Yasue Kimura

Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients.

Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser‐473. Eighty‐four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease‐free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy.

Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.

Interrelation Between Expression of Matrix Metalloproteinase 7 and β-Catenin in Esophageal Cancer

Matrix metalloproteinase 7 (MMP-7) may play a key role in the progression of various human malignant tumors. Nuclear β-catenin enhances the activating expression of MMP-7 genes by binding with the T-cell factor/lymphoid enhancer factor family of transcription factors. We immunohistochemically examined the expression of MMP-7 and β-catenin to better understand the significance of these factors in the progression of esophageal squamous cell carcinoma. The entire coding region of β-catenin exon 3 was also analyzed by direct sequencing in all cases. We found that MMP-7 was expressed in 7 (20.6%) of 34 esophageal squamous cell carcinomas. There was a significant relationship between MMP-7 expression and tumor invasion into adjacent structures (P < 0.05). Aberrant nuclear expression of β-catenin was found in 12 of 34 (35.3%) esophageal cancers and correlated with MMP-7 expression, the statistical difference being (P < 0.05). None of the 34 esophageal cancers examined carried mutations in β-catenin exon 3. MMP-7 expression correlates with penetrating tumor progression in esophageal cancer. Nuclear translocation of β-catenin, without mutations in β-catenin exon 3, is associated with MMP-7 expression.

S-1 in the treatment of advanced and recurrent gastric cancer: Current state and future prospects

BackgroundS-1 (TS-1®) is a novel oral anticancer drug. Because of the excellent results of phase II studies, we continued to prescribe S-1 for advanced or recurrent gastric cancer after we participated in the phase I and II studies.MethodsTwenty-nine patients with advanced or recurrent gastric cancer were treated with S-1. Clinicopathological features, survival, and adverse reactions were analyzed.ResultsOne course of treatment consisted of 40, 50, or 60 mg/body twice a day for 28 days followed by withdrawal for 2 weeks. The mean number of treatments was 3.6 courses (range, 1–12 courses). The response rate was 37.9% (11 partial responses [PRs] in 29 patients). Although the response rate of patients who did not receive prior chemotherapy was 47.6% (10 PRs in 21 patients), that of patients with prior chemotherapy was 12.5% (1 PR in 8 patients). The median survival time was 14.1 months, and that of patients who responded to treatment was 22.1 months, which was significantly longer than that of nonresponder patients. One-year and 2-year survivals in the 29 patients were 50.2% and 24.3%, respectively. Adverse reactions were noted in 17 of 29 patients, and the most frequent one was leukocytopenia. Only 2 patients experienced grade 3 leukocytopenia and neutrocytopenia.ConclusionBecause of the high response rate and low incidence of severe adverse reactions, S-1 is a first-line chemotherapy that can be used for outpatients, especially for patients without prior chemotherapy. As the response rate for patients with prior chemotherapy was low, combined therapy with S-1 is worth evaluating for these patients.

No Hypersensitive Estrogen Receptor-α Mutation (K303R) in Japanese Breast Carcinomas

Recently, a common somatic mutation, A-to-G transition at nucleotide 908, in the estrogen receptor-α (ERα) gene has been reported. This mutation causes an amino acid change in the ER hinge domain (lysine 303 to arginine, K303R) and confers an increased sensitivity to estrogen and an increased cellular proliferative potential. This mutation has been observed more frequently in breast cancers than in premalignant lesions. According to the previously published reports, the mutation was found in 62% of invasive breast cancers, 85% of the node-positive tumors, and 30% of proliferative breast hyperplasias in the study of US women. The purpose of our study was to investigate whether or not this mutation is present in breast cancers found in Japanese women. We performed mutation analysis using the genomic PCR and direct sequencing in 101 cases of breast cancer and eight cases of benign breast lesions. No K303R mutation was found in the ERα gene in these breast lesions obtained from Japanese patients.

Podoplanin is expressed at the invasive front of esophageal squamous cell carcinomas and is involved in collective cell invasion.

The expression of podoplanin is reportedly involved in collective cell invasion, which is independent from the epithelial–mesenchymal transition (EMT). We focused on the expression of podoplanin in esophageal squamous cell carcinomas (ESCC) and investigated the correlation of podoplanin and EMT‐related markers, and evaluated its prognostic significance. Five ESCC cell lines were subjected to western blot analysis for podoplanin and EMT markers. The effects of podoplanin on EMT and carcinoma invasion were evaluated with wound healing assays, invasion assays and 3‐D culture. Transfection of ectopic podoplanin into a podoplanin‐negative ESCC cell line (TE‐15) induced cell migration and invasive activity (P < 0.001 and P < 0.05, respectively) without downregulation of E‐cadherin. In contrast, transfection of si‐podoplanin RNA into a podoplanin‐positive ESCC cell line (TE‐13) reduced cell migration and invasive activity (P < 0.05). We reviewed 101 patients who had undergone esophagectomy for ESCC. Podoplanin expression was observed in 58 patients (57.4%), and positive expression was positively correlated with expression of E‐cadherin (P < 0.01), deeper wall invasion (P < 0.01), venous invasion (P < 0.05) and poorer prognosis (P < 0.01). Multivariate Cox analysis revealed that expression of podoplanin was a significant and independent unfavorable predictor of survival (P < 0.05). These data suggest that podoplanin is significantly associated with and likely contributes to ESCC invasion in the absence of EMT.

Gastric cancer in the reconstructed gastric tube after radical esophagectomy: A single-center experience

PurposeMetachronous gastric carcinoma arising in a gastric tube used for esophageal reconstruction has been occasionally encountered in long-term survivors of esophageal cancer. This study investigated 10 cases of gastric tube cancer in order to clarify the characteristics and the outcome of these patients.MethodsFour hundred and seventy-one patients underwent a radical esophagectomy at Kyushu University Hospital between 1989 and 2003. There were 10 cases of gastric tube cancer after an esophagectomy.ResultsThe interval between the esophagectomy and the development of the gastric tube cancer ranged from 1.1 to 7 years. There was no peak for the incidence of gastric tube cancer. In 6 of 10 cases of gastric tube cancer, endoscopic or surgical resection were performed for the treatment; however, chemotherapy was administered to the other 4 cases for several reasons. The prognosis of patients who underwent resection was better than that of the other patients.ConclusionsFrequent endoscopic examinations are therefore important even several years after performing an esophagectomy, since the risk of gastric tube cancer is higher than the risk of a recurrence of esophageal cancer several years after an esophagectomy. Only an early diagnosis permits a less invasive and appropriate approach for the treatment of gastric tube cancer.

Loss of Heterozygosity of PTEN (Encoding Phosphate and Tensin Homolog) Associated with Elevated HER2 Expression Is an Adverse Prognostic Indicator in Gastric Cancer

Objective: PTEN (the encoding phosphate and tensin homolog) is a well-known cancer suppressor gene and its mutation and loss of heterozygosity (LOH) occurs in various types of carcinomas. This study aimed to examine the association between LOH of PTEN and prognosis in HER2-expressing and nonexpressing gastric cancer patients. Methods: Fresh-frozen tumor samples of 221 gastric cancer patients with a primary diagnosis of gastric carcinoma were examined for LOH of PTEN. The results were compared with pathological parameters and the HER2 status. To elucidate the role of LOH of PTEN, the activation of the PI3K/AKT pathway was examined immunohistochemically using a phosphorylation-specific antibody. Results: LOH of PTEN was observed in 20% of the patients (39 of 195 cases). LOH of PTEN was associated with vascular involvement (25 of 39 cases; p = 0.0083), equivocal to positive staining for HER2 (p = 0.0080), and phospho-Akt expression (p = 0.0067). Patients with HER2-expressing gastric cancer with LOH of PTEN had a significantly worse prognosis (p = 0.0050). Conclusions: Although HER2 expression itself was not a prognostic factor, the combination of HER2 expression and LOH of PTEN exacerbates the malignant potential of gastric cancer through its proliferative function.

Surgical strategies for esophageal cancer associated with head and neck cancer

Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol’s staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis.

Prognostic Impact of Des-γ-carboxyl Prothrombin in Living-Donor Liver Transplantation for Recurrent Hepatocellular Carcinoma

BACKGROUND Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-γ-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. METHODS Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. RESULTS The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alpha-fetoprotein concentration ≥ 300 ng/mL, DCP concentration ≥ 300 mAU/mL, tumor number ≥ 4, tumor size ≥ 5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP ≥ 300 mAU/mL (P = .03) and duration from last treatment to LDLT <3 months (P = .01) were independent predictors of RFS. CONCLUSIONS DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC.