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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