Serum thymidine kinase and beta-2 microglobulin in monoclonal gammopathies

We evaluated the serum thymidine kinase (TK) and beta-2 microglobulin (beta-2) levels of 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and of 29 patients with multiple myeloma (MM). Both parameters were significantly lower in MGUS than in MM patients and in early (stage I + II) than in advanced (stage III) MM. TK was also lower in MGUS than in stage I MM (p less than 0.025). A seven-fold increase of TK level was documented in one patient who developed a full blown picture of MM 6 years after a diagnosis of MGUS. In 3 patients with stage III MM, a sharp decrease in TK (40-77%) and in beta-2 (29-53%) levels at remission was evident with respect to the levels measured at diagnosis. Patients with high levels of TK or beta-2 had a shorter survival than those with low levels; however, this was statistically significant only for beta-2 levels (p less than 0.02). Serum TK as well as beta-2 levels appear to be of clinical value in monoclonal gammopathies and related to the course of the disease.     

Experience with poorly myelosuppressive chemotherapy schedules for advanced myeloma. The Cooperative Group of Study and Treatment of Multiple Myeloma.

In a multicentre study, 83 patients with advanced and previously uniformly treated multiple myeloma (MM) were randomised between cyclophosphamide (600 mg m-2) and epirubicin (70 mg m-2), administered every 3 weeks for three courses and both associated with prednisone and interferon-alpha2b. Both regimens were administered on an outpatient basis and had low haematological toxicity. Clinical results were similar. Overall response rate (43%) and median response and survival (5.9 and 14.1 months respectively) compare well with those obtained with more aggressive chemotherapy schedules.     

Treatment of multiple myeloma according to the extension of the disease: a prospective, randomised study comparing a less with a more aggressive cystostatic policy. Cooperative Group of Study and Treatment of Multiple Myeloma.

The purpose of the study was to ascertain whether the prognostic significance of staging in multiple myeloma (MM) is influenced by the aggressiveness of effective induction treatment and/or by continuing or discontinuing maintenance chemotherapy. Patients with untreated stage I MM (defined according to Durie and Salmon) were randomised between being followed without cytostatics until the disease progressed and receiving six courses of melphalan and prednisone (MP-P) just after diagnosis; stage II patients were uniformly treated with MPH-P and stage III patients were randomised between MPH-P and four courses of combination chemotherapy with Peptichemio, vincristine and prednisone (PTC-VCR-P). Within each stage, responsive patients were randomised between receiving additional therapy only until maximal tumour reduction was reached (plateau phase) and continuing induction therapy indefinitely until relapse. With resistant, progressive or relapsing disease, patients originally treated with MPH-P for induction received combination chemotherapy and vice versa. The overall first response rate was 43.8% (42.2% in 206 stage I, II and III patients treated with MPH-P and 48.0% in 75 stage III patients treated with combination chemotherapy, P = NS). Combination chemotherapy was more myelotoxic than MPH-P and, in particular, caused more non-haematological side-effects. Both the less and the more aggressive induction policies gave the same disease control. Progression of disease was statistically similar in stage I patients who were initially left untreated and in t hose who received MPH-P just after diagnosis; median duration of first response was similar in stage III patients receiving MPH-P and in those on combination chemotherapy. In all stages, discontinuing or continuing maintenance did not alter the median duration of first response. The overall second response rate was 28.5% (34.0% to MPH-P and 25.3% to combination chemotherapy, P = NS). Median survival was greater than 78 months in stage I, was 46.3 months in stage II and was 24.3 months in stage III patients, still independent of both induction and post-induction policies. In MM, the significance of staging for survival is independent of both the aggressiveness of induction and of continuing or discontinuing maintenance chemotherapy after the maximal tumor reduction has been achieved. Both MPH-P and and the association of PTC, VCR and P are effective in inducing first response and also second response in patients failing on the alternative regimen, but PTC-VCR-P causes more side effects. Thus, the overwhelming majority of patients with MM can safely be given MPH-P as first therapy, and this treatment may be delayed in early diseases.     

Impact of Interferon at Induction Chemotherapy and Maintenance Treatment for Multiple Myeloma Preliminary results of a multicenter study by the Italian Non-Hodgkin's Lymphoma Cooperative Study Group (NHLCSG)

In 1990 the Italian Non-Hodgkin's Lymphoma Cooperative Study Group (NHLSG) started a multicenter study on the role of interferon (IFN) in multiple myeloma (MM). The schedule of treatment was based on the assumption that melphalan plus prednisone (MP) would be better for good-prognosis patients, whereas poor-prognosis patients would benefit from polychemotherapy. Accordingly, IFN was included randomly for the induction treatment of good-prognosis patients and randomly as maintenance of the response achieved in both groups. Up to now 78 patients of the 124 enrolled have completed the induction treatment and are evaluable for response and response duration. The overall response rate was 59%. Sixty-two percent of good-prognosis patients obtained objective response, 9/14 (64%) with MP and 9/15 (60%) with MP + IFN. Up to now, with a median follow-up of 9 months from the evaluation of response, no difference has been recorded between the maintenance and no maintenance groups on relapse rate, neither in good- nor in poor-prognosis patients.     

多发性骨髓瘤诊治进展

多发性骨髓瘤（Multiple Myeloma,MM）又称浆细胞骨髓瘤,是发生在骨髓的多灶性浆细胞恶性肿瘤。MM占所有恶性肿瘤的1％,血液系统恶性肿瘤的10％,在欧美国家已成为仅次于非霍奇金淋巴瘤的第二大常见血液系统恶性肿瘤。中老年人多发,至今尚不能完全治愈。但随着新的检测手段和新药的不断开发应用,多发性骨髓瘤的诊治及预后已发生了很大的改观,现综述如下。     

Relevance of age on survival of 341 patients with multiple myeloma treated with conventional chemotherapy: updated results of the MM87 prospective randomized protocol. Cooperative Group of Study and Treatment of Multiple Myeloma.

Age could influence the prognosis of multiple myeloma patients treated with conventional chemotherapy. Between January 1987 and March 1990, 341 consecutive previously untreated patients with multiple myeloma received chemotherapy within the prospective, multicentre, randomized Protocol MM87. Survival was evaluated in patients aged > or < or = 66 years (the median age for the whole series) and in a subgroup of patients aged < 55 years. These groups were similar for main clinical characteristics, including results of cytostatic treatment. As of May 1996, 271 (79%) of the 341 patients had died, and median follow-up of the 70 (21%) living patients was 82 months. Overall, younger patients survived longer than older ones. In fact, in patients > and < or = 66 years, median survival was 31 and 44 months (P < 0.00095) and the percentage of patients surviving over 72 months was 17% and 32% (P = 0.0018) respectively; in patients < 55 years, these figures were 57 months and 35% respectively (P = 0.02 and 0.01, with respect to patients aged > 55 years). In all groups, about 50% of the patients surviving over 72 months had stage I disease. For multiple myeloma patients treated with chemotherapy, survival is favourably affected by relatively young age and early stage of disease.     

The Value of Computed Tomography in Radiation Treatment for Multiple Myeloma

Plain radiography has traditionally been used in the radiological evaluation of multiple myeloma. Frequently, however, plain radiographs are inconclusive even in the presence of active disease. Computed tomography is a specific and sensitive modality that can detect early destructive bone lesions not shown by plain radiographs.     

Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma

We conducted a randomized trial to evaluate whether melphalan-prednisone (MPH-P) treatment administered just after diagnosis improves survival of stage I multiple myeloma (MM). Between January 1987 and March 1993, 145 consecutive previously untreated patients with stage I MM were randomized between treatment with MPH-P (administered for 4 days every 6 weeks) just after diagnosis and treatment only at disease progression. Survival was not influenced by MPH-P treatment either administered just after diagnosis or at disease progression (64 vs 71 months respectively). Comparing the first with the second group the odds ratio of death is 1.17 (95% confidence interval 0.57-2.42; P = 0.64). Disease progression occurred within a year in about 50% of patients who were initially untreated. Response rate was similar in both groups, but duration of response was shorter in patients who were treated at disease progression (48 vs 79 months, P = 0.044). Patients actually treated at disease progression (34/70) survived shorter than those who had neither disease progression nor treatment (56 vs > 92 months; P = 0.005). Starting MPH-P just after diagnosis does not improve survival and response rate in stage I MM, with respect to deferring therapy until disease progression. However, patients with stage I MM randomized to have treatment delayed and who actually progressed and were treated had shorter survival than those with stable disease and no treatment. Biologic or other disease features could identify these subgroups of patients.     

The Role of Recombinant Erythropoietin for the Treatment of Anemia in Multiple Myeloma

The key role of a blunted production of endogenous erythropoietin (EPO) in determining anemia of patients with multiple myeloma (MM) has been definitively established. Thus, several clinical trials have investigated the effects of recombinant EPO (r-EPO) in anemic MM patients. The results of these studies have demonstrated that r-EPO is a safe and effective drug, which results in an increase in Hb levels in the majority of treated patients. However, several factors, such as serum levels of endogenous EPO, severity of anemia, presence of normal ery-throid progenitors, serum levels of some cytokines with inhibitory activity on erythroid function and previous treatments, may significantly affect the possibility of response, thereby suggesting the need for careful selection of MM patients for treatment with r-EPO.     

A Randomized Study of MOD Versus VAD in the Treatment of Relapsed and Resistant Multiple Myeloma

67 patients with relapsed or resistant multiple myeloma were randomized to receive either VAD (vincristine, doxorubicin, dexamethasone) or MOD (mitozantrone, vincristine, dexamethasone). 12/30 (40%) patients receiving VAD and 15/37 (41%) patients receiving MOD achieved plateaux. The median duration of plateaux was significantly longer on VAD (15 months) than on MOD (8 months). No significant difference in overall survival was seen between the two treatment arms. The only toxicity which was severe in more than 5% of treatment cycles on either treatment arm was myelosup-pression. No toxicity was significantly more severe on MOD than VAD. However, hair loss was significantly more severe on VAD than MOD. The frequencies of thrombocytopenia, haematuria and cutaneous toxicity were significantly greater on VAD than on MOD. Raised serum direct bilirubin levels were seen significantly more often on MOD than VAD. MOD and VAD have similar efficacy in relapsed/resistant multiple myeloma. MOD is the less toxic of the two regimens.     

多发性骨髓瘤患者血清血管生成素水平的测定及意义

目的研究血管生成素（Angs）与多发性骨髓瘤（MM）的关系并探讨其临床意义。方法用双抗体夹心酶联免疫吸附测定法检测60例MM患者不同时期的Angs血清浓度,观察其与MM临床分期、肿瘤量分级和治疗效果的关系。结果MM患者血清中Ang-2较正常对照组明显升高;血清Ang-1含量与正常对照组差异无统计学意义。MM患者Ⅱ期的Ang-2血清水平显著低于Ⅲ期。不同肿瘤量分级的MM患者血清Ang-2含量差异有统计学意义。MM治疗有效者,血清Ang-2水平比治疗前明显降低,血清Ang-1水平与治疗前差异无统计学意义;治疗无效者,其血清Ang-1、Ang-2含量与治疗前比较差异均无统计学意义。结论MM患者血清Ang-2水平测定对MM的发病机制研究、病情评价、疗效监测、预后预测有一定意义。     

Multi-drug combination therapy with vincristine-melphalan-cyclophosphamide-prednisolone was more effective than cyclophosphamide-prednisolone in stage III myeloma. The Nagoya Myeloma Cooperative Study Group

A cooperative randomized clinical trial to compare the effectiveness of multi-drug combination chemotherapy (VMCP), vincristine-melphalan-cyclophosphamide-prednisolone) with CP (cyclophosphamide-prednisolone) for the treatment of multiple myeloma was performed. When the whole group of patients was evaluated, the choice of chemotherapy (VMCP or CP) was not a significant prognostic factor associated with response or survival by uni- or multivariate analysis, and the difference between the survival curves of the treatment groups was only marginally significant. However, when the analysis was confined to stage III patients, the choice of chemotherapy became a significant prognostic factor associated with both response rate and survival, and the statistical difference between survival curves was significant. Taking the disease characteristics of multiple myeloma into consideration, the better result obtained with multi-drug combination chemotherapy in the treatment of stage III patients is consistent with other studies supporting the superiority of multi-drug combination chemotherapy for patients with overt systemic disease.     

Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma

The prognosis of patients with multiple myeloma (MM) has improved dramatically with the introduction of new therapeutic drugs, but the disease eventually becomes drug-resistant, following an intractable and incurable course. A myeloma niche (MM niche) develops in the bone marrow microenvironment and plays an important role in the drug resistance mechanism of MM. In particular, adhesion between MM cells and bone marrow stromal cells mediated by adhesion molecules induces cell adhesion-mediated drug resistance (CAM-DR). Analyses of the role of mitochondria in cancer cells, including MM cells, has revealed that the mechanism leading to drug resistance involves exchange of mitochondria between cells (mitochondrial transfer) via tunneling nanotubes (TNTs) within the MM niche. Here, we describe the discovery of these drug resistance mechanisms and the identification of promising therapeutic agents primarily targeting CAM-DR, mitochondrial transfer, and TNTs.     

MPV方案治疗难治性复发性多发性骨髓瘤18例临床观察

目的评估MPV方案治疗难治性复发性多发性骨髓瘤（MM）的疗效。方法18例难治性复发性MM患者,均给予MPV方案化疗,治疗4个周期观察疗效。观察项目包括血清M蛋白、肝肾功能、尿蛋白、骨髓像、血像等。结果经4个周期治疗,7例完全缓解,8例部分缓解,总有效率为83．33％。结论MPV方案是治疗难治性复发性MM较好的选择。     

硼替佐米和沙利度胺联合VAD方案治疗多发性骨髓瘤疗效分析

目的探讨硼替佐米、沙利度胺联合VAD方案治疗多发性骨髓瘤（MM）的临床疗效。方法 18例初诊MM患者采用硼替佐米、沙利度胺联合VAD方案治疗（A组）,硼替佐米1.3 mg/m2,沙利度胺从100 mg/d开始口服,逐渐增加剂量,至200 mg/d。单纯使用VAD方案（B组）治疗的23例初诊MM患者作为对照组。结果 A组的治疗有效率优于B组（P〈0.05）,联合治疗组的不良反应有皮疹、便秘、神经毒性、乏力、嗜睡、脱发及感染。结论硼替佐米和沙利度胺联合VAD方案治疗MM疗效明显优于VAD方案,缓解率高,对于初诊性MM是疗效较好而又较安全的方案,在选择化疗方案时可优先考虑。     

Serum Levels of Interleukin-8 and Soluble Interleukin-6 Receptor in Patients with Stage-I Multiple Myeloma: A Case-Control Study

Objective: Multiple myeloma (MM) remains an incurable disease that needs better recognition and further research. Previous studies elucidated the interaction between myeloma cells and showed the necessity of bone marrow stromal cells for the initiation and progression of MM. Many chemokines and their receptors including interleukin-8 (IL-8) and soluble interleukin-6 receptor (sIL-6R) play important roles in this interaction. The main purpose of this study is evaluating the serum level of IL-8 and sIL-6R on stage-I of MM patients and healthy controls. Methods: Serum samples from 30 stage-I MM  patients (13 males and 17 females) and 30 healthy subjects as controls (13 males and 17 females) were examined in this study. The protein concentrations of serum IL-8 and sIL-6R were assessed by enzyme-linked immunosorbent assay (ELISA). Results: The mean level of IL-8 and sIL-6R were significantly elevated in stage-I MM. The mean levels of IL-8 were 1246.57±279.22 ng/ml in stage-I MM and 902.53± 294.61 ng/ml in controls (P<0.001). The mean levels of sIL-6R were 5.39±1.38 ng/ml and 4.1±1.14 ng/ml in stage-I MM and controls, respectively (P<0.001). The mean levels of IL-8 were 1342.18±193.4 ng/ml in patient females and 859± 278.2ng/ml in control females (P <0.001). The mean levels of sIL-6R were 5.21±1.55 ng/ml and 3.91±1.22 ng/ml in patient females and control females, respectively (P=0.01). The mean level of sIL-6R in patient males and control males were 5.63±1.43 ng/ml and 4.34±1.04 ng/ml, respectively (P=0.01). A significant correlation (Pearson’s correlation = 0.45, P=0.008) was observed in the population of females (patients and controls). Conclusion: The results of study suggest the possible involvement of IL-8 and the sIL-6R at stage-I MM and can better characterize the role of chemokines and their receptors in the disease process, especially in the early stages.     

Phase II study of natural interferon-gamma. Natural Interferon-gamma Cooperative Study Group

Naturally produced interferon-gamma was evaluated in 187 cases with advanced cancer. Interferon was given by the i.v. routes in doses ranging from 1 X 10(5) IU to 2 X 10(5) IU/day daily or every other day for more than 2 months. Overall, clinical anticancer spectrum, effectiveness, toxicities, and pharmacokinetics were similar to that seen with preparations of interferon-alpha, and beta.     

改良VAD方案治疗多发性骨髓瘤临床观察

[目的]探讨改良VAD方案治疗多发性骨髓瘤的疗效.[方法] 32例多发骨髓瘤患者随机分为两组,均应用阿霉素和长春新碱.研究组16例给予甲基强的松龙80～120mg,d1～4、d9～12、d17～20静脉滴注,对照组16例给予地塞米松40mg口服,用药时间同研究组.[结果]研究组总有效率81％(13/16),对照组总有效率88％(14/16),两组疗效无显著性差异(P＞0.05);感染发生率治疗组12.5％,对照组31.2％;消化道出血发生率治疗组6％,对照组19％;研究组感染及消化道出血发生率明显低于对照组(P＜0.05).[结论]以静脉应用甲基强的松龙的改良VAD方案治疗多发性骨髓瘤疗效较好,毒副作用较传统VAD方案轻.     

Serum thymidine kinase in diagnosis and follow-up of the small cell carcinoma of the lung.

Serum thymidine-kinase (sTK) was assayed in 48 males affected by small cell carcinoma of the lung (SCCL) at the time of diagnosis. On the same drawing carcinoembryonic antigen (CEA) and beta 2microglobulin (beta 2 microG) were assayed in 19 of these subjects. For staging, the criterion of limited (LD) and extensive (ED) disease was used. Mean sTK and CEA values were above normal range in both the LD and ED groups, while mean beta 2 microG value remained below normal range. Thirty-two patients were subsequently submitted to therapy; sTK was assayed at the end of each treatment cycle. Mean sTK concentrations differed depending on response to therapy. From the data obtained it is concluded that sTK assay is helpful for diagnosis of SCCL; CEA to a lesser extent, above all in association with sTK, and beta microG not at all. sTK assay can also be useful for prognosis and follow-up.