Esophageal replacement by colon interposition with microvascular surgery for patients with thoracic esophageal cancer: the utility of superdrainage

Replacing the thoracic esophagus with the colon is one mode of reconstruction after esophagectomy for esophageal cancer. There is, however, a high incidence of postoperative necrosis of the transposed colon. This study evaluated the outcomes of colon interposition with the routine use of superdrainage by microvascular surgery. Twenty‐one patients underwent colon interposition from 2004 to 2009. The strategy for colon interposition was to: (i) use the right hemicolon; (ii) reconstruct via the subcutaneous route; (iii) perform a microvascular venous anastomosis for all patients; and (iv) perform a microvascular arterial anastomosis when the arterial blood flow was insufficient. The clinicopathologic features, surgical findings, and outcomes were investigated. The colon was used because of a previous gastrectomy in 18 patients (85.7%) and synchronous gastric cancer in three patients (14.3%). Eight patients (38.1%) underwent preoperative chemoradiotherapy including three (14.3%) treated with definitive chemoradiotherapy. Seven patients (33.3%) underwent microvascular arterial anastomosis to supplement the right colon blood supply. Pneumonia occurred in four patients (19.0%). Anastomotic leakage was observed in five patients (23.8%); however, no colon necrosis was observed. The 3‐year and 5‐year overall survival rates were both 50.6%. Colon interposition with superdrainage results in successful treatment outcomes. This technique is one option for colon interposition employing the right hemicolon.     

Mizoribine for crescentic glomerulonephritis with sarcoidosis: effectiveness not only for urinalysis abnormalities but also for hilar lymph node enlargement

Sarcoidosis is a multisystem disease related to helper T cell responses. We recently experienced the case of a 57-year-old woman with sarcoidosis complicated by crescentic glomerulonephritis with low levels of myeloperoxidase-antineutrophil cytoplasmic antibody. We herein describe the details of her clinical course and discuss the effectiveness of mizoribine, which has an immunosuppressive effect equivalent to that of mycophenolate mofetil, not only for urinalysis abnormalities but also for hilar lymph node enlargement.     

Primary amelanotic malignant melanoma of the small intestine diagnosed by esophagogastroduodenoscopy before surgical resection

A 67-year-old man, presenting with anemia and suspected gastric cancer, was referred to our hospital, where he underwent esophagogastroduodenoscopy (EGD). Biopsy revealed densely populated semi-circular cells with abundant cytoplasm that were positive for S-100 protein, melanoma antigen, and HMB-45, resulting in a diagnosis of malignant melanoma. A gastrointestinal barium study for further exploration demonstrated a filling defect 6 cm in size at the ligament of Treitz. Follow-up EGD of this finding revealed an ulcerated, half-circumferential lesion with a distinct ulcer mound extending from the ascending part of the duodenum to the jejunum, and additional biopsy also indicated malignant melanoma. Computed tomography scans showed wall thickening from the ascending part of duodenum to the proximal jejunum, whereas positron emission tomography revealed accumulation at the upper gastric body, the duodenum to the jejunum, and the left adrenal gland. Systemic exploration of the patient, including the skin, anus, and eyeballs, revealed no other lesions, and primary small intestinal malignant melanoma with metastasis to the stomach and adrenal gland was diagnosed. Partial duodenojejunectomy, partial gastrectomy, and left adrenalectomy were performed, and adjuvant chemotherapy with dacarbazine, nimustine hydrochloride, and vincristine sulfate was administered. No postoperative recurrence has been observed in the past 3 years.     

Endoscopic diagnosis of small intestinal diseases

The technological development in endoscopy is directed toward improved accuracy of the diagnoses of novel diseases. The capsule endoscope and balloon-assisted endoscope are examples of such technological development. By these novel technologies, the small intestine can be examined in more detail. Therefore, an increasing number of novel diseases have been discovered, requiring the establishment of diagnosis and treatment strategies for these unknown diseases. In particular, obscure gastrointestinal bleeding, Crohn’s disease, and nonsteroidal anti-inflammatory drug-induced enteropathy are of great interest to endoscopists. The capsule endoscope is the best method for screening the small intestine; however, the development of supporting methods such as the patency capsule is eagerly desired.     

Galectin-9 prolongs the survival of septic mice by expanding tim-3-expressing natural killer T cells and PDCA-1+ CD11c+ macrophages

Introduction

Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. However, the effect of galectin-9 on polymicrobial sepsis has not been assessed.

Methods

We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in mice. The survival rate was compared between galectin-9- and PBS-treated CLP mice. An ELISA was used to compare the levels of various cytokines in the plasma and culture supernatants. Fluorescence-activated cell sorting analysis was further performed to compare the frequencies of subpopulations of spleen cells.

Results

Galectin-9 exhibited a protective effect in polymicrobial sepsis as demonstrated in galetin-9 transgenic mice and therapeutic galectin-9 administration. In contrast, such effect was not observed in nude mice, indicating the involvement of T cells in galectin-9-mediated survival prolongation. Galectin-9 decreased TNFα, IL-6, IL-10 and, high mobility group box 1 (HMGB1) and increased IL-15 and IL-17 plasma and spleen levels. Galectin-9 increased the frequencies of natural killer T (NKT) cells and PDCA-1⁺ CD11c⁺ macrophages (pDC-like macrophages) but did not change the frequency of CD4 or CD8 T cells, γδT cells or conventional DC. As expected, galectin-9 decreased the frequency of Tim-3⁺ CD4 T cells, most likely Th1 and Th17 cells. Intriguingly, many spleen NK1.1⁺ NKT cells and pDC-like macrophages expressed Tim-3. Galectin-9 increased the frequency of Tim-3-expressing NK1.1⁺ NKT cells and pDC-like macrophages. Galectin-9 further increased IL-17⁺ NK1.1⁺ NKT cells.

Conclusion

These data suggest that galectin-9 exerts therapeutic effects on polymicrobial sepsis, possibly by expanding NKT cells and pDC-like macrophages and by modulating the production of early and late proinflammatory cytokines.     

Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

High-mobility group box 1 (HMGB1) is a DNA-binding protein abundantly expressed in the nucleus that has gained much attention for its regulation of immunity and inflammation. Despite this, whether and how HMGB1 contributes to protective and/or pathological responses in vivo is unclear. In this study, we constructed Hmgb1-floxed (Hmgb1^f/f) mice to achieve the conditional inactivation of the gene in a cell- and tissue-specific manner by crossing these mice with an appropriate Cre recombinase transgenic strain. Interestingly, although mice with HMGB1 ablation in myeloid cells apparently develop normally, they are more sensitive to endotoxin shock compared with control mice, which is accompanied by massive macrophage cell death. Furthermore, these mice also show an increased sensitivity to Listeria monocytogenes infection. We also provide evidence that the loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or L. monocytogenes infection. Thus, intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection by mediating autophagy in macrophages. These newly generated HMGB1 conditional knockout mice will serve a useful tool with which to study further the in vivo role of this protein in various pathological conditions.Of the four members of the high-mobility group box (HMGB) family, HMGB1 is the best studied, given its versatile functions in various aspects of cellular responses (1–5). Ubiquitously expressed in all cells, HMGB1 is found en masse in the nucleus and is supposedly released into the extracellular fluid through an endoplasmic reticulum–Golgi pathway-independent mechanism from immune cells such as monocytes or macrophages after stimulation with lipopolysaccharide (LPS), proinflammatory cytokines, or nitric oxide (1, 6). The release of HMGB1 is also regulated by the inflammasome, a multiprotein oligomer that activates caspase-1 to promote the maturation of inflammatory cytokines, interleukin-1β (IL-1β) and IL-18, and by dying cells, typically those undergoing necrosis (7–10). Secreted or released, HMGB1 is known to participate in the activation of cell surface innate immune receptors, typically Toll-like receptors (TLRs), thereby affecting many aspects of the host’s inflammatory responses upon infection or noxious stresses (1–5). Perhaps most notably is the crucial role of HMGB1 in LPS-induced endotoxemia, whereby administration of an anti-HMGB1 antibody significantly protects mice from lethality (1, 11). The study of released HMGB1 is complicated by a number of complex posttranslational modifications made to the protein, including acetylation and redox modifications that may regulate HMGB1 function (12–14).HMGB1 can regulate immune reactions in several ways. Cytosolic HMGB1, together with the other members of the family, function as universal sentinels or chaperones for immunogenic nucleic acids by facilitating the recognition of nucleic acids by more discriminative, nucleic acid-sensing innate receptors (15–17). In addition, HMGB1 regulates autophagy, a cellular response that functions in clearing long-lived proteins and dysfunctional organelles to generate substrates for adenosine triphosphate (ATP) production during periods of starvation and other types of cellular stress events (13, 18–20). This mechanism contributes to antimicrobial responses against invading microorganisms (21, 22). Indeed, microorganisms can induce autophagy by stimulating innate immune receptors, such as TLRs, by a process in which bacteria are captured by phagocytosis but remain within intact vacuoles, an autophagic process termed microtubule-associated protein light chain 3 (LC3)-associated phagocytosis (LAP), which promotes the maturation of autophagosomes into autolysosomes (23, 24).Collectively, these studies place HMGB1 in the center of immunological events where it uniquely functions intracellularly and extracellularly as a mediator of immune and inflammatory responses. The biological and clinical importance of HMGB1 is underscored by the dysregulation of this protein in a number of pathological conditions, including sepsis, ischemia–reperfusion injury, arthritis, and cancer (1, 3–5). Nonetheless, in vivo validation of the versatile functions described above is lacking due to the lethality of the Hmgb1-deficient mice, thought to cause lethal hypoglycemia in newborn mice (25). In the present study, we describe the generation of Hmgb1-floxed (Hmgb1^f/f) mice that enabled the cell- and tissue-specific deletion of the gene when crossed with an appropriate Cre recombinase transgenic strain. We demonstrate in this study a protective role of intracellular HMGB1 in macrophages where it serves as a crucial regulator of autophagosome formation in the context of LPS stimulation or bacterial infection in vivo. Finally, we will discuss the future prospects of HMGB1 research using these newly generated mutant mice.