[Show abstract][Hide abstract] ABSTRACT: Poor nutritional status is common in ovarian cancer. It is well known that the nutritional status of a patient with malignant disease is associated with survival, and that it can be assessed by serum levels of rapid turnover proteins (RTPs), such as retinol binding protein, prealbumin and transferrin. Systemic inflammation, usually observed in the form of elevated C-reactive protein (CRP) or neutrophil/lymphocyte ratio (NLR), occurs by various mechanisms involving numerous pro-inflammatory cytokines. These include interleukin (IL)-17 and other soluble protein mediators, such as soluble IL-2 receptor (sIL-2R) and vascular endothelial growth factor (VEGF). In this study, circulating levels of RTP were decreased in advanced stages of ovarian cancer, and significant inverse correlations were found between RTP levels and serum levels of CRP or NLR. CRP levels were also correlated with serum levels of VEGF and sIL-2R. Moreover, NLR, VEGF and sIL-2R levels, and IL-17 production, were all inversely correlated with RTP levels. These findings indicate that chronic inflammation may be associated with compromised immune function, such as an impaired T-cell response, via various inflammatory proteins, including sIL-2R, VEGF and IL-17. The key mechanisms leading to cancer cachexia, in which nutritional impairment is a major clinical issue, appear to be primarily immune reactions caused by chronic inflammation. Anti-inflammatory treatments may be effective in clinically improving various symptoms associated with these mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Purpose:To examine the clinical utility of intra-tumor micro (mi)RNAs as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC). Experimental Design:The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-polymerase chain reaction-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and non-responders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. A miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principle component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Results:A signature comprising three miRNAs (miR-1290, miR-196b, and miR-135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power. Conclusions:The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based chemotherapy in patients with LADC recurrence.
[Show abstract][Hide abstract] ABSTRACT: Recently there is a great advance in anti-colorectal cancer treatment. Several molecular targeting agents, mostly are antibody drugs, are playing an important role. It has recently been proven that new approaches using antibody to immunological checkpoints are effective against certain types of cancer. This is one of the reasons why cancer immunotherapy is now focused in the clinics. In this chapter, several effective immunotherapy against cancer are shown and discussed. Among several types of cancer immunotherapy, immunological cell therapy including lymphokine activated killer (LAK) cell, cytotoxic T lymphocytes (CTL), gamma delta T cell and dendritic cell therapies are reviewed. Major mechanisms that disturb cancer immunotherapy such as escape mechanisms are also discussed.
Nippon rinsho. Japanese journal of clinical medicine 01/2014; 72(1):42-8.
[Show abstract][Hide abstract] ABSTRACT: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive neoplasms in humans and myeloid-derived suppressor cells (MDSCs) contribute to the negative regulation of immune responses in the context of cancer and inflammation. In order to investigate the pathophysiology of thyroid cancer, peripheral blood mononuclear cells (PBMCs) were obtained from 49 patients with thyroid cancer, 18 patients with non-cancerous thyroid diseases and 22 healthy volunteers. The MDSC levels were found to be higher in patients with any type of thyroid cancer (P<0.05), patients with ATC (P<0.001) and patients with medullary thyroid carcinoma (P<0.05), when compared to patients with non-cancerous thyroid diseases. The MDSC levels were also higher in patients with stage III-IV thyroid cancer compared to those in patients with non-cancerous thyroid diseases (P<0.05). The stimulation index (SI) of phytohemagglutinin (PHA)-induced lymphocyte blastogenesis was significantly lower, the C-reactive protein (CRP) levels were significantly higher and the serum albumin levels were significantly lower in patients with ATC compared to those in patients with non-cancerous thyroid diseases. The SI was significantly lower in stage III and IV thyroid cancer compared to that in non-cancerous thyroid disease (P<0.05). Furthermore, the CRP levels were higher and the concentration of albumin was lower in stage IV thyroid cancer compared to those in non-cancerous thyroid disease (P<0.05). Patients with thyroid carcinoma were then classified into one of two groups according to a %PBMC of MDSC cut-off level of 1.578, which was the average %PBMC of MDSC of patients with any type of thyroid carcinoma. In patients with higher MDSC levels, the production of CRP and interleukin (IL)-10 was significantly higher (P<0.05) and the albumin levels were significantly lower (P<0.05) compared to those in patients with lower MDSC levels. These data indicate that MDSCs are increased in patients with ATC. Furthermore, these patients exhibited suppression of cell-mediated immune responses, chronic inflammation and nutritional impairment.
Molecular and clinical oncology. 11/2013; 1(6):959-964.
[Show abstract][Hide abstract] ABSTRACT: Pancellular dysplasia involving neuroendocrine cells has been shown to be comparatively rare but crucially implicated in the development of neuroendocrine tumors in ulcerative colitis (UC). We attempted to clarify the prevalence of chromogranin A expression as a marker of neuroendocrine differentiation in UC-associated neoplasia by immunohistochemical analyses of 26 lesions of low-grade dysplasia (LGD), 32 high-grade dysplasias (HGDs) and 27 invasive cancers (INVs), along with p53 expression. We additionally assessed the utility of these proteins for differential diagnosis between LGD and HGD. Chromogranin A was considered positive when immunoreactive cells were more than 5% of neoplastic lesions, and the positivity tended to be higher in HGDs (57.7%) or INVs (46.7%) than LGDs (32.0%). Focal or diffuse nuclear staining for p53 was defined as positive. The positive rate for p53 was also higher in HGDs (59.4%; P = 0.037) or INVs (59.3%) than LGDs (30.8%). A similar trend was found in co-positivity for both proteins (HGDs, 30.7%/INVs, 26.7% versus LGDs, 12.0%). No positivity for both proteins was identified in the non-neoplastic mucosa. The combination of the two proteins improved the sensitivity (66.7%), specificity (80.0%), positive predictive value (72.7%) and negative predictive value (75.0%) for HGD as compared to p53 alone (sensitivity, 57.7%; specificity 68.0%; positive predictive value, 65.2%; negative predictive value, 60.7%). In conclusion, we show here that neuroendocrine differentiation is relatively common and represents an early event in the UC-neoplasia pathway in which p53 and chromogranin A are coordinately up-regulated. Immunohistochemical assessment of their expression might provide a useful adjunct tool for grading dysplasia in UC.
[Show abstract][Hide abstract] ABSTRACT: Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cell mechanisms mediating this relationship have not been elucidated. Th17 cells, which produce the proinflammatory cytokine interleukin 17 (IL-17), have been recognized as one of the key factors in the regulation of inflammatory bowel disease and rheumatoid arthritis. This study demonstrated that, in patients with various types of gastrointestinal cancer, IL-17 production was correlated with myeloid-derived suppressor cell (MDSC) levels and with markers for nutritional impairment, immune suppression and chronic inflammation. IL-17 was significantly higher in patients with various types of gastrointestinal cancer compared to normal volunteers. In addition, IL-17 levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio (NLR) and significantly inversely correlated with cell-mediated immune response indicators [lymphocyte phytohemagglutinin (PHA)-blastogenesis and IL-12 induction] and patient nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism contributing to disease progression through enhancement of immune suppression or cachexia. Controlling the activation of Th17 cells may prove to be a valuable strategy for the treatment of gastrointestinal cancer patients.
Molecular and clinical oncology. 07/2013; 1(4):675-679.
[Show abstract][Hide abstract] ABSTRACT: A 64-year-old male patient was diagnosed with rectal gastrointestinal stromal tumor(GIST)by prostate biopsy, because of high PSA. We considered that a radical operation was impossible because the tumor occupied the pelvis, and we suspected prostate invasion. After neoadjuvant chemotherapy(imatinib mesylate 400 mg/day), the tumor size was reduced(90×85 mm→60×50mm), and we could thus perform radical resection. The patient is currently receiving adjuvant chemotherapy (imatinib mesylate 400 mg/day), without recurrence.
Gan to kagaku ryoho. Cancer & chemotherapy 07/2013; 40(7):937-41.
[Show abstract][Hide abstract] ABSTRACT: Prognostic tests for early stage lung cancer patients may provide needed guidance on postoperative surveillance and therapeutic decisions. We used a novel strategy to develop and validate a prognostic classifier for early stage lung cancer. Specifically, we focused on 42 genes with roles in lung cancer or cancer prognosis. Expression of these biologically relevant genes and their association with relapse-free survival were evaluated using microarray data from 148 stage I lung adenocarcinoma patients. Seven genes associated with relapse-free survival were further examined by quantitative RT-PCR in 291 lung adenocarcinoma tissues from Japan, the United States and Norway. Only BRCA1, HIF1A, DLC1, and XPO1 were each significantly associated with prognosis in the Japan and US/Norway cohorts. A Cox regression-based classifier was developed using these four genes on the Japan cohort and validated in stage I lung adenocarcinoma from the US/Norway cohort and three publically available lung adenocarcinoma expression profiling datasets. The results suggests that the classifier is robust across ethnically and geographically diverse populations regardless of the technology used to measure gene expression. We evaluated the combination of the four-gene classifier with microRNA miR-21 (MIR21) expression and found that the combination improved associations with prognosis, which were significant in stratified analyses on stage IA and stage IB patients. Thus, the four coding gene classifier, alone or with miR-21 expression, may provide a clinically useful tool to identify high risk patients and guide recommendations regarding adjuvant therapy and postoperative surveillance of stage I lung adenocarcinoma patients.
[Show abstract][Hide abstract] ABSTRACT: A 59-year-old woman was diagnosed with triple-negative breast cancer(TNBC)(T2N0M0)and treated with primary systemic therapy. The patient was treated with 4 courses of epirubicin and cyclophosphamide(EC)therapy every 3 weeks, followed by weekly gemcitabine-paclitaxel combination therapy. As she was judged to have achieved a partial response(PR) by ultrasound and CT examination after eight courses, she underwent partial resection of the left breast. CR was revealed by the pathological examination of the resected specimen. Gemcitabine-paclitaxel combination therapy seems to be a one of the useful preoperative chemotherapies for TNBC.
Gan to kagaku ryoho. Cancer & chemotherapy 05/2013; 40(5):623-5.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Lynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer, and is associated with a high incidence of multiple primary neoplasms in various organs. METHODS: A 79-year-old woman (patient 1) diagnosed with ascending colon cancer had a history of previous carcinomas of the uterus, stomach, uroepithelial tract, and colon. One year later, she developed a brain tumor (glioblastoma). A 54-year-old female (patient 2) was diagnosed with endometrial cancer and sigmoid colon cancer. Both patients underwent genetic evaluations independently. RESULTS: No mutations were found in an exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR. However, multiplex ligation-dependent probe amplification (MLPA) identified genomic duplication spanning from exon 7 to exon 14 of the MSH2 gene in both patients. Due to the presence of this characteristic gene duplication, their pedigrees were investigated further, and these showed that they are paternal half-sisters, consistent with paternal inheritance. CONCLUSION: Large genomic duplication from intron 6 through intron 14 in MSH2 is a very rare cause of Lynch syndrome and is difficult to identify with conventional methods. MLPA may be an alternative approach for detecting large-scale genomic rearrangements.
Journal of Gastroenterology 04/2013; · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF) report‑ edly has an important role in the progression of malignant neoplasms and has been reported to induce myeloid‑derived suppressor cells (MDSCs) that appear in cancer and inflam‑ mation. In the present study, serum concentrations of VEGF were measured in patients with digestive system cancer and the correlations with nutritional damage, immune suppres‑ sion and systemic inflammation were analyzed. A significant increase in VEGF serum levels was observed in patients with esophageal, gastric and colorectal cancers compared with healthy volunteers. Levels of VEGF were inversely correlated with the serum concentrations of albumin, prealbumin and retinol‑binding protein. The serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)‑12 and correlated with MDSC counts. VEGF levels were also correlated with neutrophil and neutrophil/lymphocyte counts and inversely correlated with lymphocyte count. Serum VEGF levels were divided at a cutoff of 500 pg/ml, with levels of prealbumin and retinol‑binding protein significantly decreased in patients with higher VEGF levels. The stimulation index and IL‑12 production were significantly decreased in the group with higher VEGF levels and MDSC counts tended to be higher in this group. These results demonstrated that increased production of VEGF was correlated with systemic inflamma‑ tion, nutritional impairment and the inhibition of cell‑mediated immunity involving MDSCs.
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF) reportedly plays an important role in the progression of malignant neoplasms. In the present study, measured serum concentrations of VEGF were measured in patients with ovarian cancer and correlations with nutritional damage and chronic inflammation were analyzed. A significant increase in serum levels in patients compared to healthy volunteers was observed. Levels of VEGF were inversely correlated with serum concentrations of prealbumin, transferrin and retinol-binding protein. VEGF levels were also correlated with serum levels of c-reactive protein (CRP), an effective marker of inflammation. CRP levels were significantly elevated in patients with stage III and IV disease and inversely correlated with serum concentrations of total protein, prealbumin, transferrin and retinol-binding protein. These results demonstrated that an increased production of VEGF correlated with nutritional impairment and inflammation.
[Show abstract][Hide abstract] ABSTRACT: We report a case of hemorrhagic cytomegalovirus (CMV) colitis, occurring in a postoperative patient due to a weakened immune system. An 85-year-old woman with a medical history, including chronic renal failure treated with oral administration of prednisolone, underwent colectomy due to an ascending colon cancer. While the postoperative course was favorable, she exhibited acute severe abdominal pain and massive bloody discharge after 11 days of surgery. Her colonoscopic examination showed multiple longitudinal ulcers on the anastomosis. In addition to these endoscopic findings, her past medical history helped suggest CMV colitis. Because serological testing revealed positive CMV antigen, she was finally given a diagnosis of CMV colitis and received intravenous ganciclovir for the initial treatment. Hemorrhagic CMV colitis after colectomy is an important postoperative complication; we therefore present our case with diagnosis and treatment experience.
[Show abstract][Hide abstract] ABSTRACT: We report a case of pre-disseminated intravascular coagulation caused by secondary suppurative inflammation in a patient with immunoglobulin (Ig) G4-related sclerosing cholangitis. The patient was a 78-year-old man in whom a localized stenosis of the intrahepatic bile duct was found without any other bile duct stricture or symptoms. He underwent surgical resection 6 months later for acute severe cholangitis and sepsis caused by bile duct obstruction. The resected specimen contained an abscess and nodulary mass in the liver. Immunohistochemical analysis revealed IgG4-positive plasma cell infiltration, whereby we diagnosed IgG4-related sclerosing cholangitis. As IgG4-related sclerosing cholangitis limited to within the intrahepatic portion is extremely rare, we present this case with a review of the literature.
[Show abstract][Hide abstract] ABSTRACT: Myeloid-derived suppressor cells(MDSCs) have been reported to be induced by inflammation, to suppress immune function, and promote tumor progression, and to be found in circulating blood, tumor tissue, and lymph nodes. MDSCs were found in pleural effusions and ascites of patients with malignant diseases and these results are described in this report. Changes in the levels of MDSCs during clinical responses to cancer chemotherapy are also reported. MDSC levels in malignant effusions have also been shown to change with the levels of MDSCs in peripheral blood and with clinical responses. MDSCs seem to play an important role in inflammation that is strongly related to advancing malignant diseases. The results also suggested that MDSCs may be reduced after effective chemotherapy, which may be effective as an adjuvant treatment with cancer immunotherapy.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2012; 39(12):2088-91.
[Show abstract][Hide abstract] ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are one of the major cell populations responsible for regulating immune responses. MDSCs have been reported to accumulate in the blood, lymph nodes, and at tumor sites in most patients during tumor progression and chronic infection, where they potentially suppress T cell functions. We analyzed MDSCs (CD11b+ CD14- CD33+) in peripheral blood mononuclear cells by flow cytometry in 222 patients with esophageal, gastric, colorectal, hepatocellular, cholangiocellular, pancreatic, breast, ovarian, thyroid, and lung cancer, and 18 healthy volunteers. MDSCs were significantly higher in patients with esophageal, gastric, colorectal, hepatocellular, pancreatic, and breast cancer than in healthy volunteers, and the differences were not significant in patients with cholangiocellular, ovarian, thyroid, and lung cancer. Production of the cytokines IFN-γ and IL-6 in response to phytohemagglutinin was assayed using enzyme-linked immunosorbent assay (ELISA) test kits. Serum concentrations of sIL-2R were measured by ELISA. The percentages of MDSCs in patients with colorectal cancer positively correlated with neutrophil counts and the concentration of sIL-2R(both p<0.05), and inversely correlated with the production of IFN-γ( p<0.0001), serum albumin concentration(p<0.005), and lymphocyte counts (p<0.05). These data suggested that MDSCs are strongly related to chronic inflammation and nutritional impairment.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2012; 39(12):1797-9.
[Show abstract][Hide abstract] ABSTRACT: We report a case of metastatic liver carcinoma treated by radiofrequency ablation (RFA) and hepatectomy. A 53-year-old man suffering from sigmoid colon carcinoma and unresectable multiple liver metastases was treated with capecitabine and oxaliplatin and bevacizumab. After the seventh course, tumor reduction was confirmed but liver dysfunction meant that it was difficult to continue the same regimen. Because preoperative evaluation of liver function showed a high risk of postoperative liver failure, a combination of partial hepatectomy and RFA was planned in order to reduce the amount of liver resection. High anterior resection, partial hepatectomy and RFA were performed as planned. He underwent S-1 therapy following 7 courses of irinotecan, S-1, and bevacizumab therapy. To date, no recurrence has been observed 18 months after the operation. A combination of hepatectomy and RFA is expected to be an effective local treatment for multiple liver metastases of colorectal cancer, although the evidence is currently insufficient.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2012; 39(12):1846-8.
[Show abstract][Hide abstract] ABSTRACT: Abrams predicted that the pharmacoangiogram theory may improve intraarterial chemotherapy. We provide the following evidence to support this hypothesis from an experimental study on Walker-256 xenograft tumors: (1) selective drug delivery to tumor vessels, (2) increased injection pressure, and (3) low tumor blood flow, which are induced by noradrenalin to enhance anti-tumor activity. Walker-256 tumors are divided into 2 groups, hypovascular and hypervascular tumors that arise 2 and 4 days after tumor inoculation, respectively. Noradrenalin mediates anti-tumor activity against hypervascular tumors. The concentrations of Evans blue in Walker-256 tumors are increased in the hypervascular phase and decreased in the hypovascular phase by 4 μg/mL noradrenalin. These data indicate that norepinephrine may decrease capillary circulation, which may increase the blood flow to hypervascular tumor tissues that lack sphincter muscles due to the contraction of precapillary vessels. Mitomycin C concentrations in hypervascular tumors are increased in tumor tissues and decreased in normal tissues. A higher injection pressure than interstitial pressure(20 mmHg) in hypervascular tumors may improve the delivery of antitumor agents to the tumor interstitium and enhance anti-tumor activity. Low blood flow and reperfusion of the tumor due to the contraction reflex of the tumor-feeding artery enhance anti-tumor activity against hypervascular tumors induced by continuous infusion of noradrenalin. Therefore, noradrenalin decreased the tumor tissues blood flow and induced the tumor necrosis.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2012; 39(12):1863-6.
[Show abstract][Hide abstract] ABSTRACT: The patient was a 47-year-old man with a 24-year history of anal fistula. A carcinoma associated with anal fistula was diagnosed after a biopsy was performed because the anal fistula was not improving. Computed tomography and magnetic resonance imaging showed that the tumor had invaded the spongy urethra. Therefore, preoperative chemotherapy(S-1 plus radiation at a dose of 60 Gy/body) was performed. Because the size of tumor decreased, we performed abdominoperineal resection with reconstruction using a gracilis musculocutaneous flap, which enabled the spongy urethra to be fully preserved. Histopathologically, no cancer cells were found to exist on the surgical margin. This case suggested that surgical treatment combined with preoperative chemoradiotherapy may be effective for locally advanced carcinoma associated with anal fistula. Furthermore, improvement of the reconstruction technique for both pelvic and perianal skin defects due to extended resection is an important element of curative surgery.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2012; 39(12):1957-9.
[Show abstract][Hide abstract] ABSTRACT: Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) binds to methylated promoters of a number of tumor-suppressor genes, including p16INK4A and p14ARF, by forming complexes with DNA methyltransferases and HDAC1, resulting in the induction of carcinogenesis. Altered UHRF1 expression has been demonstrated in various types of cancers. Previous reports indicate that UHRF1 expression is regulated by E2F-1 expression. We investigated UHRF1 expression using immunohistochemical staining in 231 colorectal cancer and 40 adenoma specimens, analyzed the relationship between UHRF1 expression and clinicopathological findings and the association between UHRF1 and E2F-1 expression. To better understand the biological function of UHRF1 in colorectal cancer, knockdown of UHRF1 expression was performed using siRNA methods. High UHRF1 expression was observed in 152 of 231 (65.8%) colorectal cancer patients, and was detected in 35 of 40 adenoma specimens samples (87.5%). UHRF1 staining was detected in the nucleus of cancer cells, while it was not detected in colonic normal mucosa. High UHRF1 expression was significantly observed in right compared with left hemicolon cancer (p=0.008). Moreover, high UHRF1 expression tended to be associated with depth of invasion (p=0.051). UHRF1 expression was significantly associated with E2F-1 expression (p<0.0001). Knockdown of UHRF1 expression suppressed cellular growth in colon cancer cell lines, HCT116 and SW620. In conclusion, we demonstrated that UHRF1 expression was upregulated in approximately two-thirds of colorectal cancer specimens and was particularly expressed in right compared with left hemicolon cancer. Moreover, knockdown of UHRF1 expression induced growth inhibition in colon cancer cell lines. UHRF1 may be involved in cellular proliferation and molecular pathogenesis of colorectal cancer in the right hemicolon.