A novel combined carbohydrate antigen 19-9 and lymphocyte-to-monocyte ratio score can predict early recurrence of resectable pancreatic ductal adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) often recurs early after radical resection, which causes a poor prognosis. This study aimed to establish a scoring model to assess the optimal treatment in patients who underwent surgery for PDAC. METHODS: This single-center retrospective study included 127 patients who underwent radical resection for PDAC between 2005 and 2021. Early recurrence (ER) was defined as recurrence within 12 months after resection. The predictive effect for ER was evaluated using receiver operating characteristic (ROC) curves of preoperative parameters. RESULTS: ER occurred in 43 (33.9%) patients. The ER group had a significantly worse prognosis than the non-ER group (p < 0.0001). The carbohydrate antigen 19-9 (CA19-9) level and lymphocyte-to-monocyte ratio (LMR) were the strongest diagnostic factors (areas under the ROC curves: 0.74 and 0.68, respectively). The ER prediction score was calculated using optimal cutoff values. A higher CA19-9-LMR score was associated with a worse prognosis in terms of the overall and recurrence-free survival (p = 0.0017 and p < 0.0001, respectively). A multivariate analysis identified a high CA19-9-LMR score as an independent predictor of ER. CONCLUSIONS: The CA19-9-LMR scoring model can predict ER after surgery and is applicable for risk stratification in the assessment of patients with resectable PDAC.

Usability of Intraoperative Fluorescence Imaging with Indocyanine Green During Laparoscopic Cholecystectomy After Percutaneous Transhepatic Gallbladder Drainage.

BACKGROUND: Patients with persistent symptoms of acute cholecystitis for >72 h who cannot undergo urgent laparoscopic cholecystectomy (LC) often undergo percutaneous transhepatic gallbladder drainage (PTGBD) and delayed LC. However, intraoperative near-infrared fluorescence with indocyanine green (ICG) has recently become available in various surgical settings. Therefore, we evaluated the usability of intraoperative fluorescence imaging with ICG for LC after PTGBD in patients with acute cholecystitis. METHODS: The preoperative and postoperative clinical characteristics of patients who underwent LC after PTGBD were retrospectively analyzed. RESULTS: In total, 130 patients were reviewed. Intraoperative ICG fluorescence imaging was used in 39 (30.0%) patients, and none developed adverse reactions. Patients with ICG fluorescence imaging had a significantly shorter operative time (129 ± 46 vs. 150 ± 56 min, p = 0.0455), markedly lower conversion rate (2.6% vs. 22.0%, p = 0.0017), and lower proportion of subtotal cholecystectomy (0.0% vs. 6.6%, p = 0.0359) than patients without ICG fluorescence imaging. Independent risk factors for conversion to laparotomy during LC after PTGBD were the performance of PTGBD after 48 h from onset (OR 3.52; 95% CI 1.11-12.21; p = 0.0322), an unremoved PTGBD tube on LC (4.48, 1.46-15.00, p = 0.0084), and surgery without ICG (8.00, 1.28-159.47, p = 0.0231). CONCLUSION: Intraoperative ICG fluorescence imaging produced better surgical outcomes without any adverse reactions. Early performance of PTGBD and intraoperative ICG fluorescence imaging can reduce the surgical difficulties in LC after PTGBD for acute cholecystitis.

Evaluation of techniques to prevent colorectal anastomotic leakage.

BACKGROUND: Anastomotic leakage is a major complication after anterior resection for rectal cancer. The double-stapling technique (DST) is the main method for creating a colorectal anastomosis. However, the rate of anastomotic leakage after DST remains high, and the technical risk factors have not been well established. MATERIALS AND METHODS: Five methods of colorectal anastomosis were performed on the porcine rectum and colon: single-stapled double-purse-string (SSDP), DST, side-to-side with a linear stapler (SS-L), side-to-side with a circular stapler (SS-C), and SS-C with hand-sewn reinforcement (n = 6 for each method). In each group, burst pressures were tested, paying special attention to the locations of the first disruptions. The anastomosis line, including staples, was embedded in polyester resin, and polished sections were examined histologically. RESULTS: Burst pressures were significantly higher in the SS-L and SS-C than those in the SSDP and DST groups (P < 0.001) and were higher in the SS-C with hand-sewn reinforcement than those in the SS-L and SS-C groups (P < 0.001). Remarkably, in the SSDP, DST, and SS-C groups, the first disruptions occurred on the staple line created by the circular stapler. CONCLUSIONS: The experimentally strongest colorectal anastomosis created with instruments currently in use was a SS-C. This anastomosis does not overlap staple lines and does not require a purse-string suture. Hand-sewn reinforcement was effective in increasing the anastomotic strength.

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.

A case of invasive micropapillary carcinoma of the breast involving extensive lymph node metastasis.

We herein report a case of invasive micropapillary carcinoma (IMPC) involving extensive lymph node metastasis with no recurrence for over 7 years. A 41-year-old female presented with pain and a swelling mass in the left axillary region, which had been present for several months. The tumor measured 1.6 cm in diameter in the middle of upper area of the left breast. Based on the findings of a core needle biopsy the pathological diagnosis was IMPC or mucinous carcinoma. The cytology of the left axillary lymph node was positive for metastatic carcinoma. The patient underwent a left mastectomy and a left axillary dissection (level I to III). The postoperative pathological diagnosis was IMPC with mucin production, and the number of metastatic lymph nodes was 59. The patient was given adjuvant chemotherapy (four courses of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and four courses of docetaxel), radiation for the left chest wall, supraclavicular and internal thoracic area, and then received tamoxifen for 5 years. The patient has remained recurrence-free for over 7 years. IMPC is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and a poor prognosis. It seems that long-term survival was obtained by performing sufficient medical treatment. Prognostic factors other than the number of lymph node metastases may also exist.

Luteinizing hormone-releasing hormone agonist plus an aromatase inhibitor as second-line endocrine therapy in premenopausal females with hormone receptor-positive metastatic breast cancer.

PURPOSE: The aim of the current study was to explore the efficacy and safety of combination therapy using a luteinizing hormone-releasing hormone (LHRH) agonist plus an aromatase inhibitor (AI) as second-line therapy in premenopausal females with hormone receptor (HR)-positive recurrent or metastatic breast cancer (MBC). METHODS: A retrospective analysis was conducted in patients registered in the breast cancer database of our institution between January 2001 and December 2012. The breast cancer database identified 14 premenopausal patients who had been treated with an LHRH agonist plus AI for HR-positive recurrent or MBC. RESULTS: Fourteen patients with recurrent breast cancer (N = 10) or metastatic disease at primary diagnosis (N = 4) were included in the present study. All patients had previously been treated with an LHRH agonist plus tamoxifen. The clinical benefit rate was 71.4% and the median TTP was 11 months (95% confidence interval 1.7-20.3 months). One patient discontinued treatment because of liver dysfunction (grade 3). CONCLUSIONS: The combination of an LHRH agonist plus an AI is a treatment option for premenopausal females with HR-positive MBC that can prolong the chemotherapy-free interval and yield effective disease stabilization.

Early discontinuation of adjuvant hormone therapy is associated with a poor prognosis in Japanese breast cancer patients.

PURPOSE: It is important for patients to complete the planned hormone therapy to reduce both the recurrence and mortality rates of hormone receptor-positive breast cancer. We investigated the rates and factors related to the early discontinuation of adjuvant hormone therapy at our institution. METHODS: We identified 145 females prescribed adjuvant hormone therapy who were followed up for longer than 5 years. The rate of completing the planned hormone therapy and factors related to early discontinuation were examined. The relapse-free survival rate was examined between the completion group and the discontinuation group. RESULTS: The completion rate was 90.6 %. The primary reason for discontinuing hormone therapy within 5 years was side effects, such as arthritic pain. The primary factor related to early discontinuation was a significantly younger age. The relapse-free survival rate was significantly lower in the discontinuation group (p = 0.025). CONCLUSIONS: More than 90 % of the patients completed the planned adjuvant hormone therapy, and early discontinuation was related to a shorter RFS. To improve the rate of the successful completion of adjuvant hormone therapy, it is important to provide supportive care to reduce the occurrence of side effects and to care for young females with a desire to become pregnant.

Prognostic Impact of a Novel Albumin-Platelet Index as Selection Criterion for Hepatic Resection in Intermediate Stage Hepatocellular Carcinoma.

BACKGROUND/AIM: Hepatic resection for Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate-stage) hepatocellular carcinoma (HCC) is not recommended by BCLC treatment algorithms. We sought to develop a new prognostic model for determining appropriate treatment strategies in patients with intermediate-stage HCC. PATIENTS AND METHODS: This single-center retrospective study included patients who underwent hepatic resection for HCC between 2000 and 2018. A total of 498 patients were classified according to the BCLC staging system (0, n=116; A, n=319; B, n=63). The predictive impact for surgical outcomes was evaluated using receiver operating characteristic (ROC) curves. Based on a survival outcome probability formula, a new predictive model was established. RESULTS: The preoperative albumin level and platelet count were the strongest diagnostic values in patients with intermediate-stage HCC (areas under the ROC curves, AUCs: 0.710 and 0.676, respectively). Logistic regression analysis provided the albumin-platelet index [API; 156.2×albumin (g/dl)+platelet count (×109/l)] was defined as a new prognostic model for the probability of poor survival. The optimal cutoff value (781.2; AUC 0.755) divided patients with BCLC-B into B1 (>781.2, n=27) and B2 (≤781.2, n=36) categories. Patients in substage B2 had a significantly worse prognosis than patients in other stages (p<0.0001), whereas there was no difference in prognosis between patients in substage B1 and those in other stages. CONCLUSION: The API stratifies prognosis in patients with intermediate-stage HCC. For subgroup B1, hepatic resection can be considered a radical treatment, even for intermediate-stage HCC.

The stress response gene ATF3 is a direct target of the Wnt/ß-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells.

Aberrant Wnt/ß-catenin signaling is implicated in tumorigenesis and the progression of human colorectal cancers, and mutations in the components of the Wnt/ß-catenin signaling pathway are observed in the majority of patients. Therefore, extensive studies on the Wnt signaling pathway and its target genes are crucial to understand the molecular events of tumorigenesis and develop an efficacious therapy. In this study, we showed that the stress response gene ATF3 is transcriptionally activated by the binding of ß-catenin and TCF4 to the redundant TCF4 site at the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the Wnt/ß-catenin pathway. The loss of function or overexpression studies showed that ATF3 inhibited the migration or invasion of HCT116 cells. The expression of some MMP and TIMP genes and the ratio of MMP2/9 to TIMP3/4 mRNAs was differentially regulated by ATF3. Therefore, though ATF3 is activated downstream of the Wnt/ß-catenin pathway, it acts as a negative regulator of the migration and invasion of HCT116 human colon cancer cells exhibiting aberrant Wnt/ß-catenin activity. ATF3 is a candidate biomarker and target for human colorectal cancer treatment and prevention.

The Local Recurrence of Breast Cancer with Squamous Metaplasia and Obvious Histological Heterogeneity.

CASE REPORT: We herein report a case of local recurrence of breast cancer with squamous metaplasia and obvious intratumoral and intertumoral heterogeneity. A 39-year-old female patient was diagnosed with T3N2M0 stage IIIB right breast cancer and underwent right total mastectomy and axillar lymph node dissection. At four years after surgery, she became aware of chest wall pain and diagnostic imaging revealed recurrence in the lung, right thoracic wall and sternum. The recurrent lesions remained stable for 18 months with endocrine therapy. Thereafter, the lesion in the right thoracic wall suddenly became enlarged. Moreover, liver metastasis was confirmed on FDG-PET/CT. She underwent right thoracic wall tumor resection. A biopsy was simultaneously performed to obtain a specimen from the site of liver metastasis. Postoperatively, the right chest wall mass showed obvious intratumoral heterogeneity; squamous differentiation with aggressive features and a papillotubular component similar to the primary tumor. The metastatic liver tumor showed similar pathological features to the primary tumor. CONCLUSION: Intratumoral and intertumoral heterogeneity within primary tumors and associated metastatic sites may contribute to treatment failure and drug resistance.

Biological and clinical significance of loss of heterozygosity at the INPP4B gene locus in Japanese breast cancer.

PURPOSE: INPP4B is considered to function as a putative tumor suppressor through its inhibitory function of Akt. In various malignant tumors, loss of heterozygosity (LOH) at the chromosomal region containing INPP4B and lower expression of INPP4B has been reported. The purpose of this study was to examine the frequency of the INPP4B LOH and its association with the clinicopathological characteristics and prognosis in breast cancer of Japanese women. METHODS: The allelic alteration at the INPP4B and PTEN gene loci was analyzed in 277 invasive primary breast carcinomas. The relationships between INPP4B LOH and the clinicopathological features were investigated. RESULTS: Among the 238 informative cases for the evaluation, LOH at the INPP4B gene locus was observed in 43 tumors (18.1%). INPP4B LOH was significantly correlated with ER and PR negativity (p = 0.0009 and p = 0.0029, respectively), higher nuclear grade (p < 0.0001), higher Ki67 labeling index (p = 0.0006), triple-negative (TN) subtype (p = 0.0005) and PTEN LOH (p < 0.0001). INPP4B LOH was significantly associated with poorer prognosis, in terms of the relapse-free survival (RFS) and overall survival (OS). According to the multivariate analyses, INPP4B LOH was not independently associated with the prognosis. CONCLUSION: The incidence of INPP4B LOH was significantly higher in the TN subtype and positively correlated with PTEN LOH. INPP4B LOH was associated with more aggressive and proliferative phenotype. INPP4B LOH was also associated with poorer prognosis.

Retrograde Jejunojejunal Intussusception After Gastrectomy: Report of Four Cases.

BACKGROUND: Retrograde intussusception of the small bowel is extremely rare. We experienced four cases of retrograde jejunojejunal intussusception that needed emergency surgery. The aim of the present report was to expand awareness of retrograde jejunojejunal intussusception as an urgent complication following gastrectomy.

Characteristics and Treatment Strategies for Small Bowel Adenocarcinoma in Advanced-stage Cases.

BACKGROUND: Small bowel adenocarcinoma is an uncommon disease with poor prognosis. Therefore, characteristics and treatment strategies for small bowel adenocarcinoma should be elucidated sufficiently, not only for surgery, but also for chemotherapy. PATIENTS AND METHODS: Medical records were abstracted to identify patients with small bowel adenocarcinoma who were treated at the Iizuka Hospital, Fukuoka, Japan, between 2004 and 2014. The results of surgical treatment for stage II/III cases and the efficacy of chemotherapy for unresectable stage IV cases were investigated. RESULTS: The median tumor size was 25.6 ± 19.2 mm, and tumor size was not associated with primary symptoms. Nine of the patients were diagnosed with stage II/III disease and underwent surgical resection. The other three patients were diagnosed with stage IV disease, and two out of those three cases received definitive chemotherapy. In two out of the nine resected cases, recurrence was observed; however, surgical resection of the recurrent tumor was associated with a good prognosis. In stage IV cases that received chemotherapy, survival durations of over 11 months were achieved. In contrast, overall survival in the stage IV case without chemotherapy was 3.3 months. CONCLUSION: Curative resection and definitive chemotherapy for unresectable cases are effective treatment strategies for small bowel adenocarcinoma.

Necessity for resection of gastric gastrointestinal stromal tumors ≤ 20 mm.

BACKGROUND/AIM: To evaluate whether surgical intervention was useful in patients undergoing surgery for gastric gastrointestinal stromal tumors (GISTs), for tumors ≤ 20 mm in size. PATIENTS AND METHODS: Between August 2002 and July 2014, 138 patients with GIST underwent surgery at our Hospital, including 112 patients with gastric GISTs. The medical records of these patients were retrospectively reviewed. RESULTS: Postoperative recurrence was observed in three patients, each having tumors with high mitotic rates and ≥ 21 mm in size. In 89 patients undergoing gastric wedge resection, the incidence of postoperative complications was 10.1%; 5.6% of the patients developed late sequelae, all of which were mild. The group classified as having tumors ≥ 21 mm in size had a higher proportion of elderly patients (p=0.0010), more complications (p=0.0152), and longer hospital stay (p=0.0589). CONCLUSION: To prevent recurrence, definitive diagnosis and aggressive resection while the tumor size is 20 mm or less is recommended. However, because some patients also carry surgical risks, sufficient consideration must be given to the needs of individual patients.

Impact of GATA-3 and FOXA1 expression in patients with hormone receptor-positive/HER2-negative breast cancer.

BACKGROUND: Determining the indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/HER2-negative breast cancer are difficult. The transcription factors GATA-binding protein 3 (GATA-3) and Forkhead-box protein A1 (FOXA1) are crucial for the hormone responsive phenotype of breast cancer. This study evaluated whether the expression of GATA-3 and FOXA1 is a prognostic and predictive marker of outcomes in patients with HR-positive/HER2-negative breast cancer. METHODS: The expression of GATA-3 and FOXA1 was analyzed immunohistochemically in 214 patients with invasive breast cancer to evaluate the association with the clinicopathological features and the prognosis. RESULTS: GATA-3 expression was positively correlated with FOXA1 expression (P < 0.0001). Both GATA-3 and FOXA1 were positively correlated with ER (P < 0.0001 each) and PR expression (P = 0.0001 and P = 0.0009, respectively), and inversely correlated with nuclear grade (P = 0.0002 and P = 0.0018, respectively) and Ki67 index (P = 0.0052 and P = 0.0049, respectively). Expression of GATA-3 and FOXA1 was associated with better prognosis. FOXA1 was an independent favorable prognostic marker in HR-positive/HER2-negative breast cancer. Disease-free survival rates were similar in patients with HR-positive/HER2-negative breast cancer and high FOXA1 expression given adjuvant hormone therapy (HT) alone and those given CT plus HT. CONCLUSION: GATA-3 and FOXA1 are associated with a less aggressive phenotype and a better prognosis in patients with HR-positive/HER2-negative breast cancer. FOXA1 may be useful in identifying those patients who may not require adjuvant CT.

Epigenetic Inactivation of BRCA1 Through Promoter Hypermethylation and Its Clinical Importance in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases. PATIENTS AND METHODS: Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry. RESULTS: BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P < .0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P = .02), high nuclear grade (P = .05), low BRCA1 mRNA expression (P < .0001), and loss of BRCA1 protein expression (P = .0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P = .038). CONCLUSION: BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1.

Spontaneous regression of breast cancer with axillary lymph node metastasis: a case report and review of literature.

Spontaneous regression (SR) of cancer is a rare but well-documented biological phenomenon. However, the mechanism remains to be elucidated. We herein report a case of the SR of breast cancer at both the primary site and metastatic axillary lymph node with spontaneously-induced T cell-mediated immunological responses. A 52-year-old female with a lump in the left axilla was diagnosed to have a small breast carcinoma with a distinct axillary lymph node metastasis. During the preoperative systemic examination, she was diagnosed to have severe type 2 diabetes mellitus, was treated with insulin, and the hyperglycemia was normalized after one month. Surgery for left breast cancer was then performed. The postoperative histopathological examination revealed the SR of breast cancer at both the primary site and metastatic axillary lymph node. Immunohistochemical studies revealed that estrogen receptor positive, AE1/AE3-positive ductal carcinoma completely underwent necrosis associated with extensive infiltration of CD3-positive T cells in the tumor nodule in the lymph node. In addition, primary ductal carcinoma cells also underwent single cell necrosis with infiltration of T cells with lymph follicle-like organization of B cells in the mammary gland. The features were suggestive that the tumor eradication in the metastatic lymph node and regression of the primary ductal carcinoma could be due to host T cell response to the ductal carcinoma. As far as we know it is the first report that shows the spontaneous regression of breast cancer, probably due to the spontaneously-induced T cell response.

Clinical outcomes and prognostic factors after surgery for non-occlusive mesenteric ischemia: a multicenter study.

BACKGROUND: To date, no large-scale study has been undertaken to understand the clinical features of non-occlusive mesenteric ischemia (NOMI) after surgery. We thus performed a multicenter investigation to clarify the clinical outcomes and prognostic factors of NOMI. PATIENTS AND METHODS: Clinical databases from 22 Japanese facilities were reviewed for evaluation of patients who received surgery for NOMI between 2004 and 2012. NOMI patients (n = 51) were divided into two groups: group I (n = 28) consisted of patients who survived, and group II (n = 23) consisted of patients who did not survived. Prognostic factors were compared between the two groups. RESULTS: NOMI surgery represented 0.04% of the total number of operations performed in this time period. The overall mortality rate for NOMI surgery was 45%. Hemodialysis was a significant negative prognostic factor (p = 0.027). Preoperative elevation of transaminases, potassium, and white blood cell count, as well as metabolic acidosis and colon ischemia was poor prognostic factors. The mean Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) score of group I versus group II was 54.5 ± 3.6 and 85.2 ± 4.1, respectively (p < 0.001). CONCLUSIONS: Currently, NOMI surgery has a 45% mortality rate. POSSUM scores can be used to predict the clinical outcome of patients who receive NOMI surgery.

Vimentin as a poor prognostic factor for triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, is a highly heterogeneous disease. Recent studies suggest that there are links between TNBC and the epithelial-mesenchymal transition (EMT). To identify prognostic biomarkers and novel therapeutic targets, vimentin, one of the most major factors associated with EMT was investigated in TNBC. MATERIALS AND METHODS: Sporadic invasive ductal carcinoma specimens were obtained from 659 Japanese patients, and 90 (14 %) cases were diagnosed as TNBC. The vimentin mRNA and protein expression levels were evaluated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: The mRNA expression of vimentin was significantly upregulated in the basal-type breast cancer cell line. Immunohistochemically, the vimentin expression was significantly higher (p = 0.0042) in TNBC compared with the other subtypes. Vimentin expression was associated with a younger age (p = 0.016), high nuclear grade (p = 0.023) and high Ki67 expression (p < 0.0001), and a poorer prognosis in terms of both the recurrence-free survival (RFS) (p = 0.0058) and overall survival (OS) (p = 0.013) in TNBC patients. A multivariate analysis showed that vimentin expression was an independent prognostic factor for the RFS (p = 0.043). Vimentin expression was also associated with a significantly shorter RFS (p = 0.021) and OS (p = 0.017) in patients with basal-like breast cancer (BLBC). CONCLUSIONS: The elevated expression of vimentin contributes to the aggressive phenotype and poor prognosis in TNBC. Vimentin expression might be useful as a biomarker for the prognosis of TNBC.

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.