Ei Miyamoto

Right and left inverted lobar lung transplantation.

Adult recipients frequently withdraw from living‐donor lobar lung transplantation because of the small size of donor grafts. The right lower lobe is 120% larger than the left lower lobe. We developed a novel surgical technique in which an inverted right lower lobe graft can be transplanted into the left thorax. The first patient was a 43‐year‐old woman with end‐stage idiopathic interstitial pneumonia. Her husband was the only eligible donor for living‐donor lobar lung transplantation. His right lower lobe was estimated to provide 45% of the recipients predicted forced vital capacity, which would provide the borderline function required for living‐donor lobar lung transplantation. Since lung perfusion scintigraphy of the recipient showed a right‐to‐left ratio of 64:36, transplanting the right lower lobe graft into the left thorax and sparing the native right lung was considered the only treatment option. We simulated this procedure using three‐dimensional models produced by a three‐dimensional printer. In living‐donor lobar lung transplantation, all anastomoses were performed smoothly as planned preoperatively. Because of the initial success, this procedure was performed successfully in two additional patients. This procedure enables larger grafts to be transplanted, potentially solving critical size matching problems in living‐donor lobar lung transplantation.

Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis

Purpose: We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1+ myeloid cells through the CCL15-CCR1 axis, which contributes to invasion and liver metastasis. However, the molecular mechanism of lung metastasis is yet to be elucidated. Our purpose is to determine whether similar mechanism is involved in the lung metastasis of colorectal cancer. Experimental Design: In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1+ myeloid cells using several cell-type–specific markers. Results: In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1+ cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of lung metastases from colorectal cancer patients revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive metastases recruited approximately 1.9 times more numbers of CCR1+ cells than CCL15-negative metastases. Importantly, patients with CCL15-positive metastases showed a significantly shorter relapse-free survival (RFS) than those with CCL15-negative metastases, and multivariate analysis indicated that CCL15 expression was an independent predictor of shorter RFS. Immunofluorescent staining showed that most CCR1+ cells around lung metastases were tumor-associated neutrophil, although a minor fraction was granulocytic myeloid-derived suppressor cell. Conclusions: CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a biomarker indicating poor prognosis of colorectal cancer patients with lung metastases. Clin Cancer Res; 23(3); 833–44. ©2016 AACR.

Stenosis of the segmental bronchus is a characteristic airway complication in living-donor lobar lung transplantation

Stenosis of the segmental bronchus is a characteristic airway complication in living-donor lobar lung transplantation Ei Miyamoto, MD, Toyofumi F. Chen-Yoshikawa, MD, PhD, Hirokazu Higuchi, MS, Akihiro Aoyama, MD, PhD, and Hiroshi Date, MD, PhD From the Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and the Department of Medical Supply Clinical Engineering, Kyoto University Hospital, Kyoto, Japan

Unilateral chronic lung allograft dysfunction is a characteristic of bilateral living-donor lobar lung transplantation

OBJECTIVES Living-donor lobar lung transplantation (LDLLT) has been established as a life-saving procedure for critically ill patients who cannot wait for cadaveric lung transplantation. Chronic lung allograft dysfunction (CLAD) is the main cause of late morbidity and mortality in lung transplantation. Studies on CLAD in cadaveric lung transplantation have been extensively reported, but few reports have been reported concerning CLAD after LDLLT. The aim of this study was to determine the prevalence, characteristics and prognosis of CLAD after LDLLT. METHODS Among 38 patients who survived more than 3 months after LDLLT at Kyoto University Hospital between June 2008 and December 2013, 8 patients (21%) were diagnosed with CLAD. The mean follow-up period after LDLLT was 33 months. Clinical course, pulmonary function and radiological findings were reviewed retrospectively in all the 38 patients as of May 2014. RESULTS Six patients were female and 2 were male. The median age at LDLLT was 31 years, and the median interval between LDLLT and the initial diagnosis of CLAD was 23 months. Among 8 patients who developed CLAD, 2 patients underwent right single LDLLT and 6 patients underwent bilateral LDLLT. The former 2 patients survived 44 and 47 months after the treatment. Five out of 6 patients with bilateral LDLLT developed unilateral CLAD at the time of initial diagnosis according to ventilation scintigraphy. In 3 of these 5 patients, the progression of CLAD was halted by treatment, and the median follow-up period of 33 months after treatment. In the remaining 2 of 5 patients, CLAD progressed to the contralateral lung metachronously; 1 patient survived without oxygen supplement, but the other patient required reperformance of LDLLT 3 years after the first one. One patient with bilateral CLAD at the time of detection died of disease progression 4 years after LDLLT. CONCLUSIONS Despite a relatively short observation time, CLAD developed in approximately one-fifth of the patients who survived more than 3 months after LDLLT. In bilateral LDLLT, CLAD developed unilaterally in most cases, which might be beneficial in the long term because the unaffected contralateral lung may function as a reservoir.

Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I With the Progression of Chronic Rejection of Lung Allografts

Background Antibody-mediated rejection may lead to chronic lung allograft dysfunction, but antibody-mediated rejection may develop in the absence of detectable donor-specific antibody (DSA) in recipient serum. This study investigated whether humoral immune responses develop not only systemically but locally within rejected lung allografts, resulting in local production of DSA. Methods Lewis rats received orthotopic left lung transplantation from Lewis (syngeneic control) or Brown-Norway (major histocompatibility complex-mismatched allogeneic) donor rats. Rats that underwent allogeneic lung transplantation were subsequently administered cyclosporine until day 14 (short immunosuppression) or day 35 (long immunosuppression). The lung grafts and spleens of recipient animals were tissue cultured for 4 days, and the titer of antibody against donor major histocompatibility complex molecules was assayed by flow cytometry. Explanted lung grafts were also evaluated pathologically. Results By day 98, DSA titers in supernatants of lung graft (P = 0.0074) and spleen (P = 0.0167) cultures, but not serum, from the short immunosuppression group were significantly higher than titers in syngeneic controls. Cultures and sera from the long immunosuppression group showed no production of DSA. Microscopically, the lung grafts from the short immunosuppression group showed severe bronchiole obliteration and parenchymal fibrosis, along with lymphoid aggregates containing T and B cells, accompanying plasma cells. These findings suggestive of local humoral immune response were not observed by days 28 and 63. Conclusions DSA can be locally produced in chronically rejected lung allografts, along with intragraft immunocompetent cells. Clinical testing of DSA in serum samples alone may underestimate lung allograft dysfunction.

Successful bilateral lung transplantation from a deceased donor with a ruptured main bronchus

Major tracheobronchial trauma may lead to underestimation of the potential for lung donation due to insufficient alveolar ventilation and resulting poor oxygenation, bronchoscopic findings and radiographic findings (e.g. atelectasis). Here, we report a case of successful bilateral lung transplantation from a deceased donor whose right bronchus was ruptured by a trauma from the main bronchus to the bronchus intermedius. Although poor oxygenation and a collapsed right lung detected by computed tomography scanning precluded the use of the donor lungs by multiple transplant centres, careful bronchoscopic evaluation and intraoperative assessment convinced us that the parenchyma of the donor lungs was preserved sufficiently well for transplantation. Upon transplantation, the donor right bronchus was anastomosed at two levels, the upper lobe bronchus and the bronchus intermedius, and the lacerated portion was removed. The recipients postoperative course was uneventful and the bronchial anastomoses healed excellently. Careful preoperative evaluation and appropriate surgical techniques might enable successful lung transplantation, using seemingly suboptimal donor lungs with major airway trauma.

Transition of the programmed death 1 pathway from the primary colorectal cancer to its corresponding pulmonary metastasis

The inhibition of the programmed death 1 (PD‐1)/its ligand 1 (PD‐L1) pathway may be associated with clinical responses in colorectal cancer (CRC). We aimed to characterize the transition of PD‐1/PD‐L1 expression through pulmonary metastasis (PM) and its clinical relevance.

GATA6‐positive lung adenocarcinomas are associated with invasive mucinous adenocarcinoma morphology, hepatocyte nuclear factor 4α expression, and KRAS mutations

GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyse GATA6 expression in lung adenocarcinomas (LAs) by immunohistochemistry (IHC) in order to define its association with clinicopathological characteristics.

Completely resected follicular dendritic cell sarcoma of the posterior mediastinum: report of a case

Follicular dendritic cell sarcoma is a rare malignant neoplasm originating from follicular dendritic cells, and most of them develop in lymph nodes of the head and neck. One third of follicular dendritic cell sarcomas occur in the extranodal sites such as the tonsils, mesentery, and retroperitoneal organs, but those of mediastinal origin are rare. Here, we present the case of a 16-year-old female with a large follicular dendritic cell sarcoma of posterior mediastinal origin. The tumor was found by a chest X-ray mass examination at her high school, and she had no subjective symptoms or significant past medical history. The tumor was diagnosed as a follicular dendritic cell sarcoma by computed tomography-guided needle biopsy. Although the tumor compressed the mediastinal organs and showed moderate uptake in 18-fluorodeoxyglucose positron emission tomography imaging, it was completely resected through posterolateral incision. Histological examination revealed that spindle-shaped tumor cells formed fascicular or storiform pattern with cellular pleomorphism. By immunohistochemical examination, the tumor cells were found to be positive for CD21 and follicular dendritic cell antigen. Two years after surgery, the patient remains alive with no signs of tumor recurrence.

Immersing lungs in hydrogen-rich saline attenuates lung ischaemia–reperfusion injury†

Objectives Anti-oxidant effects of hydrogen have been reported in studies examining ischaemia-reperfusion injury (IRI). In this study, we evaluated the therapeutic efficacy of immersing lungs in hydrogen-rich saline on lung IRI. Methods Lewis rats were divided into three groups: (i) sham, (ii) normal saline and (iii) hydrogen-rich saline. In the first experiment, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline for 1 h. Then, we measured the hydrogen concentration in the left lung using a sensor gas chromatograph ( N = 3 per group). In the second experiment, lung IRI was induced by occlusion of the left pulmonary hilum for 1 h, followed by reperfusion for 3 h. During the ischaemic period, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline. After reperfusion, we assessed lung function, histological changes and cytokine production ( N = 5-7 per group). Results Immersing lungs in hydrogen-rich saline resulted in an elevated hydrogen concentration in the lung (6.9 ± 2.9 μmol/1 g lung). After IRI, pulmonary function (pulmonary compliance and oxygenation levels) was significantly higher in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Similarly, pro-inflammatory cytokine levels (interleukin-1β and interleukin-6) in the left lung were significantly lower in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Conclusions Immersing lungs in hydrogen-rich saline delivered hydrogen into the lung and consequently attenuated lung IRI. Hydrogen-rich solution appears to be a promising approach to managing lung IRI.