[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.

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation.

Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.

Successful management of a mediastinum abscess with sternum destruction caused by MSSA bloodstream infection.

BACKGROUND: Multiple deep organ abscesses associated with Staphylococcus aureus bloodstream infection (SAB) have a high mortality rate, requiring rapid removal or drainage of infective foci with long-term appropriate antimicrobial therapy. Cases in which infective foci cannot be completely removed are challenging for their management. CASE PRESENTATION: A 77-year-old man developed multiple deep organ abscesses associated with SAB. The left anterior chest subcutaneous abscess continued into the right anterior mediastinum and had extensively destroyed the sternum. Necrotizing fasciitis was observed in the bilateral feet. The anterior mediastinum abscess was drained percutaneously, and the chest wall abscess was incised cautiously without causing an external pneumothorax. On the next day, right-sided pyothorax had developed, requiring pleural drainage. On the third day, debridement of anterior chest wall abscess followed by concurrent thoracoscopic pleural curettage and debridement of bilateral feet were performed. Thorough sternal debridement was not performed, considering the risk of respiratory failure due to the sternal defects. On the 24th day, sternum debridement and incisional drainage of sciatic rectus fossa abscess, which had been present since the time of admission, were performed to control persistent infection. The caudal half of the sternal body was resected, leaving the costal cartilage attachments. The general condition further improved without postoperative respiratory failure after the second surgery, leading to a transfer to the general ward on the 43rd day. CONCLUSIONS: We successfully treated the severe multiple deep organ abscesses, including a mediastinum abscess with sternum destruction, by repeated removal of the infective foci while avoiding respiratory failure due to excessive debridement of the anterior chest wall, including the sternum.

Bilobectomy for synchronous multiple lung cancer after COVID-19 pneumonia: a case report.

Coronavirus disease 2019 (COVID-19) is a novel emerging disease and a major risk factor for postoperative complications, especially in thoracic surgery. However, it is unclear how previous COVID-19 infection may affect perioperative management of lung resection patients. A 70-year-old woman visited her primary doctor complaining of chest pain. Chest computed tomography (CT) revealed three abnormal nodules in the right upper and middle lung lobes and synchronous triple primary cancer was suspected. Before we could assess the patient for surgery, she developed a persistent fever. A second chest CT scan revealed newly emerged subpleural ground-glass opacities (GGO) in the right lung. The patient was diagnosed with COVID-19 pneumonia and hospitalized. She was treated for COVID-19 (Clinical Trial: jRCTs031200196) and discharged in a satisfactory condition 10 days later. A right upper and middle bilobectomy was performed 60 days after the patient's initial COVID-19 diagnosis without any complications. Histopathological examination of the nodules identified synchronous triple primary lung cancer. The subpleural right upper and middle lung lobe tissue showed peribronchial lymphocyte infiltration and interstitial thickening. However, immunohistochemical staining for the SARS-CoV-2 antigen and PCR testing for SARS-CoV-2 were both negative. In this case, bilobectomy for triple primary lung cancer was performed safely after COVID-19 pneumonia. Further studies are needed to establish a safe and appropriate perioperative management system for thoracic surgery in patients recovering from COVID-19 pneumonia.

Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer.

BACKGROUND: Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC. METHODS: Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan. RESULTS: Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs. CONCLUSIONS: The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy. TRIAL REGISTRATION NUMBER: UMIN000007321.

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.

Regulatory T cells induce CD4- NKT cell anergy and suppress NKT cell cytotoxic function.

BACKGROUND: Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells. METHODS: Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4+ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array. RESULTS: Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4- NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs. CONCLUSION: Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4- NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.

Precise Anatomical Sublobar Resection Using a 3D Medical Image Analyzer and Fluorescence-Guided Surgery With Transbronchial Instillation of Indocyanine Green.

We developed a novel approach combined with 3D image analyzer and infrared thoracoscopy for pulmonary sublobar resection. The purpose of this study was to investigate the feasibility of this procedure. From October 2014 to April 2018, 65 cases were enrolled, and 58 cases were evaluated. For each case, several virtual sublobar resections were created by 3D image analyzer preoperatively. The surgical margin was measured in each simulated sublobar resection and the most appropriate procedure was selected. Surgical resection with matching virtual sublobar resection was performed using infrared thoracoscopy with transbronchial indocyanine green (ICG) instillation. We evaluated the border clarity of ICG fluorescence to investigate success of ICG injection and compared pre- and postoperative CTs to determine whether the correct area could be removed according to the simulation. We also compared short-term surgical outcomes between the ICG cases and historical segmentectomy cases by propensity score matching. The success rate of transbronchial ICG injections was 89.2% (58/65). These 58 patients were eligible for evaluation of our procedure. Sublobar resection included subsegmental resection (5), simple segmentectomy (15), complex segmentectomy (16), and extended segmentectomy (22). The shortest distances to the surgical margin by simulation and by actual measurement were 21.5 ± 11.2 mm and 23.5 ± 8.3, respectively (P = 0.190). Fifty-four of 58 cases underwent sublobar resection matched with the simulation (93.1% concordance rate). Operative results and short-term outcomes were similar between the 2 groups by propensity score matching. ICG-guided sublobar resection by transbronchial ICG instillation is feasible and applicable to any type of sublobar resection.

Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation.

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.

Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer.

Invariant natural killer T (iNKT) cells exhibit potent antitumor effects upon activation by recognizing a specific glycolipid antigen. We previously performed phase I-II clinical studies to utilize iNKT cells using α-galactosylceramide-pulsed dendritic cells and identified leukotriene B4 12-hydroxydehydrogenase (LTB4DH) as a biomarker highly expressed in T cells derived from non-small cell lung cancer (NSCLC) patients who showed prolonged survival in respond to the iNKT cell immunotherapy. Because LTB4DH expression correlated with prolonged survival of NSCLC patients, we considered LTB4DH to play a role in iNKT cell immunotherapy. We herein demonstrate that the overexpression of LTB4DH in CD4+ or CD8+ T cells increases interferon-γ production and tumoricidal activity in the presence of prostaglandin E2. Moreover, the expression of granzyme a, granzyme b, and perforin mRNA was increased in LTB4DH-overexpressing cells.

A surgical case of lung cancer with poor general status associated with parathyroid hormone-related protein.

Parathyroid hormone-related protein (PTHrP), which is released in the presence of malignant disease, is associated with hypercalcemia. Complete resection of the tumor in such patients is rarely performed because of their poor general condition. We herein report a case of lung cancer associated with PTHrP in a patient whose condition dramatically improved after surgery. We also review the literature on the benefits of various surgical options. Although only a few cases of complete resection in such patients have been reported, the mental and physical condition of the patients improved postoperatively and the median survival time was longer than 12 months. A poor general status is frequently considered a contraindication for surgery, even in a palliative setting; however, we conclude that resection of lung cancer may lead to improved symptom control and survival when the patient's condition is induced by hypercalcemia secondary to PTHrP secretion from the tumor.

Intravenous Immunoglobulin Monotherapy for Granulomatous Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a heterogeneous subset of immunodeficiency disorders. Recurrent bacterial infection is the main feature of CVID, but various non-infectious complications can occur. A 42-year-old woman presented with cough and abnormal chest X-ray shadows. Laboratory tests showed remarkable hypogammaglobulinemia. Computed tomography revealed multiple consolidation and nodules on the bilateral lung fields, systemic lymphadenopathy, and splenomegaly. A surgical lung biopsy specimen provided the final diagnosis of lymphoproliferative disease in CVID, which was grouped under the term granulomatous lymphocytic interstitial lung disease. Interestingly, the lung lesions of this case resolved immediately after the initiation of intravenous immunoglobulin monotherapy.

Chylopericardium following thoracoscopic resection of a mediastinal cyst: A case report.

INTRODUCTION: Thoracic duct cysts are very rare, and diagnosis is often difficult. We report a rare case of chylopericardium following thoracic duct cyst resection. There are no established guidelines on the management of such cases. We reviewed the literature on postoperative complications after thoracic duct cyst resection, and conducted the first thorough review of the etiology and management of chylopericardium in surgical cases. PRESENTATION OF CASE: A 54-year-old male presented with cardiac tamponade due to chylopericardium. He had undergone resection of a thoracic duct cyst 2 years previously, which was complicated by postoperative chylothorax. Chyle accumulation resolved with conservative treatment. DISCUSSION: Chylothorax is a frequent complication following thoracic duct cyst resection, especially in cases where no intraoperative diagnosis is reached. Diagnosis may be difficult due to anomalous location of the cyst, as in our case. Chylopericardium is rarely reported, and may have occurred in our case because of prior pleurodesis. Chyle accumulation can reportedly be managed with diet restrictions in over half of reported cases, especially in cases of lung or mediastinal tumor resection. CONCLUSION: The most important points highlighted by this rare case of chylopericardium secondary to thoracic duct cyst resection are: 1) pedicles should be ligated in cyst resections, regardless of location; 2) careful assessment in the initial surgery may help identify the point of leakage; 3) low-fat diet is the first choice in the initial management of postoperative chylopericardium, but surgical repair may be considered in cases with no response after>2 weeks of conservative treatment.

A case of respiratory infection possibly caused by Mycobacterium triviale: Current problems on diagnostic and therapeutic strategies.

Mycobacterium triviale is a subspecies of the Mycobacterium terrae complex, which rarely causes disease in humans. We encountered a case of respiratory infection, possibly caused by M. triviale, which was successfully treated by levofloxacin and clarithromycin. Although DNA-DNA hybridization identified M. triviale in one of three samples, clinical validations convinced us that it was the pathogen. 16s ribosomal RNA sequencing would have been reliable and ideal to perform in this case, although it is not covered by the insurance system in Japan. Nevertheless, this experience remains to be instructive because the clinical course, guidelines on the diagnosis, and therapeutic strategies for respiratory infections caused by M. triviale are not well-known or have not been established. Awareness of the possibility of respiratory infections caused by M. triviale and further collection and analysis of its predisposing conditions are essential.

Rosai-Dorfman Disease of the Lung Overlapping with IgG4-related Disease: The Difficulty in Its Differential Diagnosis.

We herein report a case of Rosai-Dorfman disease (RDD) overlapping with IgG4-related disease (IgG4-RD), which presented as diffuse interstitial lung disease with a perilymphatic pattern, followed by submandibular gland and eyelid swelling. The pathological findings of the submandibular gland biopsy specimen were indicative of IgG4-RD alone. We diagnosed the patient with RDD with overlapping IgG4-RD. However, the optimal method for differentiating between these two entities is still controversial. It is important that clinicians are aware that RDD should be included in the differential diagnoses of diffuse interstitial lung disease with a perilymphatic pattern and that RDD can overlap with IgG4-RD.

Extrathymic malignancies associated with thymoma: a forty-year experience at a single institution.

Objectives: Patients with thymoma are reported to have an increased risk for developing second malignancies. The aim of this study was to assess the incidence of second malignancies among patients with thymoma. We focused especially on the impact that lung cancer has on survival in these patients. Methods: Three hundred and thirty-five patients who underwent surgery for thymoma in Chiba University Hospital from January 1971 to November 2012 were included in this study. Patient records were reviewed retrospectively for data on background, treatment, second malignancies and clinical outcome. Results: Fourteen patients had a history of malignancy until the time of operation, with an additional 20 diagnosed simultaneously with the thymoma. Forty-three malignant lesions in 33 patients were found post-thymectomy. Lung cancer was diagnosed in 17 patients, far exceeding the expected number in the cohort, which was calculated according to Japanese national data. The median survival time of the thymoma patients who had lung cancer at the time of surgery was 5.8 years. The survival of patients with thymoma and lung cancer was poor in comparison with that of others. Conclusions: Secondary lung cancer is frequently found in thymoma patients and could be one of the factors limiting survival. We recommend an annual computed tomographic scan of the thorax to detect not only recurrent thymoma but also lung cancer at an early stage in order to improve the survival of these patients.

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.

Giant bronchogenic cyst with pericardial defect: a case report & literature review in Japan.

Congenital pericardial defects are a rare anomaly, found during autopsy and cardiothoracic surgery. We describe a case of a 69-year-old female, with a right-sided congenital pericardial defect associated with a giant bronchogenic cyst (BC) found during surgery. The cyst was resected and the patient developed arrhythmia following surgery. A review of the literature in Japan was performed, focusing on congenital anomalies associated with pericardial defects and its pathogenesis. We paid particular attention to complications following thoracic surgery in patients with pericardial defects and indications of pericardial reconstruction in such patients.

Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells.

Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti-GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma.