Weeks Of Combination Therapy Research Articles

Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844).

Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8+ effector:FoxP3+ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase inhibitor entinostat with nivolumab ± ipilimumab in advanced solid tumors. Patients received an entinostat run-in (5 mg, weekly × 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design [dose level (DL)1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + ipilimumab]. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy. Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n = 7, 21%), anemia (n = 9, 27%), and neutropenia (n = 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone. The combination of entinostat with nivolumab ± ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.

Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment: Results from the randomized FOCUS4-N trial.

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]

Successful Combination of Systemic Agents for the Treatment of Atopic Dermatitis Resistant to Dupilumab Therapy

Background: Dupilumab, a monoclonal antibody inhibiting the signaling pathway of IL-4/IL-13, was shown to be safe and effective in the treatment of moderate/severe atopic dermatitis (AD) in several clinical trials and real-life experiences, with only a small percentage of patients showing to be resistant or to lose disease control. Objectives: In this study, we investigated the effectiveness and safety in combining dupilumab with systemic agents or phototherapy in patients experiencing an inadequate response to dupilumab. Methods: This retrospective, monocentric, observational study consecutively included patients aged >18 years, with moderate-severe AD, under treatment with dupilumab. In this cohort of patients, we analyzed data of subjects who experienced an inadequate response to dupilumab, even when combined with topical corticosteroids, and for whom an additional systemic treatment or phototherapy was combined to dupilumab. Results: In this study, we included a total population of 69 patients treated with dupilumab. In 12/69 patients (17.4%) showing an inadequate response to dupilumab, a combined treatment consisting of dupilumab plus methylprednisolone (n = 5), cyclosporine (n = 4), methotrexate (n = 2), or narrow band-UVB (n = 1) was administered. Overall, after 8 weeks of combined therapy, the majority of patients (11 of 12) obtained an improvement of signs and symptoms of AD. Patients treated with combined therapy did not experience any adverse events, neither did they withdraw treatment because of the occurrence of adverse events. Conclusions: This study suggests that the combination of dupilumab with a conventional drug or phototherapy may represent a valid therapeutic choice, maintaining a good safety profile in AD patients recalcitrant to dupilumab monotherapy.

Efficacy and Safety of Calcipotriene 0.005%/Betamethasone Dipropionate 0.064% Foam With Apremilast for Moderate Plaque Psoriasis

Objective: To demonstrate the efficacy and safety of adding fixed-dose combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam to oral apremilast in treating moderate plaque psoriasis. Methods: A 16-week, investigator-blinded study in patients with moderate psoriasis (Physician’s Global Assessment [PGA] score of 3). Patients were randomized 1:1 to Cal/BD foam plus apremilast or vehicle foam plus apremilast for 4 weeks, followed by 8 weeks of apremilast monotherapy, and then 4 weeks of combination therapy as in the original randomization schedule. Efficacy assessments – Psoriasis Area and Severity Index (PASI), PGA, body surface area (BSA), visual analog scale (VAS) for pruritus, and quality of life (QoL) – and safety were evaluated at weeks 1, 2, 3, 4, 12, and 16. Results: 28 subjects were enrolled (mean age, 64 years; 67.9% males). Cal/BD foam plus apremilast group achieved statistically significantly greater improvement than vehicle foam plus apremilast in PASI75 (50% vs 7%; P=.003), PGA score of “clear” or “almost clear” (43% vs 7%; P=.001), and VAS score (2 vs 5; P=.0079) at week 4. BSA and QoL improvements were also observed. Most efficacy assessments worsened after withdrawing Cal/BD foam for 8 weeks but recovered after reinitiating Cal/BD foam from week 12 to week 16. Cal/BD foam plus apremilast appeared to be safe and well tolerated. Conclusions: In the treatment of moderate plaque psoriasis, Cal/BD foam plus apremilast provided more benefits than with apremilast alone. These improvements appeared to be lost when Cal/BD foam was withdrawn but recovered when Cal/BD foam was reinitiated. J Drugs Dermatol. 2020;19(9):874-880. doi:10.36849/JDD.2020.5020

Pharmacological monitoring of the clinical course of an overactive bladder without urinary incontinence

The aim of the study was to evaluate the effectiveness of therapy with the tetracyclic antidepressant Mirtazapine in combination with the anticonvulsant Gabapentin in the complex treatment of OAB without urinary incontinence. The study involved 54 patients, treatment was prescribed for 8 weeks, and 5 visits to the clinic were planned. Comparing the variability of dysuric symptoms before, during and after treatment, most patients showed improvements in the main “markers” of functional disorders of the lower urinary tract. This is confirmed by the intensity of the reduction of the main objective and subjective symptoms of the disease, which was manifested in a decrease in the frequency of pollakiuria by 40.25%, nocturia by 62.04%, and episodes of urgency by 73.59%, and in general, according to the results of 8 weeks of combination therapy, a good treatment result was observed in 41% of patients, a satisfactory treatment result in 49%, which indicates the effectiveness of therapy with good tolerability of drugs.

Role of combined immunomodulator therapy in severe steroid intolerant vernal keratoconjunctivitis

To describe the role of combined topical cyclosporine (CsA) 0.1% and tacrolimus 0.03% in cases with severe steroid intolerant vernal keratoconjunctivitis (VKC). Medical records of patients with acute exacerbation of VKC and steroid intolerance referred from glaucoma to cornea clinic were reviewed from March 2017 to December 2018. Eleven patients (22 eyes), (nine with steroid-induced glaucoma, two with steroid-induced cataract and glaucoma) were found. All were started on topical CsA 0.1% QID. Due to suboptimal response at 2 weeks, topical tacrolimus 0.03% BD was also included. The mean total subjective score at presentation was 13 ± 1.4, which reduced to 11.2 ± 1.3 at 2 weeks of topical CsA therapy and further reduced to 5 ± 0 at 2 weeks of combination therapy (p < 0.001). The mean total objective score at presentation was 9.4 ± 1.4 that reduced to 8.0 ± 1.3 at 2 weeks of topical CsA therapy and further reduced to 4.3 ± 1.6 at 2 weeks of combination therapy (p < 0.001). Similar results were obtained in a sub-group analysis including the worse eye or right eye of the cases only. The absolute change in the total subjective and objective score was much more with combination therapy. Photophobia and conjunctival hyperemia resolved within 4 weeks of combined therapy. No recurrence was observed till 6 months follow-up. Combined use of cyclosporine and tacrolimus may lead to rapid resolution of symptoms and reduced recurrence rate in cases with severe VKC where steroid has to be avoided.

Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

Nucleic acid polymers (NAPs) inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles. We performed an open-label, phase 2 study of the safety and efficacy of the NAPs REP 2139 or REP 2165 combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (pegIFN) in patients with chronic HBV infection who were negative for hepatitis B e antigen. Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF+ pegIFN+ REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF+ pegIFN) followed by 48 weeks of experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. Primary outcomes were the safety and tolerability of REP 2139-Mg or REP 2165-Mg in combination with TDF+ pegIFN compared with TDF+ pegIFN alone through the first 48 weeks of therapy and subsequently throughout 48 weeks of NAP-based combination therapy (treatment weeks 24-72 in the experimental group and weeks 48-96 in the control group). Secondary outcomes were reductions in hepatitis B surface antigen (HBsAg) in control and experimental groups over the first 48 weeks of the study and throughout 48 weeks of combination therapy and virologic control (HBsAg positive, HBV DNA below 2000 IU/mL, normal level of alanine aminotransferase) or functional cure (HBsAg below 0.05 IU/mL, HBV DNA target not detected, normal level of alanine aminotransferase) after removal of all therapy. Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. PegIFN-induced thrombocytopenia (P= .299 vs controls) and neutropenia (P= .112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P < .001 vs controls) and greater (P= .002 vs controls) in the NAP groups (but did not produce symptoms), correlated with initial decrease in HBsAg, and normalized during therapy and follow-up. During the first 24 weeks of TDF and pegIFN administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P < .001 vs control) and HBsAg seroconversion (P= .046 vs control). At the time patients completed the TDF+ pegIFN+ NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants (all with seroconversion up to 233,055 mIU/mL). During 48 weeks of treatment-free follow-up, virologic control persisted in 13 of 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion. One participant had a viral rebound during follow-up with hepatic decompensation and was placed on TDF therapy. In a phase 2 randomized trial, we found that addition of NAPs to TDF+ pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy. Clinicaltrials.gov no: NCT02565719.

Effectiveness of Combined Behavioral and Drug Therapy for Overactive Bladder Symptoms in Men

First-line behavioral and drug therapies for overactive bladder (OAB) symptoms in men are effective but not usually curative. To determine whether combining behavioral and drug therapies improves outcomes compared with each therapy alone for OAB in men and to compare 3 sequences for implementing combined therapy. In this 3-site, 2-stage, 3-arm randomized clinical trial, participants were randomized to 6 weeks of behavioral therapy alone, drug therapy alone, or combined therapy followed by step-up to 6 weeks of combined therapy for all groups. Participants were recruited from 3 outpatient clinics and included community-dwelling men 40 years or older with urinary urgency and 9 or more voids per 24 hours. Data were collected from July 2010 to July 2015 and analyzed from April 2016 to September 2019. Behavioral therapy consisted of pelvic floor muscle training with urge suppression strategies and delayed voiding. Drug therapy included an antimuscarinic (sustained-release tolterodine, 4 mg) plus an α-blocker (tamsulosin, 0.4 mg). Seven-day bladder diaries completed before and after each 6-week treatment stage were used to calculate reduction in frequency of urination (primary outcome) and other symptoms (ie, urgency, urgency incontinence, and nocturia). Other secondary outcomes included validated patient global ratings of improvement and satisfaction, Overactive Bladder Questionnaire score, and International Prostate Symptom Score. Of the 204 included men, 133 (65.2%) were white, and the mean (SD) age was 64.1 (11.1) years. A total of 21 men discontinued treatment and 183 completed treatment. Mean (SD) voids per 24 hours decreased significantly in all 3 groups from baseline to 6-week follow-up (behavioral therapy: 11.7 [2.4] vs 8.8 [2.1]; change, 2.9 [2.4]; percentage change, 24.7%; P < .001; drug therapy: 11.8 [2.5] vs 10.3 [2.7]; change, 1.5 [2.3]; percentage change, 12.7%; P < .001; combined therapy: 11.8 [2.4] vs 8.2 [2.3]; change, 3.6 [2.1]; percentage change, 30.5%; P < .001). Intention-to-treat analyses indicated that posttreatment mean (SD) voiding frequencies were significantly lower in those receiving combined therapy compared with drug therapy alone (8.2 [2.3] vs 10.3 [2.7]; P < .001) but not significantly lower compared with those receiving behavioral therapy alone (8.2 [2.3] vs 8.8 [2.1]; P = .19) and were lower for behavioral therapy alone compared with drug therapy alone (8.8 [2.1] vs 10.3 [2.7]; P < .001). At 12-week follow-up, after all groups had received combined therapy, improvements in mean (SD) voids per 24 hours were also greatest for those receiving initial combined therapy compared with baseline (behavioral therapy: 11.7 [2.4] vs 8.0 [2.2]; change, 3.7 [2.3]; percentage change, 31.6%; P < .001; drug therapy: 11.8 [2.5] vs 8.6 [2.3]; change, 3.2 [2.5]; percentage change, 27.1%; P < .001; combined therapy: 11.8 [2.4] vs 8.0 [2.2]; change, 3.8 [2.1]; percentage change, 32.2%; P < .001), but there were no statistically significant group differences on primary or secondary measures. Combining behavioral and drug therapy yields greater improvements in OAB symptoms than drug therapy alone but not behavioral therapy alone. When using a stepped approach, it is reasonable to begin with behavioral therapy alone. ClinicalTrials.gov identifier: NCT01175382.

Nonsurgical management of gastroduodenal tuberculosis: Nine-year experience from a tertiary referral center.

Background and study aims Gastroduodenal tuberculosis (GDTB) is an uncommon disease. Surgery has been standard of care both for diagnosis and management of GDTB. The aim of this study was to evaluate the efficacy of non-surgical management of GDTB using a combination of anti-tuberculous therapy (ATT) along with endoscopic dilatation of the tuberculous stricture. Patients and methods Patients suspected to have gastroduodenal TB were evaluated: clinical, endoscopic, radiological, and histopathological data were recorded. Patients in whom a definite diagnosis of tuberculosis could not be confirmed on mucosal biopsies underwent endoscopic mucosal resection (EMR). Patients were treated with ATT and endoscopic dilatation was done if indicated. Patients were followed up to evaluate clinical, radiological and endoscopic response. Results Over a 9-year period from 2009 to 2017, 52 patients (mean age 28.5yrs) were diagnosed with GDTB. The most common presenting symptoms were vomiting (n = 51, 98 %) and weight loss (n = 52,100 %). The most common anatomical site of involvement was D1–D2 junction (n = 22, 42 %). Histopathological diagnosis could be made in 43 patients (82.6 %); 36 (69 %) on mucosal biopsies and in 7 of 10 patients (70 %) who underwent snare biopsy/EMR. Endoscopic dilatation was done in 37 patients (71 %) and median dilatation sessions were two. Failure of endotherapy occurred in four patients (7.6 %). All responders had complete amelioration of symptoms after 4 to 6 weeks of combination therapy. Median period of follow-up was 23.5 months and none of the patients reported any recurrence of symptoms. Conclusion ATT and endoscopic dilatation combined has a high success rate in management of GDTB and should be considered the standard of care.

Lactococcus garvieae, an unusual pathogen in infective endocarditis: case report and review of the literature

BackgroundLactococcus garvieae is an unusual cause of infective endocarditis (IE). No current diagnostic and therapeutic guidelines are available to treat IE caused by these organisms. Based on a case report, we provide a review of the literature of IE caused by L. garvieae and highlight diagnostic and treatment challenges of these infections and implications for management.Case presentationA 50-year-old Asian male with mitral prosthetic valve presented to the hospital with intracranial haemorrhage, which was successfully treated. Three weeks later, he complained of generalized malaise. Further work up revealed blood cultures positive for Gram-positive cocci identified as L. garvieae by MALDI-TOF. An echocardiogram confirmed the diagnosis of IE. Susceptibility testing showed resistance only to clindamycin. Vancomycin plus gentamicin were started as empirical therapy and, subsequently, the combination of ceftriaxone plus gentamicin was used after susceptibility studies were available. After two weeks of combination therapy, ceftriaxone was continued as monotherapy for six additional weeks with good outcome.ConclusionsTwenty-five cases of IE by Lactococcus garvieae have been reported in the literature. Compared to other Gram-positive cocci, L. garvieae affects more frequently patients with prosthetic valves. IE presents in a subacute manner and the case fatality rate can be as high as 16%, comparable to that of streptococcal IE (15.7%). Reliable methods for identification of L. garvieae include MALDI-TOF, 16S RNA PCR, API 32 strep kit and BD Automated Phoenix System. Recommended antimicrobials for L. garvieae IE are ampicillin, amoxicillin, ceftriaxone or vancomycin in monotherapy or in combination with gentamicin.

Abstract PD2-10: Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer

Abstract Background: Abemaciclib is a selective inhibitor of CDK4 &amp; 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- metastatic breast cancer (MBC) patients (pts) in combination with endocrine therapy or as monotherapy. Recent studies have demonstrated the potential for CDK4 &amp; 6 inhibitors, including abemaciclib, to promote anti-tumor immunity. Schaer et al., (Cell Reports 2018) showed that abemaciclib monotherapy results in upregulation of antigen presentation on tumor cells and increases T-cell activation. These activities synergized with anti-PD-L1 therapy to further enhance immune activation leading to complete tumor rejection in murine tumor models (Schaer et al., Cell Reports 2018). In this exploratory analysis, we evaluated the early and late immune-modulating effects of abemaciclib in the neoadjuvant study neoMONARCH (NCT02441946). Methods: NeoMONARCH is a Phase II trial in women with stage I-IIIB HR+, HER2- BC evaluating neoadjuvant treatment with 2 weeks of abemaciclib, alone or in combination with anastrozole (abemaciclib+ANZ), or ANZ alone. All patients received 14 weeks of abemaciclib +ANZ after the first 2 weeks of treatment. Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early - after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor biopsies at each time point and subjected to whole transcriptome RNA sequencing. The curated data were subjected to statistical analysis using ANOVA tests followed by pathway analysis using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Results: Consistent with the known activity of abemaciclib to inhibit the cell cycle, we observed at the early and late time points a significant treatment induced downregulation of genes related to mitotic spindle organization, replication stress response, G2M checkpoint, and E2F targets. Abemaciclib treatment for 2 weeks, alone or in combination with ANZ, followed by 14 weeks of combination therapy was associated with upregulation of gene expression signatures related to T-cell immune response and antigen presentation. Importantly, this phenomenon was notobserved with 2 weeks of ANZ treatment alone followed by 14 weeks of combination therapy. Conclusion: These data lend support that continuous inhibition of CDK4 &amp; 6 signaling by abemaciclib treatment leads to prolonged cell cycle arrest resulting in tumor cell apoptosis &amp; senescence, which then leads to an enhanced immune activation. Citation Format: Hurvitz S, Martin M, Press M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-10.

EFFICIENCY OF COMBINED ANTIHYPERTENSIVE THERAPY IN PATIENTS WITH ARTERIAL HYPERTENSION AND OBESITY DEPENDING ON THE POLYMORPHISM OF CYP2C9 GENE

Aim. To assess the efficiency of combined antihypertensive therapy in patients with arterial hypertension and obesity depending on the polymorphism of CYP2C9 gene. Materials and methods. Patients with uncontrolled arterial hypertension (1-2 stage) and obesity were included in our study. They were randomized by the method of converts into two groups: the first group (n=70) took the fixed-dose combinations of the valsartan and amlodipine and the second group took the fixed-dose combinations of the perindopril and amlodipine. Blood pressure of all patients was measured according to the recommendation for diagnosis and treatment of arterial hypertension (ESH/ESC, 2013) before and after 8 weeks of the initial treatment. All tested people had venous blood sampling succeeded by DNA extraction and amplification in real time mode polymorphic variants CYP2C9 gene. The improvement of health self-esteem by QALY was determined like increase of index from initial by 10 % and more. Results. It is shown that people with heterozygosis polymorphisms *1/*2 and *1/*3 reached the target level of arterial blood pressure after 8 weeks of combined therapy of valsartan and the amlodipine (93,1% against 57,1% respectively). In addition to the above, the frequency of reaching the target level of the arterial blood pressure in the group of tested people who get angiotensin II receptor blocker and calcium-channel blocker was for certain higher among the patients with polymorphisms *1/*2 and *1/*3 in comparison with the polymorphic variants CYP2C9 gene (91,3% against 57,1% respectively). The improvement of the health self-esteem by QALY of the tested patients with polymorphisms *1/*2 and *1/*3 CYP2C9 gene is seen more often between the patients of the first group than between patients of the second group (95,6% against 66,7% respectively). Conclusion. Determined interrelation between the efficiency level of the combined antihypertensive therapy with the CYP2C9 gene polymorphism can be considered in cases of insufficient effect of assigned therapy or the uncontrolled character of the arterial hypertension. In our opinion, appropriate personalized correction of therapy will contribute to its optimization relating to the patients with arterial hypertension and obesity.

Utility of dermoscopy for evaluating the therapeutic efficacy of tacrolimus ointment plus 308-nm excimer laser combination therapy in localized vitiligo patients.

The aim of the present study was to assess the function of dermoscopy in evaluating the therapeutic efficacy of tacrolimus ointment plus 308-nm excimer laser combination therapy in patients with localized vitiligo. A total of 147 patients with localized vitiligo (progressive disease, n=92; stable period, n=55) were enrolled and received combination therapy for 12 weeks. The condition of the skin lesions was monitored by dermoscopy and visual observation. At the initial visit, skin lesions were observed in 61 progressive and 19 stable patients. Residual perifollicular pigmentation was more abundant in progressive-stage patients than in stable-stage patients, whereas the presence of perilesional hyperpigmentation was obviously lower in patients with progressive vitiligo. After 12 weeks of combination therapy, marked differences in residual perifollicular pigmentation were identified between the progressive- and stable-stage patients. Dermoscopy and visual observation indicated that the 12-week treatment efficacy in patients with progressive disease was significantly higher than in those with stable disease and that assessment by dermoscopy was superior to visual observation at 8 or 12 weeks of treatment. Binary logistic regression analysis revealed that the disease stage, vitiliginous areas and disease course were risk factors associated with the treatment efficacy of the combination therapy. In conclusion, dermoscopy may be used as an effective means of vitiligo therapy assessment to provide an accurate and scientific evaluation of treatment efficacy for localized vitiligo patients.

Abstract LB-A25: Biological modulation of PARP inhibition in triple negative breast cancer: A case report of combinational approach implementing histone deacetylase inhibition with PARP inhibition in advanced breast cancer

Abstract The introduction of PARP inhibitors as active agents to inhibit DNA repair was a revolution in cancer therapeutics. However, this approach only has shown results for a short duration in the majority of cases, due to secondary mutations and promoter gene methylation. Studies of patients with triple-negative breast cancer in particular, treated with PARP inhibitors show benefit from the agents for only a short time, until the tumor shows resistance and further the therapy fails. [1,2,3,4] We discuss a case report of a patient with Stage IV refractory and resistant BRCA1 mutated triple-negative breast cancer, who responded to a combinational therapy, consisting of a PARP inhibitor and an epigenetic modifier. The purpose of this case report is to show that combination treatment of epigenetic therapies and PARP inhibitors is synergistic and results in improved clinical outcomes. The patient in this case had already exhausted a PARP inhibitor, which was evident by the presence of excessive BRCA positive altered circulating tumor DNA (ctDNA). The initial finding was 93% mutation allele fraction (MAF) of BRCA gene on liquid biopsy by Guardant360 laboratory. The liquid biopsy for ctDNA was repeated after two weeks of combination therapy, and showed complete disappearance (resolution of positive BRCA gene in ctDNA), reflecting a synergism by proposed modulation of resistance, as mechanism of action. The response reflects the epigenetic therapy as back-bone of treatment, as no other changes were made that could account for the response. To our knowledge, this is the first study of combinational therapies in a human. Our finding in this case could potentially change the standard of care in treating BRCA positive tumors, by providing a superior treatment to current standards.

Biological Modulation of Parp Inhibition in Triple Negative Breast Cancer, a Combinational Approach Implementing Multitargeted Epigenetic Therapy (Mtet) with Parp Inhibition, in Advanced Breast Cancer: A Case Study

The introduction of PARP inhibitors as active agents to inhibit the DNA repair was a revolution in the cancer therapeutics, however, such approach only has shown promising results for a short time in majority of cases due to secondary mutations and promoter gene methylation, and most of patients with triple negative breast cancer when treated with such agents only benefit for a short time, until the tumor shows resistance and further the therapy fails [1]. Considering this category of drugs and their mechanism of action in DNA repair [2] [3], several recent studies have focused on combination of PARP inhibitors with chemotherapy, immune therapy and interestingly relevant to this article, epigenetic therapies [4]. That said, to our knowledge the human data in this regard is missing. Here we discuss a case report of a patient with stage four refractory and resistant BRCA1 mutated triple negative breast cancer who responded in matter of two weeks to a combinational therapy, consisting of PARP inhibitor and epigenetic therapies. As the patient already had exhausted the PARP inhibitor by excessive presence of BRCA positive altered circulatory DNA, the response merely reflects the epigenetic therapy as back bone of treatment. The liquid biopsy repeated after two weeks of combination therapy showed complete disappearance (resolution of positive BRCA gene/c DNA), reflecting a synergism by proposed modulation of resistance as mechanism of action. (The initial c DNA showed 93 percent mutation allele fraction of BRCA gene.) To our knowledge, this is the first study on combinational therapy in human. The finding in this case could potentially change the standard of care in treating BRCA positive tumors, by providing a superior treatment to current standards.

Effect of adding roflumilast or ciclesonide to glycopyrronium on lung volumes and exercise tolerance in patients with severe COPD: A pilot study

COPD is a chronic inflammatory disease characterized by partially reversible airflow limitation. Currently, phosphodiesterase4 inhibitors and inhaled corticosteroids are anti-inflammatory agents that can be used in patients with severe COPD, always added to at least one bronchodilator. In this prospective interventional pilot study, we investigated the effect of adding oral roflumilast 500 μg once-daily or inhaled ciclesonide 160 μg once-daily to glycopyrronium 44 μg once-daily on lung volumes and exercise tolerance in 16 patients with severe COPD, of which 8 received roflumilast and 8 ciclesonide for 8 weeks. Detailed pulmonary function and endurance shuttle tests were performed at time 0, after 2 weeks of glycopyrronium and after 8 weeks of add-on of either roflumilast or ciclesonide. Glycopyrronium increased significantly (p < .05) FEV1, and IC at rest and at the peak of exercise and improved the walking distance. In particular, it induced a bronchodilation similar to that elicited by salbutamol 800 μg. After 8 weeks of combination therapy, both the trough and the post bronchodilator FEV1 further improved but the increase was very small and not significant. Furthermore, adding either roflumilast or ciclesonide did not provide a further improvement in IC and walking distance. This study provides further evidence of the efficacy of glycopyrronium 44 μg once daily, confirming that improvements in airflow are associated with increases in IC and improvements in exercise tolerance. The addition of anti-inflammatory drugs, regardless of class used, does not seem to add benefits on lung function and exercise tolerance, likely because of the large effect induced by glycopyrronium.

Combining MAD and CPAP as an effective strategy for treating patients with severe sleep apnea intolerant to high-pressure PAP and unresponsive to MAD.

IntroductionThis study aimed to determine the effect of combining positive airway pressure (PAP) therapy and mandibular advancement device (MAD) in patients with severe obstructive sleep apnea (OSA) who were pressure intolerant for PAP and were unresponsive to MAD.MethodsThis retrospective study reviewed the medical records of severe OSA patients with apnea-hypopnea index (AHI) ≥ 30/hr who were diagnosed between October 1, 2008 and June 30, 2014. Patients were initially treated with 2 weeks of PAP, and those who were intolerant to high-pressure PAP (≥15 cm H2O) were switched to 12 weeks of MAD, which is a monobloc designed at 75% of maximum protrusion. Patients who had high residual AHI (≥15/hr) on MAD underwent 12 weeks of combination therapy (CT) with MAD and CPAP and were enrolled in the present study. Enrolled subjects who completed the 12-week CT were followed-up until June 30, 2016.ResultsA total of 14 male patients were included. All three treatments effectively reduced AHI, oxygen desaturation index (ODI), and total sleep time with SpO2 <90% (% TST-SpO2<90%) compared to pretreatment values. The residual AHI and ODI on CT was lower than that on MAD or PAP. The residual % TST-SpO2<90% was lower than that on MAD and similar to that on PAP. The therapeutic pressure on CT was on average 9.2 cm H2O lower than that on PAP. For the 11 patients who completed CT, only CT reduced ESS compared to pretreatment value. No treatment had significant impact on % slow wave sleep or overnight change of blood pressure. For patients who completed CT, the average usage was 5.9±1.7 hr/night at 12th week and 6.4±1.5 hr/night at a median follow-up of 36.5-months.ConclusionsCombining MAD and CPAP showed additive effects on reducing AHI and ODI, and lowered the therapeutic pressures.

Interaction between regorafenib and warfarin therapy.

651 Background: Regorafenib is an oral multi kinase inhibitor with clinical activity in colorectal cancer, gastrointestinal stromal tumors and hepatocellular cancer. Drug- drug interactions are commonly encountered in clinical practice and warfarin continues to be the most commonly prescribed anticoagulant among cancer patients in the clinic. The interaction of regorafenib with warfarin has not been studied. Methods: Patients at a single institution being prescribed regorafenib were identified and charts reviewed for concurrent warfarin therapy. Baseline characteristics, indications for regorafenib and warfarin therapy was determined. Patients were followed up to the first 8 weeks of combination therapy. Results: We identified 6 patients on concurrent regorafenib and warfarin. All patients had refractory colon cancer. Median age was 74, 4 were male and 5 white. Indication for warfarin was venous thromboembolism in 5 and atrial fibrillation in 1. Baseline INR ranged from 1.1 to 2.4. An increase in INR was seen in all six patients (peak INR range 4.5 to &gt; 12) which improved with dose modification. Time to peak INR was less than 6 weeks (INR trends in all patients shown in figure 1). There were no bleeding complications noted in any patient. Conclusions: We report a clinically significant interaction between warfarin and regorafenib with patients demonstrating an increase in INR. Patients who are anticoagulated with warfarin and start regorafenib should be closely monitored and upfront warfarin dose reduction should be considered. Further drug-drug interaction studies are needed to determine the exact mechanism of drug-drug interaction between these medications.

Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study

Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections. In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882. Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients). Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4. NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and Gilead Sciences.

A phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer.

274 Background: There is cross-talk between PI3-kinase (PI3K) pathway and androgen receptor (AR) signaling pathways, respectively, which are both critical for cell survival in castrate-resistant prostate cancer (CRPC). The primary study objective is to determine the safety profile and MTD of BKM120 (B, pan-PI3K inhibitor) in combination with abiraterone/prednisone (A/P) in CRPC patients. The secondary objectives are to assess the impact of PTEN status on duration of response/time to progression in the expansion cohort, and to evaluate the impact of B on a PI3-kinase activation fingerprint in metastatic bone or lymph node tissue samples. An exploratory objective is to assess the effect of B on transcription of a set of AR-regulated genes in metastatic bone biopsy samples. Methods: The trial design involves a 14 day lead-in phase with B alone, to assess single-agent toxicity and perform correlative studies. A/P is combined with B at the end of 14 days using the standard 3+3 dose-escalation design with 3 dose levels of B, and participants are assessed for safety and MTD on the combination therapy. To determine PD impact of single agent B on the PI3K activation signature at a metastatic site, a mandatory CT-guided bone or lymph node biopsy is performed prior to B initiation and at the end of 2 weeks on B single-agent therapy. Immunohistochemical (IHC) stains for three markers (p-AKT, p-S6 and PTEN) are used to obtain a semi-quantitative PI3K activation score, based on the quartile levels of continuous staining scores of each marker. Results: Patient 1 had symptomatic bone pain improvement, marked decline in narcotic pain requirements and a biochemical decline in PSA from 156.5 to a PSA nadir of 9.2 within 4 weeks of combination therapy. Patient 3 had a symptomatic and &gt;90% biochemical improvement and has currently completed 15 cycles on treatment, and remains on study to date. RT-PCR analysis showed that the feedback circuitry between PI3K and AR signaling is heterogeneous in the metastatic prostate cancer-bone microenvironment, and dependent on tumor PTEN status. Conclusions: Preliminary data shows promising anti-tumor activity in CRPC patients from dual targeting of PI3K and AR pathways with B and A/P, respectively. Clinical trial information: NCT01741753.