Toshikazu Kimura

An assessment of the feasibility of sentinel lymph node-guided surgery for gastric cancer

BackgroundSentinel node-guided surgery has received increasing attention in tumor surgery. To ascertain whether sentinel lymph node (SLN)-guided surgery is feasible for gastric cancers 4 cm or less in size, we conducted a multicenter clinical study.MethodsOne milliliter of isosulfan blue was injected endoscopically into the gastric wall at four sites around a gastric cancer lesion. Approximately 15 min after the injection of the dye, the surgeons resected (picked-up) the stained blue nodes (defined as SLNs) around the stomach.ResultsSLNs were detected in 140 of 144 patients (97.2%). The average number of SLNs was 3.3. In 99 patients with D2 lymph node dissection, the false-negative rate (FNR) was evaluated. In 14 T1 patients with pathological positive lymph node metastasis (pN(+)), the FNR was 29%. In 9 T2,3 pN(+) patients, the FNR was 44%. In T1 patients with pN(+) but macroscopically normal lymph nodes during surgery (sN0), the FNR was 11% (1/9).ConclusionT1 and sN0 patients may be a target group for the study of SLN-guided surgery. A larger multicenter trial should be performed to clarify the application of sentinel node navigation surgery for gastric cancer.

Expression of Phosphorylated Ser70 of Bcl-2 Correlates with Malignancy in Human Colorectal Neoplasms

Purpose: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser70 to substantially alter its molecular function. Previous studies further suggest that such phospho-Bcl-2 regulation may influence tumor progression in colorectal and other cancers; however, phosphorylation status of the Ser70 of Bcl-2 (pSer70) in vivo in tumors remains obscure. To elucidate this question that may suggest the biological role, we molecularly screened a panel of human colorectal adenomas and adenocarcinomas for endogenous expression of pSer70 Bcl-2. Experimental Design: An antibody specific against pSer70 Bcl-2 was generated for thorough immunohistochemical examination of paraffin-embedded tumor specimens, allowing detection of the endogenously expressed antigen among a range of Bcl-2-positive colorectal neoplasms, including 75 tubular adenomas, 114 adenocarcinomas, and 15 cases of cancer in adenomas. Results: Loss of pSer70 Bcl-2 expression was observed in adenocarcinomas in a differentiation-dependent manner (positivities: well differentiated 63%, moderately differentiated 52%, and poorly differentiated 12%), whereas tubular adenomas maintained their expression (positivity 88%). Interestingly, an inverse correlation was found between expression of pSer70 Bcl-2 and Ki-67 antigen in those cases of cancer in adenoma (P < 0.01). It was further observed that loss of pSer70 Bcl-2 expression was associated with significantly shorter survival (P < 0.05) and correlated with clinical stages and lymph node metastasis (P < 0.05 and P < 0.05, respectively). Conclusions: Loss of pSer70 Bcl-2 expression is closely linked to biological aggressiveness in colorectal tumors and represents a statistically significant molecular index for prognosis of patients with these tumors.

Inhibitory effect of nafamostat mesilate on metastasis into the livers of mice and on invasion of the extracellular matrix by cancer cells

Although many agents that interfere with clotting mechanisms have been investigated for their potential to inhibit metastasis, their toxicity has prevented administration of sufficiently high doses to achieve inhibition of metastasis in clinical trials. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, inhibited liver metastasis in a CDF1 mice model with colon 26 adenocarcinoma cells. The apparently dose-dependent inhibitory effect was seen 21 days after all of the doses tested (0.3, 1.0, 3.0 and 10.0 nig/kg for 7 days) but the effect was only statistically significant (P < 0.01) at the highest dose. The blood concentrations 3 min after dosing were less than 10−6 M for all of the doses tested. At a concentration of 10−5 M or less nafamostat mesilate was not cytotoxic towards colon 26 cells in vitro. The results indicate that it may not be difficult to achieve blood nafamostat mesilate concentrations that inhibit metastasis in mouse liver. Possible mechanisms of nafamostat mesilate are inhibition of extravasation and invasion of cancer cells, inactivation of collagenase due to inhibition of plasmin activity and inhibition of the formation of the cancer cell thrombus, and arrest in the capillaries through inhibition of thrombin activity. These preliminary results suggest that peri-operative administration of nafamostat mesilate may prevent metastasis into the liver after surgery for gastrointestinal malignancies.

Immunohistochemical studies of colorectal cancers that developed following pelvic irradiation.

Radiation therapy is believed to be a predisposing factor in the development of carcinoma. During the period from 1974 to 1997, we treated five colorectal cancers in four patients who had undergone pelvic irradiation for cervical cancer. Radiation-induced changes in the remaining bowel were recognized in all of these patients. Of the five tumors, two were histologically diagnosed as mucinous adenocarcinoma, demonstrating a higher distribution than usual: To clarify the characteristics of the tumors, we examined the frequency of mutation in K-ras and p53 genes, and the proliferating cell nuclear antigen (PCNA) proliferation activity. The K-ras and PCNA stains did not show any clear characteristics of radiation-induced colorectal cancers in comparison with ordinary colorectal cancers; however, it was of interest that strongly positive staining was observed in our mucinous adenocarcinomas, even though a low frequency of p53 gene mutation has been reported in ordinary mucinous adenocarcinomas.

Multicenter retrospective study to evaluate the efficacy and safety of the double-flap technique as antireflux esophagogastrostomy after proximal gastrectomy (rD-FLAP Study)

As a result of the difficulty in effective prevention of gastroesophageal reflux, no standard reconstruction procedure after proximal gastrectomy (PG) has yet been established. The double‐flap technique (DFT), or Kamikawa procedure, is an antireflux reconstruction procedure in esophagogastrostomy. The efficacy of DFT has recently been reported in several studies. However, these were all single‐center studies with a limited number of cases.

A Clinicopathological Study of Multiple Colorectal Cancers.

当科における大腸多発癌は358例中24例, 6.7%であった.男女比は16: 8で対照群と有意差なく, 発病年齢は56.8歳で, 対照群より4.4歳若かった.同時性多発癌では23病変中16病変, 70.0%が第1癌腫の10cm以内に存在し, 10cm以上離れた病変は進行癌が多かった.進行癌-早期癌の組合せが最多であったが, 異時性では後発癌は全例進行癌であった.多発癌群では癌家族歴, 他臓器重複癌の併存が高率の傾向があり, ポリープ併存率は83.3%で対照群より有意に高率であった.同時性症例で術前正診できたのは77.8%であり, 正診不可能であったのは肛門側の癌腫のため, その口側の検索が不十分であったものがほとんどであった.現在のところ, 大腸多発癌の予測は困難であり, 大腸癌を診断した場合は多発癌および他臓器重複癌を念頭に置き, 他臓器も含めた十分な術前検査および術後の経過観察が必要であると考えられた.