Celecoxib promotes the efficacy of STING-targeted therapy by increasing antitumor CD8+ T-cell functions via modulating glucose metabolism of CD11b+ Ly6G+ cells.

Recent studies have shown that activation of the cGAS-STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX-2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX-2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD-1 expression on tumor-infiltrating T-cells and enhanced T-cell activation in tumor-draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4+ CD25+ Foxp3+ regulatory T-cells, it enhanced the expression of costimulatory molecules and glycolysis-associated genes in tumor-infiltrating CD11b+ Ly6G+ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN-γ- and TNF-α-producing CD8+ T-cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists.

Expression of soluble CD27 in extranodal natural killer/T-cell lymphoma, nasal type: potential as a biomarker for diagnosis and CD27/CD70-targeted therapy.

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein-Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.

A Case of Pneumothorax Ex Vacuo Associated with COVID-19.

Pneumothorax is a known complication of coronavirus disease 2019 (COVID-19). The concept of pneumothorax ex vacuo has also been proposed to describe pneumothorax that occurs after malignant pleural effusion drainage. Herein, we present the case of a 67-year-old woman who had abdominal distension for 2 months. A detailed examination led to the suspicion of an ovarian tumor and revealed an accumulation of pleural effusion and ascitic fluid. Thoracentesis was performed, raising the suspicion of metastasis of high-grade serous carcinoma arising from the ovary. An ovarian biopsy was scheduled to select subsequent pharmacotherapy, and a drain was inserted preoperatively into the left thoracic cavity. Thereafter, a polymerase chain reaction analysis revealed that the patient was positive for COVID-19. Thus, the surgery was postponed. After the thoracic cavity drain was removed, pneumothorax occurred, and mediastinal and subcutaneous emphysema was observed. Thoracic cavity drains were then placed again. The patient's condition was conservatively relieved without surgery. This patient may have developed pneumothorax ex vacuo during the course of a COVID-19 infection. Since chronic inflammation in the thoracic cavity is involved in the onset of pneumothorax ex vacuo, careful consideration is required for the thoracic cavity drainage of malignant pleural effusion and other fluid retention.

[Thymic Neuroendocrine Tumor Associated with Multiple Endocrine Neoplasia Type 1].

Multiple endocrine neoplasia (MEN) type 1 is a hereditary syndrome characterized by hyperplasia and adenoma of the parathyroid gland, pancreatic tumor, and pituitary tumor. We report a rare case of thymic neuroendocrine tumor diagnosed after removal of a thymic tumor following pancreatic and parathyroid surgery. A 35-year-old man was diagnosed with MEN type 1 by hypercalcemia and gastrinemia with a ureteral tone. Two well defined nodules in the anterior mediastinum on computed tomography (CT), and a high degree of accumulation on positron emission tomography (PET) was noted. Surgery was performed through a median sternotomy with anterior mediastinal tumor resection. Pathology showed thymic neuroendocrine tumor (NET). Immunostaining results were different from pancreatic NET and duodenal NET, and a diagnosis of primary thymic NET was made. Postoperative radiation therapy was completed as adjuvant therapy, and the patient is alive without reccurrence.

A tumor metastasis-associated molecule TWIST1 is a favorable target for cancer immunotherapy due to its immunogenicity.

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen-derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor-specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1140-162 , which effectively activated TWIST1-specific CD4+ T-cells. In a short-term culture system, we detected more TWIST1-specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1-reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.

Broad locations of antigenic regions for anti-TRPM1 autoantibodies in paraneoplastic retinopathy with retinal ON bipolar cell dysfunction.

PURPOSE: Cancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. METHODS: The antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. RESULTS: The clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients' clinical course. CONCLUSIONS: The antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.

INNER MACULAR CHANGES AFTER VITRECTOMY WITH INTERNAL LIMITING MEMBRANE PEELING FOR RHEGMATOGENOUS RETINAL DETACHMENT: Similarity With Alport Syndrome.

PURPOSE: The internal limiting membrane (ILM), the innermost basement membrane of the retina, is peeled occasionally during vitreous surgery. This study aimed to investigate the effect of ILM loss on the retina. METHODS: We used optical coherence tomography to retrospectively evaluate retinal changes in 26 eyes (11 ILM-peeled and 15 ILM-unpeeled eyes) of 26 patients after vitrectomy for retinal detachment. In addition, we studied six eyes of three patients with Alport syndrome, in which ILM is genetically impaired. RESULTS: We observed significant inner retinal displacement of the foveal pit toward the optic disk with inner retinal thickening in the nasal area (fellow, 191.9 ± 24.3 µm vs. affected, 210.3 ± 31.4 µm; P = 0.048), inner retinal thinning in the temporal area (fellow, 174.3 ± 18.3 µm vs. affected, 142.2 ± 23.6 µm; P < 0.001), foveal thickening (ILM-unpeeled, 217.0 ± 39.4 µm vs. ILM-peeled, 302.0 ± 86.2 µm; P = 0.006), inner retinal dimples predominantly in the temporal area, and deviation between the foveal pit and foveal bulge. Eyes with Alport syndrome exhibited similar findings. CONCLUSION: Internal limiting membrane loss seems to cause characteristic inner retinal changes of the macula in both congenital and acquired conditions.

CLINICAL COURSE OF PARANEOPLASTIC RETINOPATHY WITH ANTI-TRPM1 AUTOANTIBODY IN JAPANESE COHORT.

PURPOSE: To report the clinical course of eyes with paraneoplastic retinopathy caused by an autoantibody against transient receptor potential cation channel, subfamily M, member 1 (TRPM1). METHODS: Ten paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction, including six melanoma-associated retinopathy, from eight institutions in Japan were evaluated for the presence of an anti-TRPM1 antibody. The results of ophthalmic examinations and the presence of anti-TRPM1 antibody were analyzed. RESULTS: Five patients were positive for the anti-TRPM1 antibody. These patients had similar clinical findings in both eyes at the time of diagnosis; relatively preserved best-corrected visual acuity, absence of fundus and optical coherence tomography abnormalities, and specific abnormalities of the electroretinography (ERG); and negative-type ERGs with bright stimulus flashes. One patient whose retinal ON-bipolar cells remained dysfunctional for the entire testing period, although the anti-TRPM1 antibody had disappeared. On the other hand, the ERGs recovered in 2 cases within 2 years after the onset. One case progressed to additional impairment of the photoreceptors with deterioration of ERGs. One case died and the clinical course was unavailable. CONCLUSION: Paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction possess autoantibodies against TRPM1 at the onset of the disease process; however, the clinical course of these eyes can be different.

BETTER PROGNOSIS FOR EYES WITH PRESERVED FOVEAL DEPRESSION AFTER INTRAVITREAL RANIBIZUMAB INJECTION FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION.

PURPOSE: To determine the prognosis of eyes with central retinal vein occlusion that had a preserved foveal depression at the baseline and were treated by intravitreal ranibizumab injections (IRIs). METHODS: The authors reviewed the medical records of 23 eyes of 23 consecutive treatment-naive patients who received IRIs to treat the macular edema due to central retinal vein occlusion. Eyes were classified by the pre-IRI presence or absence of a foveal depression. A foveal depression was defined as a central foveal thickness that was <50 µm thinner than the average thickness at 200 µm temporal and nasal to the central fovea. The characteristics of the two groups were compared. RESULTS: Seven of 23 eyes had a preserved foveal depression before the IRI. The mean number of injections within 12 months after the initial IRI was significantly fewer (P < 0.001) in eyes with foveal depression (1.6 ± 0.5) than in eyes without foveal depression (4.3 ± 1.3). The mean best-corrected visual acuity at 12 months after the initial IRI was significantly better (P = 0.003) in eyes with foveal depression (0.10 ± 0.17 logarithm of the minimum angle of resolution [logMAR] units; 20/25 Snellen units) than in eyes without foveal depression (0.77 ± 0.54 logMAR units; 20/118 Snellen units). CONCLUSION: These results indicate that the prognosis is better for eyes with a foveal depression before the IRI treatment for a macular edema secondary to central retinal vein occlusion.

[Wedge Bronchoplastic Left Upper Lobectomy for Lung Cancer Patient with Abnormal Mediastinal Left Basal Pulmonary Artery].

A 65-year-old man with left lung squamous cell carcinoma was admitted to our hospital for operation. His tumor was located left upper lobe and invaded to the orifice of left upper bronchus. We diagnosed the tumor as cT2aN0M0 and intended to perform radical operation. Preoperative three-dimensional computed tomography (3D-CT) revealed that A9+10 which descended along lower bronchus was arisen from the left main pulmonary artery as a 1st branch of it. A wedge bronchoplastic left upper lobectomy was safely done with preserving the branch. Although this abnormal branching of left pulmonary artery is very rare, we should pay more attention this type of anomaly because unintended injury of the branch causes massive bleeding or ischemia of left lower lobe. Preoperative 3D-CT is useful for detecting the anomaly of pulmonary vessels.

[Two-staged Operation for Bilateral Giant Bullae Successfully Performed with Veno-venous Extracorporeal Membrane Oxygenation( V-V ECMO) for First Surgery].

57-year-old man with bilateral giant lung bullae was admitted to our hospital for dyspnea on exertion as his chief complaint. The size and shape of right lung bullae were bigger and more complicated than those of left lung bullae. He underwent 2-staged bullectomy by video-assisted thoracoscopic surgery (VATS). Left lung bullectomy was expected to be more safely done, and was performed with veno-venous extracorporeal membrane oxygenation( V-V ECMO) prior to right side without any complications. The right lung bullectomy was performed 6 months after 1st operation without V-V ECMO. These reoperations were necessary due to postoperative air leak, however, his respiratory condition was well maintained by his left lung which had already been remarkably improved.

EVALUATION OF SHORT-TERM OUTCOMES OF INTRAVITREAL AFLIBERCEPT INJECTIONS FOR AGE-RELATED MACULAR DEGENERATION USING FOCAL MACULAR ELECTRORETINOGRAPHY.

PURPOSE: To evaluate the relationship between morphological changes and functional improvements assessed using focal macular electroretinograms after intravitreal aflibercept (IVA) injections in eyes with wet age-related macular degeneration. METHODS: The clinical records of 42 eyes of 42 consecutive patients with naive, wet age-related macular degeneration received 3 monthly IVA were reviewed. The best-corrected visual acuity, central foveal thickness, outer retinal thickness, inner retinal thickness at baseline and 1 month after each IVA, and focal macular electroretinograms at baseline and 1 month after the first and third IVA were compared. RESULTS: Best-corrected visual acuity was improved after the third IVA (P = 0.0091). Central foveal thickness and outer retinal thickness showed decreases after every IVA (P < 0.001, respectively). Inner retinal thickness showed a decrease after the second IVA (P = 0.002), after and third IVA (P = 0.001). On focal macular electroretinograms, a- and b-wave amplitudes showed increases after the third IVA (P = 0.0028, P = 0.0012, respectively). Significant correlations were observed between best-corrected visual acuity and central foveal thickness, a-wave amplitude and outer retinal thickness, and b-wave amplitude and inner retinal thickness changes after the third IVA. CONCLUSION: All parameters significantly recovered after three monthly IVA, with a correlation between functional improvements and morphological changes.

Increased Retinal Thinning after Combination of Internal Limiting Membrane Peeling and Silicone Oil Endotamponade in Proliferative Diabetic Retinopathy.

BACKGROUND: The aim of this study was to examine the change in retinal thickness after vitrectomy with internal limiting membrane (ILM) peeling and/or silicone oil (SO) endotamponade in proliferative diabetic retinopathy (PDR). METHODS: The actual amount and ratio of changes in the retinal thickness were calculated. RESULTS: Compared to control eyes in the ILM peeling (-)/SO (-) group, the central, superior inner, and temporal inner retina in the ILM peeling (+)/SO (-) group, the central and superior inner retina in the ILM peeling (-)/SO (+) group, and the central, inferior inner, temporal inner, and nasal inner retina in the ILM peeling (+)/SO (+) group showed a significant reduction of the retinal thickness. The central, superior inner, and temporal inner retina in the ILM peeling (+)/SO (-) group, the central and superior inner retina in the ILM peeling (-)/SO (+) group, and the central, superior inner, inferior inner, and temporal inner retina in the ILM peeling (+)/SO (+) group showed a significantly increased reduction rate of the retinal thickness compared to the control group. CONCLUSIONS: Macular retinal thinning in PDR was observed after ILM peeling and SO endotamponade, and it was increased by the combination of these 2 factors.

Bilateral lacrimal caruncle lesions.

A 65-year-old man was referred to our hospital for the treatment of a lesion on the medial lacrimal canthus of both eyes. He had a history of perinuclear anti-neutrophil cytoplasmic antibodies, i.e., pANCA-positive interstitial pneumonia. Orbital magnetic resonance imaging excluded space occupying lesions, and laboratory testing excluded thyroid-related diseases. The masses were excised, and histopathological examinations showed sebaceous gland hyperplasia and inflammatory changes around the gland. In addition, the specimen from the left eye showed a retention cyst possibly caused by an infection. It was also possible that the use of steroid was involved in the development of the lesions. A relationship between the ANCA and the lesions was not completely eliminated.

[Pulmonary Mucoepidermoid Carcinoma with Hilar Lymph Node Metastasis Complicated by Myelodysplastic Syndrome].

A 65-year-old woman was found to have a mass shadow on chest computed tomography. The patient had been diagnosed as having myelodysplastic syndrome 3 years before admission. She was transferred to our hospital for further examination of the mass in the lower lobe of left lung. The mass was positron emission tomography-positive (SUVmax of 8.6)suggesting a malignant neoplasm. Serum concentrations of carcinoembryonic antigen was elevated to 8.7 ng/ml. Preoperative laboratory studies showed anemia (hemoglobin 6.9 g/dl). Transfusion of red blood cells was performed prior to surgery. Under the video-assited thoracoscopic surgery, left lower lobectomy and lymph node dissection were perfomed. The histopathological diagnosis was mucoepidermoid carcinoma, and the hilar lymph node metastasis positive. There were no postoperative complications, such as infection or bleeding. Chemotherapy with tegafur/uracil was performed after the operation. The patient is currently alive without any recurrence 2 years after the operation.

[Post-pneumonectomy Empyema Successfully Treated with Negative Pressure Wound Therapy].

A 61-year-old man underwent right pneumonectomy for primary lung cancer. Four weeks later, he was referred to our hospital for empyema. After 2 months of irrigation with saline, vacuum-assited closure therapy followed by the open thoracotomy was started. After cleaning thoracic cavity bacteriologically, the thoracoplasty and muscle flap transposition was performed, and the empyema completely disappeared.

[Post-thymectomy Myasthenia Gravis ; Report of a Case].

A 46-year-old woman was referred to our hospital for a tumor in the anterior mediastinum. She had no symptoms of myasthenia gravis(MG). Acetylcholine receptor antibody(AchR-Ab) was within the normal range. The tumor was completely resected by thymectomy. Pathological examination of the tumor identified it as a type AB thymoma (Masaoka stage I). Five days after the surgery, she experienced post-thymectomy MG (raised AchR-Ab and positive tensilon test). Her symptoms improved with anti-cholinesterase and tacrolimus therapy.

Robot-assisted distal gastrectomy and local resection for gastric cancer and gastrointestinal stromal tumor.

Gastrointestinal stromal tumors surrounding the esophagogastric junction are often challenging to resect, with no consensus regarding the optimal surgical technique. Here in, we present a case of concurrent gastric cancer in the antrum and gastrointestinal stromal tumors adjacent to the esophagogastric junction. The patient underwent simultaneous distal gastrectomy and local resection assisted by a surgical robot, avoiding the need for total gastrectomy. The utilization of robot-assisted surgery has become an increasingly popular technique, holding promise for simplifying complex surgical procedures across diverse medical settings.

Primary Dedifferentiated Liposarcoma of the Posterior Mediastinum With a Positive Surgical Margin.

Liposarcoma often occurs in the extremities and retroperitoneum. Primary mediastinal liposarcoma is uncommon, and there is no settled opinion regarding adjuvant therapy after surgery. We have recently experienced a relatively rare case of primary dedifferentiated liposarcoma of the posterior mediastinum. The patient was a 76-year-old woman. An abnormal shadow was noted in the posterior mediastinum. Esophageal submucosal tumor and gastrointestinal stromal tumor were suspected; endoscopic ultrasound-guided fine needle aspiration was performed, but a definitive diagnosis could not be obtained. As the tumor tended to slowly grow, surgical resection was performed. Based on histopathological findings, the patient was diagnosed with primary dedifferentiated liposarcoma of the posterior mediastinum. Owing to the presence of a positive surgical margin, postoperative radiotherapy (60 Gy/24 fr/6 w) was administered. No recurrence was observed after three and a half years of follow-up. The prognosis of primary dedifferentiated liposarcoma of the posterior mediastinum with a positive surgical margin is poor, but postoperative radiotherapy may be useful.

Synchronous multiple lung cancers with hilar lymph node metastasis of small cell carcinoma: A case report.

BACKGROUND: Synchronous multiple lung cancers are rare and refer to the simultaneous presence of two or more primary lung tumors, which present significant challenges in terms of diagnosis and treatment. CASE SUMMARY: We report a case of multiple synchronous lung cancers with hilar lymph node metastasis of small cell carcinoma of unknown origin in a 73-year-old man. Transbronchial lung biopsy revealed squamous cell carcinoma. Although enlargement of lymph node 12u was detected, no distant metastases were observed. The patient was preoperatively diagnosed with T1cN0M0 and underwent thoracoscopic right upper lobectomy with nodal dissection (ND2a). Based on histopathological findings, the primary lesion was squamous cell carcinoma. A microinvasive adenocarcinoma was also observed on the cranial side of the primary lesion. Tumors were detected in two resected lymph nodes (#12u and #11s). Both tumors were pathologically diagnosed as small cell carcinomas. The primary lesion of the small cell carcinoma could not be identified even by whole-body imaging; however, chemotherapy was initiated for hilar lymph node metastasis of the small cell carcinoma of unknown origin. CONCLUSION: Multiple synchronous lung cancers can be accompanied by hilar lymph node metastasis of small cell carcinomas of unknown origin.