Months Of Combined Treatment Research Articles

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

The Risk of Bleeding in Patients Receiving Ibrutinib Combined with Novel Direct Oral Anticoagulants

Introduction: Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, is an established therapeutic agent in a variety of B-cell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction and concurrent treatment with ibrutinib and warfarin was shown to significantly increase the risk of bleeding. The current study was designed to investigate the safety of direct oral anticoagulants (DOACs) in patients receiving ibrutinib, considering their expanding employment together with the lack of data regarding their safety in patients receiving ibrutinib. Methods: We conducted a retrospective cohort study to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders (CLL, MCL, DLBCL, MZL or WM) that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy, between January 2010 and October 2018 in 5 participating centers. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage (including the adjustment for renal function), blood count and chemistry tests, bleeding site and grade. Results: The study included 30 patients, median age at starting concurrent administration of ibrutinib and DOACs was 71.58 years (range 50.9-88.2). Most patients were treated for CLL (n=18, 60%) and MCL (n=8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63.3% and 30% of patients respectively. None of the patients received an additional antiplatelet agent. Twenty-three patients were treated with apixaban (76.7%), 4 with rivaroxaban (13.3%) and 3 (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). The median follow-up after initiation of the ibrutinib-DOAC combination was 13.4 months (range 1.8-47.9 months). Bleeding was reported in 22 patients (73.3%), mostly mucocutaneous (n=12, 40%) and gastrointestinal tract (n=7, 23.3%), followed by CNS bleeding (n=4, 13.3%). Mucocutaneous bleedings were all grade 1-2 and gastrointestinal tract and CNS bleeding events were grade 1-4. Major bleeding events, defined as grade 3 or 4, occurred in 5 patients (16.6%) and did not result in death of any of the patients. The median time for bleeding following ibrutinib-DOAC initiation was 5.6 months. Over a follow-up period of 21 months of combined treatment, the incidence of bleeding events (of all grades) increased to 75% (Figure 1). Incidence of bleeding events (including all grades) was quite similar between all DOAC subtypes (73.9% with apixaban, 75% with rivaroxaban and 66.7% with dabigatran). No statistically significant predictors for increased risk of bleeding in patients receiving ibrutinib combined with DOACs were detected. Ibrutinib was stopped in 8 patients (26.7%) due to grade 1 to 4 bleeding events and was re-initiated in 6 patients, resulting in recurrent grade 3 and 4 bleeding events in 2 patients. Conclusions: Concurrent administration of DOACs and ibrutinib appears to be feasible. However, risk of bleeding is not neglectable, and treatment resumption in patients that experienced a significant bleeding event should be considered with caution. Disclosures Arnason: Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Herishanu:Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria.

Seguridad del tratamiento combinado de metotrexato y leflunomida en pacientes con artritis reumatoidea.

Rheumatoid Arthritis (RA) is a chronic discase leacling to functional impairrncnt and early mortality. Treatment with diseasernodifying antirheumat.ic drugs have shown to achicvc disease remission and improves its evolution. The use of combined therapy should have a biological efficacy, no increased toxicity and have an acceptable dose interval. Also, it shoulcl begin its action quickly and he cost-effective. Aims: to assess the security of the combinen treatment withMethotrexate (MTX) and Leflunomide (LF) in patients with Rheurnatoid Arthritis (RA) and to evaluate whethcr the dose and route of MTX administration influence on the toxicity. Patients and Methocls: Patients with RA who fulfihlecl ACR entena and they attencled to the Rheumatology Unit at Córdoba Hospital in the Iast 2 years were assessed. All the patients that received combined treatment with MTX in doses from 7.5 mg to 25 mg weekly orally (PO) orintramuscularly (TM) that started LF treatment in doses of 20 mg/day due to disease activity persistericc were retrospectively assessed.Patients having at least 6 months of combined treatment were inclucled. Data ontreatment and adverse events were collected. They were evaluated at the hegirining, at 6 and 12 months of treatment. The presence of adverse events as well as the stop of combined treatment was evaluated at 6 and 12 months 01treatment. Adverse events in patients with oral and IM MTX treatment and in different doses were compared for the analyses. P<0.05 was considered significant. Results: 62 patients with a mean age of 54 were included. 89% were female and had positive rheumatoid factor and 83% had radiological erosions. Eighty eight percent were in doses of I5mg MTX, 4.9%with lomg and 2flrngattheheginning of LE treatment. Twentv four percent suffered from adverse events and 33% left the medication by 6 months. Among adverse events, 6 patients had cliarrhea, 5 increased hepatic enzymes, 3 alopecia, 3 weight loss, and2 had anemia and leucopenia. Eight patients stopped the medication in 6 months, but only 5 did because of adverse events. There was not significant statistical differcncc in adverse events hetween patients with different dose or routes of administration of MTX. Conclusions: The presence of adverse events in MTX and LF combined treatment was low and it developed dunng the first 6 months of treatment in our patients. The MTX route of administration and doses did not influence on the toxicity of the combined treatment with LF. The combinedtherapy seems to be a sale treatment option in RA patients.

How to approach CLL in clinical practice.

How to approach CLL in clinical practice.

SAT-308 Obsessive and Compulsive Behavioral Change during Combination Treatment of Aromatase Inhibitor and Recombinant Human Growth Hormone in Early Puberty Patient: A Case Report

Aromatase inhibitor (AI), mostly combined with recombinant human growth hormone (rhGH), has been proposed as a effective treatment to improve the final adult height in short pubertal boys by delaying growth plate closure. However, safety concerns also remain, because of limited safety profile of AI usage in pediatric population. Several recent studies have revealed adverse effects of AI, including possible alterations in vertebral bone growth and vertebral anomalies, decreased HDL, increased hematocrit. Although that estrogens might have a role in the regulations of cognitive functions and AIs that block estrogen synthesis cross the blood-brain barrier, a recent trial suggested that AI did not impact the cognitive performance in peripubertal boys. In this report, we would like to introduce a rare case of showing obsessive and compulsive behavioral change in a early pubertal boy who was co-treated with AI and rhGH. A 13 years and 5 months-old boy visited our clinic and his initial examination revealed as follows; height was 160.5cm (45th percentile) and weight was 47.6kg (29th percentile); secondary sexual characteristics of Tanner stage IV. His pelvis x-ray showed risser stage 2, which is assessed to be about 16 years of bone age. He was otherwise healty with no other medical problems. His father's height was 170cm, his mother's height was 151cm, and his midparental height was calculated as 167cm. The patient and his parents wanted to improve his final adult height, and we commenced combination treatment of AI and rhGH after taking agreement. We prescribed letrozole 2.5mg once a day. After 2 months of the start of AI treatment, his parents compaint of his obsessive and compulsive behavioral change, which was not noticed before taking the drug. He complaint of obsessive thoughts and unwanted emotional pull that caused anxiety and distress. Also, he showed compulsive behavior of repeating reading one phrases of the same page. He was in intense stressful situation of preparing important test, however, we could not rule out the possibility of potential adverse effect of AI. Therefore, we discontinued AI. After discontinuing the drug, the symptom improved. During 3 months of combination treatment, he has achieved his height as 162.4cm with a gain of 1.9cm. The progression of bone age was successfully suppressed during the treatment. In conclusion, no significant influence on cognitive performance has been reported in previous studies, however, those studies focused on memory function. Potential effects on other behavioral change have not heen extensively evaluated. Therefore, clinicicans should be aware of possibility of compulsive behavioral change in AI-treated early pubertal boys, and further studies are needed to reveal the relationship.

Ibrutinib and Obinutuzumab in CLL: Improved MRD Response Rates with Substantially Enhanced MRD Depletion for Patients with >1 Year Prior Ibrutinib Exposure

Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naive, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naive trial participants compared to those treated with >1 year prior ibrutinib. Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naive with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved 1 year prior to combination with obinutuzumab (see Table 1). Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving PB MRD levels continued to improve in ibrutinib-naive patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD 1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab. Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naive patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour bulk was low. For patients with persistent disease during/ following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates. Disclosures Rawstron:Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity9s Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity9s Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study.

478 Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m2 gemcitabine and a fixed dose of cisplatin 25 mg/m2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.

Disseminate recurrent folliculitis as the presenting picture of hidradenitis suppurativa

Hidradenitis suppurativa (HS) has a polymorphous clinical presentation. Herein we report two cases of HS revealed by disseminate recurrent folliculitis. PATIENTS AND METHODS CASE 1: A 31-year-old woman consulted for disseminate recurrent folliculitis on the trunk and proximal segments of the limbs that had been ongoing for several years. No other cutaneous lesions were seen, particularly in the classic area for HS lesions. Weight loss and treatment with azithromycin 500mg/day resulted in complete remission, but relapse occurred on dosage reduction. CASE 2: The elder sister of patient 1, who was also obese and 10 years her senior, presented a similar clinical history, although in addition, she was presenting lesions characteristic of HS on her armpits and inguinal folds; further, she had undergone an operation 3 years earlier for pilonidal sinus. Three months of combined treatment with rifampicin and clindamycin 900 mg/day followed by long-term doxycycline 200mg/day resulted in marked improvement. Disseminate folliculitis is not infrequent during the course of HS; it forms part of the clinical picture and is particularly common in the follicular phenotypic variant; however, it is not part of the diagnostic criteria as defined consensually by the Hidradenitis Suppurativa Foundation. The cases we report suggest that a setting of disseminate recurrent folliculitis may constitute the mode of presentation of HS, and may even represent an atypical monosymptomatic form of HS. Disseminate recurrent folliculitis constitutes part of the clinical picture of HS; if it is isolated, screening should be performed for personal or familial signs of HS.

Role of plasma growth factor in the healing of chronic ulcers of the lower legs and foot due to ischaemia in diabetic patients.

IntroductionIt has been demonstrated that plasma growth factor (PGF) responsible for proliferation of smooth muscle cells and fibroblasts significantly shortens treatment duration.AimTo determine the role of human growth factor in the healing of ulcers due to ischaemic diabetic foot syndrome (DFS) following previous angioplasty of the blood vessels of the lower leg and foot.Material and methodsThe study group included 50 patients with ischaemic diabetic foot complicated by lower leg ulcers in which angioplasty of the stenotic arteries in the distal lower leg and foot was performed. It has been assumed that the area of the ulcer cannot exceed 5 cm2. Following surgical debridement, each patient received platelet-rich plasma in the form of dressings applied on an ulcer, followed by hydrocolloid dressings. Each dressing was replaced after 10 days, and this procedure was repeated after 20 and 30 days of treatment. The control group included 50 patients with ischaemic diabetic foot complicated by an ulcer up to 5 cm2. Angioplasty of the lower leg arteries was also performed in this group. However, after surgical debridement, wounds were covered with hydrocolloid dressings.ResultsAfter 3 months of combined treatment, all wounds in the study group healed whereas in the control group, only wounds of the smallest size healed.ConclusionsCombined treatment of ulcers due to ischaemic DFS with endovascular procedures to re-establish blood flow to the vessels and dressings with autologous platelet-rich plasma significantly shortens the healing time.

Addition of Obinutuzumab to Ibrutinib Enhances Depletion of CLL Cells in the Peripheral Blood and Bone Marrow after 1 Month of Combination Therapy: Initial Results from the Bloodwise TAP Iciclle Extension Study

Background: A major aim of treatment in CLL is to eradicate detectable minimal residual disease (MRD). Ibrutinib is a major step forward in the treatment of CLL but results in an immediate lymphocytosis that persists in most patients for at least several months. Obinutuzumab is a second generation anti-CD20 monoclonal antibody which appears to be highly effective in CLL resulting in a rapid eradication of peripheral blood lymphocytosis and the eradication of MRD in a proportion of patients. The IcICLLe Extension Study expands on the IcICLLe trial (ISRCTN 12695354) to examine the efficacy and safety of the combination treatment of obinutuzumab and ibrutinib.Patients: The IcICLLetrial recruited 40 participants with CLL requiring treatment (20 treatment-naïve, 20 relapsed/refractory disease) receive continuous ibrutinib therapy until achievement of <0.01% residual disease in bone marrow or disease progression. The IcICLLe Extension Study involves 40 participants with relapsed/refractory CLL requiring treatment who will all receive continuous oral therapy with ibrutinib and 6 cycles of obinutuzumab. Of the 40 participants, >20 will have had no prior Ibrutinib treatment (ibrutinib naive), and ≤20 will have received at least 12 months of Ibrutinib monotherapy as part of the IcICLLe trial before enrolling in the Extension Study . Adverse Events (AEs) are collected from registration until 30 days after treatment cessation and reported at 1, 3 and 6 months, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0.Results: 17 participants (12 ibrutinib naïve and 5 IcICLLe monotherapy patients) are evaluable for response assessment after one month of combination treatment. In the 12 Ibrutinib-naïve cases, the peripheral CLL counts remained at or below baseline levels in most (9/12) cases from week 1 onwards. After one month of combination therapy the peripheral B-cell count was a median 35% of baseline levels (range <1% to 174%) compared to a median 215% (range 29% to 3570%) for relapsed/refractory patients on Ibrutinib monotherapy. The percentage of CLL cells in the bone marrow aspirate for patients after 1 month of combination therapy showed a median 20% reduction (range 1% increase to 55% decrease, paired t-test P<0.001, baseline median 74% CLL cells, range 23-94%) while there was no change for relapsed/refractory patients on ibrutinib monotherapy (median 1% increase, range 39% increase to 24% decrease, paired t-test P=0.35, baseline median 85% CLL cells, range 11-96%). The reduction in bone marrow aspirate CLL percentage was also evident by morphological assessment of the trephine biopsy with all 10 evaluable patients showing improvements in the cellularity and/or extent of infiltration.Bone marrow assessment was not mandated for the 5 patients previously on ≥12 months (range 14-20 months) continuous ibrutinib monotherapy because they had already undergone 4 biopsies in the prior year, however all five patients showed a reduction in peripheral CLL counts (median 1.3 log reduction, range 0.3 to 2.4 log) which was significantly greater than the reduction seen in the prior 6 months of ibrutinib monotherapy (median 0.5 log reduction, range -1.0 to 0.8, paired t-test P=0.043)Of the 17 participants recruited to the IcICLLe Extension Study there have been no reports of Tumour Lysis Syndrome within the first month of combination treatment. There was a single report of a grade 2 Infusion Related Reaction (IRR) for one participant following the first infusion (100mg) of obinutuzumab. No further IRRs have been reported.Conclusions: The data indicate that the addition of obinutuzumab to ibrutinib results in a substantial improvement in the depletion of CLL cells from the peripheral blood and bone marrow after only one month of combination therapy.Date of Data Freeze: 19-Jul-2016 DisclosuresRawstron:Gilead: Consultancy, Honoraria, Research Funding; BD Biosciences: Other: Remuneration; Celegene: Honoraria; Roche: Honoraria; Janssen: Research Funding; GlaxoSmithKline: Honoraria; AbbVie: Honoraria; Genzyme: Honoraria. Munir:Alexion pharmaceuticals: Honoraria. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Pettitt:Roche: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Infinity: Research Funding. Fox:Roche: Consultancy; Janssen: Honoraria, Other: Travel support. Fegan:Gilead Sciences: Honoraria; Roche: Honoraria; AbbVie: Honoraria. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; GSK: Consultancy; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding.

Effects of Dasatinib and Interferon-α Combination Treatment on the Immune System in CML

Background: In chronic myeloid leukemia (CML) the combination treatment of tyrosine kinase inhibitors (TKIs) with interferon-α (IFN-α) has proved to be effective and well-tolerated. IFN-α has long-term immunomodulatory effects, and when combined to TKI therapy, it may increase the success rates for treatment free remission. In our recent clinical trial NordCML007, a low-dose pegylated IFN-α was combined with dasatinib therapy. As dasatinib is also known to have immunostimulatory effects (activation of T and NK cells and downregulation of regulatory T cells), we aimed to monitor the immune effects of dasatinib and IFN-α combination treatment.Methods: 40 newly diagnosed CML patients participated in the NordCML007 clinical trial (NCT01725204). Patients were treated with 100 mg dasatinib QD and after 3 months IFN-α treatment was added (first 3 months 15 μg/week, then 25 μg/week of pegylated IFN-α). After 12 months of combination treatment, patients resumed to dasatinib monotherapy. In this immunological substudy, peripheral blood samples were collected at the diagnosis, 3, 12, and 24 months after the start of therapy. T- and NK-cells were phenotyped with multicolor flow cytometry, and their function (degranulation and cytokine secretion) was studied. In addition, a multiplexed cytokine and growth factor panel was performed (Proseek Multiplex Inflammation I96×96, Olink).Results: Dasatinib monotherapy led to an increase of NK-cell frequencies when compared to pre-treatment values (median diagnosis 6.8% vs. 3 months 12.8%, p<0.0001, Figure 1). In contrast, the proportion of B cells decreased (6.0% vs. 3.8%, p=0.001). Also moderate effects on the T cell subsets were observed (CD4+ 53% vs. 58%, p=0.02; CD8+ 47% vs. 43%, p=0.03).The more detailed immunophenotyping showed that at 3 months NK cells were more mature when compared to pre-treatment values. This could be observed as the increased proportion of CD16+ (86% vs. 77%, p=0.008) and CD57+ (79% vs. 67%, p=0.0001) NK cells. Correspondingly, the frequencies of CD56bright (median 3 months 3.9% vs. dg 6.1%, p<0.0001) and CD27+ (median 3 months 31.2% vs. dg 58.2%, p=0.004) NK cells decreased. The degranulation responses of NK cells when stimulated with K562 cells were also decreased (median 27.4% vs. 35.5% of CD56+ NK cells, p=0.02).Similar effects of dasatinib treatment were also observed within the T cell population, and at 3 months patients had more CD8+ terminally differentiated effector memory CD45RA+ (Temra) cells (22% vs. 32%, p=0.03). Correspondingly, both CD8+ and CD4+ effector memory (EM) populations decreased (CD8+ EM 34% vs. 24%, p=0.007; CD4+ EM 21 % vs. 14 %, p=0.0003). As observed with the NK cells, the degranulation and Th1 type cytokine secretion of T cells decreased during dasatinib treatment (CD107a/b+ 19.4% vs. 18.4% of CD8+ T cells, p=0.02; CD107a/b+ 12.7% vs. 8.8% of CD4+ T cells, p=0.005). Interestingly, 3 out of 4 patients who suffered from pleural effusion (PE) had exceptionally high CD57+CD8+ T cell frequencies (>70% of CD8+ T cells, median 38% in all patients) at diagnosis and during the treatment.The combination of IFN-α did not significantly affect the number of NK cells. Interestingly however, the addition of IFN-α treatment seemed to have an opposite effect on the NK cell phenotype than dasatinib treatment. The proportion of CD56bright NK cells increased (median 3 months 3.9% vs. 12 months 5.2%, p=0.03), and a decreasing trend was observed among CD16+ and CD57+ NK cells at 12 months. Similarly, the T cell surface markers shifted towards more immature phenotype (CD4+ EM 14% vs. 19%, p=0.002; CD4+ CM 36% vs. 28%, p=0.002; CD8+ Temra 32% vs. 17%, p=0.003) and the degranulation of CD4+ T cells and NK cells returned to the diagnosis level.The initiation of dasatinib treatment was associated with a decrease in several plasma protein concentrations (IL-18, IL-8, CXCL5, MCP-2, MCP-3, VEGF-A, CD244, LAP TGFβ1, TGFA, 4E-BP1, ADA, STAMPB, Casp8, OSM) and an increase in others (SCF, MCP-1). After IFN-α addition, the concentration of MCP-1 was further increased.Conclusions: These results show that dasatinib and IFN-α modulate both innate and adaptive immune systems. Interestingly, where dasatinib seems to induce a more mature immunophenotype, IFN-α counteracts this by driving a shift towards a more immature phenotype. Comparative analysis of the changes in the immunophenotype and function with the clinical outcome of the patients is ongoing. [Display omitted] DisclosuresStentoft:Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Bristol-Myers-Squibb: Research Funding. Richter:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Höglund:Akinion Pharmaceuticals: Consultancy; Janssen-Cilag: Honoraria. Mustjoki:Ariad: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Therapeutic effect of budesonide/formoterol, montelukast and N-acetylcysteine for bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

BackgroundBronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is currently treated with systemic corticosteroids despite poor efficacy and side effects. This study investigated the therapeutic effect of budesonide/formoterol, montelukast and n-acetylcysteine, which are suggested as treatment options for BOS after HSCT.MethodsAfter diagnosis of BOS, 61 patients were treated with budesonide/formoterol, montelukast and n-acetylcysteine for 3 months. Pulmonary function test and COPD assessment test (CAT) were performed before and after the combination therapy. Therapeutic response was evaluated by changes in forced expiratory volume in 1 s (FEV1) or CAT score.ResultsAfter 3 months of combination treatment, mean FEV1 increased by 220 mL (p < 0.001) and residual volume decreased by 200 mL (p =0 .005). Median CAT score also significantly decreased from 15.5 to 11.0 (p = 0.001). The overall response rate to combination therapy was 82 %. Comparing the no-response group and the response group, the forced vital capacity (% predicted) decline between pre-HSCT and BOS diagnosis was significantly greater in the response group (p = 0.036).ConclusionCombination treatment with budesonide/formoterol, montelukast and n-acetylcysteine significantly improved lung function and respiratory symptoms in patients with BOS after allogeneic HSCT without serious side effects.

LONG-TERM RESULTS OF TARGET THERAPY WITH FIRST AND * SECOND-LINE TYROSINE KINASE INHIBITORS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA

Цель – оценка эффективности лечения ингибиторами тирозинкиназ 1-й и 2-й линий неселективной группы пациентов с хроническим миелолейкозом в реальной клинической практике по отдаленным результатам.Материал и методы. В научную оценку включены отдаленные результаты проспективного одноцентрового сравнительного клинического исследования с использованием неселективного принципа формирования групп из 116 исследуемых больных хроническим миелолейкозом в различных фазах, получающих ингибитор тирозинкиназ 1-го поколения иматиниб, и из 44 пациентов, находящихся на терапии ингибитором тирозинкиназ 2-го поколения нилотинибом. Анализировали показатели общей выживаемости, беспрогрессивной выживаемости за период с апреля 2005 по апрель 2013 ; медиана наблюдения составила 128 месяцев. Результаты. Медиана общей выживаемости 116 больных хроническим миелолейкозом, получающих терапию иматинибом, исчисляемая методом Каплана – Мейера, составила 120 месяцев. У 44 пациентов в ранней хронической фазе 5-летняя общая и беспрогрессивная выживаемость отмечена в 93,2% случаев, 8-летняя общая и беспрогрессивная выживаемость – 79,5%. У 44 пациентов в поздней хронической фазе 5-летняя общая и беспрогрессивная выживаемость была 95,5%, 8-летняя общая и беспрогрессивная выживаемость – 72,7%. У 28 больных в фазе акселерации 5-летняя общая выживаемость составила 78,6%, 8-летняя общая выживаемость – 46%. Медиана общей выживаемости пациентов, находящихся на лечении нилотинибом, не достигнута. В течение 78,6 месяца комплексного лечения препаратами общего цитостатического действия, ингибиторами тирозинкиназ 1-й (иматинибом) и 2-й (нилотинибом) линий общая выживаемость составила 100%. Заключение. Включение больных хроническим миелолейкозом с резистентностью к иматинибу (рецидивом заболевания) либо непереносимостью иматиниба в программу лечения хронического миелолейкоза на первом этапе препаратами общего цитостатического действия, затем ингибиторами тирозинкиназ 1-й и 2-й линий существенно увеличивает общую выживаемость больных в клинической практике.

What happens when oral tuberculosis is not treated?

Pulmonary tuberculosis (TB) is the most important form of the disease, although infection may also occur by way of the intestinal tract, tonsils and skin. Oral lesions consist of persistent ulcers or granulomatous masses. A 50 year old man had been diagnosed "necrotising granulomatous inflammation" following a biopsy of a lesion on lower lip, 21 months before at a medical centre. A chest-X-ray had not been performed and he had not been given any advise in respect of treatment. He was admitted to the hospital with cough, sputum, weakness, weight loss and lesions on his lower lip. In radiology, it was detected that he had supraclavicular, submental, cervical, mediastinal lymphadenopathies, pulmonary infiltrations with cavities, thickening and roughness on left oropharengial tonsil, thickenning on inner parts of larynx and bilateral surrenal thickening. The biopsy of lesions on larynx, tonsil and epiglottis revealed "necrotising granulomatous inflammation" and histopathology supported TB infection. Sputum acid-fast bacilli was positive and culture was positive for Mycobacterium tuberculosis complex. Two months of combination treatment resulted in a gradual relief of the symptoms, radiological response, disappearing of neck swelling and healing of lesions on lip, tonsil and larynx. Although unusual oral cavity manifestations of TB are rare, clinicians should be aware of possible occurrance.

Solifenacin and Tamsulosin Combination Therapy Decreases Urine Nerve Growth Factor/Creatinine Levels in Men

To evaluate urinary nerve growth factor (NGF)/creatinine (Cr) levels from men with symptomatic lower urinary tract symptoms (LUTS) and measure the effect of combination therapy with solifenacin and tamsulosin. From January 2012 to February 2014, all male patients referred for evaluation and management of LUTS were screened for enrollment. In all subjects, urinary NGF and Cr levels were measured and normalized to the urinary Cr concentrations (NGF/Cr). Uroflow, postvoid residual, and symptom questionnaires were measured at baseline, 4 weeks, 8 weeks, and 12 weeks after starting combination therapy with solifenacin 5 mg and tamsulosin 0.4 mg. The primary endpoint was urinary NGF and NGF/Cr change from baseline compared with week 12. Ten patients were recruited into the study. Peak urine flow at baseline 20.3 ± 2.5 ml/s and postvoid residual 45.3 ± 13.6 ml did not significantly change with 3 months of combination treatment 14.9 ± 1.8 ml/s and 58.5 ± 23.9 ml. However, urine NGF/Cr (pg/mg) levels were significantly reduced following treatment with levels of 39.7 ± 6.6 at baseline to 17.9 ± 5.1 at 3 months (P value <.05). The decrease in urine NGF/Cr levels correlated with significant decreases in patient reported outcomes. Male patients with LUTS had decreased urinary NGF/Cr levels after treatment with combination solifenacin and tamsulosin in this novel pilot study. This corresponded with improvement in patient reported outcomes.

Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: results from prospective and randomized study of treatment with renin-angiotensin system blockade.

The extracellular miRNAs circulate in the bloodstream and may serve as novel diagnostic and therapeutic biomarkers. The aim of the present study was to investigate circulating Toll-like receptor 4 (TLR4)-responsive miRNA expression in patients with coronary artery disease (CAD) and to examine the effects of renin-angiotensin system (RAS) blockade and statins on miRNA levels. This study included 41 patients with CAD and 20 subjects without CAD (non-CAD). Plasma TLR4-responsive miRNA samples were analysed using a microarray assay for 1700 human miRNA. The candidate miRNAs were verified with real-time reverse transcription (RT)-PCR. Patients with CAD were randomized to 12 months of combined treatment with either telmisartan and atorvastatin [angiotensin II receptor blocker (ARB)] or enalapril and atorvastatin [angiotensin-converting enzyme inhibitor (ACEI)]. Plasma samples were obtained from peripheral blood at baseline and after 12 months. The microarray assay showed significant differences in seven TLR4-responsive miRNAs between the CAD and non-CAD groups (P<0.05). Real-time PCR verified that miR-31, miR-181a, miR-16 and miR-145 were significantly lower in the CAD group than in the non-CAD group (P<0.01). Levels of TLR4 protein were higher in the CAD group than in the non-CAD group (P<0.01) and were negatively correlated with levels of TLR4-responsive miRNAs. Receiver operating characteristic (ROC) curve analysis revealed that a panel of these four miRNAs was sensitive and specific enough to distinguish CAD from non-CAD [area under the curve (AUC)=0.93, 95% CI (confidence interval)=0.99-0.87]. Both ARB and ACEI groups showed increased TLR4-responsive miRNAs and diminished levels of TLR4 protein (P<0.05). Changes in miRNAs and TLR4 levels were greater in the ARB group than in the ACEI group (P<0.05). Circulating TLR4-responsive miRNAs including miR-31, miR-181a, miR-16 and miR-145 were significantly lower in patients with CAD compared with controls and these miRNAs may be involved in the pathogenesis of CAD.

Final Clinical Results with Laboratory Correlates in the Phase I Trial of Lenalidomide Plus Plerixafor in Previously Treated Chronic Lymphocytic Leukemia (CLL)

Introduction: Lenalidomide is an immunomodulatory small molecule with efficacy in CLL, though monotherapy responses are typically partial and delayed. Plerixafor, a small molecule inhibitor of the CXCR4 receptor responsible for homing CLL to the microenvironment, has been safely utilized in CLL. The combination of plerixafor with lenalidomide offered a novel non-cytotoxic alternative to improve anti-tumor activity through targeting of the essential pro-survival microenvironment. [Display omitted] Methods: The primary objective of this single institution, open label, phase I clinical trial (NCT01373229) was to evaluate safety of daily lenalidomide in combination with escalating dose levels of plerixafor. Secondary objectives examined objective response rates, disease symptom improvement, and laboratory correlatives of the drugs’ synergy or resistance. The 3 stage study design is outlined in Figure 1. All adverse events (AEs) on combined therapy were recorded according to CTCAEv4, with dose limiting toxicity (DLT) assessment period defined as the first 28 days of combination therapy. Blood was collected throughout study conduct for analyses including an extended CLL phenotyping by flow cytometry with analysis of CLL subpopulations by CXCR4 expression levels. Phospho-protein analysis was performed by phospho-flow cytometry (phosflow). [Display omitted] Results: Fifteen subjects (4 female) with a median age of 62 years were enrolled, and all have completed treatment on the trial. Subjects received a median 4 (range 1-8) prior chemotherapy regimens (100% with previous alkylator and rituximab, 93% with prior fludarabine) and had poor prognostic features (73% with del 17p, 93% with unmutated IGHV). Ten subjects initiated plerixafor, and 7 completed at least 1 combination cycle. Two dose limiting toxicities (neutropenia, thrombocytopenia) occurred in plerixafor dose 2 (0.32 mg/kg), thus MTD was exceeded at this level. A total of 6 subjects completed dose cohort 1 confirming 0.24 mg/kg as the MTD. Most common grade 3/4 toxicities (>20%) on combination therapy included neutropenia (60%), thrombocytopenia (60%), and anemia (40%). Six patients reached interval response assessment and each had stable disease (SD). All response-evaluable patients derived improvement in nodal/splenic mass and disease symptoms. Of 4 subjects who completed the planned combination therapy, 2 continued on amended lenalidomide monotherapy with 1 subject obtaining a PR. Phenotyping demonstrated CD40, CD95, CD80 and CD86 significantly increased within the CXCR4 high population 4 hours post first plerixafor dose. For the five subjects completing greater than 4 months of combination treatment with end on study (EOS) samples, CD52 declined significantly; and although total WBC decreased over treatment course, the proportion of the high CXCR4 population increased with time (Figure 2). Phosflow demonstrated a significant increase of p-Erk (T202/Y204) by EOS.Conclusions: The MTD was oral lenalidomide 10mg daily with plerixafor SQ 0.24mg/kg thrice weekly for 3 weeks of a 28 day cycle. The majority of grade 3/4 toxicities (and DLTs) were cytopenias (anemia, neutropenia, thrombocytopenia). These toxicities may have been augmented from the combination treatment, or may be a reflection of study subjects with preexisting disease or therapy related marrow suppression. Other emerging lenalidomide clinical results suggest that lower doses may produce less myelosuppression while maintaining or improving clinical benefits by decreasing treatment disruptions that precipitate disease symptoms or tumor flare. Overall, the SD and single PR among heavily pretreated subjects with very high risk features are encouraging given the duration these subjects remained on trial without progression.Correlates demonstrated a decrease in CD52, a marker that has been previously associated to poorer CLL outcomes, and suggests a possible therapeutic effect given these subjects did not have disease progression while on treatment. Increases of CD40, CD95, CD80 and CD86 on lenalidomide monotherapy within 4 hours of plerixafor addition suggest immunomodulatory actions in circulating CLL cells (CXCR4 high expressing). Increased p-Erk by the end of trial may be an emerging resistance marker, and exploration of this effect in select patients could translate into other combination strategies that target this mechanism. DisclosuresBrander:Celgene: Mentor received research funding Other. Off Label Use: This is a phase I clinical investigational study of lenalidomide and plerixafor combination in previously treated CLL/SLL.. Rizzieri:Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy. Lanasa:MedImmune, LLC: Employment; Genentech/Roche: Consultancy; Celgene: Research Funding.

Access to diagnostic tests and essential medicines for cardiovascular diseases and diabetes care: cost, availability and affordability in the West Region of Cameroon.

ObjectiveTo assess the availability and affordability of medicines and routine tests for cardiovascular disease (CVD) and diabetes in the West region of Cameroon, a low-income setting.MethodsA survey was conducted on the availability and cost of twelve routine tests and twenty medicines for CVD and diabetes in eight health districts (four urban and four rural) covering over 60% of the population of the region (1.8 million). We analyzed the percentage of tests and medicines available, the median price against the international reference price (median price ratio) for the medicines, and affordability in terms of the number of days’ wages it would cost the lowest-paid unskilled government worker for initial investigation tests and procurement for one month of treatment.ResultsThe availability of tests varied between 10% for the ECG to 100% for the fasting blood sugar. The average cost for the initial investigation using the minimum tests cost 29.76 days’ wages. The availability of medicines varied from 36.4% to 59.1% in urban and from 9.1% to 50% in rural settings. Only metformin and benzathine-benzylpenicilline had a median price ratio of ≤1.5, with statins being largely unaffordable (at least 30.51 days’ wages). One month of combination treatment for coronary heart disease costs at least 40.87 days’ wages.ConclusionThe investigation and management of patients with medium-to-high cardiovascular risk remains largely unavailable and unaffordable in this setting. An effective non-communicable disease program should lay emphasis on primary prevention, and improve affordable access to essential medicines in public outlets.

Efficacy and safety of combined oral iron chelation therapy with deferasirox and deferiprone in a patient with beta-thalassemia major and persistent iron overload.

Efficacy and safety of combined oral iron chelation therapy with deferasirox and deferiprone in a patient with beta-thalassemia major and persistent iron overload.

Scarring of lupus miliaris disseminatus faciei: treatment with a combination of trichloroacetic acid and carbon dioxide laser

We present a case of a 35-year-old man having a 12-month history of multiple reddish-brown papules on the chin, forehead, cheeks, and eyelids. Histopathologic findings revealed epithelioid cell granulomas with central necrosis consistent with a diagnosis of lupus miliaris disseminatus faciei. After 9 months of combined treatment with ethambutol, rifampin, and pyrazinamide, most lesions gradually resolved but remained as severe disfiguring scars. After 10 sessions of treatments with 100% trichloroacetic acid and CO2 laser, the lupus miliaris disseminatus faciei scars have been much improved and the patient has never experienced a recurrence of disease during subsequent years of follow-up.