Hypoxia-Inducible Factor Stabilizers: a New Avenue for Reducing BP While Helping Hemoglobin?

Anemia of chronic kidney disease (CKD) is common and is associated with diminished quality of life, cognitive impairment, cardiovascular morbidity, hospitalizations, and mortality. As the prevalence of end-stage renal disease continues to rise, the management of anemia represents a growing economic burden. Erythropoiesis-stimulating agents (ESA) are the mainstay of anemia management but their use is limited due to the associated cardiovascular adverse events. Prolyl hydroxylase domain enzyme (PHD) inhibitors are a new class of drugs that stabilize the hypoxia-inducible factors and are under clinical investigation for the treatment of renal anemia. The advantages of PHD inhibitors include the oral route of administration, improved iron profile, restoration of diurnal rhythm of erythropoietin secretion, and endogenous erythropoietin production near physiological range. Emerging but limited data indicates a small blood pressure lowering effect of PHD inhibitors. The effect of PHD inhibitors on cardiovascular endpoints and the potential risks of CKD progression and pulmonary hypertension remains to be addressed in the ongoing clinical trials.     

PARP1: A potential biomarker for gastric cancer

Gastric cancer (GC) is the third leading cause of cancer mortality worldwide, with an overall 5-y survival rate of 25%. The majority of GCs are caused by infectious agents, including the bacterium Helicobacter pylori (H. pylori) and Epstein–Barr virus (EBV). Furthermore, inappropriate repair of DNA damage can also result in genomic instability, which has shown to be a key factor in carcinogenesis of different regions including gastric region. Present study was designed to explore the association between base excision repair pathway genes, PARP1 and APEX1 and gastric pathology and H. pylori infection. Two hundred gastric cancer tissue samples (114 H. pylori positive and 86 H. pylori negative) and adjacent uninvolved area taken as controls was used for expression analysis of BER pathway genes at mRNA level and protein levels using quantitative PCR (qPCR) and immunohistochemistry (IHC) respectively. Oxidative stress and DNA damage was also determined by measuring the level of antioxidant enzymes and comet assay respectively. Significant upregulation in PARP1 (p < 0.001) and APEX1 (p < 0.02) was observed in GC tissue samples compared to controls and this upregulation was more pronounced in H. pylori positive cases (HPGC) (PARP1, p < 0.02: APEX1, p < 0.04) than H. pylori negative cases (HNGC). Upregulation of BER pathway genes in HPGC was found correlated with smoking status (p < 0.0001), T stage (p < 0.01) and lymph node metastasis (p < 0.03). Moreover, immunohistochemical staining of BER pathway genes was found correlated with a number of clinicopathological characteristics such as tumor type (p < 0.03), tumor size (p < 0.01) and lymph node metastasis (p < 0.01). Expression levels of APEX1 and PARP1 gene also correlated with increased oxidative burden (p < 0.0001) and DNA damage (p < 0.001) in GC patients. Survival analysis showed that upregulation of PARP1 gene was associated with poor overall survival outcome of gastric cancer patients (HR = 2.04 (95% CI = 1.10–3.76; p < 0.02). Univariate and multivariate cox regression analysis showed the upregulated PARP1 gene (HR = 5.03; 95%CI (2.22–11.35); p = 0.0001), positive smoking status (HR = 3.58; 95%CI (1.67–7.65); p = 0.001), positive status for H pylori infection (HR = 4.38; 95%CI (1.82–10.56); p = 0.001) and advance N-stage (HR = 5.29; 95%CI (2.28–12.24); p = 0.0001) were independent prognostic factors for gastric cancer and may serve as a valuable biomarker for the diagnosis and progression of GC and can be helpful in developing individualized treatment strategies for treating GC.     

Clinical Outcomes of Patients With Recurrent Lung Cancer Reirradiated With Proton Therapy on the Proton Collaborative Group and University of Florida Proton Therapy Institute Prospective Registry Studies

PurposeWe sought to assess clinical outcomes and toxicities of patients with recurrent lung cancer reirradiated with proton beam therapy (PBT) who were enrolled in 2 prospective registry trials.Methods and MaterialsSeventy-nine consecutive patients were reirradiated with PBT at 8 institutions. Conventionally fractionated radiation therapy was used to treat the previous lung cancer in 68% of patients (median equivalent dose in 2 Gy fractions [EQD₂], 60.2 Gy) and hypofractionated/stereotactic body radiation therapy in 32% (median EQD₂, 83.3 Gy). Nine patients (11%) received ≥2 courses of thoracic irradiation before PBT. Eastern Cooperative Oncology Group (ECOG) performance status was 2 to 3 in 13%. Median time from prior radiation therapy to PBT was 19.9 months. PBT was delivered with conventional fractionation in 58% (median EQD₂, 60 Gy), hyperfractionation in 3% (median EQD₂, 62.7 Gy), and hypofractionation in 39% (median EQD₂, 60.4 Gy). Twenty-four patients (30%) received chemotherapy concurrently with PBT.ResultsAll patients completed PBT as planned. At a median follow-up of 10.7 months after PBT, median overall survival (OS) and progression-free survival (PFS) were 15.2 months and 10.5 months, respectively. Acute and late grade 3 toxicities occurred in 6% and 1%, respectively. Three patients died after PBT from possible radiation toxicity. On multivariate analysis, ECOG performance status ≤1 was associated with OS (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80; P = .014) and PFS (hazard ratio, 0.32; 95% confidence interval, 0.14-0.73; P = .007).ConclusionsThis is the largest series to date of PBT reirradiation for recurrent lung cancer and indicates that reirradiation with PBT is well tolerated with acceptable toxicity and encouraging efficacy. ECOG performance status was associated with OS and PFS.     

A Retrospective Study of Comorbidities and Complications in Elderly Acute Myeloid Leukemia Patients in the United States

BackgroundComorbidities in acute myeloid leukemia (AML) patients have been shown to increase with age. However, few studies have described the disease burden in elderly AML patients, a population generally underrepresented in clinical trials. We aimed to characterize the comorbidities and complications in elderly AML patients.Patients and MethodsPatients aged ≥ 65 years with a primary diagnosis of AML were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (2000-2013) and were followed until the end of 2014. AML patients were matched 1:1 to noncancer patients by age, sex, geographic region, and race. A subset of patients with relapsed and/or refractory (R/R) AML was identified by modifying a previously validated algorithm. Baseline comorbidities and complications (eg, infectious, hematologic, cardiovascular) during follow-up were assessed using ICD-9 codes. Cox proportional hazards models were used to determine associations between AML and developing select complications.ResultsCompared to matched noncancer controls, AML patients (n = 3911) had higher baseline National Cancer Institute comorbidity index scores (1.81 vs. 1.63, P < .01), higher incidence rates (per 100 person-years) for all events of interest, and a higher risk of developing cardiovascular disease (hazard ratio = 4.61; 95% confidence interval, 4.07-5.21), type 2 diabetes mellitus (hazard ratio = 3.85; 95% confidence interval, 3.35-4.42), and stroke (hazard ratio = 2.60; 95% confidence interval, 2.32-2.92). R/R AML patients were younger, had lower National Cancer Institute comorbidity scores, lower incidence rates of events of interest, and a longer follow-up time compared to non-R/R AML patients.ConclusionElderly AML patients had more comorbidities and higher rates of complications compared to noncancer controls. Considering comorbidities and complications in elderly AML patients may improve clinical decision making.     

Whole-genome sequencing for optimized patient management

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.     

Echinacea plants as antioxidant and antibacterial agents: From traditional medicine to biotechnological applications

The genus Echinacea consists of 11 taxa of herbaceous and perennial flowering plants. In particular, Echinacea purpurea (L.) Moench is widely cultivated all over the United States, Canada, and in Europe, exclusively in Germany, for its beauty and reported medicinal properties. Echinacea extracts have been used traditionally as wound healing to improve the immune system and to treat respiratory symptoms caused by bacterial infections. Echinacea extracts have demonstrated antioxidant and antimicrobial activities, and to be safe. This survey aims at reviewing the medicinal properties of Echinacea species, their cultivation, chemical composition, and the potential uses of these plants as antioxidant and antibacterial agents in foods and in a clinical context. Moreover, the factors affecting the chemical composition of Echinacea spp. are also covered.     

Cost-efficacy of acceleration partial-breast irradiation compared with whole-breast irradiation

The purpose of this study was to analyze the cost-efficacy of multiple accelerated partial-breast irradiation (APBI) techniques compared with whole breast irradiation (WBI) delivered utilizing 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). A previously reported matched-pair analysis consisting of 199 patients receiving WBI and 199 patients receiving interstitial APBI formed the basis of this analysis. Cost analyses included a cost minimization analysis, incremental cost- effectiveness ratio (ICER) analysis, and cost per quality adjusted life year (QALY) analysis. Per 1,000 patients treated, the cost savings with the utilization of APBI compared to WBI IMRT is $14.9 million, $10.9 million, $8.8 million, $5.0 million, and $9.7 million for APBI 3D-CRT, APBI IMRT, APBI single-lumen (SL), APBI multi-lumen (ML), and APBI interstitial, respectively. Per 1,000 patients treated, the cost savings with the utilization of APBI compared to WBI 3D-CRT is $6.0 million, $2.0 million, and $0.7 million for APBI 3D-CRT, APBI IMRT, and APBI interstitial, respectively. The cost per QALY for APBI SL, APBI ML, and APBI interstitial compared with APBI 3D-CRT are $12,273, $66,032, and $546, respectively. When incorporating non-medical costs and cost of recurrences the cost per QALY was $54,698 and $49,009 for APBI ML compared with APBI 3D-CRT. When compared to WBI IMRT, all APBI techniques are cost-effective based on cost minimization, ICER, and QALY analyses. When compared to WBI 3D-CRT, external beam APBI techniques represent a more cost-effective approach based on cost minimization with brachytherapy representing a cost-effective approach based on cost per QALY.