[A Case of Pulmonary Pleomorphic Carcinoma in a Hemodialysis Patient Treated with Pembrolizumab].

The patient was a 67-year-old male undergoing maintenance hemodialysis due to chronic renal failure caused by diabetic nephropathy. A left upper lobe resection was carried out for non-small cell lung cancer of the left upper lobe. It was histologically confirmed as pleomorphic carcinoma pT3N0M0, Stage ⅡB. He suffered a relapse with multiple metastases occurring in both lungs 3 months following surgery. The PD-L1 tumor proportion score(TPS)was 90%, indicating a high level of expression; 200mg of pembrolizumab was administered every 3 weeks on non-dialysis days. Two courses of administration achieved a partial response. A total of 17 courses were administered until discontinuation due to drug-induced lung injury.

The enhancing effects of heparin on the biological activity of FGF-2 in heparin-FGF-2-calcium phosphate composite layers.

Orthopedic and dental implants coated with fibroblast growth factor-2 (FGF-2)-calcium phosphate composite layers promote dermis formation, bone formation, and angiogenesis because of the biological activity of FGF-2. Enhancing the biological activity of FGF-2 in the composite layers is important for its wider application in orthopedics and dentistry. This study incorporated low-molecular-weight heparin (LMWH) into the FGF-2-calcium phosphate composite layers and clarified the enhancing effects of LMWH on the biological activity of FGF-2 in the composite layers in vitro. LMWH-FGF-2-calcium phosphate composite layers were successfully formed on zirconia in supersaturated calcium phosphate solutions. The composite layers comprised continuous and macroscopically homogeneous layers and particles smaller than 500 nm in size composed of amorphous calcium phosphate. The amounts of Ca and P deposited on zirconia remained almost unchanged with the addition of LMWH under the presence of FGF-2 in the supersaturated calcium phosphate solution. The LMWH in the supersaturated calcium phosphate solution increased the stability of FGF-2 in the solution and the amount of FGF-2 in the composite layers. The LMWH in the composite layers increased the mitogenic and endothelial tube-forming activities of FGF-2, and FGF-2 activity of inducing osteogenic differentiation gene expression pattern in the composite layers. Our results indicate that the enhanced biological activity of FGF-2 in the LMWH-FGF-2-calcium phosphate composite layers is attributed to an LMWH-mediated increase in the amount of FGF-2, which maintains its biological activity in the supersaturated calcium phosphate solution and the composite layers. The LMWH-FGF-2-calcium phosphate composite layer is a promising coating for orthopedic and dental implants. STATEMENT OF SIGNIFICANCE: Orthopedic and dental implants coated with fibroblast growth factor-2 (FGF-2)-calcium phosphate composite layers promote dermis formation, bone formation, and angiogenesis because of the biological activity of FGF-2. Enhancing the biological activity of FGF-2 in the layers is important for wider its application in orthopedics and dentistry. This study demonstrates the enhancing effects of low-molecular-weight heparin (LMWH) contained within LMWH-FGF-2-calcium phosphate composite layers on the biological activity of FGF-2 in vitro. Our results indicate that the enhanced biological activity of FGF-2 within the composite layers arises from an LMWH-mediated increase in the amount of FGF-2, which maintains its biological activity in the LMWH-FGF-2-calcium phosphate composite layers and supersaturated calcium phosphate solutions used for coating the composite layers.

Impacts of chemically different surfaces of implants on a biological activity of fibroblast growth factor-2-apatite composite layers formed on the implants.

BACKGROUND: Implants coated with fibroblast growth factor-2 (FGF-2)-apatite composite layers were previously reported to enhance soft-tissue formation, bone formation, and angiogenesis around the implants owing to the biological activity of FGF-2. However, it is unclear whether the chemistries of the material and surface of implants have some impact on the retention of the biological activity of FGF-2 in FGF-2-apatite composite layers on them. Since magnitude of the impact should be evaluated for extensive application of the composite layer to coat various implants, following items were examined; (1) surface chemistries of six implants, (2) mitogenic activities of FGF-2 in FGF-2-apatite composite layers on the implants, and (3) improved synthesis method of the composite layer for retention of the mitogenic activity of FGF-2. HYPOTHESIS: The biological activity of FGF-2 in the composite layer is affected by the chemistries of the material and surface of implants. MATERIALS AND METHODS: Six commercial products of pins and screws having different surface chemistries were coated with FGF-2-apatite composite layers. The composite layers were quantitatively analyzed for calcium (Ca), phosphorus (P) and FGF-2, and also evaluated the mitogenic activities of FGF-2. Improvement of the synthesis method was then attempted using two pin products. RESULTS: Each commercial product had a chemically and morphologically characteristic surface. FGF-2-apatite composite layers were formed on all the commercial products. Although the Ca, P, and FGF-2 contents (4.7±0.9µg/mm, 2.2±0.4µg/mm, and 21.1±3.7ng/mm, respectively) and the Ca/P molar ratios (1.69±0.01) of the composite layers were almost the same, rate of retention of the mitogenic activity of FGF-2 in the composite layers significantly decreased on some pin products (3/12-4/12). The decrease in rate of retention of the mitogenic activity of FGF-2 was prevented by a two-step synthesis method to form a composite layer on a precoating with calcium phosphate (9/12-12/12). DISCUSSION: The chemistries of the implant surfaces had a significant impact on the retention of the mitogenic activity of FGF-2 in the composite layers formed on the implant. The two-step synthesis method was useful to retain mitogenic activity of FGF-2 regardless of the surface chemistries of the implants. The two-step synthesis method has potential to expand the applicability of FGF-2-apatite composite layers to a wider range of implants. LEVEL OF EVIDENCE: III, Case control in vitro study.

Epidemiological features after emergency declaration in Hokkaido and report of 15 cases of COVID-19 including 3 cases requiring mechanical ventilation.

The ongoing spread of coronavirus disease (COVID-19) is a worldwide crisis. Hokkaido Prefecture in Japan promptly declared a state of emergency following the rapid increase of COVID-19 cases, and the policy became an example to mitigate the spread of COVID-19. We herein report 15 cases of COVID-19 including 3 cases requiring mechanical ventilation. Based on review of our cases, among patients over 50 years of age with underlying diseases such as hypertension and diabetes mellitus, and those who required oxygen administration tended to deteriorate. These cases highlight the importance of understanding the background and clinical course of severe cases to predict prognosis.

Therapy-related Secondary Malignancy After Treatment of Childhood Malignancy: Cases from a Single Center.

BACKGROUND: Therapeutic outcomes for childhood malignancy have dramatically improved. However, secondary malignancies are a major concern, as they greatly affect the quality of life of survivors. This retrospective study evaluated the cumulative incidence, clinical features, and outcomes of secondary malignancies at Nippon Medical School Hospital. METHODS: We examined data from 275 cases of primary childhood malignancy diagnosed between 1980 and 2014. Information regarding treatment of the primary malignancy, including irradiation dose, site, and cumulative dose of anticancer drugs, was assessed. We also collected data on secondary malignancy, including patient sex, age at diagnosis, malignancy site, time from primary to secondary malignancy, and outcomes. RESULTS: Secondary malignancies developed in 11 patients and included acute myeloid leukemia (AML) (4), meningioma (4), Ewing sarcoma (1), germ cell tumor (1), and malignant parotid gland tumor (1). The primary malignancies included acute lymphoblastic leukemia (ALL) (9), non-Hodgkin lymphoma (1) and brain tumor (1). In 7 of the 9 ALL patients, chemoradiotherapy was the primary treatment. The meningiomas and 1 solid tumor developed within the radiation field. All AMLs and meningiomas developed within 5 years and after 20 years, respectively, of the primary diagnosis. The 10- and 20-year cumulative incidence rates for secondary malignancy in our hospital were 1.9% and 5.8%, respectively. CONCLUSIONS: Our results revealed that the type of secondary malignancy depends on the interval after the end of treatment for primary malignancy. Meningioma, notably, develops many years after completion of primary malignancy treatment. Early detection during long-term follow-up is therefore essential.

Initial clinical trial of pins coated with fibroblast growth factor-2-apatite composite layer in external fixation of distal radius fractures.

BACKGROUND: Pin tract infection and loosening are major complications and challenges in the treatment of fractures by external fixation. To address this issue, we developed titanium pins coated with a fibroblast growth factor 2 (FGF-2)-apatite composite layer. The purpose of this initial clinical trial is to clarify the safety and feasibility of using these pins for the external fixation of distal radius fractures. METHODS: Unstable, displaced fractures of the distal radius that were medically suitable for external fixation were treated using external fixation pins coated and uncoated with an FGF-2-apatite composite layer. The coated pin group (n = 5) comprised 5 women (average age, 70.4 ±â€¯5.9 years), whereas the uncoated pin group (n = 10) comprised 8 women and 2 men (average age, 64.4 ±â€¯11.7 years). The average duration of external fixation was 40.8 ±â€¯1.3 and 41.6 ±â€¯2.1 days for the coated and uncoated pin groups, respectively. RESULTS: All patients achieved fracture union. One patient in the uncoated group had severe pin tract infection on the day of pin extraction. No pin loosening or difficulty in pin removal was observed in either group. Bacterial growth was present in 5% and 25% of the pin sites in the coated and uncoated groups, respectively (p = 0.059). No adverse events such as tumor formation were observed for more than 2 years after surgery in the coated pin group. CONCLUSIONS: This study clarified the safety and feasibility of using pins coated with an FGF-2-apatite composite layer for the external fixation of distal radius fractures.

Production of autoantibodies by murine B-1a cells stimulated with Helicobacter pylori urease through toll-like receptor 2 signaling.

Helicobacter pylori infection is associated with several autoimmune diseases, in which autoantibody-producing B cells must be activated. Among these B cells, CD5-positive B-1a cells from BALB/c mice were confirmed to secrete autoantibodies when cocultured with purified H. pylori urease in the absence of T cells. To determine the mechanisms for autoantibody production, CD5-positive B-1a cells were sorted from murine spleen cells and stimulated with either purified H. pylori urease or H. pylori coated onto plates (referred to hereafter as plate-coated H. pylori), and autoantibody production was measured by enzyme-linked immunosorbent assay (ELISA). Complete urease was not secreted from H. pylori but was visually expressed over the bacterium-like endotoxin. Urease-positive plated-coated H. pylori stimulated B-1a cells to produce autoantibodies, although urease-deficient isotype-matched H. pylori did not. Autoantibody secretion by B-1a cells was inhibited when bacteria were pretreated with anti-H. pylori urease-specific antibody having neutralizing ability against urease enzymatic activity but not with anti-H. pylori urease-specific antibody without neutralizing capacity. The B-1a cells externally express various Toll-like receptors (TLRs): TLR1, TLR2, TLR4, and TLR6. Among the TLRs, blocking of TLR2 on B-1a cells with a specific monoclonal antibody (MAb), T2.5, inhibited autoantibody secretion when B-1a cells were stimulated with plate-coated H. pylori or H. pylori urease. Moreover, B-1a cells from TLR2-knockout mice did not produce those autoantibodies. The present study provides evidence that functional urease expressed on the surface of H. pylori will directly stimulate B-1a cells via innate TLR2 to produce various autoantibodies and may induce autoimmune disorders.

Effect of AOB, a fermented-grain food supplement, on oxidative stress in type 2 diabetic rats.

Reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic complications. Antioxidant Biofactor (AOB) is a mixture of commercially available fermented grain foods and has strong antioxidant activity. This study investigated the effect of AOB supplementation of standard rat food on markers of oxidative stress and inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes. Blood glucose, hemoglobin A1c, plasma free fatty acid, triacylglycerol and plasminogen activator inhibitor-1 (PAI-1) were significantly higher in OLETF rats than in non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats at 29 weeks. AOB (6.5% of diet) was given to rats during 29-33 weeks of diabetic phase in OLETF rats. OLETF rats with AOB supplementation showed decreased blood glucose, hemoglobin A1c, triacyglycerol, low density lipoprotein, cholesterol and PAI-1. Mitochondrial ROS production was significantly increased in heart, aorta, liver and renal artery of OLETF rats. Uncoupling protein 2 (UCP2) is known to regulate ROS production. We found aortic UCP2 protein expression increased in OLETF rats, and AOB returned UCP2 expression to normal. Aortic endothelial NO synthase (eNOS) was also increased in OLETF rats more than in LETO rats at 33 weeks. In contrast, phosphorylated vasodilator-stimulated phosphoprotein, an index of the NO-cGMP pathway, was significantly diminished. AOB increased eNOS proteins in LETO and OLETF rats. In conclusion, AOB significantly improved the NO-cGMP pathway via normalizing ROS generation in OLETF rats. The data suggest that dietary supplementation with AOB contributes to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus.