Conventional Combination Therapy Research Articles

A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer.

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

Impact of virtual reality-based rehabilitation on functional outcomes in patients with acute stroke: a retrospective case-matched study.

To date, the efficacy of the virtual reality (VR) application for acute stroke compared with conventional therapy (CT) remains unclear. This retrospective study aims to assess the impact of adjuvant VR technology on multidimensional therapy for patients with acute-stage stroke. 100 acute ischemic stroke patients with onset within 7 days who underwent combined adjuvant VR-based rehabilitation program and CT (intervention group-VR + CT) were compared to an equal number of cross-matched patients who received CT alone. While the intervention group received 40-min CT plus 20-min VR program (seven times for 1 week), the comparison group received time-matched CT alone. The National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), medical cost-effectiveness, and shortening of hospital stay were used as outcome measures. Posttreatment, the VR + CT group revealed significantly improved NIHSS and mRS (P < 0.001), whereas only the mRS improvement was remarkable in the CT group. In between-group comparisons, the intervention group had better improvements of symptom severity (NIHSS percentage improvement from the baseline; 20.18% vs. 4.59%, P < 0.005), functional outcomes (mRS improvement from the baseline; - 0.58 vs. - 0.23, P < 0.001), and reduced medical cost (Taiwan dollar; 49474 vs. 66306, P < 0.005). Furthermore, the VR + CT group reached markedly higher proportion of functional independence in activities of daily living (mRS, 0-2) at discharge compared with the CT group (68% vs. 60%, P < 0.001). This study suggests that the combination of VR-based rehabilitation and traditional therapy could be more effective for neurorehabilitation than CT alone in the early improvement of symptom severity, functional outcomes, and lower medical expenditure in acute stroke patients.

Artificial intelligence in nanomedicine.

The field of nanomedicine has made substantial strides in the areas of therapeutic and diagnostic development. For example, nanoparticle-modified drug compounds and imaging agents have resulted in markedly enhanced treatment outcomes and contrast efficiency. In recent years, investigational nanomedicine platforms have also been taken into the clinic, with regulatory approval for Abraxane® and other products being awarded. As the nanomedicine field has continued to evolve, multifunctional approaches have been explored to simultaneously integrate therapeutic and diagnostic agents onto a single particle, or deliver multiple nanomedicine-functionalized therapies in unison. Similar to the objectives of conventional combination therapy, these strategies may further improve treatment outcomes through targeted, multi-agent delivery that preserves drug synergy. Also, similar to conventional/unmodified combination therapy, nanomedicine-based drug delivery is often explored at fixed doses. A persistent challenge in all forms of drug administration is that drug synergy is time-dependent, dose-dependent and patient-specific at any given point of treatment. To overcome this challenge, the evolution towards nanomedicine-mediated co-delivery of multiple therapies has made the potential of interfacing artificial intelligence (AI) with nanomedicine to sustain optimization in combinatorial nanotherapy a reality. Specifically, optimizing drug and dose parameters in combinatorial nanomedicine administration is a specific area where AI can actionably realize the full potential of nanomedicine. To this end, this review will examine the role that AI can have in substantially improving nanomedicine-based treatment outcomes, particularly in the context of combination nanotherapy for both N-of-1 and population-optimized treatment.

Antimicrobial and Antibiofilm Activity of Synergistic Combinations of a Commercially Available Small Compound Library With Colistin Against Pseudomonas aeruginosa.

Biofilm-associated Pseudomonas aeruginosa infections remain a significant clinical challenge since the conventional antibiotic treatment or combination therapies are largely ineffective; and new approaches are needed. To circumvent the major challenges associated with discovery of new antimicrobials, we have screened a library of compounds that are commercially available and approved by the FDA (Prestwick Chemical Library) against P. aeruginosa for effective antimicrobial and anti-biofilm activity. A preliminary screen of the Prestwick Chemical Library alone did not yield any repositionable candidates, but in a screen of combinations with a fixed sub-inhibitory concentration of the antibiotic colistin we observed 10 drugs whose bacterial inhibiting activity was reproducibly enhanced, seven of which were enhanced by more than 50%. We performed checkerboard assays of these seven drugs in combination with colistin against planktonic cells, and analysis of their interactions over the complete combination matrix using the Zero Interaction Potency (ZIP) model revealed interactions that varied from highly synergistic to completely antagonistic. Of these, five combinations that showed synergism were down-selected and tested against preformed biofilms of P. aeruginosa. Two of the five combinations were active against preformed biofilms of both laboratory and clinical strain of P. aeruginosa, resulting in a 2-log reduction in culturable cells. In summary, we have identified synergistic combinations of five commercially available, FDA-approved drugs and colistin that show antimicrobial activity against planktonic P. aeruginosa (Clomiphene Citrate, Mitoxantrone Dihydrochloride, Methyl Benzethonium Chloride, Benzethonium Chloride, and Auranofin) as well as two combinations (Auranofin and Clomiphene Citrate) with colistin that show antibiofilm activity.

Effect of low-level LASER therapy combined with conventional physiotherapy on pain and quality of life in patients with Myofascial pain dysfunction syndrome

Background: Temporomandibular Joint Disorders (TMDs) are considered the most commonchronic orofacial pain conditions. It is characterized by pain in the Temporomandibular Joint (TMJ)area, masticatory muscles and associated musculoskeletal structures with the affection of mouthopening. Conventional physiotherapy and Low-Level LASER Therapy (LLLT ) are safe and noninvasivemodalities that each therapist focuses on to relieve pain and increase the quality of life.Aim: The aim of this study was to investigate the effect of low-level LASER therapy combinedwith conventional physiotherapy on pain and quality of life in patients with Myofascial paindysfunction syndrome (MPDS).Methods: 60 patients (45 females and 15 males) with MFDS of TMJ were divided randomlyinto study and control groups. The study group received conventional physiotherapy consisting ofactive and stretching exercises for mandibular muscles with ultrasound and LLLT application onTMJ area. Control group received conventional physiotherapy only. Pressure pain threshold wasevaluated using hand-held pressure algometer and quality of life was evaluated using the WorldHealth Organization Quality of Life (WHOQOL-BREF) assessment instrument at baseline and 4weeks after the treatment.Results: There was a significant increase (p<0.05) in the quality of life, with a significantincrease (p<0.05) in pressure pain threshold for TMJ, masseter and anterior temporalis muscles atboth sides in the study group compared with control group.Conclusion: The combination of conventional therapy with LLLT was more effective in painrelief and improvement of the quality of life than the conventional therapy alone for patients withMPDS.

Comparison of Conventional Physiotherapy with Pulsed Electromagnetic Field Therapy in Breast Cancer Patients with Lymph-Edema

Background: Lymphedema in addition to arm pain and movement restriction following breast cancer surgery is common challenge to physiotherapy. PEMF therapy is proving good adjunct for enhancing fracture healing, reducing inflammation and symptom relief. The same is exempt for benefit in stated problems of post-breast cancer surgery patients. Methods: 60 patients each were sequentially enrolled following informed consent, administering either conventional physiotherapy or combined PEMF therapy with conventional physiotherapy for 3 weeks. The parameters examined were pain score, range of movement and arm circumference for edema. Results: Physiotherapy benefited pain and range of movement but not lymphedema. PEMF combined therapy significantly reduced lymphedema in addition to other benefits. Conclusions: PEMF therapy with reported bioenergetic effects appears to effect reduction of lymphedema as well as pain relief and betterment of joint movements. The study emphasizes need for establishing PEMF as adjunct root in therapy for the kind of patients. This would need larger and wider evaluation.

Sex-associated Treatment Differences and Their Outcomes in Rheumatoid Arthritis: Results from the METEOR Register.

To assess differences in initial treatment and treatment response in male and female patients with rheumatoid arthritis (RA) in daily clinical practice. The proportion of patients with RA starting different antirheumatic treatments (disease-modifying antirheumatic drugs; DMARD) and the response to treatment were compared in the international, observational METEOR register. All visits from start of the first DMARD until the first DMARD switch or the end of followup were selected. The effect of sex on time to switch from first to second treatment was calculated using Cox regression. Linear mixed model analyses were performed to assess whether men and women responded differently to treatments, as measured by Disease Activity Score (DAS) or Health Assessment Questionnaire. Women (n = 4393) more often started treatment with hydroxychloroquine, as monotherapy or in combination with methotrexate (MTX) or a glucocorticoid, and men (n = 1142) more often started treatment with MTX and/or sulfasalazine. Time to switch DMARD was shorter for women than for men. Women had a statistically significantly higher DAS over time than men (DAS improvement per year β -0.69, 95% CI -0.75 to -0.62 for men and -0.58, 95% CI -0.62 to -0.55 for women). Subanalyses per DMARD group showed for the conventional synthetic DMARD combination therapy a slightly greater decrease in DAS over time in men (-0.89, 95% CI -1.07 to -0.71) compared to women (-0.59, 95% CI -0.67 to -0.51), but these difference between the sexes were clinically negligible. This worldwide observational study suggests that in daily practice, men and women with RA are prescribed different initial treatments, but there were no differences in response to treatment between the sexes.

Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via suppression of the JAK2/STAT3 and p38MAPK signaling pathway

Although conventional combination therapy is effective for most patients with rheumatoid arthritis (RA), many still do not respond to current therapies. Therefore, novel combination regimens that better target cellular processes involved in RA pathogenesis are required. Preliminary studies have demonstrated the beneficial effects of a combination of cyclophosphamide (CTX) and methotrexate (MTX) in models of RA. Using western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and immunofluorescent staining, we demonstrated that the combination of 4-hydroperoxy CTX (4-H-CTX) and MTX inhibited the expression of receptor activator of nuclear factor-κB ligand (RANKL) in fibroblast-like synoviocytes (FLS) treated with the interleukin (IL)-6/soluble IL-6 receptor (sIL-6R) complex. To elucidate the mechanisms underlying this effect, we treated RA-FLS with the JAK2/STAT3 inhibitor AG490 or p38MAPK inhibitor SB203580. The results showed that IL-6/sIL-6R-induced RANKL upregulation required phosphorylation-mediated activation of STAT3 and p38 signaling, and that 4-H-CTX and/or MTX inhibited RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3 and p38MAPK signaling. This study demonstrated for the first time the inhibitory effects of 4-H-CTX and MTX on RANKL expression in IL-6/sIL-6R-stimulated FLS via suppression of STAT3 and p38MAPK phosphorylation. These results identify promising therapeutic agents that might have clinical applications in patients with RA who are at high risk of bone erosion or do not respond well to conventional therapy.

Abstract B200: Using “omics” to select immunotherapy and conventional therapy combinations

Abstract Background: As only a subset of patients respond to immunotherapies, therapeutic biomarkers are needed to predict which patients will benefit and which should be spared from potentially toxic treatment. Proteins expressed by tumor cells and by the immune microenvironment may predict response to immune checkpoint inhibitors. In noninflamed tumors, chemotherapy and targeted therapy may stimulate an immune response, thereby affecting the relationship between tumor and immune system. Combinations of immunotherapies and conventional therapies are the subject of ongoing clinical trials. We hypothesized that genomic and proteomic evaluation of multiple immune biomarkers in tumor tissue and in lymphocytes would identify a signature that could (a) differentiate between responders and nonresponders to checkpoint inhibitors and (b) identify candidates for combination therapy. Methods: A pathologist marked areas of tumor and tumor-associated lymphocytes on archived tissue sections (N=2) of non-small cell lung cancer (NSCLC) and melanoma. The marked areas were microdissected and solubilized to tryptic peptides. In each liquefied tumor sample, 110 protein biomarkers, including 60 immunomarkers, were quantified with a mass spectrometry-based proteomic assay. The genomic material was analyzed by whole genome sequencing and RNA-seq. Results: Tumor and lymphocytes expressed several immunomarker proteins (eg, PDL1, IDO1, B7H3, B7-2, STAT1, GBP1). The melanoma patient’s tumor and lymphocytes expressed markers for response to immunotherapy (PDL1 and IDO1). Genomic and proteomic analysis suggested sensitivity to BRAF inhibitors and resistance to platinum and taxane. The NSCLC patient’s tumor and lymphocytes expressed IDO1 protein, but genomic analysis suggested a noninflamed tumor. Based on expression levels of ERCC1 and hENT1, one possible regimen for this patient is platinum plus gemcitabine followed by immunotherapy. In the NSCLC patient, comparison of protein expression in tumor-associated lymphocytes versus distal lymphocytes (&amp;gt;1 mm from marked tumor areas) showed variation &amp;lt;10% for 11 proteins and &amp;lt;30% for 14 proteins. Conclusions: Both lymphocytes and tumor expressed immunoproteins that may be used to select patients for approved immunotherapies or clinical trials. Proteomic and genomic profiling also characterized biomarkers that inform selection of targeted therapies and chemotherapies. Ongoing clinical trials of immunotherapy and combination therapies could benefit from precise, quantitative molecular stratification of patients. Protein level cutoffs that correlate with response to immunotherapy are in development. Citation Format: Sarit Schwartz, Robert Heaton, Yuan Tian, Zack Sanborn, Shankar Sellappan, Fabiola Cecchi, Steve Benz, Todd Hembrough. Using “omics” to select immunotherapy and conventional therapy combinations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B200.

Comparison of Combined Therapy Using Conventional Chemoembolization and Radiofrequency Ablation Versus Conventional Chemoembolization for Ultrasound-Invisible Early-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Cancer Stage 0 or A).

ObjectiveTo compare the therapeutic efficacy between conventional transarterial chemoembolization (cTACE) and combined therapy using cTACE and radiofrequency ablation (RFA) in ultrasound (US)-invisible early stage hepatocellular carcinoma (HCC).Materials and MethodsFrom January 2008 to June 2016, 167 patients with US-invisible early stage HCCs were treated with cTACE alone (cTACE group; n = 85) or cTACE followed by immediate fluoroscopy-guided RFA targeting intratumoral iodized oil retention (combined group; n = 82). Procedure-related complications, local tumor progression (LTP), time to progression (TTP), and overall survival (OS) were compared between the two groups. Multivariate analyses were performed to identify prognostic factors.ResultsThere was no major complication in either group. The cTACE group showed higher 1-, 3-, and 5-year LTP rates than the combined group; i.e., 12.5%, 31.7%, and 37.0%, respectively, in the cTACE group; compared to 7.3%, 16.5%, and 16.5%, respectively, in the combined group; p = 0.013. The median TTP was 18 months in the cTACE group and 24 months in the combined group (p = 0.037). Cumulative 1-, 3-, and 5-year OS rates were 100%, 93.2%, and 87.7%, respectively, in the cTACE group and 100%, 96.6%, and 87.4%, respectively, in the combined group (p = 0.686). Tumor diameter > 20 mm and cTACE monotherapy were independent risk factors for LTP and TTP.ConclusionCombined therapy using cTACE followed by fluoroscopy-guided RFA is a safe and effective treatment in US-invisible early stage HCCs. It provides less LTP and longer TTP than cTACE alone.

Abstract 2666: Using “omics” to select immunotherapy and conventional therapy combinations

Abstract Background: As only a subset of patients respond to immunotherapies, therapeutic biomarkers are needed to predict which patients will benefit and which should be spared from potentially toxic treatment. Proteins expressed by tumor cells and by the immune microenvironment may predict response to immune checkpoint inhibitors. In non-inflamed tumors, chemotherapy and targeted therapy may stimulate an immune response thereby affecting the relationship between tumor and immune system. Combinations of immunotherapies and conventional therapies are the subject of ongoing clinical trials. We hypothesized that genomic and proteomic evaluation of multiple immune biomarkers in tumor tissue and in lymphocytes would identify a signature that could (a) differentiate between responders and non-responders to checkpoint inhibitors and (b) identify candidates for combination therapy. Methods: A pathologist marked areas of tumor and tumor-associated lymphocytes on archived tissue sections (N=2) of non-small cell lung cancer (NSCLC) and melanoma. The marked areas were microdissected and solubilized to tryptic peptides. In each liquefied tumor sample, 110 protein biomarkers, including 60 immunomarkers were quantified with a mass spectrometry-based proteomic assay. The genomic material was analyzed by whole genome sequencing (WGS) and RNA-seq. Results: Tumor and lymphocytes expressed several immunomarker proteins (eg, PDL1, IDO1, B7H3, B7-2, STAT1, GBP1). The melanoma patient’s tumor and lymphocytes expressed protein markers for response to immunotherapy (PDL1 and IDO1), and the tumor had high mutational burden as identified by WGS. Furthermore, biomarker analysis suggested sensitivity to BRAF inhibitors and resistance to platinum and taxane. The NSCLC patient’s tumor and lymphocytes expressed IDO1 protein, but genomic analysis suggested a non-inflamed tumor. Based on expression levels of ERCC1 and hENT1, one possible regimen for this patient is platinum plus gemcitabine followed by immunotherapy. In one patient, comparison of protein expression in tumor-associated lymphocytes versus distal lymphocytes (&amp;gt;1 mm from marked tumor areas) showed variation &amp;lt; 10% for 11 proteins and &amp;lt; 30% for 14 proteins. Conclusions: Both lymphocytes and tumor expressed immunoproteins that may be used to select patients for approved immunotherapies or clinical trials. Proteomic and genomic profiling also characterized biomarkers that inform selection of targeted therapies and chemotherapies. Ongoing clinical trials of immunotherapy and combination therapies could benefit from precise, quantitative molecular stratification of patients. Protein level cutoffs that correlate with response to immunotherapy are in development. Citation Format: Sarit Schwartz, Robert Heaton, Yuan Tian, Zack Sanborn, Shankar Sellappan, Kerry Scott, Fabiola Cecchi, Steve Benz, Todd Hembrough. Using “omics” to select immunotherapy and conventional therapy combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2017-2666

ADDING CHINESE HERBAL MEDICINE TO CONVENTIONAL THERAPY BRINGS COGNITIVE BENEFITS TO PATIENTS WITH ALZHEIMER’S DISEASE: A TWO-YEAR STUDY

Conventional therapy (CT), such as donepezil and memantine are well-known short-term treatments for the symptoms of Alzheimer's disease (AD). They, however, have little disease-modifying effects after 18 months. In a two-year study, combined CT with Chinese herbal medicines (CT+H) significantly ameliorated cognitive decline in patients with mild to moderate AD. A cohort of outpatients (n=344) meeting criteria for clinical diagnosis of AD were treated with either CT+H (n=243) or CT alone (n=101) for two years. All participants underwent standardized neuropsychological assessments. Coronary MRI scans were used to assess the age-adjusted medial temporal lobe atrophy. Cognitive function was assessed by the mini–mental state examination (MMSE) every 3 months. Most of the patients were initially diagnosed with mild (MMSE=21–26, n=177) and moderate (MMSE=10–20, n=137) dementia. At 18 months, CT+ H patients scored on average 1.76 (P=0.002) better than CT patients, and at 24 months, patients scored on average 2.52 (P<0.001) better (Figure 1). Patients with mild AD received the most robust benefit from CT+H therapy. The deterioration of the cognitive function was largely prevented at 24 months (ΔMMSE=-0.06), a significant improvement from CT alone (ΔMMSE=-2.66, P=0.005). Overall number of patients with improved (ΔMMSE≥0) or deteriorated (ΔMMSE≥-4) were showed over time (Table 1).

High-dose intravenous steroid pulse therapy in ocular involvement of Behcet's disease: a pilot double-blind controlled study.

To evaluate the efficacy of intravenous high-dose pulses of methylprednisolone (IVPM) for treatment of ocular involvement in Behcet's disease (BD). In a double-blind control study, we randomized BD patients with posterior uveitis (PU) and/or retinal vasculitis (RV) into two groups. They received either IVPM (1000 mg methylprednisolone) or placebo for 3 consecutive days. Both groups received combination therapy with IV cyclophosphamide, azathioprine and prednisolone for 6 months. Visual acuity (VA), Disease Activity Index (DAI) based on the inflammatory state of each section of each eye, total inflammatory (TIAI) and adjusted DAI (TADAI) for each patient were calculated. The comparisons were done by paired t- and Mann-Whitney U-test. Seventeen patients in each group completed the treatment. The mean VA improved from 0.5 to 0.8 (P < 0.000001) for the study and from 0.6 to 0.7 (P < 0.02) for the placebo group. The difference was significant (P = 0.01). The comparison showed no significant difference regarding DAI improvement in other items (P > 0.2): PU, 1.9 to 0.5 (P < 0.0006) versus 2.3 to 0.8 (P < 0.0002); RV: 4.0 to 1.1 (P < 0.0004) versus 3.1 to 1.1 (P < 0.0005); TIAI: 23 to 5.7 (P < 0.0002) versus 24.8 to 8.4 (P < 0.003); TADAI: 24.1 to 7.3 (P < 0.0002) versus 25.9 to 7.9 (P < 0.004). We had one flare in the study versus seven in the placebo group (P < 0.005). Adding high-dose intravenous steroid pulse therapy to conventional combination therapy for severe ocular lesions of BD may cause better improvement on VA and fewer flares during the first 6 months of treatment.

Cytokine-induced killer cells/dendritic cells and cytokine-induced killer cells immunotherapy for the treatment of esophageal cancer in China: a meta-analysis.

BackgroundImmunotherapy based on cytokine-induced killer cells or combination of dendritic cells and cytokine-induced killer cells (CIK/DC-CIK) showed promising clinical outcomes for treating esophageal cancer (EC). However, the clinical benefit varies among previous studies. Therefore, it is necessary to systematically evaluate the curative efficacy and safety of CIK/DC-CIK immunotherapy as an adjuvant therapy for conventional therapeutic strategies in the treatment of EC.Materials and methodsClinical trials published before October 2016 and reporting CIK/DC-CIK immunotherapy treatment responses or safety for EC were searched in Cochrane Library, EMBASE, PubMed, Wanfang and China National Knowledge Internet databases. Research quality and heterogeneity were evaluated before analysis, and pooled analyses were performed using random- or fixed-effect models.ResultsThis research covered 11 trials including 994 EC patients. Results of this meta-analysis indicated that compared with conventional therapy, the combination of conventional therapy with CIK/DC-CIK immunotherapy significantly prolonged the 1-year overall survival (OS) rate, overall response rate (ORR) and disease control rate (DCR) (1-year OS: P=0.0005; ORR and DCR: P<0.00001). Patients with combination therapy also showed significantly improved quality of life (QoL) (P=0.02). After CIK/DC-CIK immunotherapy, lymphocyte percentages of CD3+ and CD3−CD56+ subsets (P<0.01) and cytokines levels of IFN-γ, -2, TNF-α and IL-12 (P<0.00001) were significantly increased, and the percentage of cluster of differentiation (CD)4+CD25+CD127− subset was significantly decreased, whereas analysis of CD4+, CD8+, CD4+/CD8+ and CD3+CD56+ did not show significant difference (P>0.05).ConclusionThe combination of CIK/DC-CIK immunotherapy and conventional therapy is safe and markedly prolongs survival time, enhances immune function and improves the treatment efficacy for EC.

PSEUDOTUBERCULOSIS AND INTESTINAL YERSINIOSIS: THE ADVANCEMENT OF NONSPECIFIC PROPHYLAXIS AND THERAPY

Recent years have witnessed the development and clinical implementation of the new approaches to prophylaxis and treatment of different nosological forms of diseases – combination of conventional therapy and immunocorrection. The review analyzes present-day state of nonspecific prophylaxis and treatment of pseudotuberculosis and intestinal yersiniosis. Information is presented on the effectiveness of immunomodulators, products of vital activity of plant cells and sea creatures, prebiotics, immunoglobuline complex (CIP) in prophylaxis and therapy of these diseases.

Infliximab Versus Conventional Combination Treatment and Seven-Year Work Loss in Early Rheumatoid Arthritis: Results of a Randomized Swedish Trial.

ObjectiveTo compare long‐term work loss in methotrexate‐refractory early rheumatoid arthritis (RA) patients randomized to the addition of infliximab or conventional combination treatment.MethodsThis study was a multicenter, 2‐arm, parallel, randomized, active‐controlled, open‐label trial. RA patients with <1‐year symptom duration were recruited from 15 rheumatology clinics in Sweden between 2002–2005. Patients who did not achieve low disease activity after 3–4 months of methotrexate therapy were randomized to the addition of infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. Yearly sick leave and disability pension days >7 years after randomization were retrieved from nationwide registers kept by the Swedish Social Insurance Agency.ResultsOf 210 working‐age patients, 109 were randomized to infliximab (mean age 48.4 years, 73% women) and 101 to conventional treatment (mean age 48.7 years, 77% women). The year before randomization, the mean number of annual work days lost was 127 in the infliximab arm and 118 in the conventional treatment group (mean difference 9 [95% confidence interval (95% CI) −23, 39]). Compared to the year before randomization, the mean changes at 7 years were −25 days in the infliximab and −26 days in the conventional treatment group (adjusted mean difference 10 [95% CI −25, 46]). The cumulative mean for work‐loss days was 846 in the infliximab group and 701 in the conventional treatment group (adjusted mean difference 104 [95% CI −56, 284]).ConclusionLong‐term work loss improved significantly in early RA patients randomized to infliximab plus methotrexate or conventional combination therapy. No difference was detected between strategies, and the level of work‐loss days remained twice that observed in the general population.

Impact of Treatment-Related Beliefs on Medication Adherence in Immune-Mediated Inflammatory Diseases: Results of the Global ALIGN Study.

IntroductionMedication adherence is critical in chronic immune-mediated inflammatory diseases (IMIDs) and could be affected by patients’ treatment-related beliefs. The objective of this study was to determine beliefs about systemic medications in patients with IMIDs and to explore the association of those beliefs and other factors with adherence.MethodsThis was a multi-country, cross-sectional, self-administered survey study. Included were adults diagnosed with one of six IMIDs receiving conventional systemic medications and/or tumor necrosis factor inhibitors (TNFi). Patients’ necessity beliefs/concerns towards and adherence to treatments were assessed by the Beliefs about Medicines Questionnaire and four-item Morisky Medication Adherence Scale. Correlation of patients’ beliefs about treatment and other factors with adherence were evaluated by multivariable regression analyses.ResultsAmong studied patients (N = 7197), 32.0% received TNFi monotherapy, 27.7% received TNFi–conventional combination therapy, and 40.3% received conventional medications. Across IMIDs, high adherence to systemic treatment was more prevalent in TNFi groups (61.3–80.7%) versus corresponding conventional treatment groups (28.4–64.7%). In at least four IMIDs, greater perception of the illness continuing forever (P < 0.001), of the treatment helping (P < 0.001), and more concerns about the illness (P < 0.01), but not clinical parameters, were associated with higher treatment necessity beliefs. Higher treatment necessity beliefs, older age, Caucasian race, and TNFi therapy were associated with high medication adherence in at least four IMIDs.ConclusionsTreatment necessity beliefs were higher than concerns about current medication in patients with IMID. Illness perceptions had a greater impact on treatment necessity beliefs than clinical parameters. Older age, greater treatment necessity beliefs, and TNFi therapy were associated with high self-reported medication adherence in at least four IMIDs.Trial registrationACTRN12612000977875.FundingAbbVie.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0441-3) contains supplementary material, which is available to authorized users.

Interferon Alpha-2a Therapy in Patients with Refractory Behçet Uveitis

ABSTRACTPurpose: To report the results of IFNα2a therapy in patients with Behçet uveitis refractory to azathioprine-cyclosporine combination treatment.Methods: In a retrospective study, 39 patients treated with either azathioprine-cyclosporine combination treatment (group 1, n = 23) or IFNα2a (group 2, n = 16) with a diagnosis of ocular Behçet disease (BD), were included in the study. Group 2 consisted of patients who did not respond to conventional combination therapy, and were therefore treated with IFNα2a. Clinical response and relapse rates were recorded for each group.Results: The mean number of uveitis attacks/year per patient was 0.8 ± 1.6 in Group 1. In Group 2, a significant decrease in the mean number of uveitis attacks/year per patient was observed after initiation of IFNα2a (2.4 ± 1.8 vs 1.3 ± 2.0) (p<0.05). When the two groups were compared after administration of IFNα2a therapy, no statistical difference was found in terms of uveitis attack/year and attack-free intervals, with a partial response to both treatments.Conclusions: IFNα2a therapy is an effective alternative for Behçet uveitis patients where conventional combination therapy fails.

Challenges in the Diagnosis and Treatment of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic disorder characterized by an absence or impairment of low-density lipoprotein receptor (LDLR) function resulting in significantly elevated low-density lipoprotein cholesterol (LDL-C) levels. The cholesterol exposure burden beginning in utero greatly increases the risk for atherosclerotic cardiovascular disease (ASCVD) and premature death. The genetic heterogeneity of HoFH results in a wide range of LDL-C levels among both untreated and treated patients. Diagnosis of HoFH should, therefore, be based on a comprehensive evaluation of clinical criteria and not exclusively LDL-C levels. As treatment goals, the European Atherosclerosis Society and International FH Foundation suggest target LDL-C levels of <100 mg/dL (<2.5 mmol/L) in adults or <70 mg/dL (<1.8 mmol/L) in adults with clinical coronary artery disease or diabetes. The National Lipid Association (NLA) recommends that LDL-C levels be reduced to <100 mg/dL (<2.5 mmol/L) or by at least ≥50 % from pretreatment levels. Conventional therapy combinations that lower atherogenic lipoproteins levels in the blood, such as statins, ezetimibe, bile acid sequestrants and niacin, as well as lipoprotein apheresis, are usually unable to reduce LDL-C levels to recommended targets. Two recently approved agents that reduce lipoprotein synthesis and secretion by the liver are lomitapide, a microsomal triglyceride transfer protein inhibitor, and mipomersen, an apolipoprotein B antisense oligonucleotide. The newly approved inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), evolocumab, also shows promise for the management of FH. Because of the extremely high risk for ASCVD, HoFH patients should be identified early.

A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4)

AbstractPromising reports of combination immunosuppression with high-dose dexamethasone and rituximab for the treatment of primary immune thrombocytopenia (ITP) have recently emerged. They suggest a potential to further optimize the efficacy of therapy. We investigate the use of a novel combination of conventional therapies in ITP given over 4 weeks. From 2011 to 2014, 20 patients were prospectively enrolled onto a single-arm phase 2b study to describe the safety, efficacy, and tolerability of oral dexamethasone 40 mg for days 1 to 4, oral cyclosporine 2.5 to 3 mg/kg daily for day 1 to 28, and intravenous low-dose rituximab 100 mg for days 7, 14, 21, and 28. There were no therapy-related serious adverse side effects, 6-month response rate was 60%, and treatment was well tolerated. Responders enjoyed relapse-free survivals of 92% and 76%, respectively, at 12 and 24 months. This study highlights the possibility of achieving an enduring remission from 4 weeks of therapy. This study is registered at www.anzctr.org.au (#ANZCTRN12611000015943).