The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Cardiac Biomarkers in Calves with Diarrhea-Induced Neonatal Sepsis

Bu çalışmada genetik materyal başta olmak üzere büyük ekonomik kayıplara neden olan ishal kaynaklı neonatal sepsisli buzağılarda kardiyak biyobelirteçlerin [kardiyak troponin I (cTnI), atriyal natriüretik peptid (ANP), kardiyak troponin I (cTnI), belirlenmesi amaçlanmıştır. N-terminal pro-beyin natriüretik peptid (NT-proBNP), homosistein (HCY), C-reaktif protein (CRP), kreatin kinaz-miyokardiyal bant (CK-MB) seviyeleri ve bu belirteçler arasındaki korelasyonlar. Çalışmada ishale bağlı yenidoğan sepsisli 40 yenidoğan buzağı ve klinik olarak sağlıklı 0-10 günlük 10 yenidoğan buzağı kullanıldı. Çalışmada neonatal sepsisli buzağıların serum cTnI, ANP, NT-proBNP, HCY, CRP ve CK-MB düzeyleri kontrol grubuna göre istatistiksel olarak anlamlı derecede yüksek bulundu (P<0.001). Korelasyon çalışmasında, çalışmada kullanılan kardiyak belirteçler arasında yüksek korelasyon olduğu ve en yüksek korelasyonun ANP ile CK-MB arasında olduğu belirlendi (R=0,836). Çalışmada elde edilen sonuçlara göre cTnI, ANP, NT-proBNP, HCY, CRP ve CK-MB sepsis şüphesi olan buzağılarda kardiyak disfonksiyonların prognostik ve diagnostik biyobelirteçleri olarak önerilebilir. Ayrıca sonuçlar ANP seviyesindeki yaklaşık 10 kat artışın sepsisin erken teşhisi için en iyi belirteç olacağını gösterse de ANP kısa yarı ömrü ve satılamaması nedeniyle ideal bir belirteç değildir. Bu nedenle sepsisli buzağılarda diğer tüm belirteçlerle çok anlamlı korelasyon gösteren ve yaklaşık 7 kat artan NT-proBNP'nin sepsisin saptanmasında ve erken teşhisinde önemli bir belirteç olduğuna inanıyoruz. 836). Çalışmada elde edilen sonuçlara göre cTnI, ANP, NT-proBNP, HCY, CRP ve CK-MB sepsis şüphesi olan buzağılarda kardiyak disfonksiyonların prognostik ve diagnostik biyobelirteçleri olarak önerilebilir. Ayrıca sonuçlar ANP seviyesindeki yaklaşık 10 kat artışın sepsisin erken teşhisi için en iyi belirteç olacağını gösterse de ANP kısa yarı ömrü ve satılamaması nedeniyle ideal bir belirteç değildir. Bu nedenle sepsisli buzağılarda diğer tüm belirteçlerle çok anlamlı korelasyon gösteren ve yaklaşık 7 kat artan NT-proBNP'nin sepsisin saptanmasında ve erken teşhisinde önemli bir belirteç olduğuna inanıyoruz. 836). Çalışmada elde edilen sonuçlara göre cTnI, ANP, NT-proBNP, HCY, CRP ve CK-MB sepsis şüphesi olan buzağılarda kardiyak disfonksiyonların prognostik ve diagnostik biyobelirteçleri olarak önerilebilir. Ayrıca sonuçlar ANP seviyesindeki yaklaşık 10 kat artışın sepsisin erken teşhisi için en iyi belirteç olacağını gösterse de ANP kısa yarı ömrü ve satılamaması nedeniyle ideal bir belirteç değildir. Bu nedenle sepsisli buzağılarda diğer tüm belirteçlerle çok anlamlı korelasyon gösteren ve yaklaşık 7 kat artan NT-proBNP'nin sepsisin saptanmasında ve erken teşhisinde önemli bir belirteç olduğuna inanıyoruz. CRP ve CK-MB, sepsis şüphesi olan buzağılarda kardiyak disfonksiyonların yararlı prognostik ve tanısal biyobelirteçleri olarak önerilebilir. Ayrıca sonuçlar ANP seviyesindeki yaklaşık 10 kat artışın sepsisin erken teşhisi için en iyi belirteç olacağını gösterse de ANP kısa yarı ömrü ve satılamaması nedeniyle ideal bir belirteç değildir. Bu nedenle sepsisli buzağılarda diğer tüm belirteçlerle çok anlamlı korelasyon gösteren ve yaklaşık 7 kat artan NT-proBNP'nin sepsisin saptanmasında ve erken teşhisinde önemli bir belirteç olduğuna inanıyoruz. CRP ve CK-MB, sepsis şüphesi olan buzağılarda kardiyak disfonksiyonların yararlı prognostik ve tanısal biyobelirteçleri olarak önerilebilir. Ayrıca sonuçlar ANP seviyesindeki yaklaşık 10 kat artışın sepsisin erken teşhisi için en iyi belirteç olacağını gösterse de ANP kısa yarı ömrü ve satılamaması nedeniyle ideal bir belirteç değildir. Bu nedenle sepsisli buzağılarda diğer tüm belirteçlerle çok anlamlı korelasyon gösteren ve yaklaşık 7 kat artan NT-proBNP'nin sepsisin saptanmasında ve erken teşhisinde önemli bir belirteç olduğuna inanıyoruz

Mesenteric Artery Stenosis is a Risk Factor for Anastomotic Leakage in Colorectal Surgery

Objective: Anastomotic leakage (AL) after colorectal surgery leads to substantial morbidity and mortality. Theoretically, compromised blood flow caused by mesenteric artery (MA) stenosis may create suboptimal healing conditions at the anastomotic site, increasing susceptibility to AL. The association between MA stenosis on pre-operative computed tomography (CT) scans and AL in patients undergoing colorectal surgery was investigated.Methods: A multicentre, retrospective, frequency matched, nested 1:5 case control study was conducted in the Netherlands. For each patient with AL, five controls without AL were recruited from the same database matched for age and body mass index. Pre-operative CT scans were blindly assessed to identify MA stenosis ≥ 50% as the primary outcome and atherosclerotic burden and vascular pathology as secondary outcomes.Results: A total of 130 patients with AL and 627 matched controls without AL were included. The prevalence of stenosis ≥ 50% in the superior mesenteric artery (SMA) was higher in patients with AL compared with controls (13.8% vs. 2.2%; p < .001). Stenosis ≥ 50% in the inferior mesenteric artery (IMA) also showed a higher prevalence in patients with AL (24.6% vs. 12.1%; p < .001). Multivariate regression analysis showed a 5.9 times higher risk (95% confidence interval [CI] 2.78 – 12.60,; p < .001) of AL in patients with SMA stenosis and 2.1 times higher risk for patients with IMA stenosis (95% CI 1.11 – 3.63; p = .007). Stenosis ≥ 50% of the coeliac artery showed no association with the occurrence of AL.Conclusion: The presence of SMA or IMA stenosis ≥ 50% on pre-operative CT scans isassociated with a six and two times higher odds for AL, respectively, when corrected for known risk factors for AL. Whether preventive stent placement reduces the risk of AL still needs to be investigated

Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>In the era of cytokines, patients with brain metastases (BM) from renal cell carcinoma had a significantly shorter survival than patients without. Targeted agents (TA) have improved the outcome of patients with metastatic renal cell carcinoma (mRCC) however, their impact on patients with BM is less clear. The aim of this analysis was to compare the outcome of patients with and without BM in the era of targeted agents.</p> <p>Methods</p> <p>Data from 114 consecutive patients who had access to targeted agent were analyzed for response rates (ORR), progression free survival (PFS) and overall survival (OS). All patients diagnosed with BM underwent local, BM-specific treatment before initiation of medical treatment.</p> <p>Results</p> <p>Data of 114 consecutive patients who had access to at least one type of targeted agents were analyzed. Twelve out of 114 renal cell carcinoma (RCC) patients (10.5%) were diagnosed with BM. Systemic treatment consisted of sunitinib, sorafenib, temsirolimus or bevacizumab. The median PFS was 8.7 months (95% CI 5.1 - 12.3) and 11.4 months (95% CI 8.7 - 14.1) for BM-patients and non-BM-patients, respectively (p = 0.232). The median overall survival for patients with and without BM was 13.4 (95% CI 1- 43.9) and 33.3 months (95% CI 18.6 - 47.0) (p = 0.358), respectively. No patient died from cerebral disease progression. ECOG Performance status and the time from primary tumor to metastases (TDM) were independent risk factors for short survival (HR 2.74, p = 0.001; HR: 0.552, p = 0.034).</p> <p>Conclusions</p> <p>Although extracerebral metastases determine the outcome of patients with BM, the benefit from targeted agents still appears to be limited when compared to patients without BM.</p

The role of hemodialysis machines dedication in reducing Hepatitis C transmission in the dialysis setting in Iran: A multicenter prospective interventional study

BACKGROUND: Hepatitis C virus (HCV) infection is a significant problem among patients undergoing maintenance hemodialysis (HD). We conducted a prospective multi-center study to evaluate the effect of dialysis machine separation on the spread of HCV infection. METHODS: Twelve randomly selected dialysis centers in Tehran, Iran were randomly divided into two groups; those using dedicated machines (D) for HCV infected individuals and those using non-dedicated HD machines (ND). 593 HD cases including 51 HCV positive (RT-PCR) cases and 542 HCV negative patients were enrolled in this study. The prevalence of HCV infection in the D group was 10.1% (range: 4.6%– 13.2%) and it was 7.1% (range: 4.2%–16.8%) in the ND group. During the study conduction 5 new HCV positive cases and 169 new HCV negative cases were added. In the D group, PCR positive patients were dialyzed on dedicated machines. In the ND group all patients shared the same machines. RESULTS: In the first follow-up period, the incidence of HCV infection was 1.6% and 4.7% in the D and ND group respectively (p = 0.05). In the second follow-up period, the incidence of HCV infection was 1.3% in the D group and 5.7% in the ND group (p < 0.05). CONCLUSIONS: In this study the incidence of HCV in HD patients decreased by the use of dedicated HD machines for HCV infected patients. Additional studies may help to clarify the role of machine dedication in conjunction with application of universal precautions in reducing HCV transmission

Steroids in the Treatment of IgA Nephropathy to the Improvement of Renal Survival: A Systematic Review and Meta-Analysis

Studies have shown that steroids can improve kidney survival and decrease the risk of proteinuria in patients with Immunoglobulin A nephropathy, but the overall benefit of steroids in the treatment of Immunoglobulin A nephropathy remains controversial. The aim of this study was to evaluate the benefits and risks of steroids for renal survival in adults with Immunoglobulin A nephropathy.We searched the Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE and EMBASE databases. All eligible studies were measuring at least one of the following outcomes: end-stage renal failure, doubling of serum creatinine and urinary protein excretion. Fifteen relevant trials (n = 1542) that met our inclusion criteria were identified. In a pooled analysis, steroid therapy was associated with statistically significant reduction of the risk in end-stage renal failure (RR: 0.46, 95% CI: 0.27 to 0.79), doubling of serum creatinine (RR = 0.34, 95%CI = 0.15 to 0.77) and reduced urinary protein excretion (MD = −0.47g/day, 95%CI = −0.64 to −0.31).We identified that steroid therapy was associated with a decrease of proteinuria and with a statistically significant reduction of the risk in end-stage renal failure. Moreover, subgroup analysis also suggested that long-term steroid therapy had a higher efficiency than standard and short term therapy

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.</p> <p>Methods</p> <p>In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.</p> <p>Results</p> <p>Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.</p> <p>Conclusions</p> <p>Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.</p