A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas

Publication date: Available online 31 December 2015
Source:Cancer Cell
Author(s): Alice Soragni, Deanna M. Janzen, Lisa M. Johnson, Anne G. Lindgren, Anh Thai-Quynh Nguyen, Ekaterina Tiourin, Angela B. Soriaga, Jing Lu, Lin Jiang, Kym F. Faull, Matteo Pellegrini, Sanaz Memarzadeh, David S. Eisenberg
Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.

Graphical abstract

Teaser

Using p53-mutant, high-grade, serous ovarian carcinoma as model systems, Soragni et al. show that a cell-penetrating peptide designed to inhibit p53 amyloid formation rescues p53 functions and reduces in vivo xenograft growth and metastasis.


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Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

Abstract

Background

Preclinical results showing therapeutic effect and low toxicity of metronomic chemotherapy with cyclophosphamide (Cy) + celecoxib (Cel) for mammary tumors encouraged its translation to the clinic for treating advanced breast cancer patients (ABCP).

Patients and methods

A single-arm, mono-institutional, non-randomized, phase II, two-step clinical trial (approved by Bioethics Committee and Argentine Regulatory Authority) was designed. Patients received Cy (50 mg po.d) + Cel (200 mg p.o.bid). Patient eligibility criteria included: ABCP who progressed to anthracyclines, taxanes and capecitabine, ≤4 chemotherapy schemes, with good performance status. Several pro- and anti-angiogenic molecules and cells were determined as biomarkers. Informed consent was signed by all patients. Primary endpoint was clinical benefit (CB).

Results

Twenty patients were enrolled. Main clinical outcomes were prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively. CB was 55 %, and time to progression (TTP) was 21.1 weeks. Median TTP in patients who achieved CB was 35.6 weeks, and mean overall survival was 44.20 weeks. There were no grade 3/4 toxicities associated with treatment. Circulating endothelial cells (CECs) increased at the time of progression in patients who showed CB (P = 0.014). Baseline CECs and circulating endothelial progenitor cells showed marginal associations with TTP. Serum VEGF decreased (P = 0.050), sVEGFR-2 increased (P = 0.005) and VEGF/sVEGFR-2 ratio decreased during treatment (P = 0.041); baseline VEGF and VEGF/sVEGFR-2 were associated with TTP (P = 0.035 and P = 0.030, respectively), while sVEGFR-2 did not.

Conclusions

Treatment was effective, showing low toxicity profile and excellent tolerability. The combination had anti-angiogenic effect. Increased levels of CEC could be useful for detecting progression. Baseline VEGF and VEGF/sVEGFR-2 values could be useful as early predictors of response.

Trial registration

ANMAT#4596/09.

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Feasibility of Single-incision Laparoscopic Surgery plus One Assist Port for Anterior Resection

Background: We previously reported single-incision laparoscopic surgery plus one assist port (SPO) in 2010 as a type of reduced-port surgery for anterior resection. However, the feasibility and usefulness of SPO for patients with rectal cancer has not been elucidated. Patients and Methods: Between January 2009 and December 2011, 49 patients with rectal cancer underwent laparoscopic surgery, 36 of these patients underwent multiport surgery (MPS) and the remaining 13 patients underwent SPO at the Kashiwa Hospital, Jikei University. Results: The mean surgical time was 178.5 (range: 115.0-245.0) min for SPO, and 173.3 (110.0-240.0) min for MPS. The mean intraoperative bleeding was 7.7 (0-60) ml for SPO, and 11.4 (0-70) ml for MPS. The postoperative hospital stay was 10.3 (9-12) days for SPO, 10.8 (6-12) days for MPS. There were no significant differences between the groups with respect to surgical time, intraoperative blood loss, and postoperative hospital stay. No postoperative complications or postoperative recurrences were encountered in either group. Conclusion: Although single-incision laparoscopic surgery cannot be easily introduced for anterior resection, SPO for the treatment of rectal cancer yields outcomes comparable to MPS and is feasible, safe, and oncologically acceptable.

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Potential of Amifostine for Chemoradiotherapy and Radiotherapy-associated Toxicity Reduction in Advanced NSCLC: A Meta-Analysis

Background/Aim: The addition of amifostine to chemoradiotherapy (CRT) or radiotherapy (RT) in advanced, inoperable NSCLC presents varying toxicity. The present study examined amifostine's effect on toxicity and efficacy of CRT or RT alone. Materials and Methods: Database searches yielded 16 eligible trials comprising of 1,057 patients. Results of randomised trials were pooled and used to estimate the overall effect. Results: Amifostine reduced the risk of >grade 2 acute oesophagitis by 26% [risk ratio (RR), 0.74; 95% confidence interval (CI)=0.65-0.86; p<0.0001] and the risk of acute pulmonary toxicity by 44% (RR, 0.56; 95%CI=0.41-0.75; p=0.0001). Risk of complete response was unchanged (RR, 1.64; 95%CI=0.99-2.73; p=0.06), partial response was unchanged (RR, 0.92; 95% CI=0.73-1.16; p=0.48). Statistical heterogeneity was high for toxicity but low for response. Conclusion: Statistical heterogeneity of retrived results casts doubt over amifostine's efficacy in this setting, despite decreased acute oesophageal and pulmonary toxicity. Amifostine did not compromise treatment efficacy.

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18F-Fluorodeoxyglucose Positron Emission Tomography for Evaluating the Response to Neoadjuvant Chemotherapy in Advanced Esophageal Cancer

Background/Aim: The purpose of the present study was to improve the diagnostic precision of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) after neoadjuvant chemotherapy (NAC) in patients with advanced esophageal cancer. Patients and Methods: Thirty patients underwent FDG-PET/CT before and after NAC. The maximum standardized uptake value (SUV_max) and metabolic tumor volume (MTV) were measured. Patients were divided into two pathological response groups: "responders" (grades 1b-3) or "non-responders" (grades 0-1a). Results: Overall, 11 patients were responders. Significant differences were present for the post-NAC SUV_max (p=0.070), %decrease in SUV_max (p=0.017), post-NAC MTV (p=0.014), and %decrease in MTV (p=0.003). Conclusion: Receiver operating characteristic curve analysis showed that the %decrease in MTV of the primary tumor was the best indicator of response to NAC. We are currently striving to improve the accuracy of this assessment method.

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Factors Affecting Survival in Patients with Lung Metastases from Colorectal Cancer. A Short Meta-analysis

Liver and pulmonary metastases (PMs) are relatively common in patients with colorectal cancer. The majority of metastases are suitable for surgical resection, and the effectiveness of metastasectomy is usually assessed based on overall survival (OS). Metastasectomy provides a mean 5-year OS rate of approximately 50%, but the results are better in patients with liver metastases compared to those with PMs. Unfortunately, the presence of bilateral or multiple PMs represents a relative contraindication to surgical metastasectomy. Unresectable PMs can be safely treated with percutaneous radiofrequency ablation or radiotherapy, but the reported results vary widely. Several clinical prognostic factors affecting OS after metastasectomy have been reported, such as number of PMs, hilar or mediastinal lymph node involvement, disease-free interval, age and gender, resection margins, size of the metastases, neoadjuvant chemotherapy administration, and histological type of the primary cancer. The accurate evaluation of all clinical prognostic factors, circulating and immunohistochemical markers, and the study of gene mutational status will lead to a more accurate selection of patients scheduled to metastasectomy, with the aim of improving outcome.

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Bioactive Sphingolipids in Cancer Biology and Therapy

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TAS-102 an Emerging Oral Fluoropyrimidine

Colon cancer is a common type of cancer with high mortality. The standard therapy for colon cancer is 5-FU-based regimen, although the current response rate to 5-FU is only 10-15%. Various approaches have been used to improve the efficacy of 5-FU including inhibition of its degradation enzyme dihydropyrimidine dehydrogenase (DPD) such as S1, UTF, use of 5-FU pro-drug capecitabine to exploit thymidine phosphorylase (TP) and supplementation of reduced folate acid to increase cytotoxicity. TAS-102 is a newly-developed anti-folate drug containing the 5-FU analogue trifluridine (TFD) and tipiracil hydrochloride (TPI). TPI is an inhibitor of TFD degradation enzyme thymidine phosphorylase and thus increases the bioavailability of TFD. In the present review, we summarize recent progress with regard to TAS-102, including pre-clinical tests and clinical trials. We further propose several approaches to further improve the efficacy of TAS-102 including combination with targeted therapy and immune therapy.

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Perioperative Paravertebral Regional Anaesthesia and Breast Cancer Recurrence

Aim: Retrospective and basic science data suggest that perioperative regional anaesthesia (PRA) may reduce tumour recurrence after cancer surgery. This retrospective archive study tested the anti-metastatic effect of PRA. Patients and Methods: We screened the database of the Helsinki University Hospital for patients with breast cancer who had either perioperative paravertebral block (PVB) or sham block (SHAM) in 2000-2003. The exclusion criteria were previous cancer, no cancer, and loss to follow-up. The end-points were disease-free (DFS), distant recurrence-free (DRFS), breast cancer-specific (BCSS) and overall (OS) survival. Results: The median follow-up time of the 45 PVB and 41 SHAM patients analysed was 12 years. DFS was 79% and 83%, DRFS 84% and 92%, BCSS 81% and 95%, OS 74% and 93% in the PVB and SHAM groups, respectively (p-value for OS = 0.035). Conclusion: The results do not demonstrate any anti-metastatic effect of PRA.

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Inhibition of Chronic Pancreatitis and Murine Pancreatic Intraepithelial Neoplasia by a Dual Inhibitor of c-RAF and Soluble Epoxide Hydrolase in LSL-KrasG12D/Pdx-1-Cre Mice

Mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and chronic pancreatitis are the most common pathogenic events involved in human pancreatic carcinogenesis. In the process of long-standing chronic inflammation, aberrant metabolites of arachidonic acid play a crucial role in promoting carcinogenesis, in which the soluble epoxide hydrolase (sEH), as a pro-inflammatory enzyme, generally inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs). Herein, we determined the effect of our newly-synthesized novel compound trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM), a dual inhibitor of sEH and RAF1 proto-oncogene serine/threonine kinase (c-RAF), on inhibiting the development of pancreatitis and pancreatic intraepithelial neoplasia (mPanIN) in LSL-Kras^G12D/Pdx1-Cre mice. The results showed that t-CUPM significantly reduced the severity of chronic pancreatitis, as measured by the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The progression of low-grade mPanIN I to high-grade mPanIN II/III was significantly suppressed. Inhibition of mutant Kras-transmitted phosphorylation of mitogen-activated protein kinase's kinase/extracellular signal-regulated kinases was demonstrated in pancreatic tissues by western blots. Quantitative real-time polymerase chain reaction analysis revealed that t-CUPM treatment significantly reduced the levels of inflammatory cytokines including tumor necrosis facor-α, monocyte chemoattractant protein-1, as well as vascular adhesion molecule-1, and the levels of Sonic hedgehog and Gli transcription factor (Hedgehog pathway). Analysis of the eicosanoid profile revealed a significant increase of the EETs/dihydroxyeicosatrienoic acids ratio, which further confirmed sEH inhibition by t-CUPM. These results indicate that simultaneous inhibition of sEH and c-RAF by t-CUPM is important in preventing chronic pancreatitis and carcinogenesis.

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Precision Molecular Pathology of Breast Cancer

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HUHS1015 Suppresses Colonic Cancer Growth by Inducing Necrosis and Apoptosis in Association with Mitochondrial Damage

Background: The newly-synthesized naftopidil analog HUHS1015 suppresses tumor growth and induces apoptosis of cells from a variety of cancer types. The present study was conduced to assess the effect of HUHS1015 on human colonic cancer cells and to clarify the underlying mechanism. Results: HUHS1015 reduced cell viability of Caco-2 and CW2 human colonic cancer cell lines in a concentration (0.3-100 mM)-dependent manner. HUHS1015 increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in both cell lines. In flow cytometry using propidium iodide and annexin V, HUHS1015 significantly increased the populations of cells undergoing primary necrosis, early apoptosis, and late apoptosis/secondary necrosis in both cell lines. In the cell-cycle analysis, HUHS1015 increased the proportion of the sub-G₁ phase of cell, which corresponds to apoptotic cells. HUHS1015 perturbed the mitochondrial membrane potential and reduced the intracellular ATP level. HUHS1015 activated caspases 3, -4, -8, and -9, particularly caspase-3. HUHS1015 promoted cytochrome c release from the mitochondria. HUHS1015 significantly inhibited tumor growth in mice inoculated with CW2 cells. Conclusion: HUHS1015 induces necrosis by lowering the intracellular ATP level in association with mitochondrial damage and caspase-dependent apoptosis. This occurs in part by stimulating cytochrome c release from the mitochondria to activate caspase-9 followed by the effector caspase-3, responsible for suppression of colonic cancer proliferation in the mouse xenograft model.

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Hematopoietic Differentiation of Human Pluripotent Stem Cells

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A Novel Sirtuin-3 Inhibitor, LC-0296, Inhibits Cell Survival and Proliferation, and Promotes Apoptosis of Head and Neck Cancer Cells

Background: The survival rate of patients with head and neck squamous cell carcinoma (HNSCC) stands at approximately 50% and this has not improved in decades. This study developed a novel sirtuin-3 (SIRT3) inhibitor (LC-0296) and examined its role in altering HNSCC tumorigenesis. Materials and Methods: The effect of the SIRT3 inhibitor, LC-0296, on cell survival, proliferation, and apoptosis, and reactive oxygen species levels in HNSCC cells were studied. Results: LC-0296 reduces cell proliferation and promotes apoptosis of HNSCC cells but not of normal human oral keratinocytes. This inhibitory effect is mediated, in part, via modulation of reactive oxygen species levels. Additionally, LC-0296 works synergistically to increase the sensitivity of HNSCC cells to radiation and cisplatin treatment. Conclusion: Development of novel SIRT3 inhibitors, such as LC-0296, might enable the development of new targeted therapies to treat and improve the survival rate of patients with head and neck cancer.

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Implication of 18F-Fluorodeoxyglucose Uptake of Affected Axillary Lymph Nodes in Cases with Breast Cancer

In order to evaluate affected axillary lymph nodes in breast cancer by positron-emission tomography using ¹⁸F-fluorodeoxyglucose (FDG-PET), an understanding of FDG avidity is important. In the present study, we examined whether certain factors, including lymphatic spread and size of metastatic lymph nodes, were associated with FDG avidity in order to evaluate the benefits of a FDG-PET assessment of axillary node metastases. We retrospectively investigated the cases of 179 consecutive patients with primary breast cancer who underwent FDG-PET preoperatively. Among the 179 patients, 48 (26.8%) had axillary lymph node metastases. The sensitivity, specificity, overall accuracy, and false-negative rates in the diagnosis of axillary lymph node status by FDG-PET were 47.9%, 98.5%, 84.9%, and 52.1%, respectively. The 48 cases with lymph node metastases were divided into two groups based on the presence or not of FDG uptake in the axillary lesions. Clinicopathological features of the primary tumor, including tumor size, standardized uptake value (SUV_max and biomarkers, were not statistically significant factors; only the clinicopathological features of metastatic lymph nodes, including the size of node metastasis, were significantly associated with FDG uptake in the axillary lymph nodes. Among the eight cases of micrometastasis, seven were not detected by FDG-PET. The number of cases with only one affected node was significantly higher in the group without FDG uptake in the axillary lesion. Although the number of lymph node metastases was relatively higher in the FDG-PET-positive patients, the difference was not statistically significant. FDG-PET may help identify patients with high axillary lymph node burden. Our findings imply that preoperative FDG-PET evaluation of lymph nodes is not sufficient to predict lymphatic spread or micrometastasis because FDG avidity is mainly influenced by the size of the tumor.

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LPA Increases Tumor Growth and Bone Destruction Through Enhancement of Osteoclastogenic Cytokines

Background: Lysophosphatidic acid (LPA) production in osteoblasts has multiple effects on osteoclast formation and function and raises the possibility that LPA may serve as a signaling molecule for the reciprocal conversation of both osteoblasts and osteoclasts within the tumor–bone microenvironment for bone resorption. However, little is known on the effect of LPA in regulating the function of both cancer cells and osteoclasts in the bone microenvironment. Materials and Methods: PC-3 tumor growth and bone destruction upon LPA administration were observed in a mouse calvarium xenograft. The osteoclastogenic cytokines produced by LPA-stimulated prostate cancer cells were also defined. Results: LPA administration was found to increase PC-3 tumor growth and bone destruction in a mouse calvarium xenograft. Using a cytokine antibody array, LPA highly stimulated the expression and release of osteoclastogenic cytokines from PC-3 cells. Conditioned medium from LPA-stimulated PC-3 cells containing enhanced levels of osteoclastogenic cytokines facilitated osteoclast formation. Histopathologically, LPA administration supports the erosive type of bone destruction by PC-3 prostate cancer cells. Conclusion: LPA is a critical regulator in the tumor–bone microenvironment and may be a therapeutic target for patients with prostate cancer. In addition, LPA-enhanced osteoclastogenic cytokines are critical to therapeutic strategies targeting osteolytic prostate cancer.

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Book Reviews

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Effects of Administered Cardioprotective Drugs on Treatment Response of Breast Cancer Cells

Background: Anticancer drug treatment, particularly with anthracyclines, is frequently associated with cardiotoxicity, an effect exacerbated by trastuzumab. Several compounds are in use clinically to attenuate the cardiac-damaging effects of chemotherapy drugs, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, the anti-diabetic drug metformin, and dexrazoxane. However, there is concern that the cardiac-preserving mechanisms of these drugs may also limit the anticancer efficacy of the chemotherapeutic agents. Materials and Methods: Herein two breast cancer cell lines, SKBr3 and BT474, overexpressing human epithelial receptor 2 (HER2), the target of the humanised antibody trastuzumab, were treated with a range of concentrations (20-2000 nM) of doxorubicin with and without trastuzumab in the presence of clinically relevant doses of the ACE inhibitor enalapril, the beta-blocker carvedilol, metformin or dexrazoxane, and cell survival determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: None of the drugs reduced the anticancer effect of doxorubicin or trastuzumab (nor of the two drugs combined). Using Chou and Talalay's combination index, dexrazoxane and doxorubicin were found to act synergistically on the SKBr3 cells. ¹⁸F-Fluoro-2-deoxy-D-glucose (¹⁸F-FDG) incorporation was reduced by treatment of SKBr3 cells with doxorubicin and this was shown to be due to reduced phosphorylation of ¹⁸F-FDG in doxorubicin-treated cells. Treatment of SKBr3 cells with doxorubicin and dexrazoxane further reduced ¹⁸F-FDG incorporation, indicating that the synergy in the cytotoxicity of these two drugs was reflected in their combined effect on ¹⁸F-FDG incorporation. Conclusion: Commonly administered cardioprotective drugs do not interfere with anticancer activity of doxorubicin or tratsuzumab. Further studies to establish the effect of cardioprotective drugs on anticancer drug efficacy would be beneficial.

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CRCT1 regulated by microRNA-520 g inhibits proliferation and induces apoptosis in esophageal squamous cell cancer

Abstract

Cysteine-rich C-terminal 1 (CRCT1) is encoded by the epidermal differentiation complex (EDC), a gene cluster that was recently linked to esophageal cancer. However, the role of CRCT1 in esophageal squamous cell cancer (ESCC) and the underlying mechanism remain unclear. In the present study, we show that CRCT1 is downregulated in ESCC in association with TNM stage and lymph node metastasis. Restoring CRCT1 in ESCC cells by lentivirus-mediated gene transfer inhibited cell proliferation and xenograft tumor formation. CRCT1 overexpression promoted ESCC cell apoptosis and upregulated the expression of apoptosis-related proteins. CRCT1 expression was inversely correlated with the levels of microRNA-520 g (miR-520 g) in ESCC tissues, and CRCT1 was identified as a direct target gene of miR-520 g in ESCC cells. Consistent with the effects of CRCT1 overexpression, knockdown of miR-520 g inhibited growth and induced apoptosis in ESCC cells. Our results suggest that CRCT1 functions as a tumor suppressor gene in ESCC and is regulated by miR-520 g, providing potential therapeutic targets for the treatment of ESCC.

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LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that maintains energy homeostasis in both normal and cancerous cells, and has emerged as a tumor suppressor. The present study aims to delineate the functional relationship between AMPK and transforming growth factor beta (TGF-β). Our results showed that expression of liver kinase B1 (LKB1), an upstream kinase of AMPK, impeded TGF-β-induced Smad phosphorylation and their transcriptional activity in breast cancer cells, whereas knockdown of LKB1 or AMPKα1 subunit by short hairpin RNA (shRNA) enhanced the effect of TGF-β. Furthermore, AMPK activation reduced the promoter activity of TGF-β1. In accordance, type 2 diabetic patients taking metformin displayed a trend of reduction of serum TGF-β1, as compared with those without metformin. A significant reduction of serum TGF-β1 was found in mice after treatment with metformin. These results suggest that AMPK inhibits the transcription of TGF-β1, leading to reduction of its concentration in serum. Finally, metformin suppressed epithelial-to-mesenchymal transition of mammary epithelial cells. Taken together, our study demonstrates that AMPK exerts multiple actions on TGF-β signaling and supports that AMPK can serve as a therapeutic drug target for breast cancer.

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Place du curage ganglionnaire avant radiothérapie exclusive dans la prise en charge des carcinomes épidermoïdes localement évolués des voies aérodigestives supérieures

Publication date: Available online 31 December 2015
Source:Cancer/Radiothérapie
Author(s): A. Modesto, J. Sarini, A. Benlyazid, M. Ouali, A. Laprie, P. Graff, S. Vergez, E. Uro-Coste, I. Fauquet, J.-P. Delord, M. Rives
IntroductionLa place du curage cervical dans la prise en charge conservatrice des carcinomes épidermoïdes localement évolués des voies aérodigestives supérieures demeure largement débattue. L'objectif de cette étude était d'analyser les caractéristiques, les facteurs pronostiques et le suivi des patients qui ont bénéficié d'un curage cervical avant une irradiation exclusive (traitement dissocié).Patients et méthodesSoixante-trois patients chez qui une atteinte ganglionnaire volumineuse (de 3cm ou plus) ou nécrotique a été mise en évidence lors de la scanographie initiale ont fait l'objet d'un traitement dissocié entre 2000 et 2012 à l'institut Claudius-Regaud (Toulouse, France). La lésion primitive était oropharyngée, hypopharyngée ou laryngée dans respectivement 63, 21 et 13 % des cas.RésultatsLes taux de contrôle locorégional et de survie globale à 3ans étaient de 88 % et 68 % avec un suivi médian de 4ans. Un seul patient a été atteint d'une récidive ganglionnaire isolée. En analyse unifactorielle, les variables significativement associées à un allongement de la survie sans maladie étaient : la réalisation d'un curage fonctionnel par opposition à non conservateur, (hazard ratio [HR] : 0,39 ; intervalle de confiance à 95 % [IC 95 %] : 0,16–0,94 ; p=0,03) et l'indice de performance de l'OMS (1–2 contre 0 ; HR=6,27 ; IC 95 %=2,73–14,39 ; p<0,0001). En analyse multifactorielle, seul l'indice de performance de l'OMS reste significatif.ConclusionLa réalisation d'un curage cervical avant la réalisation d'une (chimio)radiothérapie exclusive permet un bon taux de contrôle locorégional malgré une atteinte ganglionnaire initiale importante et permet de s'affranchir de la complexité d'une chirurgie cervicale de rattrapage en territoire irradié tout en gardant l'avantage d'une approche conservatrice sur la lésion primitive.PurposeOptimal timing of neck dissection remains debated in the conservative management of patients with locoregionally advanced squamous cell carcinoma of the head and neck.Patients and methodsThe files of 63 patients with radiographic evidence of bulky or necrotic nodal metastases treated by up-front neck dissection and definitive radiotherapy between 2000 and 2012 at two institutions were retrospectively reviewed.ResultsThe primary site was oropharyngeal, hypopharyngeal or laryngeal in 63%, 21% and 13% cases, respectively. Overall, 83% of the tumours were staged pN2b or more. Extracapsular spread was found in 48 cases (77%). After a 48-month median follow-up, the 3-year locoregional control and overall survival were 88% and 68%, respectively. Only one isolated failure occurred in the dissected neck.ConclusionThis combination therapy provides a good locoregional tumour control. It should be considered as an option in laryngeal, hypopharyngeal or oropharyngeal squamous cell carcinomas with bulky or necrotic nodal metastases at presentation.



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Virtual colonoscopy an alternative to fecal occult blood test and colonoscopy for colorectal cancer screening?

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Reduced and Full-Preparation CT Colonography, Fecal Immunochemical Test, and Colonoscopy for Population Screening of Colorectal Cancer: A Randomized Trial

Background:

Population screening for colorectal cancer (CRC) is widely adopted, but the preferred strategy is still under debate. We aimed to compare reduced (r-CTC) and full cathartic preparation CT colonography (f-CTC), fecal immunochemical test (FIT), and optical colonoscopy (OC) as primary screening tests for CRC.

Methods:

Citizens of a district of Florence, Italy, age 54 to 65 years, were allocated (8:2.5:2.5:1) with simple randomization to be invited by mail to one of four screening interventions: 1) biennial FIT for three rounds, 2) r-CTC, 3) f-CTC, 4) OC. Patients tested positive to FIT or CTC (at least one polyp ≥6mm) were referred to OC work-up. The primary outcomes were participation rate and detection rate (DR) for cancer or advanced adenoma (advanced neoplasia). All statistical tests were two-sided.

Results:

Sixteen thousand eighty-seven randomly assigned subjects were invited to the assigned screening test. Participation rates were 50.4% (4677/9288) for first-round FIT, 28.1% (674/2395) for r-CTC, 25.2% (612/2430) for f-CTC, and 14.8% (153/1036) for OC. All differences between groups were statistically significant (P = .047 for r-CTC vs f-CTC; P < .001 for all others). DRs for advanced neoplasia were 1.7% (79/4677) for first-round FIT, 5.5% (37/674) for r-CTC, 4.9% (30/612) for f-CTC, and 7.2% (11/153) for OC. Differences in DR between CTC groups and FIT were statistically significant (P < .001), but not between r-CTC and f-CTC (P = .65).

Conclusions:

Reduced preparation increases participation in CTC. Lower attendance and higher DR of CTC as compared with FIT are key factors for the optimization of its role in population screening of CRC.

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Human Leukocyte Antigen-Presented Macrophage Migration Inhibitory Factor is a Surface Biomarker and Potential Therapeutic Target for Ovarian Cancer

T cells recognize cancer cells via human leukocyte antigen (HLA)/peptide complexes and, when disease overtakes these immune mechanisms, immunotherapy can exogenously target these same HLA/peptide surface markers. We previously identified an HLA-A2-presented peptide derived from macrophage migration inhibitory factor (MIF) and generated antibody RL21A against this HLA-A2/MIF complex. The objective of the current study was to assess the potential for targeting the HLA-A2/MIF complex in ovarian cancer. First, MIF peptide FLSELTQQL was eluted from the HLA-A2 of the human cancerous ovarian cell lines SKOV3, A2780, OV90, and FHIOSE118hi and detected by mass spectrometry. By flow cytometry, RL21A was shown to specifically stain these four cell lines in the context of HLA-A2. Next, partially matched HLA-A*02:01+ ovarian cancer (n=27) and normal fallopian tube (n=24) tissues were stained with RL21A by immunohistochemistry to assess differential HLA-A2/MIF complex expression. Ovarian tumor tissues revealed significantly increased RL21A staining compared to normal fallopian tube epithelium (p<0.0001), with minimal staining of normal stroma and blood vessels (p<0.0001 and p<0.001 compared to tumor cells) suggesting a therapeutic window. We then demonstrated the anti-cancer activity of toxin-bound RL21A via the dose-dependent killing of ovarian cancer cells. In summary, MIF-derived peptide FLSELTQQL is HLA-A2-presented and recognized by RL21A on ovarian cancer cell lines and patient tumor tissues, and targeting of this HLA-A2/MIF complex with toxin-bound RL21A can induce ovarian cancer cell death. These results suggest that the HLA-A2/MIF complex should be further explored as a cell-surface target for ovarian cancer immunotherapy.

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A cyclin-dependent kinase inhibitor, dinaciclib, impairs homologous recombination and sensitizes multiple myeloma cells to PARP inhibition

Poly(ADP-ribose) polymerases 1 and 2 (PARP1/2) are required for single-strand break repair, and their inhibition causes DNA replication-fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. Synthetic lethality thus exists between PARP and HR functions. Multiple myeloma (MM) cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDKs), upstream modulators of HR, are dysregulated in MM. Here we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes MM cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased H2AX foci. Dinaciclib treatment reduces expression of HR-repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosomal DSBs. Co-treatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of MM cells, but not normal CD19⁺ B cells, and slowed growth of MM xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for MM therapy.

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The role of HMGB1 in radio-resistance of bladder cancer.

Although radical cystectomy surgery is the standard of care for muscle-invasive bladder cancer, it entails complete removal of the bladder and surrounding organs which leads to substantial loss in patient quality of life. Radiation therapy, which spares the bladder, would be a more appropriate treatment modality if we can utilize molecular markers to select patients with better response to radiation. In this study we investigate a protein called HMGB1 (High Mobility Group Box protein 1) as a predictive marker for radiation therapy response in bladder cancer. Our in vitro results indicate a positive correlation between higher levels of HMGB1 protein and resistance to radiation in various cell lines. Upon HMGB1 protein knockdown highly significant (more than 1.5 fold) sensitization to radiation therapy was achieved. We saw that loss of HMGB1 was associated with atleast 2 times higher (P<0.001) DNA damage in cell lines post radiation. Our results also depicted that autophagy was inhibited more than 3 fold (P<0.001) upon HMGB1 knockdown implicating its role in autophagy as another cause of bladder cancer radioresistance. Further validation was done in vivo by conducting mice tumor xenograft experiments, where HMGB1 knockdown tumors showed a significantly better (P<0.001) response to radiation therapy and decreased autophagy (shown by P62 staining) as compared to controls. The cumulative findings of our in vitro and in vivo studies highlight the significance of HMGB1 as a radiation response marker as well as its utility in radio-sensitization of bladder cancer.

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Optimization of RGD containing cyclic peptides against {alpha}v{beta}3 integrin

We have previously reported the use of one-bead-one-compound (OBOC) combinatorial technology to develop a disulfide cyclic, Arg-Gly-Asp containing octapeptide LXW7 (cGRGDdvc), that targets αvβ3 integrin with high affinity and specificity (Mol Cancer Ther, 9:2714-23, 2010). αvβ3 integrin is known to be over-expressed in many cancers and in tumor vasculature, and it has been established as a cancer therapeutic target. To further optimize LXW7, we have performed systematic structure activity relationship (SAR) studies. Based on the results, two highly focused OBOC peptide libraries were designed, synthesized and screened against αvβ3 integrin transfected K562 cells. One of the best ligands, LXW64 was found to have 6.6-fold higher binding affinity than LXW7, and showed preferential binding to cells expressing αvβ3 integrin. In addition to binding strongly to U-87MG glioblastoma cells in vitro, LXW64 also targets U-87MG xenografts implanted in nude mice, indicating that it is an excellent vehicle for delivery of cytotoxic payload to tumors and tumor blood vessels that overexpress αvβ3 integrin.

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An HRE-binding Py-Im polyamide impairs hypoxic signaling in tumors.

Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration and cancer. HIF-1, a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis and cell survival. Py-Im polyamide 1 has been shown to inhibit HIF-1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1 in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1 distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels and suppresses tumor growth. Tumors treated with 1 show no increase in HIF-1a and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF-1a positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF-1 has potent anti-tumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response.

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Prospective cohort study of ultrasound-ultrasound and ultrasound-MR enterography agreement in the evaluation of pediatric small bowel Crohn disease

Abstract

Background

There is a paucity of published literature describing ultrasound (US)-US and US-MR enterography (MRE) inter-radiologist agreement in pediatric small bowel Crohn disease.

Objective

To prospectively assess US-US and US-MRE inter-radiologist agreement in pediatric small bowel Crohn disease.

Materials and methods

Institutional Review Board approval and informed consent/assent were obtained for this HIPAA-compliant prospective cohort study of children with newly diagnosed distal small bowel Crohn disease (July 2012 to December 2014). Enrolled subjects (n = 29) underwent two small bowel US examinations performed by blinded independent radiologists both before and at multiple time points after initiation of medical therapy (231 unique US examinations, in total); 134 US examinations were associated with concurrent MRE. The MRE examination was interpreted by a third blinded radiologist. The following was documented on each examination: involved length of ileum (cm); maximum bowel wall thickness (mm); amount of bowel wall and mesenteric Doppler signal, and presence of stricture, penetrating disease and/or abscess. Inter-radiologist agreement was assessed with single-measure, three-way, mixed-model intra-class correlation coefficients (ICC) and prevalence-adjusted, bias-adjusted kappa statistics (κ). Numbers in brackets are 95% confidence intervals.

Results

Ultrasound-US agreement was moderate for involved length (ICC: 0.41 [0.35-0.49]); substantial for maximum bowel wall thickness (ICC: 0.67 [0.64-0.70]); moderate for bowel wall Doppler signal (ICC: 0.53 [0.48-0.59]); slight for mesenteric Doppler signal (ICC: 0.25 [0.18-0.42]), and moderate to almost perfect for stricture (κ: 0.54), penetrating disease (κ: 0.80), and abscess (κ: 0.96). US-MRE agreement was moderate for involved length (ICC: 0.42 [0.37-0.49]); substantial for maximum bowel wall thickness (ICC: 0.66 [0.65-0.69]), and substantial to almost perfect for stricture (κ: 0.61), penetrating disease (κ: 0.72) and abscess (κ: 0.88).

Conclusion

Ultrasound-US agreement was similar to US-MRE agreement for assessing pediatric small bowel Crohn disease. Discrepancies in US-US and US-MRE reporting question the utility of US as an accurate, reproducible radiologic biomarker for assessing response to medical therapy and disease-related complications.

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Direct visualization of crossing renal vessels on MRU achieved by splitting intravenous contrast dose

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Utility of late gadolinium enhancement in pediatric cardiac MRI

Abstract

Late gadolinium enhancement (LGE) cardiac magnetic resonance (MR) imaging sequence is increasingly used in the evaluation of pediatric cardiovascular disorders, and although LGE might be a normal feature at the sites of previous surgeries, it is pathologically seen as a result of extracellular space expansion, either from acute cell damage or chronic scarring or fibrosis. LGE is broadly divided into ischemic and non-ischemic patterns. LGE caused by myocardial infarction occurs in a vascular distribution and always involves the subendocardial portion, progressively involving the outer regions in a waveform pattern. Non-ischemic cardiomyopathies can have a mid-myocardial (either linear or patchy), subepicardial or diffuse subendocardial distribution. Idiopathic dilated cardiomyopathy can have a linear mid-myocardial pattern, while hypertrophic cardiomyopathy can have fine, patchy enhancement in hypertrophied and non-hypertrophied segments as well as right ventricular insertion points. Myocarditis and sarcoidosis have a mid-myocardial or subepicardial pattern of LGE. Fabry disease typically affects the basal inferolateral segment while Danon disease typically spares the septum. Pericarditis is characterized by diffuse or focal pericardial thickening and enhancement. Thrombus, the most common non-neoplastic cardiac mass, is characterized by absence of enhancement in all sequences, while neoplastic masses show at least some contrast enhancement, depending on the pathology. Regardless of the etiology, presence of LGE is associated with a poor prognosis. In this review, we describe the technical modifications required for performing LGE cardiac MR sequence in children, review and illustrate the patterns of LGE in children, and discuss their clinical significance.

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Neuroimaging differential diagnoses to abusive head trauma

Abstract

Trauma is the most common cause of death in childhood, and abusive head trauma is the most common cause of traumatic death and morbidity in infants younger than 1 year. The main differential diagnosis of abusive head trauma is accidental traumatic brain injury, which is usually witnessed. This paper also discusses more uncommon diagnoses such as congenital and acquired disorders of hemostasis, cerebral arteriovenous malformations and metabolic diseases, all of which are extremely rare. Diagnostic imaging including CT and MRI is very important for the distinction of non-accidental from accidental traumatic injury.

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Diagnostic imaging of child abuse (3rd edn), by P. K. Kleinman (ed)

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Utility of ultrasound in noninvasive preoperative workup of neonatal brachial plexus palsy

Abstract

Background

Ultrasound has been utilized in the evaluation of compressive and traumatic peripheral nerve pathology.

Objective

To determine whether US can provide comprehensive evaluation of the post-ganglionic brachial plexus in the setting of neonatal brachial plexus palsy and whether this information can be used to guide preoperative nerve reconstruction strategies.

Materials and methods

In this retrospective cohort study, preoperative brachial plexus ultrasonography was performed in 52 children with neonatal brachial plexus palsy who were being considered for surgery. The 33 children who had surgery compose the patient cohort. The presence and location of post-ganglionic neuromas were evaluated by US and compared to the surgical findings. US evaluation of shoulder muscle atrophy was conducted as an indirect way to assess the integrity of nerves. Finally, we correlated glenohumeral joint laxity to surgical and clinical management.

Results

Ultrasound correctly identified 21 of 25 cases of upper trunk and middle trunk neuroma involvement (84% sensitivity for each). It was 68% sensitive and 40% specific in detection of lower trunk involvement. US identified shoulder muscle atrophy in 11 of 21 children evaluated; 8 of these 11 went on to nerve transfer procedures based upon the imaging findings. US identified 3 cases of shoulder joint laxity of the 13 children evaluated. All 3 cases were referred for orthopedic evaluation, with 1 child undergoing shoulder surgery and another requiring casting.

Conclusion

Ultrasound can provide useful preoperative evaluation of the post-ganglionic brachial plexus in children with neonatal brachial plexus palsy.

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A phase I clinical trial of the effect of belinostat on the pharmacokinetics and pharmacodynamics of warfarin

Abstract

Purpose

Belinostat is a potent small molecule inhibitor that exerts its antitumor effect through inhibition of histone deacetylase. The purpose of this study was to evaluate the pharmacokinetics and pharmacodynamics of warfarin (as a reference drug metabolized by CYP2C9) in the presence and absence of belinostat.

Methods

We conducted a phase I, single-center, open-label, drug–drug interaction study between belinostat and warfarin. In part I, patients were given warfarin 5 mg orally (day−14 and 3) and belinostat 1000 mg/m² (days 1 through 5). Patients receiving benefit continued belinostat on days 1 through 5 every 21 days until disease progression, unacceptable toxicity, or per patient preference.

Results

A total of 18 patients were treated. With belinostat, the least-squared means for maximum concentration (C _max), area under the curve_0–∞, and area under the curve_0–t of R-warfarin were slightly increased. However, for the more potent S-warfarin isomer, the same parameters were primarily contained within the pre-specified equivalence limits of 0.80 and 1.25, indicating there was no statistically significant interaction between S-warfarin and belinostat. The most common adverse events were nausea, vomiting, and fatigue. Three grade 3 adverse events (diarrhea 5.6 %, nausea 5.6 %, and vomiting 5.6 %) were thought to be treatment related. Progression-free survival ranged from 0.2 to 13.8 months in all patients.

Conclusions

Belinostat did not significantly affect the pharmacokinetics and pharmacodynamics of warfarin, indicating no clinically relevant effect on the enzymatic activity of CYP2C9.

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MiR-214 suppressed ovarian cancer and negatively regulated semaphorin 4D

Abstract

Ovarian cancer is one of the most common human malignancies in women. MiR-214 and semaphorin 4D (sema 4D) were found to be abhorrently expressed and involved in the progress of several kinds of malignant cancers. This study is aimed to investigate the cellular role of miR-214 and demonstrate that miR-214 negatively regulated sema 4D in ovarian cancer cells. The data showed that miR-214 expression was consistently lower in ovarian cancer tissues and cells than those in the normal controls. Over-expression of miR-214 in ovarian cancer SKOV-3 cells inhibited cell proliferation and induced apoptosis. It was suggested that miR-214 functioned as the tumor suppressor in ovarian cancer. Bioinformatic analysis indicated that miR-214 possibly regulated sema 4D by binding the sema 4D messenger RNA (mRNA) 3′-untranslated region (UTR). Sema 4D mRNA and protein levels were up-regulated in ovarian cancer tissues and SKOV-3 cells. Up-regulation of miR-214 in SKOV-3 cell line suppressed the sema 4D expression in both protein and nucleic acid levels. While, down-regulation of miR-214 in SKOV-3 cells would increase sema 4D protein and nucleic acid expression levels. The effects of miR-214 up- and down-regulation on luciferase activities of wild-type (WT) sema 4D 3′-UTR were completely removed upon introduction of mutation in 3′-UTR of WT sema 4D. Therefore, the data also demonstrated that sema 4D was the direct target of miR-214 and was negatively regulated by miR-214 in ovarian cancer cells.

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Fusobacterium nucleatum , inflammation, and immunity: the fire within human gut

Abstract

Fusobacterium nucleatum is an identified proinflammatory autochthonous bacterium implicated in human colorectal cancer. It is also abundantly found in patients suffering from chronic gut inflammation (inflammatory bowel disease), consequently contributing to the pathogenesis of colorectal cancer. Majority of the studies have reported that colorectal tumors/colorectal adenocarcinomas are highly enriched with F. nucleatum compared to noninvolved adjacent colonic tissue. During the course of multistep development of colorectal cancer, tumors have evolved many mechanisms to resist the antitumor immune response. One of such favorite ploy is providing access to pathogenic bacteria, especially F. nucleatum in the colorectal tumor microenvironment, wherein both (colorectal tumors and F. nucleatum) exert profound effect on each other, consequently attracting tumor-permissive myeloid-derived suppressor cells, suppressing cytotoxic CD8+ T cells and inhibiting NK cell-mediated cancer cell killing. In this review, we have primarily focused on how this bug modulates the immune response, consequently rendering the antitumor immune cells inactive.

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Long non-coding RNAs: emerging players in osteosarcoma

Abstract

Osteosarcoma is the most common kind of primary bone tumors with high morbidity in infants and adolescents. While the molecular mechanism of osteosarcoma has gained considerable attention, the mechanisms underlying its initiation and progression remain unclear. Recent studies have discovered that long non-coding RNAs (lncRNAs) play an important role in multiply biological processes including cell development, differentiation, proliferation, invasion, and migration. Deregulated expression of lncRNAs has been found in cancers including osteosarcoma. This review summarized the deregulation and functional role of lncRNAs in osteosarcoma and their potential application for diagnosis and treatment of osteosarcoma.

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Stimulation of the hypoxia pathway modulates chemotherapy resistance in Hodgkin’s lymphoma cells

Abstract

Hodgkin's lymphoma (HL) is a malignant disease of the lymphatic system. The therapy has been improved during the last decades but there are still patients who cannot be cured, and the therapy is associated with several adverse late effects. Therefore, we asked which genes might be involved in the chemotherapy resistance of HL cells. We observed that HL cells became more resistant against cisplatin after treatment with cobalt chloride. Therefore, we analyzed which genes were differentially expressed between cells incubated in medium with or without cobalt chloride. We found several genes which were up- or downregulated in the presence of cobalt chloride and might be involved in the modulation of chemotherapy resistance. Cobalt chloride is a hypoxia-mimetic agent. Therefore, we tested chemo-resistance and gene expression of HL cells under hypoxic conditions and confirmed the results from the cobalt chloride experiments. Taken together, activation of the hypoxia pathway led to altered gene expression and drug resistance of HL cells. Differentially expressed genes might be interesting targets for the development of future treatment strategies against drug-resistant HL.

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New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies

Abstract

ATP-binding cassette (ABC) transporters make up a superfamily of transmembrane proteins that play a critical role in the development of drug resistance. This phenomenon is especially important in oncology, where superfamily member ABCG2 (also called BCRP – breast cancer resistance protein) is known to interact with dozens of anti-cancer agents that are ABCG2 substrates. In addition to the well-studied and well-reviewed list of cytotoxic and targeted agents that are substrates for the ABCG2 transporter, a growing body of work links ABCG2 to multiple photodynamic therapy (PDT) agents, and there is a limited body of evidence suggesting that ABCG2 may also play a role in resistance to radiation therapy. In addition, the focus of ABC transporter research in regards to therapeutic development has begun to shift in the past few years. The shift has been away from using pump inhibitors for reversing resistance, toward the development of therapeutic agents that are poor substrates for these efflux pump proteins. This approach may result in the development of drug regimens that circumvent ABC transporter-mediated resistance entirely. Here, it is our intention to review: 1) recent discoveries that further characterize the role of ABCG2 in oncology, and 2) advances in reversing and circumventing ABC transporter-mediated resistance to anti-cancer therapies.

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Enhancing safety and quality through preplanning peer review for patients undergoing stereotactic body radiation therapy

Publication date: Available online 30 December 2015
Source:Practical Radiation Oncology
Author(s): Martha M. Matuszak, Scott W. Hadley, Mary Feng, James A. Hayman, Kristy K. Brock, Pamela Burger, Dawn Owen, Krithika Suresh, Matthew Schipper, Theodore S. Lawrence, Jean M. Moran
PurposeBecause of its high dose per fraction delivery, stereotactic body radiation therapy (SBRT) requires real-time process assurance to promote safe, high-quality treatments. In an effort to assure safety and first-time quality, we instituted a pilot, single-institution, SBRT peer review process before treatment planning. Here, we present a summary of the results of that process over a 26-month period.Methods and MaterialsBefore planning, all patients were presented at an SBRT "rounds" that required, at a minimum, the treating attending or resident physician, an independent attending physician, a physicist, and a dosimetrist. Items reviewed included imaging, image registration, target contours, prescription, and planning goals. The results of peer review were prospectively recorded and logistic regression models were used to assess the relationship between various physician and case characteristics and the odds of a change being made.ResultsA total of 513 SBRT cases were peer reviewed before planning. In 22.6% of cases, at least 1 change was made because of this process. A lower change rate was observed in higher volume SBRT body sites (lung and liver). In all body sites, gross and planning target volume contours were changed 8.2% and 5.5% of the time, respectively. The prescription was changed 4.9% of the time, and organs at risk goals were changed 7.2% of the time. The odds of having a change were significantly lower when the treating oncologist had more SBRT experience.ConclusionsPreplanning peer review by an independent physician, physicist, and dosimetrist resulted in changes in nearly one-quarter of SBRT patients, potentially preventing suboptimal treatments. The odds of a change being required were decreased in higher volume body sites and when the treating oncologist was more experienced with SBRT, underscoring the potential importance of peer review in uncommon SBRT sites and at low-volume SBRT centers.



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The dog prostate cancer (DPC-1) model: a reliable tool for molecular imaging of prostate tumors and metastases

Abstract

Background

Clinical applicability of newly discovered reagents for molecular imaging is hampered by the lack of translational models. As the dog prostate cancer (DPC-1) model recapitulates in dogs the natural history of prostate cancer in man, we tested the feasibility of single-photon emission computed tomography (SPECT)/CT imaging in this model using an anti-prostate-specific membrane antigen (PSMA)/17G1 antibody as the radiotracer.

Methods

Immunoblots and immunohistochemistry (IHC) with 17G1 were performed on canine and human prostate cancer cell lines and tissues. Five dogs with DPC-1 tumors were enrolled for pelvic and, in some instances, thoracic SPECT/CT procedures, also repeated over time. Controls included ¹¹¹indium (In)-17G1 prior to DPC-1 implantation and ¹¹¹In-immunoglobulins (IgGs) prior to imaging with ¹¹¹In-17G1 in dogs bearing prostatic DPC-1 tumors.

Results

17G1 cross-reactivity with canine PSMA (and J591) was confirmed by protein analyses on DPC-1, LNCaP, and PC-3 cell lines and IHC of dog vs. human prostate tissue sections. 17G1 stained luminal cells and DPC-1 cancer cells in dog prostates similarly to human luminal and cancer cells of patients and LNCaP xenografts. SPECT/CT imaging revealed low uptake (≤2.1) of both ¹¹¹In-17G1 in normal dog prostates and ¹¹¹In-IgGs in growing DPC-1 prostate tumors comparatively to ¹¹¹In-17G1 uptake of 3.6 increasing up to 6.5 values in prostate with DPC-1 lesions. Images showed a diffused pattern and, occasionally, a peripheral doughnut-shape-like pattern. Numerous sacro-iliac lymph nodes and lung lesions were detected with contrast ratios of 5.2 and 3.0, respectively. The highest values were observed in pelvic bones (11 and 19) of two dogs, next confirmed as PSMA-positive metastases.

Conclusions

This proof-of-concept PSMA-based SPECT/CT molecular imaging detecting primary prostate tumors and metastases in canines with high cancer burden speaks in favor of this large model's utility to facilitate technology transfer to the clinic and accelerate applications of new tools and modalities for tumor staging in patients.

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Evaluation of the utilization of external radiotherapy in the treatment of localized prostate cancer in Andalusia, Spain

Abstract

Background

Around 27,000 new cases of prostate cancer are diagnosed every year in Spain and 5400 die from this disease. Radiotherapy (RT), alone or combined, has proven to be effective as initial treatment in patients with localized disease. Our objective was to evaluate the use of external beam RT (EBRT) in our region, comparing the indication rate and irradiation rate and examining variability in its application among hospitals.

Methods

We conducted a review of RT guidelines and indication studies for prostate cancer (% expected irradiation). Data were gathered from all twelve public healthcare centers in Andalusia (Spain) on RT-treated prostate cancer patients during 2013 (% actual irradiation) and from nine of the centers on RT discharge reports. Information was classified according to type of hospital, tumor risk category and RT treatment (technique, dosage, volume, toxicity).

Results

The estimated RT rate was 67 % (1289/1917), 43 % were aged > 70 years, 44.7 % had ECOG performance status of 0); 44.7 % had high-risk tumors; 57 % underwent RT associated with hormone therapy; 70 % of patients receiving RT were treated with 3D planning (30 % IGRT); and doses were 70–76 Gy in 70 % of cases and >76 Gy in 10.7 %. Acute gastrointestinal and genitourinary toxicities were < grade 2 in 79 and 89 % of patients, respectively. An irradiation rate significantly below the mean for the study was found in four provinces. There was a significant difference among provinces in the distribution of risk groups.

Conclusions

Underutilization of EBRT was estimated to be around 30 % in prostate cancer patients, with an elevated variability in irradiation rates among hospitals related to differences in available technology and in the distribution of patients with different risk levels. These data should be a matter of concern to regional health managers, given the negative and measurable impact on the survival of patients.

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Cardiac dose reduction during tangential breast irradiation using deep inspiration breath hold: a dose comparison study based on deformable image registration

Abstract

Background

Radiation therapy (RT) for a left-sided breast cancer often involves some incidental exposure of the heart and increase in the rate of major coronary events. One method to reduce the dose to the heart during a tangential breast irradiation is the deep inspiration breath hold (DIBH) technique. Our department adopted DIBH for selected left breast cancer patients with a maximum cardiac distance ≥ 10 mm. We evaluated the effect of the DIBH on cardiac dose compared to normal free breathing (FB). The secondary objective of our present study was to use modeled risk estimates to quantify the risk of coronary events after RT with DIBH.

Methods and materials

Thirty-two patients who underwent RT with DIBH at our hospital were retrospectively analyzed. For each patient, two computed tomography (CT) scans were acquired, FB-CT and DIBH-CT. Using a deformable image registration tool, the target volume was deformed from DIBH-CT to FB-CT, and conventional tangential treatment planning was performed, focusing on the equality of target coverage between the two plans. Doses to the heart, left anterior descending (LAD) artery, and ipsilateral lung were assessed.

Results

By using DIBH, the average mean heart dose was reduced from 724.1 cGy to 279.3 (p < 0.001). The relative heart volume irradiated with 10 Gy–50 Gy was consistently reduced. The mean dose to the LAD coronary artery was reduced from 4079.1 cGy to 2368.9 cGy (p < 0.001). The ipsilateral lung volume receiving 20 Gy or more and 40 Gy or more was reduced by 2.2 % in both cases. Estimated risks of coronary events at 10 years were 4.03 and 2.55 % for RT with FB and DIBH, respectively (p < 0.001).

Conclusions

The use of DIBH during RT of the left-sided breast considerably reduces the doses delivered to the heart and LAD artery with similar target coverage. For the current study patients, the probability of major coronary events was reduced with DIBH.

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Frequent induction of chromosomal aberrations in in vivo skin fibroblasts after allogeneic stem cell transplantation: hints to chromosomal instability after irradiation

Abstract

Background

Total body irradiation (TBI) has been part of standard conditioning regimens before allogeneic stem cell transplantation for many years. Its effect on normal tissue in these patients has not been studied extensively.

Method

We studied the in vivo cytogenetic effects of TBI and high-dose chemotherapy on skin fibroblasts from 35 allogeneic stem cell transplantation (SCT) patients. Biopsies were obtained prospectively (n = 18 patients) before, 3 and 12 months after allogeneic SCT and retrospectively (n = 17 patients) 23–65 months after SCT for G-banded chromosome analysis.

Results

Chromosomal aberrations were detected in 2/18 patients (11 %) before allogeneic SCT, in 12/13 patients (92 %) after 3 months, in all patients after 12 months and in all patients in the retrospective group after allogeneic SCT. The percentage of aberrant cells was significantly higher at all times after allogeneic SCT compared to baseline analysis. Reciprocal translocations were the most common aberrations, but all other types of stable, structural chromosomal aberrations were also observed. Clonal aberrations were observed, but only in three cases they were detected in independently cultured flasks. A tendency to non-random clustering throughout the genome was observed. The percentage of aberrant cells was not different between patients with and without secondary malignancies in this study group.

Conclusion

High-dose chemotherapy and TBI leads to severe chromosomal damage in skin fibroblasts of patients after SCT. Our long-term data suggest that this damage increases with time, possibly due to in vivo radiation-induced chromosomal instability.

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Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: A propensity score–matched analysis

BACKGROUND

The role of adjuvant chemotherapy (AC) in the treatment of small bowel adenocarcinoma is poorly defined. Previous analyses have been limited by small sample sizes and have failed to demonstrate a survival advantage.

METHODS

Patients with resected small bowel adenocarcinoma (American Joint Committee on Cancer [AJCC] pathologic stage I-III) who were receiving AC (n = 1674) or surgery alone (SA; n = 3072) were identified in the NCDB (1998-2011). Cox regression identified covariates associated with overall survival (OS). AC and SA cohorts were matched (1:1) by propensity scores based on the likelihood of receiving AC or the survival hazard from Cox modeling. OS was compared with Kaplan-Meier estimates.

RESULTS

The omission of AC conferred an increased risk of death (hazard ratio, 1.36; 95% confidence interval, 1.24-1.50; P < .001). After propensity score matching, there was a nonsignificant trend toward improved OS with AC in AJCC stage I patients (158.8 vs 110.7 months; P = .226) and AJCC stage II patients (104.0 vs 79.6 months; P = .185), including the subset with a T4 tumor classification (64.0 vs 47.4 months; P = .130) or a positive resection margin (44.4 vs 31.0 months; P = .333). Median OS was superior for patients with AJCC stage III disease who were receiving AC versus SA (42.4 vs 26.1 months; P < .001).

CONCLUSIONS

These data support the use of AC for resected stage III small bowel adenocarcinoma. The trend toward improved OS for patients without nodal metastasis, including those who have T4 tumors or have undergone positive-margin resection, may justify the use of AC in select patients with earlier stage disease. Cancer 2015. © 2015 American Cancer Society.

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Radiation modality use and cardiopulmonary mortality risk in elderly patients with esophageal cancer

BACKGROUND

It is currently unclear whether the superior normal organ-sparing effect of intensity-modulated radiotherapy (IMRT) compared with 3-dimensional radiotherapy (3D) has a clinical impact on survival and cardiopulmonary mortality in patients with esophageal cancer (EC).

METHODS

The authors identified 2553 patients aged > 65 years from the Surveillance, Epidemiology, and End Results (SEER)-Medicare and Texas Cancer Registry-Medicare databases who had nonmetastatic EC diagnosed between 2002 and 2009 and were treated with either 3D (2240 patients) or IMRT (313 patients) within 6 months of diagnosis. The outcomes of the 2 cohorts were compared using inverse probability of treatment weighting adjustment.

RESULTS

Except for marital status, year of diagnosis, and SEER region, both radiation cohorts were well balanced with regard to various patient, tumor, and treatment characteristics, including the use of IMRT versus 3D in urban/metropolitan or rural areas. IMRT use increased from 2.6% in 2002 to 30% in 2009, whereas the use of 3D decreased from 97.4% in 2002 to 70% in 2009. On propensity score inverse probability of treatment weighting-adjusted multivariate analysis, IMRT was not found to be associated with EC-specific mortality (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.80-1.10) or pulmonary mortality (HR, 1.11; 95% CI, 0.37-3.36), but was significantly associated with lower all-cause mortality (HR, 0.83; 95% CI, 0.72-0.95), cardiac mortality (HR, 0.18; 95% CI, 0.06-0.54), and other-cause mortality (HR, 0.54; 95% CI, 0.35-0.84). Similar associations were noted after adjusting for the type of chemotherapy, physician experience, and sensitivity analysis removing hybrid radiation claims.

CONCLUSIONS

In this population-based analysis, the use of IMRT was found to be significantly associated with lower all-cause mortality, cardiac mortality, and other-cause mortality in patients with EC. Cancer 2015. © 2015 American Cancer Society.

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Baseline dietary glutamic acid intake and the risk of colorectal cancer: The Rotterdam study

BACKGROUND

Animal studies have shown that glutamine supplementation may decrease colon carcinogenesis, but any relation with glutamine or its precursors has not been studied in humans. The primary aim of this study was to assess whether dietary glutamic acid intake was associated with colorectal cancer (CRC) risk in community-dwelling adults. A secondary aim was to evaluate whether the association could be modified by the body mass index (BMI).

METHODS

This study was embedded in the Rotterdam study, which included a prospective cohort from 1990 onward that consisted of 5362 subjects who were 55 years old or older and were free of CRC at the baseline. Glutamic acid was calculated as a percentage of the total protein intake with a validated food frequency questionnaire at the baseline. Incident cases of CRC were pathology-based.

RESULTS

During follow-up, 242 subjects developed CRC. Baseline dietary glutamic acid intake was significantly associated with a lower risk of developing CRC (hazard ratio [HR] per percent increase in glutamic acid of protein, 0.78; 95% confidence interval [CI], 0.62-0.99). After stratification for BMI, the risk reduction for CRC by dietary glutamic acid was 42% for participants with a BMI ≤ 25 kg/m² (HR per percent increase in glutamic acid of protein, 0.58; 95% CI, 0.40-0.85), whereas no association was found in participants with a BMI > 25 kg/m² (HR per percent increase in glutamic acid of protein, 0.97; 95% CI, 0.73-1.31).

CONCLUSIONS

Our data suggest that baseline dietary glutamic acid intake is associated with a lower risk of developing CRC, but this association may be mainly present in nonoverweight subjects. Cancer 2015. © 2015 American Cancer Society.

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The evolution and clinical relevance of prognostic classification systems in myelofibrosis

Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2015. © 2015 American Cancer Society.

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The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy

The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms. Cancer 2015. © 2015 American Cancer Society.

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Direct costs of care for hepatocellular carcinoma in patients with hepatitis C cirrhosis

BACKGROUND

Hepatitis C virus (HCV) is the commonest cause of hepatocellular carcinoma (HCC) in the United States. The benefits of HCV therapy may be measured in part by the prevention of HCC and other complications of cirrhosis. The true cost of care of the HCV patient with HCC is unknown.

METHODS

One hundred patients were randomly selected from a cohort of all HCC patients with HCV at a US transplant center between 2003 and 2013. Patients were categorized by the primary treatment modality, Barcelona class, and ultimate transplant status. Costs included the unit costs of procedures, imaging, hospitalizations, medications, and all subsequent care of the HCC patient until either death or the end of follow-up. Associations with survival and cost were assessed in multivariate regression models.

RESULTS

Overall costs included a median of $176,456 (interquartile range [IQR], $84,489-$292,192) per patient or $6279 (IQR, $4043-$9720) per patient-month of observation. The median costs per patient-month were $7492 (IQR, $5137-$11,057) for transplant patients and $4830 for nontransplant patients. The highest median monthly costs were for transplant patients with Barcelona A4 disease ($11,349) and patients who received chemoembolization whether they underwent transplantation ($10,244) or not ($8853). Transarterial chemoembolization and radiofrequency ablation were independently associated with a 28% increase and a 22% decrease in costs, respectively, with adjustments for the severity of liver disease and Barcelona class.

CONCLUSIONS

These data represent real-world estimates of the cost of HCC care provided at a transplant center and should inform economic studies of HCV therapy. Cancer 2015. © 2015 American Cancer Society.

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Mols F, van de Poll-Franse LV, Vingerhoets AJJM, Hendrikx A, Aaronson NK, Houterman S, Coebergh JWW and Essink-Bot ML. Long-term quality of life among Dutch prostate cancer survivors. Cancer. 2006;107:2186-2196.

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Pricey pills for an even pricier problem

With more than 3 million people in the United States infected with hepatitis C, the price of treating all prevalent cases could potentially top $200 billion. Tapper et al provide support for the idea that appropriate hepatocellular carcinoma cost inputs have been used in recent cost-effectiveness analyses of direct-acting antiviral drugs for chronic hepatitis C infection.

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Expression of cancer-associated fibroblast-related proteins in thyroid papillary carcinoma

Abstract

The purpose of this study was to evaluate the association between expression of cancer-associated fibroblast (CAF)-related proteins in papillary thyroid carcinoma (PTC) and clinicopathologic factors. Using tissue microarray (TMA) constructed from 339 cases of PTC (303 classic type, 36 follicular variant), we performed immunohistochemical staining for podoplanin, prolyl 4-hydroxylase, FAPα, S100A4, PDGFRα, PDGFRβ, NG2, 5-meC, and BRAF V600E and evaluated the association with clinicopathologic parameters. We classified the stroma of PTC as desmoplastic type, sclerotic type, pauci type, or inflammatory type. The expression of prolyl 4-hydroxylase (p = 0.042), FAPα (p = 0.044), PDGFRα (p < 0.001), and 5-meC (p = 0.030) in cancer cells differed according to the histologic subtype, higher in classic type than follicular type. The expression of FAPα (p = 0.034) and 5-meC (p = 0.021) in stromal cells was higher in the classic type than follicular type. PTC with BRAF mutation showed higher expression of podoplanin (p < 0.001), prolyl 4-hydroxylase (p = 0.013), FAPα (p < 0.001), S100A4 (p < 0.001), PDGFRα (p < 0.001), and 5-meC (p < 0.001) in the tumor cell compartment and of FAPα (p = 0.004), S100A4 (p < 0.001), PDGFRα (p = 0.002), PDGFRβ (p < 0.001), and 5-meC (p < 0.001) in the stromal cell compartment. There was also a difference in the expression of CAF-related proteins according to stromal phenotype; the expression of FAPα, S100A4, and PDGFRα was higher in desmoplastic type than in other subtypes, whereas NG2 expression was higher in inflammatory type (p < 0.001). Tumoral podoplanin negativity (p = 0.043) was associated with shorter DFS, and tumoral S100A4 positivity (p = 0.044) and stromal PDGFRβ positivity (p = 0.035) were associated with shorter OS. In conclusion, the expression of CAF-related proteins in cancer cells and stromal cells of PTC was different according to histologic subtype, BRAF V600E mutation, and subtype of stroma, and was related to prognosis.

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Glucose-regulated protein 94 mediates metastasis by CCT8 and the JNK pathway in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Cancer metastasis is a major obstacle in clinical cancer therapy. The mechanisms underlying the metastasis of HCC remain unclear. Glucose-regulated protein 94 (GRP94) is a key protein involved in mediating cancer progression, and it is highly expressed in HCC specimens. However, the role of GRP94 in cancer metastasis is unclear. A specific short hairpin RNA (shRNA) was employed to knock down GRP94 gene expression in HCC cell lines. Wound-healing migration, transwell migration, and invasion assays were performed to determine the migration and invasive ability of HCC cells. We demonstrated that silencing GRP94 inhibited HCC cell wound healing, migration, and invasion. Furthermore, our findings indicated that GRP94 knockdown might attenuate HCC cell metastasis by inhibiting CCT8/c-Jun/EMT signaling. Our study indicated that silencing GRP94 significantly reduced the migration and invasion abilities of HCC cells. Moreover, depleting GRP94 inhibited cell migration and invasion by downregulating CCT8/c-Jun signaling. Thus, our data suggest that the GRP94/CCT8/c-Jun/EMT signaling cascade might be a new therapeutic target for HCC.

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Misconstrued versatility of Ganoderma lucidum : a key player in multi-targeted cellular signaling

Abstract

A Basidiomycetes fungus belonging to polypore family of mushrooms, Ganoderma lucidum (GL), has been known since a long time for their myriad therapeutic indications. Renowned as an invaluable resource of cardinal mycoconstituents they encompass numerous terpenoids polysaccharides and proteins. Possessing the therapeutically potent lanosteroidal skeleton, terpenoids are upheld for their invariable participation in therapeutically diverse bioactivities. Polysaccharides and proteins exhibiting distinguishable bioactivities provide this oriental mushroom with additional edges over immune function and anti-cancer potential. This review is a concerted effort to throw light upon the therapeutic versatility of the fungus, shadowed by various other natural products. An effort has been made towards conglomerating the mycoconstituents decisive for the many activities portrayed by this fungus. More importantly, this review seeks to fathom the inextricable role played by derivatives in modulating signaling cascades such as downregulation of various mitogenic pathways, inhibiting growth factors, or upregulating certain pathways enhancing cellular integrity.

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Interleukin 10-expressing B cells inhibit tumor-infiltrating T cell function and correlate with T cell Tim-3 expression in renal cell carcinoma

Abstract

Renal cell carcinoma is among the leading causes of cancer-related death and was found to induce IL-10. We started by focusing on IL-10-secreting cells in tumor-infiltrating lymphocytes in renal cell carcinoma patients and observed that both CD3⁺ T cells and CD19⁺ B cells contributed to an elevated IL-10 expression. We then focused on IL-10-expressing B cells, and found that compared to non-IL-10-producing B cells, the IL-10-expressing B cells had significantly lower levels of CD19 and CD20 expression, a lack of IgM and IgD expression, while the level of CD27 was elevated. Moreover, culturing under unstimulated conditions resulted in higher antibody production by these IL-10-producing B cells than their peripheral blood counterparts, which strongly suggested that they are plasmablast-differentiating cells. Both IgA and IgG subtypes were found but IgA had a higher relative abundance in the tumor-infiltrating fraction. We then observed inverse correlations between the frequency of IL-10-producing B cells and pro-inflammatory cytokine-producing T cells and T cell proliferation. The expression of T cell exhaustion marker Tim-3, however, was upregulated in patients with high frequencies of IL-10-producing B cells. Moreover, supernatant from tumor B cells suppressed T cell inflammation. In addition, frequencies of IL-10-producing tumor-infiltrating B cells were inversely correlated with resected tumor size, and were higher in later stage tumors. Together, our data demonstrated that IL-10-producing B cells had plasmablast-differentiating phenotype, and could contribute to T cell immunosuppression in renal cell carcinoma.

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MicroRNA-145 inhibits growth and migration of breast cancer cells through targeting oncoprotein ROCK1

Abstract

MicroRNAs are small non-coding RNAs that may also function as oncogenes and tumor suppressor genes, as the abnormal expression of microRNAs is associated with various human tumors. MicroRNA-145 (miR-145) inhibits growth and increases chemo- or radiosensitivity in various cancers. However, the role of miR-145 in breast cancer progression remains unknown. In this study, miR-145 expression level was measured via quantitative real-time PCR in 88 pairs of human breast cancer tissues and adjacent normal tissues and in a panel of human breast cancer cell lines. Cell proliferation and cell migration were assessed by cell viability assay and transwell assay. Western blot was used to verify Rho-associated protein kinase 1 (ROCK1) as a novel target gene of miR-145. Our results showed that miR-145 was frequently downregulated in breast cancer tissues and cell lines. Overexpression of miR-145 in MCF-7 and BT-549 cell lines significantly inhibited cell proliferation, migration, and invasion in vitro. ROCK1 was identified as a target of miR-145, and ectopic expression of miR-145 downregulated ROCK1. Our findings indicate that miR-145 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression of breast cancer through a mechanism involving ROCK1, suggesting miR-145 as a potential new diagnostic and therapeutic target for the treatment of breast cancer.

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ERK inhibition sensitizes cancer cells to oleanolic acid-induced apoptosis through ERK/Nrf2/ROS pathway

Abstract

Oleanolic acid (OA) is a natural triterpenoid that is widely distributed in edible and medicinal plants. OA exerts anti-tumor activity on a wide range of cancer cells primarily through inducing apoptosis. Dysregulated ERK signaling is closely complicated in the biology of cancer, such as metastasis, proliferation, and survival, and it can be activated by various stimuli. In this study, we found that OA induced the activation of ERK in cancer cells. ERK activation compromised the apoptosis induced by OA. Blocking ERK activation by U0126 or siRNAs was able to potentiate the pro-apoptotic activity of OA on cancer cells. OA was shown to promote ERK-dependent Nrf2 expression in cancer cells, and in turn, Nrf2 expression was able to suppress OA-induced ROS generation. Blockade of Nrf2 expression was able to increase ROS levels and apoptotic death in cancer cells. In conclusion, we provided evidences that ERK activation is a mechanism underlying the resistance of cancer cells to OA-induced apoptosis and targeting ERK is a promising strategy to enhance the anti-tumor efficacy of OA.

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Early diagnosis of lymph node metastasis: importance of intranodal pressures

Abstract

Regional lymph node status is an important prognostic indicator of tumor aggressiveness. However, early diagnosis of metastasis using intranodal pressure, at a stage when lymph node size has not changed significantly, has not been investigated in murine models. Here, we use an MXH10/Mo-lpr/lpr mouse model of lymph node metastasis to show that intranodal pressure increases in both the subiliac lymph node and proper axillary lymph node, which are connected by lymphatic vessels, when tumor cells are injected into the subiliac lymph node to induce metastasis to the proper axillary lymph node. We found that intranodal pressure in the subiliac lymph node increased at the stage when metastasis was detected by in vivo bioluminescence, but when proper axillary lymph node volume (measured by high-frequency ultrasound imaging) had not increased significantly. Intravenously injected liposomes, encapsulating indocyanine green, were detected in the interstitial space in solid tumors by in vivo bioluminescence, but not in the interstitial space in the proper axillary lymph node. Basic blood vessel and lymphatic channel structures were maintained in the proper axillary lymph node, although sinus histiocytosis was detected. These results demonstrate that intranodal pressure in the proper axillary lymph node increases at early stages when metastatic tumor cells have not fully proliferated. Intranodal pressure may be a useful parameter for facilitating early diagnosis of lymph node metastasis.

This article is protected by copyright. All rights reserved.

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Establishment of a Novel Method to Evaluate Peritoneal Microdissemination and Therapeutic Effect Using Luciferase Assay

Summary

Peritoneal dissemination is a major cause of recurrence in patients with malignant tumors in the peritoneal cavity. Effective anticancer agents and treatment protocols are necessary to improve outcomes in these patients. However, previous studies using mouse models of peritoneal dissemination have not detected any drug effect against peritoneal micrometastasis. Here we used the luciferase assay to evaluate peritoneal micrometastasis in living animals and established an accurate mouse model of early peritoneal microdissemination to evaluate tumorigenesis and drug efficacy. There was a positive correlation between luminescence intensity in in vivo luciferase assay and the extent of tumor dissemination evaluated by ex vivo luciferase assay and mesenteric weight. This model has advantages over previous models because optimal luciferin concentration without cell damage was validated and peritoneal microdissemination could be quantitatively evaluated. Therefore, it is a useful model to validate peritoneal micrometastasis formation and to evaluate drug efficacy without sacrificing mice.

This article is protected by copyright. All rights reserved.

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Cancers, Vol. 8, Pages 4: Studies of Tumor Suppressor Genes via Chromosome Engineering

The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor suppressor genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related genes plays a crucial role in our understanding of the development and progression of malignant tumors. Chromosome engineering technology based on microcell-mediated chromosome transfer (MMCT) is an effective approach for identification of tumor suppressor genes. The studies have revealed at least five tumor suppression effects. The discovery of novel tumor suppressor genes provide greater understanding of the complex signaling pathways that underlie the development and progression of malignant tumors. These advances are being exploited to develop targeted drugs and new biological therapies for cancer.

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Estimates of prostate cancer burden in Italy

Publication date: February 2016
Source:Cancer Epidemiology, Volume 40
Author(s): R. Capocaccia, R. Foschi, A. Zucchetto, R. Valdagni, N. Nicolai, M. Maffezzini, G. Gatta
Age-standardized incidence rates of prostate cancer (PC) sharply increased during the period 1990–2005 in Italian areas covered by cancer registries, while corresponding mortality rates remained nearly constant. The latest observations have reported on a reversal of the incidence trend with decreasing values after 2005. We provided incidence, mortality, and prevalence estimates at national and geographical area levels, together with time projections up to the year 2020.We applied the MIAMOD method, using as input national mortality data for the years 1970–2010 and population-based survival data for the period of diagnosis (1985–2002). We assumed relative survival of prostate cancer remained constant after the year of diagnosis (2005).The age-standardized incidence rates of PC were estimated to increase during the period 1984–2005, from 31 per 100,000 in 1984 to 93 per 100,000 in 2005. From 2005 onwards, the estimated rates declined to 71 in 2015 and to 62 in 2020. Age-standardized mortality rates slightly increased from 1970 up to about 19 per 100,000 in 1999 and then started to decrease with an estimated reduction of about 2.3% per year. Mortality projections indicated a continuing reduction, with a predicted age-standardized rate of about 12 per 100,000 in 2020. Prevalence was estimated to continuously increase up to a crude prevalence value of 1.2% in the year 2020.The results indicate that the epidemic peak of PC was reached around the year 2005 followed by declining incidence rates, while a substantial decrease in mortality, starting during the early 2000s, is expected to continue during the 2010s.



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Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy

We investigated the clinical outcome and the toxicity of trimodal therapy of malignant pleural mesothelioma (MPM) treated with neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant intensity-...

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Frequent induction of chromosomal aberrations in in vivo skin fibroblasts after allogeneic stem cell transplantation: hints to chromosomal instability after irradiation

Total body irradiation (TBI) has been part of standard conditioning regimens before allogeneic stem cell transplantation for many years. Its effect on normal tissue in these patients has not been studied exten...

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Cardiac dose reduction during tangential breast irradiation using deep inspiration breath hold: a dose comparison study based on deformable image registration

Radiation therapy (RT) for a left-sided breast cancer often involves some incidental exposure of the heart and increase in the rate of major coronary events. One method to reduce the dose to the heart during a...

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Evaluation of the utilization of external radiotherapy in the treatment of localized prostate cancer in Andalusia, Spain

Around 27,000 new cases of prostate cancer are diagnosed every year in Spain and 5400 die from this disease. Radiotherapy (RT), alone or combined, has proven to be effective as initial treatment in patients wi...

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New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies

ATP-binding cassette (ABC) transporters make up a superfamily of transmembrane proteins that play a critical role in the development of drug resistance. This phenomenon is especially important in oncology, whe...

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C-arm computed tomography parenchymal blood volume measurement in evaluation of hepatocellular carcinoma before transarterial chemoembolization with drug eluting beads

Abstract

Background

C-arm computed tomography (CT) guided intervention is an increasingly applied technique in transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). The aim of this study was to analyse the value of parenchymal blood volume (PBV) maps acquired during C-arm CT acquisition, for pre-treatment evaluation and planning of TACE in HCC patients.

Methods

A total of 64 HCC lesions in 29 patients (median age, 73 years, range, 62–77 years) were included in this retrospective study. All patients received cross-sectional imaging (MRI or CT) prior to TACE and C-arm CT PBV measurement acquisition before performing TACE. Results of cross-sectional imaging regarding the number of HCC lesions and maximum diameter were compared to PBV–maps. Number of lesions and tumour feeding vessels detected in PBV-maps were compared to conventional angiography. Results of PBV were analysed concerning different tumour morphologies (pre-treated, encapsulated and diffuse).

Results

Pre-interventional cross-sectional imaging and PBV maps showed an excellent agreement in lesion diameter (p = 0.88, MD = −0.28 mm) and number of detected lesions (κ = 1.0). Compared to conventional angiography, PBV maps showed an increased number of detected lesions (κ = 0.77, p = 0.001) and tumour feeding vessels (κ = 0.71, p < 0.0001). Diffuse HCC lesion revealed a significantly lower PBV compared to encapsulated lesions (p = 0.0001).

Conclusions

C-arm CT acquired PBV measurements detect HCC tumours with a lesion detectability comparable to pre-interventional cross-sectional imaging. Furthermore, this technique facilitates TACE, allowing a more precise localization of HCC lesions and tumour feeding vessels compared to conventional angiography. Additionally, calculated PBV values enable a real time quantitative assessment of tumour perfusion.

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Electrochemotherapy as First Line Cancer Treatment: Experiences from Veterinary Medicine in Developing Novel Protocols.

Electrochemotherapy as First Line Cancer Treatment: Experiences from Veterinary Medicine in Developing Novel Protocols.

Curr Cancer Drug Targets. 2015;16(1):43-52

Authors: Spugnini EP, Azzarito T, Fais S, Fanciulli M, Baldi A

Abstract
Tumor microenvironment is one of the major obstacles to the efficacy of chemotherapy in cancer patients. The abnormal blood flow within the tumor results in uneven drug distribution. Electrochemotherapy (ECT) is a tumor treatment that adopts the systemic or local delivery of anticancer drugs with the application of permeabilizing electric pulses having appropriate amplitude and waveforms. This allows the use of lipophobic drugs that frequently have a narrow therapeutic index maintaining at the same time a reduced patient morbidity and preserving appropriate anticancer efficacy. Its use in humans is addressed to the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. On the other hand, in veterinary oncology this approach is gaining popularity, thus becoming a first line treatment for different cancer histotypes, in a variety of clinical conditions due to its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model and reports the new protocols in terms of drugs and therapy combination that have been developed.

PMID: 26712353 [PubMed - in process]

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T Cell Redirecting Therapies for Cancer Treatment.

T Cell Redirecting Therapies for Cancer Treatment.

Curr Cancer Drug Targets. 2015;16(1):22-33

Authors: Sasu B, Chaparro-Riggers J

Abstract
T cell activity has been stimulated to enhance anti-tumor activity for several decades. Tumor infiltrating lymphocytes have been expanded and reinfused to treat melanoma and other solid tumor cancers, and adaptive immune modulators have been used to increase endogenous T cell activity against cancer. Both of these strategies rely on the pre-existence of adequate recognition of cancer cells by the T cells which are being activated. Redirected T cell therapies represent a paradigm shift in treatment. They do not rely on endogenous T cell recognition but instead focus the T cells onto a defined tumor antigen. This review summarizes both molecular and cellular T cell redirecting therapies, compares their success in the clinic and highlights both their limitations and some potential future solutions.

PMID: 26712352 [PubMed - in process]

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