Identification and evaluation of a panel of serum biomarkers for predicting response to thalidomide in multiple myeloma patients

Evaluation of: Rajpal R, Dowling P, Meiller J et al. A novel panel of protein biomarkers for predicting response to thalidomide-based therapy in newly diagnosed multiple myeloma patients. Proteomics 11(8), 1391-1402 (2011). Predicting response to thalidomide-based therapy remains a challenging task faced by clinicians in the treatment of multiple myeloma. The pioneering work reported by Rajpal et al. moves one step further towards solving this challenge. They developed a proteomics-based approach that combines immunodepletion, 2D-difference gel electrophoresis analysis and mass spectrometry to search for serum proteins with expressions that show significant correlations to thalidomide treatment. This integrated approach allowed them to identify a panel of protein biomarkers. By using ELISA-based validation and strict statistical analysis, the authors have achieved an overall 84.0% predictive accuracy, with associated sensitivity and specificity values of 81.8 and 86.2%, respectively. Their methods and significant findings are reviewed within this article. This panel of biomarkers may not only guide initial therapy, but can also provide direct implications for personalized medicine in multiple myeloma patients.     

Potentially Functional SNPs (pfSNPs) as Novel Genomic Predictors of 5-FU Response in Metastatic Colorectal Cancer Patients

5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.     

Toward the proteomic identification of biomarkers for the prediction of HBV related hepatocellular carcinoma

Early detection is a key step for effective intervention of hepatocellular carcinoma (HCC), the lack of sensitive and specific biomarkers is a major reason for the high rate of HCC-related mortality. This report described an integrated strategy by combining SELDI-ProteinChip, sophisticated algorithm analysis, acetonitrile (ACN) pre-treatment and two-dimensional electrophoresis (2DE)-peptide mass fingerprinting (PMF) techniques to identify serological markers for the prediction of HBV-related HCC. Proteomic profiling of three groups of serum specimens from HBV-related HCC (50 cases), HBV infection (45 cases), and normal subjects (30 cases) was conducted by using SELDI-ProteinChip system and the resulting different protein peaks were subjected to stepwise statistical analyses. Three most discriminatory peaks at 5890, 11615, and 11724 Da, respectively, were screened out from the statistical algorithm and a predictive model based on the three peaks was constructed and tested using the newly enrolled serum samples. 2DE was applied to separate and compare the serum samples that were pre-treated by ACN precipitation. The protein spots obviously intensified in HCC sera in the 2DE region of 12 kDa were identified by PMF to be serum SAA, which was validated by SELDI-TOF spectra of HCC sera after immunoprecipitation using anti-SAA antibody and by Western blot experiments. Given the fact that SAA is not a specific biomarker, further attempt is being made to identify the other two most discriminatory peaks to realize the possibility of using the predictive model for HCC surveillance and prediction.     

Aggravation of inappropriate luteinizing hormone secretion by bromocriptine in polycystic ovary syndrome with elevated serum dehydroepiandrosterone sulfate

Ten clomiphene-resistant, normoprolactinemic women with polycystic ovary syndrome (PCOS) were treated by continuous and increasing administration of bromocriptine (Brc), and changes in hormonal profiles as well as therapeutic efficacy were examined. Ovulation was restored in four patients (responders), and two of them became pregnant, whereas the other six patients did not ovulate with Brc alone (non-responders). Endocrine analyses revealed distinct differences between responders and non-responders: 1) pretreatment serum levels of dehydroepiandrosterone sulfate (DHAS) in non-responders were significantly higher than those in responders: 2) exaggerated LH secretion was definitely aggravated with Brc therapy in non-responders, but unchanged or slightly reduced in responders: 3) basal PRL secretions showed a marked reduction in both groups, whereas this response to TRH in responders decreased more markedly than in non-responders with the therapy. It is concluded that low DHAS group patients of PCOS are likely to respond to Brc, whereas high DHAS group patients appear contraindicated for this treatment due to its aggravating effect on LH secretion.     

Serum levels of leptin in multiple myeloma patients and its relation to angiogenic and inflammatory cytokines

BACKGROUND: Leptin, apart from the regulation of food intake, has been implicated in hematopoiesis, the immune response and angiogenesis. Leptin has been found to be decreased in various hematological malignancies. In the present study leptin was measured in multiple myeloma (MM) patients before and after treatment and correlated with other angiogenic molecules and markers of disease activity. METHODS: Serum leptin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), interleukin-1 beta (IL-1beta), beta 2 microglobulin (beta2M) and C-reactive protein (CRP) were measured in 62 newly diagnosed MM patients, 22 of whom obtaining disease stabilization after treatment. The same parameters were measured in 20 healthy controls. Disease stage was defined according to the Durie-Salmon criteria. RESULTS: Leptin, VEGF, b-FGF, IL-1beta, and beta2M were significantly higher in newly diagnosed MM patients than in controls (p<0.05). VEGF, b-FGF, IL-1beta, beta2M, CRP but not leptin increased with advancing stage of disease (p<0.01). All parameters decreased significantly following treatment (p<0.001). Although IL-1beta correlated positively with VEGF, beta2M, b-FGF and CRP, leptin did not correlate with any of the measured parameters. CONCLUSION: Leptin serum levels do not reflect disease severity in MM. However, there seems to be a decrease in leptin following treatment, which may be associated with an alteration in the metabolic state or the chemokine milieu.     

Endogenous interleukin-11 (IL-11) levels in newly diagnosed children with acquired severe aplastic anemia (SAA)

BACKGROUND: Impaired hematopoietic growth factor production is a hypothetical contributing factor to the development of acquired severe aplastic anemia (SAA). The serum levels of most hematopoietic cytokines in SAA patients are elevated. OBJECTIVE: To measure interleukin-11 levels in newly diagnosed SAA children and attempt to correlate levels with disease severity and response to therapy. DESIGN/METHODS: Following enrollment into a clinical study but prior to treatment, serum samples were obtained from 11 newly diagnosed children with acquired SAA. These samples were collected between May 2000 and September 2002. IL-11 levels were quantified utilizing an ELISA technique. RESULTS: Ten of the 11 patients had low or normal levels of IL-11 (<85 pg/mL) and one had an elevated level of 409 pg/mL (normal range 15-200 pg/mL). CONCLUSIONS: The production of IL-11 does not increase in response to thrombocytopenia in most children with SAA. The significance of this laboratory observation is not clear at this time. Further studies are warranted to determine what, if any, role this plays in the development of this disorder and if the administration of recombinant human IL-11 might be beneficial in the treatment of acquired SAA.     

Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study

Response to treatment of rheumatoid arthritis shows large inter-individual variability. This heterogeneity is observed with all the anti-rheumatic drugs, including the commonly used TNF inhibitors. It seems that drug-specific and target-specific factors lead individual patients to respond or not to a given drug, although this point has been challenged. The search of biomarkers distinguishing responders from non-responders has included shotgun proteomics of serum, as a previous study of response to infliximab, an anti-TNF antibody. Here, we have used the same study design and technology to search biomarkers of response to a different anti-TNF antibody, adalimumab, and we have compared the results obtained for the two anti-TNF drugs. Search of biomarkers of response to adalimumab included depletion of the most abundant serum proteins, 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) labeling, two-dimensional liquid chromatography fractionation and relative quantification with a hybrid Orbitrap mass spectrometer. With this approach, 264 proteins were identified in all the samples with at least 2 peptides and 95% confidence. Nine proteins showed differences between non-responders and responders (P < 0.05), representing putative biomarkers of response to adalimumab. These results were compared with the previous study of infliximab. Surprisingly, the non-responder/responder differences in the two studies were not correlated (r_s = 0.07; P = 0.40). This overall independence with all the proteins showed two identifiable components. On one side, the putative biomarkers of response to either adalimumab or infliximab, which were not shared and showed an inverse correlation (r_s = -0.69; P = 0.0023). On the other, eight proteins showing significant non-responder/responder differences in the analysis combining data of response to the two drugs. These results identify new putative biomarkers of response to treatment of rheumatoid arthritis and indicate that they are notably drug-specific.     

Response to thalidomide in multiple myeloma: impact of angiogenic factors

Thalidomide has antiangiogenic and immunomodulatory effects, mediated by several cytokines such as vascular endothelial growth factor (VEGF), fibroblastic growth factor (FGF-2), hepatocyte growth factor (HGF), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Although extramedullary plasmacytomas (EMP) have a high vascularization, the response of these patients to thalidomide is controversial. Thirty-eight patients with refractory/relapsed MM were treated with thalidomide. Eleven patients had EMP when therapy was initiated. Serum specimens were obtained in patients before treatment was started and at the time of maximum response in responding patients or at thalidomide discontinuation in non-responders. Serum levels of VEGF, HGF and FGF-2 were determined in 18 patients whereas IL-6 and TNF-alpha were measured in 19 patients. Sixteen of the 38 patients (42%) responded to thalidomide. The response rate was significantly higher in patients without EMP (59% vs 0%, p = 0.0006 ). VEGF serum levels were significantly higher in responding patients. In contrast, baseline serum levels of HGF were significantly lower in responders. Neither VEGF nor HGF serum levels showed correlation with the presence of EMP. Baseline TNF-alpha serum levels were significantly lower in responding patients and in those without EMP. The serum levels of FGF-2 and IL-6 did not correlate with response to treatment or presence of EMP.     

Inhibition of the oxidative burst response of N-formyl peptide-stimulated neutrophils by serum amyloid-A protein

Strong binding of the acute phase protein serum amyloid-A (SAA) to human neutrophils was found using flow cytometry. This binding was shown to be functionally relevant with respect to the oxidative burst reaction assayed on N-formyl peptide-stimulated neutrophils by the intracellular oxidation of non-fluorescent dihydrorhodamine to fluorescent rhodamine 123. The results show reduction of the oxidative burst response by isolated SAA (and recombinant SAA2). Inhibition was also demonstrated by acute phase as compared to normal human serum. This inhibitory effect was abolished by the purified monoclonal anti-amyloid A antibody mc29, strongly suggesting that SAA counteracts neutrophil responses to cytokines or bacterial products. This newly recognized function of SAA may help to prevent oxidative tissue destruction.     

血清锌-α2-糖蛋白、骨硬化蛋白、胎球蛋白A水平与维持性血液透析患者冠状动脉钙化的关系及其诊断价值研究

目的:研究血清锌-α2-糖蛋白(ZAG)、骨硬化蛋白(SOST)及胎球蛋白A(FA)水平与维持性血液透析(MHD)患者冠状动脉钙化的关系及其诊断价值。方法:将2018年1月~2021年4月于我院接受MHD的203例患者纳入研究。将其按照冠状动脉钙化积分分作钙化组133例以及无钙化组70例。分析两组各项基线资料以及实验室指标水平的差异,并以多因素Logistic回归分析明确MHD患者冠状动脉钙化的影响因素。另外,通过受试者工作特征(ROC)曲线分析明确血清ZAG、SOST及FA诊断MHD患者冠状动脉钙化的效能。结果:钙化组年龄及血磷、SOST水平均高于无钙化组,而血清ZAG、FA水平均低于无钙化组(P<0.05)。经多因素Logistic回归分析可得:年龄、血磷以及血清SOST、ZAG、FA均是MHD患者冠状动脉钙化的影响因素(P<0.05)。经ROC曲线分析发现:血清ZAG、SOST及FA联合诊断MHD患者冠状动脉钙化的曲线下面积、灵敏度、特异度以及约登指数均高于上述三项指标单独诊断。结论:血清ZAG、SOST及FA均和MHD患者冠状动脉钙化密切相关,可作为辅助诊断MHD患者冠状动脉钙化的生物学标志物。     

Prognostic value of serial serum interleukin-6 level estimation in patients with lung cancer: a preliminary report.

In the present report, we serially measured the levels of interleukin-6 (IL-6) and some acute-phase proteins (APP) in 61 lung cancer patients undergoing radiotherapy in order to investigate the relationship between the response to the treatment and the changes in parameters of systemic inflammatory response. The patients were divided into two groups depending on the response to the treatment. The first group (referred to as responders) comprised 32 patients with stable disease, partial remission or total remission. Twenty-nine patients with progression of the disease were included to the second group (referred to as non-responders). Six patients died due to the lung cancer during the study. We showed a decrease in IL-6 serum level and C-reactive protein (CRP) level in responders but not in non-responders. However, the most interesting results were obtained after retrospective analysis of the data of six deceased patients. In these patients we observed an elevation of IL-6 and CRP before the patients'' deaths. Following the changes in acute-phase response and interleukin-6 serum levels in lung cancer patients seems to be helpful in prognosis of the outcome of the disease. Based on our data, we conclude that an elevation in IL-6 and/or CRP level in patients with lung cancer may serve as an adverse prognostic factor.     

Serum concentrations of sIL-2R, IL-6, TGF-beta1, neopterin, and zinc in chronic hepatitis C patients treated with interferon-alpha

T lymphocytes and immunoregulatory cytokines play an important role in the host response to hepatitis C virus (HCV) infection. Zinc is required for a wide spectrum of immune functions, including T-cell activity. To determine the clinical significance of the cytokines sIL-2R, IL-6, TGF-beta1, neopterin, and of zinc in chronic heptatitis C virus (HCV) infection, we investigated their concentrations in the serum of 16 patients with chronic HCV infection before, during and at the end of therapy with interferon (IFN) alpha (Roferon A), and after 6 months follow-up. Elevated concentrations of sIL-2R, IL-6, TGF-beta1, and neopterin were found in the serum of all patients prior to therapy, as compared to healthy controls. sIL-2R patterns differed in responders and non-responders. While the mean concentration of sIL-2R (335.75 pg/ml) before therapy was about 40% higher in complete responders (n=4) than in controls (272.20 pg/ml), the mean concentration in non-responders (n=6) was 4-fold higher than in controls (1153.33 pg/ml). During therapy, sIL-2R levels in responders decreased by about 40%. Mean IL-6 concentrations in both complete and partial responders (n=6) decreased continuously during treatment, while mean concentrations in non-responders decreased for only a short time, and increased again after cessation of therapy. Mean levels of TGF-beta1 behaved similarly to those of IL-6. Only negligible differences in mean neopterin levels were found between responders and non-responders over the entire observation time. The mean serum zinc concentrations slightly decreased in all 3 patient groups, the greatest reduction occurring in 3 of the 4 responders. The present findings underscore the importance of the immune system in the pathogenesis of chronic HCV infection. Serum sIL-2R levels may be used as a serological marker of outcome following IFN-alpha treatment.     

Volumetric Response beyond Six Months of Cardiac Resynchronization Therapy and Clinical Outcome

AimsResponse to cardiac resynchronization therapy (CRT) is often assessed six months after implantation. Our objective was to assess the number of patients changing from responder to non-responder between six and 14 months, so-called late non-responders, and compare them to patients who were responder both at six and 14 months, so-called stable responders. Furthermore, we assessed predictive values of six and 14-month response concerning clinical outcome.Methods105 patients eligible for CRT were enrolled. Clinical, laboratory, ECG, and echocardiographic parameters and patient-reported health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were assessed before, and six and 14 months after implantation. Response was defined as ≥15% LVESV decrease as compared to baseline. Major adverse cardiac events (MACE) were registered until 24 months after implantation. Predictive values of six and 14-month response for MACE were examined.ResultsIn total, 75 (71%) patients were six-month responders of which 12 (16%) patients became late non-responder. At baseline, late non-responders more often had ischemic cardiomyopathy and atrial fibrillation, higher BNP and less dyssynchrony compared to stable responders. At six months, late non-responders showed significantly less LVESV decrease, and higher creatinine levels. Mean KCCQ scores of late non-responders were lower than those of stable responders at every time point, with the difference being significant at 14 months. The 14 months response was a better predictor of MACE than six months response.ConclusionsThe assessment of treatment outcomes after six months of CRT could be premature and response rates beyond might better correlate to long-term clinical outcome.     

Interferon therapy in chronic hepatitis C virus infection

Abstract: Antiviral treatment of chronic hepatitis C with interferon is reviewed. Alpha-interferon, both recombinant alpha-2a, -2b and human lymphoblastoid interferon given at a dose of ≥3MU t.i.w. for 6–12 months will result in normalisation of ALT levels complete response) in some 50–60% of treated patients with chronic hepatitis C virus (HCV) infection. Approximately half of the complete responders to interferon will relapse within 6 months once treatment is withdrawn (non-sustained response). Longer treatment schedules (6 vs. 12 months) seem to diminish the relapse rate and increase the percentage of sustained response. In patients with sustained response to interferon treatment with continuously normal ALT levels ≥6 months after treatment stop a concomitant eradication of the viraemia is usually seen, whereas a non-sustained or non-response to interferon usually will indicate a continuous viraemia. Factors predictive of a favourable response are low pretreatment HCV RNA levels in serum, genotypes other than type II according to Okamoto, short disease duration, female gender and less pronounced liver damage, whereas high serum HCV RNA levels, having genotype II and cirrhosis, are predictive of a less favourable response. Patients with a sustained response and eradication of the viraemia will also improve their liver inflammation with diminishing scores for portal inflammation, piecemeal necrosis, lobular inflammation and also fibrosis after treatment. For non-responders and non-sustained responders to interferon, ribavirin especially in combination with interferon will offer some hope for the future.     

Variation in resistance to haemonchosis: selection of female sheep resistant to Haemonchus contortus.

Seventy female lambs (6-7 months old) which were exposed to natural infections of Haemonchus contortus were designated as responders or non-responders on the basis of 10 weekly cumulative faecal egg counts. Selected responder and non-responder lambs were treated with ivermectin, housed separately and 6 weeks post-housing, seven lambs from each group were given a trickle infection of Haemonchus contortus at 1000 L3 daily for 5 days per week up to 2 weeks and examined weekly for 10 weeks after first infection. Analysis of data revealed significantly lower mean faecal egg counts and non-significantly less weight loss in responder than non-responder lambs. Mean values of haemoglobin, packed cell volume, total serum protein and peripheral eosinophil counts were significantly higher in responders than non-responders. In contrast, serum pepsinogen concentration was significantly less in responders than in non-responders. At 10 weeks post-infection, there were fewer pathological lesions and significantly lower worm burdens in responders than in non-responders. These results demonstrate a distinct resistance in responders to Haemonchus contortus infection.     

Preliminary characterizations of a serum biomarker for sarcoidosis by comparative proteomic approach with tandem-mass spectrometry in ethnic Han Chinese patients

Background

The diagnosis of sarcoidosis is still a significant challenge in China because of the need to exclude other diseases including granulomatous infections and malignancies that may be clinically and radiographically similar. The specific aim of the study is to search for serum protein biomarkers of sarcoidosis and to validate their clinical usefulness in differential diagnosis.

Methods

Serum samples were collected from patients with sarcoidosis (n = 37), and compared to those from patients with tuberculosis (n = 20), other pulmonary diseases (n = 20), and healthy volunteers (n = 20) for determination of sarcoidosis-specific or -associated protein expression profiles. The first part of this study focused on proteomic analysis of serum from patients with sarcoidosis to identify a pattern of peptides capable of differentiating the studied populations using the ClinProt profiling technology based on mass spectrometry. Enzyme Linked Immunosorbent Assay (ELISA) was then used to verify corresponding elevation of the serum protein concentration of the potential biomarkers in the same patients sets. Receiver operating characteristic curve (ROC) analyses was performed to determine the optimal cutoff value for diagnosis. Immunohistochemistry was carried out to further confirm the protein expression patterns of the biomarkers in lung tissue.

Results

An unique protein peak of M/Z 3,210 Daltons (Da) was found to be differentially expressed between the sarcoidosis and control groups and was identified as the N-terminal peptide of 29 amino acids (94-122) of serum amyloid A (SAA). ELISA confirmed that the serum SAA level was significantly higher in the sarcoidosis group than that of the other 3 control groups (p < 0.05). The cutoff for serum SAA concentration determined by ROC analysis was 101.98 ng/ml, with the sensitivity and specificity of 96.3% and 52.5%, respectively. Immunohistochemical staining showed that the SAA depositions in lung tissue of the sarcoidosis patients were also significantly more intense than in non-sarcoid lung tissue (p < 0.05).

Conclusion

This is the first study to investigate serum protein markers in Chinese subjects with sarcoidosis. This study shows that the serum SAA expression profiles were different between the sarcoidosis and non-sarcoidosis groups. SAA may be a potential serum biomarker for ruling-out the diagnosis of sarcoidosis in Chinese subjects.     

Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala,Arg184Serand Ser7Ala) and therapeutic response to deferiprone in β-thalassemia major patients

Deferiprone is used as a chelation agent in chronic iron overload in β-thalassemia patients. Patients on deferiprone therapy show variable response to this drug in terms of reduction in iron overload as well as adverse drug reactions (ADRs). The pharmacogenetic studies on deferiprone have not carried out in patients with blood disorders in India. Therefore, the present study was carried out to evaluate the three most common nonsynonymous UGT1A6 polymorphisms Thr181Ala (541 A/G), Arg184Ser (552 A/C) and Ser7Ala (19 T/G) and therapeutic response to deferiprone in β-thalassemia major patients. Two hundred and eighty six (286) β-thalassemia major patients were involved in the study. Serum ferritin levels were estimated periodically to assess the status of the iron overload and the patients were grouped into responders and non-responders depending on the ferritin levels. The UGT1A6*2 polymorphisms were detected by PCR-RFLP methods. The association between the genotypes and outcome as well as ADRs was evaluated by Open EPI software. A significant difference was observed in the genotypic distribution of UGT1A6*2 Thr181Ala polymorphism in responders and non-responders. However, there was no difference in the genotypic distribution between patients with and without ADRs. As far as the UGT1A6*2 Arg184Ser polymorphism is concerned, no significant difference was observed between responders and non-responders. Further, evaluating the association of UGT1A6*2 Ser7Ala polymorphism with drug response, there was no significant difference in the genotypic distribution between responders and non-responders. However, there was a significant difference between responders with and without ADRs and non-responders with and without ADRs. In addition to this haplotype analysis was also carried out. However, we did not find any specific haplotype to be significantly associated with the deferiprone response in β-thalassemia major patients.     

Serum proinflammatory mediators at different periods of therapy in patients with multiple myeloma

Multiple myeloma (MM) is a malignant disease characterized by the clonal proliferation of plasma cells within the bone marrow. Several cytokines have been demonstrated to be involved in the control of growth, progression, and dissemination of MM. We determined serum levels of interleukin-1beta (IL-1beta), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) in 14 newly diagnosed MM patients. The median age of the patients was 63.4 +/- 10.8 years and all of the patients were stage III (classified according to the Durie-Salmon classification). The same parameters were measured in 15 healthy controls. In addition, we also examined the effects of vincristine-adriamycin-dexamethasone (VAD) therapy on the same parameters and mediators as well as the relationship among the parameters in the same patient groups. The serum concentrations of TNF-alpha, IL-1beta, sIL-2R, IL-6, IL-8, and CRP (18.6 +/- 3.7 pg/mL, 10.1 +/- 2.8 pg/mL, 730 +/- 220 U/mL, 11.4 +/- 3.3 pg/mL, 23.9 +/- 8.3 pg/mL, and 49.9 +/- 19.5 mg/dL, resp) were significantly higher in newly diagnosed MM patients than in healthy controls (P < .0001). All of the parameters were found to be significantly reduced after chemotherapy. In conclusion, we found that after the VAD therapy, the level of these cytokines which are thought to play an important role in the pathogenesis of MM was significantly suppressed. This is the first study demonstrating strong impact of VAD treatment on circulating mediators of sIL-2R and IL-8 levels parameters.     

Elevation in Inflammatory Serum Biomarkers Predicts Response to Trastuzumab-Containing Therapy

Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.     

SERUM CONCENTRATIONS OF sIL-2R, IL-6, TGF-β1, NEOPTERIN, AND ZINC IN CHRONIC HEPATITIS C PATIENTS TREATED WITH INTERFERON-ALPHA

T lymphocytes and immunoregulatory cytokines play an important role in the host response to hepatitis C virus (HCV) infection. Zinc is required for a wide spectrum of immune functions, including T-cell activity. To determine the clinical significance of the cytokines sIL-2R, IL-6, TGF-β1, neopterin, and of zinc in chronic heptatitis C virus (HCV) infection, we investigated their concentrations in the serum of 16 patients with chronic HCV infection before, during and at the end of therapy with interferon (IFN) α (Roferon A), and after 6 months follow-up. Elevated concentrations of sIL-2R, IL-6, TGF-β1, and neopterin were found in the serum of all patients prior to therapy, as compared to healthy controls. sIL-2R patterns differed in responders and non-responders. While the mean concentration of sIL-2R (335.75 pg/ml) before therapy was about 40% higher in complete responders (n=4) than in controls (272.20 pg/ml), the mean concentration in non-responders (n=6) was 4-fold higher than in controls (1153.33 pg/ml). During therapy, sIL-2R levels in responders decreased by about 40%. Mean IL-6 concentrations in both complete and partial responders (n=6) decreased continuously during treatment, while mean concentrations in non-responders decreased for only a short time, and increased again after cessation of therapy. Mean levels of TGF-β1 behaved similarly to those of IL-6. Only negligible differences in mean neopterin levels were found between responders and non-responders over the entire observation time. The mean serum zinc concentrations slightly decreased in all 3 patient groups, the greatest reduction occurring in 3 of the 4 responders. The present findings underscore the importance of the immune system in the pathogenesis of chronic HCV infection. Serum sIL-2R levels may be used as a serological marker of outcome following IFN-α treatment.