Influenza vaccine showed a good preventive effect against influenza-associated hospitalization among elderly patients, during the 2016/17 season in Japan.

The 2016/17 influenza season in Japan was characterized by a predominance of influenza A (H3N2) activity; with H3N2 accounting for 85% of all detected influenza virus infections. We assessed the vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine (IIV4) in adult patients, using a test-negative case-control design study based on the results of a rapid influenza diagnostic test (RIDT). Between November 2016 and March 2017, a total of 1048 adult patients were enrolled: including 363 RIDT positive for influenza A, 9 RIDT-positive for influenza B, and 676 RIDT-negative. During the 2016/17 season, the overall adjusted VE was 28.8% (95% confidence interval [CI]: 6.3-46%). The adjusted VE against influenza A was 27.4% (95%CI: 4.4-45%). The VE against influenza B could not be estimated because of the very low number of influenza B patients. Twenty-nine patients were hospitalized due to influenza-associated illness-during the present study, all of whom were infected with influenza A virus. The adjusted VE, determined using a case-control study, for preventing hospitalization for influenza A infection was 72.6% (95%CI: 30.7-89.1%). In addition, the VE for preventing hospitalization of influenza patients with comorbidities was 78.2% (95%CI: 41.1-92%). Our study showed that, during the 2016/17season, IIV4 was effective for preventing both the onset of influenza and influenza-associated hospitalization.

TIM-3: a novel regulatory molecule of alloimmune activation.

T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4(+)FoxP3(-) and CD8(+) T cells in acutely rejecting graft recipients. A blocking anti-TIM-3 mAb accelerated allograft rejection only in the presence of host CD4(+) T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-γ-, IL-6-, and IL-17-producing splenocytes, enhanced CD8(+) cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4(+) T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4(+) T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response.

Micro-arteriovenous fistula in patients with lower limb lymphedema.

BACKGROUND: A micro-arteriovenous fistula (AVF) is a minute, short shunt between an artery and a vein that does not pass through a capillary. We investigated the association between micro-AVFs and lymphedema using computed tomography angiography (CTA) and venous blood gas analysis. METHODS: In 95 patients with lower limb lymphedema, the presence or absence of early venous return (EVR) was compared between patients with primary and secondary lymphedema. Furthermore, we investigated the difference in the timing of edema onset in patients with secondary lymphedema with or without EVR using CTA. In 20 patients with lower limb lymphedema with confirmed early EVR in a unilateral lower limb, the partial pressure of oxygen (PO2) was compared between the lower limb with EVR and the contralateral lower limb. RESULTS: Secondary lymphedema with or without EVR occurred at an average of 36.0±59.3 months and 93.5±136.1 months, respectively; however, no significant difference was noted. PO2 was 57.6±11.7 mmHg and 44.1±16.4 mmHg in the EVR and non-EVR limbs, respectively, which was a significant difference (P=0.005). CONCLUSIONS: EVR and venous blood gas analysis suggested the presence of micro-AVFs in patients with lower extremity edema. Further research is warranted to examine the cause of micro-AVFs, to advance technology to facilitate the confirmation of micro-AVFs by angiography, and to improve lymphedema by ligation of micro-AVFs.

Divergent role of donor dendritic cells in rejection versus tolerance of allografts.

Little is known about heart tissue/donor dendritic cells, which play a key role in mounting alloimmune responses. In this report, we focus on three primary features of donor dendritic cells: their generation, their trafficking after transplantation, and their role in regulating tolerance versus rejection. Using transgenic mice as donors of heart allografts enabled us to monitor trafficking of donor dendritic cells after transplantation. Donor dendritic cells rapidly migrated into secondary lymphoid tissues within 3 h of transplantation. We found that the chemokine receptor CX3CR1 regulates the generation of heart tissue dendritic cells constitutively. Compared with wild-type hearts, CX3CR1(-/-) hearts contained fewer dendritic cells, and heart allografts from CX3CR1(-/-) donors survived significantly longer without immunosuppression. Unexpectedly, though, co-stimulatory blockade with anti-CD154 or CTLA4-Ig induced long-term survival for wild-type heart allografts but not for CX3CR1(-/-) heart allografts. Increasing the dendritic cell frequency in CX3CR1(-/-) hearts by treatment with Flt3L restored the anti-CD154-induced prolongation of CX3CR1(-/-) heart allograft survival. Compared with wild-type donors, depleting transgenic donors of dendritic cells before heart transplantation also markedly worsened chronic rejection under anti-CD154 treatment. These data indicate the importance of the CX3CR1 pathway in the generation of heart tissue dendritic cells and the divergent role of tissue/dendritic cells in rejection versus tolerance.

[A patient with pulmonary metastasis from breast cancer after surgery who responded to S-1].

We report a 60-year-old female with pulmonary metastasis from breast cancer who responded to S-1. In November 2001, she underwent surgery. In October 2005, relapse was detected. As there was no hormone sensitivity, chemotherapy was selected, and oral administration of S-1 at 120 mg/day (2 divided doses) was initiated. After the fourth course, the tumor marker level returned to the reference value. Thoracic CT at the end of the sixth course revealed the disappearance of the metastatic focus. Adverse reactions during the administration period were mild. S-1 showed potent antitumor effects and good tolerance, and it may be useful for treating metastatic/recurrent breast cancer.

JNK (c-Jun NH2 terminal kinase) and p38 during ischemia reperfusion injury in the small intestine.

BACKGROUND: In small intestinal ischemia reperfusion injury, we investigated the pathophysiological role of c-Jun NH2 terminal kinase (JNK) and p38 in order to determine whether the dual inhibition of JNK and p38 was beneficial. METHODS: Ischemia reperfusion injury was induced by clamping the superior mesenteric artery for 30 min in Wistar male rats. The inhibition of JNK and p38 was achieved with LL-Z1640-2 as a novel JNK and p38 dual inhibitor in vivo. Between the non-treatment group (Control group) and the LL-Z1640-2 treatment group (LL-Z group), the following findings were compared; histological damage by hematoxylin and eosin (H. E.) staining, JNK and p38 activation by a kinase assay, the localization of apoptosis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, the localization of activated JNK and activated p38 based on immunohistochemistry. RESULTS: The activation of JNK and p38 increased remarkably after reperfusion according to a kinase assay. In immunohistochemistry for activated JNK and activated p38, a remarkable degree of positive staining was revealed in the nucleus of the detached epithelial cells from the tip of villi after reperfusion. In addition, many TUNEL positive cells were observed in the detached epithelial cells where JNK and p38 were activated. Pretreatment of LL-Z1640-2 inhibited the activation of JNK and p38, and also significantly improved the histological damage. CONCLUSIONS: These results suggest that JNK and p38 both play a key role during small intestinal ischemia reperfusion injury through a proapoptotic action on the tip of villi.

[Examination of the safety of docetaxel/cyclophosphamide combination therapy for advanced recurrent breast cancer].

In the treatment of recurrent breast cancer in patients previously treated with anthracycline drugs, taxane drugs are generally used. This time, we retrospectively studied the safety of docetaxel/cyclophosphamide combination therapy (hereinafter referred to as TC therapy). Ten patients (mean age: 52.8 years old) were included in the study. Metastatic/recurrent sites included 3 skin, 2 each of contralateral breast, lung and bone, and 1 each of liver, carcinomatous pleurisy and supraclavicular lymph node. Seven patients had a history of anthracycline treatment. The patients received TC at doses of 60 mg/m(2) and 500 mg/m(2), respectively, every 3 weeks. With regard to adverse events, non-hematotoxic events included alopecia in all the patients, generalized malaise in 5, and abnormal nail in 1. Hematotoxic events were grades 2 and 3 decreased neutrophil count in 5 patients. One patient had grade 4 pyrexia associated with oral candida. The patient was admitted and treated with fluid replacement and granulocyte colony-stimulating factor (G-CSF). There were no other patients in whom the treatment was prolonged or dosage was reduced due to adverse reactions. TC therapy is considered to be a beneficial treatment method in terms of safety since it can be instituted on an outpatient basis.

[A case of postoperative pulmonary metastasis of breast cancer treated with docetaxel and cyclophosphamide therapy].

A 55-year-old woman underwent a partial breast resection in our hospital for breast cancer in May 2002. For adjuvant therapy, she received cyclophosphamide, pirarubicin and 5-FU infusion a total of 6 times, and anastrozole. Then, in May of 2004, an abnormal shadow was detected on her of chest X-ray. After CT scan we diagnosed multiple pulmonary metastasis of breast cancer. We used combination therapy of docetaxel 60 mg/m(2) and cyclophosphamide 500 mg/m(2). After 9 months, pulmonary metastasis disappeared on her CT scan. During chemotherapy, she showed no major side effect.

PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.

The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-gamma-producing alloreactive T cells and expansion of effector CD8(+) T cells in the periphery, and a decline in the percentage of Foxp3(+) graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.

One-stage surgical management of concomitant abdominal aortic aneurysm and gastric or colorectal cancer.

One-stage surgical management of concomitant abdominal aortic aneurysm (AAA) and gastric or colorectal cancer should provide certain benefits. We reviewed the records of 21 patients with both AAA and gastric or colorectal cancer who underwent one-stage surgical management. Four had distal gastrectomy, 2 had total gastrectomy, and 5 had abdominoperineal rectal resection transperitoneally; 3 had total gastrectomy transperitoneally and AAA repair extraperitoneally. Two underwent right hemicolectomy and thromboexclusion of the AAA. Two had creation of a temporary ileostomy and implantation of an interposition graft. Two underwent left hemicolectomy, creation of a temporary transversostomy, and implantation of an interposition graft. One had a Hartmann's procedure and implantation of a bifurcated prosthetic interposition graft for AAA. There were no operative deaths or serious postoperative complications. One patient had colorectal ischemia that resolved with conservative treatment. Eighteen of the 21 patients (85.7%) were alive 10 months to 14 years postoperatively. In conclusion, one-stage surgical treatment of concomitant AAA and gastric or colorectal cancer is well tolerated and can avoid the time, financial costs, and patient anxiety involved in a second operation.

Effects of preinjury administration of corticosteroids on pseudointimal hyperplasia and cytokine response in a rat model of balloon aortic injury.

Restenosis occurs in approximately one-third of patients with coronary or peripheral vascular disease who undergo balloon angioplasty or a surgical bypass procedure primarily because of the development of pseudointimal hyperplasia (PIH). Corticosteroids were effective in suppressing PIH in several experimental studies, but no clinical studies have been reported. To resolve this discrepancy, we studied the effects of preinjury administration of several doses of methylprednisolone (MP) at targeted times in a rat model of balloon aortic injury. Rats were given either no treatment or an intravenous injection of MP (0.5, 5.0, 50, or 500 mg/kg) 2 hours before aortic injury. Four hours later interleukin-6 (IL-6), IL-10, and macrophage migration inhibitory factor (MIF) concentrations in serum and tissue of injured aortas were assessed. Two weeks after injury, damaged aortas were harvested and studied histopathologically. Compared with results in controls, MP at a dose of 5 mg/kg significantly inhibited increases in plasma and tissue levels of IL-6 and significantly reduced the pseudointimal area, pseudointimal/medial area ratio, and proliferating cell nuclear antigen index in injured vessels. Administration of MP had no significant effect on the IL-10 or MIF level. Thus in a rat model of balloon aortic injury, preinjury administration of MP 5 mg/kg mitigated the development of PIH and cell proliferation and suppressed the postinjury increase in serum and tissue IL-6 concentrations. These results suggest that there is an appropriate dosage as well as appropriate timing for MP administration to suppress PIH.