Toshiko Kamata

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.

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.

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.

GLUT-1 expression of pulmonary mixed squamous cell and glandular papilloma may be associated with high SUVmax on fluorodeoxyglucose-positron emission tomography: Letter to the Editor

To the Editor: Pulmonary mixed squamous cell and glandular papilloma (PMSGP) is an extremely rare tumor; fewer than 20 cases having been reported according to the 4th edition of the World Health Organization classification. Only two of the published PMSGP cases underwent fluorodeoxyglucosepositron emission tomography (FDG-PET) examination; FDG uptake was abnormally high in both. GLUT-1 is a glucose transporter and its expression on non-small lung cancer cells is thought to correlate with high FDG uptake. We recently encountered a patient with a PMSGP who also showed abnormally high FDG uptake. We therefore surmised that the tumor would express GLUT-1 and confirmed GLUT-1 expression immunohistochemically from the specimen. Our findings thus support the contention that GLUT-1 expression by tumors correlates with high SUVmax on FDG-PET examination. We obtained a comprehensive, preoperative agreement from the patient. A 56-year-old Japanese woman was admitted to our hospital because a routine health check had revealed an abnormal shadow in her right lung base, suggestive of lung cancer. She was a current smoker (one pack per day for 36 years). Computed tomography (CT) revealed a solid mass adjacent to a cystic lesion; the cystic component was contiguous with the bronchus. Longitudinal CT scanning showed a sharp pleural indentation towards the solid mass from the base of the lung. The maximum diameter of the solid mass was 13mm and that of the cystic space 20mm (Fig. 1a). FDG-PET examination revealed high SUVmax in both early and late phases (Fig. 1a, right lower inset), the SUVmax in late phase being higher than in early phase (3.4 in early phase and 4.1 in late phase). We considered these findings highly suggestive of lung cancer with cystic bronchial dilation and removed the lesion. Intraoperative histological biopsy specimen showed PMSGP that extended to the cut end of the bronchus. Although PMSGPs are benign, we performed a right lower lobectomy because the tumor was too close to the main bronchus and the tumor to allow segmentectomy for the residual tumor. Definitive histological examination revealed a papillary tumor arising from the bronchus with ciliated pseudostratified epithelium and protruding into the bronchial lumen, resulting in dilatation of the affected bronchus (Fig. 1b). The tumor had fibrovascular and inflammatory cores that were covered by pseudostratified epithelial cells together with squamoid epithelial cells with basal palisading. Some mucin-containing cells were seen in the outer layer and some ciliated epithelial cells on the outer surfaces of the tumor papillae (Fig. 1c). All these findings are characteristic of PMSGP. Immunohistochemically, the pseudostratified epithelial cells diffusely expressed CK19 and CAM5.2: whereas the basal and parabasal cells expressed CK19 and CAM5.2 weakly, and MIB1, p63 and p40 more strongly. Neither the pseudostratified epithelial cells of the tumor nor the epithelial cells of the nontumorous bronchus surrounding the tumor expressed TTF-1 or Napsin A. GLUT-1 was diffusely expressed on the cell membranes of the tumor epithelial cells, but not on the non-tumorous bronchial epithelial cells or interstitial cells, including inflammatory cells in the papillary core. Within the tumor, GLUT-1 was expressed more strongly on the outer epithelial cells than on the basal cells (Fig. 1d). As solid cancers become more malignant, they generally produce new blood vessels. However, when angiogenesis does not keep pace with tumor growth, tumors need glycolysis because of the resulting hypoxia: they therefore overexpress GLUT. In particular, malignant tumors overexpress GLUT-1, and increased GLUT-1 expression in lung cancer reportedly correlates with poor prognosis. FDG-PET imaging is based on glucose metabolism. GLUT-1 is thought to play a crucial role in FDG accumulation. Including our case, three patients with PMSGP have been documented to have tumors with abnormally high FDG uptake. Tumor GLUT-1 expression was not investigated in these previously reported PMSGP cases. In our case, having been motivated to investigate a possible association between GLUT-1 expression on tumorous epithelial cells, we found that GLUT-1 was diffusely expressed on the tumourous epithelial cells. Indeed, PMSGP is histologically benign. It has fibrovascular core and faces toward bronchial space. It is uncertain whether its microenvironment is hypoxic and therefore needs glycolysis through GLUTs. However, GLUT-1 expression could indicate a relationship between tumorous epithelial cells and malignant transformation. Lagana et al. reported a patient with pleomorphic (spindle and squamous cell) carcinoma that arose from a PMSGP. GLUT-1

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 patients condition is induced by hypercalcemia secondary to PTHrP secretion from the tumor.

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 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.

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

Highlights • A resection of a thoracic duct cyst in the right upper mediastinum resulted in post-operative chylopericardium.• Chylous complications in thoracic duct cysts are frequent when intraoperative diagnosis is not reached, such as in cases with anomalous cyst location.• A review on post-surgical chylopericardium is performed, which will provide information for future management of this rare complication.

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.

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.