Yoshihisa Sakaguchi

Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention

Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case–control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.

Signet ring cell carcinoma of the stomach

Between 1965 and 1985, 51 of 1500 patients (3.4%) with gastric cancer who had gastric resection had signet ring cell gastric cancer. Patients with this form of cancer tended to be younger and female; the tumors were smaller and involved the stomach body, serosal invasion was less prominent, and lymph node metastases were less likely to be present. Early mucosal and submucosal cancer was present in 54.9% of the patients with the signet ring cell and in 24.6% with other types of gastric cancer. In 15.7% of patients with signet ring cell cancer, a noncurative resection was performed. The 5‐year survival rate was 74.5% for patients with signet ring cell cancer and 52.4% for those with other types of gastric cancer (P < 0.01). In patients with signet ring cell gastric cancer, the lesion is less extensive; thus, these patients probably can expect a longer survival time.

Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis

Esophageal cancer is the eighth most common incident cancer in the world and ranks sixth among all cancers in mortality. Esophageal cancers are classified into two histological types; esophageal squamous cell carcinoma (ESCC), and adenocarcinoma, and the incidences of these types show a striking variety of geographic distribution, possibly reflecting differences in exposure to specific environmental factors. Both alcohol consumption and cigarette smoking are major risk factors for the development of ESCC. Acetaldehyde is the most toxic ethanol metabolite in alcohol-associated carcinogenesis, while ethanol itself stimulates carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Cigarette smoke contains more than 60 carcinogens and there are strong links between some of these carcinogens and various smoking-induced cancers; these mechanisms are well established. Synergistic effects of cigarette smoking and alcohol consumption are also observed in carcinogenesis of the upper aerodigestive tract. Of note, intensive molecular biological studies have revealed the molecular mechanisms involved in the development of ESCC, including genetic and epigenetic alterations. However, a wide range of molecular changes is associated with ESCC, possibly because the esophagus is exposed to many kinds of carcinogens including alcohol and cigarette smoke, and it remains unclear which alterations are the most critical for esophageal carcinogenesis. This brief review summarizes the general mechanisms of alcohol- and smoking-induced carcinogenesis and then discusses the mechanisms of the development of ESCC, with special attention to alcohol consumption and cigarette smoking.

Role of tumor-associated macrophages in the progression of hepatocellular carcinoma

Recent studies have shown that the tumor microenvironment plays an important role in cancer progression. Tumor-associated macrophages (TAMs), in particular, have been found to be associated with tumor progression. Macrophages have multiple biological roles, including antigen presentation, target cell cytotoxicity, removal of foreign bodies, tissue remodeling, regulation of inflammation, induction of immunity, thrombosis, and endocytosis. Recent immunological studies have identified two distinct states of polarized macrophage activation: the classically activated (M1) and the alternatively activated (M2) macrophage phenotypes. Bacterial moieties such as lipopolysaccharides and the Th1 cytokine interferon-γ polarize macrophages toward the M1 phenotype. The M2 polarization was discovered as a response to the Th2 cytokine interleukin-4. In general, M2 macrophages exert immunoregulatory activity, participate in polarized Th2 responses, and aid tumor progression. TAMs have recently been found to play an important role in hepatocellular carcinoma (HCC) progression. Based on the properties of TAMs, obtained from pathological examination of resected specimens, we have identified new therapeutic approaches, involving the targeting of TAMs with adjuvant therapy after hepatic resection for HCC. This review discusses the roles of TAM in HCC progression and the possibility of new therapies targeting TAMs.

New technique for the retraction of the liver in laparoscopic gastrectomy.

We developed a new technique for the retraction of the liver using a Penrose drain and a J-shaped retractor, which is both an easy and time-saving method that provides a good view during laparoscopic gastrectomy without damaging the liver.

Multidrug resistance-associated protein expression in clinical gastric carcinoma

We examined the relationship between the expression of a multidrug resistance‐associated protein (MRP) and the biologic factors regarding invasion and metastasis of human gastric cancer.

Growth pattern and p53 overexpression in patients with early gastric cancer

Background. The growth pattern of early gastric carcinoma, based on a volumetric analysis, reflects well biologic characteristics of the tumor. The penetrating growth (Pen) type tumor has an unfavorable prognosis, compared with a superficially spreading (Super) type.

High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer

(Cancer Sci 2010; 101: 639–645)

The triangulating stapling technique for cervical esophagogastric anastomosis after esophagectomy.

PurposeTo evaluate the safety and feasibility of the triangulating stapling technique (TST) for cervical esophagogastric anastomosis after esophagectomy (CEGA).MethodsThe subjects were 123 patients who underwent transthoracic esophagectomy with three-field lymph node dissection and reconstruction with a 3.5-cm wide gastric tube, for thoracic esophageal cancer. We performed the TST for CEGA in 33 patients operated on after December, 2006 (TST group) and hand-sewn anastomosis in 90 patients operated on between 2002 and 2006 (HSA group).ResultsIn the TST group, CEGA was performed in an end-to-end fashion using three linear staplers. The first anastomosis was applied to the posterior walls of the remnant esophagus and gastric tube in an inverted fashion. The second and the third anastomoses were done in an everted fashion to make the anterior wall. The end-to-end HSA was performed with interrupted sutures using 4-0 absorbable material. Anastomotic leakage occurred in only 1 (3.0%) of the 33 TST patients, but in 13 (14.4%) of the 90 HSA patients (P = 0.07). The frequency of anastomotic stenosis was 9.1% and 25.6% in the TST and HSA groups, respectively (P < 0.05).ConclusionsCervical esophagogastric anastomosis using TST may reduce the frequency of anastomotic leakage and stenosis. This technique is a safe and reliable alternative for CEGA after esophagectomy.

Flavone Acetic Acid Increases the Antitumor Effect of Hyperthermia in Mice

The combined effects of flavone acetic acid (FAA), a synthetic flavonoid, and hyperthermia on B16 melanoma cells were investigated. In vitro, FAA alone at concentrations below 100 micrograms/ml was not cytotoxic with a 60-min exposure at 37 degrees C. Hyperthermia at 43 degrees C for 60 min enhanced the cytotoxicity of FAA only at concentrations over 100 micrograms/ml. Inhibition of the growth of B16 melanoma solid tumor by FAA and/or hyperthermia was examined in vivo. FAA (100-200 mg/kg) inhibited tumor growth in a dose-dependent manner. The combined treatment of FAA (200 mg/kg) and hyperthermia (43 degrees C, 15 min) significantly inhibited tumor growth compared to a treatment of FAA or hyperthermia alone. The maximum antitumor effect of FAA combined with hperthermia was obtained when FAA was administered 2 or 4 h before heat. The significantly increased cytotoxicity of FAA combined with hyperthermia seems to relate to specific decreases in tumor blood flow, a reduction in tumor pH, and an increased tumor temperature, without altering pH in the normal tissues. This combined treatment of FAA and hyperthermia warrants further study for treating subjects with solid tumors.