Bromodomain and extraterminal protein (BET) inhibitors suppress the expression of c-MYC. U266, a human myeloma cell line, expresses the MYCL gene, but not the c-MYC gene. Our aim was to analyse the antimyeloma activity of BET inhibitors on U266 cells. Two BET inhibitors, I-BET151 and JQ1, were tested. U266 cell proliferation decreased to 61.5 and 54.0% of the control after incubation with 500 nmol/l I-BET151 for 72 and 96 h and to 53.5 and 56.4% of control after incubation with 500 nmol/l JQ1 for 72 and 96 h by MTS tetrazolium, respectively. BET inhibitors induced cell cycle arrest at the G1 phase in U266 cells, but did not induce apoptosis by flow cytometry. According to Gene Set Enrichment Analysis, MYC-related genes were significantly downregulated in U266 cells treated with I-BET151 similar to KMS11 cells that expressed c-MYC. The MYCL1 was expressed in U266 cells, whereas c-MYC and MYCN were not by quantitative real-time reverse-transcription-PCR. Incubation with I-BET151 induced downregulation of MYCL1 in U266 cells. BET inhibitors decreased the cell proliferation in U266 cells with overexpression of MYCL less than those without overexpression of MYCL. BET inhibitors induce G1 arrest without apoptosis and interfere with the proliferation of U266 myeloma cells, which express MYCL, but not c-MYC. BET inhibitors might be active in cancers that express MYCL, but not c-MYC. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1hexVwJ Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 8 Ιουνίου 2016
Identification and characterization of two cleavage fragments from the Aquareovirus nonstructural protein NS80
Abstract
Aquareovirus species vary with respect to pathogenicity, and the nonstructural protein NS80 of aquareoviruses has been implicated in the regulation of viral replication and assembly, which can form viral inclusion bodies (VIBs) and recruit viral proteins to its VIBs in infected cells. NS80 consists of 742 amino acids with a molecular weight of approximately 80 kDa. Interestingly, a short specific fragment of NS80 has also been detected in infected cells. In this study, an approximately 58-kDa product of NS80 was confirmed in various infected and transfected cells by immunoblotting analyses using α-NS80C. Mutational analysis and time course expression assays indicated that the accumulation of the 58-kDa fragment was related to time and infection dose, suggesting that the fragment is not a transient intermediate of protein degradation. Moreover, another smaller fragment with a molecular mass of approximately 22 kDa was observed in transfected and infected cells by immunoblotting with a specific anti-FLAG monoclonal antibody or α-NS80N, indicating that the 58-kDa polypeptide is derived from a specific cleavage site near the amino terminus of NS80. Additionally, different subcellular localization patterns were observed for the 22-kDa and 58-kDa fragments in an immunofluorescence analysis, implying that the two cleavage fragments of NS80 function differently in the viral life cycle. These results provide a basis for additional studies of the role of NS80 played in replication and particle assembly of the Aquareovirus.
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Association of the miR-146a rs2910164 polymorphism with gastric cancer susceptibility and prognosis
Future Oncology Ahead of Print.
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Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer
Future Oncology Ahead of Print.
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Association of the miR-146a rs2910164 polymorphism with gastric cancer susceptibility and prognosis
Future Oncology Ahead of Print.
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Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer
Future Oncology Ahead of Print.
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Extension of overall survival beyond objective responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2
Abstract
Purpose
In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16–20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment.
Materials and methods
All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988–2013) and University of Michigan (1997–2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months.
Results
391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48–1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39–1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09–0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23–0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable.
Conclusions
Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.
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68 Ga-PSMA ligand PET/CT in patients with prostate cancer: How we review and report
Abstract
Recently, positron emission tomography (PET) imaging using PSMA-ligands has gained high attention as a promising new radiotracer in patients with prostate cancer (PC). Several studies promise accurate staging of primary prostate cancer and restaging after biochemical recurrence with 68Ga-PSMA ligand Positron emission tomography/computed tomography (PET/CT). However, prospective trials and clinical guidelines for this new technique are still missing. Therefore, we summarized our experience with 68Ga-PSMA ligand PET/CT examinations in patients with primary PC and biochemical recurrence. It focuses on the technical and logistical aspects of 68Ga-PSMA ligand PET/CT examination as well as on the specific background for image reading discussing also potential pitfalls. Further, it includes relevant issues on free-text as well as structured reporting used in daily clinical routine.
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Extension of overall survival beyond objective responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2
Abstract
Purpose
In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16–20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment.
Materials and methods
All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988–2013) and University of Michigan (1997–2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months.
Results
391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48–1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39–1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09–0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23–0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable.
Conclusions
Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.
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Rare occurrence of metastasis from lung cancer to the anus: case report and review of the literature
Abstract
Background
Anal metastases from lung cancer are infrequent, and there are only 10 published cases. Life expectancy is no longer than 1 year after diagnosis because of the typically advanced stage of disease. Treatment, which is typically inefficient, is administered with the intent to cure or avoid local complications.
Case presentation
We report a case of a patient with non-small cell lung cancer presenting with perianal metastasis mimicking an abscess.
Conclusions
Because perianal masses may be misdiagnosed, patients with lung and other cancers should be evaluated for metastatic disease.
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Has the ‘Fast-Track’ referral system affected the route of presentation and/or clinical outcomes in patients with colorectal cancer?
Abstract
Background
The aim of this study is to determine whether the 'Fast-Track' referral system has changed the route by which patients present with colorectal cancer (CRC) and whether the route of presentation has any effect on clinical outcome.
Methods
A retrospective cohort study of patients diagnosed with CRC under the care of two consultant colorectal surgeons between April 2006 and December 2012. The route by which patients presented was categorised as Fast-Track (FT), non-Fast-Track (non-FT) or acute. Outcome variables were operative intent, disease stage and 2- and 5-year survival.
Results
A total of 558 patients were identified. One hundred ninety-seven patients (35.3 %) were referred as FT, 108 (19.4 %) presented acutely and 253 patients (45.3 %) presented via other routes (non-FT). Over the study period, the route of presentation did not change significantly (P = 0.135). There was no significant difference between FT and non-FT groups in terms of the proportion of patients undergoing potentially curative surgery (70.6 vs 74.3 %, P = 0.092) or with node-negative disease (48.2 vs 52.2 %, P = 0.796) nor was there any difference in 2-year or 5-year survival (74.1 vs 73.9 %, P = 0.837 and 52.3 vs 53.8 %, P = 0.889, respectively). Patients who presented acutely were less likely to undergo curative resection, had more advanced disease and had worse 2- and 5-year survival.
Conclusions
The Fast-Track referral system has not affected the route by which patients present with CRC nor has it had any effect on clinical outcomes. Alternative strategies are required if the desired improvement in outcomes is to be achieved.
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Identification of eight novel SDHB , SDHC , SDHD germline variants in Danish pheochromocytoma/paraganglioma patients
Abstract
Background
Germline mutations in the succinate dehydrogenase complex genes SDHB, SDHC, and SDHD predispose to pheochromocytomas and paragangliomas. Here, we examine the SDHB, SDHC, and SDHD mutation spectrum in the Danish population by screening of 143 Danish pheochromocytoma and paraganglioma patients.
Methods
Mutational screening was performed by Sanger sequencing or next-generation sequencing. The frequencies of variants of unknown clinical significance, e.g. intronic, missense, and synonymous variants, were determined using the Exome Aggregation Consortium database, while the significance of missense mutations was predicted by in silico and loss of heterozygosity analysis when possible.
Results
We report 18 germline variants; nine in SDHB, six in SDHC, and three in SDHD. Of these 18 variants, eight are novel. We classify 12 variants as likely pathogenic/pathogenic, one as likely benign, and five as variants of unknown clinical significance.
Conclusions
Identifying and classifying SDHB, SDHC, and SDHD variants present in the Danish population will augment the growing knowledge on variants in these genes and may support future clinical risk assessments.
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Circulating activin A is a novel prognostic biomarker in malignant pleural mesothelioma – A multi-institutional study
Publication date: August 2016
Source:European Journal of Cancer, Volume 63
Author(s): Mir Alireza Hoda, Yawen Dong, Anita Rozsas, Thomas Klikovits, Viktoria Laszlo, Bahil Ghanim, Paul Stockhammer, Judit Ozsvar, Marko Jakopovic, Miroslav Samarzija, Luka Brcic, Matyas Bendek, Ildiko Szirtes, Glen Reid, Michaela B. Kirschner, Steven C. Kao, Isabelle Opitz, Walter Weder, Thomas Frauenfelder, Thi Dan Linh Nguyen-Kim, Clemens Aigner, Walter Klepetko, Nico van Zandwijk, Walter Berger, Balazs Dome, Michael Grusch, Balazs Hegedus
IntroductionThe deregulation of activin expression is often observed in various malignancies. Previous studies indicate that activin A plays a protumourigenic role in malignant pleural mesothelioma (MPM). The aim of the study was to evaluate circulating activin A level as a biomarker in MPM.MethodsPlasma samples were collected from 129 MPM patients in four institutions at the time of diagnosis or before surgical resection. Samples from 45 healthy individuals and from 16 patients with non-malignant pleural diseases served as controls. Circulating activin A was measured by enzyme-linked immunosorbent assay and correlated to clinicopathological variables.ResultsPlasma activin A level was significantly elevated in MPM patients (862 ± 83 pg/ml) when compared to healthy controls (391 ± 21 pg/ml; P < 0.0001). Patients with pleuritis or fibrosis only showed a modest increase (versus controls; 625 ± 95 pg/ml; P = 0.0067). Sarcomatoid (n = 10, 1629 ± 202 pg/ml, P = 0.0019) and biphasic (n = 23, 1164 ± 233 pg/ml, P = 0.0188) morphology were associated with high activin A levels when compared to epithelioid histology (n = 94, 712 ± 75 pg/ml). The tumour volume showed a positive correlation with increased circulating activin A levels. MPM patients with below median activin A levels had a significantly longer overall survival when compared to those with high activin A levels (median survival 735 versus 365 d, P < 0.0001). Importantly, circulating activin A levels were exclusively prognostic in epithelioid MPM.ConclusionsOur findings suggest that the measurement of circulating activin A may support the histological classification of MPM and at the same time help to identify epithelioid MPM patients with poor prognosis.
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The Radiation Oncology Job Market: The Economics and Policy of Workforce Regulation
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Benjamin P. Falit, Hubert Y. Pan, Benjamin D. Smith, Brian M. Alexander, Anthony L. Zietman
Examinations of the US radiation oncology workforce offer inconsistent conclusions, but recent data raise significant concerns about an oversupply of physicians. Despite these concerns, residency slots continue to expand at an unprecedented pace. Employed radiation oncologists and professional corporations with weak contracts or loose ties to hospital administrators would be expected to suffer the greatest harm from an oversupply. The reduced cost of labor, however, would be expected to increase profitability for equipment owners, technology vendors and entrenched professional groups. Policymakers must recognize that the number of practicing radiation oncologists is a poor surrogate for clinical capacity. There is likely to be significant opportunity to augment capacity without increasing the number of radiation oncologists by improving clinic efficiency and offering targeted incentives for geographic redistribution. Payment policy changes significantly threaten radiation oncologist income, which may encourage physicians to care for greater patient loads, thereby obviating the need for more personnel. Furthermore, the implementation of alternative payment models such as Medicare's Oncology Care Model, threatens to decrease both the utilization and price of radiotherapy by turning referring providers into cost-conscious consumers. Medicare funds the vast majority of Graduate Medical Education, but it is unclear the extent to which the expansion in radiation oncology residency slots has been externally funded. Excess physician capacity carries a significant risk of harm to society by suboptimally allocating intellectual resources and creating comparative shortages in other, more needed disciplines. There are practical concerns associated with a market-based solution in which medical students self-regulate according to job availability, but antitrust law would likely forbid collaborative self-regulation that purports to restrict supply. Since Congress is unlikely to create one central body to govern residency controls for all specialties, we recommend better reporting of program-specific employment metrics and careful, intellectually honest re-evaluation of existing ACGME accreditation standards.
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CD24 Expression May Play a Role as a Predictive Indicator and a Modulator of Cisplatin Treatment Response in Head and Neck Squamous Cellular Carcinoma
by Vishnu Modur, Pooja Joshi, Daotai Nie, K. Thomas Robbins, Aziz U. Khan, Krishna Rao
Platinum-based therapy is most often used to treat advanced cases of head and neck cancers, but only a small fraction of the patient population responds to cisplatin, with a median survival time of less than a year. Although gene signatures and molecular etiology of head and neck cancers have been previously described, none of them are predictive indicators of cisplatin treatment response in particular. Therefore, currently, there is a lack of clinically employable predictive indicators of the disease beyond HPV status to specifically predict patients' response to platinum-based therapy. It beckons a substantial effort to look for predictive indicators of cisplatin treatment response. In this regard, CD24 expression level appears to be a significant molecular phenotype of cisplatin-resistant residual cells in laryngeal carcinoma lines. CD24 expression level directly affects cisplatin sensitivity and affects the expression of critical apoptotic, stem and drug resistance genes. A relatively small retrospective patient tumor analysis suggests that CD24 high tumors go on to show an unfavorable response to cisplatin treatment. Overall, based on the strength of further analysis, CD24 presents a strong rationale to be utilized as a predictive indicator to stratify head and neck cancer patients for platinum-based therapy. It also provides a rationale for using CD24 as a therapeutic adjuvant target along with standard cisplatin therapy.from Cancer via ola Kala on Inoreader http://ift.tt/2187eiY
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Different outcomes among favourable and unfavourable intermediate-risk prostate cancer patients treated with hypofractionated radiotherapy and androgen deprivation therapy
to evaluate the role of a risk stratification system in intermediate-risk prostate cancer (PCa) treated with hypofractionated radiotherapy (HyRT).
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A Nomogram to predict parotid gland overdose in head and neck IMRT
To generate a nomogram to predict parotid gland (PG) overdose and to quantify the dosimetric benefit of weekly replanning based on its findings, in the context of intensity-modulated radiotherapy (IMRT) for lo...
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Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy
Abstract
The rapidly expanding feto-placental vasculature needs tight control by paracrine and endocrine mechanisms. Here, we focused on paracrine influence by trophoblast, the placental epithelium. We aimed to identify differences in regulation of feto-placental angiogenesis in early versus late pregnancy. To this end, the effect of conditioned media (CM) from early and late pregnancy human trophoblast was tested on network formation, migration and proliferation of human feto-placental endothelial cells. Only CM of late pregnancy trophoblast reduced network formation and migration. Screening of trophoblast transcriptome for anti-angiogenic candidates identified pigment epithelium-derived factor (PEDF) with higher expression and protein secretion in late pregnancy trophoblast. Addition of a PEDF-neutralizing antibody restored the anti-angiogenic effect of CM from late pregnancy trophoblast. Notably, human recombinant PEDF reduced network formation only in combination with VEGF. Also in the CAM assay, the combination of PEDF with VEGF reduced branching of vessels below control levels. Analysis of phosphorylation of ERK1/2 and FAK, two key players in VEGF-induced proliferation and migration, revealed that PEDF altered VEGF signaling, while PEDF alone did not affect phosphorylation of ERK1/2 and FAK. These data suggest that the trophoblast-derived anti-angiogenic molecule PEDF is involved in restricting growth and expansion of the feto-placental endothelium predominantly in late pregnancy and targets to modulate the intracellular effect of VEGF.
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Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites
Abstract
Purpose
Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects.
Methods
Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC.
Results
No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4–9.3 and 4.7–7.3 h, maximum concentration of 795.6–3742.6 and 493.3–3746 ng/mL, half-life of 1.7–5.9 and 2.3–6.9 h, and 0–12 h area under the curve of 4518.7–20,781.4 and 1987.7–22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30–60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed.
Conclusions
Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.
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Dose to specific subregions of pelvic bone marrow defined with FDG-PET as a predictor of hematologic nadirs during concomitant chemoradiation in anal cancer patients
Abstract
To test the hypothesis that irradiated volume of specific subregions of pelvic active bone marrow as detected by 18FDG-PET may be a predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation, we analyzed 44 patients submitted to IMRT and concurrent chemotherapy. Several bony structures were defined: pelvic and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. Active BM was characterized employing 18FDG-PET and characterized in all subregions as the volume having standard uptake values (SUVs) higher than SUVmean. All other regions were defined as inactive BM. On dose–volume histograms, dosimetric parameters were taken. Endpoints included white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin (Hb) and platelet (Plt) nadirs. Generalized linear modeling was used to find correlations between dosimetric variables and blood cells nadirs. WBC nadir was significantly correlated with LSBM mean dose (β = −1.852; 95 % CI −3.205/−0.500; p = 0.009), V10 (β = −2.153; 95 % CI −4.263/−0.721; p = 0.002), V20 (β = −2.081; 95 % CI −4.880/−0.112; p = 0.003), V30 (β = −1.971; 95 % CI −4.748/−0.090; p = 0.023) and IBM V10 (β = −0.073; 95 % CI −0.106/−0.023; p = 0.016). ANC nadir found to be significantly associated with LSBM V10 (β = −1.878; 95 % CI −4.799/−0.643; p = 0.025), V20 (β = −1.765; 95 % CI −4.050/−0.613; p = 0.030) and IBM V10 (β = −0.039; 95 % CI −0.066/−0.010; p = 0.027). Borderline significance was found for correlation between Plt nadir and LSBM V30 (β = −0.056; 95 % CI −2.748/−0.187; p = 0.060), V40 (β = −0.059; 95 % CI −3.112/−0.150; p = 0.060) and IBM V30 (β = −0.028; 95 % CI −0.074/−0.023; p = 0.056). No inactive BM subsites were found to be correlated with any blood cell nadir. 18FDG-PET is able to define active bone marrow within pelvic osseous structures. LSBM is the strongest predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation.
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Patients with hepatic breast cancer metastases demonstrate highly specific profiles of matrix metalloproteinases MMP-2 and MMP-9 after SIRT treatment as compared to other primary and secondary liver tumours
Abstract
Background
Patients with primary and metastatic liver malignancies represent a highly heterogeneous patient pool characterised by some of the shortest life expectancies amongst oncology patients. Investigation and better understanding of liver malignancies is an emerging field which requires high-quality multidisciplinary research and collaboration.
Methods
A study of 158 patients with primary hepatic carcinomas and secondary liver metastases, altogether 15 cancer types of different origin, who underwent selective internal radiation therapy (SIRT) with Yttrium90 or transarterial chemoembolisation, was undertaken in an effort to detect distinguishing features with respect to activity profiles of both blood matrix metalloproteinase (MMP-2 and MMP-9).
Results
Noteworthy, stratification of all hepatic cancer groups with respect to MMP-2 and MMP-9 activities revealed characteristic patterns specifically in patients with hepatic breast cancer metastases who had undergone SIRT. In contrast to all other groups, these patients demonstrated well-consolidated profiles of both MMPs, reflecting a common feature, namely an immediate and durable increase of their activity after the SIRT treatment. Although the total number of patients in the breast cancer group is relatively small (15 patients), since increased activities of MMP-2 and MMP-9 are well known prognostic factors for poor outcomes of oncologic patients, the significance and clear group-specificity (from 15 ones investigated here) of this previously unanticipated finding requires particular attention and further investigations. Particularly important is to determine, whether this increase of the metalloproteinase activity was provoked by SIRT, as well as whether special selection criteria are required for patients with breast cancer metastases to the liver who are being considered for SIRT.
Conclusions
It is recommended that a more focused, multidisciplinary and large-scaled investigations of the possible adverse effects of SIRT in patients with advanced metastatic disease of breast cancer be undertaken, with an appropriate patients' stratification, set-up of the relevant patient profiles and disease modelling.
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Different outcomes among favourable and unfavourable intermediate-risk prostate cancer patients treated with hypofractionated radiotherapy and androgen deprivation therapy
Abstract
Background
to evaluate the role of a risk stratification system in intermediate-risk prostate cancer (PCa) treated with hypofractionated radiotherapy (HyRT).
Methods
131 patients affected by intermediate-risk PCa were treated with HyRT at the total dose of 54,75 Gy in 15 fraction plus 9 months of androgen deprivation therapy (ADT). Patients were classified as favourable risk (FIR) if they had a single NCCN intermediate-risk factor (IRF), a Gleason score ≤3 + 4 = 7, and <50 % of biopsy cores containing cancer (PBCC). If these criteria were not met were classified as unfavourable risk (UIR). Univariate and multivariate analyses using Cox proportional hazards model were calculated for biochemical recurrence-free survival (bRFS), the risk of local recurrence and metastasis-free survival (MFS).
Results
After a median follow-up of 56.7 months (range 9.8 to 93.7 months), 11 patients (8.4 %) died, of whom 2 (1.5 %) for PCa. In the univariate analysis, Gleason score, PPBCs, IRFs and PSA at first follow-up were prognostic factors for bRFS and LF while Gleason score, PPBCs and PSA at first follow-up were significant predictor for MFS. In the multivariate analysis only the PSA at first follow-up resulted a prognostic factor for bRFS and MFS. Patients with a value of PSA at first follow-up <0.7 ng/mL respect to those with PSA ≥0,7 ng/mL had a 5y-bRFS of 93.3 % vs. 57.5 %, 5y-MFS of 99.0 % vs. 78.9 % and 5y-LF of 5.8 % vs. 38.3 %. Patients in the UIR PCa group with a PSA value <0.7 ng/mL at first follow-up had significant better bRFS, LF and MFS.
Conclusions
Risk factors currently not included in the guidelines are useful to stratify patients with intermediate-risk PCa in two groups of different prognosis even when HyRT is delivered. PSA at first follow-up is useful in UIR PCa to guide the overall length of ADT.
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A Nomogram to predict parotid gland overdose in head and neck IMRT
Abstract
Purposes
To generate a nomogram to predict parotid gland (PG) overdose and to quantify the dosimetric benefit of weekly replanning based on its findings, in the context of intensity-modulated radiotherapy (IMRT) for locally-advanced head and neck carcinoma (LAHNC).
Material and methods
Twenty LAHNC patients treated with radical IMRT underwent weekly computed tomography (CT) scans during IMRT. The cumulated PG dose was estimated by elastic registration. Early predictors of PG overdose (cumulated minus planned doses) were identified, enabling a nomogram to be generated from a linear regression model. Its performance was evaluated using a leave-one-out method. The benefit of weekly replanning was then estimated for the nomogram-identified PG overdose patients.
Results
Clinical target volume 70 (CTV70) and the mean PG dose calculated from the planning and first weekly CTs were early predictors of PG overdose, enabling a nomogram to be generated. A mean PG overdose of 2.5Gy was calculated for 16 patients, 14 identified by the nomogram. All patients with PG overdoses >1.5Gy were identified. Compared to the cumulated delivered dose, weekly replanning of these 14 targeted patients enabled a 3.3Gy decrease in the mean PG dose.
Conclusion
Based on the planning and first week CTs, our nomogram allowed the identification of all patients with PG overdoses >2.5Gy to be identified, who then benefitted from a final 4Gy decrease in mean PG overdose by means of weekly replanning.
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Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites
Abstract
Purpose
Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects.
Methods
Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC.
Results
No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4–9.3 and 4.7–7.3 h, maximum concentration of 795.6–3742.6 and 493.3–3746 ng/mL, half-life of 1.7–5.9 and 2.3–6.9 h, and 0–12 h area under the curve of 4518.7–20,781.4 and 1987.7–22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30–60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed.
Conclusions
Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.
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Giant Cell Tumor with Secondary Aneurysmal Bone Cyst Shows Heterogeneous Metabolic Pattern on 18 F-FDG PET/CT: A Case Report
Abstract
Giant cell tumor (GCT) is a generally benign bone tumor accounting for approximately 5 % of all primary bone neoplasms. Cystic components in GCTs that indicate secondary aneurysmal bone cysts (ABCs) are reported in 14 % of GCTs. Although both of them have been described separately in previous reports that may show considerable fluorodeoxyglucose (FDG) uptake despite their benign nature, the findings of GCT with secondary ABC on 18F-FDG positron emission tomography/computed tomography (PET/CT) have not been well-known. We report a case of GCT with secondary ABC in a 26-year-old woman. 18F-FDG PET/CT revealed a heterogeneous hypermetabolic lesion in the left proximal femur with the maximum standardized uptake value of 4.7. The solid components of the tumor showed higher FDG uptake than the cystic components. These observations suggest that the ABC components in GCTs show heterogeneous metabolic patterns on 18F-FDG PET/CT.
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Making Cancer Health Text on the Internet Easier to Read for Deaf People Who Use American Sign Language
Abstract
People with relatively limited English language proficiency find the Internet's cancer and health information difficult to access and understand. The presence of unfamiliar words and complex grammar make this particularly difficult for Deaf people. Unfortunately, current technology does not support low-cost, accurate translations of online materials into American Sign Language. However, current technology is relatively more advanced in allowing text simplification, while retaining content. This research team developed a two-step approach for simplifying cancer and other health text. They then tested the approach, using a crossover design with a sample of 36 deaf and 38 hearing college students. Results indicated that hearing college students did well on both the original and simplified text versions. Deaf college students' comprehension, in contrast, significantly benefitted from the simplified text. This two-step translation process offers a strategy that may improve the accessibility of Internet information for Deaf, as well as other low-literacy individuals.
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Phase I trial of dovitinib (TKI258) in recurrent glioblastoma
Abstract
Purpose
Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood–brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM).
Patients and methods
Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off). A modified 3 + 3 design in three cohorts (500, 400, 300 mg) was used.
Results
Twelve patients were enrolled. Seventy-two adverse events (AEs) occurred and 16.7 % of AEs were classified as ≥CTC grade 3 toxicity, mainly including hepatotoxicity and hematotoxicity. Only one out of six patients of the 300-mg cohort showed grade 3 toxicity. The PFS-6 rate was 16.7 %, and it was not associated with detection of the FGFR-TACC gene fusion in the tumor.
Conclusion
Dovitinib is safe in patients with recurrent GBM and showed efficacy in only some patients unselected for target expression. The recommended phase II dose of 300 mg would be substantially lower than the recently established MTD in systemic cancer patients. Further personalized trials are recommended.
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Oncological outcomes of patients with incidental pathological T3a stage small renal cell carcinoma after partial nephrectomy
Abstract
Purpose
This study was designed to evaluate and compare the oncological outcomes of patients with pathological T1a (pT1a) small renal cell carcinomas (RCCs) with those with incidental pathological T3a (pT3a) RCCs who have been treated using partial nephrectomy (PN).
Methods
We retrospectively evaluated the records of 1367 consecutive patients who underwent PN for small RCCs (≤4 cm) between 1997 and 2014. The curves for recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan–Meier method. Cox regression analysis was used to estimate the prognostic significance of each variable.
Results
Of the 1367 small RCC patients identified, 1324 (96.8 %) had pT1a lesions and 43 (3.2 %) had pT3a lesions. The median ages of the pT1a and pT3a patients were 53.9 and 58.1 years, respectively. Patients received follow-up for a median of 54 months. The 5- and 10-year RFS rates in patients with pT1a and pT3a RCCs were 98.0 and 95.2 %, and 94.4 and 95.2 %, respectively (P = 0.521). None of the patients with recurrent tumors in the pT3a group have died by the time of the writing of this report. A multivariate Cox proportional hazards model showed that tumor size was a significant predictor of RFS and CSS (P < 0.05). However, pT stage (pT3a vs. pT1a) was not a significant predictor of RFS, CSS, or OS (P = 0.104, P = 0.573, and P = 0.441, respectively).
Conclusions
Our study found that pT3a stage disease following PN for small RCCs (≤4 cm) had similar oncological outcomes to those of pT1a stage.
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Long noncoding RNA NEAT1 is an unfavorable prognostic factor and regulates migration and invasion in gastric cancer
Abstract
Background
Long noncoding RNAs (LncRNAs) have been demonstrated as playing important roles in diverse biological processes including tumorigenesis. However, the clinical significance and biological function of LncRNA nuclear-enriched abundant transcript 1 (NEAT1) in gastric cancer are still unknown. The aim of this study was to identify the role of LncRNA NEAT1 in gastric cancer.
Methods
The expression of LncRNA NEAT1 was detected in gastric cancer samples and cell lines by real-time PCR. The clinical and prognostic significance of LncRNA NEAT1 in gastric cancer patients was analyzed. Furthermore, the biological function of LncRNA NEAT1 on tumor cell growth and mobility were explored through MTT, colony formation, transwell migration, and invasion assays in vitro. The potential mechanism of LncRNA NEAT1 was identified by Western blot.
Results
LncRNA NEAT1 was overexpressed in gastric cancer tissues and cell lines and corrected with clinical stage, histological type, lymph node metastasis, and distant metastasis. Furthermore, patients with high levels of LncRNA NEAT1 had poorer survival than those with lower levels of LncRNA NEAT1. Univariate and multivariate Cox regression analyses showed that LncRNA NEAT1 overexpression was a poor independent prognostic factor for gastric cancer patients. Moreover, knocking down LncRNA NEAT1 expression significantly suppressed the gastric cancer cell migration and invasion in vitro and regulated EMT-associated proteins expression.
Conclusion
LncRNA NEAT1 plays an important role on gastric cancer tumorigenesis and progression and may act as a potential biomarker for therapeutic strategy and prognostic prediction.
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Rapid staining and imaging of subnuclear features to differentiate between malignant and benign breast tissues at a point-of-care setting
Abstract
Purpose
Histopathology is the clinical standard for tissue diagnosis; however, it requires tissue processing, laboratory personnel and infrastructure, and a highly trained pathologist to diagnose the tissue. Optical microscopy can provide real-time diagnosis, which could be used to inform the management of breast cancer. The goal of this work is to obtain images of tissue morphology through fluorescence microscopy and vital fluorescent stains and to develop a strategy to segment and quantify breast tissue features in order to enable automated tissue diagnosis.
Methods
We combined acriflavine staining, fluorescence microscopy, and a technique called sparse component analysis to segment nuclei and nucleoli, which are collectively referred to as acriflavine positive features (APFs). A series of variables, which included the density, area fraction, diameter, and spacing of APFs, were quantified from images taken from clinical core needle breast biopsies and used to create a multivariate classification model. The model was developed using a training data set and validated using an independent testing data set.
Results
The top performing classification model included the density and area fraction of smaller APFs (those less than 7 µm in diameter, which likely correspond to stained nucleoli).When applied to the independent testing set composed of 25 biopsy panels, the model achieved a sensitivity of 82 %, a specificity of 79 %, and an overall accuracy of 80 %.
Conclusions
These results indicate that our quantitative microscopy toolbox is a potentially viable approach for detecting the presence of malignancy in clinical core needle breast biopsies.
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Molecular monitoring of tyrosine kinase inhibitor therapy of chronic myeloid leukemia in China
Abstract
Purpose
Explore molecular monitoring patterns of patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors therapy in China and identify variables associated with monitoring patterns.
Methods
Non-interventional, cross-sectional study using questionnaires distributed to persons with CML and answered anonymously.
Results
A total of 819 respondents in chronic phase outside clinical trials were evaluable; 477 respondents (58 %) were male. Median age was 41 years (range 18–88 years). A total of 609 (74 %) respondents received a TKI <1 year after diagnosis and 665 (81 %) were on a branded TKI. Median TKI therapy duration was 3 years (range <1–13 years). A total of 255 (31 %) respondents had a molecular test every 3 months, and 280 (34 %), every 6 months. Multivariate analyses showed that older age, starting TKI therapy >1 year after diagnosis and generic TKI use were associated with deviation from recommended monitoring frequency (both every 3 months and every 3 or 6 months). In addition, TKI therapy duration >3 years and imatinib use were associated with under-testing every 3 months. Rural household registration was associated with less testing at every 3 or 6 months. The most commonly stated reasons for under-testing were no requirement by physician (60 %), followed by cost (19 %), no necessity (10 %) and no eligible lab nearby (10 %).
Conclusions
Many Chinese with chronic phase CML receiving TKI therapy do not have response monitoring compliant with recommended guidelines. Older age, financial burden and physician non-adherence to guideline recommendations are associated with low monitoring frequencies.
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Parotid melanoma of unknown primary
Abstract
Purpose
Rarely, melanoma is discovered in the parotid gland without an identifiable primary site. It is not known how patients with parotid melanoma of unknown primary (PMUP) compare to those with a known primary (PMKP). As such, we describe the largest series of patients with PMUP to date and compare them to patients with PMKP.
Methods
We analyzed cases from three sources: (1) the University Hospitals Case Medical Center pathology database (n = 45), (2) the Surveillance, Epidemiology, and End Results 18 database (n = 33), and (3) a comprehensive literature search (n = 32).
Results
PMUP patients were predominately male and presented at a mean age of 56 years. When compared to PMKP, PMUP cases were more likely to be diagnosed in the parotid parenchyma, present with stage IV disease, and develop distant metastases during follow-up in a shorter amount of time. However, there was no difference in overall survival between patients with PMUP and PMKP presenting with stage-matched disease.
Conclusions
Overall survival is similar for stage-matched patients with parotid melanoma presenting with an unknown and known primary site.
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Interstitial growth as an aggressive growth pattern in primary lung cancer
Abstract
Purpose
Interstitial growth (IG), which is defined as tumor cells continuously growing into the alveolar septa at the tumor periphery, was originally reported as a growth pattern of metastatic sarcoma of the lung. On the other hand, IG in the primary lung cancers has not been well described. This study aimed to examine clinicopathological features of primary lung cancer that harbors IG.
Methods
A total of 2558 primary lung cancers which were resected from 2003 to 2012 in our hospital were examined for IG. We compared clinicopathological data and prognoses between patients with IG+ and IG− specimens.
Results
Thirty-three cases out of 2558 (1.3 %) had IG components. IG was significantly more associated with positive smoking history, advanced pathological stage, presence of vascular invasion and pleural invasion. Thirty-three IG+ cases include nine pleomorphic carcinoma, nine squamous cell carcinoma and eight adenocarcinoma. Interestingly, nine (24 %) out of 38 pleomorphic carcinoma specimens had IG components, which was a higher rate than any other histological subtypes. The IG+ cancers had significantly shorter overall and recurrence-free survival than did the IG− cancers.
Conclusions
We firstly reported on IG in various types of primary lung cancer. IG appears to be a sign of an aggressive lung cancer phenotype, mainly found in pleomorphic carcinoma.
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Improved survival boosts the prevalence of chronic myeloid leukemia: predictions from a population-based study
Abstract
Purpose
Due to prolonged survival, there will be many more chronic myeloid leukemia (CML) patients alive in the future. The aims of this work were to estimate the current prevalence of CML by using routine data and to project future patient numbers in Germany.
Methods
Data were available for about 10.5 million people in the statutory health insurance system in Bavaria for the years 2008–2013. Survival rates were adapted from two recent publications.
Results
The mean estimated age-standardized (Old European Standard Population) incidence rates per 100,000 inhabitants were 1.300 and 1.768 for women and men. Based on the population data, we estimated a total number of about 9000 CML patients in Germany for 2012. We expect the number of CML patients to increase further until at least 2040–2050 with a maximum of more than 20,000 CML patients as the most probable scenario.
Conclusions
Using a restrictive definition for case patients, we do not think that there is much overestimation. As a consequence of this considerable increase of the prevalence of CML the burden for the health care system will increase with respect to costs and medical care needed. The procedure presented here allows to estimate the expected number of CML patients in other countries, too.
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Low-dose DNA-demethylating agent enhances the chemosensitivity of cancer cells by targeting cancer stem cells via the upregulation of microRNA-497
Abstract
Purpose
The DNA-demethylating agent decitabine has shown clinical response for the treatment of hematological malignancies and solid tumors, while the mechanisms underlying its antitumor capacity are not fully understood.
Methods
The sensitivities of cancer cells to different chemotherapeutic drugs, such as cisplatin, paclitaxel, and 5-FU, were detected. The tumor sphere formation assay was used to evaluate the effects of low-dose decitabine on cancer-initiating stem cells.
Results
We observed that the chemotherapy sensitivity of various cancer cells was enhanced following non-toxic low-dose decitabine treatment. Moreover, low-dose decitabine treatment suppressed the self-renewal of cancer-initiating cells and inhibited the expression of pluripotency markers. Strikingly, low-dose decitabine was able to augment chemosensitivity in cancer stem cells, likely by the upregulation of miRNA-497, which was reported to be downregulated and to have promoted cell apoptosis in multiple cancers.
Conclusions
These results indicated that the DNA-demethylating agent could target cancer stem cells and reverse their chemotherapeutic resistance by regulating the endogenous expression of microRNAs.
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Testicular seminoma clinical stage 1: treatment outcome on a routine care level
Abstract
Purpose
Clinical stage 1 (CS1) testicular seminoma involves an almost 100 % disease-specific survival in controlled clinical trials. We aimed to find out whether these results can be matched in patients managed on the routine care level.
Patients, methods
In total, 725 patients with seminoma CS1 were prospectively enrolled from 130 institutions. Adjuvant management as decided by local physicians involved surveillance (n = 256), radiotherapy (41), 1× Carboplatin (362), and 2× Carboplatin (66). We registered type of management, age, duration of follow-up (F/U), relapse, rete testis invasion (RTI), and tumor size. Actuarial relapse-free survival curves were calculated for treatment modalities and stratified for tumor sizes and RTI. A Cox regression model was calculated to explore for factors influencing relapses.
Results
Disease-specific survival was 100 %. Crude relapse rates were 8.2, 2.4, 5.0, and 1.5 % for surveillance, radiotherapy, 1× Carboplatin, and 2× Carboplatin after a median F/U of 30 months. RTI and tumor size were not associated with progression in surveillance patients. One course Carboplatin caused relapses in 6.8 % in tumor sizes >4 cm and 9.3 % (actuarial 13 %) in sizes >5 cm. The Cox model revealed the association of tumor size with recurrence in the entire seminoma population (Hazard ratio 1.17; 95 % confidence intervals 1.03–1.33).
Conclusions
The overall outcome of CS1 seminoma managed on the routine care level mirrors that of controlled trials. Unexpectedly, the risk factors in surveillance patients were not confirmed, but tumor size proved to be a risk indicator in the entire group of seminoma. Importantly, one course Carboplatin involved low efficacy to control the disease in large tumors.
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Young age and high cost are associated with future preference for stopping tyrosine kinase inhibitor therapy in Chinese with chronic myeloid leukemia
Abstract
Purpose
To explore therapy-goals and patients' expectations regarding discontinuing tyrosine kinase inhibitors (TKIs) therapy in Chinese with chronic myeloid leukemia (CML). To identify variables associated with these expectations and preferences.
Methods
Noninterventional, cross-sectional study using questionnaires distributed to persons with CML and answered anonymously.
Results
With CML in chronic phase, 888 respondents were evaluable. In total, 513 respondents (58 %) were male. Median age was 41 years (range 18–88 years). Median TKI therapy duration was 3 years (range <1–13 years). In total, 735 respondents (83 %) paid part or all of the cost of TKI. As their treatment goal, 430 of 888 respondents (48 %) reported treatment-free remission (TFR). In the future, 734 respondents (83 %) expected to discontinue TKI. Multivariate analyses confirmed younger age [HR = 1.3; (1.1, 1.4); P < 0.001] and higher out-of-pocket expense [HR = 1.2; (1.1, 1.4); P < 0.001] were associated with TFR as a therapy-goal. Both variables were also associated with patients' hope to stop TKI therapy in the future: HR = 1.4; (0.8, 1.7; P < 0.001) and HR = 1.5; (1.3, 1.8; P < 0.001). Achieving a complete molecular response [HR = 1.8 (1.1, 2.9); P = 0.017] and decreased quality of life resulting from adverse effects [HR = 1.2; (1.0, 1.5); P = 0.021] were factors associated with the expectation of discontinuing TKI therapy.
Conclusions
Younger age and higher out-of-pocket cost are associated with patients' preference for stopping TKI therapy.
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Oroxylin A, a natural anticancer flavonoid compound, induces differentiation of t(8;21)-positive Kasumi-1 and primary acute myeloid leukemia cells
Abstract
Purpose
AML1/ETO fusion gene is one of disease-causing genes of t(8;21)-positive acute myeloid leukemia (AML). Oroxylin A (OA) has showed anticancer effects on other cancer cells. Here, studies were conducted to determine the antileukemia effect of OA on t(8;21)-positive AML cells in vitro and in vivo.
Materials and methods
The effects of OA on cell viability of t(8;21)-positive Kasumi-1 and primary AML cells were analyzed by MTT assay. Cell differentiation was examined by NBT reduction assay, flow cytometry analysis for CD11b/CD14, and Giemsa stain. Protein expressions were determined by Western blots. Immunofluorescence assay was used to verify the effect of OA on HDAC-1 expression in vivo. Immunohistochemical staining was applied to evaluate leukemic infiltration of AML-bearing NOD/SCID mice.
Results
OA enhanced NBT reduction activity and CD11b/CD14 expression of AML1/ETO-positive AML cells markedly. Results of Giemsa staining also demonstrated that OA could induce the morphologic changes with reduction of nuclear/cytoplasmic ratios, suggesting the cell differentiation induced by OA. Further study showed that OA decreased the expression of fusion protein AML1/ETO and down-regulated HDAC-1 protein levels in vitro and in vivo. Moreover, OA increased the expression of differentiation-related proteins C/EBPα and P21. Acetylation levels of histones were also advanced obviously after treatment of OA. In vivo study indicated that OA could prolong the survival of AML-bearing NOD/SCID mice and reduce leukocytic infiltration of the spleen.
Conclusions
All these results suggested that OA might be a novel candidate agent for differentiation therapy for AML1/ETO-positive AML and the mechanism required further investigation.
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Urothelial cancer associated 1: a long noncoding RNA with a crucial role in cancer
Abstract
Background
Urothelial cancer associated 1 (UCA1) is a long noncoding RNA (lncRNA) which has gained more attention in recent years due to its aberrant expression in embryogenesis and a broad range of cancer tissues and cells. Importantly, multiple studies have shown that UCA1 plays oncogenic roles in tumor growth and metastasis, and it may act as a potential biomarker and therapeutic target for human cancers. However, the molecular mechanism of UCA1 in cancer initiation, progression and metastasis remains incompletely understood. Thus, gaining a better understanding of the functional mechanism of UCA1 in cancer onset and progression is of the utmost significance for evaluating the potential application of UCA1.
Results and discussion
In this review, we discuss UCA1 expression profiling, isoform, expression regulation, biological role and mechanism for UCA1 tumor-promoting effect. We further discuss the potential clinical application of UCA1 as a promising diagnostic biomarker or therapeutic target for human cancers.
Conclusion
UCA1 functions as an oncogenic lncRNA in several malignancies, and it might become a potential biomarker or therapeutic target for human cancers.
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Benefit of uridine triacetate ( Vistogard ) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase ( DPYD ) deficiency
Abstract
Background
5-Fluorouracil (5-FU), an analog of uracil, is one of the most commonly used chemotherapeutic agents and like other agents has a narrow therapeutic index limited by toxicity. Compared to previous attempts, uridine triacetate (Vistogard) has shown to increase the potential efficacy of 5-FU by allowing administering a higher dose and decreasing the toxicity. Recently, Vistogard received orphan drug designation from the FDA as an antidote in the treatment of 5-FU poisoning and from the European Medicines Agency as a treatment for 5-FU overdose. However, no data have been published to date in humans who were rescued by this agent following severe toxicity associated with 5-FU due to dihydropyrimidine dehydrogenase (DPYD) deficiency, the enzyme which is responsible for the elimination of approximately 80 % of the administered dose of 5-FU.
Patients and methods
We identified two patients with advanced pancreatic cancer who were referred to us for testing of DPYD status following severe toxicity associated with 5-FU administered at a dose of 1400 mg/m2 weekly bolus high-dose 5-FU followed by oral uridine triacetate as a part of a clinical trail. One patient developed grade 3 thrombocytopenia and grade 3 skin rash that resolved with discontinuation of 5-FU and supportive care, while second patient developed grade 4 thrombocytopenia, grade 3 coagulopathy and grade 3 neurological toxicity with a fatal outcome. DPYD status was evaluated as we have previously published.
Results
The first patient was found to have an abnormally low DPYD activity of 0.087-nmol/min/mg protein by radioisotopic assay (reference normal range 0.182–0.688 nmol/min/mg protein). Because of pancytopenia, DPYD enzyme activity could not be assessed in patient 2; genotypic analysis of DPYD during autopsy revealed the presence of the heterozygous mutation, IVS14+1 G>A, DPYD*2A, now recognized as the most common cause of DPYD deficiency.
Conclusion
These two patients present the first two cases of DPYD deficiency that had either delay in severe toxicity or recovered from severe toxicity as they received oral Vistogard as a part of the conical trial. Toxicity was delayed in both patients by a mean of 3.5 weeks (range 3–4 weeks), indicating that Vistogard might be able to delay 5-FU toxicity despite higher doses than standard bolus dose of 5-FU used in gastrointestinal malignancies and the appearance of a potentially less toxic adverse effect of 5-FU at an unusual site (cutaneous) in one patient. The role of uridine triacetate with 5-FU in DPYD-deficient patients needs further investigation.
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Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment
Background
Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon-α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports.
Procedure
We performed a single-institution retrospective review of four children with BRBNS, who received sirolimus as part of their treatment regimens. A diagnosis of BRBNS was based on clinical, radiologic, and pathologic criteria.
Results
Median age was 6.5 years (range: 2–16 years). Pathologic evaluations revealed a combined malformation with venous and lymphatic components. The novel finding of a lymphatic component was confirmed with PROX-1 immunostaining. Patients received oral sirolimus with target drug levels between 10 and 13 ng/ml. Responses to treatment were defined as stabilization/decrease in size of lesions; resolution of transfusion requirements; reduction in pain, and improvement in quality of life (QOL). Median time to response was 1.5 months (SD ± 0.96 month, range: 1–3 months). Median follow-up was 21 months (range: 18–26 months). Lesion size and characteristics improved in all patients. All patients reported decrease in pain and improvement in QOL. All three patients requiring transfusions became transfusion-independent. One patient had resolution of coagulopathy. Adverse effects of sirolimus consisted of mucositis in three patients and neutropenia in one patient.
Conclusions
Sirolimus is safe and efficient for the treatment of BRBNS. Further prospective studies are needed to evaluate the long-term effectiveness of this drug. This is the first report that identifies a lymphatic component as part of BRBNS.
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Bone marrow transplantation for CVID-like humoral immune deficiency associated with red cell aplasia
Abstract
Patients with common variable immunodeficiency (CVID) have a higher incidence of autoimmune disease, which may mark the disease onset; however, anemia secondary to pure red cell aplasia is an uncommon presenting feature. Here, we describe a case of CVID-like humoral immune deficiency in a child who initially presented with red cell aplasia and ultimately developed progressive bone marrow failure. Although bone marrow transplantation (BMT) has been associated with high mortality in CVID, our patient was successfully treated with a matched sibling BMT and engrafted with >98% donor chimerism and the development of normal antibody titers to diphtheria and tetanus toxoids.
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Making Cancer Health Text on the Internet Easier to Read for Deaf People Who Use American Sign Language
Abstract
People with relatively limited English language proficiency find the Internet's cancer and health information difficult to access and understand. The presence of unfamiliar words and complex grammar make this particularly difficult for Deaf people. Unfortunately, current technology does not support low-cost, accurate translations of online materials into American Sign Language. However, current technology is relatively more advanced in allowing text simplification, while retaining content. This research team developed a two-step approach for simplifying cancer and other health text. They then tested the approach, using a crossover design with a sample of 36 deaf and 38 hearing college students. Results indicated that hearing college students did well on both the original and simplified text versions. Deaf college students' comprehension, in contrast, significantly benefitted from the simplified text. This two-step translation process offers a strategy that may improve the accessibility of Internet information for Deaf, as well as other low-literacy individuals.
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Cancers, Vol. 8, Pages 54: Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area. Membrane E3 ligase ZNRF3 and RNF43 are critical negative feedback regulators of the Wnt pathway, which function through promoting ubiquitination and degradation of Wnt receptors. R-spondin proteins (RSPO1-4) serve as natural antagonists of ZNRF3/RNF43. To maintain strong and sustained Wnt/β-catenin signaling, cancers need to overcome ZNRF3/RNF43-mediated feedback inhibition. Indeed, mutations of RNF43/ZNRF3 and recurrent translocations of RSPO2/RSPO3 have recently been identified in various cancers. Significantly, genetic alterations in RNF43/ZNRF3/RSPO2/RSPO3 have shown promise as predictive biomarkers in pre-clinical models for the efficacy of upstream Wnt inhibitors. In this review, we will discuss the biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module, and their value as biomarkers to identify Wnt-addicted tumors.
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Benefit of uridine triacetate ( Vistogard ) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase ( DPYD ) deficiency
Abstract
Background
5-Fluorouracil (5-FU), an analog of uracil, is one of the most commonly used chemotherapeutic agents and like other agents has a narrow therapeutic index limited by toxicity. Compared to previous attempts, uridine triacetate (Vistogard) has shown to increase the potential efficacy of 5-FU by allowing administering a higher dose and decreasing the toxicity. Recently, Vistogard received orphan drug designation from the FDA as an antidote in the treatment of 5-FU poisoning and from the European Medicines Agency as a treatment for 5-FU overdose. However, no data have been published to date in humans who were rescued by this agent following severe toxicity associated with 5-FU due to dihydropyrimidine dehydrogenase (DPYD) deficiency, the enzyme which is responsible for the elimination of approximately 80 % of the administered dose of 5-FU.
Patients and methods
We identified two patients with advanced pancreatic cancer who were referred to us for testing of DPYD status following severe toxicity associated with 5-FU administered at a dose of 1400 mg/m2 weekly bolus high-dose 5-FU followed by oral uridine triacetate as a part of a clinical trail. One patient developed grade 3 thrombocytopenia and grade 3 skin rash that resolved with discontinuation of 5-FU and supportive care, while second patient developed grade 4 thrombocytopenia, grade 3 coagulopathy and grade 3 neurological toxicity with a fatal outcome. DPYD status was evaluated as we have previously published.
Results
The first patient was found to have an abnormally low DPYD activity of 0.087-nmol/min/mg protein by radioisotopic assay (reference normal range 0.182–0.688 nmol/min/mg protein). Because of pancytopenia, DPYD enzyme activity could not be assessed in patient 2; genotypic analysis of DPYD during autopsy revealed the presence of the heterozygous mutation, IVS14+1 G>A, DPYD*2A, now recognized as the most common cause of DPYD deficiency.
Conclusion
These two patients present the first two cases of DPYD deficiency that had either delay in severe toxicity or recovered from severe toxicity as they received oral Vistogard as a part of the conical trial. Toxicity was delayed in both patients by a mean of 3.5 weeks (range 3–4 weeks), indicating that Vistogard might be able to delay 5-FU toxicity despite higher doses than standard bolus dose of 5-FU used in gastrointestinal malignancies and the appearance of a potentially less toxic adverse effect of 5-FU at an unusual site (cutaneous) in one patient. The role of uridine triacetate with 5-FU in DPYD-deficient patients needs further investigation.
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