Masayuki Nakau

Hepatocellular carcinoma development induced by conditional β-catenin activation in Lkb1+/− mice

The development of hepatocellular carcinomas (HCC) appears to be a multistep process that takes several decades in humans. However, the identities of specific gene alterations and their contribution to HCC pathogenesis remain poorly understood. We previously reported that Lkb1+/− mice spontaneously develop multiple hepatic nodular foci (NdFc) followed by HCC, and that the conditional activation of β‐catenin in Catnblox(ex3) mouse livers alone does not cause tumor formation. We show here that the conditional activation of β‐catenin accelerates HCC development in Catnb+/lox(ex3)Lkb1+/− compound mutant mice, affecting displastic hepatocytes in NdFc that suffered LOH at the Lkb1 locus. We further show that β‐catnin activation provides HCC with a growth advantage as well as transplantability. These results suggest that the loss of Lkb1 contributes to the formation of dysplastic NdFc, and that Wnt signaling activation is involved in ensuing progression toward HCC. A combination of these sequential changes can be a practical model for a subset of human HCC. (Cancer Sci 2009)

Interleukin-12-gene transduction makes DCs from tumor-bearing mice an effective inducer of tumor-specific immunity in a peritoneal dissemination model

Dendritic cells (DCs) from cancer patients, as well as tumor-infiltrating DCs, are reported to have suppressed immunostimulatory capacity. One of the major problems in the clinical use of DCs for treating tumors is that the DCs must be autologous ones obtained from patients. Compared with normal DCs (nDCs), flow-cytometric analysis and allogeneic mixed lymphocyte reaction (MLR) have revealed lower expression of the costimulatory molecules and suppressed T-cell-stimulatory activity in DCs derived from tumor-bearing mice (tDCs) despite of culture. We reported previously that the interleukin-12 (IL-12)-gene-transduced nDCs inhibited tumor growth due to induced tumor-specific Th1 and cytotoxic T cells (CTLs) in a murine established subcutaneous tumor model. In the present study, we examined whether tDCs could induce immune responses against tumors after IL-12-gene transduction in an established peritoneal dissemination model. The intraperitoneal injection of IL-12-gene-transduced tDCs resulted in prolonged survival of some treated mice (log-rank test; P=0.001) and tumor-specific Th1 and CTL activity. The injection of IL-12-gene-transduced nDCs prolonged the survival of all treated mice (P<0.0001) and elicited tumor-specific immunity, which were better than those of IL-12-gene-transduced tDCs. Taken together, DC modification of IL-12-gene transduction is an effective and promising approach for cancer therapy even when immunosuppressive tDCs are employed.

Upper mediastinal lymph node dissection for esophageal cancer through a thoracoscopic approach

Surgical treatment with extended mediastinal lymph node dissection is considered essential for the cure of esophageal cancer [1, 2]. Especially because lymph node metastasis to the upper mediastinal region is common [3], radical lymphadenectomy in this area is important. Recently, thoracoscopic esophagectomy has been introduced to offer less morbidity [4]. The authors present their procedure for the radical dissection of lymph nodes along both sides of the recurrent laryngeal nerves and below the aortic arch. A total of 45 patients with esophageal cancer underwent thoracoscopic esophagectomy. For this operation, the patient is placed in the left lateral decubitus position. Five or six thoracic trocars are introduced in the right chest without minithoracotomy. Monitors placed above a patient’s head show the same direction without a reversed view so that all the surgeons and a scrub nurse can share the same view. First, the azygos vein is ligated and divided. The mediastinal pleura then are divided to expose the esophagus, and lymph node dissection along the right recurrent laryngeal nerve is performed. The upper part of the thoracic esophagus is circumferentially mobilized, which results in exposure of the left recurrent laryngeal nerve. Sharp dissection of lymph nodes around this nerve is performed. The entire esophagus is mobilized, and the infraaortic lymph nodes are dissected carefully. For the authors’ 45 patients, the mean number of retrieved lymph nodes was 22 (range, 2–52). The pathologic stages of the tumors were pStage 1 (15 cases), pStage 2A (7 cases), pStage 2B (4 cases), pStage 3 (13 cases), and pStage 4 (6 cases). All of the stage 4 cases were classified due to non-regional lymph node metastasis M1 (LYM). Five patients manifested irreversible hoarseness (11.1%), which happened, however, especially in early period. Three airway injuries were experienced, whose postoperative courses were uneventful. There were no hospital deaths in this series. The authors believe the thoracoscopic approach for lymphadenectomy is refined because of the enhanced visualization.

Pathogenic mechanisms of intestinal pneumatosis and portal venous gas: should patients with these conditions be operated immediately?

We aimed to histologically observe portal venous gas (PVG)-causing intestinal pneumatosis (IP) and evaluate pathogenic mechanisms and therapeutic strategies, including decisions on whether emergency surgery should be performed. Autopsy was performed in two cases of nonocclusive mesenteric ischemia (NOMI). We directly histologically observed the pathogenic mechanisms of IP caused by gas-producing bacteria and IP considered to be caused by mechanical damage to the intestinal mucosa. IP can be classified hypothetically into the following types according to pathogenesis: (1) infection, (2) rupture (damage) of the intestinal mucosa + increased intestinal intraluminal pressure, and (3) mixed type. In cases of IP caused by gas-producing bacteria or IP associated with intestinal wall damage extending beyond the mucosa to the deep muscular layer, emergency surgery should be considered. However, it is highly possible that patients who test negative for infection with gas-producing bacteria whose intestinal wall damage remains only in the mucosa can be conservatively treated.