Usefulness of free subcutaneous fat pads for refractory secondary pneumothorax due to lung cancer.

Surgical treatment for a pneumothorax involves resection of the pulmonary pleural fistula, and closure of the fistula or coverage of the fistula using pericardial fat pads or an intercostal muscle flap. In some cases, however, these treatments are difficult because of thickened pleura or dense pleural adhesions in the thoracic cavity. We report two cases of refractory secondary pneumothorax due to lung cancer that were successfully treated using free subcutaneous fat pads to cover the pulmonary pleural fistulas. Both patients had advanced lung cancer, and each developed a pneumothorax after chemotherapy or the administration of osimertinib. Each had a prolonged air leak despite chest tube drainage. We harvested a free subcutaneous fat pad around the thoracotomy site and sutured it to cover the fistula. After the operation, the air leak disappeared immediately, and the chest tube was removed from each patient on postoperative day 2. Computed tomography at 2 or 4 months postoperatively demonstrated that the free subcutaneous fat pads were still present with no sign of pneumothorax. Application of free subcutaneous fat pads to cover a persistent pulmonary pleural fistula is useful for the treatment of secondary pneumothorax due to lung cancer.

Granzyme B (GZMB)-Positive Tumor-Infiltrating Lymphocytes in Lung Adenocarcinoma: Significance as a Prognostic Factor and Association with Immunosuppressive Proteins.

BACKGROUND: Granzyme B (GZMB) is a serine protease produced by cytotoxic lymphocytes that reflects the activity of anti-tumor immune responses in tumor-infiltrating lymphocytes (TILs); however, the prognostic significance of GZMB+ TILs in lung adenocarcinoma is poorly understood. METHODS: We analyzed 273 patients with pathological stage (pStage) I-IIIA lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We evaluated GZMB+ TIL counts by immunohistochemistry. We set the cut-off values at 12 cells/0.04 mm2 for GZMB+ TILs and divided the patients into GZMB-High (n = 171) and GZMB-Low (n = 102) groups. Then, we compared the clinicopathological characteristics of the two groups and clinical outcomes. Programmed cell death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumor cells was also evaluated, and combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 were performed. RESULTS: GZMB-Low was significantly associated with pStage II-III, PD-L1 positivity, and IDO1 positivity. Disease-free survival (DFS) and overall survival (OS) in the GZMB-Low group were significantly worse than in the GZMB-High group. In multivariable analysis, GZMB-Low was an independent prognostic factor for both DFS and OS. Furthermore, combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 showed that GZMB-Low with high expression of these immunosuppressive proteins had the worst prognosis. CONCLUSIONS: We analyzed GZMB+ TIL counts in lung adenocarcinoma and elucidated its prognostic significance and association with PD-L1 and IDO1. GZMB+ TIL counts might reflect the patient's immunity against cancer cells and could be a useful prognostic marker of lung adenocarcinoma.

Differences in clinical and cost-effectiveness between cefmetazole and flomoxef for the prevention of surgical site infection in elective colorectal surgery: A single-center, retrospective cohort study.

INTRODUCTION: Surgical site infection (SSI) is associated with increased morbidity and mortality rates, postoperative length of stay (pLOS), and medical costs. In colorectal surgery, cefmetazole (CMZ) and flomoxef (FMOX) are predominantly used in Japan, and they have almost the same spectrum of antibiotic activity against SSI pathogens, and an approximately four-fold cost difference (CMZ: ∼4$, FMOX: ∼16$). However, the difference between these antibiotics in SSI prophylaxis in colorectal surgery remains poorly understood. METHODS: We performed a single-center retrospective cohort study to investigate the prophylactic effects of these antibiotics, pLOS, and hospitalization costs. Patients who underwent elective colorectal surgery between April 2016 and March 2020 were considered for this study. RESULTS: Of the 634 patients, 316 (49.8%) were eligible. The SSI rates in the CMZ and FMOX groups were 14.7% and 12.5%, respectively. The incidence of organ/space SSI was approximately two-fold lower in the CMZ group than in the FMOX group (4.4% vs. 9.4%). Multivariable regression analysis revealed that CMZ was not significantly related to SSI, with an adjusted odds ratio of 1.21 (95% confidence interval [CI]: 0.52-2.82) and did not induce a significant difference in pLOS (difference ratio: 0.951 [95% CI: 0.868-1.041]). Hospitalization costs were reduced in the CMZ group (difference ratio, 0.951 [95% CI: 0.907-0.998], p = 0.042). The sensitivity analysis also showed results similar to the above findings. CONCLUSION: Our study showed that CMZ could be a cost-effective antibiotic with similar efficacy for SSI prophylaxis in colorectal surgery, compared with FMOX.

Novel case of laparoscopically resected gastric adenocarcinoma concurrent with lanthanum deposition.

A 73-year-old man taking lanthanum carbonate for hemodialysis showed progressing gastric mucosal changes with lanthanum deposition. Regular examination revealed concurrent gastric carcinoma. The extent and depth of its invasion were ambiguous because of the surrounding lanthanum deposition. Furthermore, there could be other potent carcinomas, and curative laparoscopic gastrectomy was performed.

[Locally Advanced Gastric Cancer Showing Marked Tumor Shrinkage after the First Dose of Nivolumab for Fourth-Line Chemotherapy].

We report a case of locally advanced gastric cancer, which showed marked tumor shrinkage after the first dose of nivolumab. A 75-year-old woman was diagnosed with locally advanced gastric cancer with pancreatic invasion and pyloric stenosis. We performed gastrojejunostomy before chemotherapy. The first-line, second-line, and third-line chemotherapies were not effective, resulting in tumor progression and necrosis with abdominal wall penetration. Her performance status was good, so we started nivolumab therapy as the fourth-line chemotherapy. Nine days after the first dose of nivolumab, she had a severe abdominal pain and a sense of fatigue. CT imaging showed a remarkable degree of tumor necrosis just beneath the skin. We diagnosed progressive disease and discontinued the chemotherapy. However, her general condition gradually improved and CT imaging 4 months after the first dose of nivolumab showed marked tumor shrinkage. We restarted nivolumab therapy and she has been alive for 2 years 10 months since the introduction of chemotherapy. It was suggested that a single dose of nivolumab only could lead to marked tumor shrinkage in chemotherapy for advanced gastric cancer.

Dramatic response to pembrolizumab with chemotherapy followed by salvage surgery in a lung cancer patient.

Immune checkpoint inhibitors with chemotherapy have been shown to exhibit remarkable efficacy for advanced non-small-cell lung carcinoma and are under investigation as an induction therapy. However, the significance of preoperative therapy with pembrolizumab + chemotherapy for surgically resectable non-small-cell lung carcinoma still remains unclear. Here, we report a case of stage IIIB non-small-cell lung carcinoma that underwent salvage surgery after three cycles of pembrolizumab + carboplatin + nab-paclitaxel. Computed tomography revealed the remarkable decrease in tumor volume by 81%. A pathological examination showed that viable neoplastic cells were observed in <1% of the total tumorous lesion suggesting near pathological complete response. This case suggests that this regimen might be a good option as induction therapy for non-small-cell lung carcinoma.

Axillary arterial angiosarcoma in a nonfunctioning arteriovenous fistula limb of a patient undergoing hemodialysis: case report with literature review.

A 54-year-old man was admitted to our hospital with a painful left axillary mass. He had a 27-year history of hemodialysis for end-stage kidney disease because of chronic glomerulonephritis. He had a right radial artery-cephalic vein arteriovenous fistula and left nonfunctioning arteriovenous fistula. Computed tomography imaging showed a left axillary arterial mass with peripheral hematoma and multiple lung tumors. On hospital day 3, he showed disturbances in consciousness as well as enlargement of the axillary mass and hematoma. We performed emergency surgery to resect the left axillary tumor. The patient was diagnosed with angiosarcoma upon histopathological examination of the resected specimen on hospital day 15. Because his condition was extremely poor, we provided supportive care to him, not chemotherapy. He expired on hospital day 25. Angiosarcoma remains a rare disease; however, this case highlights the importance of including angiosarcoma in the differential diagnosis for upper extremity pain in patients undergoing hemodialysis.

Efficacy of D- red blood cell transfusion and rituximab therapy in autoimmune hemolytic anemia with anti-D and panreactive autoantibodies arising after hematopoietic stem cell transplant.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is caused by autoantibodies to red blood cells (RBCs), which can be panreactive and/or specific to Rh/other blood group antigens. We report a severe case of AIHA after bone marrow transplantation (BMT) due to autoanti-D triggered by reactivation of Epstein-Barr virus (EBV) infection. A combined strategy of D- RBC transfusion and administration of anti-CD20 monoclonal antibody (MoAb) resolved the hemolysis. CASE REPORT: A 33-year-old male underwent allogeneic BMT from an ABO-identical and HLA-matched unrelated male donor. Five months later, while having mild chronic graft-versus-host disease, he manifested AIHA, with a hemoglobin (Hb) level of 5.1 g/dL on AIHA Day 2 (Posttransplant Day 156) and was refractory to D+ RBCs, with a Hb level of 2.4 g/dL on AIHA Day 6. Anti-D-like autoantibodies (titer 1280, subclass immunoglobulin G1 , monocyte monolayer assay 28.7%) and panreactive (titer 40) were identified. Changing the RBC transfusion strategy to D- increased his Hb level to 6.7 g/dL on Day 10. Administration of anti-CD20 MoAb mitigated EBV-related B-cell proliferation and reduced anti-D autoantibody titer to 320 by Day 16 with normalized Hb concentration after 6 months. CONCLUSION: In severe AIHA, when standard treatment and regular RBC transfusions are ineffective, transfusion of RBCs lacking the target antigen(s) of autoantibodies and administration of anti-CD20 MoAb should be considered.

A possible role of low regulatory T cells in anti-acetylcholine receptor antibody positive myasthenia gravis after bone marrow transplantation.

BACKGROUND: Chronic graft-versus-host disease (GVHD) appears several months following allogenic hematopoietic stem cell transplantation (HSCT) and is clinically analogous to autoimmune disorder. Polymyositis is a common neuromuscular disorder in chronic GVHD, but myasthenia gravis (MG) is extremely rare. Hence, its pathophysiology and treatment have not been elucidated. CASE PRESENTATION: A 63-year-old man with a history of chronic GVHD presented with ptosis, dropped head, and dyspnea on exertion, which had worsened over the previous several months. He showed progressive decrement of compound muscle action potential in the deltoid muscle evoked by 3-Hz repetitive nerve stimulation, a positive edrophonium test, and elevated levels of serum anti-acetylcholine receptor antibodies, which suggested a diagnosis of generalized MG. No thymoma was found. Flow cytometric analysis revealed a remarkable depletion of peripheral Tregs (CD4+CD25highFOXP3+ cells, 0.24% of the total lymphocytes). Administration of prednisolone and tacrolimus was insufficient to alleviate his symptoms; however, the use of rituximab successfully improved his condition. CONCLUSIONS: Myasthenic symptoms appeared in the process of tapering prednisolone for the treatment of chronic GVHD, supporting the diagnosis of MG associated with chronic GVHD. The present case proposes a possibility that reduction of Tregs might contribute to the pathogenesis of MG underlying chronic GVHD. Immunotherapy with rituximab is beneficial for treatment of refractory MG and GVHD.

Persistent complete remission of acute leukemic-phase CCR4-positive gamma-delta peripheral T-cell lymphoma by autologous stem cell transplantation with mogamulizumab.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), frequently shows a poor outcome. Especially, expressions of CC chemokine receptor 4 (CCR4) and γδ T-cell receptor (TCR) are associated with worse prognosis in PTCL-NOS. We here report successful treatment with autologous peripheral blood stem cell transplantation (auto-PBSCT) combined with anti-CCR4 antibody mogamulizumab for a very rare case of CCR4+γδTCR+ PTCL-NOS that coexisted with Hodgkin's lymphoma. PTCL-NOS in this patient progressed to leukemic phase, whereas Hodgkin's lymphoma disappeared with standard chemotherapies within 4 years of the initial diagnosis. Leukemic-phase PTCL-NOS was refractory to several chemotherapies. However, auto-PBSCT following high-dose chemotherapy combined with pre- and post-transplant mogamulizumab, which is a humanized monoclonal antibody to CCR4, provided persistent complete remission of PTCL-NOS, despite residual γδTCR+ in the transplanted stem cell product, suggesting a purging effect of mogamulizumab. At 15 months after transplantation, we also found markedly fewer effector regulatory T cells, which may have contributed to prolonged remission. This case suggests that autologous stem cell transplantation combined with mogamulizumab may have a potential to cure T-cell neoplasms that express CCR4 including leukemic-phase PTCL-NOS.

Severe immune thrombocytopenia possibly elicited by the anti-influenza viral agent peramivir.

A 44-year-old man whose platelet count had been at the lower limit of the normal range for years visited the urgent care department of our hospital for treatment of a high fever and severe fatigue. The influenza A virus was detected, and the patient therefore received the intravenous antiviral agent, peramivir. One week later, he developed systemic petechial rashes. A peripheral blood examination showed a markedly decreased platelet count (3.0×10(9) cells/L), and the bone marrow findings were compatible with a diagnosis of immune thrombocytopenia (ITP). Furthermore, a drug-induced lymphocyte-stimulating test was positive for peramivir. The thrombocytopenia slowly responded to treatment with oral prednisolone. This case suggests that neuraminidase inhibitors, including peramivir, can elicit or worsen ITP.

Graft reconditioning with nitric oxide gas in rat liver transplantation from cardiac death donors.

BACKGROUND: Liver transplant outcomes using grafts donated after cardiac death (DCD) remain poor. METHODS: We investigated the effects of ex vivo reconditioning of DCD grafts with venous systemic oxygen persufflation using nitric oxide gas (VSOP-NO) in rat liver transplants. Orthotopic liver transplants were performed in Lewis rats, using DCD grafts prepared using static cold storage alone (group-control) or reconditioning using VSOP-NO during cold storage (group-VSOP-NO). Experiment I: In a 30-min warm ischemia model, graft damage and hepatic expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1) were examined, and histologic analysis was performed 2, 6, 24, and 72 hr after transplantation. Experiment II: In a 60-min warm ischemia model, grafts were evaluated 2 hr after transplantation (6 rats/group), and survival was assessed (7 rats/group). RESULTS: Experiment I: Group-VSOP-NO had lower alanine aminotransferase (ALT) (P<0.001), hyaluronic acid (P<0.05), and malondialdehyde (MDA) (P<0.001), hepatic interleukin-6 expression (IL-6) (P<0.05), and hepatic tumor necrosis factor-alpha (TNF-α) expression (P<0.001). Hepatic eNOS expression (P<0.001) was upregulated, whereas hepatic iNOS (P<0.01) and ET-1 (P<0.001) expressions were downregulated. The damage of hepatocyte and sinusoidal endothelial cells (SECs) were lower in group-VSOP-NO.Experiment II: VSOP-NO decreased ET-1 and 8-hydroxy-2'deoxyguanosine (8-OHdG) expression and improved survival after transplantation by 71.4% (P<0.01). CONCLUSION: These results suggest that VSOP-NO effectively reconditions warm ischemia-damaged grafts, presumably by decreasing ET-1 upregulation and oxidative damage.

Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis.

AIM: Liver fibrosis is a common pathway leading to cirrhosis. Cilostazol, a clinically available oral phosphodiesterase-3 inhibitor, has been shown to have antifibrotic potential in experimental non-alcoholic fatty liver disease. However, the detailed mechanisms of the antifibrotic effect and its efficacy in a different experimental model remain elusive. METHODS: Male C57BL/6J mice were assigned to five groups: mice fed a normal diet (groups 1 and 2); 0.1% or 0.3% cilostazol-containing diet (groups 3 and 4, respectively); and 0.125% clopidogrel-containing diet (group 5). Two weeks after feeding, groups 2-5 were intraperitoneally administered carbon tetrachloride (CCl4 ) twice a week for 6 weeks, while group 1 was treated with the vehicle alone. To investigate the effects of cilostazol on hepatic cells, in vitro studies were conducted using primary hepatic stellate cells (HSC), Kupffer cells and hepatocytes with cilostazol supplementation. RESULTS: Sirius red staining revealed that groups 3 and 4 exhibited a lesser fibrotic area (2.49 ± 0.43% and 2.31 ± 0.30%, respectively) than group 2 (3.17 ± 0.67%, P < 0.05 and P < 0.001, respectively). In vitro studies showed cilostazol dose-dependently suppressed HSC activation (assessed by morphological change, cell proliferation, and the expression of HSC activation markers), suggesting the therapeutic effect of cilostazol is mediated by its direct action on HSC. CONCLUSION: Cilostazol could alleviate CCl4 -induced hepatic fibrogenesis in vivo, presumably due, at least partly, to its direct effect to suppress HSC activation. Given its clinical availability and safety, it may be a novel therapeutic intervention for chronic liver diseases.