Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 26 Μαρτίου 2016
Population pharmacokinetic analysis of patritumab, a HER3 inhibitor, in subjects with advanced non-small cell lung cancer (NSCLC) or solid tumors
Abstract
Purpose
The purpose of this analysis was to develop a population pharmacokinetic (PK) model for patritumab, a fully human monoclonal antibody that targets human epidermal growth factor receptor 3.
Methods
A total of 833 serum concentrations were included in this analysis; serum concentrations were obtained from 145 subjects (136 with non-small cell lung cancer, nine with solid tumors) treated with patritumab [9 or 18 mg/kg intravenously every 3 weeks (q3w)] in one phase 1 and one phase 1b/2 study. Data were analyzed by nonlinear mixed-effect modeling.
Results
Patritumab PKs were best described through a two-compartment model with first-order elimination and interindividual variability on clearance (CL), volume of the central compartment (V c), distributional clearance, and volume of the peripheral compartment. In the final model, CL and V c were estimated as 0.0238 L/h and 3.62 L, respectively. Body weight (BW) and baseline albumin were found to be covariates for CL and BW was a covariate for V c. Covariates associated with hepatic and renal impairment were not significant on CL. Simulations showed that BW-based dosing reduced interindividual variability in patritumab exposure compared with fixed dosing.
Conclusions
The PK of patritumab was linear at the doses studied and well described by the two-compartment model. Hepatic and renal impairment did not appear to affect PK. Our results support BW-based dosing of patritumab on a q3w schedule.
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Role of adjuvant therapy after R0 resection for patients with distal cholangiocarcinoma
Abstract
Background
The optimal treatment strategy for cholangiocarcinoma (CC) after curative resection remains controversial. The aim of this study was to analyze the role of adjuvant therapy in R0-resected distal CC.
Methods
We retrospectively reviewed the medical records of patients who underwent R0 resection for distal CC at six cancer centers in Korea. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of the study were overall survival (OS) and recurrence-free survival (RFS).
Results
A total of 158 patients were included in the analysis; 47 patients (29.7 %) had lymph node involvement. Fifty-six patients (35.4 %) received adjuvant therapy (CT/CRT/RT: 27/20/9, respectively). Patients with advanced TNM stage (P < 0.001), T3/T4 disease (P = 0.009), positive lymph nodes (LN; P = 0.052), and elevated baseline carbohydrate antigen 19-9 (P = 0.071) were more likely to receive adjuvant therapy. The effect of adjuvant therapy varied according to treatment modality. A multivariable analysis showed a significant improvement in OS after CT [hazard ratio (HR) 0.21, 95 % confidence interval (CI) 0.08–0.53, P = 0.001] and CRT (HR 0.25, 95 % CI 0.08–0.83, P = 0.024). However, RT alone was associated with shorter OS (HR 2.38, P = 0.040), along with T3/T4 disease (HR 2.12, P = 0.012) and positive LN (HR 2.30, P = 0.008). RFS benefited from adjuvant treatment with CT (HR 0.34, P = 0.002) and CRT (HR 0.33, P = 0.004), but not with RT alone (HR 1.42, P = 0.361). In the subset analysis according to LN status, adjuvant therapy not including RT alone was associated with a significant OS and RFS advantage in both LN-negative and LN-positive patients.
Conclusions
Our results show that patients receiving CT or CRT had significant improvements in OS and RFS. In addition, a benefit of adjuvant therapy (except RT alone) was observed even in LN-negative patients.
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Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib
Abstract
Myelofibrosis (MF) and polycythemia vera (PV) are BCR-ABL1-negative myeloproliferative neoplasms associated with somatic hematopoietic stem cell mutations leading to over activation of JAK–STAT signaling. MF and PV are pathogenically related and share specific clinical features such as splenomegaly and constitutional symptoms. The MF phenotype is dominated by the effects of progressive bone marrow fibrosis resulting in shortened survival. In contrast, elevated thrombosis risk due to erythrocytosis is the primary clinical concern in PV. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is approved in the USA for the treatment of patients with intermediate- or high-risk MF and patients with PV who have had an inadequate response to or are intolerant of hydroxyurea. For MF, results of two phase III studies demonstrated that ruxolitinib therapy reduced spleen volume and MF-related symptom burden, improved quality-of-life measures, and was associated with prolonged overall survival. Treatment benefits were generally sustained with continued therapy. Dose-dependent cytopenias were common but generally manageable with transfusions (for anemia), dose reduction, or treatment interruption. Optimal dosing management is critical to maintain long-term treatment benefit, because cessation of therapy resulted in rapid return of symptoms to baseline levels. Results of the phase III PV trial showed that ruxolitinib was significantly more effective than standard therapy in controlling hematocrit levels and improving splenomegaly and PV-related symptoms. Only 1 of 110 patients in the ruxolitinib arm compared with 6 of 112 patients in the control arm experienced a thromboembolic event through week 32. Grade ≥3 cytopenias were uncommon.
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Correlation between the severity of cetuximab-induced skin rash and clinical outcome for head and neck cancer patients: The XXXX experience
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Voichita Bar-Ad, Qiang (Ed) Zhang, Paul M. Harari, Rita Axelrod, David I. Rosenthal, Andy Trotti, Christopher U. Jones, Adam S. Garden, Guobin Song, Robert L. Foote, David Raben, George Shenouda, Sharon A. Spencer, Jonathan Harris, Quynh-Thu Le
PurposeThe purpose of the present study was to evaluate severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients with head and neck squamous cell carcinoma treated with chemoradiotherapy and cetuximab.Materials & MethodsAnalysis included patients who received loading dose and ≥ 1cetuximab dose concurrent with definitive chemoradiotherapy (70Gy + cisplatin) or postoperative chemoradiotherapy (60-66Gy + docetaxel or cisplatin).ResultsSix hundred two patients were analyzed; 383 (63.6%) developed Grade 2-4 cetuximab rash. Patients manifesting Grade 2-4 rash had younger age (p<0.001), fewer pack-years smoking history (p<0.001), were more likely to be males (p=0.04), and had p16-negative (p=0.04) oropharyngeal tumors (p=0.003).In univariate analysis, Grade 2-4 rash was associated with better overall survival (OS) (hazard ratio [HR] 0.58, p<0.001) and progression-free survival (PFS) (HR 0.75, p=0.02), and reduced distant metastasis (DM) rate (HR 0.61, p=0.03), but not local-regional failure (LRF) (HR 0.79, p=0.16) relative to Grade 0-1 rash. In multivariable analysis, HRs for OS, PFS, DM, and LRF were 0.68 (p=0.008), 0.85 (p=0.21), 0.64 (p=0.06), and 0.89 (p=0.48). Grade >2 rash was associated with improved survival in p16 negative patients (HR 0.28 (0.11-0.74)) but not in p16 positive patients (HR 1.10 (0.42-2.89)) (p=0.05 for interaction). Twenty-five percent of patients with Grade 2-4 acute in-field radiation dermatitis experienced Grade 2-4 late skin fibrosis vs. 14% of patients with Grade 0-1 acute in-field radiation dermatitis (p=0.002).ConclusionGrade 2-4 cetuximab rash was associated with better survival possibly due to reduction of distant metastasis. This observation was noted mainly in p16 negative patients. Grade 2-4 acute in-field radiation dermatitis was associated with higher rate of late Grade 2-4 skin fibrosis.
Teaser
Present study evaluated the severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients HNSCC treated with chemoradiotherapy and cetuximab in two prospective randomized trials. Grade 2-4 cetuximab rash was associated with better survival possibly due to reduction of distant metastasis. This observation was noted mainly in p16 negative patients. Grade 2-4 acute in-field radiation dermatitis was associated with higher rate of late Grade 2-4 skin fibrosis.from Cancer via ola Kala on Inoreader http://ift.tt/1VOapfA
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Post-Operative Spine Stereotactic Body Radiotherapy (SBRT): A critical review to guide practice
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kristin J. Redmond, Simon S. Lo, Charles Fisher, Arjun Sahgal
Post-operative stereotactic body radiotherapy (SBRT) for metastatic spinal tumors is increasingly being performed in clinical practice. Whereas the fundamentals of SBRT practice for intact spinal metastases are established, there are as yet no comprehensive practice guidelines for the post-operative indication. In particular, there are unique considerations for patient selection and treatment planning specific to post-operative spine SBRT that are critical for safe and effective management. The purpose of this critical review is to discuss the rationale for treatment, describe those factors impacting surgical decision making, introduce modern surgical trends, and summarize treatment outcomes for both conventional post-operative conventional external beam radiotherapy and post-operative spine SBRT. Lastly, an in-depth practical discussion with respect to treatment planning and delivery considerations is provided to help guide optimal practice.
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Quercitrin treatment protects endothelial progenitor cells from oxidative damage via inducing autophagy through extracellular signal-regulated kinase
Abstract
Atherosclerosis is a disease resulting from impaired endothelial function, often caused by oxidant injury or inflammation. Endothelial progenitor cells (EPCs) play a critical role in repairing damaged endothelium and protecting against atherosclerosis. Quercitrin, a plant-derived flavonoid compound, displays antioxidant and anti-inflammatory activities. In this study, we showed that quercitrin treatment reduced the apoptosis of EPCs caused by oxidized low-density lipoprotein (ox-LDL) in a dose-dependent manner. Quercitrin improved tube formation, migration and adhesion of ox-LDL-treated EPCs. To determine the effect of quercitrin in vivo, EPCs treated with or without ox-LDL and quercitrin were locally injected into the ischemic hind limb muscle of nude mice. Those injected with EPCs treated with ox-LDL and quercitrin showed significantly increased local accumulation of EPCs, blood flow recovery and capillary density compared with the control and ox-LDL only groups. Furthermore, we showed that quercitrin enhanced autophagy and upregulated mitogen-activated protein kinase and ERK phosphorylation in a dose-dependent manner in vitro. Autophagy inhibitors, chloroquine and 3-methyladenine, abrogated quercitrin-enhanced autophagy caused by ox-LDL as evidenced by decreased numbers of branch points, migratory cells and adherent cells, and increased numbers of apoptotic cells. The ERK inhibitor PD98059 abrogated quercitrin-enhanced autophagy, as identified by decreased autophagosome formation and downregulated ERK phosphorylation. The inhibition of ERK did not affect the expression of Rac1, but enhanced phosphorylation of Akt. Quercitrin treatment also increased the expression of E-cadherin, and PD98059 abrogated the upregulation of E-cadherin induced by quercitrin. Our findings suggested that autophagy is a protective mechanism in EPCs exposed to oxidative damage. Quercitrin can promote autophagy through the activation of ERK and the ERK signaling pathway is therefore thought to play a pivotal role in mediating the protective effects on EPCs.
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Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1
Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Kimberly J. Johnson, Nancy L. Zoellner, David H. Gutmann
BackgroundIndividuals with Neurofibromatosis Type 1 (NF1) are strongly predisposed to developing pediatric brain tumors (PBTs), especially optic pathway gliomas (OPGs). Although developmental factors have been implicated in the origins of PBTs in both human and animal studies, associations between early-life factors and PBTs have not been evaluated in individuals with NF1. Our objective was to evaluate associations between peri-gestational characteristics and PBTs in this population.MethodsWe conducted a cross-sectional study, ascertaining questionnaire and medical record data for 606 individuals<18years old who enrolled in the NF1 Patient Registry Initiative (NPRI) from 6/9/2011-6/29/2015. One hundred eighty-four individuals had reported PBT diagnoses, including 65 who were identified with OPG diagnoses. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PBT and OPG diagnoses and peri-gestational characteristics (prematurity, birth weight, parental age, plurality, family history of NF1, assisted reproductive technology, maternal vitamin supplementation, and parental smoking).ResultsWe observed no significant associations between any of the assessed characteristics and PBTs overall or OPGs with the exception of birth weight. After controlling for potential confounding variables, we observed a significant positive association between birth weight quartile and OPGs with a HR of 3.32 (95% CI 1.39–7.94) for the fourth (≥3915.5g) compared to the first (≤3020g) quartile (p for trend=0.001).ConclusionsConsistent with results for PBTs in the general population, these results suggest that higher birth weights increase OPG risk in individuals with NF1.
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Epigenetic mediated silencing of EYA4 contributes to tumorigenesis in oral dysplastic cells
Abstract
Five-year survival rates for oral squamous cell carcinoma (OSCC) have remained at a dismal 50% for the past several decades. Molecular analyses of premalignant tissues are a key means of identifying early foundational drivers of disease, which may be exploitable as biomarkers or therapeutic targets for improving disease outcomes. We previously identified EYA4 as frequently hypermethylated and silenced in premalignant disease based on an analysis of lesion-adjacent normal, dysplasia, and carcinoma in situ/squamous cell carcinoma tissues from the oral cavity. Herein, we further evaluate the role of this putative tumor suppressor gene in transformation of oral tissues and OSCC. By an initial assessment, EYA4 promoter hypermethylation was found in 24/32 (75%) of paired tumor samples in The Cancer Genome Atlas oral cancer data set, with significant correlation noted between methylation status and relative gene expression. To assess the impact of EYA4 in oral tumorigenesis, we overexpressed EYA4 in two oral dysplasia cell lines. Expression of EYA4 caused an increase in cell proliferation, DNA damage repair capabilities, and increased the level of apoptosis. Taken together, we find evidence that EYA4 is a novel tumor suppressor in oral cancer, which becomes methylated and silenced at the premalignant stage and appears to be epigenetically regulated. Further studies are warranted to investigate its role as a marker for progression in oral cancer. This article is protected by copyright. All rights reserved.
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Lycopene's effects on cancer cell functions within monolayer and spheroid cultures.
Lycopene's effects on cancer cell functions within monolayer and spheroid cultures.
Nutr Cancer. 2016 Mar 25;:1-14
Authors: Holzapfel NP, Holzapfel BM, Theodoropoulos C, Kaemmerer E, Rausch T, Feldthusen J, Champ S, Clements JA, Hutmacher DW, Loessner D
Abstract
Lycopene, a compound that blocks the action of free radicals and oxygen molecules, is found in tomatoes and tomato-based products and linked to a reduced incidence of cancer. Increasing willingness of patients to maintain a healthy lifestyle by supplemental intake of nutrients and acceptance of alternative therapeutics has boosted research into nutraceuticals. The potential of lycopene to prevent or treat cancer has been investigated, but outcomes are inconsistent and its mode of action is still unknown. Further studies are needed to understand the role of lycopene in cancer prevention and treatment. The impact of lycopene on viability, proliferation, migration, and invasion of five different cancer cell lines was determined using monolayer and spheroid cultures. Cell viability was significantly reduced upon lycopene treatment at physiologically attainable concentrations. Cell proliferation, migration, and invasion did not change upon lycopene treatment. Ovarian cancer spheroids initially showed a decreased proliferation and after 14 days increased cell viability upon lycopene treatment, confirming the potential of lycopene to reduce cancer cell growth in short-term cultures and also indicate enhanced cell viability over prolonged exposure. This study cannot substantiate that lycopene inhibits cell functions associated with tumor growth, even in a 3D cancer model that mimics the natural tumor microenvironment.
PMID: 27015041 [PubMed - as supplied by publisher]
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Mast cells in lymphomas
Publication date: Available online 25 March 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Domenico Ribatti
Tumor microenvironment is involved in the pathogenesis and progression of human lymphomas. The lymphoma microenvironment is composed by stromal cells, immune cells (macrophages, plasma cells, mast cells, eosinophils, basophils, T- and B-cells), blood vessels and extracellular matrix proteins. This article is focused on the role of mast cells in lymphoma progression and angiogenesis. Mast cells might be regarded in a future perspective as a new target for the adjuvant treatment of tumors, including lymphomas.
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Smoking in pregnancy and risk of cancer among young children: A population-based study
Abstract
Smoking during pregnancy is a plausible risk factor for childhood cancer, yet previous studies have yielded conflicting results, and few prospective studies have been published.
Data on maternal smoking were obtained from California birth certificates. We linked California birth certificates (births 2007-2011) with California Cancer Registry records for childhood cancer cases (diagnosed January 2007- September 2013) that were ages 5 or younger at diagnosis (N cases=2,021). Controls (N=40,356) were frequency-matched by birth year and randomly selected from birth certificate records. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI) to assess the association between smoking during pregnancy and childhood cancer.
We observed positive associations for gliomas (OR=1.8, 95% CI: 1.0-3.4) and retinoblastoma (OR=3.0, 95% CI: 1.4-6.6), particularly bilateral retinoblastoma (OR=9.4, 95% CI 3.6-24.7) with maternal smoking in pregnancy.
Maternal smoking during pregnancy may be a risk factor for retinoblastoma and certain types of childhood brain tumors. This article is protected by copyright. All rights reserved.
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Introduction of the non-technical skills for surgeons (NOTSS) system in a Japanese cancer center
Abstract
Purpose
Non-technical skills rating systems, which are designed to support surgical performance, have been introduced worldwide, but not officially in Japan. We performed a pilot study to evaluate the "non-technical skills for surgeons" (NOTSS) rating system in a major Japanese cancer center.
Methods
Upper gastrointestinal surgeons were selected as trainers or trainees. The trainers attended a master-class on NOTSS, which included simulated demo-videos, to promote consistency across the assessments. The trainers thereafter commenced observing the trainees and whole teams, utilizing the NOTSS and "observational teamwork assessment for surgery" (OTAS) rating systems, before and after their education.
Results
Four trainers and six trainees were involved in this study. Test scores for understanding human factors and the NOTSS system were 5.89 ± 1.69 and 8.00 ± 1.32 before and after the e-learning, respectively (mean ± SD, p = 0.010). The OTAS scores for the whole team improved significantly after the trainees' education in five out of nine stages (p < 0.05). There were no differences in the NOTSS scores before and after education, with a small improvement in the total scores for the "teamwork and communication" and "leadership" categories.
Conclusion
These findings demonstrate that implementing the NOTSS system is feasible in Japan. Education of both surgical trainers and trainees would contribute to better team performance.
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Dependence of treatment planning accuracy in peptide receptor radionuclide therapy on the sampling schedule
Abstract
Background
Peptide receptor radionuclide therapy (PRRT) plays an important role in the treatment of neuroendocrine tumors (NET). Pre-therapeutic dosimetry using the area under the measured time-activity curve (AUC) is important. The sampling schedule for this dosimetry determines the accuracy and reliability of the obtained AUC.
The aim of this study was to investigate the effect of reduced number of measurement points (i.e., gamma camera image acquisition or serum measurements) on treatment planning accuracy in PRRT using 111In-labeled-diethylenetriaminopentaacetic acid-octreotide (DTPAOC; Octreoscan™).
Methods
Pre-therapeutic biokinetic data of 15 NET patients were investigated using a recently developed physiologically based pharmacokinetic (PBPK) model. Two parameter sets were determined (standard or iterative approach) and used for calculation of time-integrated activity coefficients (TIACs) for the tumor, kidneys, liver, spleen, serum, and whole body. TIACs obtained using the full data sets were used as reference. To evaluate the effect of sampling on individual treatment planning, reduced sampling schedules were generated omitting either 1, 2, 3, or 4 organ and serum measurements or all serum measurements for each patient. Relative deviations (RDs) between these and reference TIACs were calculated and used as criterion for treatment planning accuracy. An RD < 0.1 was considered acceptable.
Results
When omitting serum measurements, TIAC accuracy remained acceptable (RD < 0.1) for the standard approach. The kidney TIACs could be estimated for both approaches with acceptable RDs using two time points (t = 4 h; 2 d); tumor RDs were <0.3. The iterative approach reduced the range of RD, but did not further reduce the number of needed measurement points (i.e., to achieve an RD <0.1). For both approaches RDs for liver, spleen and whole body were larger than 0.1. However, in the clinical setting these RDs are less relevant as liver and spleen are not organs at risk due to the low absorbed doses.
Conclusions
When using a priori information of a PBPK model structure combined with Bayesian information about PBPK model parameter distribution, the administered activity could be determined with acceptable accuracy using only two time points (4 h, 2 d) and thus allow a considerable reduction of needed data for individual dosimetry.
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