Shinsuke Takeno

The purpose of this study was to evaluate the prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in patients with colorectal cancer. A total of 97 adenocarcinomas of the colon and rectum were examined. Immunohistochemical staining was performed by the standard avidin-biotin-peroxidase complex method using antibodies to CD8 and CD68. Peritumoral infiltration by CD8+ T cells or macrophages was evaluated along the invasive margin of the cancer in each specimen. The area with the most abundant infiltration was selected, and the number of immunoreactive positive cells counted at x400 magnification. Patients were divided into two groups based on the degree of infiltration by each cell type: namely those with a high level of infiltration (more than the mean number of positive cells) and those with a low level of infiltration (less than the mean number of positive cells). Patients with a low level of macrophage infiltration had a significantly deeper depth of invasion than patients with a high level of macrophage infiltration (P=0.027). The percentage of patients with a high level of macrophage infiltration was significantly higher in vascular invasion-negative cases (46.7%) than in vascular invasion-positive cases (22.7%; P=0.045), and in lymph node metastasis-negative cases (52.9%) than in lymph node metastasis-positive cases (28.3%; P=0.014). Overall survival was significantly shorter for patients with a low level of CD8+ T cell infiltration than those with a high level of CD8+ T cell infiltration (P=0.01). The survival rate for patients with a high level of both CD8+ T cell and macrophage infiltration was 100%. In conclusion, both CD8+ T cell and macrophage peritumoral infiltration indicates anti-tumoral action in patients with colorectal cancer.

The mitotic spindle assembly checkpoint modulates the timing of anaphase initiation in response to improper alignment of chromosomes at the metaphase plate. The BUB gene family encodes proteins which are part of a large multi-protein kinetochore complex and which are believed to be key components of the checkpoint regulatory pathway. Failure of this surveillance system can lead to genomic instability and could be responsible for the increased incidence of aneuploidy in gastric cancer. Since mutations of BUB genes have not been identified in gastric cancer to date, altered BUB expression levels may significantly impair mitotic checkpoint function. To explore this possibility, the expression levels of BUB1, BUBR1, and BUB3 were determined in 43 gastric carcinomas and corresponding normal gastric mucosa by reverse transcription-polymerase chain reaction (RT-PCR). Gene expression levels were compared with histopathological parameters and DNA ploidy, as well as with proliferative activity, measured by Ki-67 mRNA expression. To the authors' knowledge, this is the first study to investigate the expression levels of mitotic checkpoint genes together with DNA ploidy in gastric cancer. BUB1 was overexpressed in 84%, BUBR1 in 68%, and BUB3 in 79% of gastric cancers. This study also revealed that all three genes were simultaneously overexpressed in 61% of the tumours and that there was a statistically significant positive correlation between overexpression of BUB1, BUBR1 or BUB3 and Ki-67 expression (p < 0.001). Eighty-one per cent of the tumours were classified as aneuploid. However, no correlation was found between ploidy and BUB transcript expression levels. These results suggest that inactivation of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 by epigenetic silencing does not seem to play a role in gastric carcinogenesis. The strong correlation of BUB expression level and tumour cell proliferation suggests that BUB overexpression is a proliferation-dependent phenomenon in gastric cancer. However, overexpression due to lack of normal BUB protein function or due to a yet unknown additional BUB function has to be considered.

BACKGROUND: Vascular endothelial growth factor C (VEGF-C) plays an important role in lymphangiogenesis and activates VEGF receptor 3 (VEGFR-3). By contrast, lymphatic spread is an important prognostic factor in patients with nonsmall cell lung carcinoma (NSCLC). The objective of the current study was to determine whether the expression of VEGF-C and VEGFR-3 correlates with clinicopathologic factors and prognosis in patients with primary NSCLC. METHODS: The authors conducted a retrospective review of 180 consecutive patients who underwent complete resection for NSCLC and who did not receive any chemotherapy or radiotherapy prior to surgery. Immunohistochemical staining for VEGF-C and VEGFR-3 was performed. The clinicopathologic implications of VEGF-C and VEGFR-3 expression were analyzed statistically. RESULTS: Of 180 patients with NSCLC, 137 patients (76.1%) were positive for VEGF-C, and 40 patients (22.2%) were positive for VEGFR-3. VEGF-C expression was observed frequently in patients with adenocarcinoma (P = 0.026). For VEGFR-3 expression, significant correlations were demonstrated with age (P = 0.02), gender (P = 0.008), and histologic differentiation in patients with squamous cell carcinoma (P = 0.03). Patients who had positive staining for VEGF-C showed significantly less favorable survival rates compared with patients who had negative staining for VEGF-C (P = 0.003). The survival rates of patients who had positive staining for VEGFR-3 also were significantly lower compared with patients who had negative staining for VEGFR-3 (P < 0.001). Patients who had positive staining for both VEGF-C and VEGFR-3 exhibited the most unfavorable prognoses. Univariate analysis revealed the following prognostic factors: gender (P = 0.03), tumor status (T1,T2 vs. T3; P < 0.01), lymph node status (negative vs. positive; P < 0.01), tumor size (< or = 35 mm vs. > 35 mm; P < 0.01), disease stage (Stage I vs. Stages II and III; P < 0.01), VEGF-C expression (negative vs. positive; P < 0.01), VEGFR-3 expression (negative vs. positive; P < 0.01) and combined VEGF-C and/or VEGFR-3 expression (both positive vs. VEGF-C or VEGFR-3 positive; P < 0.01). Multivariate analysis demonstrated that VEGFR-3 expression was the only independent negative prognostic factor (P < 0.01). CONCLUSIONS: VEGF-C and VEGFR-3 expression may be indicative of survival rates for patients with NSCLC.

Survivin is a novel member of the inhibitor of apoptosis family and determines the susceptibility of tumour cells to pro-apoptotic stimuli. Recently, we identified two novel alternative splice variants of survivin, differing in their anti-apoptotic properties: whereas the anti-apoptotic potential of survivin-DeltaEx3 is preserved, survivin-2B has lost its anti-apoptotic potential and may act as a naturally occurring antagonist of survivin. Because the in vivo expression of these alternative splice variants has not been explored so far, we analysed gastric carcinomas of different histological subtypes, grades and stages. Since no antibodies are currently available to determine the novel splice variants, quantitative reverse transcriptase polymerase chain reaction was performed, using RNA samples obtained from 30 different gastric carcinomas. Polymerase chain reactions products were quantified by densitometric evaluation. We found that all gastric carcinomas, irrespective of their histological types, grades or stages, express survivin-DeltaEx3, survivin-2B and survivin, the latter being the dominant transcript. Comparing the disease stages I+II with III+IV, expression of survivin and survivin-DeltaEx3 remained unchanged. In contrast, a significant (P=0.033) stage-dependent decrease in the expression of survivin-2B became evident. Our study demonstrates for the first time the expression of alternative splice variants in gastric carcinomas and provides a first clue to a role of survivin-2B in tumour progression.

BACKGROUND/AIMS: Patients with postoperative pulmonary complications after esophagectomy often have increased mortality. The purpose of the study was to examine the efficacy of preventing postoperative pulmonary complications by an intensive preoperative respiratory rehabilitation (PR) program for esophageal cancer patients. METHODS: This study was a prospective randomized controlled study. Thirty patients in the PR group and 30 patients in the no preoperative respiratory rehabilitation (NPR) group were included. The PR group received preoperative rehabilitation for more than 7 days, while the NPR group did not receive any preoperative rehabilitation. All patients underwent postoperative rehabilitation from the first postoperative day. The postoperative pulmonary complications were evaluated using the Clavien-Dindo classification (CDC) and the Utrecht Pneumonia Scoring System (UPSS). RESULTS: The CDC grade in the PR group was significantly lower than that in the NPR group (p = 0.014). The UPSS score in the PR group was significantly lower than that in the NPR group at postoperative day 1 (p = 0.031). In the multivariate analysis, NPR was an independent risk factor for postoperative pulmonary complications greater than CDC grade II (OR: 3.99, 95% CI: 1.28-12.4, p = 0.017). CONCLUSIONS: This study showed that the intensive PR program was capable of reducing the postoperative pulmonary complications in esophageal cancer patients.