Preoperative Hypoalbuminemia Predicts Early Mortality Following Open Abdominal Surgery in Patients Above 60 Years of Age.

BACKGROUND: Major abdominal surgery in older and frail patients is associated with considerable morbidity and mortality. Plasma albumin is routinely measured in the clinic and has been proposed as an indicator of frailty. This study aimed to investigate if plasma albumin is a predictor of mortality in older patients undergoing open abdominal surgery. MATERIALS AND METHODS: We conducted a single-center, register-based retrospective study of patients, aged ⩾60 years who underwent one of 81 open abdominal surgical procedures. Patients operated on during the period from January 1st, 2000 to May 31st, 2013 were consecutively identified in the Danish National Patient Registry. Plasma albumin was measured within 30 days prior to surgery and the primary endpoint was 30-day postoperative mortality. RESULTS: 3,639 patients were included of whom 68.2% underwent emergency surgery. The rate of severe hypoalbuminemia (plasma albumin < 28 g/L) was 43.4%. Preoperative plasma albumin was lower in patients with a fatal 30-day outcome (mean 20.6 g/L vs 30.1 g/L in survivors, p < 0.0001). Other independent predictive parameters of 30-day mortality were age, male sex, and emergency surgery. We present an algorithm including these four variables for the prediction of 30-day mortality for patients aged ⩾60 years undergoing open abdominal surgery. CONCLUSION: Preoperative plasma albumin is a predictor of 30-day mortality in patients above 60 years of age following open abdominal surgery. Assessment of plasma albumin in conjunction with other risk factors such as age, sex, and surgical priority may improve preoperative decision-making.

Fabrication of spectrally sharp Si-based dielectric resonators: combining etaloning with Mie resonances.

We use low-resolution optical lithography joined with solid state dewetting of crystalline, ultra-thin silicon on insulator (c-UT-SOI) to form monocrystalline, atomically smooth, silicon-based Mie resonators in well-controlled large periodic arrays. The dewetted islands have a typical size in the 100 nm range, about one order of magnitude smaller than the etching resolution. Exploiting a 2 µm thick SiO2 layer separating the islands and the underlying bulk silicon wafer, we combine the resonant modes of the antennas with the etalon effect. This approach sets the resonance spectral position and improves the structural colorization and the contrast between scattering maxima and minima of individual resonant antennas. Our results demonstrate that templated dewetting enables the formation of defect-free, faceted islands that are much smaller than the nominal etching resolution and that an appropriate engineering of the substrate improves their scattering properties. These results are relevant to applications in spectral filtering, structural color and beam steering with all-dielectric photonic devices.

Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists.

Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor-associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR-domain-containing adapter-inducing interferon-ß adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-γ-producing CD4(+) and CD8(+) T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers.

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines.

Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4(+) and CD8(+) T cells producing interferon-γ. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-cell-depleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

Extracorporeal photochemotherapy induces arginase 1 in patients with graft versus host disease.

The benefits of extracorporeal photochemotherapy (ECP; psoralen and UVA exposure of blood mononuclear cells) in graft-versus-host-disease (GVHD) are well-recognized, but the mechanisms of action remain elusive. As the metabolism of l-arginine in immune cells is known to play a role in immune tolerance, we investigated the effect of ECP on arginine metabolism, and the influence of extracellular l-arginine concentration on the response to ECP in cells from patients on therapy by ECP for a GVHD and healthy donors cultured before and after ECP in the presence of different concentrations of arginine (0, 50, 100, 200 and 1000 µmol/l). At baseline arginine was not metabolized through the same pathway in patients and donors. When cells were exposed to ECP, the production of ornithine but not NO° was enhanced, while mRNA of arginase 1 was up-regulated but not INOS. In GVHD patients, increasing arginine concentration resulted in down-regulation of IFNγ and TNFα mRNA expression, whereas IL10 was up-regulated especially at physiological plasma levels (between 0 and 100 µM). Overall, our study shows that ECP orients the metabolism of arginine toward the arginase pathway together with shifting the cytokine profile toward IL-10, providing new insights into the enigmatic mechanism of action of ECP.

[Rationale for the use of extracorporeal photochemotherapy in children]. / Argumentaire pour une utilisation plus large de la photochimiothérapie extracorporelle chez l'enfant.

The management of immune diseases in children remains challenging, although significant advances have been made. In addition to pharmacological approaches, extracorporeal photochemotherapy (ECP) is distinctive in its ability to provide immunomodulation without immune suppression or toxicity. However, in practice, this therapy is not widely used because of logistical issues and the lack of robust clinical pediatric studies. Here, we discuss the potential clinical applications of ECP in children and emphasize the need for a rigorous and specifically pediatric clinical evaluation of ECP.

[Extracorporeal photochemotherapy or immunotherapy using cells modified by photochemistry]. / La photochimiothérapie extracorporelle ou l'immunothérapie par cellules modifiées par photochimie.

Extracorporeal photochemotherapy (ECP) is an autologous cell therapy used for the treatment of diseases involving pathogenic cells: cutaneous T-cell lymphoma, organ rejection and graft versus host disease. During an ECP procedure, patients receive a cellular product consisting of autologous mononuclear cells, containing the pathogenic cells, treated with a photosensitising agent and an UV-A radiation. The aim of the treatment is to induce a specific immune reaction modulating the activity of untreated pathogenic lymphocytes responsible for the disease and therefore an improvement of clinical manifestations. The precise mechanisms of action remain to be defined in humans. Its efficacy coupled with the absence of side effects could lead to decrease the use of immunosuppressive drugs. PCE appears as an immunotherapy using cells modified by photochemistry, which allows specific immune modulation of pathogenic lymphocytes.