以顺铂为主经腹腔内联合化疗治疗晚期卵巢癌的临床观察

晚期卵巢癌多合并腹水,临床上单靠全身用药效果不甚满意.我们于1988年初开始应用以顺铂为主的联合化疗行腹腔注射治疗晚期卵巢癌合并腹水,取得了较好效果,有效率达90％.DDP是卵巢癌化疗的关键药物,腹腔内注入比静脉更具优点,浓度比静脉高25倍,对组织渗透性好,不引起腹腔局部中毒,副作用也较轻;且与其它药物无交叉耐药性,值得临床推广.     

Immunotherapy, with OK-432 for cases of nasopharyngeal carcinoma

The prognosis of nasopharyngeal carcinoma (NPC) is very poor, due to the extreme failure of the immuno-surveillance mechanism in such cases. As an immunotherapeutic agent, OK-432 was administered to NPC patients. Cases were divided into two groups. One was given OK-432 for less than 6 months (short-term group), while a long-term group, was treated with OK-432 for over 6 months. These two groups were evaluated for immunological activity and prognosis. As immunological parameters, the numbers of white blood cells and lymphocytes were counted, and delayed skin reactivities with Su-PS and PPD were determined. No influence on the number of white blood cells and lymphocytes could be observed in either of the two groups. However, the skin tests showed better improvement of immunity in the long-term group than in the short-term cases. Furthermore, these reactivities correlated well with the clinical status of NPC patients. As to the absolute number of lymphocytes, improvement in the long-term NPC group was delayed in comparison to that of another head and neck carcinoma group given long-term OK-432 treatment. The prognosis of the long-term administered group was apparently better than that of the short-term group. Long-term administration of OK-432 is therefore indispensable for the treatment of NPC cases, because of the extreme decline of their immunity.     

OK-432治疗晚期乳腺癌临床疗效观察

目的 :观察、分析OK 4 32在晚期乳腺癌治疗中的近期疗效。方法 :选择我院门诊就医的晚期乳腺癌患者 18例 ,应用OK 4 32作临床治疗 ,取病情相似的患者 10例作统计配对 ,观察其治疗效果并作分析。结果 :治疗组的有效率为 94 .5% ,对照组中除 1例稳定外 ,其他病例的病情均恶化。OK 4 32的治疗效果明显好于对照组。结论 :OK 4 32治疗晚期乳腺癌的近期疗效优于一般支持治疗。     

OK-432与化疗剂联合腹腔用药治疗癌性腹水的疗效观察与机制探讨

目的:观察OK-432与MMC、5-FU联合腹腔给药治疗癌性腹水的疗效,并探讨这种联合用药的优势机理。方法:对34例腹腔恶性肿瘤合并癌性腹水患者采用MMC6mg/m2、5-FU0.5g/m2、OK-4325KE腹腔给药,1次/周,观察临床疗效与不良反应。测定了荷瘤小鼠腹水中细胞因子在OK-432腹腔给药前后的变化。结果:OK-432联合5-FU、MMC腹腔给药治疗癌性腹水的总有效率(CR+PR)为70.6%,其中CR为41.2%、PR为29.4%;患者的中位生存期为144天;腹水中癌细胞消失率为35.3%。主要不良反应有发热(6例体温超过38.5℃),粘连性肠梗阻(3例)。OK-432腹腔给药可使荷瘤小鼠腹水中IL-12、IFN-γ的浓度显著升高,IL-10的浓度显著降低(P<0.01)。结论:OK-432在腹腔内可诱导IL-12、IFN-γ的产生、抑制IL-10的分泌,从而增强化疗剂的疗效。与MMC、5-FU联合腹腔应用,能有效地控制恶性腹水,提高患者的生活质量,延长生存期。     

OK-432 Suppresses Proliferation and Metastasis by Tumor Associated Macrophages in Bladder Cancer

OK-432, a Streptococcus-derived anticancer immunotherapeutic agent, has been applied in clinic for manyyears and achieved great progress in various cancers. In the present study, we investigated its anticancer effecton bladder cancer through tumor associated macrophages (TAMs). MTS assay validated OK-432 could inhibitproliferation in both T24 and EJ bladder cell lines. OK-432 also induced apoptosis of bladder cancer cells in vitro.Consequently, we demonstrated that OK-432 could suppress the bladder cancer cells migration and invasion byaltering the EMT-related factors. Furthermore, using SD rat model, we revealed that OK-432 inhibited tumorgrowth, suppressed PCNA expression and inhibited metastasis in vivo. Taken together, these findings stronglysuggest that OK-432 inhibits cell proliferation and metastasis through inducing macrophages to secret cytokinesin bladder cancer.     

Anti-tumor immunity induced by OK-432-derived DNA

We have tried to identify the effective components of OK-432, a Streptococcus-derived anti-cancer immunotherapeutic agent. In the current study, we investigated the effect of OK-432-derived DNA (OK-DNA) in augmenting anti-cancer immune response. Analysis of OK-DNA with the restriction enzymes Hpa II and Msp I revealed that OK-DNA contained unmethylated CpG motifs. OK-DNA induced Th1-type cytokines, such as IFN-gamma and IL-12, and augmented killer cell activities in vitro on human peripheral blood mononuclear cells, whereas the methylated OK-DNA did not. Cytokines were also produced by OK-DNA-stimulated splenocytes derived from wild-type mice but not from TLR9-deficient mice. In the in vivo study, a peritumoral administration of OK-DNA resulted in a significant inhibition of tumor growth in syngeneic tumor-bearing wild-type and TLR4-deficient mice but not in TLR9-deficient mice. Anti-tumor effect of OK-432 in TLR9-deficient mice was significantly but partially reduced as compared with that in wild-type mice, while the effect of OK-432 was almost completely eliminated in TLR4-deficient mice. These findings suggest that unmethylated CpG-DNA in OK-432 functions as an active component in OK-432-induced anti-cancer immunity via TLR9, at least in part.     

Antitumor effect of OK-432 (3)--mechanisms of tumor growth inhibition by OK-432 induced activated macrophages

Spleen cells and peritoneal exudate cells obtained from BALB/c mice which had received an i.p. injection of 0.1 mg of OK-432 4 days previous to sacrifice, were examined by Winn's neutralization assay for their antitumor activity against Meth-A sarcoma cells in BALB/c mice. Both of the cell preparations clearly inhibited the growth of admixed Meth-A cells, but when these same cell populations were treated on a Sephadex G-10 column, the effector activity seen in Winn's assay disappeared. The effector cells responsible for tumor inhibition were therefore considered to be cytotoxic macrophages. However, the inhibitory effect of these cytotoxic macrophages in Winn's assay was not evident in either X ray (300 rad)-irradiated BALB/c mice or in nu/nu BALB/c mice. These results indicate that the antitumor activity of cytotoxic macrophages is associated with a sequential immune mechanism in which T cells may play an important role.     

顺铂与洛铂腹腔灌注治疗晚期卵巢癌术后合并腹腔积液比较观察

目的比较观察顺铂与洛铂腹腔灌注治疗晚期卵巢癌术后合并腹腔积液的疗效及毒副反应。方法36例晚期卵巢癌术后合并腹腔积液患者分为2组,均接受多西他赛全身化疗,顺铂组16例患者同时给予顺铂腹腔灌注,而洛铂组20例患者同时给予洛铂腹腔灌注。结果 2组不同时段CA125水平比较差异均无统计学意义（P均〉0.05）;而术后有肉眼残留病灶的患者第1次、第2次化疗后,2组CA125水平比较差异有统计学意义（P均〈0.05）。2组血小板减少、肾功能损伤发生率比较差异有统计学意义（P均〈0.05）,其他毒副反应相近,所有毒副反应均可耐受。结论对于晚期卵巢癌术后合并腹腔积液患者,给予顺铂或洛铂腹腔灌注化疗均安全有效,对有肉眼残留病灶的患者前者见效更快。     

Clinical Variables Associated With Overall Survival in Metastatic Castration-Resistant Prostate Cancer Patients Treated With Sipuleucel-T Immunotherapy

Background

Sipuleucel-T is an autologous cell-based cancer immunotherapy for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its approval by the Food and Drug Administration was based on demonstration of an overall survival (OS) benefit in randomized placebo-controlled phase III trials. However, treatment was associated with a prostate-specific antigen (PSA) decline in only a small minority of patients. Understanding the clinical factors that are associated with OS could help guide treatment decisions, including patient selection and the timing of sipuleucel-T relative to other therapies.

外周血NLR和PLR在接受免疫治疗肿瘤患者中的预后价值

持续的全身慢性炎症在恶性肿瘤的发生、进展、转移过程中起着重要作用。外周血中性粒细胞与淋巴细胞比值(neutrophil-to-lymphocyte ratio,NLR)和血小板与淋巴细胞比值(platelet-to-lymphocyte ratio,PLR)与多种恶性肿瘤如肺癌、恶性黑色素瘤、消化道恶性肿瘤、肝癌等免疫治疗的预后具有显著相关性,同时NLR和PLR检测具有价格低、创伤小、易获得、可重复性高的特点。研究表明,较高的基线或用药后NLR和PLR水平与患者对免疫治疗的反应、预后均呈负相关,且患者出现免疫治疗抵抗、肿瘤进展或死亡的风险更高,预期无进展生存期(progression free survival,PFS)、总生存期(overall survival,OS)相较于低NLR和低PLR患者更短。该文就NLR和PLR与多种接受免疫治疗的恶性肿瘤患者预后的相关研究作一综述,为寻找针对免疫治疗的最佳预后指标、早期筛选出免疫治疗潜在获益患者以及预测他们的治疗结局提供依据。     

Intraperitoneal administration of OK-432 and rIL-2 in a case of peritonitis carcinomatosa with chronic renal failure

Recombinant interleukin-2 (rIL-2) was administered intraperitoneally for 15 days, 2 days after intraperitoneal administration of Streptococcal preparation OK-432 to a patient of peritonitis carcinomatosa occurred eight months after second look operation, in which residual tumor could not be removed completely. The patient had been maintained by hemodialysis three times a week for over ten years. Combination chemotherapy using CDDP and Ifosfamide, or CDDP and THP-Adriamycin had not been effective to control rapidly increasing ascites. Negative cytological exam, was achieved on day 7 and ascites disappeared by day 15. No severe side effects including fluid retention were observed. Fever up was controllable by Indomethacin. Flow cytometric analysis revealed dominant (73%) CD4+, CD29+ helper inducer subset, while CD4+, CD45RA+ was 6%, in the lymphocytes in ascites on day 8. It was suggested that intraperitoneal administration of rIL-2 after OK-432 was safe and effective for peritonitis carcinomatosa with chronic renal failure.     

Induction of mouse peritoneal cytotoxic factor by OK-432. (3). Comparison between LPS and OK-432 as eliciting agents

By injection of OK-432, a cytotoxic factor was induced in peritoneal fluids of mice which had been primed with OK-432. Two-step stimulation (priming and eliciting) was always necessary to induce the cytotoxic factor. OK-432-primed mice did not produce soluble cytotoxic factor spontaneously and no cytotoxic activity was detected in the mice treated by a single injection of OK-432 as an eliciting agent. High doses of OK-432 were required to prime mice for the production of cytotoxic factor, whereas a small amount was enough to elicit it. Pathological studies were also conducted in order to clarify whether the mice were safe under the conditions in which PCF had been induced. Moderate liver damage was observed in the mice injected with OK-432 and LPS, whereas no histological change in the liver or spleen was observed in the mice treated with OK-432 alone. These results suggest that OK-432 is a good candidate as an inducer of cytotoxic factor in the peritoneal cavity.     

Immunotherapy of terminal-stage malignant tumors with the immunopotentiator OK-432--a comparison between SU-PS test-responder and -nonresponder patients

We treated terminal malignant tumor cases with the immunopotentiator OK-432 and determined the absolute numbers of neutrocytes, lymphocytes, and lymphocyte subpopulations, carrying out the SU-PS and PPD skin tests. After the start of therapy, SU-PS test changed to positive in one-third of the patients. The SU-PS -responder patients showed an increase in lymphocytes and Leu 11A-positive cells, and an elevation of the OK T4/T8 ratio two weeks later. In the SU-PS-nonresponder group, OKT4-positive cells declined, while OKT8-positive cells increased with time. That is, the OKT4/T8 ratio remained low throughout the test period. In the SU-PS-responder group, OK-432 therapy was found to prolong the survival period.     

靶向肿瘤相关巨噬细胞治疗卵巢癌的研究进展

摘 要：卵巢癌是女性生殖系统中致死率最高的恶性肿瘤,严重威胁着女性的健康。近年来越来越多的研究关注到卵巢癌与其所处免疫微环境之间的相互作用。肿瘤相关巨噬细胞是肿瘤免疫微环境中数量最多的免疫细胞,贯穿了卵巢癌发生、发展的各个阶段。多项临床研究已经证实肿瘤相关巨噬细胞的数量及极化状态与卵巢癌患者的预后密切相关。本文概述了直接靶向肿瘤相关巨噬细胞的临床研究进展,以期对卵巢癌的临床治疗提供参考。     

紫杉醇联合顺铂腹腔注射晚期卵巢癌患者的疗效及对生存期的影响

目的探讨紫杉醇联合顺铂腹腔注射治疗晚期卵巢癌的临床疗效,以及对患者生存期的影响。方法选取卵巢癌患者120例,随机分为观察组与对照组。两组均采用紫杉醇联合顺铂静脉化疗,观察组同时给予腹腔注射治疗。结果观察组治疗有效率为78.33%,对照组有效率为60.00%。观察组有效率明显高于对照组(P<0.05)。观察组腹腔积液控制有效率为84.21%,对照组有效率为63.89%,观察组明显高于对照组(P<0.05)。观察组1年生存率为91.67%,2年生存率为78.33%,3年生存率为68.33%。对照组1年生存率为78.33%,2年生存率为60.00%,3年生存率为50.00%。观察组生存率明显高于对照组(P<0.05)。两组患者不良反应发生率比较无显著差异(P>0.05)。结论紫杉醇联合顺铂腹腔注射治疗晚期卵巢癌的临床疗效显著,且生存期长。     

顺铂腹腔注入治疗卵巢癌腹水的临床观察

晚期卵巢癌腹水的治疗相当困难,目前虽有一些治疗卵巢癌腹水的方法,但用顺铂腹腔内注入治疗卵巢癌腹水尚未见报道。我们在术前和术中用顺铂(各100mg)腹腔注入治疗20例晚期卵巢癌腹水患者。所有患者的全身状况在术前均得到明显改善,19例上皮性卵巢癌腹水患者一年内无腹水生长。该方法简单、安全,控制腹水生长效果明显,副作用少。     

卵巢癌腹腔化疗的应用价值

自１９８１年７月至１９９１年１２月，我科对８３例中晚期卵巢癌患者术后给予腹腔化疗为主，配合全身化疗的方案，随诊７５例（９０．３６％），结果显示，残存肿瘤直径≤２ｃｍ的患者５５例（７３．４％）完全缓鲜，生存期为６－１０８个月；残存肿瘤＞２ｃｍ例（２６．６）部分缓解，生存期为６－４１个月。     

Synergistic activation of rat alveolar macrophages by cepharanthine and OK-432

We studied the synergistic activation of rat alveolar macrophages (AM) by cepharanthine (Ceph.) and OK-432. Rat AM could be rendered much more tumoricidal against Walker-256 tumors in vitro after the i.v. injection of ceph. (5 mg/Kg) and OK-432 (5 KE/rat) thao of ceph. or OK-432 only. Radioactivity of 14C-acetate-OK-432 trapped in murine lung after the i.v. injection of mixed of ceph. was much higher than of 14C-acetate-OK-432 only. Rat AM could be rendered tumoricidal by incubation in vitro with OK-432, but not with ceph. This finding suggests that if OK-432 is injected intravenously with mixed of with ceph., of OK-432 is trapped much more up by the lung without mixture, therefore AM can be much more tumoricidal. Intravenous administration of OK-432 with ceph. may be useful for reduction of lung metastasis by tumoricidal AM.