Kiichi Miya

Antitumor effects of residual tumor after cryoablation: the combined effect of residual tumor and a protein-bound polysaccharide on multiple liver metastases in a murine model.

Cryoablation is a low-invasive surgical treatment for malignant tumors. It may induce an immunological response leading to the eradication of distant metastases or alternatively it might promote the growth of residual tumors. In this paper we confirm the occurrence of both phenomena and we describe the preventive effect of a protein-bound polysaccharide preparation. Metastatic liver tumors were produced in BALB/c mice by the intrasplenic inoculation of colon 26 cells and cryoablation was carried out using liquid nitrogen (-170 degrees C) applied by a contact method. The value of combining cryoablation with administration of the polysaccharide preparation in the prevention of growth of residual tumors was investigated. It was shown that the number of metastatic liver nodules and the size of the primary tumor at the site of inoculation in the spleen were significantly lower when the volume that was frozen was small. The production by splenocytes of the tumor necrosis factor TNF-alpha, interferon INF-gamma, and the interleukins IL-4 and IL-10 increased significantly after freezing and thawing of the tumor tissue. The polysaccharide treatment significantly reduced the production of IL-4 and IL-10 following cryoablation; the production of TNF-alpha and INF-gamma was slightly promoted; the natural killer and cytotoxic T-cell activities of splenocytes were slightly enhanced. It was concluded that the polysaccharide preparation was beneficial by suppressing IL-4 and IL-10 production and might inhibit the growth of residual tumor that is sometimes induced by large-volume cryoablation.

Human inflammatory cells within the tumor microenvironment of lung tumor xenografts mediate tumor growth suppression in situ that depends on and is augmented by interleukin-12

The human tumor microenvironment includes a mixture of tumor cells, inflammatory cells, fibroblasts, and endothelial cells, all of which are tethered to an extracellular matrix. It has been difficult to study the dynamic interactions of these cells in human tumors in situ for obvious ethical and logistical considerations that prohibit experimental manipulations of tumors while still in patients. Fresh tissue from human lung tumor biopsy implanted into SCID mice was shown to remain viable, and the histologic appearance of the tumor microenvironment was maintained in the tumor xenografts for at least 3 months. In this study, the authors established that the inflammatory cells within human tumor xenografts can suppress tumor growth, and that this suppression is a result, in part, of endogenously produced interleukin-12 (IL-12) because IL-12 neutralizing antibodies enhance the growth of the tumor xenografts. The tumor-inhibitory activity of the inflammatory leukocytes is also enhanced by the local and sustained release of human recombinant IL-12 into the tumor microenvironment from cytokine-loaded biodegradable microspheres. Neither the anti–IL-12 neutralizing antibody nor the delivery of exogenous IL-12 from microspheres had any effect on tumor xenografts in the absence of the inflammatory leukocytes. In conclusion, the inflammatory cells within the tumor microenvironment of human lung tumor xenografts are functional and can suppress tumor growth, and the dynamic effects of the inflammatory cells can be modulated by exogenous cytokines.

Immunological response of regional lymph nodes after tumor cryosurgery: Experimental study in rats

Seven days after inoculation of metastasizing rat mammary tumor No. 1 into the thigh of 5-week-old female Sprague-Dawley rats, the tumor was treated cryosurgically by two-cycle freezing and by contact methods at -170 degrees C. Weights of the thymus and the spleen, histological findings of the lumbar lymph nodes, phytohemagglutinin (PHA)-induced blastogenesis of lymphocytes obtained from the lumbar lymph nodes and peripheral blood, and resistance rate to tumor rechallenge were examined 1, 3, 6, 10, and 17 week(s) after cryosurgery, with the following results: Thymus weight gradually decreased by 3 weeks after cryosurgery, while spleen weight increased by 1 week, recovering the preoperative level at 6 weeks. Paracortical hyperplasia of the lumbar lymph nodes markedly increased in 1 week and sinus histiocytosis increased after 3 weeks, both remaining at high values until 10 weeks, while germinal center hyperplasia showed a high value at 3 weeks and thereafter decreased gradually. PHA-induced blastogenesis of the lumbar lymph nodes significantly increased 1 week after cryosurgery and remained at its high value until 10 weeks. PHA-induced blastogenesis of peripheral lymphocytes showed the lowest value at 3 weeks and then significantly increased at 6 weeks. Resistance rate to rechallenge showed the lowest value at 3 weeks, reaching the highest level 10 weeks after cryosurgery. From the above results, it was suggested that anti-tumor immunity (resistance to tumor rechallenge) induced by cryosurgery was at the lowest level at 3 weeks after cryosurgery, and gradually increased starting at 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of lymph-node metastases in patients with gastric carcinoma: comparison of three MR imaging pulse sequences.

AbstractBackground: To compare the diagnostic accuracy of magnetic resonance (MR) images obtained with three different pulse sequences for lymph-node metastases in patients with gastric cancer. Methods: T1-weighted spin-echo (SE), breath-hold T2-weighted fast SE, and triphasic gadolinium-enhanced dynamic gradient-recall-echo (GRE) MR images obtained in 16 patients with gastric carcinoma were retrospectively reviewed. Regional lymph nodes were assigned to four different groups, and image review was conducted on a lymph-node group-by-group basis; 64 lymph-node groups were reviewed by two radiologists. Relative sensitivity, specificity, and accuracy were determined based on the findings with definitive surgery and follow-up imaging. Diagnostic accuracy was determined by means of receiver-operating-characteristic (ROC) analysis. Results: Relative sensitivities for lymph-node metastases with T1-weighted SE, breath-hold T2-weighted fast SE, and dynamic GRE images were 61%, 94%, and 59%, respectively. Relative sensitivity with breath-hold T2-weighted fast SE images was significantly greater than that with T1-weighted SE (p < 0.05) and dynamic GRE (p < 0.05) images. Diagnostic accuracy determined by ROC analysis was marginally higher with breath-hold T2-weighted fast SE (area under ROC curve [Az]= 0.87) than with T1-weighted SE (Az = 0.78, p= 0.08) and dynamic GRE (Az = 0.79, p= 0.12) images. Conclusion: Breath-hold T2-weighted fast SE sequence is useful in the detection of regional lymph-node metastases in patients with gastric carcinoma.

Experimental study on mechanism of absorption of cryonecrotized tumor antigens

On Day 7 of subcutaneous MRMT-1 tumor inoculation in the thigh of Sprague-Dawley rats, the tumor was treated cryosurgically by contact method. Postoperative changes in local blood circulation were observed by colloidal carbon perfusion and hydrogen-clearance methods, and the pathway and time course of tumor antigen absorption were observed by measuring uptake in serum and lymph nodes of [3H]thymidine injected intratumorally. Results were: At 0.5 to 1 hr after cryosurgery, vascular stasis, dilatation, and tortuosity were observed. There was no inflow of carbon and almost no uptake of [3H]thymidine. At 6 hr, vascular stasis and sludging become more marked. There was no inflow of carbon, while uptake of [3H]thymidine markedly increased. At 24 hr, some carbon inflow in fin vessels and partial recovery of blood circulation in the peritumoral region were observed. Rate of [3H]thymidine uptake was further increased. At 72 hr, carbon inflow and blood circulation increased further, while the cryonecrotized tumor showed hyaline degeneration. At 168 hr, increase of newly formed vessels and recovery of blood circulation were remarkable, but uptake of [3H]thymidine was decreased in parallel with increased demarcation of the cryonecrotized tumor. From these results, it was suggested that the absorption of cryonecrotized tumor antigens started through lymphatic channels in the early period and then took place also through newly formed capillaries surrounding the tumor at 24 hr after cryosurgery and continued until 72 hr after cryosurgery.

A case of intermittent bleeding Meckel's diverticulum

The initial technetium-99m pertechnetate abdominal scintigraphy revealed equivocal or normal results. However, a second scintigraphy without pentagastrin demonstrated a focal area of persistently increasing radioactivity in the right lower quadrant of the abdomen.At surgery, Meckel’s diverticulum was confirmed, and histological examination of the excised specimen revealed that it was lined with ectopic gastric mucosa.It has not been satisfactorily explained why the initial imaging failed to demonstrate the ectopic gastric mucosa. The necessity to perform repeated scintigraphy must be emphasized because 50 to 91 percent of bleeding Meckel’s diverticula in the pediatric age group are said to contain gastric mucosa.

Recurrence of giant adrenocortical carcinoma in the contralateral adrenal gland 6 years after surgery: Report of a case

We report herein the case of a patient in whom a giant adrenocortical carcinoma was found to have recurred in the contralateral adrenal gland and intrapelvic cavity 6 years after his initial operation. A 52-year-old man had consulted our hospital complaining of right upper abdominal pain and weight loss, and was subsequently diagnosed as having a giant adrenal tumor by computed tomography scans and echography. A laparotomy was performed and the tumor, located in the right retroperitoneal cavity and infiltrating the liver and right kidney, was surgically removed. The lesion, 29 × 19 × 10cm in size and 4700 g in weight, was histopathologically diagnosed as an adrenocortical carcinoma. Adjuvant chemotherapy with mitotane was given for 3 months and his postoperative course was uneventful until a recurrence in the contralateral adrenal gland and peritoneal cavity was found 6 years later. The second resection was successful, and he is currently alive with no further sign of recurrence 8 years after his first operation. We report this unusual case as it provides much useful information on the biological features of adrenocortical carcinomas and the state of tumor dormancy.

Characterization of certain hepatocyte-proliferating and/or protective factors induced by the sensitization of freezing-thawing hepatic tissue

Although tumor cryosurgery would be expected to produce beneficial immunological effects from the enhancement of anti-tumor activity, under certain conditions the tumor may become enlarged and metastases promoted due to increased immunosuppressive activity and a high zone tolerance. In the present study, we examined whether hepatocyteproliferating factors were produced by the inoculation of freezing-thawing hepatic tissue (FTHT). Serum obtained from rats inoculated with FTHT increased DNA synthesis, according to measurement by [3H]thymidine incorporation in primary cultured rat hepatocytes. This increase was dependent on the serum concentration, with serum obtained on day 14 after the inoculation being the most potent for hepatocyte proliferation. The sensitized serum promoted DNA synthesis nearly as much as serum obtained from a 70% hepatectomized rat, but slightly less than 10ng/ml hepatocyte growth factor. The sensitized serum also protected hepatocytes from carbon tetrachloride (CCI4)-induced hepatotoxicity. Optical density measured by the 3-(4,5-dimethyl-thiazole-2-yl)-2,5-diphenyl tetrozolium bromide (MTT) cytotoxicity assay was increased, and the release of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in medium was decreased by treating hepatocytes damaged by CCI4 with the sensitized serum. These results suggest that certain hepatocyte-proliferating and protective factors are induced in serum by the inoculation of freezing-thawing hepatic tissue, and that the sensitized serum may be useful in the treatment of liver failure.

A Case of Choledochal Carcinoid with Liver Metastasis Responding to Hepatic Arterial Infusion Immuno-chemotherapy.

肝転移巣に対して肝動脈注入免疫化学療法が奏効した極めてまれな胆管カルチノイドの1例を経験した. 症例: 42歳の女性. 主訴: 全身倦怠感, 黄疸. 現病歴: 1989年8月頃全身倦怠感を自覚し近医を受診したところ, 黄疸を指摘され精査治療目的で当科に入院した. 腹部CT, PTCD, ERCPにて肝転移を伴う胆管癌と診断の上, 手術を施行した. 開腹すると肝転移 (S4, S2, S7領域) とリンパ節転移 (No.12, 8) を伴う小指頭大の腫瘍が下部胆管に存在し, D1郭清を伴う胆管切除術と肝動注用ポート設置術を施行した. 摘出標本では12×10×6mm大の堅い腫瘤が認められ, 病理検索では腫瘍細胞が胞巣状, 索状に配列し, 胆管カルチノイドと診断された. 辺縁に低分化型腺癌組織が混在していた. 術後MMC, rIL-2, OK-432による動注免疫化学療法を8コース施行したところ, 肝転移巣は著明に縮小し, 血清CEA値も正常化した. その後の化学療法を拒否し来院せず術後3年5か月目に肝転移と腹膜転移にて死亡した.

A Case of Villous Tumor of the Rectum with Adenoacanthoma Invaded to the Submucosal Layer Followed by Fuluminant Course by Liver Matastasis.

まれな組織型を呈し, 術後1年で肝転移にて死亡した深達度smの絨毛型直腸癌の1例を経験した. 症例は75歳の女性で, 1990年4月, 肛門出血を主訴として某医を受診し, 直腸腫瘍を指摘され紹介入院となった. 諸検査の結果, 癌合併直腸絨毛腫瘍と診断し, 経仙骨的腫瘍切除術を施行した. 腫瘍は95×88mm大の平板状で, 粘膜層に限局した高分化腺癌が主体であったが, 7mmの範囲で粘膜下層に浸潤し, 癌先進部に腺扁平上皮癌が認められた. また壁在転移リンパ節を認めたため再手術を勧めたが, 患者の了解が得られず, 厳重経過観察とした. しかし, 術後7か月目に強い疼痛を伴う局所再発と肝転移が確認され, 再入院の上後方骨盤内臓摘除術を施行した. 術後2か月目に皮膚転移が出現し, 肝転移巣も急速に増大し, 初回手術から1年後に死亡した. 局所切除が一般化しつつある直腸絨毛腫瘍の中にも, 非常に予後不良な症例が存在することを, 念頭におくべきであると考えられた.