Pretreatment Serum Levels of IL-1 Receptor Antagonist and IL-4 are Predictors of Overall Survival in Multiple Myeloma Patients Treated with Bortezomib

Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The aim of the present study was to assess the impact of pretreatment serum levels of 27 selected cytokines on progression-free survival (PFS) and overall survival (OS) in MM patients before first-line therapy with bortezomib-based regimens. Serum cytokine levels were assayed with a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad) including IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. A total of 61 MM patients were examined. Most patients received a bortezomib, cyclophosphamide and dexamethasone (VCD) chemotherapy regimen. In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, p = 0.0302), and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, p=0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, p=0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, p=0.0059) and two cytokine levels- IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, p= 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, p = 0.0147) were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

Prognostic significance of pretreatment serum free fatty acid in patients with diffuse large B-cell lymphoma in the rituximab era: a retrospective analysis

Background Fatty acid metabolism is reportedly associated with various cancers. However, the role of pretreatment serum free fatty acid (FFA) levels in diffuse large B-cell lymphoma (DLBCL) prognosis is still unclear, and our study aimed to better elucidate its influence on clinical outcomes. Methods The medical records of 221 newly diagnosed DLBCL patients admitted to Fujian Medical University Union Hospital from January 2011 to December 2016 were analysed retrospectively. Receiver operating characteristic curve analysis was used to determine a cut-off value for pretreatment serum FFA levels for prognostic prediction in DLBCL patients. The relationship between pretreatment serum FFA levels and clinical and laboratory parameters was analysed. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). Results Newly diagnosed DLBCL patients with high pretreatment serum FFA levels (≥0.495 mmol/l) had more B symptoms, higher serum lactate dehydrogenase levels (> upper limit of normal), >1 extranodal site, and higher International Prognostic Index score (3–5) compared to those with low pretreatment serum FFA levels (<0.495 mmol/l). Higher serum FFA levels were independent prognostic factors for poor OS, but not PFS. Conclusions High pretreatment serum FFA levels are associated with lower survival in untreated DLBCL patients.

Relationship between Pretreatment Serum Albumin Levels with the Risk of Malignant Pleural Mesothelioma

Background: Malignant Pleural Mesothelioma (MPM) is a very rare and aggressive form of cancer. Recently it was found that pretreatment Serum Albumin (SA), the main circulating protein in blood is a significant prognostic factor for MPM patients. The objective of this present article is to show the relationship between pretreatment Serum albumin (SA) levels with the risk of MPM. Methods: Generalized additive model (GAM), an advanced regression analysis method has been introduced here to find this mathematical relationship between the response variable (SA) and the cofactors. Results: The main determinates of SA are identified - asbestos exposure, hemoglobin, disease diagnosis status (patients having MPM) are the factors having significant association with SA, whereas duration of asbestos exposure, duration of disease symptoms, total protein (TP), Pleural lactic dehydrogenise (PLD), pleural protein (PP), pleural glucose (PG) and C-reactive protein (CRP) are the significant continuous variables for SA. The non-parametric estimation part of this model shows Lactate dehydrogenase (LDH) and Glucose level are the significant smoothing terms. Additionally it is also found that, second and third order interactions between cofactors are highly significant for SA. Conclusions: The findings of this present work can conclude that - serum albumin may play the role of a very significant prognostic factor for MPM disease and it has been established here through mathematical modeling. Few of the findings are already been exist in MPM research literature whereas some of the findings are completely new in the literature.

Construction and Validation of a Serum Albumin-to-Alkaline Phosphatase Ratio-Based Nomogram for Predicting Pathological Complete Response in Breast Cancer

BackgroundBreast cancer patients who achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have favorable outcomes. Reliable predictors for pCR help to identify patients who will benefit most from NAC. The pretreatment serum albumin-to-alkaline phosphatase ratio (AAPR) has been shown to be a prognostic predictor in several malignancies, but its predictive value for pCR in breast cancer is still unknown. This study aims to investigate the predictive role of AAPR in breast cancer patients and develop an AAPR-based nomogram for pCR rate prediction.MethodsA total of 780 patients who received anthracycline and taxane-based NAC from January 2012 to March 2018 were retrospectively analyzed. Univariate and multivariate analyses were performed to assess the predictive value of AAPR and other clinicopathological factors. A nomogram was developed and calibrated based on multivariate logistic regression. A validation cohort of 234 patients was utilized to further validate the predictive performance of the model. The C-index, calibration plots and decision curve analysis (DCA) were used to evaluate the discrimination, calibration and clinical value of the model.ResultsPatients with a lower AAPR (&lt;0.583) had a significantly reduced pCR rate (OR 2.228, 95% CI 1.246-3.986, p=0.007). Tumor size, clinical nodal status, histological grade, PR, Ki67 and AAPR were identified as independent predictors and included in the final model. The nomogram was used as a graphical representation of the model. The nomogram had satisfactory calibration and discrimination in both the training cohort and validation cohort (the C-index was 0.792 in the training cohort and 0.790 in the validation cohort). Furthermore, DCA indicated a clinical net benefit from the nomogram.ConclusionsPretreatment serum AAPR is a potentially valuable predictor for pCR in breast cancer patients who receive NAC. The AAPR-based nomogram is a noninvasive tool with favorable predictive accuracy for pCR, which helps to make individualized treatment strategy decisions.

Trough levels of ipilimumab in serum as a potential biomarker of clinical outcomes for patients with advanced melanoma after treatment with ipilimumab

BackgroundImmune checkpoint blockade (ICB) using anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of advanced cancer. However, ICB is effective for only a small fraction of patients, and biomarkers such as expression of PD-L1 in tumor or serum levels of CXCL11 have suboptimal sensitivity and specificity. Exposure–response (E-R) relationships have been observed with other therapeutic monoclonal antibodies. There are many factors influencing E-R relationships, yet several studies have shown that trough levels of anti-PD-1/PD-L1 correlated with clinical outcomes. However, the potential utility of anti-CTLA-4 levels as a biomarker remains unknown.MethodsSerum was obtained at trough levels at weeks 7 and 12 (after doses 2 and 4) from patients with advanced melanoma who received ipilimumab alone (3 mg/kg every 3 weeks for four treatments) via an expanded access program (NCT00495066). We have successfully established a proteomics assay to measure the concentration of ipilimumab in serum using an liquid chromatography with tandem mass spectrometry-based nanosurface and molecular-orientation limited proteolysis (nSMOL) approach. Serum samples from 38 patients were assessed for trough levels of ipilimumab by the nSMOL assay.ResultsWe found that trough levels of ipilimumab were higher in patients who developed immune-related adverse events but did not differ based on the presence or absence of disease progression. We found that patients with higher trough levels of ipilimumab had better overall survival when grouped based on ipilimumab trough levels. Trough levels of ipilimumab were inversely associated with pretreatment serum levels of CXCL11, a predictive biomarker we previously identified, and soluble CD25 (sCD25), a prognostic biomarker for advanced melanoma, as well as C reactive protein (CRP) and interleukin (IL)-6 levels at week 7.ConclusionsOur results suggest that trough levels of ipilimumab may be a useful biomarker for the long-term survival of patients with advanced melanoma treated with ipilimumab. The association of ipilimumab trough levels with pretreatment serum levels of CXCL11 and sCD25 is suggestive of a baseline-driven E-R relationship, and the association of ipilimumab trough levels with on-treatment levels of CRP and IL-6 is suggestive of response-driven E-R relationship. Our findings highlight the potential utility of trough levels of ipilimumab as a biomarker.Trial registration numberNCT00495066.

Prospective Analysis of Serum HE4 as an Independent Prognostic Factor in Non Small Cell Lung Cancer

Background HE4 is expressed in most lung adenocarcinomas and in a significant number of squamous, small cell and large cell carcinomas of the lung, suggesting that it could be used as a diagnostic and/or prognostic factor to refine the standard pathologic analysis. Methodology Data was collected prospectively in the form of blood sample withdrawn from patients with NSCLC confirmed with pathology presented to bronchogenic clinic in Oncology department of Ain Shams University in pretreatment state & from healthy controls with matched age & sex. The Human HE4 (Epididymal Protein 4) was measured in serum samples using Enzyme linked immunosorbent assay [ELISA], the assay was performed using Human HE4 9Epididymal protein 4) ELISA kit, cat no: EH0365 (Fine Test, Wuhan Fine Biotech Co., China). Results 77 patients with NSCLC cases & 30 healthy controls were enrolled in the study. Serum HE4 showed to have to a diagnostic tendency were its value in NSCLC cases was from 42 to 130 pmol/l (median= 72pmol/l). but in controls its value was from 10 to 67 pmol/l (median = 35 pmol/l), which was highly statistically significant (P = 0.001). The cut off value of serum HE4 was 60 pmol/l with sensitivity 77% & specificity 96% (95% CI 0.9-1). Serum HE4 showed to be a poor prognostic marker to OS with statistically significant difference were those with pretreatment serum HE4&lt; 72 pmol/l mean survival time 17.6 months in comparison to the group with pretreatment serum HE4 &gt; 72pmol/l mean survival time 13.2 months (p = 0.02). Conclusion There is a negative correlation between Serum HE4 in NSCLC & overall survival, the highest the serum level the shortest the survival. This result can present serum HE4 as a novel prognostic & probably diagnostic marker for NSCLC.

Discrete Survival Model Analysis of Plasmodium falciparum Response to Artemisinin-Based Combination Therapies among Children in Regions of Varying Malaria Transmission in Cameroon

The need to monitor changes in parasite clearance following treatment with artemisinin-based combination therapies (ACTs) is important in the containment of drug resistance. This study aimed to model Plasmodium falciparum response to ACTs among children in two different transmission settings (Mutengene and Garoua) in Cameroon. Using the step function, a discrete-time survival model was fitted with all the covariates included that might play a role in parasite clearance. The probability of clearing parasites within 24 h following treatment was 21.6% and 70.3% for younger children aged 6 to 59 months and 29.3% and 59.8% for older children aged 60 to 120 months in Mutengene and Garoua, respectively. After two days of treatment, the conditional probability of clearing parasites given that they were not cleared on day 1 was 76.7% and 96.6% for children aged 6–59 months and 83.1% and 93.5% for children aged 60–120 months in Mutengene and Garoua, respectively. The model demonstrated that the ecological setting, age group and pretreatment serum levels of creatinine and alanine aminotransferase were the main factors that significantly influenced parasite clearance in vivo after administration of ACTs (p < 0.05). The findings highlight the need for further investigations on host differential response to ACTs in current practice.