Masahiko Ikebe

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.

AKT phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer

Growth factor receptor‐mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. We describe a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996–2000. AKT activation was investigated by immunostaining with a phosphorylation‐specific antibody, and LOH (loss of heterozygosity) of PTEN was studied in the same samples. AKT was phosphorylated in 22 cases (28.9%) of gastric cancer cases. AKT and phosphorylated AKT were not correlated with any clinicopathological factor. We found that the gastric cancer patients who had higher AKT phosphorylation (activated AKT) seemed to have LOH of PTEN (p = 0.0008). When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents (5‐fluorouracil, adriamycin, mitomycin C and cis‐platinum). The results of our study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad‐spectrum chemoresistance in gastric cancer patients. It also indicates that AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of gastric cancer patients.

Endoscopic diagnosis of early carcinoma of the esophagus using Lugol's solution

Small esophageal lesions, particularly intraepithelial cancers, are extremely difficult to detect. We used Lugols iodine solution with panendoscopic examination to detect the presence and spread of small squamous cell carcinomas of the esophagus. Serial histologic specimens of the surgically removed esophagus from 32 patients with Lugols combined endoscopic diagnosis of early esophageal carcinoma were examined to determine the correlation between endoscopic and histologic findings. All of the early staged carcinomas clearly remained unstained by Lugols solution. We believe that the application of Lugols solution will greatly aid in instances when a suspicious mucosal lesion is noted, when the margin of the lesion is unclear, or when there is suspicion that a mucosal lesion may have been overlooked.

Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus—A prospective randomized trial

From 1988 to 1990, 53 patients with squamous cell carcinoma of the thoracic oesophagus underwent subtotal oesophagectomy after either preoperative hyperthermo-chemoradiotherapy (HCR therapy) or chemoradiotherapy without hyperthermia (CR therapy), in a prospective randomized trial carried out to examine the effects of hyperthermia given preoperatively. The two groups (27 patients given HCR therapy and 26 given CR therapy) were found to be comparable with regard to prognostic factors of age, site of carcinoma, TNM stage, etc. Following preoperative evaluation by an upper GI series and endoscopy, a subtotal oesophagectomy was done for all 53 patients. All the resected specimens, including the lymph nodes, were histopathologically examined, and the effects of preoperative treatment were evaluated by findings in the upper GI series and endoscopy, as well as based on the histopathology of the excised tissues. There were no viable cancer cells in the resected specimens of seven patients in the HCR therapy group (26.9%) and of two patients in the CR therapy group (7.7%). In addition, no hyperthermia complications were observed. The study suggests that preoperative HCR therapy may be a more beneficial therapy than preoperative CR therapy in patients with squamous cell carcinoma of the oesophagus who undergo a subtotal oesophagectomy.

Laparoscopy-assisted surgery: A new technique for transhiatal esophageal dissection

Esophageal dissection under laparoscopic monitoring is performed during total esophagectomy to treat patients with cervical esophageal carcinoma. Using this technique, a safe esophageal dissection can be made from the surrounding mediastinal tissues. Some of the disadvantageous consequences of a blunt dissection, including the blind maneuver, may thus be prevented and various intraoperative and postoperative complications may be avoided.

Squamous epithelial dysplasia associated with squamous cell carcinoma of the esophagus

To investigate the relationship between dysplasia and carcinoma of the esophagus, 159 cases of esophageal carcinoma without any preoperative treatment were reviewed retrospectively. There were 75 dysplastic lesions in 32 cases (20.1%). The incidence of co-existence of dysplastic lesions was 0, 58.3, 31.3, 20.8 and 11.4% in intra-epithelial, mucosal and submucosal cancers and those invading the proper muscular layer and adventitia, respectively. Thus, excluding the cases of intra-epithelial carcinoma, the less advanced the lesion, the higher the incidence of dysplasia. Epithelial dysplastic lesions were classified as 12 with mild, 33 with moderate and 30 with severe degrees of dysplasia. Although the continuity of dysplastic lesions to the areas of carcinoma was not so frequent (48.0%), it was more often encountered in severe dysplasia rather than in moderate or mild dysplasia, which suggested some relationship between the severity of dysplasia and carcinoma. In the cases with a dysplastic lesion the multiplicity of squamous cell carcinoma and the intra-epithelial spread of the main lesion were more frequently seen (P < 0.001), suggesting a multicentric occurrence of dysplastic lesions and carcinomas.

Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer

Background and Aim:  Encoding phosphate and tensin homolog (PTEN) is a cancer suppressor gene and it has been assumed that gene mutation and loss of heterozygosity (LOH) occurs frequently in various types of carcinoma. However, the role of LOH of PTEN and its outcome variables in gastric cancer have not been well established. In the present study, we investigated the roles of PTEN, LOH and their outcomes.

Incidence and predictors of deep venous thrombosis after abdominal oncologic surgery: Prospective Doppler ultrasound screening

BACKGROUND Venous thromboembolism is a relatively rare but serious complication of abdominal surgery. This study evaluated the incidence and risk factors for the development of deep venous thrombosis (DVT) after abdominal oncologic surgery using color Doppler ultrasonography (DUS). METHODS This study enrolled 132 consecutive patients who underwent elective abdominal surgery for malignant tumors. Patients were investigated for DVT using DUS on postoperative day 7 ± 2. Correlations between the incidence of DVT and clinicopathologic parameters and the postoperative course were evaluated. RESULTS DVT was found in 15 patients (11.4%) using DUS. Clinically evident venous thromboembolism, including pulmonary embolism, was not found in these patients. The incidence of DVT was significantly higher in females (P=0.002), patients with a lower body mass index (P=0.008), and patients with a higher preoperative D-dimer level (P<0.0001). CONCLUSIONS DUS is noninvasive and is useful for postoperative DVT screening. Thromboprophylaxis is essential in high-risk patients who have undergone abdominal oncologic surgery.

Neoadjuvant therapy for advanced esophageal cancer: the impact on surgical management

Multidisciplinary therapies have been developed to prolong the survival of patients with resectable esophageal cancer. Worldwide, neoadjuvant therapy has become the standard treatment for locally advanced resectable esophageal cancer. In this article, we briefly review the clinical trials and meta-analyses of neoadjuvant therapy for advanced esophageal cancer. In Europe and the USA, neoadjuvant chemoradiotherapy is regarded as the standard treatment, while neoadjuvant chemotherapy has become the standard treatment in Japan based on the results of clinical trials. Changes in treatment, according to the period and the results of up-to-date studies, are discussed. As neoadjuvant therapy is administered with the assumption that surgery will be performed, it is important for surgeons to be familiar with its impact on surgical management. We also review the impact of neoadjuvant therapy on surgical management. Issues such as the timing of surgery after neoadjuvant therapy, the extent of lymph node dissection, and the operative approach in relation to the esophagus are matters to be elucidated in the future.

An unusual enteropathy-associated T-cell lymphoma with MYC translocation arising in a Japanese patient: a case report.

Enteropathy-associated T-cell lymphoma (EATL) is a rare peripheral T-cell lymphoma classified into 2 types, with or without celiac disease, based on histology. Type 2 EATL is less commonly associated with celiac disease, in which cells are characterized by being monomorphic and small- to medium-sized. Cells are characterized by CD8 and CD56 expression and c-MYC oncogene locus gain. We present an atypical case of type 2 EATL in the jejunum, with human T-lymphotropic virus-1 that was CD4- CD8+ CD56- CD30- CD25- TIA-1+ and granzyme B+ on immunohistological staining. It also displayed translocation of chromosome 8p24 (c-MYC), as determined by fluorescent in situ hybridization. Mucosal spreading and intraepithelial invasion by lymphoma with villous atrophy were detected adjacent to the mucosal layer. The lymphoma may be derived from intraepithelial CD8+ T cells, similar to celiac disease.