Kenji Taketani

Differential impact of the expression of the androgen receptor by age in estrogen receptor–positive breast cancer

We evaluated the expression of the androgen receptor (AR) to determine its significance in breast cancer. AR expression levels were analyzed in 250 invasive breast cancers by immunohistochemistry and any association with the clinicopathological features was evaluated. AR expression was higher in estrogen receptor (ER)‐positive cases than in ER‐negative cases (P < 0.0001). AR expression was associated with ER level, and it increased with age in ER‐positive cases. The cut‐off value was determined to be 75% (Cancer Res. 2009;69:6131–6140), and AR expression was considered to be high in 155 (62%) cases. High AR expression significantly correlated with lower nuclear grade (P < 0.0001), ER and progesterone receptor (PR) positivity (P < 0.0001 and P = 0.0022), HER2 negativity (P = 0.0113), lower Ki67 index (P < 0.0001) and a longer disease‐free survival (DFS) and distant metastasis‐free survival (DMFS) (P = 0.0003 and 0.0107). This association between a high AR expression and a good DFS and DMFS was significant for ER‐positive tumors (P < 0.0001 and P = 0.0018); however, no association existed between AR expression and prognosis for ER‐negative tumors. In patients ≤51 years old, a high AR expression level significantly correlated with a better prognosis, but this was not significant in patients who were 50 or younger. Multivariate Cox hazard analyses revealed AR expression to be independently associated with a good prognosis in overall patients (HR 0.46, P = 0.0052) and in the ER‐positive cohort (HR 0.34, P = 0.0009). AR expression is associated with a less aggressive phenotype and a good prognosis in patients with ER‐positive breast cancer. This is considered to be a specific phenomenon for postmenopausal breast cancer patients.

Contribution of BubR1 to oxidative stress-induced aneuploidy in p53-deficient cells.

DNA aneuploidy is observed in various human tumors and is associated with the abnormal expression of spindle assembly checkpoint (SAC) proteins. Oxidative stress (OS) causes DNA damage and chromosome instability that may lead to carcinogenesis. OS is also suggested to contribute to an increase in aneuploid cells. However, it is not clear how OS is involved in the regulation of SAC and contributes to carcinogenesis associated with aneuploidy. Here we show that an oxidant (KBrO3) activated the p53 signaling pathway and suppressed the expression of SAC factors, BubR1, and Mad2, in human diploid fibroblast MRC5 cells. This suppression was dependent on functional p53 and reactive oxygen species. In p53 knockdown cells, KBrO3 did not suppress BubR1 and Mad2 expression and increased both binucleated cells and cells with >4N DNA content. BubR1 and not Mad2 downregulation suppressed KBrO3‐induced binucleated cells and cells with >4N DNA content in p53 knockdown cells, suggesting that BubR1 contributes to enhanced polyploidization by a mechanism other than its SAC function. In analysis of 182 gastric cancer specimens, we found that BubR1 expression was significantly high when p53 was positively stained, which indicates loss of p53 function (P = 0.0019). Moreover, positive staining of p53 and high expression of BubR1 in tumors were significantly correlated with DNA aneuploidy (P = 0.0065). These observations suggest that p53 deficiency may lead to the failure of BubR1 downregulation by OS and that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy.

Endoscopic evaluation of clinical colorectal anastomotic leakage

BACKGROUND Anastomotic leakage (AL) is a major complication after anterior resection. However, its therapeutic strategies and technical risk factors have not been well established. Therefore, we endoscopically evaluated anastomotic regions after laparoscopic colorectal anastomosis using a double-stapling technique (DST) for determination of treatment and investigation of technical factors. METHODS In total, 191 consecutive patients underwent laparoscopic anterior resection with a DST from September 2008-January 2013. Anastomotic regions were endoscopically evaluated in patients suspected to have AL after surgery. RESULTS Anastomotic dehiscence was observed in 19 patients, and AL was diagnosed in 18 (9.3%). Of the 19 patients, 12 were treated by creation of an intestinal stoma and 7 were treated conservatively based on their clinical status and endoscopic findings. Twenty-three dehiscences were observed among 19 anastomotic regions; all 23 were observed on the circular stapler anastomosis lines. Of these 23 dehiscences, 13 (56.5%) were located at the point at which the anastomosis lines of the circular and linear staplers overlapped, and 10 (43.5%) were located on the circumferential aspect between the overlapping points. CONCLUSIONS Endoscopic evaluation of anastomotic regions is safe and useful for the determination of therapeutic strategies. The DST anastomotic technique itself may be closely related to the development of AL.