Kun-Yun Yeh

Malignant melanoma in Taiwan: a prognostic study of 181 cases.

This study was performed to determine the characteristics and clinical outcome of patients with cutaneous malignant melanoma in Taiwan. The medical records of patients with primary cutaneous melanoma between 1992 and 2001 at Chang Gung Memorial Hospital (CGMH) were retrieved from the cancer registry. Survival was analysed by the Kaplan–Meier method. Univariate and multivariate analyses of factors associated with survival were performed using the Cox proportional hazard model. One hundred and eighty-one cases were retrieved from the cancer registry of CGMH. The male to female ratio was 1u2009:u20091.13. The most common age of onset was the sixth decade. The median age of onset was 61u2009years (2–95u2009years). There were 105 cases (58%) of acral lentiginous melanoma (ALM), 55 cases (30.4%) of nodular melanoma (NM), 19 cases (10.5%) of superficial spreading melanoma (SSM) and two cases (1.1%) of lentigo maligna melanoma. The median survival of the 181 patients was 3.71u2009years, and the 5-year survival rate was 45.63%. Five-year survival rates of patients with stages I, II, III and IV disease were 84.39%, 56.03%, 34.7% and 0%, respectively. Sex, Breslow thickness, Clarks level, pathological type and age were significant prognostic factors. There were no survival differences between ALM and NM. Both ALM and NM were associated with a poor prognosis when compared with SSM. In conclusion, ALM is the most common type of cutaneous malignant melanoma in Taiwan. The prognostic factors in Taiwan are similar to those in melanoma-prevalent countries.

Interleukin-6 (IL-6) released by macrophages induces IL-6 secretion in the human colon cancer HT-29 cell line

The level of interleukin-6 (IL-6) is correlated with prognosis and liver metastasis in colon cancer. However, the relationship between macrophage-derived and tumor-derived IL-6 in colon cancer remains unclear. We harvested the macrophage supernatant and studied the IL-6-inducing ability of the macrophage supernatant on the colon cancer cell line HT-29. The macrophage supernatant effectively induced IL-6 secretion of colon cancer cells in vitro. The macrophage supernatant and recombinant IL-6 neutralized with anti-IL-6 or ant-gp130 antibodies dramatically decreased the IL-6-induction ability of cancer cells. IL-6-induction occurred through phosphorylation of STAT3. We analyzed the surgical specimens of 126 patients with colon cancer using an immunohistochemical staining method and demonstrated the colocalization of macrophages and the expression of IL-6 in colon cancer patients. These results indicate that macrophages in tumor infiltrates could release IL-6, which in turn conditions colon cancer cells, causing them to secrete IL-6 themselves via phosphorylation of STAT3.

Pretreatment performance status and nutrition are associated with early mortality of locally advanced head and neck cancer patients undergoing concurrent chemoradiation

Unexpected fatal events in patients with head and neck cancers undergoing concurrent chemoradiation therapy are a clinical concern. Malnutrition, which is reported frequently in head and neck cancer patients, are associated with immunity derangement. The purpose of this study was to identify risk factors for early death of patients undergoing chemoradiation. We retrospectively analyzed the records of 194 stage III, IVA, and IVB head and neck cancer patients who were treated with chemoradiation between 2007 and 2009. We defined early death as death while receiving chemoradiation or within 60xa0days of treatment completion. Risk factors for early death were tested using univariate and multivariate analyses. Fourteen patients (7.2xa0%) experienced early death, 78.6xa0% of whom died of infection. Univariate analysis revealed significant correlations between early death and several pretreatment variables, including Eastern Cooperative Oncology Group performance status (PS) >1, hemoglobin <10xa0g/dL, albumin <3xa0g/dL, body mass index (BMI) <19xa0kg/m2, and peripheral blood total lymphocyte count <700/μL. Multivariate analysis showed that PS >1, BMI <19xa0kg/m2, and peripheral blood total lymphocyte count <700/μL were independent variables associated with early death. Poor performance status and malnutrition before chemoradiation independently predict early death in locally advanced head and neck cancer patients undergoing chemoradiation. Cautious management of head and neck cancer patients with these risk factors is required throughout chemoradiation period.

Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia

OBJECTIVEnTo evaluate whether an oral nutritional supplement enriched with omega-3 fatty acids, micronutrients, and probiotics affected body weight (BW) changes, serum albumin and prealbumin levels in patients with head and neck cancer (HNC) cachexia.nnnSTUDY DESIGNnSixty-eight HNC patients were randomly assigned to receive either an Ethanwell/Ethanzyme (EE) regimen enriched with omega-3 fatty acids, micronutrients, and probiotics, or control (Isocal) for a 3-month period. Analysis of covariance was used to examine the association between BW change and variables.nnnRESULTSnPatients with body mass index (BMI) <19 and those receiving the EE regimen consumed fewer daily calories but showed significantly increased BW and maintained higher serum albumin and prealbumin levels than other patients (P<.05). Their BW changes were significantly associated with changes in serum albumin and prealbumin levels.nnnCONCLUSIONSnEE regimen improved BW as well as serum albumin and prealbumin levels in HNC patients with BMI <19.

Analysis of the Effect of Serum Interleukin-6 (IL-6) and Soluble IL-6 Receptor Levels on Survival of Patients with Colorectal Cancer

OBJECTIVEnThe correlations of serum interleukin-6 and soluble interleukin-6 receptor concentrations with clinicopathological features and survival of patients with colorectal cancer were studied.nnnMETHODSnWe measured the serum levels of interleukin-6 and soluble interleukin-6 receptor in 99 colorectal cancer patients at the Chang Gung Memorial Hospital, Taiwan. The interleukin-6 and soluble interleukin-6 receptor levels were tested for their association with each other, and with the clinical parameters and outcomes.nnnRESULTSnBoth interleukin-6 and soluble interleukin-6 receptor concentrations were significantly higher in colorectal cancer patients than in normal individuals. Unlike patients with serum interleukin-6 levels >10 pg/ml, who have increased carcinoembryonic antigen levels and shorter survival, serum soluble interleukin-6 receptor levels >800 pg/ml were found in patients with stages I-II and no regional lymph nodal invasion and appeared to be a positive prognostic factor for improved survival. Especially, patients with serum interleukin-6 <10 pg/ml and soluble interleukin-6 receptor >800 pg/ml lived significantly longer. Nonetheless, the multivariate analysis showed that only tumor-node metastasis stage, metastatic status and serum interleukin-6 level were independent prognostic factors, whereas the serum soluble interleukin-6 receptor level became marginally important for survival.nnnCONCLUSIONSnWe suggest the clinical relevance of interleukin-6 and soluble interleukin-6 receptor for the survival of colorectal cancer patients. From a practical point of view, detection of the serum interleukin-6 level alone, rather than combined measurement of interleukin-6 and soluble interleukin-6 receptor, may be sufficient to independently predict survival in colorectal cancer patients.

Macrophage-derived interleukin-6 up-regulates MUC1, but down-regulates MUC2 expression in the human colon cancer HT-29 cell line

Little is known regarding the effects of IL-6 released by tumor-infiltrating macrophages on the mucin expression of colon cancer cells. We isolated macrophages from healthy donors and harvested the supernatant after 48-h cultures. Using flow cytometry and intracellular staining methods, we found that macrophage supernatant effectively induced MUC1 up-regulation and MUC2 down-regulation of colon cancer cells in vitro. Western blotting analysis using monoclonal antibody against IL-6 or gp 130 verified that this IL-6-driven activity was through the activation of tyrosine phosphorylation (Tyr(705)) of STAT3 in cancer cells. We analyzed the surgical specimens of 29 patients with colon cancer by an immunohistochemical staining method and demonstrated the co-localization of macrophages, and the expression of IL-6, CD68, and MUC1 in colon cancer patients. Therefore, macrophage-derived IL-6 modulates the mucin expression of colorectal cancer cells that might in turn produce a permissive milieu favorable to cancer spread.

The -174 G/C polymorphism in interleukin-6 (IL-6) promoter region is associated with serum IL-6 and carcinoembryonic antigen levels in patients with colorectal cancers in Taiwan.

IntroductionWe investigated the associations between −174 G/C polymorphism of interleukin-6 (IL-6) gene promoter and serum IL-6 and carcinoembryonic antigen (CEA) levels in Taiwanese patients with colorectal cancer (CRC).Results and DiscussionThe frequency of the G allele was only 0.043, which is significantly lower compared to Western analogs. On grouping genotypes as G-positive (GG and CG) and G-negative (GG), the average IL-6 level and CEA levels were significantly lower in G-positive patients than in G-negative analogs (IL-6, 3.56u2009±u20094.38 vs. 15.38u2009±u20099.52xa0pg/ml, Pu2009=u20090.021; CEA, 27.7u2009±u200925.7 vs. 157.7u2009±u200959.6xa0ng/ml, Pu2009=u20090.012). The patients without the G allele had higher incidences of synchronous cancers of other origins (Pu2009=u20090.003).ConclusionIn conclusion, ethnicity affects the status of −174 G/C IL-6 polymorphism. This polymorphism status consequently influences the expressions of serum IL-6 and CEA and incidences of synchronous cancers of other origins.

Pretreatment serum interleukin‐1β, interleukin‐6, and tumor necrosis factor‐α levels predict the progression of colorectal cancer

The correlations of pretreatment serum concentrations of proinflammatory cytokines such as interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α (TNFα) with the clinicopathologic features and progression of colorectal cancer (CRC) were investigated. The pretreatment serum levels of IL‐1β, IL‐6, and TNFα were measured in 164 CRC patients before treatment. The relationships between changes in proinflammatory cytokine and C‐reactive protein (CRP) levels and both clinicopathologic variables and disease progression were examined by univariate and multivariate analysis. Advanced tumor stage was associated with a poorer histologic differentiation, higher CRP level, lower albumin level, and inferior progression‐free survival rate (PFSR). Furthermore, high levels of CRP (>5 mg/L) were associated with proinflammatory cytokine intensity, defined according to the number of proinflammatory cytokines with levels above the median level (IL‐1β ≥10 pg/mL; IL‐6 ≥ 10 pg/mL; and TNFα ≥55 pg/mL). Under different inflammation states, proinflammatory cytokine intensity, in addition to tumor stage, independently predicted PFSR in patients with CRP <5 mg/L, whereas tumor stage was the only independent predictor of PFSR in patients with CRP ≥5 mg/L. Proinflammatory cytokine intensity and the CRP level are clinically relevant for CRC progression. Measurement of IL‐1β, IL‐6, and TNFα serum levels may help identify early cancer progression among patients with CRP <5 mg/L in routine practice.

Zoledronic acid induces cell-cycle prolongation in murine lung cancer cells by perturbing cyclin and Ras expression.

Zoledronic acid (ZOL) was shown earlier to prolong survival in animal models of lung cancer. The aim of this study was to examine whether alteration of intracellular cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, retinoblastoma, and Ras protein expression and E2F localization are among the possible antilung cancer mechanisms driven by ZOL. Furthermore, we used geranylgeraniol to test whether the mevalonate pathway is involved in the antitumor effects of ZOL against lung cancer. Line-1 cells, a murine lung adenocarcinoma cell line, were examined. ZOL significantly slowed the growth of these cells both in vitro and in vivo. The ZOL-treated cells typically arrested at the S/G2/M phase of the cell cycle, accompanied by increased intracellular levels of cyclin A, B1, and CDC2 and decreased levels of cyclin D, p21, p27, phosphorylated retinoblastoma, and Ras. In addition, ZOL affected the distribution of E2F. When geranylgeraniol was added to the ZOL-treated cells, either in vitro or in vivo, tumor growth, cell-cycle progression, the expression of certain cyclins, and cyclin-related regulatory proteins were partially returned to that of untreated controls. Therefore, ZOL elicits cell-cycle prolongation that seems to be associated with alterations in the levels of certain cyclins and cyclin-related regulatory proteins. Furthermore, the mevalonate pathway regulates ZOL-induced murine lung cancer inhibition both in vitro and in vivo.

Neutralization of interleukin (IL)-10 released by monocytes/macrophages enhances the up-regulatory effect of monocyte/macrophage-derived IL-6 on expressions of IL-6 and MUC1, and migration in HT-29 colon cancer cells.

The interactions between monocyte-derived IL-6 and IL-10 in colon cancer are unknown. We continued previous work that showed monocyte/macrophage-derived IL-6 induces IL-6 and MUC1 expression in HT-29 cancer cells, and evaluated if IL-10 present in monocyte/macrophage is involved in this IL-6-mediated effect. We treated HT-29 cells with monocyte/macrophage supernatant following neutralization of monocyte/macrophage-released IL-10. Neutralization markedly enhanced monocyte/macrophage-derived IL-6 effects on HT-29 cells including IL-6 and MUC1 production and cell migration. Double blocking of IL-6 and IL-10 in monocyte/macrophage supernatants abolished this enhancement. Western blot analysis of STAT3 phosphorylation showed that this augmented response in HT-29 cells following IL-10 neutralization is probably mediated through enhanced IL-6-induced phosphorylation (Tyr(705)) of STAT3 proteins. Therefore, monocytes/macrophages have the capacity to release the functionally associated cytokines IL-6 and IL-10 whose interactions can account for the pathogenesis and progression of colon cancer.