Enhanced metastasis after local therapy in a murine model using C-1300 neuroblastoma

BACKGROUND/PURPOSE: In the treatment of advanced neuroblastoma, the role of surgery has been controversial. This study was carried out to determine the effect of surgery, irradiation, and chemotherapy in inhibiting or promoting distant metastases. METHODS: Transplanted C-1300 neuroblastomas in hind legs of syngeneic mice were treated by surgery, radiation, and chemotherapy. The liver was evaluated 18 days after each treatment modality for metastases. RESULTS: Mice developed no liver metastasis when leg tumors received no treatment or chemotherapy. In the mice who had the tumor resected, liver metastases were found in 8 of 16 mice that had 7-mm tumors. One hundred percent of the mice that had 9- or 12-mm tumors presented with metastases to the liver. In mice who received radiation therapy, 100% had liver metastases. CONCLUSIONS: Local control by surgery and single-dose radiation induced liver metastasis in a murine model. Surgery to remove tumors should be used in conjunction with chemotherapy to prevent secondary liver metastases.     

Local immunotherapy with streptococcal preparation, OK-432 in superficial bladder tumors, and common antigens between OK-432 and the tumor

In 38 patients with superficial bladder, local immunotherapy with streptococcal preparation OK-432 has been performed. We investigated whether OK-432 was an effective biological response modifier (BRM) against bladder tumors or not, and the relationship between the common antigens which OK-432 shared with the tumors, and antitumor effects of OK-432. In six out of 28 patients treated by intravesical instillation, and three out of 10 cases treated by intratumor injection, tumors were eliminated endoscopically. In the other patients, the tumors did not change. The PAP study using an anti-OK-432 antibody, showed a positive reaction in 66.7% of the instillation cases and in 40.0% in the injection cases. In 66.7% of the patients with the common antigens treated by the instillation and in 75.0% of patients with the antigens treated by the injection, tumors were eliminated. However, the PAP study showed a positive reaction in 9.1% of the no-change cases treated by the instillation and in 14.3% out of the no-change cases treated by the injection. We concluded that OK-432 was a favorable BRM for topical immunotherapy against bladder tumor and the presence of the common antigens between OK-432 and tumor may enhance the immune response of patients and promote tumor regression.     

Adoptive immunotherapy for malignant brain tumors using human peripheral blood mononuclear cells activated by the Streptococcal preparation OK-432

Adoptive immunotherapy using OK-432-activated mononuclear cells (OK-MCs) offers cell-mediated and cytokine-mediated pathways for antitumor activity. The effectiveness of direct intratumoral administration of OK-MCs via a catheter/reservoir system was studied in patients with malignant brain tumors. Seventeen patients, 12 with malignant glioma, four with metastatic adenocarcinoma, and one with primary sarcoma of the brain, were treated by OK-MC therapy (1.0 to 11.2 x 10(7) cells/person) between June 1989 and April 1999. The OK-MC therapy was given to patients with tumors progressing despite previous cytoreductive surgery, radiation, or chemotherapy. Adverse effects seen after the therapy were fever in 10 patients, seizure in two patients, and hypotension in one patient. Evaluation by computed tomography or magnetic resonance imaging revealed that seven patients showed no change including three with minor response, and 10 showed progressive disease. Adoptive immunotherapy using OK-MC was safe and well tolerated, but the therapeutic potential is limited.     

Improved therapeutic effect of sequential immunotherapy with cyclophosphamide, large doses of OK-432 and recombinant interleukin-2 in breast cancer patients with disseminated metastatic liver tumors

It has been generally agreed that the prognosis of widely spreaded "surgically unresectable" metastatic liver tumor originated from breast cancer is very poor. We reported here the result of clinical efficacy of sequential immunotherapy with intra-tumoral injection of large dose OK-432, after oral administration of cyclophosphamide during 7-10 days, and continuous perfusion of purified human recombinant interleukin-2 (rIL-2) from hepatic artery for the breast cancer patients with unresectable metastatic liver tumors. In all of 3 cases, metastatic liver tumor revealed overwhelming tumor reduction more than 50% of preoperative total tumor burden evaluated by computed tomography. Only 1 day after operation, large doses of OK-432 was injected intratumorally, both activity of Natural Killer (NK) cells and lymphokine activated killer (LAK) cells in peripheral blood lymphocytes were 5-20 folds augmented in all clinical trials. Serum tumor markers, i.e., Carcinoembryonic Antigen (CEA) and CA15-3, were rapidly decreased in all cases, respectively. Our clinical data indicate that intratumoral injection of large dose OK-432 and continuous administration of rIL-2 via hepatic artery, pretreated with cyclophosphamide, were clinically effective immunotherapy for reduction of metastatic liver tumor.     

Efficacy of streptococcal preparation OK-432 for gastric cancer patients--comparison between intradermal and intramuscular injection

Nonspecific immunotherapy with OK-432, penicillin and heat treated lyophilized powder of Su-strain of streptococcus pyogens A3, was evaluated in patients with recurrent or unresectable stomach cancer to assess the relative benefit of the preparation administered by different routes. Comparative studies were made of the variation in immunological parameters, the survival rate and the incidence of adverse reactions in two groups of patients with uniform background factors: 24 receiving the preparation intradermally and 18 receiving intramuscular doses of the preparation. In for former group, no serious adverse reaction occurred but more marked improvement was achieved in various immunological parameters examined. The survival rate was significantly higher (P = 0.005) for patients receiving intradermal than those receiving intramuscular doses of the preparation. The results of the present study showed that the preparation is of greater value when it is administered intradermally than intramuscularly.     

A comprehensive multi-institutional study on postoperative adjuvant immunotherapy with oral streptococcal preparation OK-432 for patients after gastric cancer surgery. Kyoto Research Group for Digestive Organ Surgery.

The current study was designed to compare the effects of oral administration of the streptococcal preparation, OK-432, as an adjuvant immunotherapy versus those of intradermal administration of OK-432 on the survival of patients after surgery for gastric cancer. The patients were stratified into two groups after surgery: a curative surgery stratum and a palliative surgery stratum. Then the patients in each stratum were randomly assigned into three groups: an oral placebo group, an oral OK-432 group, and an intradermal OK-432 group. All of the patients were given fluoropyrimidines orally in combination with OK-432 or placebo for 2 years after surgery. A total of 1011 patients were registered between 1982 and 1985, and 970 patients were eligible for statistical analysis. The survival rate of the oral OK-432 group was significantly higher than those of the other two groups after curative surgery. There were no significant difference in the survival rates between the three groups after palliative surgery, however. The effect of oral OK-432 was quite pronounced in patients after curative surgery for stage II to IV gastric cancer, especially in those patients with regional node involvement. Furthermore, it was found that the spleen is necessary for effective immunotherapy with oral OK-432, because the survival rate of the oral OK-432 group was significantly improved in patients whose spleens were preserved, when compared with splenectomized patients. These results demonstrate that oral adjuvant immunotherapy with OK-432 is beneficial after curative surgery for gastric cancer.     

Efficacy of streptococcal preparation OK-432 for gastric cancer patients—comparison between intradermal and intramuscular injection

Nonspecific immunotherapy with OK-432, penicillin and heat treated lyophilized powder of Su-strain of streptococcus pyogens A3, was evaluated in patients with recurrent or unresectable stomach cancer to assess the relative benefit of the preparation administered by different routes. Comparative studies were made of the variation in immunological parameters, the survival rate and the incidence of adverse reactions in two groups of patients with uniform background factors: 24 receiving the preparation intradermally and 18 receiving intramuscular doses of the preparation. In the former group, no serious adverse reaction occurred but more marked improvement was achieved in various immunological parameters examined. The survival rate was significantly higher (P=0.005) for patients receiving intradermal than those receiving intramuscular doses of the preparation. The results of the present study showed that the preparation is of greater value when it is administered intradermally than intramuscularly.     

肝移植患者出院准备服务流程的建立及应用

目的 建立肝移植患者出院准备服务流程,探讨其在临床实践中的应用效果。方法 选取2015年7月至2016年12月行原位肝移植术后患者141例为对照组,给予常规护理及出院宣教指导;以2017年1月至2018年5月行原位肝移植术后患者135例为干预组,多学科团队制定出院准备服务流程,责任护士于干预组患者围术期不同阶段实施出院准备服务。结果 干预组住院时间及30 d内再入院率显著短于和低于对照组（P<0.05,P＜0.01）;干预组家属出院时照护能力得分显著高于入院时（P＜0.01）。结论 出院准备服务流程的应用有利于缩短肝移植患者住院时间,降低30 d内再入院率,提高家属照护能力。     

Clinical studies on streptococcal preparation (OK-432) combined with mitomycin-C, 5-FU and cytosine arabinoside in advanced cancer patients.

Streptococcal preparation (OK-432), a new type of anti-cancer agent, was given to the patients with advanced cancer in combination with Mitomycin-C, 5-FU and Cytosine arabinoside. OK-432 was administered intramuscularly with a daily dose of 2.0 KE consecutively or locally into the tumor with a large-dose of 100 KE. Most cases tolerated the long term administration of OK-432 without any severe side effects and the highest dose reached was 314 KE during 161 days of treatment. Of the 53 patients evaluated, 31 were given the initial large dose intratumoral OK-432. Thirteen were judged 0-C and Category 1 according to the Karnofsky criteria for a response rate of 44.8 per cent as compared with 12.5 per cent in the group without the initial large-dose administration.     

Multidisciplinary treatment of head and neck cancer using BCG,OK-432, and GE-132 as biologic response modifiers

Since 1979, we have performed multidisciplinary treatment using intensive immunotherapy with biologic response modifiers (BRM) in combination with surgical treatment of oral cancer. Chemotherapy and radiotherapy were also included as part of the therapy. A historic control study was performed. Adjuvant therapy was administered by standardized methods, and the distribution of patients at various stages was similar between groups. The immunotherapy group showed a shorter treatment period, lower rates of recurrence, metastases, and side effects, greater histologic effects at the end of the first treatment, and a higher survival rate than the nonimmunotherapy group. Immunologically, immunotherapy tended to promote positive immune reactions and inhibit negative immune reactions. © 1994 John Wiley & Sons, Inc.     

增生性瘢痕动物实验模型的建立与应用

目的建立由动物自身产生的增生性瘢痕实验模型.方法选用47只日本大耳白兔,在耳腹侧面制作6mm圆形全层皮肤缺损创面、1.5cm×4.5cm长方形创面以及耳背圆形创面共388个,进行组织学等多项观察.结果70%兔耳圆形创面可发生与人增生性瘢痕类似的增生块,增生块持续时间最长为150d;长方形创面增生块发生率为80%以上,持续时间已超过262d.增生块内有特征性的结节或漩涡状结构.创基注入TGF-β1、IFN-y,可以促进或抑制增生块的发生.原位杂交,查明内源性TGF-β1mRNA为强阳性表达.利用此模型证实成纤维细胞凋亡在病理性瘢痕发生、发展过程中起着重要的调控作用.结论兔耳可以产生与人增生性瘢痕类似的病理改变,可以用作瘢痕研究的实验模型.     

同种异体大鼠骨髓及肝联合移植动物模型的建立及意义

目的 通过建立同种异体大鼠骨髓及肝联合移植动物模型,探讨提高大鼠肝移植模型的稳定性和存活率的方法及可行性.方法 将SD大鼠(♂)、Wistar大鼠(♀)分成三组:Ⅰ组大鼠Kamada"二袖套法"行SD→Wistar大鼠肝移植;Ⅱ组Wistar大鼠(♀)TBI(11 Gy),4 h后输人SD大鼠(♂)BMC(8×107),28 d后Kamada"二袖套法"行SD→Wistar大鼠肝移植;Ⅲ组Wistar大鼠(♀)TBI(7 Gy),4h后输入SD大鼠(♂)BMC(8×107),2 d后CTX(50 mg/kg体重)腹腔注射,28 d后Kamada"二袖套法"行SD→Wistar大鼠肝移植.分别于BMT后10、20 d通过PCR方法检测Ⅱ组和Ⅲ组Wistar大鼠体内的SD大鼠源性Y染色体特异性片段.并比较3组大鼠肝移植术后1周生存率、生存状况及生存时间.结果 Ⅱ组和Ⅲ组大鼠外周血均检测出SD大鼠源性嵌合体.DTH检查显示对SD大鼠产生免疫耐受.肝移植结果显示,Ⅰ组大鼠均在4～5 d死亡,而Ⅱ组和Ⅲ组大鼠1周存活率为80.0%和84.2%,但Ⅱ组的生存状况不如Ⅲ组.结论 应用7GyTBI+CTX+供体BMT可成功建立同种异体大鼠嵌合体模型,诱导特异性免疫耐受,大大提高肝移植术后大鼠的生存状况及生存时间.     

腰椎间盘退变动物模型的建立及影像学改变

目的建立腰椎间盘退变的动物模型。方法取新西兰大白兔6只,采用腹膜后入路进行腰椎手术,L3/L4椎间盘作为对照椎间盘;L4/L5椎间盘作为假手术椎间盘,只进行暴露;L5/L6椎间盘作为处理椎间盘,手术暴露后用24 G针头从椎间盘的前外侧针刺3次。4周后通过X线片观察针刺损伤对椎间盘高度的影响,通过MRI观察椎间盘在针刺损伤后退变的程度。结果腹膜后入路可以很好的显露新西兰大白兔腰椎间盘,所有动物均成活至术后4周,统计学分析说明针刺、手术暴露以及对照对术后4周椎间盘高度、MRI的T2加权信号强度的影响不同。用Newman-Keuls法对3样本均数两两比较结果显示：L3/L4与L4/L5之间的均数比较P〉0.05;L3/L4和L5/L6之间的均数比较P〈0.01;L4/L5和L5/L6之间的均数比较P〈0.01。结论术后4周针刺损伤实验动物椎间盘可以造成椎间盘高度、MRI的T2加权信号强度的降低,具有统计学意义。椎间盘损伤是造成椎间盘退变的原因之一。     

Establishment of composite animal model of chronic periodontitis and IgA nephropathy,and the interrelation

Objective To analyse the relationship and mechanism between chronic periodontitis (CP) and IgA nephropathy (IgAN) by establishing animal model of chronic periodontitis and IgA nephropathy in SD rats. Methods Eighty health male SD rats were divided into four groups, control group (A, n=20), IgAN group (B, n=20), CP group (C, n=20), CP accompanied with IgAN group (D, n=20). CP model was established by ligating silk suture and besmeared pathogenic bacterium in rats dental cervix. Experimental IgAN model was established by lavage of bovine serum albumin (BSA) and injection of lipopolysaccharide (LPS) and carbon tetrachloride (CCl4). Ten rats were sacrificed in every group at the end of week 8 and 12. The blood, urine, kidney tissue samples were examined. The observation index included proteinuria, kidney and liver function, renal tissue pathology and periodontal tissue pathology. The data were statistically analysed. Results Animal models were established successfully. The levels of Scr and BUN in group A, B, C were not obvious difference, but that in group D was higher than the other third groups at 8 weeks (P＜0.05). The levels of Scr and BUN in group D and group B were significantly higher than that in group A, meanwhile that in group D was significantly higher than that in group B at 12 weeks(P＜0.05). The levels of 24 h urine protein in B, C, D groups were higher than that in group A at 8 weeks(P＜0.05), but at 12 week, that in group D was higher than that in group B and C (P＜0.05). At 8 weeks, glomeruli had little mesangial broadening and renal interstitium had mild hyperplasia of fibrous tissue in group B and D, and that in the group D significantly was heavier than that in group B. The focal varying degrees were glomerular mesangial proliferation hardening, glomerular mesangialbroadening, focal segmental sclerosis, and diffuse or focal inflammatory cell infiltration in D group at the end of week 12. The score of PAS between group A and group C had no statistical significance. The scores of PASin group B and D were higher than that in group A (P＜0.01), and that in group D was higher than that in group B (P＜0.01). Obvious inflammation of periodontal tissue was observed in group C and D, and modified sulcus bleeding index (MBI) were higher than that in group A and B, and MBI in group D was significantly higher than that in group C (P＜0.01). Conclusions The model can be used to research the change of biochemistry and pathology and observe the relationship between chronic periodontitis and IgAN. This study shows that there is relationship between chronic periodontitis and IgAN. Chronic periodontitis maybe make more serious pathology damage in kidney by inflammation mechanism.     

Chemoimmunotherapy of metastatic murine renal cell carcinoma using flavone acetic acid and interleukin 2.

Metastatic renal cell carcinoma (RCC) remains largely incurable. We used a murine RCC (Renca) in BALB/c mice to investigate the treatment possibilities with chemoimmunotherapy using in vivo boosters of natural killer (NK) activity. Diffuse pulmonary metastases were induced by intravenous (i.v.) inoculation with 100,000 Renca cells. All untreated control animals died within one month from pulmonary metastases. Chemoimmunotherapy using the NK immunostimulator flavonic-8-acetic acid (FAA) at 200 mg./kg. i.v. was given on the third day post tumor inoculation, followed by four consecutive days of twice daily intraperitoneal (i.p.) administration of 10,000 units human recombinant interleukin-2 (rIL-2). This chemoimmunotherapy regimen consistently cured 70% of tumor-bearing animals. Mice cured by this chemoimmunotherapy regimen did not reject subsequent reinoculation with Renca, indicating absence of specific antitumor immunity as a result of the treatment. While FAA and rIL-2 have no demonstrable in vitro cytotoxicity for Renca, they are excellent boosters of in vivo NK activity. These data suggest a potential alternative treatment method for metastatic RCC, a tumor type for which no efficient cytostatic drugs are available.     

Dearterialization of the liver for metastatic cancer. Clinical, angiographic and pathologic observations.

Five cases of dearterialization of the liver for metastatic cancer are presented. Subjective and objective improvement was accomplished in three patients. Pre- and postoperative arteriography demonstrates the extent of devascularization and the routes of reestablished collateral. Microscopic studies demonstrated effects on tumor and on hepatic parenchyma and biochemical data indicate the extent and duration of hepatic dysfunction.