Hypoxia enhances colon cancer migration and invasion through promotion of epithelial-mesenchymal transition.

BACKGROUND: A hypoxic environment exists in most solid tumors because in rapidly growing tumors, the development of angiogenic vasculature is heterogenous, usually not enough to overcome the necessary oxygen supply. In an ischemic condition, cancer cells develop escape mechanisms to survive and leave the unfavorable environment. That result in the acquisition of increased potential for local invasion and evasion to distant organs. However, the escape mechanisms of cancer cells from hypoxic stress have not been fully characterized. MATERIALS AND METHODS: The human colon cancer cell line LoVo was cultured in hypoxia, and the adhesive and migratory properties were analyzed. The expression of cell surface and cytoplasmic molecules was also investigated. RESULTS: Under hypoxic conditions, cells developed epithelial-mesenchymal transition. The expression levels of α2, α5, and ß1 integrins were significantly upregulated and, as a consequence, the ability to adhere to and migrate on collagen and fibronectin was increased. On the other hand, the expression of 67-kDa laminin receptor and the abilities to adhere to and migrate on laminin were decreased. Additionally, the expression of CXCR4 was significantly increased on cells cultured in hypoxia, and the chemotactic activity to stromal cell-derived factor 1α was remarkably increased. CONCLUSIONS: Hypoxic stress induced active epithelial-mesenchymal transition in colon cancer cells, with the typical morphologic and functional changes. These morphologic and functional changes of ß1 integrins, the 67-kDa laminin receptor, and CXCR4 may be essential for the acquisition of the invasive and metastatic features in colorectal cancer.

Synchronous and metachronous lung metastases in patients with colorectal cancer: A 20-year monocentric experience.

There is little information regarding the recent trend of synchronous and metachronous pulmonary metastases in patients with primary colorectal cancer. We investigated patients with sporadic colorectal cancer who underwent surgery in our department between 1990 and 2009. Clinicopathological parameters of primary cancer and lung metastases and survival time were retrospectively reviewed. Of the 2,286 patients included in this study, 64 (2.8%) had synchronous lung metastases at the time of colorectal surgery. A total of 18 patients (28%) received pulmonary metastasectomy for these lesions with curative intent. Out of 2,082 curatively operated cases, 212 (10.2%) developed metachronous lung metastases. The frequency of synchronous and/or metachronous lung metastases detected in curative cases increased from 8.9% in the 1990s to 11.9% in the 2000s (p=0.03). Among predictive factors for metachronous lung metastases, the presence of distant organ metastases, i.e. initial stage IV, significantly increased over time. Notably, patients with unresectable metachronous lung metastases in the 2000s, characterized by smaller size, exhibited more favorable prognosis than in the 1990s (p=0.003). Recent improvement of imaging modalities is considered to have facilitated the prompt diagnosis of lung metastases. Moreover, marked progress in multidisciplinary treatment has presumably achieved more favorable prognosis in an increasing number of patients with advanced colorectal cancer.

A 1cm distal bowel margin is safe for rectal cancer after preoperative radiotherapy.

BACKGROUND/AIMS: Although guidelines recommend a 2 cm distal margin in sphincter-saving operations for rectal cancer, some studies have shown that it may be decreased to 1cm after preoperative radiotherapy. At the present time, there are no established guidelines that suggest a specific distal safety margin for rectal cancer after preoperative radiotherapy. This study aims to examine whether preoperative radio therapy can reduce the distal safety margin in the treatment of lower rectal cancers. METHODOLOGY: We examined the distal spread by H&E and immunohistochemical staining of CAM5.2 (epithelial marker) in serial sections of surgically resected specimens. To evaluate the extent of distal intramural spread, we defined the "DS length" as the distance between the microscopically defined distal tumor border and the distal spread. We compared the DS length between 20 patients who underwent preoperative radiotherapy followed by surgery (Rad (+) group) and 20 surgery-alone (Rad (-)group). RESULTS: The average DS length was significantly smaller in the Rad (+) group (3.2mm) than in the Rad (-) group (6.3mm) (p=0.028). Furthermore,the greatest DS length was 5.8mm in the Rad (+) group,but 11.5mm in the Rad (-) group. No patient showed a DS length of over 1cm in the Rad (+) group. CONCLUSIONS: These results suggested that the safety margin may be reduced to 1cm by preoperative radiotherapy.Therefore, preoperative radiotherapy may extend the indications for sphincter-saving operation.

Adiponectin receptor 2 is negatively associated with lymph node metastasis of colorectal cancer.

Adiponectin is a hormone secreted by adipose tissue and has a variety of functions including the inhibition of tumor growth. The expression and function of the two major adiponectin receptors, AdipoR1 and AdipoR2, in malignant tissue have not been well characterized. In the present study, we evaluated the mRNA levels of AdipoR1 and AdipoR2 expression in 48 surgically resected colorectal cancer specimens, as well as normal colonic mucosa, by quantitative RT-PCR. The values obtained were standardized by ß-actin mRNA, and the correlation between their relative expression levels and the clinicopathological characteristics of the patients was examined. The relative expression levels of AdipoR1 and AdipoR2 were significantly reduced in cancer tissue compared with normal tissue (AdipoR1: 0.97±0.39 vs. 1.37±0.41, P<0.0001; AdipoR2: 0.92±0.31 vs. 1.60±0.46, P<0.0001). AdipoR1 and AdipoR2 levels were further reduced in tumors with nodal metastases and the difference was statistically significant in the case of AdipoR2 (0.79±0.27 vs. 1.02±0.30, P=0.012). The results of this study demonstrated that the expression levels of adiponectin receptors are reduced in cancer specimens compared to normal tissue, indicating a downregulation in the course of the development and progression of colorectal cancer. Since adiponectin is abundantly present in the whole body and has inhibitory effects on cancer cells, this downregulation of the receptors may be an escape mechanism of malignant cells from the suppressive effects of adiponectin.

Vagus nerve preservation results in visceral fat maintenance after distal gastrectomy.

BACKGROUND/AIMS: Although preservation of the vaguas nerve is recommended in surgery for earlystage gastric cancer, the physiological effect of vagotomy on the postoperative course has not been well documented. We assessed the effect of vagotomy on the change in fat volume after gastrectomy. METHODOLOGY: Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in computed tomographic images taken before and more than 6 months after surgery, using Fat Scan software. The ratios of postoperative/ preoperative values of these two fat areas as well as body weight were calculated in 45 patients who underwent DG with (n=24) or without (n=21) vagotomy. RESULTS: Vagotomy did not affect the change in body weight (91.3±1.7% vs. 92.1±1.7%). In patients with vagotomy, VFA was reduced to 59.0±5.1%, which was significantly greater than the reduction in SFA (74.3±8.7%, p=0.042). In contrast, the reduction ratios of VFA and SFA were equal in vagus nerve-preserved patients (78.4±6.7% vs. 78.2±6.9%, p=0.97). CONCLUSIONS: The vagus nerve may have a function to locally regulate the intra-abdominal fat volume and preservation of the vagus nerve results in the maintenance of visceral fat after DG.

Immunohistochemical detection of CD133 is associated with tumor regression grade after chemoradiotherapy in rectal cancer.

CD133 has been identified as a putative cancer stem cell (CSC) marker in various cancers including colorectal cancer. The relation between CD133 expression and biological characteristics of colorectal cancer remains to be clarified. Protein expression of CD133 was immunohistochemically evaluated in surgical specimens of 225 patients with colorectal cancer who were treated by surgery, as well as those of 78 patients with rectal cancer who received preoperative chemoradiotherapy (CRT) followed by curative resection. The correlation between CD133 expression and clinicopathological features, tumor recurrence and overall survival was analyzed in both populations. Among 225 colorectal cancers without CRT, 93 (41.3%) were positive for CD133 expression, which was enhanced in cases with advanced T stage and venous invasion. Moreover, CD133 was positive in 47 (60.3%) of 78 cases with CRT, which was significantly higher than the CD133-positive rate in non-CRT specimens (P=0.05). Expression of CD133 was independently correlated with the histological tumor regression grade (P<0.01). These results suggest that CD133 is not a distinctive colorectal CSC marker; expression of CD133 is suggested to be one of the key factors associated with resistance to CRT in colorectal cancer.

One-stage segmental colectomy and primary anastomosis after intraoperative colonic irrigation and total colonoscopy for patients with obstruction due to left-sided colorectal cancer.

BACKGROUND: Intraoperative colonic irrigation and intraoperative on-table colonoscopy may be useful for a more accurate diagnosis of colorectal cancer before colectomy in patients with obstructive left-sided colorectal cancer, but the clinical benefit of this technique has not been investigated in large-scale studies. OBJECTIVE: The aim of this study was to evaluate the usefulness of intraoperative colonic irrigation with a Y-shaped irrigation device and intraoperative colonoscopy in the management of obstructive colorectal cancer in patients undergoing elective surgery. DESIGN AND SETTING: This was a retrospective cohort study of patients undergoing surgical treatment at a single tertiary care institution in Japan. PATIENTS AND INTERVENTION: Among 715 consecutive patients with left-sided colorectal cancer, 101 patients (14.1%) with obstructing tumor received intraoperative colonic irrigation and intraoperative colonoscopy before colectomy and primary anastomosis, and 614 patients with nonobstructive colorectal cancer underwent preoperative colonoscopy with mechanical bowel preparation. MAIN OUTCOME MEASURES: Detection rates of proximal synchronous lesions, occurrence of postoperative complications, and changes in the surgical procedure prompted by the results of the intraoperative colonoscopy were evaluated. RESULTS: Intraoperative colonoscopy detected synchronous adenomatous polyps in 27 patients (26.8%), carcinoma in 4 patients (4%), and obstructive colitis in 2 patients (2%). Findings of the intraoperative colonoscopy prompted changes in surgical procedure in 9 patients (8.9%). The overall morbidity in the intraoperative group was 17%, with anastomotic leakages in 3 patients, wound infection in 5, and postoperative ileus in 3 patients. The risk of these complications was not increased in patients with intraoperative colonoscopy with intraoperative colonic irrigation compared with those receiving preoperative colonoscopy with mechanical bowel preparation. The operation time was 28 minutes longer in the intraoperative than in the preoperative group, but neither the time to start of oral intake nor the length of postoperative hospital stay was significantly different between the 2 groups. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: : In patients with obstructive colorectal cancer, intraoperative colonic irrigation with intraoperative colonoscopy is a useful strategy for detecting synchronous lesions located proximally to the obstructing tumor, without increasing patient morbidity.

Analysis for the combination expression of CK20, FABP1 and MUC2 is sensitive for the prediction of peritoneal recurrence in gastric cancer.

Prediction of peritoneal recurrence in gastric cancer patients is important for application of adjuvant chemotherapy. After surgery, occasional patients have peritoneal recurrence despite negative cytology of the peritoneal washings. Thus, molecular detection of a subliminal number of cancer cells in peritoneal washings may overcome the sensitivity limitation of conventional cytology. In this study, expressions of five specific marker genes, namely, TFF1, TFF2, CK20, FABP1 and MUC2, were evaluated for their usefulness as markers of micro-dissemination. It was found that reverse transcriptase-polymerase chain reaction for these five genes yielded results highly specific for the depth of invasion and disease stage. Furthermore, the expression of CK20, FABP1 and MUC2 was a reliable prognostic indicator of peritoneal metastasis. Our results suggest that evaluation of the expression of CK20, FABP1 and MUC2 in peritoneal washings is a useful tool for identifying patients at high risk of peritoneal recurrence who may need adjuvant chemotherapy.

Laboratory blood data have a significant impact on tumor response and outcome in preoperative chemoradiotherapy for advanced rectal cancer.

INTRODUCTION: Although neoadjuvant chemoradiotherapy (CRT) is the standard treatment for advanced rectal cancer (RC), markers predicting response have not been adequately defined. PATIENTS AND METHODS: In 73 cases with advanced RC, we evaluated the tumor response with the reduction rate of the longitudinal size of RC using barium enema image taken before and after CRT. Then, we retrospectively examined the association with various blood values taken before CRT. The tumor size reduction rate was significantly greater in ten CR cases than in 63 non-CR cases (p < 0.001). RESULTS: Interestingly, the size reduction ratio was positively associated with hemoglobin, albumin level and lymphocyte percentage in leukocytes, while being negatively associated with platelet counts, C-reactive protein and fibrinogen levels as well as neutropliles percentage. Moreover, high lymphocyte counts (>1,800/mm(3)) had an independent association with disease-free survival. CONCLUSIONS: Blood data have a major impact on the tumor response to CRT. Control of host condition may improve the effectiveness of CRT in advanced RC.

Vagus nerve preservation selectively restores visceral fat volume in patients with early gastric cancer who underwent gastrectomy.

BACKGROUND: Body weight loss is a well-known complication after gastrectomy, and is mainly due to reduced fat volume. The effect of vagotomy on the postoperative fat volume was investigated in patients with early stage gastric cancer who underwent gastrectomy. METHODS: Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in a computed tomographic (CT) image at the level of the umbilicus using Fat Scan software. The changes in these two fat areas were determined by comparing CT images taken before and more than 6 mo after gastrectomy, and the ratio of postoperative to preoperative fat area was calculated in 77 patients. RESULTS: VFA was reduced significantly greater after total gastrectomy (TG) than distal gastrectomy (DG) (P = 0.0003). In 63 patients who underwent DG, the reduction in VFA, but not in SFA, was significantly less in vagus nerve-preserved than in vagus nerve-nonpreserved cases (59.0% ± 24.2% versus 74.9% ± 28.2%, P = 0.027). If compared in each case, VFA showed a significantly greater decrease than did SFA in vagus-nonpreserving, but not in vagus-preserving, gastrectomy (68.2% ± 37.0% versus 52.7% ± 25.2%, P < 0.0001; 76.3% ± 30.0% versus 74.9% ± 28.2%, P = 0.79). CONCLUSIONS: The vagus nerve has a function to locally regulate the amount of intra-abdominal fat tissue, and selective vagotomy in gastrectomy results in a preferential reduction of visceral fat in gastrectomy. Surgical denervation of vagus may be reconsidered as a reasonable treatment for excessive obesity.

CD133(-) cells, derived from a single human colon cancer cell line, are more resistant to 5-fluorouracil (FU) than CD133(+) cells, dependent on the ß1-integrin signaling.

BACKGROUND AND AIM: Recently, the cancer stem cells (CSCs) theory has been proposed, and CD133 has been suggested as a potential marker of CSCs in various cancer types. In the present study, we aimed evaluate CD133 as a potential marker of colorectal CSCs and, for this purpose, isolated CD133(+) and CD133(-) cells from a single colorectal cancer cell line, and compared their features, especially related to the tumor-forming and differentiation abilities, and the sensitivity to chemotherapy. METHODS AND RESULTS: CD133(+) cells had higher in vivo tumor-forming ability than CD133(-) cells, and in culture, they progressively differentiated into CD133(-) cells, but not vice-versa. On the other hand, CD133(-) cells were more resistant to 5-fluorouracil (FU) treatment than CD133(+) cells, and it was found to be dependent on the higher expression of ß1-integrins, and consequently, higher ability to bind collagen. Disruption of the ß1-integrin function abrogated the chemoresistance. CONCLUSION: From the present results, we concluded that colorectal cancer CD133(+) cells, although showing some features of CSCs, are not more resistant to 5-FU than CD133(-) cells. Therefore, definite conclusions can not be drawn yet, but it is strongly suggestive that CD133 should not be used as a single CSC marker of colorectal cancer.

Is surveillance endoscopy necessary after colectomy in ulcerative colitis?

The role of surveillance endoscopic followup in colectomized patients with long standing total colitis is controversial. Here, we aimed to clarify its usefulness for the early detection of dysplasia and cancer in this group of patients. Ninety-seven colectomised UC patients followedup by surveillance endoscopy were retrospectively investigated by reviewing the pathological reports. Patients had received either subtotal colectomy and ileo-rectal anastomosis (IRA) or total proctocolectomy and ileal anal anastomosis (IPAA). Definite dysplasia was diagnosed in 4 patients, who had received IRA; among them, 2 were carcinoma with submucosal invasion, and one was a high-grade dysplasia. Postoperative surveillance endoscopy is useful for the detection of early cancer in the remaining colonic mucosa of UC patients, and those receiving IRA, in which rectal mucosa is left intact, would be good candidates. However, its effectiveness for patients receiving IPAA, in which the rectal mucosa is resected, needs further investigation.

[FOLFOX as adjuvant chemotherapy after curative resection of distant metastatic lesions in patients with colorectal cancer].

We investigated the effectiveness of prophylactic FOLFOX after curative resection of synchronous metastases in patients with colorectal cancer (CRC). Clinicopathological information including postoperative chemotherapy, such as a therapeutic regimen, relapse-free survival (RFS), site of recurrence, etc., was retrospectively analyzed in 116 CRC patients with synchronous distant metastases, and 63 patients with metachronous metastases who had received surgery in our hospital between 2000 and 2009. Fifty-three patients (84%) out of 63 without adjuvant chemotherapy, and 38 (83%) out of 46 patients that received oral or intravenous 5-fluorouracil (5-FU) (alone or with leucovorin (LV)or isovorin) developed recurrent tumor(s) afterwards. The median RFSs were 119 and 281 days, respectively. By contrast, a single patient among 6 who underwent FOLFOX (up to 12 therapeutic courses) showed recurrence 476 days after surgery. The RFS of the FOLFOX was significantly higher than that of the 5-FU (+LV) or surgery alone (p=0. 03, p=0. 007, respectively). In conclusion, the FOLFOX regimen is more beneficial for CRC patients with synchronous metastasis as adjuvant chemotherapy than 5-FU (+LV) or other followup strategies.

Free colonic perforation in a patient with Crohn's disease and loop ileostomy: report of a case.

Free bowel perforation in Crohn's disease is a relatively rare complication. In this report, we present a case of free colonic perforation in a Crohn's disease patient with loop ileostomy previously constructed for intractable perianal abscess. Normally, fecal diversion by ileostomy results in an improvement in Crohn's colitis. However, in some cases, fecal diversion is reported to adversely affect the inflammation of the diverted bowel, and it is this unusual complication of Crohn's disease that we discuss here.

Predicting ulcerative colitis-associated colorectal cancer using reverse-transcription polymerase chain reaction analysis.

BACKGROUND: Widespread genetic alterations are present not only in ulcerative colitis (UC)-associated neoplastic lesions but also in the adjacent normal colonic mucosa. This suggests that genetic changes in nonneoplastic mucosa might be effective markers for predicting the development of UC-associated cancer (UC-Ca). This study aimed to build a predictive model for the development of UC-Ca based on gene expression levels measured by reverse-transcription polymerase chain reaction (RT-PCR) analysis in nonneoplastic rectal mucosa. PATIENTS AND METHODS: Fifty-three UC patients were examined, of which 10 had UC-Ca and 43 did not (UC-NonCa). In addition to the 40 genes and transcripts previously shown to be predictive for developing UC-Ca in our microarray studies, 149 new genes, reported to be important in carcinogenesis, were selected for low density array (LDA) analysis. The expression of a total of 189 genes was examined by RT-PCR in nonneoplastic rectal mucosa. RESULTS: We identified 20 genes showing differential expression in UC-Ca and UC-NonCa patients, including cancer-related genes such as CYP27B1, RUNX3, SAMSN1, EDIL3, NOL3, CXCL9, ITGB2, and LYN. Using these 20 genes, we were able to build a predictive model that distinguished patients with and without UC-Ca with a high accuracy rate of 83% and a negative predictive value of 100%. CONCLUSION: This predictive model suggests that it is possible to identify UC patients at a high risk of developing cancer. These results have important implications for improving the efficacy of surveillance by colonoscopy and suggest directions for future research into the molecular mechanisms of UC-associated cancer.

FOLFOX as adjuvant chemotherapy after curative resection of distant metastases in patients with colorectal cancer.

OBJECTIVES: The prophylactic effect of FOLFOX regimen, a standard regimen for unresectable colorectal cancer (CRC), was investigated in the adjuvant setting of CRC cases with distant metastases. METHODS: The study population included 116 CRC patients with synchronous metastases and 91 patients with metachronous metastases who had undergone curative operation in our hospital between 2000 and 2009. Clinicopathological parameters of CRC, postoperative chemotherapeutic regimen, recurrence rate, and relapse-free survival (RFS) were analyzed retrospectively. RESULTS: After resection of CRC and synchronous metastases, 53 (84%) out of 63 patients without chemotherapy, and 38 (83%) out of 46 that received 5-fluorouracil (5-FU) alone or with leucovorin (LV) developed recurrent tumors. By contrast, only 1 (17%) among 6 patients who underwent FOLFOX treatment showed recurrence. The FOLFOX group exhibited significantly improved RFS as compared to the 5-FU (+ LV) or surgery-alone group (p = 0.03, p = 0.007, respectively). On the other hand, in patients with metachronous metastases, tumor-relapse rate and RFS were not significantly influenced by post-metastasectomy therapies. CONCLUSIONS: In this retrospective analysis, the adjuvant administration of FOLFOX appeared to reduce the risk of relapse in a small group of CRC patients with synchronous metastases. Prospective randomized trials will be required to confirm the benefits of this management strategy.

Density of CD4(+) and CD8(+) T lymphocytes in biopsy samples can be a predictor of pathological response to chemoradiotherapy (CRT) for rectal cancer.

BACKGROUND: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. Radiosensitivity has recently been shown to be greatly affected by immune function of the host. METHODS: In 48 cases of advanced RC, we retrospectively examined the density of tumor infiltrating CD4(+) and CD8(+) T cells using immunohistochemical staining of biopsy samples before CRT, and examined the correlation with tumor response. RESULTS: The numbers of both CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL) in pre-CRT biopsy samples were strongly correlated with tumor reduction ratio evaluated by barium enema. Moreover, the densities of CD4(+) and CD8(+) TIL were significantly associated with histological grade after CRT. The density of CD8(+) TIL was an independent prognostic factor for achieving complete response after CRT. CONCLUSIONS: In RC patients, T lymphocyte-mediated immune reactions play an important role in tumor response to CRT, and the quantitative measurement of TIL in biopsy samples before CRT can be used as a predictor of the clinical effectiveness of CRT for advanced RC.

Intratumoral injection of interleukin-2 augments the local and abscopal effects of radiotherapy in murine rectal cancer.

Recent studies have suggested that tumor shrinkage in response to radiotherapy (RT) is greatly dependent on the host immune response. A Balb/c mouse model of simultaneous subcutaneous tumor and liver metastasis of Colon26 was prepared and, after irradiation of the subcutaneous tumor (2 Gy × 5 day × 2 cycles), interleukin-2 (IL-2) (2 × 10(4) U) was injected intra-tumorally, and the fate of both the subcutaneous tumor and liver metastatic lesions was evaluated. Intratumoral injection of IL-2 greatly enhanced the anti-tumor effects of RT and completely eradicated the established subcutaneous tumor. Interestingly, although RT was given locally to the subcutaneous tumor, liver metastasis formation was also inhibited in mice receiving only local RT. More impressively, the combination of RT + IL-2 completely inhibited liver metastasis formation. Splenocytes in mice receiving RT + IL-2 contained a higher percentage of CD4(+) T cells, but lower percentages of CD4(+)CD25(+) regulatory T cells and CD11b(+) Gr-1(+) myeloid-derived suppressor cells. Immunohistochemical investigation of human rectal cancer revealed that the density of CD8(+) cells infiltrating into irradiated rectal tumor was positively associated with a lower frequency of distant metastasis as well as histological response grade. Local administration of IL-2 not only enhances shrinkage of the irradiated tumor itself, but can also suppress the development of distant metastasis located outside the RT field, possibly though the induction of a systemic T cell response. Augmentation of T-cell-mediated antitumor immunity during RT might be critical for improvement of the clinical efficacy of neoadjuvant RT for the treatment of advanced rectal cancer.

Circulating lymphocyte is an important determinant of the effectiveness of preoperative radiotherapy in advanced rectal cancer.

BACKGROUND: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. In order to find other factors possibly related with radiosensitivity, we evaluated the relationships between circulating blood cell counts and RT effects. METHODS: In 179 cases with advanced RC, we retrospectively examined hemoglobin (Hb) levels and counts of white blood cells (WBC), platelets and WBC subsets before and after RT and investigated their associations with the complete response (CR) rate together with other clinicopathological factors. RESULTS: The ratio of lymphocytes in WBC taken before RT was significantly greater in 15 CR cases as compared with those in non-CR cases. Patients with high lymphocyte percentages (25.7%) showed better outcome than the counterparts. Conversely, the ratio of neutrophiles was reduced in CR cases. The lymphocyte ratio showed an independent association with CR with multivariate analysis, and tended to be maintained at relatively high levels in CR cases. CONCLUSIONS: In RC patients, peripheral blood lymphocytes have a significant impact on the CR rate in response to RT. Lymphocyte-mediated immune reactions are supposed to have positive roles on clinical response in radiotherapy for RC.

Loss of sympathetic nerve fibers around intratumoral arterioles reflects malignant potential of gastric cancer.

BACKGROUND: The role and clinical significance of the alteration of sympathetic nerve fibers (SNF) was assessed in gastric cancer. Loss of nerve fibers in malignant tumors has previously been described; however, how dysfunction of the nervous system is involved in cancer progression has not been clarified in clinical studies. MATERIALS AND METHODS: The distribution of SNF was examined in 82 surgically resected gastric cancer specimens with immunohistochemical staining of tyrosine hydroxylase (TH), and the association with clinicopathological findings as well as the clinical outcome of the patients was retrospectively evaluated. RESULTS: Arterioles in the normal gastric wall were totally covered with SNF, while the immunoreactivity to TH was markedly reduced around arterioles in cancer tissue. The degree of loss of SNF was significantly correlated with the depth of invasion (P < .0001) and lymph node metastasis (P < .0001) as well as microvessel density (MVD) (P = .0043). Moreover, patients who had tumors with marked loss of SNF showed a markedly worse clinical outcome, with an independent association by multivariate analysis. CONCLUSIONS: Loss of periarteriolar SNF is associated with aggressive phenotype of gastric cancer possibly through enhanced angiogenesis and thus could be a useful marker to predict the clinical outcome.