Toyofumi F. Chen-Yoshikawa

Update on three-dimensional image reconstruction for preoperative simulation in thoracic surgery

BACKGROUND Three-dimensional computed tomography (3D-CT) technologies have been developed and refined over time. Recently, high-speed and high-quality 3D-CT technologies have also been introduced to the field of thoracic surgery. The purpose of this manuscript is to demonstrate several examples of these 3D-CT technologies in various scenarios in thoracic surgery. METHODS A newly-developed high-speed and high-quality 3D image analysis software system was used in Kyoto University Hospital. Simulation and/or navigation were performed using this 3D-CT technology in various thoracic surgeries. RESULTS Preoperative 3D-CT simulation was performed in most patients undergoing video-assisted thoracoscopic surgery (VATS). Anatomical variation was frequently detected preoperatively, which was useful in performing VATS procedures when using only a monitor for vision. In sublobar resection, 3D-CT simulation was more helpful. In small lung lesions, which were supposedly neither visible nor palpable, preoperative marking of the lesions was performed using 3D-CT simulation, and wedge resection or segmentectomy was successfully performed with confidence. This technique also enabled virtual-reality endobronchial ultrasonography (EBUS), which made the procedure more safe and reliable. Furthermore, in living-donor lobar lung transplantation (LDLLT), surgical procedures for donor lobectomy were simulated preoperatively by 3D-CT angiography, which also affected surgical procedures for recipient surgery. New surgical techniques such as right and left inverted LDLLT were also established using 3D models created with this technique. CONCLUSIONS After the introduction of 3D-CT technology to the field of thoracic surgery, preoperative simulation has been developed for various thoracic procedures. In the near future, this technique will become more common in thoracic surgery, and frequent use by thoracic surgeons will be seen in worldwide daily practice.

Outcomes of various transplant procedures (single, sparing, inverted) in living-donor lobar lung transplantation

Objectives: In standard living‐donor lobar lung transplantation (LDLLT), the right and left lower lobes from 2 healthy donors are implanted. Because of the difficulty encountered in finding 2 donors with ideal size matching, various transplant procedures have been developed in our institution. The purpose of this retrospective study was to compare outcomes of nonstandard LDLLT with standard LDLLT. Methods: Between June 2008 and January 2016, we performed 65 LDLLTs for critically ill patients. Functional size matching was performed by estimating graft forced vital capacity based on the donors measured forced vital capacity and the number of pulmonary segments implanted. For anatomical size matching, 3‐dimensional computed tomography volumetry was performed. In cases of oversize mismatch, single‐lobe transplant or downsizing transplant was performed. In cases of undersize mismatch, native upper lobe sparing transplant or right‐left inverted transplant was performed. In right‐left inverted transplants, the donors right lower lobe was inverted and implanted into the recipients left chest cavity. Results: Twenty‐nine patients (44.6%) received nonstandard LDLLT, including 12 single‐lobe transplants, 7 native upper lobe sparing transplants, 6 right‐left inverted transplants, 2 sparing + inverted transplants, and 2 others. Thirty‐six patients (57.4%) received standard LDLLT. Three‐ and five‐year survival rates were similar between the 2 groups (89.1% and 76.6% after nonstandard LDLLT vs 78.0% and 71.1% after standard LDLLT, P = .712). Conclusions: Various transplant procedures such as single, sparing and inverted transplants are valuable options when 2 donors with ideal size matching are not available for LDLLT.

Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression

Lung cancer treatment is difficult owing to chemoresistance. Hypoxia‐inducible factor 1 (HIF‐1) and HIF‐1‐induced glycolysis are correlated with chemoresistance; however, this is not evident in lung cancer. We investigated the effect of HIF‐1α and carbonic anhydrase IX (CAIX), a transmembrane protein neutralizing intracellular acidosis, on chemoresistance and prognosis of lung cancer patients after induction chemoradiotherapy. Associations of HIF‐1α, glucose transporter 1 (GLUT1), and CAIX with chemoresistance of lung cancer were investigated using A549 lung cancer cells under normoxia or hypoxia in vitro. HIF‐1α‐induced reprogramming of glucose metabolic pathway in A549 cells and the effects of HIF‐1 and CAIX on the cytotoxicity of vinorelbine were investigated. Immunohistochemical analyses were performed to determine HIF‐1α, GLUT1, and CAIX expression levels in cancer specimens from lung cancer patients after induction chemoradiotherapy. Hypoxia induced HIF‐1α expression in A549 cells. Moreover, hypoxia induced GLUT1 and CAIX expression in A549 cells in a HIF‐1‐dependent manner. Glucose metabolic pathway was shifted from oxidative phosphorylation to glycolysis by inducing HIF‐1α in A549 cells. HIF‐1 and CAIX induced chemoresistance under hypoxia, and their inhibition restored the chemosensitivity of A549 cells. The expression levels of HIF‐1α, GLUT1, and CAIX were associated with poor overall survival of lung cancer patients after induction chemoradiotherapy. HIF‐1 and CAIX affected the chemosensitivity of A549 cells and prognosis of lung cancer patients. Therefore, inhibition of HIF‐1 and CAIX might improve prognosis of lung cancer patients after induction chemoradiotherapy. Further analysis might be helpful in developing therapies for lung cancer.

Prognostic Factors in Lung Transplantation After Hematopoietic Stem Cell Transplantation

Background Lung transplantation is the final lifesaving option for patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). Patients undergoing HSCT for hematologic diseases are thought to be high-risk candidates for lung transplantation; therefore, few lung transplants are performed for these patients, and few studies have been reported. This study aimed to describe the characteristics and outcomes of lung transplantation in patients with pulmonary complications after HSCT. Methods We retrospectively investigated 62 patients who underwent lung transplantation after HSCT. All data were collected from 6 lung transplant centers in Japan. Results Seventeen patients underwent cadaveric lung transplantation, whereas 45 underwent living-donor lobar lung transplantation (LDLLT). In the LDLLT group, 18 patients underwent LDLLT after HSCT in which one of the donors had also served as a donor for HSCT. Seven patients underwent single LDLLT for which the donor was the same as the patient from whom stem cells were obtained for HSCT. Preoperative hypercapnia was observed in 52 patients (84%). Thirteen patients (21%) required mechanical ventilation preoperatively. Fifty-five patients underwent HSCT for hematologic malignancies, and 4 (7%) relapsed after lung transplantation. The 5-year survival rate was 64.2%. In a multivariable analysis, patients younger than 45 years and those with the same donor for both procedures exhibited significantly better survival (P = 0.012 and 0.041, respectively). Conclusions Lung transplantation for pulmonary complications after HSCT was performed safely and yielded better survival, especially in younger recipients for whom both lung transplantation and HSCT involved the same donor.

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.

Inhibition of Toll-like receptor 4 signaling ameliorates lung ischemia-reperfusion injury in acute hyperglycemic conditions.

BACKGROUND Recent lung transplantation studies have shown that peri-operative hyperglycemia is an important factor affecting recipient survival; however, its underlying mechanisms are not well understood. We hypothesized that acute hyperglycemia exacerbates lung ischemia-reperfusion injury (IRI) through up-regulation of Toll-like receptor 4 (TLR4) signaling pathways. METHODS C57BL/6Ncr mice were divided into 3 treatment groups: sham; IRI; and IRI under acute hyperglycemic conditions (IRI+HG). Mice in the IRI and IRI+HG groups were exposed to IRI via clamping the left hilum for 1 hour, followed by reperfusion for 2 hours. Acute hyperglycemia was established by glucose injection. The severity of lung injury and TLR4 signaling pathway activity were assessed. Further, we performed a pharmacologic blockade of TLR4 signaling to determine the effect of TLR4 signaling inhibition on lung injury. RESULTS Compared with normoglycemic mice, hyperglycemic mice had 2-fold higher blood glucose levels (p < 0.001). Pulmonary compliance was significantly lower, and airway resistance was significantly higher, in the IRI+HG group than in the IRI group (p < 0.05). Levels of inflammatory cytokines in bronchoalveolar lavage fluid were significantly higher in the IRI+HG group than in the IRI group. Correspondingly, TLR4 signaling pathways were up-regulated in the IRI+HG group. Moreover, pharmacologic inhibition of TLR4 signaling significantly decreased lung injury markers under hyperglycemic conditions. CONCLUSIONS Acute hyperglycemia exacerbated lung IRI and was associated with up-regulation of TLR4 signaling pathways. Pharmacologic inhibition of TLR4 signaling ameliorated lung IRI with acute hyperglycemia. Targeting TLR4 appears to be a promising approach to managing coexisting pathologies in lung transplant recipients.

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

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.

Anterior mediastinal tissue volume is correlated with antiacetylcholine receptor antibody level in myasthenia gravis

Objectives: Extended thymectomy is a treatment option for myasthenia gravis (MG), but the surgical indications are controversial. Pathologic features of the thymus can be used to predict surgical outcomes, but there is no reliable method for evaluating these characteristics preoperatively. The purpose of this study was to determine whether anterior mediastinal tissue volume, as measured via 3‐dimensional computed tomography (3DCT) volumetry, correlates with serum anti‐acetylcholine receptor antibody (AChRAb) levels in patients undergoing thymectomy for myasthenia gravis. Therefore, we investigated the relationships among anterior mediastinal tissue volume determined by 3DCT volumetry and AChRAb levels. Methods: The subjects were 28 patients who underwent extended thymectomy and were enrolled retrospectively. We measured volume of the anterior mediastinum and calculated the volumes of more than −30 Hounsfield units (V−30) by using 3DCT volumetry and compared them with perioperative AChRAb levels. The significance of their volumes in MG was examined by comparison with 53 patients without MG. Results: V−30 values were related to age and were significantly greater in patients with MG than in patients without MG (P < .001). V−30 values were correlated positively with preoperative AChRAb levels (&rgr; = 0.505, P = .006) and inversely with the post/preoperative AChRAb ratio (&rgr; = −0.453, P = .018). The histologic nonadipose tissue ratio was correlated with the V−30/volume of the anterior mediastinum (&rgr; = 0.700, P < .001). Conclusions: This method for evaluation of the anterior mediastinal tissue volume and AChRAb production may be helpful in establishing a treatment plan for MG.

Pulmonary Arterioplasty With End-to-End Anastomosis of the Lingular Branch to the Interlobar Pulmonary Artery in Living-Donor Lobectomy.

In living-donor lobar lung transplantation, donor lobectomies must be performed carefully both for donors and recipients. In some cases pulmonary arterioplasty is required for preserving branches of pulmonary artery. This report describes a successful case of pulmonary arterioplasty with end-to-end anastomosis of the interlobar artery and the lingular branch in living-donor lobectomy. Because the harvest of autologous pericardium can be avoided both in donor and recipient surgical procedures by using this technique, living-donor lobar lung transplantation can be performed more safely and simply.