[Experience with Surgical Stabilization for Traumatic Rib Fractures and Sternal Fractures].

The treatment of traumatic rib fractures and sternal fractures have focused on pain and respiratory management, and conservative treatment has been recommended. Recently, however, a number of case series from abroad have been reported and demonstrated the usefulness of surgical stabilization of rib fractures (SSRF) and sternal fractures (SSSF). We have experienced seven cases of SSRF and two cases of SSSF at International University Health and Welfare Narita Hospital and Atami Hospital. Based on our experienced cases, we have outlined the preoperative evaluation, indication for surgery, timing of surgery, surgical techniques, and postoperative course. Of these nine cases, the clinical course of two cases of SSRF and one case of SSSF were detailly presented. The surgical indications and techniques for traumatic rib fractures and sternal fractures vary from institution to institution, and there is no single optimal treatment. We hope that the accumulation of cases, and discussions will help to build a higher quality evidence for surgical treatment of thoracic trauma in Japan.

Thrombus formation at the stump of the pulmonary vein after lobectomy: a prospective multi-institutional study.

PURPOSE: Recent reports suggest that postoperative cerebral infarction following lung cancer surgery is caused by thrombus formation at the stump of the pulmonary vein and that the risk is highest after left upper lobectomy (LUL). Thrombosis at the stump of the pulmonary vein and the incidence of cerebral infarction was investigated prospectively in patients who underwent lobectomy for lung cancer. METHODS: Lung cancer patients undergoing planned pulmonary lobectomy were enrolled. The endpoint was to confirm if there is a higher incidence of thrombus formation (primary) and a higher incidence of cerebral infarction (secondary) in patients undergoing LUL. We planned to accrue 600 patients. An interim analysis was scheduled for just after the data center received the final clinical review form of the 300th patient. RESULTS: The interim analysis revealed a significant difference in the primary endpoint. In the final analysis, thrombus was identified in 16 of 88 LUL patients (20.5%), and in 4 of 247 patients who underwent other types of lobectomy (1.6%) (p < 0.05). Cerebral infarction was identified in 1 of the LUL patients (1.3%) and in 9 of the other patients (3.6%) (p = 0.318). CONCLUSIONS: Thrombus frequently forms at the stump of the left superior pulmonary vein after LUL. However, our study did not identify a relationship between thrombosis and cerebral infarction.

The degree of satisfaction and level of learning in male and female surgical residents: a nationwide questionnaire survey of graduating residents in Japan.

PURPOSE: Since 2002, the Japan Surgical Society has established a board certification system for surgeons to be certified for a specialty. Surgery remains a male-dominated field in Japan. This study aimed to clarify if the Japanese surgical residency training system is equally suitable for female and male residents. METHODS: The Japan Surgical Society conducted the first questionnaire survey regarding the system of surgical training for the residents in 2016. The questionnaire included the degree of satisfaction with 7 aspects of the training system, including the number and variety of cases experienced and duration and quality of instruction, and the learning level for 31 procedures. The degree of satisfaction and level of learning were compared between female and male residents. RESULTS: The degree of satisfaction was similar for all items between female and male residents. Female residents chose breast surgery as their subspecialty more frequently than male residents and were more confident in breast surgery procedures than male residents. Conversely, fewer female residents chose gastrointestinal surgery and were less confident in gastrointestinal surgery procedures than male residents. CONCLUSION: Female residents were as satisfied with the current surgical training system as male residents. However, there may be room for improvement in the surgical system, considering that fewer applications for gastrointestinal surgery come from female residents than from males.

[The Basic Research of Antigen-antibody Reaction in Lung Transplantation].

Lung transplantation has become popular in Japan, showing better survival rate than other countries. However, the results are still not satisfactory compared with other solid organ transplantation. One of the reasons for this might be that knowledge on donor-specific antibodies or antibody-related rejection, which has been attracting attention these days, is less than that of kidney or liver transplantation. Our laboratory has continued basic research in this field using rodent lung transplantation model. We have previously shown that type V collagen is associated in chronic rejection as an autoimmune, and that oral administration of type V collagen induces tolerance. The murine chronic rejection model of the minor antigen mismatch was developed, and involvement of the humoral immunity and role of the complement activation were shown. We are now studying the effects of immune checkpoint molecules, which play a central role in the field of cancer therapy, on rejection after lung transplantation. We are also working to verify the effects of anti-complement drugs and molecular targeted drugs in the future treatment on rejection.

Immunological features of a lung cancer patient achieving an objective response with anti-programmed death-1 blockade therapy.

The role of immune checkpoint inhibitors in metastatic lung cancer has been established in recent years and the pretherapeutic profiles of the tumor microenvironment in responders have been increasingly reported. The role of salvage surgery and the immune profiles of the posttherapeutic specimens in patients achieving an objective response have rarely been studied. We report a case of metastatic lung cancer treated by anti-programmed death-1 Ab followed by surgical resection. The immune status of the tumor was assessed, showing germinal center formation, memory B cell infiltration, and a high frequency of interferon gamma -secreting T cells.

A phase I study of loco-regional immunotherapy by transbronchial injection of α-galactosylceramide-pulsed antigen presenting cells in patients with lung cancer.

We conducted a phase I study of the trans-bronchial injection of α-galactosylceramide (αGalCer)-pulsed antigen presenting cells (APCs) to evaluate their safety, immune responses, and anti-tumor activities. Patients with advanced or recurrent non-small cell lung cancer (NSCLC) refractory to standard treatments were eligible. αGalCer-pulsed APCs were administered intratumorally or intranodally by bronchoscopy. Twenty-one patients were enrolled in this study. No severe adverse events related to the cell therapy were observed during this study in any patient. After αGalCer-pulsed APCs were administrated, increased iNKT cell numbers were observed in PBMCs from eight cases, and IFN-γ producing cells were increased in the peripheral blood of 10 cases. Regarding clinical responses, one case exhibited a partial response and eight were classified as stable disease. In the tumor microenvironment, IFN-γ expression was upregulated after treatment in partial response or stable disease cases and TGF-ß was upregulated in progressive disease cases.

Is there disparity between regions and facilities in surgical resident training in Japan? Insights from a national survey.

PURPOSE: This study sought to assess the disparity between regions and facilities in surgical resident training in Japan via a national level needs-assessment. METHODS: A survey was sent to all 909 graduating residents of 2016. Residents trained in the six prefectures with a population of 7 million or more were included in the large prefecture (LP) group. Residents trained in the other 41 prefectures were included in the small prefecture (SP) group. Each group was further divided into a university hospital (UH) group and a non-university hospital (NUH) group. RESULTS: The response rate was 56.3% (n = 512). Excluding nine residents who did not report their prefectures and facilities, surveys from 503 residents were analyzed. The UH group received significantly more years of training. In the SP and UH groups, there were significantly fewer residents who had performed 150 procedures or more under general anesthesia in comparison to the LP and NUH groups, respectively. Self-assessed competencies for several procedures were significantly lower in the SP and UH groups. CONCLUSION: Disparity in surgical resident training was found between regions and facilities in Japan. The surgical residency curriculum in Japan could be improved to address this problem.

Are graduating residents sufficiently competent? Results of a national gap analysis survey of program directors and graduating residents in Japan.

PURPOSE: To evaluate the self-assessed competency of graduating residents (GRs) in Japan upon completion of their residency and to identify the gap between their competency and the competency expected by their program directors (PDs). METHOD: A list of 31 essential surgical procedures was compiled according to the consensus of surgical educators from around the country. A survey with this list was sent to all 909 GRs and their 611 PDs in 2016. The GRs rated their competency to perform these procedures and the PDs were asked to evaluate the expected competency of their GRs using the Zwisch Scale. RESULT: The response rate was 56.3% for the GRs and 76.8% for the PDs. Fewer than half of the GRs who responded felt confident performing ten (32%) of the surgical procedures evaluated. For most procedures, the GRs' self-reported competency was lower than the expectation reported by their PDs. This gap was more than 10% for 13 of the procedures. CONCLUSION: More than half of the GRs in Japan lacked the confidence in their skill to perform one-third of the surgical procedures selected for evaluation in this study. These findings should be used to update the surgical education curriculum in Japan.

A snapshot of surgical resident training in Japan: results of a national-level needs assessment survey.

PURPOSE: To evaluate the status of surgical training in Japan through a national-level needs assessment. METHODS: A survey was sent to all 909 graduating residents (GRs) and their 611 program directors (PDs) for the year 2016. A working group of surgical educators from around the country was formed under the education committee of the Japan Surgical Society. The survey items were developed by consensus of this working group. The survey investigated the knowledge and problems of the current curriculum, and the status of the current residency training. RESULTS: The response rates were 56.3% of the GRs and 76.8% of the PDs. Among the participants, 47.6% of the GRs and 29.4% of the PDs believed that the residency curriculum did not match the clinical experience. Over 80% of the GRs and PDs agreed on the importance of training outside of the OR, whereas only 13% of the GRs had received such training regularly. Trainees also reported a lower satisfaction rate about the opportunity to train outside of the OR. CONCLUSION: This national-level needs assessment of surgical training in Japan identified several gaps in the curriculum. These results provide valuable data to assist the ongoing efforts for surgical residency curriculum improvement.

Molecular Nodal Staging Using miRNA Expression in Lung Cancer Patients by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration.

BACKGROUND: The limited negative predictive value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has often been discussed. OBJECTIVE: The aim of this study was to identify a highly sensitive molecular biomarker for lymph node staging by EBUS-TBNA. METHODS: Five microRNAs (miRNAs) (miR-200a, miR-200b, miR-200c, miR-141, and let-7e) were selected as biomarker candidates for the detection of nodal metastasis in a miRNA expression analysis. After having established a cutoff level of expression for each marker to differentiate malignant from benign lymph nodes among surgically dissected lymph nodes, the cutoff level was applied to snap-frozen EBUS-TBNA samples. Archived formalin-fixed paraffin- embedded (FFPE) samples rebiopsied by EBUS-TBNA after induction chemoradiotherapy were also analyzed. RESULTS: The expression of all candidate miRNAs was significantly higher in metastatic lymph nodes than in benign ones (p < 0.05) among the surgical samples. miR-200c showed the highest diagnostic yield, with a sensitivity of 95.4% and a specificity of 100%. When the cutoff value for miR-200c was applied to the snap-frozen EBUS-TBNA samples, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 97.4, 81.8, 95.0, 90.0, and 94.0%, respectively. For restaging FFPE EBUS- TBNA samples, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 100, 60.0, 80.0, 100, and 84.6%, respectively. Among the restaged samples, 4 malignant lymph nodes were false negative by EBUS-TBNA, but they were accurately identified by miR-200c. CONCLUSIONS: miR-200c can be used as a highly sensitive molecular staging biomarker that will enhance nodal staging of lung cancer.

Concordant pattern of radiologic, morphologic, and genomic changes during compensatory lung growth.

BACKGROUND: Although compensatory lung growth (CLG) after lung resection has been reported in various mammalian species, it has generally been thought that the lung cannot regenerate in adult humans. We recently developed a method for evaluating lung weight using a radiologic analysis and demonstrated that the lung was heavier than expected in adult humans after pulmonary resection. In this study, we serially evaluated the morphologic, radiologic, and genomic status during CLG in pneumonectomized mice. METHODS: The serial changes in morphology and gene expression of the remnant right lung after left pneumonectomy were examined in adult male mice. The alveolar density was determined by the mean linear intercept, and the weight was estimated using the Hounsfield value and volumetric data from micro-computed tomography. The parameters were obtained on days 3, 7, and 30 after left pneumonectomy or thoracotomy only (sham control). RESULTS: After left pneumonectomy, the right lung became significantly progressively larger in volume and weight on postoperative days 3, 7, and 30 in comparison to the sham controls (P < 0.01). The estimated weight also significantly increased in association with the real volume on postoperative days 3, 7, and 30 (P < 0.01). The cardiac lobe markedly increased in size. During the observation period, the alveolar density was always lower in the pneumonectomized mice than in controls. A microarray analysis revealed that multiple genes related to proliferation (but not specific alveolar development) were initially upregulated until postoperative day 7 and then returned to normal after 1 mo. The morphologic and genomic changes were more evident in the cardiac lobe than in the upper lobe during the observation period. CONCLUSIONS: The morphologic, radiologic, and genomic changes during CLG were related to each other in pneumonectomized mice. The present study revealed an association between the radiologically estimated weight and other parameters, indicating a marked CLG reaction of the cardiac lobe.

Does segmentectomy really preserve the pulmonary function better than lobectomy for patients with early-stage lung cancer?

PURPOSE: Recently, segmentectomy has been considered as an alternative to lobectomy in early peripheral non-small lung cancer (NSCLC); however, controversy has remained regarding the long-term functional advantage after segmentectomy. The aim of this study was to analyze the postoperative lung function after segmentectomy and lobectomy for non-small cell lung cancer. METHODS: Patients with p-T1aN0M0 NSCLC who had undergone segmentectomy (n = 37) or lobectomy (n = 33) were retrospectively analyzed. The ratios of postoperative to preoperative forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were defined as the recovery rates. The radiological lung volume and weight were evaluated before and more than 6 months after surgery, and the postoperative values were compared with the predicted values that were calculated from the preoperative values, subtracting the resected lobes or segments. RESULTS: The clinical characteristics, including the preoperative lung function showed no significant differences between the groups. No statistical differences were recognized in the trend lines for recovery ratios of FVC and FEV1.0 (P = 0.96 and P = 0.33). The recovery ratios for radiologic lung volume and weight showed no significant differences (P = 0.46 and P = 0.22). The postoperative lung volume and weight were almost the same as the predicted values after segmentectomy, whereas those after lobectomy were significantly higher than the predicted values. CONCLUSIONS: No functional advantage for segmentectomy was observed during long-term follow-up, possibly due to compensatory lung growth after lobectomy.

Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells.

The role of invariant natural killer T (iNKT) cells in antitumor immunity has been studied extensively, and clinical trials in patients with advanced cancer have revealed a prolonged survival in some cases. In recent years, humanized blocking antibodies against co-stimulatory molecules such as PD-1 have been developed. The enhancement of T cell function is reported to improve antitumor immunity, leading to positive clinical effects. However, there are limited data on the role of PD-1/programmed death ligand (PDL) molecules in human iNKT cells. In this study, we investigated the interaction between PD-1 on iNKT cells and PDL on antigen-presenting cells (APCs) in the context of iNKT cell stimulation. The blockade of PDL1 at the time of stimulation resulted in increased release of helper T cell (Th) 1 cytokines from iNKT cells, leading to the activation of NK cells. The direct antitumor function of iNKT cells was also enhanced after stimulation with anti-PDL1 antibody-treated APCs. According to these results, we conclude that the co-administration of anti-PDL1 antibody and alpha-galactosylceramide (αGalCer)-pulsed APCs enhances iNKT cell-mediated antitumor immunity.

A phase II trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 6711 L (PEOPLE Study).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. METHODS: Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non-AE-IPF rate during postoperative days 0-30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. RESULTS: From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7-99.4 %, p = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5-99.9 %, p = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3-5 adverse events were observed. CONCLUSIONS: Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients. TRIAL REGISTRATION: This clinical trial was registered with the University Hospital Medical Information Network (UMIN) on April 16th, 2012 (REGISTRATION NUMBER: UMIN000007774 ).

Evolution of a Lung-Sparing Strategy with Sleeve Lobectomy and Induction Therapy for Non-small Cell Lung Cancer: 20-Year Experience at a Single Institution.

BACKGROUND: To elucidate the evolution of a lung-sparing strategy with sleeve lobectomy (SL) and induction therapy for non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed 205 patients with NSCLC who underwent pneumonectomy (PN, n = 54) or SL (n = 151) from 1994 to 2013. The study period was divided into four 5-year periods, and surgical trends were analyzed, focusing on the PN:SL ratio. RESULTS: PN was associated with a significantly advanced pathological stage, a larger tumor size and less pulmonary function compared with SL. The PN group had higher 30-day (3.7 vs. 0 %, p = 0.018) and 90-day (13.0 vs. 1.3 %, p = 0.0003) mortality than the SL group. The overall 5-year survival rate was significantly higher with SL (71.5 %) versus PN (42.8 %, p = 0.011) for patients with pN0-1. The ratio of PN among total surgeries decreased significantly over the four periods (1994-1998, 1999-2003, 2004-2008, and 2009-2013) from 5.63 % to 3.17, 1.40, and 1.38 %, respectively (p < 0.0001); in contrast, the PN:SL ratio increased significantly from 1.64 to 2.50, 3.71, and 5.44, respectively (p = 0.041). During the last period, when we introduced induction therapy, 38 of 651 who received surgery underwent induction therapy. The PN:SL ratios of those who did and did not undergo induction therapy were 15 (PN: 1, SL: 15) and 4.25 (PN: 8, SL: 34), respectively. CONCLUSIONS: A lung-sparing strategy with SL for NSCLC can decrease the PN rate to less than 2 % with less mortality. Induction therapy may facilitate SL and increase the PN:SL ratio.

Risk factors predictive of atrial fibrillation after lung cancer surgery.

Postoperative atrial fibrillation (POAF), the most frequent arrhythmia after pulmonary resection, is a cause of both morbidity and mortality. Being able to predict the risk of POAF before surgery would help us evaluate the surgical risk and plan prophylaxis. We investigated the reported preoperative risk factors associated with the incidence of POAF and found that the recommended predictive factors were quite variable. Therefore, we evaluated the previously reported preoperative risk factors for POAF using our institutional data. We discuss our findings in this short review. Male gender, resected lung volume, brain natriuretic peptide (BNP), and left ventricular early transmitral velocity/mitral annular early diastolic velocity (E/e') calculated by echocardiography were suggested as independent predictors for POAF, but the predictive values of each individual parameter were not high. The lack of definitive predictors for POAF warrants further investigations by gathering the reported knowledge, to establish an effective preoperative examination strategy.

Is left upper lobectomy for lung cancer a risk factor for cerebral infarction?

PURPOSE: Cerebral infarction is a rare complication of lung resection that can result in severe sequelae. Our aim was to investigate the characteristics of patients who suffer from cerebral infarction after surgery for lung cancer. METHODS: We retrospectively reviewed all patients who underwent resection of at least a single lobe for lung cancer at our institution between January 2008 and October 2013. We compared the patients who presented with cerebral infarction with those patients who did not within 30 days of surgery. RESULTS: A total of 562 patients underwent surgery, with five males and one female subsequently experiencing cerebral infarction. Five patients underwent left upper lobectomy and one underwent left lower lobectomy. Patient age, sex, body mass index, smoking index, and operative time were not significantly different between the six patients with postoperative cerebral infarction and the other 556 patients; only the type of operative procedure was significantly different (p < 0.001). Contrast-enhanced computed tomography revealed thrombosis in the stump of the left superior pulmonary vein in patients with postoperative cerebral infarction. CONCLUSIONS: Cerebral infarction occurs at a high frequency in patients who undergo left upper lobectomy for lung cancer. Thrombosis in the left superior pulmonary-vein stump might cause cerebral infarction.

[The History and Development of Experimental Rodent Models of Chronic Lung Allograft Dysfunction after Lung Transplantation].

Chronic lung allograft dysfunction (CLAD) is a critical impediment to the long-term survival after lung transplantation. A rat orthotopic lung transplantation model was developed in the early 1970s, and using this model, our laboratory has shown that the immunopathogenesis of CLAD involves both allogeneic immunity and autoimmunity. However, further investigation of CLAD is limited by the scarcity of transgenic and knockout strains. The model most widely used to study CLAD, the mouse model of heterotopic tracheal transplantation, has some incomplete pathophysiologic features of CLAD, which limits the utility of this model. Unlike other solid organ transplants, vascularized and aerated murine lung transplantation has only recently been developed. We have also reported that minor, but not major, histocompatibility antigens mismatch induced the development of CLAD in murine orthotopic lung transplants and that CLAD development was interleukin-17-dependent. This mini-review underscores the history and development of rodent models of CLAD after lung transplant, including the findings from our previous studies. In addition, the future direction of rodent models is also discussed.

Elastography for Predicting and Localizing Nodal Metastases during Endobronchial Ultrasound.

BACKGROUND: Elastography is a relatively new technology that can generate images reflective of tissue stiffness (elasticity). Neoplastic tissue is usually stiffer than normal structures. OBJECTIVES: The aim of this study was to evaluate the feasibility and utility of elastography when combined with convex-probe endobronchial ultrasound (CP-EBUS) for predicting and localizing metastatic lymph nodes during endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA). METHODS: Consecutive results of endobronchial elastography of lymph nodes performed using EBUS- TBNA were prospectively collected and retrospectively analyzed. Elastography images were acquired as JPEG images and also recorded as video clips. Stiff area ratios [(stiff areas as blue pixels) / (lymph node areas as region of interest pixels)] for each lymph node determined by elastography were collated with the results of pathological diagnosis. We also performed elastography of surgically resected lymph nodes and compared image findings with pathological sections. RESULTS: We evaluated 49 lymph nodes in 21 patients by CP-EBUS. There were 16 metastatic nodes (10 lung cancer metastases and 6 metastases from extrathoracic malignancies). Mean stiff area ratios were significantly greater for metastatic lymph nodes (0.478) than for benign nodes (0.216; p = 0.0002). Using a cutoff value of 0.311 for stiff area ratios, the sensitivity and specificity for predicting metastatic disease were 0.81 and 0.85, respectively. The stiff area was histologically compatible with metastatic distribution in surgically resected lymph nodes. CONCLUSIONS: Endobronchial elastography is feasible for lymph nodes when combined with CP-EBUS. Stiff area ratios are useful for predicting metastatic lymph nodes, which may be an efficient guide for TBNA.

Sarcomatous Components May Predict Prognosis in Patients with Pulmonary Pleomorphic Carcinoma.

OBJECTIVES AND METHODS: Pulmonary pleomorphic carcinoma often presents with clinically aggressive behavior. We retrospectively reviewed 16 patients who underwent surgery from 1999 to 2013. RESULTS: Sarcomatous components included spindle cell type in six (38%) patients, giant cell type in three (19%) patients, and mixed cell type in seven (44%) patients. The 5-year overall survival rate was 40.6%. On univariate analysis, spindle cell type, pN0, and small tumor diameter were associated with better prognosis. The 5-year survival of six patients with spindle cell type was 83.3%. CONCLUSIONS: Despite the small sample size, we suggest that patients with spindle cell type may have favorable prognoses.