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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Does Peer Review of Radiation Plans Impact Clinical Care? A Systematic Review of the Literature

Publication date: Available online 20 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kelsey Brunskill, Timothy K. Nguyen, R. Gabriel Boldt, Alexander V. Louie, Andrew Warner, Lawrence B. Marks, David A. Palma
PurposePeer review is a recommended component of quality assurance in radiation oncology, however it is resource-intensive and its effect on patient care is not well understood. We conducted a systematic review of the literature to assess the reported clinical impact of peer review on radiotherapy treatment plans.MethodsA systematic review of the English literature was executed following PRISMA guidelines, including MEDLINE, EMBASE, and abstracts published from major radiation oncology scientific meeting proceedings. For inclusion, studies were required to report the impact of peer review on at least one element of treatment planning (e.g. target volume or organat- risk delineation, dose prescription, or dosimetry).ResultsThe initial search strategy identified 882 potentially eligible studies with 11 meeting inclusion criteria for full-text review and final analysis. Across a total of 11,491 patient cases, peer review programs led to modifications in a weighted mean of 10.8% of radiation treatment plans. Five studies differentiated between major and minor changes, and reported weighted mean rates of change of 2.7% and 7.3% respectively. The most common changes related to target volume delineation (45.2% of changed plans), dose prescription or written directives (24.4%), and non-target volume delineation or normal tissue sparing (7.5%).ConclusionsOur findings suggest that peer review leads to changes in clinical care in approximately 1 out every 9 cases overall. This is similar to reported rates of change in peer review studies from other oncology-related specialties, such as radiology and pathology.



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Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiotherapy

Publication date: Available online 20 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kamalesh Dattaram Mumbrekar, Satish Rao Bola Sadashiva, Shama Prasada Kabekoddu, Donald Jerard Fernandes, Bejadi Manjunath Vadhiraja, Tomo Suga, Yoshimi Shoji, Fumiaki Nakayama, Takashi Imai, Kapaettu Satyamoorthy
PurposeHeterogeneity in radiotherapy (RT) induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcome. Besides, treatment related factors, normal tissue adverse reactions are also manifested from genetic alterations in genes of distinct pathways majorly involving DNA damage-repair, inflammatory cytokine, cell cycle regulation and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes may modify the severity of normal tissue toxicity and identification of the same may have clinical relevance as a predictive biomarker.



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Experimental platform for ultra-high dose rate FLASH irradiation of small animals using a clinical linear accelerator

Publication date: Available online 20 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Emil Schüler, Stefania Trovati, Gregory King, Frederick Lartey, Marjan Rafat, Manuel Villegas, A. Joe Praxel, Billy W. Loo, Peter G. Maxim
Backgroundand Purpose: A key factor limiting the effectiveness of radiation therapy is normal tissue toxicity, and recent preclinical data shows that ultra-high dose rate irradiation (>50 Gy/s, "FLASH") potentially mitigates this effect. However, research in this field has so far been strongly limited by the availability of FLASH irradiators suitable for small animal experiments. We present a simple methodological approach for FLASH electron small animal irradiation with a clinically available LINAC.Material and MethodsWe investigated the FLASH irradiation potential of a Varian Clinac 21EX in both clinical mode and after tuning of the LINAC. We performed detailed FLUKA Monte Carlo and experimental dosimetric characterization at multiple experimental locations within the LINAC head.ResultsAverage dose rates of up to 74 Gy/s were achieved in clinical mode, while the dose rate after tuning exceeded 900 Gy/s. We obtained 220 Gy/s at 1 cm depth for a >4 cm field size with 90% homogeneity throughout a 2 cm thick volume.ConclusionsWe present an approach for using a clinical linear accelerator for FLASH irradiations. We obtained dose rates exceeding 200 Gy/s following simple tuning of the LINAC with excellent dosimetric properties for small animal experiments. This allows for increased availability of FLASH irradiation to the general research community.



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A new functional IDH2 genetic variant is associated with the risk of lung cancer

Abstract

Recently, mutations in isocitrate dehydrogenase 1/2 (IDH1/2) were discovered in 70% of low-grade glioma and secondary glioblastoma multiforme. The discovery of an oncogenic function and the identification of onco-metabolites of IDH1/2 support new roles for metabolism in cancer. For example, some evidence indicates that IDH2 might also exhibit oncogenic functions by promoting cellular metabolism and cancer cell growth. We examined the association between IDH2 rs11540478 and lung cancer risk in 262 lung cancer patient cases and 602 healthy control subjects and also investigated the biological function of rs11540478 in vivo. We found that a higher risk was observed in lung cancer patient carriers of rs11540478 TT and CT compared with CC carriers(OR = 1.44; 95% CI = 1.04-2.00; p = 0.03). The frequency of IDH2 rs11540478 TT and CT carriers was decreased in healthy individuals between the ages of 50-77 compared to those aged 30-49 (OR = 0.67; 95% CI = 0.47-0.96; p = 0.03). Functional analysis showed the effect of rs11540478 on IDH2 expression and lung cancer cell viability, with higher IDH2 expression and cell viability among T allele compared with C allele. IDH2 mRNA was higher in peripheral blood lymphocytes from lung cancer patients compared to healthy subjects. Herein, for the first time we identified IDH2 rs11540478 as a new susceptibility locus for lung cancer. The effect of rs11540478 on mRNA expression of IDH2 and lung cancer cell viability might provide new insight for the genetic basis of lung cancer. This article is protected by copyright. All rights reserved

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Exploiting agonist biased signaling of chemokines to target cancer

Abstract

As knowledge of growth-independent functions of cancer cells is expanding, exploration into the role of chemokines in modulating cancer pathogenesis, particularly metastasis, continues to develop. However, more study into the mechanisms whereby chemokines direct the migration of cancer cells is needed before specific therapies can be generated to target metastasis. Herein, we draw attention to the longstanding conundrum in the field of chemokine biology that chemokines stimulate migration in a biphasic manner; and explore this phenomenon's impact on chemokine function in the context of cancer. Typically, low concentrations of chemokines lead to chemotactic migration and higher concentrations halt migration. The signaling mechanisms that govern this phenomenon remain unclear. Over the last decade we have defined a novel signaling mechanism for regulation of chemokine migration through ligand oligomerization and biased agonist signaling. We provide insight into this new paradigm for chemokine signaling and discuss how it will impact future exploration into chemokine function and biology. In the pursuit of producing more novel cancer therapies, we suggest a framework for pharmaceutical application of the principles of chemokine oligomerization and biased agonist signaling in cancer. This article is protected by copyright. All rights reserved

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Anthocyanidins inhibit epithelial-mesenchymal transition through a TGF-β/Smad2 signaling pathway in glioblastoma cells

ABSTRACT

Epidemiological studies have convincingly demonstrated that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the anthocyanidins are known to possess anti-inflammatory, cardioprotective, anti-angiogenic and anti-carcinogenic properties. Despite the well-known role of transforming growth factor-β (TGF-β) in high grade gliomas, the impact of anthocyanidins on TGF-β-induced epithelial mesenchymal transition (EMT), a process that allows benign tumor cells to infiltrate surrounding tissues, remains poorly understood. The objective of this study is to investigate the impact of anthocyanidins such as cyanidin (Cy), delphinidin (Dp), malvidin (Mv), pelargonidin (Pg) and petunidin (Pt) on TGF-β-induced EMT and to determine the mechanism(s) underlying such action. Human U-87 glioblastoma (U-87 MG) cells were treated with anthocyanidins prior to, along with or following the addition of TGF-β. We found that anthocyanidins differently affected TGF-β-induced EMT, depending on the treatment conditions. Dp was the most potent EMT inhibitor through its inhibitory effect on the TGF-β Smad and non-Smad signaling pathways. These effects altered expression of the EMT mesenchymal markers fibronectin and Snail, as well as markedly reducing U-87 MG cell migration. Our study highlights a new action of anthocyanidins against EMT that supports their beneficial health and chemopreventive effects in dietary-based strategies against cancer. This article is protected by copyright. All rights reserved

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Down-regulation of β-catenin and the associated migration ability by Taiwanin C in arecoline and 4-NQO-induced oral cancer cells via GSK-3β activation

Abstract

Cancer is one of the leading causes of death worldwide, and oral squamous cell carcinoma (OSCC) accounts for almost a sixth of all reported cancers. Arecoline, from areca nut is known to enhance carcinogenesis in oral squamous cells. The objective of this study is to determine the effect of Taiwanin C, from Taiwania cryptomerioides Hayata against Arecoline-associated carcinogenesis. An OSCC model was created in C57BL/6J Narl mice by administrating 0.5 mg/mL arecoline with 0.2 mg/mL 4-NQO carcinogen for 8 and 28 weeks to mimic the etiology of oral cancer patients in Asia. Mice were sacrificed and two cell lines, T28 from the tumor and N28 cancerous cell line from the surrounding non tumor area, were established. Taiwanin C showed effective anti-tumor activity in nude mice models. Taiwanin C significantly inhibited the cell viability of T28 cells in a dose dependent manner, but did not inflict any effect on N28 normal cells. Taiwanin C treatment inhibited the migration ability of T28 cells in a dose dependent manner as determined by wound healing and migration assays. Taiwanin C also reduced the levels of β-catenin and its downstream metastatic proteins, Tbx3 and c-Myc. Besides, Taiwanin C inhibited the nuclear accumulation of β-catenin and induced β-catenin degradation via proteasome-mediated pathway. Moreover, Taiwanin C enhanced GSK-3β and reduced the p-ser⁹ GSK-3β protein level to inactivate Wnt signaling. Taken together, Taiwanin C blocked the cell migration effects of T28 cells mediated through the activation of GSK-3β to enhance protein degradation and reduce nuclear accumulation of β-catenin. This article is protected by copyright. All rights reserved

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Ephrin-B2 overexpression predicts for poor prognosis and response to therapy in solid tumors

Abstract

Ephrin B2 is variably expressed on tumor cells and its blockade has been shown to inhibit angiogenesis in animal models of pancreatic, colorectal, lung and head and neck squamous cell carcinomas. However, the implications of ephrinB2 expression in cancer patients have remained elusive. In this study, we analyzed the cancer genome atlas (TCGA) for ephrinB2 expression. We report significant correlations between EFNB2 expression, overall survival and disease-free survival in head and neck squamous cell carcinoma (HNSCC, n = 519), pancreatic adenocarcinoma (n = 186) and bladder urothelial carcinoma (n = 410). In HNSCC patients, high EFNB2 mRNA expression was associated with tumor HPV negativity, oral cavity location, alcohol intake, higher TP53 mutation, and EGFR amplification. EphrinB2 overexpression also correlated with worse response to chemotherapy and radiotherapy. The therapeutic potential of blocking ephrinB2 was validated in HNSCC patient-derived tumor xenografts and showed significant improvement in survival and tumor growth delay. Our data shows that ephrinB2 overexpression can serve as a critical biomarker for patient prognosis and response to therapy. These results should guide design of future clinical trials exploring EphrinB2 inhibition in cancer patients. This article is protected by copyright. All rights reserved

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KITENIN functions as a fine regulator of ErbB4 expression level in colorectal cancer via protection of ErbB4 from E3-ligase Nrdp1-mediated degradation

ABSTRACT

Understanding the complex biological functions of E3-ubiquitin ligases may facilitate the development of mechanism-based anti-cancer drugs. We recently identified that the KITENIN/ErbB4-Dvl2-c-Jun axis works as a novel unconventional downstream signal of epidermal growth factor (EGF) in colorectal cancer (CRC) tissues. Here we addressed whether E3-ubiquitin ligases are required for operation of this axis. We found that Nrdp1, an E3-ligase for ErbB3/ErbB4, interacted with KITENIN (KAI1 C-terminal interacting tetraspanin) to form a functional KITENIN/ErbB4/Nrdp1 complex and is responsible for down-regulating Dvl2 within this complex. Interestingly, ErbB4 was resistant to degradation by Nrdp1 in KITENIN/Nrdp1-co-transfected CRC cells, and KITENIN bound to the C-terminal coiled-coil domain of Nrdp1. Chemical blockade of ErbB kinase did not block the action of EGF to increase in total/phospho-ErbB4 and phospho-ERK in KITENIN/ErbB4-cotransfected cells, whereas it blocked the action of EGF in ErbB4 alone-transfected CRC cells. In human CRC tissues, higher expressions of ErbB4 and KITENIN and lower expression of Dvl2 was observed in stage IV samples than in stage I, but a low level of Nrdp1 was expressed in both stages and it did not differ significantly by stage. These results indicated that Nrdp1 is necessary for the reduction in Dvl2 to generate c-Jun in the EGF-KITENIN/ErbB4-c-Jun axis, but more importantly, elevated KITENIN protects KITENIN-bound ErbB4 from Nrdp1-mediated degradation via physical collaboration between the KITENIN/ErbB4 complex and Nrdp1, but not via modulation of ErbB kinase activity. Thus, KITENIN functions in the maintenance of a higher expression level of ErbB4 in advanced CRC tissues, independent of ubiquitin-mediated degradation via Nrdp1. This article is protected by copyright. All rights reserved

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Prognostic value of phosphorylated Raf kinase inhibitory protein at serine 153 and its predictive effect on the clinical response to radiotherapy in nasopharyngeal carcinoma

Radiation is an effective treatment against nasopharyngeal carcinoma (NPC). However, radioresistance-induced locoregional recurrence remains as a major cause of treatment failure. Therefore, radiosensitivity i...

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Deformable image registration for adaptive radiotherapy with guaranteed local rigidity constraints

Deformable image registration (DIR) is a key component in many radiotherapy applications. However, often resulting deformations are not satisfying, since varying deformation properties of different anatomical ...

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TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway

Abstract

Background

Tissue inhibitor matrix metalloproteinase 1 (TIMP1) plays a vital role in carcinogenesis, yet its precise functional roles and regulation remain unclear. In this study, we aim to investigate its biological function and clinical significance in human colon cancer.

Methods

We analyzed the expression of TIMP1 in both public database (Oncomine and TCGA) and 94 cases of primary colon cancer and matched normal colon tissue specimens. The underlying mechanisms of altered TIMP1 expression on cell tumorigenesis, proliferation, and metastasis were explored in vitro and in vivo.

Results

TIMP1 was overexpressed in colon tumorous tissues and lymph node metastasis specimens than in normal tissues. The aberrant expression of TIMP1 was significantly associated with the regional lymph node metastasis (p = 0.033), distant metastasis (p = 0.039), vascular invasion (p = 0.024) and the American Joint Committee on Cancer (AJCC) stage (p = 0.026). Cox proportional hazards model showed that TIMP1 was an independent prognostic indicator of disease-free survival (HR = 2.603, 95 % CI: 1.115–6.077, p = 0.027) and overall survival (HR = 2.907, 95 % CI: 1.254–6.737, p = 0.013) for patients with colon cancer. Consistent with this, our findings highlight that suppression of TIMP1 expression decreased proliferation, and metastasis but increased apoptosis by inducing TIMP1 specific regulated FAK-PI3K/AKT and MAPK pathway.

Conclusion

TIMP1 might play an important role in promoting tumorigenesis and metastasis of human colon cancer and function as a potential prognostic indicator for colon cancer.

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Current state of knowledge of hepatic encephalopathy (part II): changes in brain white matter tracts integrity are associated with cognitive deficits in minimal hepatic encephalopathy

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Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice

Abstract

Among non-pharmacological treatments, the ketogenic diet (KD) has the strongest demonstrated evidence of clinical success in drug resistant epilepsy. In an attempt to model the anticonvulsant effects of the KD pre-clinically, the present study assessed the effects of the KD against electroshock-induced convulsions in mice. After confirming that exposure to the KD for 2 weeks resulted in stable ketosis and hypoglycemia, mice were exposed to electroshocks of various intensities to establish general seizure susceptibility. When compared to mice fed the standard rodent chow diet (SRCD), we found that mice fed the KD were more sensitive to electroconvulsions as reflected by a significant decrease in seizure threshold (3.86 mA in mice on the KD vs 7.29 mA in mice on the SRCD; P < 0.05) in the maximal electroshock seizure threshold (MEST) test. To examine if this increased seizure sensitivity to electroconvulsions produced by the KD would affect anticonvulsant effects of antiepileptic drugs (AEDs), anticonvulsant potencies of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) against maximal electroshock (MES)-induced convulsions were compared in mice fed the KD and SRCD. We found that potencies of all AEDs studied were decreased in mice fed the KD in comparison to those on the SRCD, with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT). Finally, the lack of differences in brain exposures of the AEDs studied in mice fed the KD and SRCD ruled out a pharmacokinetic nature of the observed findings. Taken together, exposure to the KD in the present study had an overall pro-convulsant effect. Since electroconvulsions require large metabolic reserves to support their rapid spread throughout the brain and consequent generalized tonic-clonic convulsions, this effect may be explained by a high energy state produced by the KD in regards to increased energy storage and utilization.

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Is Empathy Associated with a Self-Ascribed Sense of Meaning Among Resident Physicians Working with Patients Nearing the End of Life on a Hematology-Oncology Ward?

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Symptom Experiences in Metastatic Breast Cancer Patients: Relationships to Activity Engagement, Value-based Living, and Psychological Inflexibility

Abstract

Objective

This study examined symptom-based subgroups of metastatic breast cancer (MBC) patients and the extent to which they differed across key constructs of Acceptance and Commitment Therapy (ACT).

Methods

Eighty women with MBC completed self-report surveys assessing ten common symptoms and several ACT variables (i.e., activity engagement, psychological inflexibility, value obstruction, and value progress) during a single time point.

Results

A cluster analysis yielded three patient subgroups: low symptoms, low-moderate symptoms, and moderate-high symptoms. Relative to the subgroup with low symptoms, the other subgroups reported less activity engagement. In addition, compared to patients with low symptoms, the subgroup with moderate-high symptoms reported greater psychological inflexibility (i.e., avoidance of unwanted internal experiences) and greater difficulty living consistently with their values.

Conclusions

Women with MBC show heterogeneity in their symptom profiles, and those with higher symptom burden are more likely to disengage from valued activities and avoid unwanted experiences (e.g., thoughts, feelings, bodily sensations). Findings are largely consistent with the ACT model and provide strong justification for testing ACT to address symptom interference in MBC patients.

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Factors Associated with Oncology Patients’ Involvement in Shared Decision-Making During Chemotherapy

Abstract

Objective

Oncology patients are increasingly encouraged to play an active role in treatment decision-making. While previous studies have evaluated relationships between demographic characteristics and decision-making roles, less is known about the association of symptoms and psychological adjustment characteristics (e.g., coping styles, personality traits) and decision-making roles.

Methods

As part of a larger study of symptom clusters, patients (n = 765) receiving chemotherapy (CTX) for breast, gastrointestinal, gynecological, or lung cancer provided information on demographic, clinical, symptom, and psychological adjustment characteristics. Patient-reported treatment decision-making roles (i.e., preferred role, and role actually played) were assessed using the Control Preferences Scale. Differences among patients, who were classified as passive, collaborative, or active, were evaluated using Chi square analyses and analyses of variance.

Results

Over half (56.3%) of the patients reported both that they preferred, and that they actually played, a collaborative role. Among those patients with concordant roles, those who were older, those with less education and lower income, and those who were less resilient were more likely to prefer a passive role. Several psychological adjustment characteristics were associated with decision-making role, including coping style, personality, and fatalism.

Conclusions

Oncology patients' preferences for involvement in treatment decision-making are associated with demographic characteristics as well as with symptoms and psychological adjustment characteristics, such as coping style and personality. These results reaffirm the complexities of predicting patients' preferences for involvement in decision-making. Further study is needed to determine if role or coping style may be influenced by interventions designed to teach adaptive coping skills.

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Primary breast cancer cell culture yields intra-tumor heterogeneous subpopulations expressing exclusive patterns of receptor tyrosine kinases

Abstract

Background

It has become evident that intra-tumor heterogeneity of breast cancer impact on several biological processes such as proliferation, migration, cell death and also might contribute to chemotherapy resistance. The expression of Receptor Tyrosine Kinases (RTKs) has not been analyzed in the context of intra-tumor heterogeneity in a primary breast cancer cell culture. Several subpopulations were isolated from the MBCDF (M serial-breast cancer ductal F line) primary breast cancer cells and were successfully maintained in culture and divided in two groups according to their morphology and RTKs expression pattern, and correlated with biological processes like proliferation, migration, anchorage-independent cell growth, and resistance to cytotoxic chemotherapy drugs and tyrosine kinase inhibitors (TKIs).

Methods

Subpopulations were isolated from MBCDF primary breast cancer cell culture by limiting dilution. RTKs and hormone receptors were examined by Western blot. Proliferation was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT assay). Cell viability was evaluated by Crystal Violet. Migration was assessed using Boyden chambers. Anchorage-independent cell growth was evaluated by colony formation in soft agar.

Results

Several subpopulations were isolated from the MBCDF breast cancer cells that were divided into two groups according to their morphology. Analysis of RTKs expression pattern showed that HER1, HER3, c-Met and VEGFR2 were expressed exclusively in cells from group 1, but not in cells from group 2. PDGFR was expressed only in cells from group 2, but not in cells from group 1. HER2, HER4, c-Kit, IGF1-R were expressed in all subpopulations. Biological processes correlated with the RTKs expression pattern. Group 2 subpopulations present the highest rate of cell proliferation, migration and anchorage-independent cell growth. Analysis of susceptibility to chemotherapy drugs and TKIs showed that only Paclitaxel and Imatinib behaved differently between groups. Group 1-cells were resistant to both Paclitaxel and Imatinib.

Conclusions

We demonstrated that subpopulations from MBCDF primary cell culture could be divided into two groups according to their morphology and a RTKs excluding-expression pattern. The differences observed in RTKs expression correlate with the biological characteristics and chemoresistance of each group. These results suggest that intra-tumor heterogeneity contributes to generate groups of subpopulations with a more aggressive phenotype within the tumor.

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Microsurgical resection of vestibular schwannomas: complication avoidance

Abstract

Vestibular schwannoma (VS) surgery requires appropriate patient selection, meticulous microsurgical technique and optimal post-operative care. Focused radiation is an effective alternative for the treatment of smaller VSs. For VS surgery to remain a reasonable option, surgery must be performed with a limited number of complications. Complication rates for VS surgery have increased over the last decade. This is likely due to (1) decreased surgical volume and as a result decreased microsurgical experience, (2) larger tumors undergoing surgery while smaller tumors are reserved for radiation, and (3) surgery for previously radiated tumors resulting in more difficult anatomic dissection. Appropriate management of complications is paramount. Herein, we discuss complications related to VS microsurgery and methods of avoidance. Specifically, we discuss the most frequently encountered complications, intraoperative monitoring and finally, methods of addressing these complications. With meticulous microsurgical technique, careful intraoperative monitoring and vigilant perioperative care one will ensure optimal patient outcomes.

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Sensitive Detection of a Small Parathyroid Adenoma Using Fluorocholine PET/CT: A Case Report

Abstract

Primary hyperparathyroidism is caused by parathyroid adenoma in the majority of cases and diagnosis is usually made biochemically. Pre-surgical localization of parathyroid adenoma is essential to limit the extent of surgery and avoid missing them at ectopic sites. Anatomical and functional imaging are used for the localization, but may fail to identify the small and ectopic parathyroid adenoma. We present a case of small sized ectopic parathyroid adenoma at unusual location detected by F-18 fluorocholine (FCH) PET/CT, where other imaging modalities failed. The post-operative histopathology confirmed the diagnosis of ectopic parathyroid adenoma.

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Relation of comorbidities and patient navigation with the time to diagnostic resolution after abnormal cancer screening

BACKGROUND

Whether patient navigation improves outcomes for patients with comorbidities is unknown. The aims of this study were to determine the effect of comorbidities on the time to diagnostic resolution after an abnormal cancer screening test and to examine whether patient navigation improves the timeliness and likelihood of diagnostic resolution for patients with comorbidities in comparison with no navigation.

METHODS

A secondary analysis of comorbidity data collected by Patient Navigation Research Program sites using the Charlson Comorbidity Index (CCI) was conducted. The participants were 6,349 patients with abnormal breast, cervical, colon, or prostate cancer screening tests between 2007 and 2011. The intervention was patient navigation or usual care. The CCI data were highly skewed across projects and cancer sites, and the CCI scores were categorized as 0 (CCI score of 0 or no comorbidities identified; 76% of cases); 1 (CCI score of 1; 16% of cases), or 2 (CCI score ≥ 2; 8% of cases). Separate adjusted hazard ratios for each site and cancer type were obtained, and then they were pooled with a meta-analysis random effects methodology.

RESULTS

Patients with a CCI score ≥ 2 had delayed diagnostic resolution after an abnormal cancer screening test in comparison with those with no comorbidities. Patient navigation reduced delays in diagnostic resolution, with the greatest benefits seen for those with a CCI score ≥ 2.

CONCLUSIONS

Persons with a CCI score ≥ 2 experienced significant delays in timely diagnostic care in comparison with patients without comorbidities. Patient navigation was effective in reducing delays in diagnostic resolution among those with CCI scores > 1. Cancer 2016. © 2016 American Cancer Society.

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National patterns of care and predictors of neoadjuvant and concurrent chemotherapy use with definitive radiotherapy in the treatment of patients with oropharyngeal squamous cell carcinoma

BACKGROUND

To the authors' knowledge, the patterns of care for the radiotherapy-based treatment of patients with stage III to IVB oropharyngeal squamous cell carcinoma (OPSCC) are poorly defined. The objective of the current study was to characterize the use and predictors of chemotherapy with radiotherapy for this population using the National Cancer Database.

METHODS

Patients in the National Cancer Database with AJCC (American Joint Committee on Cancer) stage III to IV OPSCC who were treated with radiotherapy between 2003 and 2012 were eligible for analysis. Treatment was defined as radiotherapy alone, concurrent chemoradiotherapy, or induction chemotherapy (IC). Multivariable regression with multilevel modeling was used to determine predictors of any chemotherapy use and, among patients receiving chemotherapy, the predictors of IC.

RESULTS

The majority (90%) of the 30,875 eligible patients received chemotherapy, the majority of whom (71% of the total) were treated with definitive chemoradiotherapy; a sizeable percentage of patients received IC (19% of total). On multivariable regression, younger age, favorable comorbidity status, and more advanced tumor and lymph node disease were found to be independent predictors of any chemotherapy and IC use. Nonwhite patients (odds ratio [OR], 0.71; P<.0001), women (OR, 0.74; P<.0001), and individuals without private insurance were found to be significantly less likely to receive chemotherapy. Patients treated at higher-volume institutions were significantly less likely to receive IC (OR, 0.69; P = .0006). Human papillomavirus status did not appear to independently influence treatment choice.

CONCLUSIONS

The vast majority of patients with stage III to IVB OPSCC who were treated with definitive radiotherapy received chemotherapy, which is consistent with high-level data and national recommendations. However, disparities with regard to race, sex, and insurance status emerged thereby requiring additional investigation. The frequent use of IC despite limited supportive evidence warrants research on physician and patient decision making and presents an opportunity to improve evidence-based treatment delivery. Cancer 2016. © 2016 American Cancer Society.

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A phase 2 study of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

BACKGROUND

Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was sought to evaluate the activity of dalantercept in RM-SCCHN.

METHODS

Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments.

RESULTS

Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia.

CONCLUSIONS

In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016. © 2016 American Cancer Society.

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Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung: Outcomes from the randomized controlled phase 3 AFFIRM trial

BACKGROUND

Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral metastases have a worse prognosis than those with nonvisceral metastases. Treatment with the androgen receptor inhibitor enzalutamide in the phase 3 AFFIRM trial led to significant improvements in outcomes for patients with mCRPC. For the current report, the authors analyzed the efficacy of enzalutamide among patients from the AFFIRM trial who had visceral disease.

METHODS

Patients who had liver and/or lung metastases at baseline were selected for prespecified overall survival (OS) and exploratory post hoc analyses, including prostate-specific antigen (PSA) response and the time to PSA and radiographic progression.

RESULTS

In patients who had liver metastases (n = 92), enzalutamide was associated with a lower risk of radiographic progression (hazard ratio [HR], 0.645; 95% confidence interval [CI], 0.413-1.008), improved 12-month OS (37.7% vs 20.6%) and radiographic progression-free survival (rPFS) (11.6% vs 3.0%) rates, and higher PSA response rates (35.1% vs 4.8%) compared with placebo. Enzalutamide-treated patients who had lung metastases (n = 104) had improved median OS (HR, 0.848; 95% CI, 0.510-1.410), a substantially reduced risk of radiographic progression (HR, 0.386; 95% CI, 0.259-0.577), improved 12-month OS (65.1% vs 55.3%) and rPFS (30.9% vs 8.2%) rates, increased time to PSA progression (HR, 0.358; 95% CI, 0.204-0.627), and a better PSA response rate (52.1% vs 4.9%) compared with those who received placebo. No increase in treatment-related adverse events was observed for the visceral metastases cohort compared with the nonvisceral metastases cohort.

CONCLUSIONS

Across multiple endpoints, patients who have visceral metastases have better outcomes with enzalutamide than with placebo. Cancer 2016. © 2016 American Cancer Society.

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Antiangiogenic agents in head and neck squamous cell carcinoma: Tired of going solo

Antiangiogenic therapies as single agents have failed to demonstrate significant antitumor activity in heavily pretreated, unselected populations with recurrent/metastatic head and neck squamous cell carcinoma. Much work is needed to evaluate rational strategies for combining antiangiogenic agents with other systemic therapies or with radiotherapy for head and neck squamous cell carcinoma to move the field forward. See also pages 000-000.

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Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene

BACKGROUND

Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation–negative MBC cases.

METHODS

Germ-line DNA of 1 male and 2 female BRCA1/2 mutation–negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation–negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation–negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study.

RESULTS

WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation–negative MBC cases. NAT1 c.97C>T was not found in the case-control series.

CONCLUSIONS

These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation–negative families with multiple MBC and FBC cases. Cancer 2016. © 2016 American Cancer Society.

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