Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small-cell lung cancer

The benefits of immunochemotherapy with a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, OK-432 (Picibanil), were reassessed in patients with resected non-small-cell lung cancer through a meta-analysis based on data from 1,520 patients enrolled in 11 randomized clinical trials. All 11 trials were started before 1991, and the subjects had been followed up for at least 5 years after surgery and randomization. In these trials, standard chemotherapy was compared with the same therapy plus OK-432. The endpoint of interest was overall survival, and analysis was based on intent-to-treat population without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 5-year survival rate for all eligible patients in the 11 trials was 51.2% in the immunochemotherapy group versus 43.7% in the chemotherapy group. The odds ratio (OR) for overall survival was 0.70 (95% CI = 0.56-0.87, p = 0.0010). Analysis of four trials in which central randomization was performed also reconfirmed a significantly longer survival time for the immunochemotherapy group (OR = 0.66, 95% CI = 0.44-1.00, p = 0.049). Based on these results of meta-analysis, it is postulated that postoperative adjuvant immunochemotherapy using OK-432 might improve the survival of patients after resection of non-small-cell lung cancer.     

Efficacy of adjuvant immunochemotherapy with OK-432 for patients with curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials

The benefit of immunochemotherapy employing a streptococcal preparation, OK-432 (Picibanil), in patients with curatively resected gastric cancer was reassessed by meta-analysis of data from 1,522 patients enrolled in six clinical trials with central randomization. All six trials began between 1985 and 1993, and patients were followed-up for at least 3 years after surgery and enrollment of the last patient. In these trials, standard chemotherapy was compared with the same chemotherapy plus OK-432. The endpoint was overall survival and intent-to-treat analysis was done without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 3-year survival rate for all eligible patients in the six trials was 67.5% in the immunochemotherapy group versus 62.6% in the chemotherapy group. The 3-year overall survival odds ratio was 0.81 (95% confidence interval: 0.65-0.99). The treatment effect was shown to be statistically significant (p = 0.044). The results of this meta-analysis suggest that immunochemotherapy after surgery with OK-432 can improve the survival of patients with curatively resected gastric cancer.     

Adjuvant immunotherapy: two randomized controlled studies of patients with cervical cancer

In order to prolong the survival of patients with cervical cancer, adjuvant immunotherapy was undertaken in Japan. The result of two randomized controlled studies using biological response modifiers such as OK-432 or sizofiran are described. The three-year recurrence-free rates of 221 patients in the OK-432 group and 161 patients in the control group were 71.9% and 58.6%, respectively. The intergroup difference was statistically significant. Of all the patients with Stage II or III cancer, time to recurrence and survival rate in 99 patients in the sizofiran group were significantly longer than in 96 patients in the control, evaluated at 5 years. Based on the results of the 2 randomized controlled studies, we conclude that adjuvant immunotherapy is very useful for prolonging the survival of patients with cervical cancer.     

Activation of reticuloendothelial function for prevention of endotoxemia after hepatectomy in cirrhotic patients

In order to prevent endotoxemia after hepatectomy in cirrhotic patients, we administered OK-432 before and after hepatectomy to activate the reticuloendothelial function and studied its effect on postoperative endotoxemia. In the cirrhotic group without OK-432 administration (7 patients), the value of endotoxin increased significantly after hepatectomy, compared to the cirrhotic group which received OK-432 administration (5 patients) and the non-cirrhotic group (12 patients), and the endotoxin level was still higher than the preoperative value even on the 14th day. On the other hand, the cirrhotic group with OK-432 administration and the non-cirrhotic group showed minimal increases of endotoxin levels at the first day, which returned to the preoperative values at the third day. Base on these findings, it is suggested that activation of the reticuloendothelial function bears substantial significance as one of the therapeutic modalities for prevention of endotoxemia after hepatectomy in cirrhotic patients.     

Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis and Toll-like receptor 4 signaling

It has previously been reported by our group that Toll-like receptor (TLR) 4 is involved in anticancer immunity induced by OK-432, a Streptococcus-derived immunotherapeutic agent. However the detailed mechanism of the OK-432-induced immune response via TLR4 remained uncertain, because it may not be possible for OK-432, which consists of whole bacterial bodies, to bind directly to TLR4. In the current study, we conducted in vitro and in vivo experiments to investigate the hypothesis that OK-432 may first be captured and dissolved by phagocytes and that the active components released by the cells may then induce host responses via TLR4. TS-2 monoclonal antibody, which recognizes an active component of OK-432 designated OK-PSA was used in the current study. First, it was observed that OK-432-induced cytokine production by dendritic cells (DCs) and macrophages was significantly inhibited in vitro by cytochalasin B, a phagocytosis inhibitor. Immunofluorescence staining using TS-2 demonstrated that OK-432 was captured and dissolved by phagocytes. OK-PSA was detected in the supernatants derived from OK-432-treated DC culture by enzyme-linked immunosorbent assay using TS-2. Supernatants from OK-432-treated DC culture increased nuclear factor (NF)-kappaB activity in TLR4-expressing cells, and the increased activity was inhibited by TS-2 antibody. OK-432 itself did not activate NF-kappaB in these cells. In in vivo experiments, the anticancer effect of OK-432 was significantly inhibited by suppression of phagocytosis activity by cytochalasin B. In this case, the amount of OK-PSA, an active component of OK-432, in the sera was also reduced by cytochalasin B. These findings elucidated the mechanism mediated by phagocytosis and TLR4 signaling in the immune effect of OK-432.     

分次与单次口服PEG-EP进行肠道准备的效果观察

目的探讨分次与单次口服聚乙二醇电解质散(PEG-EP)进行结肠镜检查前肠道准备的清洁效果和耐受性。方法将432例进行结肠镜检查的无症状个体,随机分为A组(分次口服)和B组(单次口服)。A组于检查前夜8时和检查当日5时分别口服半包PEG-EP,B组于检查当日5时一次性口服1包PEG-EP(65.56g/袋),比较两组肠道准备的清洁效果和不良反应的发生情况。结果 A组肠道准备的清洁效果优于B组(P0.05),A组患者的耐受性优于B组(P0.05)。结论与单次口服相比,分次口服PEG-EP,既可以保证更好的肠道清洁效果,又减少不良反应,患者耐受性好,容易接受,值得临床推广应用。     

沙培林联合卡铂治疗恶性胸水的临床观察

目的：探讨沙培林联合卡铂治疗恶性胸腔积液的临床疗效。方法：将50例恶性胸水患者随机分为治疗组和对照组，治疗组27例患者采用沙培林联合卡铂胸腔内灌注，对照组23例患者单纯用卡铂治疗，观察两组治疗前后的胸水变化和副作用。结果：治疗组和对照组控制胸水的有效率分别为89％和65％，P〈0．05。治疗组副作用为发热、胸痛、骨髓抑制和消化道反应，但与对照组比较无显著性差异，P〉0．05。结论：沙培林联合卡铂胸腔内注射能有效治疗恶性胸水，且简单易行，较单药卡铂疗效好。     

Effects of the streptococcal preparation OK-432 on in vitro cytokine production of peripheral blood mononuclear cells in patients with chronic viral hepatitis.

We obtained peripheral blood mononuclear cells from 12 chronic hepatitis Type B patients, 12 Type C patients, and 15 healthy volunteers, and investigated the effects of OK-432, a streptococcal preparation, on in vitro production of 3 types of cytokines. Mononuclear cells in a concentration of 1 x 10(6) cell/ml were prepared in the culture medium. OK-432 (Chugai Pharmaceutical Co., Ltd., Tokyo) was added to this preparation and incubated for one to 4 days. Thereafter interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) levels in the culture supernatant were measured using enzyme-linked immunoassay kits. Cytokine production levels in cultures with OK-432 were significantly increased in the mononuclear cells of both patients and healthy volunteers. The largest increase was observed with IFN-gamma (p < 0.01), and then with IL-1 beta (p < 0.05). Responses of the cells from chronic hepatitis Type C patients to OK-432 were relatively good. When interferon (alpha and beta) treatment was first introduced, there were high hopes for a high efficacy. However, we now know 50-70% of patients with chronic hepatitis Type C do not respond satisfactorily to interferon. Some physicians suggest the necessity of using biological response modifier (BRM) as an adjuvant treatment for these patients. From our findings, OK-432 could be a useful BRM in patients with chronic hepatitis Type C.     

Adoptive immunotherapy in tumor-bearing mice with OK-432-induced killer cells

Murine spleen cells cultured for 3 or more days in medium with streptococcal preparation OK-432 became cytotoxic in vitro against several allogeneic and syngeneic tumor cells. These cytotoxic cells were designated OK-432-induced killer (OIK) cells. This study examined the in vivo antitumor efficacy of OIK cells in adoptive immuno- and immunochemo-therapy in mice bearing syngeneic tumors, such as EL-4 lymphoma, Meth-A fibrosarcoma, and MOPC-31C plasmacytoma. OIK cells neutralized these tumor cells, as shown by Winn-type tests, and the cell transfer prolonged the survival of mice inoculated intraperitoneally (ip) with EL-4 or Meth-A cells. Concomitant administration of OK-432 plus recombinant interleukin 2 (rIL-2) significantly improved the therapeutic efficacy of the transferred OIK cells. In mice inoculated with 1 x 10(4) EL-4 cells, chemoimmunotherapy consisting of ip administration of 200 mg/kg cyclophosphamide on day 3 followed by treatment with OIK cell (1 x 10(7)) transfer and with OK-432 (50 KE/kg) plus rIL-2 (50 units/mouse) 6 hr later and on day 6, prolonged the survival. Therefore, the immunotherapy with OIK-cell transfer followed by administration of OK-432 and rIL-2 may be clinically useful as an adjunct of cytoreductive chemotherapy for cancer.     

Treatment of HBeAg-positive chronic hepatitis with a streptococcal preparation (OK-432)

Forty-two patients with hepatitis Be antigen (HBeAg)-positive chronic hepatitis were treated by intramuscular injections with OK-432, an immunopotentiator possessing interferon-inducing activity. They were monitored with serial measurements of virological parameters to evaluate therapeutic effectiveness, and compared with a group of seventy-five untreated patients (natural course group). In the group receiving OK-432 therapy, twenty-seven patients (64.3% of the forty-two patients) became negative for HBeAg in an average observation period of 20.1 months. Of these, fourteen patients (33.3% of the forty-two patients) underwent seroconversion from HBeAg to anti-HBe antibody (anti-HBe). In the natural course group, twenty-three patients (30.7% of the seventy-five patients) lost HBeAg reactivity in a mean follow-up period of 32.3 months, and thirteen patients (17.3% of the seventy-five patients) became seroconverted. Thus, the drug group showed significantly higher percentages of patients with disappearance of HBeAg and seroconversion, notwithstanding the shorter duration of the follow-up. Young males and females, females generally, or patients with high serum GPT levels were more likely to respond to the therapy. The serum GPT level tended to stabilize more in patients receiving OK-432.     

低剂量聚乙二醇联合抗坏血酸方案对肠道黏膜损伤的影响

目的观察低剂量聚乙二醇联合抗坏血酸方案在结肠镜检查肠道准备中的效果、安全性及对肠道黏膜损伤的影响。方法选择需做结肠镜检查的患者500例,随机分为两组,实验组给予低剂量聚乙二醇联合抗坏血酸方案(A组),对照组给予磷酸钠盐方案(B组)行肠道准备。两组患者通过抽血检测血肌酐、电解质,评估其安全性。术中观察肠道清洁度,评估肠道准备效果,同时观察肠道黏膜损伤情况,并行活检、病理学检查。结果 A组患者完成肠道准备233例,完成肠镜检查226例,B组完成肠道准备238例,完成肠镜检查210例,两组患者肠道清洁度情况无明显差异(P0.05)。肠黏膜损伤及术后血肌酐、电解质紊乱等情况低剂量聚乙二醇联合抗坏血酸组均优于磷酸钠盐组,差异有统计学意义(P0.05)。结论在肠道准备效果上,两种方法都能达到检查要求,但抗坏血酸联合聚乙二醇组对肠黏膜损伤更小,且安全性更高。     

Effects of biological response modifiers on childhood ALL being in remission after chemotherapy

Of 125 children with acute lymphoblastic leukemia (ALL), who had been in continuous remission for three years on chemotherapy, 108 patients received biological response modifiers (BRM) such as Bestatin, N-CWS, OK-432 and/or PSK in order to prevent relapse after treatment suspension. From 20 patients who were treated with PSK, 6 relapsed within 13 months. This relapse rate was quite similar to the rate observed with those children who were off therapy (4 relapses in 17 patients within 13 months). In contrast to these 37 patients, only 3 out of 31 patients who received Bestatin (p less than 0.05) and 8 out of 57 patients who received N-CWS or OK-432 relapsed. Based on these findings, BRMs used in the present study seems to be effective to prevent relapse of leukemia among childhood ALL who have electively stopped chemotherapy.     

Production of tumor necrosis factor (TNF) by monocytes from cancer patients and healthy subjects induced by OK-432 in vitro, and its augmentation by human interferon gamma

A cytostatic factor was induced in the supernatants of human blood monocytes cultured in vitro with OK-432 at 0.01 KE/ml or more. This cytostatic activity was almost completely abolished by anti-human TNF antibody, and so was thought to be that of TNF. Recombinant human gamma interferon (IFN-gamma) alone did not induce TNF as described in other reports, but enhanced the induction of TNF by OK-432 when added to monocytes before or with OK-432. Monocytes of 20 patients with cancer of the digestive tract and 10 healthy donors were tested for ability to produce cytostatic activity. The frequencies of positive responses to OK-432 and the mean cytostatic activities of the two groups were similar. Moreover both groups included high responders whose monocytes produced potent cytostatic activity with OK-432 alone, and also low responders. Interestingly, marked synergistic effects of IFN-gamma and OK-432 were observed with monocytes that did not produce potent cytostatic activity with OK-432 alone. These results suggested that OK-432 may have a stronger immunomodulatory effect clinically when used in combination with IFN-gamma.     

米索前列醇用于足月妊娠引产效果观察与护理

目的探讨米索前列醇(简称米索)混悬液用于足月妊娠引产的有效性、安全性及相应护理措施.方法将有引产指征的足月妊娠妇女140例,随机分为两组.A组70例口服米索混悬液(200μg/200ml);B组70例静脉滴注催产素,作为对照.结果两组引产成功率相似,分别为88.57%和82.86%(P＞0.25).但A组从开始用药至临产的平均时间(432.45±247.91)min和用药至胎儿娩出平均时间(717.51±584.39)min较B组的(563.84±407.37)min和(946.60±542.99)min明显缩短(P＜0.05).宫颈评分≤5分的产妇A组引产成功率(84.61%)高于B组(33.33%),P＜0.05.结论口服米索混悬液用于足月妊娠引产是一种安全、有效、方便的引产方法.     

专科护士管理和常规自我管理应用于成人哮喘控制的对比研究

目的:探讨成人哮喘控制的最佳管理模式,提高哮喘管理水平。方法:采用便利抽样法选取2009年1-12月在某院呼吸科门诊就诊的中、重度哮喘患者350例,随机分为专科护士管理组(A组)和常规自我管理组(B组),每组175例,分别以专科护士定期管理模式和患者自我管理模式进行规范化治疗1年。对比研究两组患者哮喘急性发作次数、急诊就诊次数、住院次数、肺功能、圣乔治呼吸质量问卷(SGRQ)评分等指标。结果:A、B两组各有169例和152例患者完成研究。A组治疗依从性和控制情况均明显高于B组(P<0.01)。治疗结束时,与B组相比,A组的SGRQ评分更低,而FEV1和PEF则更高。结论:专科护士管理模式在患者依从性、哮喘控制和肺功能改善等方面的效果均优于患者自我管理模式。通过建立哮喘健康教育门诊,由哮喘专科护士对患者进行主动管理,有助于进一步提高我国哮喘疾病的防治水平。     

Blastogenic responses of human lymphocytes to a streptococcal preparation OK-432 and its fractions

This study was undertaken to examine the blastogenic responses of PBL to Streptococcal preparation OK-432 and its fractions. The results showed that OK-432 and its fractions, Su-PR and PM, have the mitogenic activity against human lymphocytes. The demonstration that PBL which had been cultured with OK-432 expressed IL-2 receptors and the blastogenic responses of PBL to OK-432 were inhibited by anti-IL-2 antibody suggested that IL-2 and IL-2 receptors might play a central role in OK-432-induced proliferation of human lymphocytes.     

罗哌卡因联合镇痛药蛛网膜下隙阻滞用于剖宫产术

目的：比较不同剂量罗哌卡因以及与芬太尼或吗啡联合用于蛛网膜下隙阻滞，剖剖宫产患者阻滞效果、血压、心率和不良反应的影响。方法：选择急诊剖宫产患者60例，随机分成四组，每组15例。经侧卧位L2－3间隙穿刺行阻滞麻醉。A组：罗哌卡因10mg，B组：罗吡卡因7．5mg 芬太尼25μg，C组：罗吡卡因7．5mg 吗啡0．2mg,D组：罗吡卡因5mg 芬太尼25μg。用针刺法测感觉阻滞平面，用改良Bromage法测运动阻滞，术后随访并记录开始出现切口疼痛的时间，以及头痛，恶心、呕吐等并发症。结果：A组的感觉阻滞平面上界为T2－6，高于其他组（P＜0．05），下肢运动完全阻滞百分率明显大于其他组，差异有显著性（P＜0．05），但A组感觉阻滞时间与B组相比没有差异（P＞0．05）。四组中。C组感觉阻滞持续时间最长，与其他组比较差异有显著性（P＜0．05），运动阻滞时间与B组比较没有差异（P＞0．05），明显比A组短（P＜0．05）。在D组中，有66．7％的患者因感觉阻滞平面不完善，需在硬膜外导管内注入局麻药。血流动力学的影响以A组最为明显，在注药后的5min，血压，心率显著降低，与基础值比较，差异有意义（P＜0．05），术后恶心、呕吐发生率C组最高，与其他组比较，差异有显著性（P＜0．05）；四组患者术后均无头痛症状。结论：罗吡卡因加入芬太尼25μg，能减少局麻药的用量，达到良好的麻醉效果，对机体血流动力学影响小，能延长术后镇痛时间，并且不增加术后呕吐的发生率。     

Clonidine for treatment of postoperative pain: a dose-finding study.

The aim of this double-blind randomized study was to evaluate the optimal intravenous dose of clonidine administrated during the peri-operative period, after lumbar hemilaminectomy for herniated disk repair. The "optimal intravenous dose" was defined as that providing minimal analgesic request, stable haemodynamic profile and a minimal sedation score during 12h after extubation. Eighty adult patients, ASA physical status I-II, undergoing lumbar hemilaminectomy for herniated disk (L(4)-L(5), L(5)-S(1)) were included in the study. All the patients were randomly assigned to one of four study groups (A, B, C, D), 20 patients each. The same standardized general anaesthesia was performed for each group. Thirty minutes before the end of surgery, group A, B and C patients received three different loading doses of intravenous clonidine (5 microg/kg, 3 microg/kg, 2 microg/kg respectively), followed by the same infusion of intravenous clonidine (0.3 microg/kg per hour). Group D patients received a bolus dose and a continuous infusion of NaCl 0.9%. In the recovery unit, postoperative pain was treated by a patient-controlled analgesia device, containing morphine. Pain relief was evaluated by the total morphine requirement during the postoperative period. Systolic blood pressure (SBP), heart rate and sedation were also noted during the first 12h postoperatively. Intravenous clonidine decreased morphine requirements in a dose-dependent manner. Group A, B, C and D patients requested 5 +/- 2, 11 +/- 3, 19 +/- 4 and 29 +/- 8 doses of morphine respectively. Clonidine also affected SBP in a dose-related manner. Group A, B and C patients had an SBP decrease respectively of 26 +/- 3%, 7 +/- 4% and 2 +/- 2% compared with basic values while, at the same time, in group D patients no SBP variation was registered. In conclusion, this study demonstrates that, when sedation and analgesic effect of clonidine is required, 3 microg/kg bolus dose followed by a continuous infusion of 0.3 microg/kg per hour has to be considered the optimal intravenous dose. The higher dose of intravenous clonidine (5 microg/kg) produced better analgesia but the degree of hypotension and sedation was more severe and longer lasting; it required ephedrine administration and careful monitoring of the patient. On the other hand, the bolus of intravenous clonidine 2 microg/kg (group C) was less effective in terms of pain relief but with similar side-effects to the 3 microg/kg dosage (group B).     

砷剂可以改善儿童急性早幼粒细胞白血病长期预后吗?——单中心的经验

目的 观察全反式维甲酸(ATRA)以及三氧化二砷(As2O3)联合ATRA两种化疗方案治疗儿童急性早幼粒细胞白血病(APL)的临床疗效及不良反应,探讨As2O3,是否可以改善APL患儿长期预后.方法 1992年7月至2006年3月收治的儿童APL患者45例,其中24例使用ATRA进行诱导治疗,21例使用As2O3和ATRA联合诱导治疗,观察治疗后的缓解情况、凝血功能恢复及不良反应等发生情况并进行长期随访.结果 ①ATRA组完全缓解(CR)19例,CR率为79.2%.ATRA+As2O3组21例全部达到CR,两组CR率比较差异有统计学意义(x2=4.92,P=0.027).②在诱导治疗时ATRA+As2O3组的血小板计数及凝血指标的恢复较ATRA组快(P值分别为0.015和0.009).③ATRA组随访41个月的总生存(OS)率为77.8%,无事件生存(EFS)率为66.9%.ATRA+As2O3组随访34个月的OS率为100%,EFS率为100%,两组的生存率差异有统计学意义(P=0.0357).④ATRA+As2O3组患儿PML-RARa融合基因检测转阴时间明显短于ATRA组(P=0.026).结论 APL患儿联合使用ATRA和As2O3进行诱导治疗可以获得很高的CR率,降低因脑出血及DIC的死亡率;在诱导治疗及巩固治疗时加用As2O3可以更迅速地减少白血病克隆,提高儿童APL患者的长期生存率.     

Interleukin-1 inducing activity of a streptococcal preparation OK-432 and its fractions by human monocytes

Interleukin-1 (IL-1) inducing activity of a streptococcal preparation OK-432 and its fractions by monocytes were investigated in patients with lung cancer and healthy subjects. The results showed that cell free extracts and cell wall fractions of OK-432 were the strong IL-1 inducing fractions. IL-1 activity released by OK-432-stimulated monocytes of patients with lung cancer fell within normal range. OK-432 stimulated intracellular IL-1 synthesis as well as extracellular release by monocytes. These results, therefore, suggested that OK-432 immunotherapy in patients with malignant diseases might be effective by increasing IL-1 production of monocytes.