Recombinant interferon-γ inhibits the in vitro proliferation of human myeloma cells

Summary. Interferon-α (IFN-α), interferon-γ (IFN-γ) and dexamethasone (DEX) have shown anti-tumour effects in multiple myeloma (MM) cells. Bone marrow plasma cells from 39 MM patients were cultured to clarify the intensity and specific activity of each compound on bromo-deoxyuridine (BrdUrd) uptake and immunoglobulin (Ig) secretion. BrdUrd uptake was inhibited by recombinant human IFN-γ (100 U/ml) and by DEX (10⁻⁶ m ). The stimulation index (StI), i.e. labelling index (LI) of treated samples/controls, was 0·49 0·009 (mean standard error of the mean, MSEM), P =0·0003, and 0·52·0·07 (MSEM), P <0·0001, respectively. Ig secretion was reduced by IFN-α (100 U/ml) and DEX. The secretion index (SI), i.e. Ig quantitation of treated samples/controls, was 0·04 (MSEM), P <0·0001, and 0·52·0·04 (MSEM), P <0·0001, respectively. Finally, IFN-γ inhibits BrdUrd uptake only and IFN-α secretion only. In 18 patients the simultaneous addition of IFN-α plus IFN-γ mainly paralleled the effect of IFN-γ on BrdUrd uptake and IFN-α on secretion, but did not result in any additive or synergistic effect, though both BrdUrd uptake and Ig secretion were decreased to about the same extent as with DEX. These data indicate that the combination of IFN-α plus IFN-γ and DEX are the strongest inhibitors of both BrdUrd uptake and secretion. Since IFN-α and IFN-γ appear to have a different mechanism of action, their combined use could be considered as a possible new treatment strategy.     

Interferon-alpha up-regulates bcl-2 expression and protects B-CLL cells from apoptosis in vitro and in vivo

Summary. The bcl-2 oncoprotein, which is involved in the t(14.18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-α) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro , IFN-α (500U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200±23% of control MCF, as determined by indirect immunofluorescence and flow cytometry. n = 10, P < 0.001). All of eight patients who received IFN-α (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 ± 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-α, however, DNA fragmentation was reduced to 6.6 ± 5.8% (n = 10, P < 0.001). IFN-α also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 ± 12.6% to 10.8 ± 4.5 % and from 80 ± 2.9% to 5.4 ± 1.6%, respectively, P < 0,001 for both). The protective effect of IFN-α was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-a in patients with CLL are due to a direct effect on the malignant cells.     

Induction of TNF-α in patients with myelodysplastic syndromes undergoing treatment with interleukin-3

Summary. The study was undertaken to analyse whether the presence or the induction of TNF-α, a potent inhibitor of haemopoiesis, might affect the clinical response to treatment with interleukin-3 in patients with myelodysplastic syndromes. A total of 15 patients were treated with IL-3. Baseline serum TNF-α levels were elevated in MDS patients (14·2 ± 2·4 pg/ml) compared to healthy controls (9·1 ± 1·1 pg/ml). During IL-3 therapy TNF-α levels remained unchanged in 3/14 patients in whom platelet counts increased, while in non-responders TNF-α levels increased 1·9-fold ( P < 0·025).
These findings indicate that TNF-α not only is induced during IL-3 therapy in MDS patients but that this elevation might be associated with a poor platelet response to therapy.     

Alpha-interferon (α-IFN) protects B-chronic lymphocytic leukaemia cells from apoptotic cell death in vitro

B-chronic lymphocytic leukaemia cells (CLL) are prone to apoptotic cell death when cultured in vitro . Apoptosis and loss of the bcl-2 protein is prevented in CLL cells cultured in the presence of interleukin-4. In this study we analysed the effects of α-IFN on the DNA fragmentation, bcl-2 protein levels and cell survival in purified B-cells from 16 CLL patients. α-IFN (10³ U/ml) reduced the degree of spontaneous DNA fragmentation of CLL cells after a 30 h culture period (from a mean of 22·2% in control cultures to 10·5%, P <0·01). This inhibition was accompanied by preservation of bcl-2 protein and an increased survival of CLL cells compared to control cultures. In parallel, α-IFN inhibited hydrocortisone induced DNA fragmentation in CLL cells. The effects of α-IFN on DNA synthesis of CLL cells were variable (in two patients a decrease and in seven an increase in ³H-thymidine uptake) and did not correlate with the effect on DNA fragmentation. In conclusion, our data suggest that α-IFN, like IL-4 and γ-IFN, inhibits apoptosis of CLL cells. These in vitro data indicate that the clinical responses of some CLL patients to α-IFN cannot be explained by a direct cytotoxic effect of α-IFN on circulating CLL cells. Alternatively, α-IFN may inhibit the proliferation of the small fraction of clonogenic CLL progenitors, or interfere with cellular interactions necessary for the survival and growth of CLL cells.     

Pretreatment angiogenic cytokines predict response to chemoimmunotherapy in patients with chronic lymphocytic leukaemia

Serum levels of pro-[vascular endothelial growth factor (VEGF)] and anti-[thrombospondin-1 (TSP)] angiogenic cytokines were prospectively measured in a phase II trial of chemoimmunotherapy (CIT) for chronic lymphocytic leukaemia (CLL) patients ( n  = 56). Pretreatment VEGF levels were lower among patients who achieved complete remission (CR) or nodular partial remission (nPR) relative to those with partial remission (PR) or stable/progressive disease (median 122·0 pg/ml vs. 246·8 pg/ml; P  = 0·03). VEGF:TSP ratio was lower (anti-angiogenic phenotype) among patients who achieved CR/nPR. The pretreatment VEGF:TSP ratio also correlated with overall survival ( P  = 0·008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT.     

Recombinant interferon alfa 2 a in the treatment of patients with early stage B chronic lymphocytic leukaemia

Summary. 18 patients with early stage, previously untreated H-CLL were given interferon alfa (IFNα) 2a, 3 MU thrice weekly, subcutaneously. The peripheral lymphocyte count decreased in all patients. Response was delayed in three patients until they had received a median of 5 months therapy, one of whom had an initial transient increase in lymphocytes. Two patients normalized their blood lymphocyte counts, but neither achieved complete remission (CR). Responses were transient in eight patients lasting a median of 5 months (3–21). Binding anti-IFNa antibodies were present in 9/17 patients tested (53%). Low titre binding antibodies (< 533 IBU/ml) were not associated with LHR, but high titre antibodies (>4401 IBU/ml) were. Two of 12 patients assessed had a > 3 g/1 increase in baseline serum IgG levels during IFNα therapy, one of whom reverted to pretreatment levels in association with LHR. Haematological toxicity was moderate, other than in two patients, one of whom developed autoimmune haemolytic anaemia and the other thrombo-cytopenia. We conclude that IFNα lowers the lymphocyte count in early stage CLL, that the response may be delayed and that anti-IFNcc antibodies may play a role in a proportion of those in whom the response is transient.     

Involvement of interferon-γ and macrophage colony-stimulating factor in pathogenesis of haemophagocytic lymphohistiocytosis in adults

Summary We investigated the role of monocyte/macrophage-activating cytokines in pathogenesis of haemophagocytic lymphohistiocytosis (HLH) in 21 adult patients. Sera from patients with active HLH contained extremely high levels of macrophage colony-stimulating factor (M-CSF) and of interferon-γ (IFN-γ). These levels returned to almost normal during remission. Neither interleukin-4 nor granulocyte/macrophage colony-stimulating factor could be detected. Active HLH sera also contained high concentrations of inflammatory monokines, such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Serum concentrations of soluble CD8 and soluble interleukin-2 receptor were extremely high during active HLH, and returned to virtually normal levels during remission. Circulating CD2⁺ T-cells obtained from patients with active HLH spontaneously secreted M-CSF and IFN-γ in vitro , whereas circulating monocytes did not produce detectable levels of both M-CSF and IFN-γ, but produced high levels of IL-6 and TNF-α. These findings suggest that IFN-γ and M-CSF at least partly from T-cells, such as CD8⁺ T-cells, might contribute to activation of monocytes or histiocytes, resulting in the up-regulated monokine production and haemophago-cytosis in HLH.     

HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy

Hepatitis C virus (HCV) has been proposed as a possible causative agent of chronic thrombocytopenia. We investigated HCV infection in a series of 51 unselected Spanish patients with chronic acquired thrombocytopenia. Anti-HCV and HCV viraemia were detected in 13/51 (22·5%) of cases; this prevalence was particularly significant when compared with HCV seropositivity in age-matched controls (0·4%). Anti-HCV-positive patients, four men and nine women with a median age of 59·3 years (range 36–72), had a mean platelet count of 55·8 × 10⁹/l (range 12–96). Only one of our HCV-positive thrombocytopenic patients had hypersplenism. Platelet-associated IgG (PAIgG) was negative, as measured by immunofluorescent flow cytometric analysis in 11/13 HCV-positive thrombocytopenic patients. Thus, thrombocytopenia in our HCV-positive patients appeared to be non-autoimmune mediated. In six patients, a trial of recombinant α2b-interferon (IFN-α) given at a dose of 3 MU three times per week for 6–24 months gave a durable (> 1 year) and significant increase in platelet count in all six patients. The maximum increase occurred after 6 months of IFN-α therapy. In conclusion, the ability of IFN-α to increase platelet counts in HCV-positive thrombocytopenic patients supports mechanisms involving a direct role for HCV inhibiting platelet production.     

South Asian chronic lymphocytic leukaemia patients have more rapid disease progression in comparison to White patients

Ethnicity has a major impact on the prevalence of chronic lymphocytic leukaemia (CLL) and may also influence disease phenotype. We compared the clinical features of Southern Asian and White CLL patients managed within one UK region. Asians required treatment almost twice as often as Whites (HR, 1·94) and had a shorter time to first treatment ( P  = 0·0063). This difference remained significant after adjusting for stage, lymphocyte doubling time and IGHV status ( P  = 0·026). CLL was diagnosed at younger ages in Asians and racial-specific variations in IGHV usage were demonstrated. Our findings indicate that Southern Asian race has a negative impact on CLL phenotype.     

慢性淋巴细胞白血病血清可溶性CD23及血小板生成素研究

目的 探讨慢性淋巴细胞白血病(CLL)患者血清可溶性CD23(sCD23)及血小板生成素(TPO)水平及与其他预后指标的相关性.方法 采用酶联免疫吸附试验检测25例CLL患者外周血标本中sCD23及TPO的水平;流式细胞术检测ZAP-70蛋白及CD28的表达.结果 CLL患者TPO水平为67.22～1881.77 ng/L,明显高于正常对照组70.29～147.98 ng/L(P=0.003);CLL患者血清sCD23水平为129.80～405.31 U/ml,也明显高于正常对照组0.65～32.99 U/ml(P=0.000).血清TPO水平与Binet分期、CD28具有显著相关性.Binet A期患者TPO水平为121.92～163.83 ng/L,低于BinetB和C期患者140.57～457.48 ng/L(P=0.014);CD38高表达组TPO水平113.23～199.10 ng/L,高于CD38低表达组141.34～454.92 ng/L(P=0,033).而TPO与ZAP-70表达及sCD23与CD28、ZAP-70表达无明显相关性.另外,血清sCD23及TPO与患者性别、年龄、外周血淋巴细胞计数和乳酸脱氢酶均无相关性.结论 血清TPO水平对CLL预后判断可能具有一定的价值.     

Common community acquired infections and subsequent risk of chronic lymphocytic leukaemia

Emerging evidence supports a role for immune-related factors in the causation of chronic lymphocytic leukaemia (CLL). Using the population-based U.S. Surveillance Epidemiology and End Results-Medicare database, 10 171 elderly CLL patients and 122 531 frequency-matched controls were identified in order to evaluate several community acquired infections associated with subsequent CLL risk. Odds ratios (ORs) were adjusted for gender, age, race, calendar year and number of physician claims. CLL risk was increased following Medicare claims for sinusitis (OR = 1·11; 95% CI = 1·05–1·17), pharyngitis (OR = 1·15; 1·08–1·22), bronchitis (OR = 1·14; 1·08–1·19), pneumonia (OR = 1·17; 1·11–1·24), influenza (OR = 1·10; 1·01–1·19), cellulitis (OR = 1·08; 1·02–1·14) and herpes zoster (OR = 1·26; 1·15–1·37). Associations with pneumonia and cellulitis remained significant when the 5-year period before diagnosis/control selection was excluded. CLL risk increased with increasing severity/frequency of pneumonia ( P  = 0·005), cellulitis ( P  < 0·001) and herpes zoster ( P  < 0·001). Our findings suggest that common infections may play a role in CLL aetiology. Alternatively, the associations might reflect an underlying immune disturbance present several years prior to CLL diagnosis.     

Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukaemia if adjusted according to glomerular filtration rate

Even in the era of newer and sophisticated prognostic markers, beta₂-microglobulin (B2M) remains a simple but very powerful predictor of treatment-free survival (TFS) and overall survival (OS) in patients with chronic lymphocytic leukaemia (CLL). However, B2M levels are heavily influenced by the patient's glomerular filtration rate (GFR) and this study aimed to evaluate whether GFR-adjusted B2M (GFR-B2M) had improved prognostic value compared to unadjusted B2M in a cohort of over 450 consecutive CLL patients from two separate institutions. Multivariate analysis identified a significantly shorter TFS in patients who were ZAP-70 + ( P  < 0·001), with increased GFR-B2M ( P  < 0·001), and del(11q) or del(17p) as detected by fluorescence in situ hybridization (FISH; P  < 0·001). When OS was evaluated by multivariate analysis, age 65 years or older ( P  < 0·001) and poor risk FISH abnormalities ( P  < 0·001) had a confirmed adverse prognostic impact, but the predictive value of GFR-B2M was lost in the validation analysis. In all survival models, B2M did not attain independent significance unless GFR-B2M was eliminated from the analysis. In conclusion, GFR-B2M is a better predictor of TFS than unadjusted B2M in CLL patients.     

Hepatic inflammatory cytokine mRNA expression in hepatitis C virus-human immunodeficiency virus co-infection

Summary.  Although epidemiologic studies have documented that hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infected patients have accelerated fibrogenesis, especially those with CD4⁺ cell counts <200 cells/mm³, the pathogenic mechanisms are poorly understood. We investigated whether severe immunodeficiency in co-infection is associated with changes in intrahepatic inflammatory cytokine mRNA levels. We measured interferon (IFN)-γ, tumour necrosis factor-α, transforming growth factor (TGF)-β₁, interleukin (IL)-4, IL-10, IL-12p35 and IL-12p40 mRNA levels by real-time PCR performed on liver samples from HCV mono-infected ( n  = 19) and HCV/HIV co-infected ( n  = 24) patients. Co-infected patients had decreased intrahepatic mRNA levels of IFN-γ ( P  = 0.09), IL-4 ( P  = 0.05) and IL-12p35 ( P  = 0.04) compared with mono-infected patients, while IL-10 was increased ( P  = 0.07). In co-infected patients, IFN-γ mRNA levels increased linearly with increasing peripheral CD4⁺ cell counts by 1.23 times relative to the calibrator for every 100 CD4⁺ cells/mm³ increase ( P  = 0.02). No other cytokines were significantly associated with CD4⁺ cell counts. In conclusion, HIV-induced lymphopenia may result in hepatic inflammatory cytokine suppression in HCV/HIV co-infection. Intrahepatic IFN-γ levels are significantly reduced in patients with advanced immunodeficiency. Further studies are needed to assess whether decreased IFN-γ secretion by HCV-specific CD4⁺ cells may account for accelerated fibrogenesis in these patients.     

Interleukin 8 in serum in granulocytopenic patients with infections

Serum levels of interleukin 8 (IL-8) were examined in eight patients with acute myeloid leukaemia during 16 courses of chemotherapy. The patients experienced 14 episodes of fever which occurred in periods with granulocyte counts <0·5 × 10⁹/l. Febrile episodes were classified as bacteriologically defined infection ( n = 6), clinically defined infection ( n = 2), and unexplained fever ( n = 6). IL-8 was detected in 18/25 (72%), 2/3 (67%) and 3/7 (43%) of the serum samples in the respective groups. In contrast, IL-8 was detected in 22/90 (24%) of the samples taken when no fever was present ( P <0·00003 versus bacteriologically defined infection). The median concentration of IL-8 in samples taken during febrile episodes was 194 ng/ml (range 0–6358 ng/ml) and 0 (range 0–5392 ng/ml) on days without fever (not significant). In three patients with infections caused by, respectively, Streptococcus sanguis, Acinetobacter calcoanitratus and Candida albicans , IL-8 rose to a peak levels and declined during recovery. We conclude that IL-I is released systemically during infections with gram-positive and gram-negative bacteria and Candida albicans in patients with acute myeloid leukaemia and peripheral granulocytopenia due to chemotherapy. However, IL-8 can also be detected when no sign of infection is present.     

Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia

The measurement of immunoglobulin serum free light chains (sFLC) has prognostic significance in plasma cell dyscrasias but its role in chronic lymphocytic leukaemia (CLL) is unknown. This retrospective study from three UK hospitals analysed sFLC in 181 untreated/pre-treatment CLL patients and 78 treated CLL patients, with samples taken later in their disease. An abnormal sFLC ratio was significantly associated with poor overall survival for the 181 untreated/pre-treatment patients ( P  = 0·0001) and for all patients ( P  = 0·002), irrespective of cause of death. Using multivariate analysis ( n  = 194), four independent prognostic variables for overall survival were identified namely Zap-70 ( P  = 0·0001), β2M ( P  = 0·01), IGHV mutation status ( P  = 0·017) and an abnormal sFLC ratio ( P  = 0·024). For CLL patients with unmutated IGHV genes, elevated κ/λ ratios were adversely prognostic. For patients with mutated IGHV genes, reduced κ/λ ratios were adversely prognostic and associated with the poor prognostic IGHV3-21 , IGHV3-48 and IGHV3-53 subgroups, suggesting an abnormal sFLC ratio may reflect biological subgroups within CLL. Abnormal sFLC ratios need to be studied prospectively in CLL patients and the biological rationale for their abnormality investigated.     

The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic monoclonal expansion of <5·0 × 10⁹/l circulating CLL-phenotype B-cells. The relationship between MBL and Rai 0 CLL, as well as the impact of biological risk factors on MBL prognosis, are unknown. Out of 460 B-cell expansions with CLL-phenotype, 123 clinical MBL (cMBL) were compared to 154 Rai 0 CLL according to clinical and biological profile and outcome. cMBL had better humoral immune capacity and lower infection risk, lower prevalence of del11q22-q23/del17p13 and TP53 mutations, slower lymphocyte doubling time, and longer treatment-free survival. Also, cMBL diagnosis was a protective factor for treatment risk. Despite these favourable features, all cMBL were projected to progress, and lymphocytes <1·2 × 10⁹/l and >3·7 × 10⁹/l were the best thresholds predicting the lowest and highest risk of progression to CLL. Although IGHV status, CD38 and CD49d expression, and fluorescence in situ hybridization (FISH) karyotype individually predicted treatment-free survival, multivariate analysis identified the presence of +12 or del17p13 as the sole independent predictor of treatment requirement in cMBL (Hazard ratio: 5·39, 95% confidence interval 1·98–14·44, P  = 0·001). Overall, these data showed that cMBL has a more favourable clinical course than Rai 0 CLL. Given that the biological profile can predict treatment requirement, stratification based on biological prognosticators may be helpful for cMBL management.     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Summary. Serum concentrations of tumour necrosis factor alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-γ), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr⁻) bacteraemias after 2 h (TNF-α, IL-lra and IFN-γ), 4h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-α value was higher in the Gr⁻ group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr⁺, 14pg/ ml; range 7-60 pg/ml; P < 0 05) and blood culture negative episodes (BCN, 8pg/ml; range 0-87pg/ml; P<0 05).
Furthermore, the peak values of TNF-α, IL-lra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the ^Gr- group in comparison to the Gr⁺ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in ^Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Randomized, placebo-controlled, double-blind trial with interferon-α with and without amantadine sulphate in primary interferon-α nonresponders with chronic hepatitis C

In primary interferon-α (IFN-α) nonresponders with chronic hepatitis C, retreatment with IFN-α has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN-α alone or in combination with amantadine sulphate in nonresponders to previous IFN-α monotherapy. Fifty-five IFN-α nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN-α 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate ( n =26) or a matched placebo ( n =29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN-α dose reduction in week 24, a virological end-of-treatment response with undetectable serum HCV-RNA (< 1000 copies/mL) was achieved in only five patients (IFN-α/amantadine sulphate, one patient; IFN-α/placebo, four patients). After 24 weeks follow-up a sustained virological response was observed in only two patients receiving IFN-α and placebo. Health-related quality-of-life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue ( P  < 0.05) and vigor ( P  < 0.05) in patients receiving combined IFN-α/amantadine sulphate treatment compared with those treated with IFN-α alone. IFN-α/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN-α and amantadine sulphate does not increase the low sustained virological response rates of IFN-α therapy in primary IFN-α nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health-related quality-of-life.     

Treatment of multiple myeloma with interferon alpha: the Scandinavian experience

IFNα is a biologic therapeutic agent with documented antitumoural effect in multiple myeloma. 15% of previously untreated myeloma patients achieve a clinical response to IFNα alone with a possible dose-response relationship. A particularly good effect is noted in IgA myelomas treated with natural IFNα.
A randomized study was started in April 1986 comparing melphalan/prednisone (MP) therapy with MP plus natural IFNα (MP/IFN) in untreated patients with multiple myeloma stages II and III. 220 patients had entered the study by autumn 1989. An interim report is given here. The response frequency was 48% in the MP group and 66% in the MP/IFN group ( P <0·02). Stage II patients responded better to MP/IFN (76%) than to MP alone (48%) ( P <0·01). No significant difference was noted for stage III patients. 91% of all IgA myelomas responded to MP/IFN and 52% to MP ( P <0·01). The difference in response frequency of IgG and BJ myelomas between the two treatment groups was not statistically significant. The observation period is still too short to draw firm conclusions on survival. However, a statistically significant longer response duration time and survival from response ( P <0·01) was noted for stage II patients.     

Plasma monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α are increased in patients with polycystic ovary syndrome (PCOS) and associated with adiposity, but unaffected by pioglitazone treatment

Objective  Hirsutism is most often caused by polycystic ovary syndrome (PCOS). PCOS patients are characterized by insulin resistance, abdominal obesity and low-grade inflammation. Insulin sensitizing treatment reduces the inflammatory state, but the effect on serum levels of migration inhibitor factor (MIF), monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α have not been evaluated before in PCOS.
Research design and methods  Plasma chemokine levels (MCP-1, MIP-1α and MIF) were measured in two study designs. (i) 51 hirsute patients and 63 matched controls and (ii) 30 PCOS patients before and after randomized treatment with 30 mg pioglitazone/placebo for 16 weeks. Clinical evaluations and whole body DXA-scans were performed in all participants.
Results  Hirsute patients ( n  = 51) had significantly increased MCP-1 [121 (15–950) vs. 81 (18–365) pg/ml; P  < 0·05] and MIP-1α[179 (8–4202) vs. 103 (4–1598) pg/ml; P  < 0·05] than controls of matched body composition [geometric mean (–2SD to +2SD)]. In PCOS ( n  = 30), MCP-1, MIP-1α and MIF correlated positively with central fat mass. A BMI independent positive association was found between MIF and free testosterone ( r  = 0·49, P  = 0·01) in PCOS. Pioglitazone treatment significantly improved insulin sensitivity without affecting testosterone, body composition, MCP-1, MIP-1α and MIF levels.
Conclusions  Chemokine levels were significantly increased and showed close associations with measures of adiposity in PCOS patients, but were unchanged during insulin sensitizing treatment with pioglitazone. Our data suggests a fat mass independent association between testosterone and MIF levels in PCOS and the effect of anti-androgen treatment on chemokine levels needs to be examined.