Current state of knowledge of hepatic encephalopathy (part I): newer treatment strategies for hyperammonemia in liver failure

Abstract

Alterations in interorgan metabolism of ammonia play an important role in the onset of hyperammonemia in liver failure. Glutamine synthetase (GS) in muscle is an important target for ammonia removal strategies in hyperammonemia. Ornithine Phenylacetate (OP) is hypothesized to remove ammonia by providing glutamate as a substrate for increased GS activity and hence glutamine production. The newly generated glutamine conjugates with phenylacetate forming phenylacetylglutamine which can be excreted in the urine, providing an excretion pathway for ammonia. We have also shown that OP targets glycine metabolism, providing an additional ammonia reducing effect.

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Hypofractionated boost after whole breast irradiation in breast carcinoma: chronic toxicity results and cosmesis

Abstract

Purpose

To evaluate the impact of hypofractionated boost after hypofractionated whole breast irradiation in breast carcinoma.

Methods and materials

Patients after breast conservative surgery were treated all time with hypofractionation of 2.67 Gy/day. Whole breast dose was 40.05 Gy followed in case of risk of local relapse by a boost of 16.02 Gy or 8.01 Gy. Acute and chronic toxicity results were evaluated including cosmetic software-assisted assessment and objective evaluation of fibrosis parameters (elasticity and hydration) by means of a skin tester.

Results

A total of 362 patients were evaluated. Acute toxicities comprised grade 1 dermatitis in 48.1 %, grade 2 in 44.5 % and grade 3 in 17 patients 4.7 %, respectively. After a median follow-up of 4.5 years, in 308 cases (86.6 %) there was no chronic skin or subcutaneous changes. In the first consecutive 50 patients, measures with skin tester showed no statistical differences in parameters for skin and subcutaneous fibrosis. Cosmetic results were considered excellent and good in 26 and 62 %, respectively.

Conclusions

Boost to tumour bed with hypofractionated doses is well tolerated and acute and chronic toxicities are mild with good cosmetic results. Objective systems are encouraging methods to assess skin quality and cosmesis.

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Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?

Abstract

Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.

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Diffusion and perfusion weighted magnetic resonance imaging for tumor volume definition in radiotherapy of brain tumors

Accurate target volume delineation is crucial for the radiotherapy of tumors. Diffusion and perfusion magnetic resonance imaging (MRI) can provide functional information about brain tumors, and they are able t...

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Involved field radiotherapy (IFRT) versus elective nodal irradiation (ENI) for locally advanced non-small cell lung cancer: a meta-analysis of incidence of elective nodal failure (ENF)

The use of involved field radiotherapy (IFRT) has generated concern about the increasing incidence of elective nodal failure (ENF) in contrast to elective nodal irradiation (ENI). This meta-analysis aimed to p...

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Presentation and Management of Inguinal Lymphadenopathy in Ovarian Cancer

Abstract

The symptoms in ovarian cancer are often missed leading to dubious diagnosis and staging. Inguinal lymphadenopathy (ILAP) is reported to be rare and occurring via lymphatic or hematogenous route. The paucity of studies on ILAP in ovarian cancer indicates a scope of refining its staging and management. The present study aims to document the presentation and management of ILAP in ovarian cancer, which may also reflect its incidence and mechanism of spread. All patients of ovarian cancer with inguinal lymphadenopathy presenting to our institute from 1 January 2015 to 31 December 2015 were included. All clinical, treatment, and pathological details were analyzed. Seven patients of ovarian cancer presented with ILAP. The mean age and BMI were 53.29 +/− 8.38 years and 26.23 +/− 3.03 kg/m². Presentation varied from advanced disease (adnexal, omental, peritoneal, and nodal) to isolated ILAP even without adnexal mass (n = 4). Mean CA 125 was 229.64 +/− 322 (20–924) and ovarian primary was confirmed on microscopy or immunohistochemistry. Six patients underwent surgery with (n = 4) or without neoadjuvant chemotherapy (n = 2). Complete cytoreduction could be achieved in all patients with acceptable operative and perioperative outcomes. Peritoneal surface spread, along hernia track to the groin, was seen in two patients. Histopathology showed advanced disease, isolated ILAP and no residual disease in 3, 2, and 1 patient, respectively. ILAP has diverse clinical presentation in ovarian cancers and is not that uncommon. ILAP may also occur by peritoneal surface spread and shows good results with cytoreductive surgery and chemotherapy.

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Expression and prognostic value of E2F activators in NSCLC and subtypes: a research based on bioinformatics analysis

Abstract

E2F activators (E2F1–3) codify a family of transcription factors (TFs) in higher eukaryotes. E2F activators are involved in the cell cycle regulation and synthesis of DNA in mammalian cells, and their overexpression has been detected in many human cancers. However, their clinical significance has not been deeply researched in non-small-cell lung cancer (NSCLC), and bioinformatics analysis has never been reported to explore their clinical role in NSCLC. In the current study, we investigated the expression and prognostic value of E2F activators in NSCLC patients through the "TCGA datasets" and the "Kaplan-Meier plotter" (KM plotter) database. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Compared with normal tissue samples, E2F activators were overexpressed in NSCLC tissues, in lung adenocarcinoma (LUAD) tissues, and in lung squamous cell carcinoma (LUSC) tissues. In NSCLC patients, E2F1 expression was significantly correlated with age, sex, and tumor stage. E2F2 expression was found to be significantly correlated with sex and tumor size. We further demonstrated that E2F1 and E2F2 overexpressions were significantly associated with poor prognosis. In LUAD patients, E2F1 expression was significantly correlated with tumor size and tumor stage. E2F2 expression was significantly correlated with lymph node status and tumor stage. E2F1 and E2F2 overexpression showed a significant association with poor prognosis, while E2F3 overexpression was significantly correlated to better prognosis. In LUSC patients, E2F1 was concluded to be significantly correlated with tumor stage. However, E2F activators were not found to be correlated to prognosis.

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Comparison of postoperative early and late complications between pancreas-sparing duodenectomy and pancreatoduodenectomy

Abstract

Purpose

Pancreas-sparing duodenectomy (PSD) represents an alternative procedure to pancreatoduodenectomy (PD) for patients with duodenal neoplasms.

Methods

The postoperative early and late complications of 21 patients who underwent PSD between 1992 and 2014 were compared with those of 44 patients with soft pancreatic parenchyma who underwent PD between 2009 and 2014.

Results

The median operation time and blood loss were less in the PSD group than in the PD group (P < 0.001). The overall incidence of early complications was less in the PSD group than in the PD group (PSD with ampullectomy vs. PSD without ampullectomy vs. PD; 45.5 vs. 20.0 vs. 56.8 %). The incidence of pancreatic fistula formation and overall incidence of late complications were also less in the PSD group than in the PD group (P = 0.031, 0.020). There were no complications related to the pancreatic endocrine or exocrine functions in the PSD group.

Conclusion

PSD is a less-invasive procedure and has the advantage over PD of preserving the pancreas.

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Is body mass index relevant to prognosis of papillary thyroid carcinoma? A clinicopathological cohort study

Abstract

Purpose

Obesity appears to be related to papillary thyroid carcinoma (PTC) in the observational studies, although its relationship concerning the PTC prognosis has not been established. We investigated the association between body mass index (BMI) and the prognosis of PTC.

Methods

The WHO BMI classification was used to stratify the degree of obesity. The final outcome was disease status, including recurrence and persistence, of 783 PTC patients. We reviewed patients' BMI, disease status, and other prognostic factors retrospectively.

Results

The mean BMI was 24.2 kg/m². When stratified according to the WHO BMI classification, 21 were Underweight, 482 were Normal, 232 were Overweight, and 48 were Obese. We divided patients into two groups: <25.0 kg/m² (n = 503) vs. ≥25.0 kg/m² (n = 280). The BMI ≥25.0 group was older and more likely to be male in a multivariate analysis (p < 0.001). For those with BMI <25.0 and ≥25.0, recurrence occurred in 3.0 and 2.1 % (p = 0.486), persistence in 7.2 and 5.1 % (p = 0.265), and either recurrence or persistence in 9.9 and 7.1 %, respectively (p = 0.189). A multivariate analysis revealed that older age and male gender in Overweight vs. Normal, older age in Obese vs. Normal, and advanced T stage in Normal vs. Underweight were statistically significant prognostic factors.

Conclusions

There was no significant difference in the prognosis according to BMI in PTC patients. However, old age, male gender, and advanced T-stage patients were found more frequently in the higher BMI group than in the lower BMI group.

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Do Patients Feel Well Informed in a Radiation Oncology Service?

Abstract

Information received by cancer patients has gained importance in recent decades. The aim of this study was to evaluate the perception of information received by oncological patients in a radiotherapy department and to measure the importance of the other information sources. A cross-sectional study was conducted, evaluating patients who received radiotherapy. All the patients were asked two questionnaires: the EORTC QLQ-INFO26 module evaluating their satisfaction with received information, and a questionnaire analyzing other sources of information search. One hundred patients between 27 and 84 years were enrolled. Breast cancer (26 %) was the commonest cancer. Patients felt better informed about the medical tests and secondly about the performed treatment. The younger patients were those who were more satisfied with the information received and patients with no formal education felt less satisfied, with statistically significant differences. Patients did not seek external information; at the most, they asked relatives and other people with cancer. Patients were satisfied with the received information, although a high percentage would like more information. In general, patients did not search for external information sources. Age and educational level seem to influence in the satisfaction with the received information.

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Awareness and Knowledge Levels of Turkish College Students about Human Papilloma Virus Infection and Vaccine Acceptance

Abstract

Awareness of HPV by the target population is an important determinant of vaccine acceptance. The aim of this study is to evaluate the awareness of HPV infection and acceptability of the HPV vaccines among Turkish college students. College students aged 18–30 who were attending a large public university in Ankara participated in this study. The participants were asked to complete a questionnaire to elicit demographic characteristics, awareness level of HPV and HPV vaccine, and willingness to be vaccinated. One thousand one hundred sixty students responded to the invitation email and completed the questionnaire. The mean scores of female students about HPV and HPV vaccine were 7.1/15 and 3.6/9, respectively, while these scores were 7.9/15 and 3.4/9 among male students, respectively. While 51 % percent of female and 33.5 % of male students had heard of HPV and 32.8 % and 18 % of them had heard of HPV vaccine, respectively, only 1.5 % of female and 0.4 % of male students had been vaccinated against HPV. A total of 507 students (43.7 %) had previously heard of HPV. Only 309 (26.6 %) of the participants had previously heard of the HPV vaccine, and 45.1 % of the students were willing to receive HPV vaccination. The main predictors for willingness to be vaccinated were the following: sexual experience, sexual behavior, past history of sexually transmitted infection (STI), and knowledge about HPV and HPV vaccine. Higher awareness levels of HPV and HPV vaccine are significantly related to greater willingness to be vaccinated, and the main reasons for rejecting the vaccine were insufficient information about the vaccine and possible unknown side effects.

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Hypofractionated boost after whole breast irradiation in breast carcinoma: chronic toxicity results and cosmesis

Abstract

Purpose

To evaluate the impact of hypofractionated boost after hypofractionated whole breast irradiation in breast carcinoma.

Methods and materials

Patients after breast conservative surgery were treated all time with hypofractionation of 2.67 Gy/day. Whole breast dose was 40.05 Gy followed in case of risk of local relapse by a boost of 16.02 Gy or 8.01 Gy. Acute and chronic toxicity results were evaluated including cosmetic software-assisted assessment and objective evaluation of fibrosis parameters (elasticity and hydration) by means of a skin tester.

Results

A total of 362 patients were evaluated. Acute toxicities comprised grade 1 dermatitis in 48.1 %, grade 2 in 44.5 % and grade 3 in 17 patients 4.7 %, respectively. After a median follow-up of 4.5 years, in 308 cases (86.6 %) there was no chronic skin or subcutaneous changes. In the first consecutive 50 patients, measures with skin tester showed no statistical differences in parameters for skin and subcutaneous fibrosis. Cosmetic results were considered excellent and good in 26 and 62 %, respectively.

Conclusions

Boost to tumour bed with hypofractionated doses is well tolerated and acute and chronic toxicities are mild with good cosmetic results. Objective systems are encouraging methods to assess skin quality and cosmesis.

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Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?

Abstract

Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.

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Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study

Abstract

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood–brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.

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6-gene recurrence risk score for gastric cancer

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery. Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n=267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative reverse transcription polymerase chain reaction to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort. Results: We based the RRS assay on six genes-IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B-whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence (hazard ratio, 1.6; 95% confidence interval, 1.02-2.4; P = 0.03). In patients with stage II disease, the RRS had a hazard ratio of 2.9 (95% confidence interval, 1.1-7.9; P = 0.03) and was the only significant independent predictor of recurrence. Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted.

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Coactivator involvement in Cancer

Coactivators represent a large class of proteins that partner with nuclear receptors (NRs) and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics and efforts are now being made to develop SRC-targeting agents such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers.

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Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines?

Abstract

Background

ECG and echocardiography are noninvasive screening tools to detect subclinical cardiotoxicity in childhood cancer survivors (CCSs). Our aims were as follows: (1) assess the prevalence of abnormal ECG patterns, (2) determine the agreement between abnormal ECG patterns and echocardiographic abnormalities; and (3) determine whether ECG screening for subclinical cardiotoxicity in CCSs is justified.

Procedure

We retrospectively studied ECG and echocardiography in asymptomatic CCSs more than 5 years after anthracycline treatment. Exclusion criteria were abnormal ECG and/or echocardiogram at the start of therapy, incomplete follow-up data, clinical heart failure, cardiac medication, and congenital heart disease. ECG abnormalities were classified using the Minnesota Code. Level of agreement between ECG and echocardiography was calculated with Cohen kappa.

Results

We included 340 survivors with a mean follow-up of 14.5 years (range 5–32). ECG was abnormal in 73 survivors (21.5%), with ventricular conduction disorders, sinus bradycardia, and high-amplitude R waves being most common. Prolonged QTc (>0.45 msec) was found in two survivors, both with a cumulative anthracycline dose of 300 mg/m² or higher. Echocardiography showed abnormalities in 44 survivors (12.9%), mostly mild valvular abnormalities. The level of agreement between ECG and echocardiography was low (kappa 0.09). Male survivors more often had an abnormal ECG (corrected odds ratio: 3.00, 95% confidence interval: 1.68–5.37).

Conclusions

Abnormal ECG patterns were present in 21% of asymptomatic long-term CCSs. Lack of agreement between abnormal ECG patterns and echocardiographic abnormalities may suggest that ECG is valuable in long-term follow-up of CCSs. However, it is not clear whether these abnormal ECG patterns will be clinically relevant.

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The health care experience of patients with cancer during the last year of life: Analysis of the SEER-CAHPS data set

BACKGROUND

Providing high-quality medical care for individuals with cancer during their last year of life involves a range of challenges. An important component of high-quality care during this critical period is ensuring optimal patient satisfaction. The objective of the current study was to assess factors influencing health care ratings among individuals with cancer within 1 year before death.

METHODS

The current study used the Surveillance, Epidemiology, and End Results (SEER)-Consumer Assessment of Healthcare Providers and Systems (CAHPS) data set, a new data resource linking patient-reported information from the CAHPS Medicare Survey with clinical information from the National Cancer Institute's SEER program. The study included 5102 Medicare beneficiaries diagnosed with cancer who completed CAHPS between 1998 and 2011 within 1 year before their death. Multivariable logistic regression analyses examined associations between patient demographic and insurance characteristics with 9 measure of health care experience.

RESULTS

Patients with higher general or mental health status were significantly more likely to indicate excellent experience with nearly all measures examined. Sex, race/ethnicity, and education also were found to be significant predictors for certain ratings. Greater time before death predicted an increased likelihood of higher ratings for health plan and specialist physician. Clinical characteristics were found to have few significant associations with experience of care. Individuals in fee-for-service Medicare plans (vs Medicare Advantage) had a greater likelihood of excellent experience with health plans, getting care quickly, and getting needed care.

CONCLUSIONS

Among patients with cancer within 1 year before death, experience with health plans, physicians, and medical care were found to be associated with sociodemographic, insurance, and clinical characteristics. These findings provide guidance for the development of programs to improve the experience of care among individuals with cancer. Cancer 2016. © 2016 American Cancer Society.

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Effects of ω-3 Fatty Acids and Catechins on Fatty Acid Synthase in the Prostate: A Randomized Controlled Trial.

Effects of ω-3 Fatty Acids and Catechins on Fatty Acid Synthase in the Prostate: A Randomized Controlled Trial.

Nutr Cancer. 2016 Sep 20;:1-11

Authors: Zhang Z, Garzotto M, Beer TM, Thuillier P, Lieberman S, Mori M, Stoller WA, Farris PE, Shannon J

Abstract
Animal and human studies suggest fish oil and green tea may have protective effect on prostate cancer. Fatty acid synthase (FAS) has been hypothesized to be linked to chemoprotective effects of both compounds. This study evaluated the independent and joint effects of fish oil (FO) and green tea supplement (epigallocatechin-3-gallate, EGCG) on FAS and Ki-67 levels in prostate tissue. Through a double-blinded, randomized controlled trial with 2 × 2 factorial design, 89 men scheduled for repeat prostate biopsy following an initial negative prostate biopsy were randomized into either FO alone (1.9 g DHA + EPA/day), EGCG alone (600 mg/day), a combination of FO and EGCG, or placebo. We used linear mixed-effects models to test the differences of prostate tissue FAS and Ki-67 by immunohistochemistry between pre- and post-intervention within each group, as well as between treatment groups. Results did not show significant difference among treatment groups in pre-to-post-intervention changes of FAS (P = 0.69) or Ki-67 (P = 0.26). Comparing placebo group with any of the treatment groups, we did not find significant difference in FAS or Ki-67 changes (all P > 0.05). Results indicate FO or EGCG supplementation for a short duration may not be sufficient to produce biologically meaningful changes in FAS or Ki-67 levels in prostate tissue.

PMID: 27646578 [PubMed - as supplied by publisher]

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Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.

Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Tamura RE, da Silva Soares RB, Costanzi-Strauss E, Strauss BE

Abstract
Alternative treatments for cancer using gene therapy approaches have shown promising results and some have even reached the marketplace. Even so, additional improvements are needed, such as employing a strategically chosen promoter to drive expression of the transgene in the target cell. Previously, we described viral vectors where high-level transgene expression was achieved using a p53-responsive promoter. Here we present an adenoviral vector (AdPGp53) where p53 is employed to regulate its own expression and which outperforms a traditional vector when tested in a model of gene therapy for prostate cancer. The functionality of AdPGp53 and AdCMVp53 were compared in human prostate carcinoma cell lines. AdPGp53 conferred greatly enhanced levels of p53 protein and induction of the p53 target gene, p21, as well as superior cell killing by a mechanism consistent with apoptosis. DU145 cells were susceptible to induction of death with AdPGp53, yet PC3 cells were quite resistant. Though AdCMVp53 was shown to be reliable, extremely high-level expression of p53 offered by AdPGp53 was necessary for tumor suppressor activity in PC3 and DU145. In situ gene therapy experiments revealed tumor inhibition and increased overall survival in response to AdPGp53, but not AdCMVp53. Upon histologic examination, only AdPGp53 treatment was correlated with the detection of both p53 and TUNEL-positive cells. This study points to the importance of improved vector performance for gene therapy of prostate cancer.

PMID: 27646031 [PubMed - as supplied by publisher]

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Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.

Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Egger JV, Lane MV, Antonucci LA, Dedi B, Krucher NA

Abstract
The tumor suppressor Retinoblastoma (Rb) protein is highly phosphorylated in cancer cells largely due to the overexpression of cyclins or the loss of expression of cyclin dependent kinase inhibitors (cdki). Hyperphosphorylation of Rb promotes proliferation, and plays a role in the regulation of apoptosis. Recently, inhibition of cyclin dependent activity toward Rb has been identified as a strategy that has shown clinical efficacy. We utilized a method to induce phosphatase activity toward Rb in cells by shRNA silencing of PNUTS (Phosphatase Nuclear Targeting Subunit) that regulates PP1-mediated dephosphorylation of Rb. In this study, the effect of Rb dephosphorylation on the epithelial to mesenchymal transition (EMT) was determined. The EMT transition is observed in cancer cells that have acquired invasive characteristics. In breast cancer cells grown in 3D Matrigel cultures, MCF7 cells undergo apoptosis in response to Rb dephosphorylation, whereas MDA-MB-231 and Hs578T cells exhibit a reduction in the EMT. Cells devoid of phosphorylated Rb (nontransformed MCF10A and Rb-null MDA-MB-468) lacked any response to PNUTS depletion, showing the effect is Rb-dependent. In addition, these studies showed that Rb dephosphorylation in 3D Matrigel cultures of highly invasive HT1080 cells led to the inhibition of the EMT. Furthermore we observed association between dephosphorylated Rb with ZEB1, a zinc-finger E-box-binding transcription factor that regulates expression of E- and N-cadherins. Finally Rb dephosphorylation led to inhibition of ZEB1 transcriptional activity, this data supports the notion that Rb dephosphorylation modulates the EMT. These studies suggest targeting Rb phosphorylation in mesenchymal cancer cells may decrease invasiveness.

PMID: 27645778 [PubMed - as supplied by publisher]

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Single domain antibody-based bispecific antibody induces potent specific anti-tumor activity.

Single domain antibody-based bispecific antibody induces potent specific anti-tumor activity.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Li J, Zhou C, Dong B, Zhong H, Chen S, Li Q, Wang Z

Abstract
Bispecific antibodies have emerged as powerful therapeutic agents given their high specificity and ability to induce a potent immune response. Various bispecific antibody formats have been designed and studied regarding their applications in cancer therapy, though associated with issues of short half-life or manufacturing difficulties. Herein, a novel bispecific antibody, SS-Fc, was constructed by pairing two single-domain antibodies, anti-CD16 and anti-CEA, which were fused with CH3 "knobs into holes" mutations individually. SS-Fc was expressed and purified from E.coli. In vitro and in vivo experiments confirmed that SS-Fc can form a heterodimeric bispecific antibody when expressed and purified from E. coli. By engaging natural killer (NK) cells through an anti-CD16 single domain antibody, the SS-Fc bispecific antibody exhibited potent in vitro and in vivo cytotoxicity against cancer cells with carcinoembryonic antigen (CEA) expression. Thus, SS-Fc represents a novel bispecific antibody format that can be applied to a wide range of both discovery and clinical applications.

PMID: 27645568 [PubMed - as supplied by publisher]

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The role of stem cells in benign tumors

Abstract

As stem cells contribute to the development and homeostasis of normal adult tissues, malfunction of stem cells in self-renewal and differentiation has been associated with tumorigenesis. A growing number of evidences indicating that tumor initiating cells play a crucial role, not only in malignancies, but also in generation and development of benign tumors. Here we offer an overview of the identification and functional characterization of benign tumor initiating cells in several tissues and organs, which typically show capacities of uncontrolled self-renewal to fuel the tumor growth and abnormal differentiation to give rise to tumor heterogeneity. They may originate from alteration of normal stem cells, which confer the benign tumor initiating cells with different repertoire of "stemness". The plastic functions of benign tumor initiating cells are determined by niche regulation mediated via several signaling and epigenetic cues. Therefore, targeting stem cell function represents an important strategy for understanding the biology and management of benign tumors.

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The role of stem cells in benign tumors

Abstract

As stem cells contribute to the development and homeostasis of normal adult tissues, malfunction of stem cells in self-renewal and differentiation has been associated with tumorigenesis. A growing number of evidences indicating that tumor initiating cells play a crucial role, not only in malignancies, but also in generation and development of benign tumors. Here we offer an overview of the identification and functional characterization of benign tumor initiating cells in several tissues and organs, which typically show capacities of uncontrolled self-renewal to fuel the tumor growth and abnormal differentiation to give rise to tumor heterogeneity. They may originate from alteration of normal stem cells, which confer the benign tumor initiating cells with different repertoire of "stemness". The plastic functions of benign tumor initiating cells are determined by niche regulation mediated via several signaling and epigenetic cues. Therefore, targeting stem cell function represents an important strategy for understanding the biology and management of benign tumors.

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Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.

Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Tamura RE, da Silva Soares RB, Costanzi-Strauss E, Strauss BE

Abstract
Alternative treatments for cancer using gene therapy approaches have shown promising results and some have even reached the marketplace. Even so, additional improvements are needed, such as employing a strategically chosen promoter to drive expression of the transgene in the target cell. Previously, we described viral vectors where high-level transgene expression was achieved using a p53-responsive promoter. Here we present an adenoviral vector (AdPGp53) where p53 is employed to regulate its own expression and which outperforms a traditional vector when tested in a model of gene therapy for prostate cancer. The functionality of AdPGp53 and AdCMVp53 were compared in human prostate carcinoma cell lines. AdPGp53 conferred greatly enhanced levels of p53 protein and induction of the p53 target gene, p21, as well as superior cell killing by a mechanism consistent with apoptosis. DU145 cells were susceptible to induction of death with AdPGp53, yet PC3 cells were quite resistant. Though AdCMVp53 was shown to be reliable, extremely high-level expression of p53 offered by AdPGp53 was necessary for tumor suppressor activity in PC3 and DU145. In situ gene therapy experiments revealed tumor inhibition and increased overall survival in response to AdPGp53, but not AdCMVp53. Upon histologic examination, only AdPGp53 treatment was correlated with the detection of both p53 and TUNEL-positive cells. This study points to the importance of improved vector performance for gene therapy of prostate cancer.

PMID: 27646031 [PubMed - as supplied by publisher]

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Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.

Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Egger JV, Lane MV, Antonucci LA, Dedi B, Krucher NA

Abstract
The tumor suppressor Retinoblastoma (Rb) protein is highly phosphorylated in cancer cells largely due to the overexpression of cyclins or the loss of expression of cyclin dependent kinase inhibitors (cdki). Hyperphosphorylation of Rb promotes proliferation, and plays a role in the regulation of apoptosis. Recently, inhibition of cyclin dependent activity toward Rb has been identified as a strategy that has shown clinical efficacy. We utilized a method to induce phosphatase activity toward Rb in cells by shRNA silencing of PNUTS (Phosphatase Nuclear Targeting Subunit) that regulates PP1-mediated dephosphorylation of Rb. In this study, the effect of Rb dephosphorylation on the epithelial to mesenchymal transition (EMT) was determined. The EMT transition is observed in cancer cells that have acquired invasive characteristics. In breast cancer cells grown in 3D Matrigel cultures, MCF7 cells undergo apoptosis in response to Rb dephosphorylation, whereas MDA-MB-231 and Hs578T cells exhibit a reduction in the EMT. Cells devoid of phosphorylated Rb (nontransformed MCF10A and Rb-null MDA-MB-468) lacked any response to PNUTS depletion, showing the effect is Rb-dependent. In addition, these studies showed that Rb dephosphorylation in 3D Matrigel cultures of highly invasive HT1080 cells led to the inhibition of the EMT. Furthermore we observed association between dephosphorylated Rb with ZEB1, a zinc-finger E-box-binding transcription factor that regulates expression of E- and N-cadherins. Finally Rb dephosphorylation led to inhibition of ZEB1 transcriptional activity, this data supports the notion that Rb dephosphorylation modulates the EMT. These studies suggest targeting Rb phosphorylation in mesenchymal cancer cells may decrease invasiveness.

PMID: 27645778 [PubMed - as supplied by publisher]

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Single domain antibody-based bispecific antibody induces potent specific anti-tumor activity.

Single domain antibody-based bispecific antibody induces potent specific anti-tumor activity.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Li J, Zhou C, Dong B, Zhong H, Chen S, Li Q, Wang Z

Abstract
Bispecific antibodies have emerged as powerful therapeutic agents given their high specificity and ability to induce a potent immune response. Various bispecific antibody formats have been designed and studied regarding their applications in cancer therapy, though associated with issues of short half-life or manufacturing difficulties. Herein, a novel bispecific antibody, SS-Fc, was constructed by pairing two single-domain antibodies, anti-CD16 and anti-CEA, which were fused with CH3 "knobs into holes" mutations individually. SS-Fc was expressed and purified from E.coli. In vitro and in vivo experiments confirmed that SS-Fc can form a heterodimeric bispecific antibody when expressed and purified from E. coli. By engaging natural killer (NK) cells through an anti-CD16 single domain antibody, the SS-Fc bispecific antibody exhibited potent in vitro and in vivo cytotoxicity against cancer cells with carcinoembryonic antigen (CEA) expression. Thus, SS-Fc represents a novel bispecific antibody format that can be applied to a wide range of both discovery and clinical applications.

PMID: 27645568 [PubMed - as supplied by publisher]

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Do Patients Feel Well Informed in a Radiation Oncology Service?

Abstract

Information received by cancer patients has gained importance in recent decades. The aim of this study was to evaluate the perception of information received by oncological patients in a radiotherapy department and to measure the importance of the other information sources. A cross-sectional study was conducted, evaluating patients who received radiotherapy. All the patients were asked two questionnaires: the EORTC QLQ-INFO26 module evaluating their satisfaction with received information, and a questionnaire analyzing other sources of information search. One hundred patients between 27 and 84 years were enrolled. Breast cancer (26 %) was the commonest cancer. Patients felt better informed about the medical tests and secondly about the performed treatment. The younger patients were those who were more satisfied with the information received and patients with no formal education felt less satisfied, with statistically significant differences. Patients did not seek external information; at the most, they asked relatives and other people with cancer. Patients were satisfied with the received information, although a high percentage would like more information. In general, patients did not search for external information sources. Age and educational level seem to influence in the satisfaction with the received information.

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Awareness and Knowledge Levels of Turkish College Students about Human Papilloma Virus Infection and Vaccine Acceptance

Abstract

Awareness of HPV by the target population is an important determinant of vaccine acceptance. The aim of this study is to evaluate the awareness of HPV infection and acceptability of the HPV vaccines among Turkish college students. College students aged 18–30 who were attending a large public university in Ankara participated in this study. The participants were asked to complete a questionnaire to elicit demographic characteristics, awareness level of HPV and HPV vaccine, and willingness to be vaccinated. One thousand one hundred sixty students responded to the invitation email and completed the questionnaire. The mean scores of female students about HPV and HPV vaccine were 7.1/15 and 3.6/9, respectively, while these scores were 7.9/15 and 3.4/9 among male students, respectively. While 51 % percent of female and 33.5 % of male students had heard of HPV and 32.8 % and 18 % of them had heard of HPV vaccine, respectively, only 1.5 % of female and 0.4 % of male students had been vaccinated against HPV. A total of 507 students (43.7 %) had previously heard of HPV. Only 309 (26.6 %) of the participants had previously heard of the HPV vaccine, and 45.1 % of the students were willing to receive HPV vaccination. The main predictors for willingness to be vaccinated were the following: sexual experience, sexual behavior, past history of sexually transmitted infection (STI), and knowledge about HPV and HPV vaccine. Higher awareness levels of HPV and HPV vaccine are significantly related to greater willingness to be vaccinated, and the main reasons for rejecting the vaccine were insufficient information about the vaccine and possible unknown side effects.

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A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors

Summary

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1–21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2–22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T_max was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2–22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46–97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.

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Propolis extracts from the northern region of Thailand suppress cancer cell growth through induction of apoptosis pathways

Summary

The continual increase in mortality rates and number of cancer cases is a matter of serious concern in developing countries. The incorporation of natural products into classical cancer treatment approaches is a promising direction. The mechanisms of A549 and HeLa cancer cell death induction by ethanolic extracts of propolis samples from Phayao, Chiang Mai, and Nan provinces in northern Thailand were investigated in this study. The propolis extract from Chiang Mai showed the highest antioxidant activity and the greatest total phenolic content. The propolis extract from Nan also exhibited the highest total flavonoid content. The proliferation of A549 and HeLa cells grown in the presence of the propolis extracts was suppressed in a dose- and time-dependent manner. Moreover, treatment of both cancer cells with the propolis extracts showed DNA fragmentation and significantly increased the number of the apoptotic cells. On A549 cells, the extrinsic and intrinsic pathways of caspase enzymes were activated by the propolis extracts from Phayao and Chiang Mai. In the case of the propolis extract from Nan, the mechanisms involved apoptosis on the A549 cells were caspase-independent pathway. The extrinsic pathway of the caspase enzyme was triggered by all of the propolis extracts on HeLa cells. Finally, oral administration of the propolis granule produced from the propolis extract from Nan resulted in extended survival of tumour-bearing mice. Therefore, propolis extracts from the northern region of Thailand demonstrated pharmacological properties, both antioxidant and anticancer activities. From these findings, it is evident that propolis extracts can be considered as a naturally obtained agent extremely useful in cancer treatment.

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Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.

Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Tamura RE, da Silva Soares RB, Costanzi-Strauss E, Strauss BE

Abstract
Alternative treatments for cancer using gene therapy approaches have shown promising results and some have even reached the marketplace. Even so, additional improvements are needed, such as employing a strategically chosen promoter to drive expression of the transgene in the target cell. Previously, we described viral vectors where high-level transgene expression was achieved using a p53-responsive promoter. Here we present an adenoviral vector (AdPGp53) where p53 is employed to regulate its own expression and which outperforms a traditional vector when tested in a model of gene therapy for prostate cancer. The functionality of AdPGp53 and AdCMVp53 were compared in human prostate carcinoma cell lines. AdPGp53 conferred greatly enhanced levels of p53 protein and induction of the p53 target gene, p21, as well as superior cell killing by a mechanism consistent with apoptosis. DU145 cells were susceptible to induction of death with AdPGp53, yet PC3 cells were quite resistant. Though AdCMVp53 was shown to be reliable, extremely high-level expression of p53 offered by AdPGp53 was necessary for tumor suppressor activity in PC3 and DU145. In situ gene therapy experiments revealed tumor inhibition and increased overall survival in response to AdPGp53, but not AdCMVp53. Upon histologic examination, only AdPGp53 treatment was correlated with the detection of both p53 and TUNEL-positive cells. This study points to the importance of improved vector performance for gene therapy of prostate cancer.

PMID: 27646031 [PubMed - as supplied by publisher]

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Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.

Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Egger JV, Lane MV, Antonucci LA, Dedi B, Krucher NA

Abstract
The tumor suppressor Retinoblastoma (Rb) protein is highly phosphorylated in cancer cells largely due to the overexpression of cyclins or the loss of expression of cyclin dependent kinase inhibitors (cdki). Hyperphosphorylation of Rb promotes proliferation, and plays a role in the regulation of apoptosis. Recently, inhibition of cyclin dependent activity toward Rb has been identified as a strategy that has shown clinical efficacy. We utilized a method to induce phosphatase activity toward Rb in cells by shRNA silencing of PNUTS (Phosphatase Nuclear Targeting Subunit) that regulates PP1-mediated dephosphorylation of Rb. In this study, the effect of Rb dephosphorylation on the epithelial to mesenchymal transition (EMT) was determined. The EMT transition is observed in cancer cells that have acquired invasive characteristics. In breast cancer cells grown in 3D Matrigel cultures, MCF7 cells undergo apoptosis in response to Rb dephosphorylation, whereas MDA-MB-231 and Hs578T cells exhibit a reduction in the EMT. Cells devoid of phosphorylated Rb (nontransformed MCF10A and Rb-null MDA-MB-468) lacked any response to PNUTS depletion, showing the effect is Rb-dependent. In addition, these studies showed that Rb dephosphorylation in 3D Matrigel cultures of highly invasive HT1080 cells led to the inhibition of the EMT. Furthermore we observed association between dephosphorylated Rb with ZEB1, a zinc-finger E-box-binding transcription factor that regulates expression of E- and N-cadherins. Finally Rb dephosphorylation led to inhibition of ZEB1 transcriptional activity, this data supports the notion that Rb dephosphorylation modulates the EMT. These studies suggest targeting Rb phosphorylation in mesenchymal cancer cells may decrease invasiveness.

PMID: 27645778 [PubMed - as supplied by publisher]

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Single domain antibody-based bispecific antibody induces potent specific anti-tumor activity.

Single domain antibody-based bispecific antibody induces potent specific anti-tumor activity.

Cancer Biol Ther. 2016 Sep 19;:0

Authors: Li J, Zhou C, Dong B, Zhong H, Chen S, Li Q, Wang Z

Abstract
Bispecific antibodies have emerged as powerful therapeutic agents given their high specificity and ability to induce a potent immune response. Various bispecific antibody formats have been designed and studied regarding their applications in cancer therapy, though associated with issues of short half-life or manufacturing difficulties. Herein, a novel bispecific antibody, SS-Fc, was constructed by pairing two single-domain antibodies, anti-CD16 and anti-CEA, which were fused with CH3 "knobs into holes" mutations individually. SS-Fc was expressed and purified from E.coli. In vitro and in vivo experiments confirmed that SS-Fc can form a heterodimeric bispecific antibody when expressed and purified from E. coli. By engaging natural killer (NK) cells through an anti-CD16 single domain antibody, the SS-Fc bispecific antibody exhibited potent in vitro and in vivo cytotoxicity against cancer cells with carcinoembryonic antigen (CEA) expression. Thus, SS-Fc represents a novel bispecific antibody format that can be applied to a wide range of both discovery and clinical applications.

PMID: 27645568 [PubMed - as supplied by publisher]

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Combined Analysis of ChIP Sequencing and Gene Expression Dataset in Breast Cancer

Abstract

Breast cancer is a common malignancy in women and contribute largely to the cancer related death. The purpose of this study is to confirm the roles of GATA3 and identify potential biomarkers of breast cancer. Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-Seq) (GSM1642515) and gene expression profiles (GSE24249) were downloaded from the Gene Expression Omnibus (GEO) database. Bowtie2 and MACS2 were used for the mapping and peak calling of the ChIP-Seq data respectively. ChIPseeker, a R bioconductor package was adopted for the annotation of the enriched peaks. For the gene expression profiles, we used affy and limma package to do normalization and differential expression analysis. The genes with fold change >2 and adjusted P-Value <0.05 were screened out. Besides, BETA (Binding and Expression Target Analysis) was used to do the combined analysis of ChIP-Seq and gene expression profiles. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for the functional enrichment analysis of overlapping genes between the target genes and differential expression genes (DEGs). What's more, the protein-protein interaction (PPI) network of the overlapping genes was obtained through the Human Protein Reference Database (HPRD). A total of 46,487 peaks were identified for GATA3 and out of which, 3256 ones were found to located at −3000 ~ 0 bp from the transcription start sites (TSS) of their nearby gene. A total of 236 down- and 343 up-regulated genes were screened out in GATA3 overexpression breast cancer samples compared with those in control. The combined analysis of ChIP-Seq and gene expression dataset showed GATA3 act as a repressor in breast cancer. Besides, 68 overlaps were obtained between the DEGs and genes included in peaks located at −3000 ~ 0 bp from TSS. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to cancer progression and gene regulation were found to be enriched in those overlaps. In the PPI network, NDRG1, JUP and etc. were found to directly interact with large number of genes, which might indicate their important roles in the progression of breast cancer.

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Prognostic factors of overall survival in children and adolescents enrolled in dose-finding trials in Europe: An Innovative Therapies for Children with Cancer study

Publication date: November 2016
Source:European Journal of Cancer, Volume 67
Author(s): Fernando Carceller, Francisco J. Bautista, Irene Jiménez, Raquel Hladun-Álvaro, Cécile Giraud, Luca Bergamaschi, Madhumita Dandapani, Isabelle Aerts, François Doz, Didier Frappaz, Michela Casanova, Bruce Morland, Darren R. Hargrave, Lynley V. Marshall, Gilles Vassal, Andrew D.J. Pearson, Birgit Geoerger, Lucas Moreno
ObjectivesDose-finding trials are fundamental to develop novel drugs for children and adolescents with advanced cancer. It is crucial to maximise individual benefit, whilst ensuring adequate assessment of key study end-points. We assessed prognostic factors of survival in paediatric phase I trials, including two predictive scores validated in adult oncology: the Royal Marsden Hospital (RMH) and the MD Anderson Cancer Center (MDACC) scores.MethodsData of patients with solid tumours aged <18 years at enrolment in their first dose-finding trial between 2000 and 2014 at eight centres of the Innovative Therapies for Children with Cancer European consortium were collected. Survival distributions were compared using log-rank test and Cox regression analyses.ResultsOverall, 248 patients were evaluated: median age, 11.2 years (range 1.0–17.9); 46% had central nervous system (CNS) tumours and 54% extra-CNS tumours. Complete responses were observed in 2.1%, partial responses in 7.2% and stable disease in 25.9%. Median overall survival (OS) was 6.3 months (95% confidence interval, 5.2–7.4). Lansky/Karnofsky ≤80%, no school/work attendance, elevated creatinine and RMH score ≥1 correlated with worse OS in the multivariate analysis. The RMH and MDACC scores correlated with OS in adolescents (12–17 years), p = 0.002, but not in children (2–11 years).ConclusionsPerformance status of 90–100% and school/work attendance at enrolment are strong indicators of longer OS in paediatric phase I trials. Adult predictive scores correlate with survival in adolescents. These findings provide a useful orientation about potential prognosis and could lead in the future to more paediatric-adapted eligibility criteria in early-phase trials.



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