Pharmacokinetic dose adjustment of 5-FU in modified FOLFOX7 plus bevacizumab for metastatic colorectal cancer in Japanese patients: a-JUST phase II clinical trial

Abstract

Purpose

Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC.

Methods

This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m² on day 1, infused leucovorin 200 mg/m², followed by a 2400 mg/m² infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate.

Results

The median initial area under the concentration–time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34–62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively.

Conclusions

Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.

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Prognostic contribution of mammographic breast density and HER2 overexpression to the Nottingham Prognostic Index in patients with invasive breast cancer

Abstract

Background

To investigate whether very low mammographic breast density (VLD), HER2, and hormone receptor status holds any prognostic significance within the different prognostic categories of the widely used Nottingham Prognostic Index (NPI). We also aimed to see whether these factors could be incorporated into the NPI in an effort to enhance its performance.

Methods

This study included 270 patients with newly diagnosed invasive breast cancer. Patients with mammographic breast density of <10 % were considered as VLD. In this study, we compared the performance of NPI with and without VLD, HER2, ER and PR. Cox multivariate analysis, time-dependent receiver operating characteristic curve (tdROC), concordance index (c-index) and prediction error (0.632+ bootstrap estimator) were used to derive an updated version of NPI.

Results

Both mammographic breast density (VLD) (p < 0.001) and HER2 status (p = 0.049) had a clinically significant effect on the disease free survival of patients in the intermediate and high risk groups of the original NPI classification. The incorporation of both factors (VLD and HER2 status) into the NPI provided improved patient outcome stratification by decreasing the percentage of patients in the intermediate prognostic groups, moving a substantial percentage towards the low and high risk prognostic groups.

Conclusions

Very low density (VLD) and HER2 positivity were prognostically significant factors independent of the NPI. Furthermore, the incorporation of VLD and HER2 to the NPI served to enhance its accuracy, thus offering a readily available and more accurate method for the evaluation of patient prognosis.

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Colorectal Carcinogenesis in the A/J Min/+ Mouse Model is Inhibited by Hemin, Independently of Dietary Fat Content and Fecal Lipid Peroxidation Rate

Abstract

Background

Intake of red meat is considered a risk factor for colorectal cancer (CRC) development, and heme, the prosthetic group of myoglobin, has been suggested as a potential cause. One of the proposed molecular mechanisms of heme-induced CRC is based on an increase in the rate of lipid peroxidation catalysed by heme.

Methods

In the present work, the novel A/J Min/+ mouse model for Apc-driven colorectal cancer was used to investigate the effect of dietary heme (0.5 μmol/g), combined with high (40 energy %) or low (10 energy %) dietary fat levels, on intestinal carcinogenesis. At the end of the dietary intervention period (week 3–11), spontaneously developed lesions in the colon (flat aberrant crypt foci (flat ACF) and tumors) and small intestine (tumors) were scored and thiobarbituric reactive substances (TBARS), a biomarker for lipid peroxidation was analysed in feces.

Results

Dietary hemin significantly reduced colonic carcinogenesis. The inhibitory effect of hemin was not dependent on the dietary fat level, and no association could be established between colonic carcinogenesis and the lipid oxidation rate measured as fecal TBARS. Small intestinal carcinogenesis was not affected by hemin. Fat tended to stimulate intestinal carcinogenesis.

Conclusions

Contradicting the hypothesis, dietary hemin did inhibit colonic carcinogenesis in the present study. The results indicate that fecal TBARS concentration is not directly related to intestinal lesions and is therefore not a suitable biomarker for CRC.

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Primary Immunodeficiencies Associated with EBV-Induced Lymphoproliferative Disorders

Publication date: Available online 2 November 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Mahsima Shabani, Kim E. Nichols, Nima Rezaei
Primary immunodeficiency diseases (PIDs) are a subgroup of inherited immunological disorders that increase susceptibility to viral infections. Among the range of viral pathogens involved, EBV remains a major threat because of its high prevalence of infection among the adult population and its tendency to progress to life-threatening lymphoproliferative disorders (LPDs) and/or malignancy. The high mortality in immunodeficient patients with EBV-driven LPDs, despite institution of diverse and often intensive treatments, prompts the need to better study these PIDs to identify and understand the affected molecular pathways that increase susceptibility to EBV infection and progression. In this article, we have provided a detailed literature review of the reported cases of EBV-driven LPDs in patients with PID. We discuss the PIDs associated with development of EBV-LPDs. Then, we review the nature and the therapeutic outcome of common EBV- driven LPDs in the PID patients and review the mechanisms common to the major PIDs. Deep study of these common pathways and gaining a better insight into the disease nature and outcomes, may lead to earlier diagnosis of the disease, choosing the best treatment modalities available and development of novel therapeutic strategies to decrease morbidity and mortality brought about by EBV infection.



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Quality indicators in the Intensity Modulated/Image-Guided Radiotherapy era

Publication date: Available online 2 November 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): P. Gabriele, A. Maggio, E. Garibaldi, C. Bracco, E. Delmastro, D. Gabriele, A. Rosi, F. Munoz, N. Di Muzio, R. Corvò, M. Stasi
PurposeTo propose new Quality Indicators (QIs) for the Intensity Modulated(IMRT)/Image-Guided(IGRT) Radiotherapy techniques.Materials and methodsTwo structure, 10 process and 2 outcome QIs were elaborated. A working group including Radiation Oncologist, Medical Physicist and Radiation Technologists was made up. A preliminary set of indicators was selected on the basis of evidenced critical issues; the criteria to identify more relevant and specific QIs for IMRT/IGRT were defined; structure, process and outcome QIs were defined. The elaborated indicators were tested in four Italian Radiotherapy Centers.ResultsFourteen indicators were proposed. Seven indicators were completely new while a new standard is proposed for four indicators based on Validation Centers (VC) data. No change was reported for 3 indicators. The indicators were applied in the four VC. The VC considered were able to respect all indicators except indicator 2 for one Center.Discussion and conclusionQIs may provide useful measures of workload and service performances.



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Structure of KRAS4b-PDEδ Complex

The three human RAS genes encode four proteins, HRAS, NRAS, and the alternatively spliced forms of KRAS, KRAS4a and KRAS4b. The RAS proteins are identical over their first 86 amino acids and highly homologous for the first 164 (out of 188 or 189 total). Consequently, it is thought that the involvement of different RAS mutants in different cancers is due largely to the C-terminal "hypervariable regions" (HVRs) of the proteins. All the RAS proteins are active only when they are bound to membranes, and they are localized there because their HVRs are modified with lipids, carboxymethyls (one carbon), thioether-linked farnesyl groups (three prenyls, 15 carbons) and thioester-linked palmitoyl groups (16 carbon fatty acid). All the processed RAS proteins have carboxy-terminal cysteines that are both methylated and farnesylated, and HRAS, NRAS, and KRAS4a, but not KRAS4b, have other cysteines in their HVRs that are palmitoylated. Instead, KRAS4b has a polybasic region that is believed to interact with negatively charged head groups of plasma membrane lipids. Thus, KRAS4b is thought to be uniquely dependent on farnesylation and the polybasic region for its membrane localization. Unfortunately, inhibitors of farneslyation proved disappointing as treatments for human cancers¹, as KRAS4b was found to undergo alternative prenylation by the addition of a geranylgeranyl (four prenyls, 20 carbons) group instead of a farnesyl group.

The lipid groups on RAS proteins are shielded from the aqueous environment of the cytosol by chaperones as they move to the inner leaflet of the plasma membrane. One of these, PDEδ, has been studied in some detail ^2,3. We have recently published the structures of two crystal forms of processed KRAS4b protein complexed with PDEδ⁴. The structures show for the first time all the amino acids of KRAS4b, including the HVR. Crystal form I reveals structural details of farnesylated–methylated KRAS4b binding to PDEδ, and crystal form II suggests the potential binding mode of geranylgeranylated–methylated KRAS4b to PDEδ. The structures and comparison of the HVRs of KRAS4b from other species show a 5-aa-long sequence motif in KRAS4b that may enable PDEδ to bind both forms of prenylated KRAS4b and thus may have an important and as yet unknown function in normal cells. Surprisingly, absence of the single methyl group that is normally part of the lipid modification of KRAS4b decreased its affinity for PDEδ by 30 fold. The structure revealed the basis for the higher affinity of the carboxymethylated form of the protein. Structure and sequence analysis of various prenylated proteins that have been previously tested for binding to PDEδ provides a rationale for why some prenylated proteins do not bind to PDEδ.

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Olaratumab Approved to Treat Advanced Soft Tissue Sarcoma

The Food and Drug Administration (FDA) has granted accelerated approval to olaratumab (Lartruvo®) for the treatment of some patients with soft tissue sarcoma.

The approval is for the use of olaratumab in combination with doxorubicin in patients with sarcoma that cannot be cured by radiation therapy or surgery and for whom anthracycline-based chemotherapy would be an appropriate treatment.

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Comparison of Yttrium-90 therapy for unresectable liver metastasis: glass versus biocompatible resin microspheres

Abstract

Objectives

Yttrium-90 radioembolization is a hepatic intra-arterial-based therapy using glass- or resin-based microspheres as carriers to deliver high-dose radiation to tumors to maximize dose while minimizing collateral damage. This study aimed to compare the safety and efficacy of glass (TheraSphere) versus resin (Selective Internal Radiation Spheres, SIR-Spheres) Y-90 in the treatment of intrahepatic metastatic disease.

Methods

A review of a prospectively collected, institutional review board-approved database was conducted to identify patients who underwent Y-90 therapy, excluding those with hepatocellular carcinoma (HCC).

Results

Of 119 patients, 79 received SIR-Spheres and 40 received TheraSphere therapy. For intrahepatic cholangiocarcinoma, mean survival was 10.6 months in the SIR-Spheres group compared to 29.2 months in the TheraSphere group (log-rank 0.05). In colorectal cancer (CRC), mean survival was 16.3 months for SIR-Spheres therapy and 26.8 for TheraSphere therapy (log-rank 0.097). There were no documented severe (grade 3) side effects in the TheraSphere group compared to 14 % of patients who experienced side effects in the SIR-Spheres group.

Conclusions

TheraSphere microsphere appears superior to SIR-Spheres in treating non-HCC intrahepatic malignancy. However, patient selection and better multi-disciplinary care may play a role in these differences. Continued studies in combination therapies for all hepatic malignancies is critical to the long-term success and sustainability of Y-90 therapy.

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Multi-Institutional Experience of Stereotactic Ablative Radiotherapy for Stage I Small Cell Lung Cancer

Publication date: Available online 2 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vivek Verma, Charles B. Simone, Pamela K. Allen, Sameer R. Gajjar, Chirag Shah, Weining Zhen, Matthew M. Harkenrider, Christopher L. Hallemeier, Salma K. Jabbour, Chance L. Matthiesen, Steve E. Braunstein, Percy Lee, Thomas J. Dilling, Bryan G. Allen, Elizabeth M. Nichols, Albert Attia, Jing Zeng, Tithi Biswas, Peter Paximadis, Fen Wang, Joshua M. Walker, John M. Stahl, Megan E. Daly, Roy H. Decker, Russell K. Hales, Henning Willers, Gregory M.M. Videtic, Minesh P. Mehta, Steven H. Lin
PurposeFor inoperable stage I (T1-2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with/without conventionally-fractionated radiotherapy. This multi-institutional cohort study investigated the role of stereotactic ablative radiotherapy (SABR) for this population.MethodsClinical/treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically-confirmed T1-T2N0M0 SCLC. Kaplan-Meier analysis evaluated survival outcomes. Univariate and multivariate analyses identified predictors of outcomes.ResultsFrom 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). Median age and tumor size were 72 years and 2.5cm, respectively. Chemotherapy and prophylactic cranial irradiation (PCI) were delivered in 56% and 23% of cases, respectively. Median SABR dose/fractionation was 50 Gy/5 fractions. One- and 3-year local control (LC) were 97.4% and 96.1%, respectively. Median disease-free survival (DFS) was 49.7 months (58.3% and 53.2% at 1- and 3-years, respectively). Median, 1-year, and 3-year disease-specific survival were 52.3 months, 84.5% and 64.4%, respectively. Median, 1-year, and 3-year overall survival (OS) were 17.8 months, 69.9% and 34.0% respectively. Patients receiving chemotherapy experienced increased median DFS (61.3 vs. 9.0 months, p=0.02) and OS (31.4 vs. 14.3 months, p=0.02). Chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (p=0.01). Toxicities were uncommon; 5.2% experienced grade ≥2 pneumonitis. Post-treatment failures were most commonly distant (45.8% of recurrences), followed by nodal (25.0%), and elsewhere lung (20.8%). Median times to each were between 5-7 months.ConclusionsIn the largest report on SABR for T1-2N0 SCLC to date, SABR (≥50Gy) with chemotherapy should be considered a standard option.

Teaser

For inoperable stage I (T1-2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with/without conventionally-fractionated radiotherapy. This multi-institutional cohort study demonstrated that stereotactic ablative radiotherapy together with chemotherapy provide appropriate local control and survival, and should thus be considered to treat these patients.


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Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy

Abstract

Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

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Metabolomics in pancreatic cancer biomarkers research

Abstract

Pancreatic cancer is one of the worst prognoses of all malignancies. More than 40,000 deaths a year from this disease are observed in European Union alone. The only possibly curative treatment of pancreatic cancer is surgery, yet only 15–20% of patients have operable disease and even patients, which go through surgery and adjuvant chemotherapy, survival is less than 30%. The sensitive and specific biomarkers which could be used for the advance of early diagnostics are needed and constantly researched. Metabolomics is a technology which analyzes the concentrations of low-molecular-weight metabolites (the metabolome) has lately effectively developed due to the improvements in analytical technology. Metabolome analysis can be a one of the useful approaches for the biomarker discovery and disease diagnosis. Here we discuss recent discoveries in the field of pancreatic cancer metabolomics as well as the most promising biomarkers for diagnostics, prognosis and prediction.

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rs15869 at miRNA binding site in BRCA2 is associated with breast cancer susceptibility

Abstract

BRCA1 and BRCA2 mutations confer an increased lifetime risk of breast cancer; however, the associations of microRNA (miRNA) binding site single nucleotide polymorphisms (SNPs) in 3′ untranslated region (3′-UTR) of BRCA1 and BRCA2 with breast cancer (BC) risk were rarely reported. In this case–control study (498 BC patients and 498 matched controls), three SNPs (rs8176318, rs12516 and rs15869) were selected in the 3′-UTR of BRCA1 and BRCA2 genes, which were within miRNA-binding seed regions and might have potential function to regulate the expression of BRCA1/BRCA2. Unconditional logistic regression model was used to analyze the association between three SNPs and BC risk with adjustment of reproductive factors, and Student's t test was performed to assess relative expression of BRCA2 in human breast cancer cell lines. Multifactor dimensionality reduction method was applied to calculate gene–reproductive factors interactions. A novel finding showed that AC [odds ratio (OR) 1.524; 95% confidence interval (CI) 1.141–2.035] genotype of rs15869 in BRCA2 could increase the risk of BC and recombinant plasmid-pGenesil-1-miR-627 could negatively regulate the expression of BRCA2 in MCF-7 and MDA-MB-231 cells. Gene–reproductive factors interactions analysis revealed that rs15869 together with age at menarche and number of pregnancy could increase the risk of BC by 2.39-fold and TT genotype (OR 0.316; 95% CI 0.130–0.767) of rs8176318 had a significant association with progesterone receptor status in BC patients. Our findings suggest that the miRNA-binding SNPs in BRCA1/BRCA2 and their interaction with reproductive factors might contribute to BC risk, and miR-627 might down-regulate BRCA2 expression in MCF-7 and MDA-MB-231 cells.

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Tumor lysis syndrome and metastatic melanoma

Abstract

Tumor lysis syndrome (TLS) is a potential emergent complication of oncologic treatment. TLS is commonly reported in hematological malignancies with rapid cell turnover rates, but is relatively rare in solid tumors. TLS is most frequently a result of cancer treatment in combination with a large tumor burden, but has occasionally been reported to occur spontaneously, especially in cases of advanced or metastatic disease. In this article, we describe the case of a patient with newly diagnosed metastatic melanoma that developed TLS two days after initiation of corticosteroids. In addition, we present a brief literature review of melanoma-associated TLS and review the etiology, diagnosis, and management of TLS.

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Correlation of geographic distributions of haptoglobin alleles with prevalence of multiple sclerosis (MS) – a narrative literature review

Abstract

We have proposed that the myelin damage observed in multiple sclerosis (MS) may be partly mediated through the long-term release and degradation of extracellular hemoglobin (Hb) and the products of its oxidative degradation [Cellular and Molecular Life Sciences, 71, 1789-1798, 2014]. The protein haptoglobin (Hpt) binds extracellular Hb as a first line of defense, and can serve as a vascular antioxidant. Humans have two different Hpt alleles: Hpt1 and Hpt2, giving either homozygous Hpt1-1 or Hpt2-2 phenotypes, or a heterozygous Hpt1-2 phenotype. We questioned whether those geographic regions with higher frequency of the Hpt2 allele (conversely, lower frequency of Hpt1 allele) would correlate with an increased incidence of MS, because different Hpt phenotypes will have variable anti-oxidative potentials in protecting myelin from damage inflicted by extracellular Hb and its degradation products. To test this hypothesis, we undertook a systematic analysis of the literature on reported geographic distributions of Hpt alleles to compare them with data reported in the World Health Organization Atlas of worldwide MS prevalence. We found the frequency of the Hpt1 allele to be low in European and North American countries with a high prevalence of MS, consistent with our hypothesis. However, this correlation was not observed in China and India, countries with the lowest Hpt1 frequencies, yet low reported prevalence of MS. Nevertheless, this work shows the need for continued refinement of geographic patterns of MS prevalence, including data on ethnic or racial origin, and for new clinical studies to probe the observed correlation and evaluate Hpt phenotype as a predictor of disease variability and progression, severity, and/or comorbidity with cardiovascular disorders.

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Frequency of inadequate neuromuscular blockade during general anesthesia

We used electronic health record data to define frequency of inadequate intraoperative neuromuscular blockade (NMB).

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The effect of play distraction on anxiety before premedication administration: a randomized trial

The majority of children scheduled to undergo surgery experience substantial anxiety in the preoperative holding area before induction of anesthesia. Pharmacological interventions aimed at reducing perioperative anxiety are paradoxically a source of stress for children themselves. Midazolam is frequently used as premedication, and the formula of this drug in Turkey is bitter. We aimed to assess the role of distraction in the form of playing with play dough (Play-Doh) on reducing premedication anxiety in children.

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