Abstract: Objective: Solitary pulmonary lesions (SPLs) in patients with a history of malignancy require not only the distinction between benign and malignant, but also that between metastatic and primary lesions. We aim to establish the clinical strategy for the treatment of a solitary pulmonary lesion that is detected during the postoperative surveillance for gastric cancer.
Methods: We retrospectively examined the clinical records of the patients who underwent curative resection for gastric cancer between January 1999 and December 2009. Patients who were diagnosed with solitary pulmonary lesion during the postoperative surveillance underwent pulmonary resection, and were reviewed with regard to their histological diagnosis and prognosis.
Results: Out of a total of 1017 patients who underwent gastric resections during this period, 13 patients with solitary pulmonary lesion underwent pulmonary resection. These tumors were shown to be eight primary lung cancers, four metastatic tumors (three from gastric cancer) and one benign nodule. Of the eight patients with primary lung cancer, seven remained alive after pulmonary resection, including one liver metastasis case, and the other died without recurrence. In contrast, the other three patients with metastasis from gastric cancer died with distant metastasis, despite undergoing curative pulmonary resection. One of these three metastatic patients was misdiagnosed as primary lung cancer by transbronchial biopsy before surgery.
Conclusions: Solitary pulmonary lesions detected during postoperative gastric cancer surveillance should undergo surgical resection to distinguish between primary and metastatic disease because of the quite different prognosis of these two entities.
Abstract: BACKGROUND: Lateral lymph node (LLN) metastasis sometimes occurs in patients with early rectal cancer that has invaded the submucosa (SM) and muscularis propria (MP). This study aims to identify the risk factor(s) for LLN metastasis in such patients. METHOD: We retrospectively analyzed 65 patients with pathological SM or MP lower rectal adenocarcinoma, for whom radical resection had been performed at a single institution. RESULTS: We performed LLN dissection in 52 (80%) patients. The LLN dissection rates in the case of pathological SM and MP tumors were 65.6% and 94.4%, respectively, and the corresponding LLN metastasis rates were 6.9% and 11.1%. Severe tumor budding was found to be a risk factor for LLN metastasis (P = 0.002). Further, of six patients with LLN metastasis, four did not have coincident mesenteric lymph node metastasis. CONCLUSION: In rectal cancer that has pathologically invaded SM and MP, LLN metastasis is not negligible. LLN dissection could lower the local recurrence rate of SM and MP rectal cancer. In case LLN dissection is not performed, patients with a high tumor budding grade should be administered adjuvant therapy.
Abstract: ABSTRACT Background: Inguinal lymph node (ILN) metastasis occurs with high frequency in some of the patients with lower rectal cancer. The aim of this article was to identify risk factors for ILN metastasis in patients with low rectal adenocarcinoma. Method: We retrospectively analyzed 156 patients with lower rectal adenocarcinoma who underwent radical resection (R0) at a single institution. Results: Twenty-five (16%) patients had a tumor that invaded the dentate line, seven of whom had ILN metastasis. Invasion of the dentate line was significantly associated with a high rate of ILN metastasis, worse prognosis and local recurrence than with a tumor not invading the dentate line (P=0.03). A Cox proportional hazard regression analysis revealed the histological characteristics at the invading front (Hif) also to be a risk factor for ILN metastasis. Conclusion: Tumors which invade the dentate line have a high rate of LLN metastases and worse cancer specific end points. The presence of poorly differentiated or mucinous adenocarcinoma components is an indication for bilateral groin irradiation.
Abstract: BACKGROUND: Positive peritoneal washing cytology (PWC) has been reported to be a poor prognostic factor for gastric cancer. Japanese gastric cancer classifications recommend PWC in Douglas' pouch for advanced gastric cancer. However, the sensitivity of PWC is relatively low. The goal of this study was to investigate whether PWC in multiple cavities increases its sensitivity to predict prognosis. METHODS: Between January 1996 and December 2006, a series of 992 patients with gastric cancer underwent D2 gastrectomy with intraoperative PWC. Of the 992 patients, 62 patients had positive PWC. PWC was conducted in four cavities (left subphrenic cavity, right subhepatic cavity, Douglas' pouch, and inside the omental bursa). The 62 patients were retrospectively analyzed for their background and survival. RESULTS: Eleven (17.7%) patients had negative PWC in Douglas' pouch but were positive in the other cavities. The 62 patients were classified into two groups according to the number of positive PWC cavities: 20 patients with one or two and 42 patients with three or four positive PWC cavities. No significant difference in clinicopathological features was observed between these two groups. However, the overall and progression-free survival rates of patients with one or two positive PWC cavities were significantly higher than those for patients with three or more positive PWC cavities. CONCLUSION: PWC in multiple cavities was more sensitive than only in one cavity. The number of positive cavities may indicate the grade of tumor spread in the peritoneum and predict the prognosis of patients with positive PWC.
Abstract: A common mutation in the gene encoding the cytoplasmic sensor Nod2, involving a frameshift insertion at nucleotide 3020 (3020insC), is strongly associated with Crohn's disease. How 3020insC contributes to this disease is a controversial issue. Clinical studies have identified defective production of interleukin 10 (IL-10) in patients with Crohn's disease who bear the 3020insC mutation, which suggests that 3020insC may be a loss-of-function mutation. However, here we found that 3020insC Nod2 mutant protein actively inhibited IL10 transcription. The 3020insC Nod2 mutant suppressed IL10 transcription by blocking phosphorylation of the nuclear ribonucleoprotein hnRNP-A1 via the mitogen-activated protein kinase p38. We confirmed impairment in phosphorylation of hnRNP-A1 and binding of hnRNP-A1 to the IL10 locus in peripheral blood mononuclear cells from patients with Crohn's disease who bear the 3020insC mutation and have lower production of IL-10.
Abstract: The inflammatory response of macrophages to infectious agents is a highly dynamic and orchestrated process involving the release of a variety of inflammatory mediators, including interleukin-12 (IL-12), as a consequence of the recognition of the pathogens. Regulation of IL-12 gene expression by the anti-inflammatory cytokine IL-10 represents a major homeostatic process underlying host-pathogen and host-self interactions. Our group first reported that the Th2-specific transcription factor c-Maf is expressed also in macrophages treated with lipopolysaccharide (LPS) and IL-10. When overexpressed, c-Maf can potently suppress IL-12 production. However, c-Maf does not appear to be a physiologic regulator of IL-12p40 gene transcription because p40 production is not dysregulated in c-Maf-deficient macrophages. In this study, we investigated the role of c-Maf in regulation of the transcription of the p35 gene, which encodes the chain that is rate limiting in the synthesis of the heterodimeric IL-12. We report that c-Maf is a physiologic modulator of IL-12p35 gene expression and IL-12p70 production. We identify a novel NF-kappaB element within the proximal p35 promoter and show that c-Maf inhibits p35 transcription by antagonizing the effects of NF-kappaB, especially c-Rel, on p35 activation. It does so not by directly interacting with the target DNA but by interfering with the nuclear localization of NF-kappaB c-Rel. This study contributes to our understanding of the molecular basis of the homeostatic regulation of IL-12 production by c-Maf, which plays a dual role both in the function of antigen-presenting cells (APCs) and in T helper cell differentiation.
Abstract: Production of interleukin (IL)-10, a major immunoregulatory cytokine, by phagocytes during clearance of apoptotic cells is critical to ensuring cellular homeostasis and suppression of autoimmunity. Little is known about the regulatory mechanisms in this fundamental process. We report that IL-10 production stimulated by apoptotic cells was regulated at the point of transcription in a manner dependent on p38 mitogen-activated protein kinase, partially on the scavenger receptor CD36, and required cell-cell contact but not phagocytosis. By using a reporter assay, we mapped the apoptotic-cell-response element (ACRE) in the human IL10 promoter and provide biochemical and physiological evidence that ACRE mediates the transcriptional activation of IL10 by pre-B cell leukemia transcription factor-1b and another Hox cofactor Pbx-regulating protein 1 in response to apoptotic cells. This study establishes a role of two developmentally critical factors (Pbx1 and Prep-1) in the regulation of homeostasis in the immune system.
Abstract: Interleukin-12 (IL-12) is a heterodimeric cytokine composed of the p35 and p40 subunits. It is produced by antigen-presenting cells and plays a critical role in host defense against intracellular microbial infection and control of malignancy via its ability to stimulate both innate and adaptive immune effector cells. The potency of IL-12 renders itself to stringent regulation of the timing, locality and magnitude of its production during an immune response. Subversion of the delicate control and balance frequently leads to immunologic disorders. In this article, we provide an update, since our last review of the subject four years ago, on recent advances in: (1) uncovering of novel activities of IL-12 and related molecules in various immunological settings and models; and (2) dissection of the physiological pathways involved in the modulation of IL-12 production by pathogens and immune regulators. The increased understanding of IL-12 immunobiology and expression will likely benefit the development of therapeutic modalities to correct immune dysfunctions.
