Graft protective effects and donor-specific antibody suppression by CD4+CD25+Foxp3+ regulatory T cell induced by HMG-CoA reductase inhibitor rosuvastatin in a murine heart transplant model.

BACKGROUND: We previously demonstrated that the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statins) play an important role in the regulation of alloimmune responses. However, little is known regarding the effects of statin on allograft protection or donor-specific antibodies (DSA). In this study, we investigated the graft-protective and immunomodulatory effects of rosuvastatin in a model of fully major histocompatibility complex-mismatched murine cardiac allograft transplantation. METHODS: CBA mice underwent transplantation of C57BL/6 (B6) hearts and received 50 and 500 µg/kg/day of rosuvastatin from the day of transplantation until seven days after the completion of transplantation. To confirm the requirement for regulatory T cells (Tregs), we administered an anti-interleukin-2 receptor alpha antibody (PC-61) to rosuvastatin-treated CBA recipients. Additionally, histological and fluorescent staining, cell proliferation analysis, flow cytometry, and DSA measurements were performed. RESULTS: CBA recipients with no treatment rejected B6 cardiac graft acutely (median survival time [MST], 7 days). CBA mice treated with 500 µg/kg/day of rosuvastatin prolonged allograft survival (MSTs, 77 days). Fluorescent staining studies showed that rosuvastatin-treated recipients had strong aggregation of CD4+Foxp3+ cells in the myocardium and around the coronary arteries of cardiac allografts two weeks after grafting. Flow cytometry studies performed two weeks after transplantation showed an increased number of splenic CD4+CD25+Foxp3+ T cells in rosuvastatin-treated recipients. The addition of rosuvastatin to mixed leukocyte cultures suppressed cell proliferation by increasing the number of CD4+CD25+Foxp3+ Tregs. Additionally, Tregs suppressed DSA production in rosuvastatin-treated recipients. CONCLUSION: Rosuvastatin treatment may be a complementary graft-protective strategy for suppressing DSA production in the acute phase, driven by the promotion of splenic and graft-infiltrating CD4+CD25+Foxp3+ Tregs.

Evaluation of factors affecting epidermal growth factor receptor tyrosine kinase inhibitor-induced hepatotoxicity in Japanese patients with non-small cell lung cancer: a two-center retrospective study.

BACKGROUND: Gefitinib and erlotinib, are epidermal growth factor receptor tyrosine kinase inhibitors, and are currently recommended for non-small cell lung cancer stage IV in the elderly and in patients with decreased performance status in the Japanese Lung Cancer Society Guideline, but they occasionally caused severe hepatotoxicity requiring postponement or modification of treatment. However, little is known about the risk factors for hepatotoxicity in patients receiving gefitinib and erlotinib. In this study, we investigated the factors influencing hepatotoxicity in Japanese non-small cell lung cancer (NSCLC) patients treated with gefitinib or erlotinib monotherapy. METHODS: Japanese patients with NSCLC who started gefitinib or erlotinib monotherapy from January 2005 to December 2017 at Kanazawa University Hospital or Kanazawa Medical University Hospital were included in this study. Factors affecting hepatotoxicity were retrospectively investigated by multiple logistic regression analysis. RESULTS: A total of 102 patients who received gefitinib and 95 patients who received erlotinib were included in the analysis. In the gefitinib group, a body mass index (BMI) ≥ 25 was associated with an increased risk of hepatotoxicity (OR = 4.571, 95% CI = 1.486-14.056, P = 0.008). In the erlotinib group, concomitant use of acid-suppressing medications (AS), namely proton pump inhibitors or histamine-2 receptor antagonists, was associated with a reduced risk of hepatotoxicity (OR = 0.341, 95% CI = 0.129-0.900, P = 0.030). CONCLUSIONS: BMI ≥ 25 in patients treated with gefitinib increased the risk of hepatotoxicity. In contrast, AS combination with erlotinib reduced the risk of hepatotoxicity. Thus, because different factors influence the risk of hepatotoxicity, monitoring for adverse events should take into account patient background factors and concomitant medications.

Effects of combined one-lung ventilation and intrathoracic carbon dioxide insufflation on intrathoracic working space when performing thoracoscopy in dogs.

OBJECTIVE: To evaluate the effects of combining one-lung ventilation and carbon dioxide insufflation (OLV-CDI) on intrathoracic working space (determined by means of CT) during thoracoscopy in dogs and investigate conditions that could safely improve working space compared with OLV alone. ANIMALS: 6 healthy Beagles. PROCEDURES: Dogs were anesthetized, and right- or left-sided (n = 3/side) OLV was instituted. On the blocked side, a laparoscopic trocar sleeve was placed in the ninth intercostal space for CDI. CT was performed under 3 conditions: with OLV alone, with OLV-CDI at an intrapleural pressure (IPP) of 3 mm Hg, and with OLV-CDI at an IPP of 5 mm Hg. Working space volume (WSV), ventilation space volume (VSV), and thoracic cavity volume (TCV) were determined from CT images. RESULTS: With OLV-CDI at an IPP of 3 or 5 mm Hg, WSV and TCV were significantly increased, compared with values obtained during OLV alone. With OLV-CDI at an IPP of 5 mm Hg, VSV and Spo2 were significantly decreased, compared with values obtained during OLV alone. Additionally, contralateral pneumothorax was observed in 4 dogs at an IPP of 5 mm Hg. CLINICAL RELEVANCE: Combining OLV and CDI could provide a larger working space than OLV alone, even with an IPP of 3 mm Hg, in dogs of limited size. However, an evaluation of the effects on oxygenation and cardiovascular variables is needed before clinical use.

A Case Report on Dysgraphia in a Patient Receiving Blinatumomab: Complex Characters Are Easy to Find in a Handwriting Test.

Recent advances in chemotherapy have led to the emergence of new types of anticancer agents. With these advances, cases of side effects that have not been witnessed in the past have emerged. The systems of side effect evaluation and their grading have been based on the existing knowledge, such as the CTCAE (Common Terminology Standard for Adverse Events) for evaluating adverse drug reactions in cancer chemotherapy clinical trials. Therefore, new types of side effects may be overlooked or underestimated. Blinatumomab is a bispecific T-cell-engager (BiTE) antibody with specificity for CD19 on B cells and CD3 on T cells. Neurological events, such as neuropathy and encephalopathy, are serious side effects of BiTE antibodies. We encountered a case of a 62-year-old woman who experienced short-term memory impairment and dysgraphia after the first blinatumomab administration for Philadelphia chromosome negative (Ph-) B-cell acute lymphoblastic leukemia (ALL). The CTCAE does not include dysgraphia as a classifier for antibody therapies, such as blinatumomab, and immune effector cell-associated neurotoxicity syndrome, which is defined as a Chimeric antigen receptor T cell therapy-related toxicity; dysgraphia is included in the list of symptoms but is not graded. In this case, the severity of dysgraphia differed depending on the complexity of the letters examined. There is no report that the severity of dysgraphia depends on the letters' complexity, and therefore, it may be overlooked when using simple letters. We have reported the characteristics of dysgraphia in this case and the differences observed when judging different letters.

Long-term effects of pleural defect repair using sheet materials in a canine model.

OBJECTIVE: A sheet material is widely used to repair pleural defects due to its excellent pressure resistance. We examined the long-term effects of sheet materials using an animal pleural defect model. METHODS: Beagles were used for this study. The 5-mm circular pleural defects were created at 2 sites on each of the anterior, medial, and posterior lobe and repaired using a 2 cm square sheet material. The frequency of adhesion of those sheets to the thoracic walls and histological changes was examined after 6 months. In this study, three types of sheet materials were examined: polyglycolic acid, nano-polyglycolic acid, and oxidized regenerated cellulose where each sheet was tested with or without coating with fibrin glue, for a total of 6 groups. Each group contained an equal number of defect sites and evaluation of 12 defect sites was conducted. RESULTS: Adhesion was observed in 16 of 72 sites (22%). Presence or absence of adhesion was not affected by the repair method or by the type of sheet material used. However, the use of fibrin glue significantly reduced the occurrence of adhesion (p = 0.023). At the defected sites, the posterior lobe showed significantly less adhesion (p = 0.019). Histologically, the sheet materials caused a thickening of the pleural wall 6-10 times thicker than the normal pleural wall. CONCLUSION: No statistically significant differences regarding the presence or absence of adhesion to the thoracic wall were found among the sheet materials. The use of fibrin glue significantly reduced the adhesion to the thoracic wall.

The kinetics of urinary shedding of BK virus in children with renal disease.

Children with renal diseases are typically treated with immunosuppressive drugs, which place them at high risk of reactivation of the BK virus (BKV). Currently, little is known about the impact of immunosuppressive drugs on the kinetics of urinary shedding of BKV and viral reactivation in pediatric patients with renal diseases. Urine samples were collected monthly for 1 year from 20 children (median age, 9 years; range, 4-15 years) with renal diseases and subjected to real-time PCR. Urinary shedding of BKV was detected in 35% (7/20) of the patients, three of these patients having persistent viral DNA excretion (two cases, twelve times; one case, four times) and four having intermittent viral DNA excretion. Thirty-four of the 240 urine samples contained BKV DNA (median copy numbers, 5.66 log copies/mL; range, 2.45-7.69 log copies/mL). In two of the cases with persistent viral shedding, high copy numbers (range, 4.57-7.69 log copies/mL) of BKV DNA were detected in all 12 urine samples collected. In the other case with persistent viral excretion, a range of 2.45-3.98 log copies/mL of BKV DNA was detected in the four urine samples collected between the 9th and 12th sampling time points. Additionally, high copy numbers (range, 3.12-4.36 log copies/mL) of BKV DNA were detected intermittently in the urine samples of the other four cases. No remarkable correlations were found between the kinetics of BKV DNA loads and urinary findings such as proteinuria and hematuria. The present data demonstrate the kinetics of urinary BKV shedding in pediatric patients with renal diseases. Additionally, no pathogenic role for BKV infection was identified.