the advance of the depth of invasion, while the incidence of loss on 3p21 increased along with the advancing length of the longitudinal extension. These results suggested that these chromosome regions play different roles in lung cancer progression, i.e., the 3p21 chromosome region was related to the longitudinal extension of the carcinoma while the 17p13 (p53) region was related to the depth of invasion.

MDM2 expression is associated with progress of disease and WAF1 expression in resected lung cancer.

Although MDM2, p21/WAF1, and p53 are considered as regulating each other based on in vitro studies, the relation in human lung cancer is not fully understood. The expressions of these proteins were examined immunohistochemically in 112 resected non-small cell lung cancer specimens and the correlation between them were analyzed. MDM2 was expressed in 45% of all lung cancers. In advanced stage, MDM2-positive cases were observed more frequently than in early stage, showing significant difference. No significant difference was observed in the prognosis of the patients regardless of the expression of any protein. Although no correlation was observed between MDM2 expression and p53 expression, or between p21/WAF1 expression and p53 expression, MDM2 expression was strongly related with p21/WAF1 expression. Therefore, MDM2 expression may relate to the progress of the stage of lung cancer, and MDM2 expression and p21/WAF1 expression may be associated not through the p53-related pathway.

Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer.

PTEN is a newly isolated candidate tumor suppressor gene and its mutation is the most frequently found in endometrial cancer (EC), a very common female pelvic malignant disease. Mutations of the KRAS gene are also reported in this disease. Recent analysis of the PTEN protein suggested the possibility that this protein acts in the same pathway as does the RAS protein. To elucidate this possibility further, we performed a mutation analysis of these two genes in 44 endometrial cancer specimens (38 primary tumors and 6 cell lines). Altogether 23 (52%) of 44 tumors had mutations in either PTEN or KRAS, but none of them had mutations in both of these genes. These results support the idea that the protein products of these two genes act in the same growth regulatory pathway in the endometrium.