Plasma Circulating Proteins and Bevacizumab

Purpose: We examined whether pretreatment levels of angiogenesis- or hypoxia-related proteins and their changes after one cycle of first-line bevacizumab-based therapy were associated with response, PFS, or OS in patients with metastatic breast cancer.

Experimental Design: We included 181 patients enrolled in the phase II ATX trial evaluating first-line paclitaxel and bevacizumab without or with capecitabine (NTR1348). Plasma samples were analyzed for VEGF-A, soluble VEGFR2 (sVEGFR2), angiopoietin 2 (ANG2), soluble TIE2 (sTIE2), IL6, IL8, and carbonic anhydrase 9 (CA9). Baseline serum CA15-3 was documented. HR was adjusted for confounding factors. Where appropriate, an optimal cut-off value defining a high and a low group was determined with Martingale residuals.

Results: At baseline, multiple proteins were significantly associated with PFS (ANG2, IL6, IL8, CA9, CA15-3) and OS (ANG2, sTIE2, IL6, IL8, CA9, CA15-3). After one cycle, VEGF-A, ANG2, sTIE2, and IL8 significantly decreased, while sVEGFR2 and CA9 significantly increased. The relative change in sVEGFR2 (P = 0.01) and IL8 (P = 0.001) was associated with response. Defining optimal cut-off, patients with a high CA9 rise (>2.9%) had better PFS (HR 0.45) and OS (HR 0.54) than those with low/no rise.

Conclusions: Multiple angiogenesis- or hypoxia-related proteins were prognostic for PFS and OS. Molecular agents targeting these proteins might be beneficial in patients with high levels. Changes in IL8 or sVEGFR2 levels at second cycle appear predictive for response. Changes in CA9 levels during bevacizumab-based therapy for prediction of PFS and OS merit further study. Clin Cancer Res; 1–10. ©2015 AACR.

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ADJUVANT IMMUNOTHERAPY TO IMPROVE OUTCOME IN HIGH RISK PEDIATRIC SARCOMAS

PURPOSE: Patients with metastatic or relapsed pediatric sarcomas receive cytotoxic regimens that induce high remission rates associated with profound lymphocyte depletion, but ultimately few survive long-term. We administered adjuvant immunotherapy to patients with metastatic and recurrent pediatric sarcomas in an effort to improve outcomes. EXPERIMENTAL DESIGN: Mononuclear cells were collected via apheresis and tumor lysate was acquired via percutaneous biopsy at enrollment. Participants received standard anti-neoplastic therapy, followed by autologous lymphocytes, tumor lysate/KLH pulsed dendritic cell vaccinations ± recombinant human interleukin-7. Primary outcomes were toxicity and vaccine responses. Secondary outcomes were immune reconstitution, EFS and OS. RESULTS: Forty-three patients enrolled and 29 received immunotherapy. The regimen was well tolerated. Intent-to-treat analysis demonstrated 5-yr OS of 51% with significant differences based upon histologic group (63% vs 0% for Ewing/rhabdomyosarcoma vs other sarcomas) and response to standard therapy (74% no residual disease vs 0% residual disease). 5-yr intent-to-treat OS of patients with newly diagnosed metastatic Ewing/rhabdomyosarcoma was 77%, higher than previously reported in this population and higher than observed in a similar group treated with an earlier adjuvant immunotherapy regimen (25% 5-yr OS). T cell responses to autologous tumor lysate were identified in 62% of immunotherapy recipients and survival was higher in those patients (73% 5-yr OS with vs 37% without immune response, p=.017). Immune reconstitution, measured by CD4 count recovery, was significantly enhanced in subjects treated with recombinant human interleukin-7. CONCLUSION: Adjuvant immunotherapy may improve survival in patients with metastatic pediatric sarcoma.

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Phase II study of oral vitamin B 12 supplementation as an alternative to intramuscular injection for patients with non-small cell lung cancer undergoing pemetrexed therapy

Abstract

Purpose

A vitamin B12 supplement is required in pemetrexed single agent therapy. Intramuscular administration is the method of choice; however, oral administration is simpler and easier and may be sufficiently effective. We conducted a Phase II study to evaluate the safety of oral administration of vitamin B12 in patients with advanced non-small cell lung cancer who received pemetrexed single agent therapy.

Methods

Folic acid and vitamin B12 were given orally for ˃1 week before pemetrexed administration. The primary end-point was onset of a grade ≥3 neutropenia ratio (50 % of threshold expression ratios; an expectation expression ratio of 21 %; α, 0.05; β, 0.1). Blood concentration of folic acid and homocysteine which are markers of vitamin B12 deficiency were also examined (UMIN000003180).

Results

A total of 25 cases were registered from February 2010 to July 2014. The ratio of grade ≥3 neutropenia was 36 % (95 % CI 22–52 %). Grade ≥3 non-hematologic toxicity and hematologic toxicity were seen in 20 % (5 cases) and 44 % (11 cases) of patients, respectively. In addition, the homocysteine blood concentration just before the first cycle dosage of pemetrexed was significantly elevated relative to the 2–3 cycle.

Conclusion

This study failed to meet its primary endpoint. We could not demonstrate the safety and efficacy of the 1-week vitamin B12 oral administration protocol as compared with intramuscular administration.

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Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer

Abstract

Purpose

Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer.

Methods

TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30–40 mg/m² IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling.

Results

There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R ² = 0.61, p = 0.02), particularly in patients receiving PLD alone (R ² = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands.

Conclusions

TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

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HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients

Background:

We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation.

Methods:

Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPV-DNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16^INK4a, pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16^INK4a results.

Results:

A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPV-AF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16^INK4a, were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America.

Conclusions:

HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.

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Factors associated with sinus bradycardia during crizotinib treatment: a retrospective analysis of two large-scale multinational trials (PROFILE 1005 and 1007)

Abstract

Decreases in heart rate (HR) have been described in patients receiving crizotinib. We performed a large retrospective analysis of HR changes during crizotinib therapy. HRs from vital-sign data for patients with anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer enrolled in PROFILE 1005 and the crizotinib arm of PROFILE 1007 were analyzed. Sinus bradycardia (SB) was defined as HR <60 beats per minute (bpm). Magnitude and timing of HR changes were assessed. Potential risk factors for SB were investigated by logistic regression analysis. Progression-free survival (PFS) was evaluated according to HR decrease by <20 versus ≥20 bpm within the first 50 days of starting treatment. For the 1053 patients analyzed, the mean maximum postbaseline HR decrease was 25 bpm (standard deviation 15.8). Overall, 441 patients (41.9%) had at least one episode of postbaseline SB. The mean precrizotinib treatment HR was significantly lower among patients with versus without postbaseline SB (82.2 bpm vs. 92.6 bpm). The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. PFS was comparable among patients with or without HR decrease of ≥20 bpm within the first 50 days of starting crizotinib. Decrease in HR is very common among patients on crizotinib. The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. This is the first large-scale report investigating the association between treatment with a tyrosine kinase inhibitor and the development of bradycardia. HRs should be closely monitored during crizotinib treatment.

This large-scale retrospective analysis showed that decrease in heart rate (HR) is very common among patients treated with crizotinib. HR should be closely monitored during crizotinib treatment, and oncologists prescribing crizotinib should carefully assess the need for and dosing of concomitant medications that can induce a slowing of the HR, particularly beta-blockers.

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High-risk older smokers' perceptions, attitudes, and beliefs about lung cancer screening

Abstract

The US Preventive Services Task Force recommends that smokers aged 55–80 should be screened annually with low-dose computed tomography (LDCT). This study identified demographics, smoking history, health risk perceptions, knowledge, and attitudes factors of older smokers (≥55 years) related to LDCT agreement. Using binary logistic regression, a predictive model of factors to explain LDCT agreement was produced. This is a cross-sectional, national, online survey of 338 older smokers (≥55 years) with a ≥30 pack-year smoking history. Over 82% of the sample believed that a person who continues to smoke after the age of 40 has at least a 25% chance of developing lung cancer and 77.3% would "agree to a LDCT today". Using chi-square analyses, six variables that were significant at the 0.10 level were selected for inclusion in model development. Four of the independent variables made a unique statistically significant contribution to the model: perceives accuracy of the LDCT as an important factor in the decision to have a LDCT scan; believes that early detection of LC will result in a good prognosis; believes that they are at high risk for lung cancer; and is not afraid of CT scans. Of note, only 10.9% believed that a negative CT scan result would mean that they could continue to smoke. Older smokers are aware of the risks of smoking, are interested in smoking cessation, and most are interested in and positive about LDCT. Cognitive aspects of participation in screening are key to increasing the uptake of lung cancer screening among high-risk smokers.

Older smokers are aware of the risks of smoking, interested in smoking cessation, and are positive about lung cancer screening. Cognitive aspects of participation in screening are key to increasing the uptake of lung cancer screening among high-risk smokers.

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Identification of AIM2 as a downstream target of JAK2V617F

Abstract

Background

The gain-of-function mutation JAK2V617F is frequently found in Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN) patients. However, the tumorigenic properties of JAK2V617F have mostly been characterized in in vivo and in vitro murine models due to the lack of appropriate human cell lines.

Methods

Using the multipotent hematologic cell line UT-7/GM, we established D9, a novel human cell line that expresses JAK2V617F upon tetracycline addition. We assessed cellular differentiation in UT-7/GM cells when JAK2V617F was induced, and we used microarrays to analyze changes in mRNA expression caused by JAK2V617F.

Results

Using the human D9 cell line, we demonstrated that the induction of JAK2V617F leads to cytokine-independent cell growth with increased STAT activation and erythroid differentiation, mimicking the characteristics observed in polycythemia vera, making it a suitable in vitro model for studying this disorder. Interestingly, JAK2V617F-dependent erythroid cell differentiation was blocked when GM-CSF was added to the culture, suggesting that the GM-CSF pathway antagonizes JAK2V617F-induced erythroid cell differentiation. Our microarray analysis identified several genes involved in inflammasome activation, such as AIM2, IL1B, and CASP1, which were significantly up-regulated in JAK2V617F-induced cells.

Conclusions

The observed inflammasome activation following JAK2V617F induction is consistent with a recent report demonstrating the involvement of IL1B in myelofibrosis development in a JAK2V617F model mouse. These results indicate that the D9 cell line should be useful for characterizing the signaling pathways downstream of JAK2V617F, allowing for the identification of effector molecules that contribute to the development of MPN.

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Video Intervention Helps Prepare Patients to Participate in Cancer Clinical Trials

Educating patients with cancer about clinical trials prior to their first visit with their oncologist can improve their ability to make decisions about whether to enroll in a trial, according to a new study.

Patients in the study who took part in a tailored, video-based educational program had a better understanding of clinical trials and fewer concerns about issues such as randomization and side effects than patients who received text-based educational materials, the study authors reported. Overall, however, regardless of the type of educational material patients received, eventual enrollment in a clinical trial was much higher among patients in the study than is typically seen in clinical practice.

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A prospective ascertainment of cancer incidence in sub-Saharan Africa: The case of Kaposi sarcoma

Abstract

In resource-limited areas, such as sub-Saharan Africa, problems in accurate cancer case ascertainment and enumeration of the at-risk population make it difficult to estimate cancer incidence. We took advantage of a large well-enumerated healthcare system to estimate the incidence of Kaposi sarcoma (KS), a cancer which has become prominent in the HIV era and whose incidence may be changing with the rollout of antiretroviral therapy (ART). To achieve this, we evaluated HIV-infected adults receiving care between 2007 and 2012 at any of three medical centers in Kenya and Uganda that participate in the East Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortium. Through IeDEA, clinicians received training in KS recognition and biopsy equipment. We found that the overall prevalence of KS among 102,945 HIV-infected adults upon clinic enrollment was 1.4%; it declined over time at the largest site. Among 140,552 patients followed for 319,632 person-years, the age-standardized incidence rate was 334/100,000 person-years (95% CI: 314–354/100,000 person-years). Incidence decreased over time and was lower in women, persons on ART, and those with higher CD4 counts. The incidence rate among patients on ART with a CD4 count >350 cells/mm³ was 32/100,000 person-years (95% CI: 14–70/100,000 person-years). Despite reductions over time coincident with the expansion of ART, KS incidence among HIV-infected adults in East Africa equals or exceeds the most common cancers in resource-replete settings. In resource-limited settings, strategic efforts to improve cancer diagnosis in combination with already well-enumerated at-risk denominators can make healthcare systems attractive platforms for estimating cancer incidence.

Estimation of incidence is fundamental to cancer epidemiology but poses considerable challenges in resource-limited settings. In East Africa, we demonstrate how a focused effort to improve cancer diagnosis in combination with an already well-enumerated at-risk denominator made a healthcare system-based population fertile ground for estimating the incidence of Kaposi sarcoma (KS). We show that the overall incidence of KS in HIV-infected adults far exceeds the incidence of the most common cancers in resource-rich settings.

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Clinical significance of postoperative recovery of serum albumin levels in patients with esophageal cancer who underwent transthoracic esophagectomy

Abstract

Purpose

We evaluated postoperative recovery after transthoracic esophagectomy using postoperative serum albumin (Alb) levels and investigated the correlation between postoperative Alb recovery and the survival of patients with esophageal cancer.

Methods

Esophageal cancer patients who underwent transthoracic esophagectomy were retrospectively reviewed. To evaluate postoperative Alb recovery, the recovery rate of Alb was used. We investigated the correlation between Alb recovery, clinicopathological factors, and the survival. Furthermore, the postoperative systemic inflammatory response was evaluated using serum C-reactive levels, and its impact on the Alb recovery was examined.

Results

Ninety-seven (51 %) of 191 patients were classified as having insufficient Alb recovery. In the multivariate survival analysis, pStage and insufficient Alb recovery (hazard ratio 1.863; P = 0.021) were significantly independent predictive factors for the overall survival. Patients with pStage IB–IV with insufficient Alb recovery had a significantly shorter recurrence-free survival (5-year recurrence-free survival rate, 59.5 vs. 41.5 %; P = 0.035) and significantly higher serum CRP levels at POM 3 compared with patients with sufficient Alb recovery.

Conclusions

Insufficient Alb recovery correlates with the systemic postoperative inflammatory response and a poor prognosis. Further studies are warranted to investigate the survival benefit of intervention to enhance postoperative Alb recovery.

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Differential Protein Expression Profiles in Glaucomatous Trabecular Meshwork: An Evaluation Study on a Small Primary Open Angle Glaucoma Population

Abstract

Introduction

Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis.

Methods

TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies.

Results

A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1δ/α, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGFβ1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGFβ1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes.

Conclusion

The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFαRI). A larger POAG population is required to select promising disease-associated biomarker candidates.

Funding

This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the "National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation".

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Evaluation of Effectiveness and Safety of High-Dose Daptomycin: Results from Patients Included in the European Cubicin ® Outcomes Registry and Experience

Abstract

Introduction

Daptomycin, a rapid concentration-dependent bactericidal antibiotic, is approved at a dose of 4 mg/kg/day for the treatment of complicated skin and soft tissue infections (cSSTI) and at a dose of 6 mg/kg/day for the treatment of Staphylococcus aureus right-sided infective endocarditis (RIE) and bacteremia associated with cSSTI and RIE. Studies have reported the successful use of high-dose daptomycin (>6 mg/kg/day) in patients with difficult-to-treat infections. The present analysis evaluated the effectiveness and safety of high doses (>6 mg/kg/day) of daptomycin for the treatment of different Gram-positive infections.

Methods

European Cubicin^® Outcomes Regi

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Lack of anti-tumor activity by anti-VEGF treatments in hepatic hemangiomas

Abstract

Recently, anti-vascular endothelial growth factor (anti-VEGF) agents have been described in the literature as a valid treatment option for symptomatic liver hemangiomas, but only limited evidence supports this notion. The purpose of this study was to elucidate whether or not the administration of anti-VEGF agents can reliably achieve a size reduction in liver hemangiomas. We examined patients with incidental hemangiomas who received anti-angiogenic agents for the treatment of other malignancies. Our study population consisted of 17 colorectal cancer patients and one lung cancer patient carrying 21 hemangiomas who received bevacizumab, and seven renal cell carcinoma patients carrying nine hepatic hemangiomas who received sunitinib. We have measured the liver hemangioma volume on both the pre-treatment and post-treatment computed tomography images and then calculated the volume alteration rates. No statistically significant difference (P = 0.365) in the volume of the liver hemangiomas was observed before (1.1–168.8 cm³; mean ± SD 19.8 ± 39.7 cm³) or after (1.2–163.6 cm³; 19.3 ± 38.0 cm³) bevacizumab treatment. The volume reduction rate ranged from −35.0 to 11.2 % (mean ± SD −1.3 ± 10.8 %). The sunitinib treatment group also showed no statistically significant difference (P = 0.889) in hemangioma volume before (1.2–6.5 cm³; 3.0 ± 1.8 cm³) or after (1.2–6.0 cm³; 3.0–1.7 cm³) treatment. The volume reduction rate ranged from −13.3 to 7.7 % (median: mean ± SD −2.5 ± 6.6 %). We did not observe liver hemangioma shrinkage after bevacizumab or sunitinib treatment. Our data do not support the application of anti-VEGF agents for the treatment of hepatic hemangiomas.

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