11a-N-Tosyl-5-deoxi-pterocarpan, LQB-223, a novel compound with potent antineoplastic activity toward breast cancer cells with different phenotypes

Abstract

Multidrug resistance is the major obstacle for successful treatment of breast cancer, prompting the investigation of novel anticancer compounds.

Purpose

In this study, we tested whether LQB-223, an 11a-N-Tosyl-5-deoxi-pterocarpan newly synthesized compound, could be effective toward breast cancer cells.

Methods

Human breast cell lines MCF-7, MDA-MB-231, HB4a and MCF-7 Dox^R were used as models for this study. Cell culture, MTT and clonogenic assay, flow cytometry and Western blotting were performed.

Results

The LQB-223 decreased cell viability, inhibited colony formation and induced an expressive G2/M arrest in breast cancer cells. There was an induction in p53 and p21^Cip1 protein levels following treatment of wild-type p53 MCF-7 cells, which was not observed in the mutant p53 MDA-MB-231 cell line, providing evidence that the compound might act to modulate the cell cycle regardless of p53 status. In addition, LQB-223 resulted in decreased procaspase levels and increased annexin V staining, suggesting that the apoptotic cascade is also triggered. Importantly, LQB-223 treatment was shown to be less cytotoxic to non-neoplastic breast cells than docetaxel and doxorubicin. Strikingly, exposure of doxorubicin-resistant MCF-7-Dox^R cells to LQB-223 resulted in suppression of cell viability and proliferation in levels comparable to MCF-7. Of note, MCF-7-Dox^R cells have an elevated expression of the P-glycoprotein efflux pump when compared to MCF-7.

Conclusion

Together, these results show that LQB-223 mediates cytotoxic effects in sensitive and resistant breast cancer cells, while presenting low toxicity to non-neoplastic cells. The new compound might represent a potential strategy to induce toxicity in breast cancer cells, especially chemoresistant cells.

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Arsenite inhibits the function of CD133 + CD13 + liver cancer stem cells by reducing PML and Oct4 protein expression

Abstract

Cancer stem cells (CSCs) can form new tumors and contribute to post-operative recurrence and metastasis. We showed that CD133⁺CD13⁺ hepatocytes isolated from HuH7 cells and primary HCC cells display biochemical and functional characteristics typical of CSCs, suggesting that CD133⁺CD13⁺ hepatocytes in primary HCC tumors function as CSCs. We also found that arsenite treatment reduced the viability and stemness of CD133⁺CD13⁺ hepatocytes, enhanced the sensitivity of HuH7 cells to pirarubicin, and reduced the tumorigenicity of CD133⁺CD13⁺ hepatocytes xenografts in mice. The effects of sodium arsenite treatment in CD133⁺CD13⁺ hepatocytes were mediated by the post-transcriptional suppression of PML expression and the inhibition of Oct4, Sox2, and Klf4 expression at the transcriptional level. Incomplete rescue of Oct4 expression in arsenic-treated cells ectopically expressing an siRNA-resistant PML transcript suggested that OCT4 regulation in liver CSCs involves other factors in addition to PML. Our findings provide evidence of a specific role for PML in regulating Oct4 levels in liver CSCs and highlight the clinical importance of arsenic for improving the efficacy of other chemotherapeutic agents and the prevention of post-operative HCC recurrence and metastasis.

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miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes

Abstract

Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr–Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr–Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3′-untranslated regions (3′-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.

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Patient-reported quality of life during definitive and post-prostatectomy image-guided radiation therapy for prostate cancer

Publication date: Available online 12 August 2016
Source:Practical Radiation Oncology
Author(s): Kevin Diao, Emily A. Lobos, Eda Yirmibesoglu, Ram Basak, Laura H. Hendrix, Brittney Barbosa, Seth M. Miller, Kevin A. Pearlstein, Gregg H. Goldin, Andrew Z. Wang, Ronald C. Chen
PurposeThe importance of patient-reported outcomes is well-recognized. Long-term patient-reported symptoms have been described for individuals who completed radiation therapy (RT) for prostate cancer. However, the trajectory of symptom development during the course of treatment has not been well-described in patients receiving modern, image-guided RT.Methods and MaterialsQuality of life data were prospectively collected for 111 prostate cancer patients undergoing radiotherapy using the validated Prostate Cancer Symptom Indices, which assessed 5 urinary obstructive/irritative and 6 bowel symptoms. Patients who received definitive radiotherapy (N=73) and post-prostatectomy radiotherapy (N=38) were analyzed separately. The frequency and severity of symptoms over multiple time points are reported.ResultsAn increasing number of patients had clinically-meaningful urinary and bowel symptoms over the course of radiotherapy. A greater proportion of patients undergoing definitive RT reported clinically-meaningful urinary symptoms at the end of RT compared to baseline in terms of flow (33% vs 19%) and frequency (39% vs 18%). Individuals receiving post-prostatectomy radiation also reported an increase in symptoms including frequency (29% vs 3%) and nocturia (50% vs 21%). Clinically-meaningful bowel symptoms were less commonly reported. Patients receiving definitive RT reported an increase in diarrhea (9% vs 4%) and urgency (12% vs 6%) at the completion of radiotherapy compared to baseline. Both bowel and urinary symptoms approached their baseline levels by the time of first follow-up after treatment completion. The majority of patients who had clinically-meaningful urinary or bowel symptoms during RT did not have them at 2years or beyond, and development of new symptoms long-term was uncommon.ConclusionsThere is a modest increase in urinary and bowel symptoms over the course of treatment for individuals receiving definitive and post-prostatectomy image-guided radiotherapy. These data can help inform both providers and patients regarding the trajectory of symptoms and allow for reasonable expectations regarding toxicity under treatment.



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The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice

Abstract

Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function. We show that zaragozic acids inhibit the in vivo growth of the RMA lymphoma and the Lewis lung carcinoma (LLC) without inducing side effects. Tumor growth inhibition requires an intact immune system, as immunodeficient tumor-bearing mice do not respond to zaragozic acid treatment. Of note, the effect of zaragozic acids is accompanied by a marked reduction in the LXR target genes Abcg1, Mertk, Scd1 and Srebp-1c in the tumor microenvironment. On the other hand, zoledronate, which blocks also isoprenoid formation, did not control the LLC tumor growth. Finally, we show that zaragozic acids potentiate the antitumor effects of active and adoptive immunotherapy, significantly prolonging the overall survival of tumor-bearing mice treated with the combo zaragozic acids and TAA-loaded DCs. This study identifies zaragozic acids as new antitumor compounds exploitable for the treatment of cancer patients.

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Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein

Abstract

Purpose

The present study aimed to discover a new potent BCRP inhibitor overcoming multidrug resistance.

Methods

Effects of LW6 on the functional activity and gene expression of two major efflux transporters, BCRP and P-gp, were evaluated by using MDCKII cells overexpressing each transporter (MDCKII-BCRP and MDCKII-MDR1). Its effects on the cytotoxicity and pharmacokinetics of co-administered anticancer drugs were also evaluated in transfected cells and rats, respectively.

Results

In MDCKII-BCRP cells overexpressing BCRP, LW6 enhanced significantly (p < 0.05) the cellular accumulation of mitoxantrone, a BCRP substrate, and was more potent than Ko143, a well-known BCRP inhibitor. LW6 also down-regulated BCRP expression at concentrations of 0.1–10 µM. Furthermore, cells became more susceptible to the cytotoxicity of anticancer drugs in the presence of LW6. The CC₅₀ values of mitoxantrone and doxorubicin were reduced by three- and tenfold, respectively, in MDCKII-BCRP cells, while LW6 did not affect the cytotoxicity of anticancer drugs in MDCKII-mock cells lacking BCRP transporter. Furthermore, LW6 improved the oral exposure of methotrexate by twofold in rats. In contrast to BCRP, LW6 had no inhibition effect on the functional activity and gene expression of P-gp.

Conclusion

LW6 was newly identified as a potent BCRP inhibitor and could be useful to reduce the multidrug resistance of cancer cells via the inhibition of BCRP-mediated drug efflux as well as the down-regulation of BCRP expression.

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Molecular biology of the gut

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The next generation of novel therapies for the management of relapsed multiple myeloma

Future Oncology Ahead of Print.


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Are virus-induced cancers more sensitive to checkpoint inhibitors?

Future Oncology Ahead of Print.


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miRNA-24-3p promotes cell proliferation and regulates chemosensitivity in head and neck squamous cell carcinoma by targeting CHD5

Future Oncology Ahead of Print.


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Can we improve referrals for fertility preservation? Evolution of practices after the creation of a fertility network

Future Oncology Ahead of Print.


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Radiothérapie des sarcomes des tissus mous de l’adulte

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): C. Le Péchoux, L. Moureau-Zabotto, C. Llacer, A. Ducassou, P. Sargos, M.P. Sunyach, J. Thariat
Les sarcomes des tissus mous de l'adulte font partie des tumeurs rares et relèvent d'une prise en charge pluridisciplinaire en milieu spécialisé. L'objectif de cet article est de rapporter les indications et les modalités de la radiothérapie dans les principales localisations de cette pathologie.Incidence of soft tissue sarcoma is low and requires multidisciplinary treatment in specialized centers. The objective of this paper is to report the state of the art regarding indications and treatment techniques of main soft tissue sarcoma localisations.



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Radiothérapie des cancers du rectum

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): D. Peiffert, G. Créhange, V. Vendrely, A.-S. Baumann, J.-C. Faivre, S. Huger, A.A. Serre
Les indications, doses et techniques de radiothérapie conformationnelle des cancers du rectum sont présentées. Les recommandations de délinéation des volumes cibles et organes à risque sont détaillées.Indications, doses and techniques of conformal radiotherapy for rectal carcinoma are presented. The recommendations for delineation of the target volumes and organs at risk are detailed.



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Nouvelles techniques et pratiques en radiothérapie

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie





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Radiothérapie des métastases cérébrales

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): I. Latorzeff, D. Antoni, S. Gaudaire-Josset, L. Feuvret, A. Tallet-Richard, G. Truc, G. Noël
La radiothérapie des métastases cérébrales est devenue plus complexe. En effet, l'espérance de vie des patients ayant augmenté, les effets secondaires doivent être absolument évités et les retraitements sont monnaie courante. Les effets secondaires cognitifs doivent être prévenus et les techniques les plus modernes de radiothérapie sont utilisées de façon récurrente. Les nouvelles classifications des patients atteints de métastases cérébrales permettent d'orienter le traitement de façon plus pertinente. La radiothérapie en conditions stéréotaxiques a supplanté l'irradiation encéphalique en totalité tant pour les patients atteints de métastases en place que pour ceux qui ont été opérés. La protection hippocampique est possible avec les traitements avec modulation d'intensité. Sa pertinence en termes de conservation des fonctions cognitives reste à démontrer clairement mais la demande est de plus en plus forte. Bien que s'adressant à des malades en phase palliative, la prise en charge des métastases cérébrales est l'une des localisations pour laquelle la réflexion technique est la plus exigeante.Radiotherapy for brain metastases has become more multifaceted. Indeed, with the improvement of the patient's life expectancy, side effects must be undeniably avoided and the retreatments or multiple treatments are common. The cognitive side effects should be warned and the most modern techniques of radiation therapy are used regularly to reach this goal. The new classifications of patients with brain metastases help guiding treatment more appropriately. Stereotactic radiotherapy has supplanted whole brain radiation therapy both for patients with metastases in place and for those who underwent surgery. Hippocampus protection is possible with intensity-modulated radiotherapy. Its relevance in terms of cognitive functioning should be more clearly demonstrated but the requirement, for using it, is increasingly strong. While addressing patients in palliative phase, the treatment of brain metastases is one of the localisations where technical thinking is the most challenging.



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Radiothérapie guidée par l’image

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): R. de Crevoisier, B. Chauvet, I. Barillot, C. Lafond, M. Mahé, G. Delpon
La radiothérapie guidée par l'image est décrite dans ses différents équipements et leurs mises en œuvre. Elle peut être basée soit sur des rayonnements ionisants générant une imagerie bidimensionnelle de haute (MV) ou basse (kV) énergie ou une imagerie tridimensionnelle (tomographie conique [CBCT] ou scanographie de haute énergie [MV-CT]), soit sur des rayonnements non ionisants (échographie, imagerie optique, radiofréquence ou IRM). La radiothérapie adaptative est ensuite présentée dans ses principes de réalisation. L'utilisation par les manipulateurs en électroradiologie médicale (MERM) des images de contrôle au poste de traitement est ensuite précisée, ainsi que la dose éventuellement délivrée par l'imagerie embarquée et enfin le contrôle qualité des dispositifs de guidage par l'image.The IGRT is described in its various equipment and implementation. IGRT can be based either on ionizing radiation generating 2D imaging (MV or kV) or 3D imaging (CBCT or MV-CT) or on non-ionizing radiation (ultrasound, optical imaging, MRI or radiofrequency). Adaptive radiation therapy is then presented in its principles of implementation. The function of the technicians for IGRT is then presented and the possible dose delivered by the on-board imaging is discussed. The quality control of IGRT devices is finally described.



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Radiothérapie des cancers de l’œsophage, du cardia et de l’estomac

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): G. Créhange, F. Huguet, L. Quero, T.V. N'Guyen, X. Mirabel, T. Lacornerie
Les cancers de l'œsophage et de l'estomac localisés sont des tumeurs de pronostic défavorable. La radiothérapie et une chimiothérapie concomitante font partie intégrante de la stratégie thérapeutique à visée curative des cancers œsophagiens, qu'elles soient délivrées en situation préopératoire pour des tumeurs résécables ou exclusivement pour des patients inopérables, des tumeurs localement inextirpables ou présentant un envahissement ganglionnaire étendu. L'analyse des données de la littérature montre des résultats divergents, sans traduction clinique évidente en faveur d'un protocole unique de doses ou d'un consensus concernant les volumes cibles, en situation de chimioradiothérapie exclusive. En situation préopératoire, la chimioradiothérapie a montré un intérêt en association à la chirurgie, sans preuve que la chirurgie de clôture soit bénéfique pour des tumeurs localement évoluées répondeuses à la chimioradiothérapie. Les principales causes d'échec après chimioradiothérapie exclusive sont locorégionales, ce qui témoigne d'incertitudes sur les doses et volumes adéquats. Pour les cancers de l'estomac, la radiothérapie peut être délivrée en situation adjuvante, uniquement en l'absence de chimiothérapie périopératoire. La radiothérapie préopératoire est toujours en cours d'investigation. Les évolutions techniques de la radiothérapie, en particulier la radiothérapie conformationnelle avec modulation d'intensité (RCMI) et l'arcthérapie volumétrique modulée permettent de diminuer l'irradiation cardiaque et pulmonaire, et semblent réduire la morbidité et la mortalité de ce traitement. Pour cette raison, la qualité de la radiothérapie et les protocoles de délivrance de la radiothérapie doivent être mieux standardisés. Ce chapitre s'intègre dans un ouvrage de la Société française de radiothérapie oncologique (SFRO) visant à donner des recommandations nationales techniques concernant les indications, la préparation du traitement, la prescription de doses et les techniques de délivrance de la radiothérapie dans ses différentes indications pour les cancers de l'œsophage et gastriques nécessitant une radiothérapie externe.Localized oesophageal and gastric cancers have a poor prognosis. In oesophageal cancer, external radiotherapy combined with concomitant chemotherapy is accepted as part of the therapeutic armamentarium in a curative intent in the preoperative setting for resectable tumours; or without surgery in inoperable patients or non-resectable tumours due to wide local and/or regional extension. Data from the literature show conflicting results with no clinical evidence in favour of either a unique dose protocol or consensual target volume definition in the setting of exclusive chemoradiation. In the preoperative setting, chemoradiotherapy has become the standard in oesophageal cancer, even though there is no evidence that surgery may be beneficial in locally advanced tumours that respond to radiotherapy and chemotherapy. The main cause of failure after exclusive chemoradiotherapy in oesophageal cancer is locoregional relapse suggesting that doses and volumes usually considered may be inadequate. In gastric cancer, radiotherapy may be indicated postoperatively in patients with resected tumours that include less than D2 lymph node dissection or in the absence of perioperative chemotherapy. Preoperative chemoradiotherapy in gastric cancers is still under investigation. The evolving techniques of external radiotherapy, such as image-guided radiotherapy (IMRT) and volumetric modulated arctherapy (VMAT) have reduced the volume of lung and heart exposed to radiation, which seems to have diminished radiotherapy-related morbi-mortality rates. Given this, quality assurance for radiotherapy and protocols for radiotherapy delivery must be better standardized. This article on the indications for radiotherapy and the techniques used in oesophageal and gastric cancers is included in a special issue dedicated to national recommendations from the French society of radiation oncology (SFRO) on radiotherapy indications, planning, dose prescription, and techniques of radiotherapy delivery.



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Curiethérapie des cancers de la prostate

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): P. Pommier, S. Guérif, D. Peiffert, G. Créhange, J.-M. Hannoun-Lévi, R. de Crevoisier
Les techniques de curiethérapie prostatique sont décrites, tant concernant les traitements par Iode 125 que par haut débit de dose. Les points suivants sont présentés : indications de curiethérapie, description des techniques, gestion postopératoire immédiate et évaluation post-thérapeutique et enfin, évaluation 4 à 6 semaines après la curiethérapie prostatique et modalités de suivi à long terme.Prostate brachytherapy techniques are described, concerning both Iodine 125 high dose rate brachytherapy. The following parts are presented: brachytherapy indications, technical description, immediate postoperative management and post-treatment evaluation, and 4 to 6 weeks as well as long-term follow-up.



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Radiothérapie des tumeurs intracrâniennes bénignes

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): M. Delannes, I. Latorzeff, M.E. Chand, A. Huchet, C. Dupin, P. Colin
Les tumeurs bénignes intracrâniennes sont essentiellement représentées par les méningiomes, les schwannomes vestibulaires, les adénomes hypophysaires, les craniopharyngiomes et les paragangliomes. Certaines d'entre elles sont à croissance lente et peuvent bénéficier d'une simple surveillance clinique et radiologique, en particulier si elles sont de découverte fortuite. En présence de symptômes, ou en cas d'évolution avérée, le traitement de référence est chirurgical, compte tenu de leur bénignité. La radiothérapie peut être proposée comme une alternative à la chirurgie en cas de localisation en zone fonctionnelle, de contre-indication d'ordre général, ou en complément de celle-ci s'il existe un résidu évolutif ou une récidive. Les indications doivent être posées en réunion de concertation pluridisciplinaire, après évaluation précise du rapport bénéfice-risque. Les techniques d'irradiation utilisées doivent faire appel aux modalités les plus actuelles de radiothérapie, avec l'utilisation de l'imagerie multimodalités, de la radiothérapie guidée par l'image. Elles font une large place à la stéréotaxie, soit fractionnée, soit en dose unique en fonction de la taille et de la topographie de la lésion, dans l'objectif de limiter le plus possible les risques de toxicité tardive.Most of the benign intracranial tumors are meningiomas, vestibular schwannomas, pituitary adenomas, craniopharyngiomas, and glomus tumors. Some of them grow very slowly, and can be observed without specific treatment, especially if they are asymptomatic. Symptomatic or growing tumors are treated by surgery, which is the reference treatment. When surgery is not possible, due to the location of the lesion, or general conditions, radiotherapy can be applied, as it is if there is a postoperative growing residual tumor, or a local relapse. Indications have to be discussed in polydisciplinary meetings, with precise evaluation of the benefit and risks of the treatments. The techniques to be used are the most modern ones, as multimodal imaging and image-guided radiation therapy. Stereotactic treatments, using fractionated or single doses depending on the size or the location of the tumors, are commonly realized, to avoid as much a possible the occurrence of late side effects.



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Radiothérapie des cancers du pancréas

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): F. Huguet, F. Mornex, A. Orthuon
La place de la radiothérapie chez les patients atteints de cancer du pancréas opérable ou localement évolué est actuellement controversée. En situation adjuvante, le traitement standard est une chimiothérapie par gemcitabine et capécitabine pendant six mois. En association avec une chimiothérapie concomitante, la radiothérapie postopératoire permettrait d'améliorer la probabilité de survie des patients après une résection tumorale incomplète (R1). Ceci reste à démontrer dans un essai prospectif. La chimioradiothérapie néoadjuvante est une approche prometteuse de plus en plus utilisée pour les tumeurs à la limite de la résécabilité (borderline). Pour les tumeurs localement évoluées, il n'existe pas de standard thérapeutique. Une chimiothérapie première suivie chez les patients en situation de non progression d'une chimioradiothérapie permet de diminuer le taux de rechute locale. Alors que dans les premiers essais de radiothérapie pancréatique étaient utilisés de grands faisceaux d'irradiation, les volumes traités ont été réduits afin d'améliorer la tolérance. Les mouvements de la tumeur liés à la respiration doivent être pris en compte. La radiothérapie conformationnelle avec modulation d'intensité permet de diminuer les doses reçues par les organes à risque. Bien que de plus en plus utilisée, elle n'est pas encore validée dans cette indication.Currently, the use of radiation therapy for patients with pancreatic cancer is subject to discussion. In adjuvant setting, the standard treatment is 6 months of chemotherapy with gemcitabine and capecitabine. Chemoradiation (CRT) may improve the survival of patients with incompletely resected tumors (R1). This should be confirmed by a prospective trial. Neoadjuvant CRT is a promising treatment especially for patients with borderline resectable tumors. For patients with locally advanced tumors, there is no a standard. An induction chemotherapy followed by CRT for non-progressive patients reduces the rate of local relapse. Whereas in the first trials of CRT large fields were used, the treated volumes have been reduced to improve tolerance. Tumor movements induced by breathing should be taken in account. Intensity modulated radiation therapy allows a reduction of doses to the organs at risk. Whereas widely used, this technique is not recommended.



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Démarches d’amélioration de la qualité et gestion des risques en radiothérapie

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): N. Pourel, C. Meyrieux, B. Perrin
Les démarches d'amélioration continue de la qualité et de la sécurité des soins existent depuis de nombreuses années dans les structures de soins (établissements de santé, centres libéraux). Peu à peu, elles se sont formalisées et structurées. Ce texte de recommandations a pour objectif de décrire l'articulation de la démarche qualité et de la gestion des risques en décrivant sa structuration autour de la politique qualité–sécurité, l'approche processus, la gestion documentaire et la mesure de la qualité. Des outils de gestion des risques tels que la démarche de retour d'expérience, la cartographie des risques a priori et les to-do-list et autres check-list sont donnés en exemple et proposés comme pratiques à recommander.Quality and safety management have been implemented for many years in healthcare structures (hospitals treating cancer, private radiotherapy centres). Their structure and formalization have improved progressively over time. These recommendations aim at describing the link between quality and safety management through its organization scheme based on quality–safety policy, process approach, document management and quality measurement. Dedicated tools, such as experience feedback, a priori risk mapping, to-do-lists and check-lists are shown as examples and recommended as routine practice.



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Radiothérapie des cancers du canal anal

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): D. Peiffert, G. Créhange, V. Vendrely, A.-S. Baumann, J.-C. Faivre, S. Huger
Les indications, doses et techniques de radiothérapie conformationnelle des cancers du canal anal sont présentées. Les recommandations de délinéation des volumes cibles et organes à risque sont détaillées.Indications, doses and techniques of conformal radiotherapy for anal canal cancers are presented. The recommendations for delineation of the target volumes and organs at risk are detailed.



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Metformin use and its effect on survival in diabetic patients with advanced non-small cell lung cancer

Abstract

Background

Previous population-based studies have demonstrated an association between metformin use and improved survival among diabetic patients with cancer. We sought to analyze the effects of diabetes and its treatment in terms of the survival of patients with lung cancer.

Methods

Overall, 1106 patients with non-small cell lung cancer (94.3 % with stage IV disease) were included. The outcomes were compared between the patients with (n = 186) and without diabetes (n = 920). The characteristics associated with antidiabetic treatment and proper glycemic control (defined as a mean plasma glucose <130 mg/dL) were examined at diagnosis. The overall survivals (OSs) of the different patient populations were analyzed using Kaplan-Meier curves, and a multivariate Cox proportional hazard model was used to determine the influences of the patient and tumor characteristics on survival.

Results

The OS for the entire population was 18.3 months (95 % CI 16.1-20.4). There was no difference in the OSs of the diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). The diabetic patients taking metformin exhibited a superior OS than did those on other antidiabetic treatments (25.6 vs 13.2 months, p = 0.017). Those with proper glycemic control had a better OS than did those without proper glycemic control and the non-diabetics (40.5 vs 13.2 and 18.5 months, respectively, p < 0.001). Both the use of metformin (HR 0.53, p < 0.0001 and HR 0.57, p = 0.017, respectively) and proper glycemic control (HR 0.49, p < 0.0001 and HR 0.40, p = 0.002, respectively) were significant protective factors in all and only diabetic patients, respectively.

Conclusions

The diabetic patients with proper glycemic control exhibited a better OS than did those without proper glycemic control and even exhibited a better OS than did the patients without diabetes mellitus. Metformin use was independently associated with a better OS.

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Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner

Abstract

Background

Overexpression the KCNJ3, a gene that encodes subunit 1 of G-protein activated inwardly rectifying K⁺ channel (GIRK1) in the primary tumor has been found to be associated with reduced survival times and increased lymph node metastasis in breast cancer patients.

Methods

In order to survey possible tumorigenic properties of GIRK1 overexpression, a range of malignant mammary epithelial cells, based on the MCF-7 cell line that permanently overexpress different splice variants of the KCNJ3 gene (GIRK1a, GIRK1c, GIRK1d and as a control, eYFP) were produced. Subsequently, selected cardinal neoplasia associated cellular parameters were assessed and compared.

Results

Adhesion to fibronectin coated surface as well as cell proliferation remained unaffected. Other vital parameters intimately linked to malignancy, i.e. wound healing, chemoinvasion, cellular velocities / motilities and angiogenesis were massively affected by GIRK1 overexpression. Overexpression of different GIRK1 splice variants exerted differential actions. While GIRK1a and GIRK1c overexpression reinforced the affected parameters towards malignancy, overexpression of GIRK1d resulted in the opposite. Single channel recording using the patch clamp technique revealed functional GIRK channels in the plasma membrane of MCF-7 cells albeit at very low frequency.

Discussion

We conclude that GIRK1d acts as a dominant negative constituent of functional GIRK complexes present in the plasma membrane of MCF-7 cells, while overexpression of GIRK1a and GIRK1c augmented their activity. The core component responsible for the cancerogenic action of GIRK1 is apparently presented by a segment comprising aminoacids 235–402, that is present exclusively in GIRK1a and GIRK1c, but not GIRK1d (positions according to GIRK1a primary structure).

Conclusions

The current study provides insight into the cellular and molecular consequences of KCNJ3 overexpression in breast cancer cells and the mechanism upon clinical outcome in patients suffering from breast cancer.

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Metabolic complete response with vinflunine as second-line therapy in a kidney-transplanted patient with advanced urothelial carcinoma: a case report

Abstract

Background

Patients undergone kidney transplantation present higher risk of Urothelial Carcinoma (UC) development and represent a subgroup of special interest. To date, vinflunine is the only drug approved in Europe for the treatment of advanced UC after failure of platinum-based chemotherapy. However, to our knowledge, no data on the concomitant administration of vinflunine and immunosuppressive agents are available.

Case presentation

The patient, a 45 years old Caucasian male, presented poorly differentiated UC of the bladder recurred after initial cystectomy with abdominal lymphadenopathies evidenced by FDG-PET/CT. Previously, at the age of 22, he had post-glomerulonephritis renal failure and underwent kidney transplantation from deceased donor. Since then, he has been in treatment with immunosuppressive therapy. At the time of UC recurrence, he was on treatment with cyclosporine. After progression to platinum-based chemotherapy, he received second-line therapy with vinflunine resulting in a complete metabolic response after two cycles. However, despite several dose reductions, the patient experienced severe hematologic toxicity. The pharmacological interaction between vinflunine and cyclosporine, both metabolized by CYP 3A4, may explain the excellent result and the concomitant severe toxicity.

Conclusions

Vinflunine is active on UC developed in kidney transplanted patients. However, special attention should be paid to concomitant administration with immunosuppressive agents that could result in increased toxicity.

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A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report

Abstract

Background

Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula.

Case presentation

A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16^INK4A, D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators.

Conclusions

In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

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A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib

Abstract

Background

Conjunctival malignant melanoma (CMM) is a rare malignancy and in the advanced setting there is no effective treatment. In contrast, half of cutaneous melanomas have BRAF mutations and treatment with BRAF inhibitors is established for patients with disseminated disease. The most common form of ocular melanoma, uveal melanoma, lacks these mutations, however, their presence has been reported for CMM.

Case presentation

We used the BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from a BRAF^V600E mutated metastatic CMM. The patient benefited from the treatment, a response was evident within a week and she experienced a progression free survival of four months.

Conclusions

To our knowledge, this is the first described case of response to vemurafenib treatment in a patient with ocular melanoma.

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Gd-EOB-DTPA-enhanced magnetic resonance imaging combined with T1 mapping predicts the degree of differentiation in hepatocellular carcinoma

Abstract

Background

Variable degrees of differentiation in hepatocellular carcinoma(HCC)under Edmondson-Steiner grading system has been proven to be an independent prognostic indicator for HCC. Up till now, there has been no effective radiological method that can reveal the degree of differentiation in HCC before surgery. This paper aims to evaluate the use of Gd-EOB-DTPA-Enhanced Magnetic Resonance Imaging combined with T1 mapping for the diagnosis of HCC and assessing its degree of differentiation.

Methods

Forty-four patients with 53 pathologically proven HCC had undergone Gd-EOB-DTPA enhanced MRI with T1 mapping before surgery. Out of the 53 lesions,13 were grade I, 27 were gradeII, and 13 were grade III. The T1 values of each lesion were measured before and at 20 min after Gd-EOB-DTPA administration (T1p and T1e). The absolute reduction in T1 value (T1d) and the percentage reduction (T1d %) were calculated. The one-way ANOVA and Pearson correlation were used for comparisons between the T1 mapping values.

Results

The T1d and T1d % of grade I, II and III of HCC was 660.5 ± 422.8ms、295.0 ± 99.6ms、276.2 ± 95.0ms and 54.0 ± 12.2 %、31.5 ± 6.9 %、27.7 ± 6.7 % respectively. The differences between grade Iand II, grade Iand III were statistically significant (p < 0.05), but there was no statically significant difference between grade II and III. The T1d % was the best marker for grading of HCC, with a Spearman correlation coefficient of −0.676.

Conclusions

T1 mapping before and after Gd-EOB-DTPA administration can predict degree of differentiation in HCC.

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Young patients and gastrointestinal (GI) tract malignancies - are we addressing the unmet needs?

Abstract

Background

Recent epidemiological studies indicate the rate of gastrointestinal (GI) malignancies among younger patients is increasing, mainly due to colorectal cancer. There is a paucity of data regarding the magnitude of treatment-related symptoms, psychosocial issues and potential unmet needs in this population. We aimed to characterize the needs of this population to evaluate whether unmet needs could be targeted by potential intervention.

Methods

Female and male patients diagnosed with cancer of the gastrointestinal tract <40y retrospectively completed a questionnaire to evaluate symptoms, daily function and unmet needs at pre-treatment, during and post-treatment. Comparisons were made by gender, disease stage and treatment modality. Multiple linear regression models evaluated effects of demographics, symptoms and needs on multiple domains of health-related-quality-of-life (using Short-Form Health Survey-12 and CARES).

Results

Fifty patients were enrolled (52 % female) to a pilot study. Median age at diagnosis was 35.5y (range, 21-40y). The symptoms that significantly increased from baseline to during and post-treatment were: diarrhea (37 %), sleeping disorder (32 %) and sexual dysfunction (40 %). Patients also reported significant deterioration in occupational activities and coping with children compared with baseline. Female patients reported significant unmet need for nutritional counseling and psychosocial support compared to male patients (p < 0.05). Patients treated with multimodality-treatment presented higher rates of unmet needs (p = 0.03).

Conclusions

Young patients with GI cancers represent a group with unique characteristics and needs compared with published evidence on other young-onset malignancies. The distinctive symptoms and areas of treatment-related functional impairments indicate there are unmet needs, especially in the area of psychosocial support and nutritional counseling.

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IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis

Abstract

Background

High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs.

Methods

In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols.

Results

It is shown that pre-treatment of SMAC-mimetics followed by their combined treatment with BRAF inhibitors can decrease cell viability, migration and can very efficiently sensitize colorectal tumour cells to apoptosis. Moreover, co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize resistant tumour cells to apoptosis synergistically, as shown by median effect analysis. Finally, Birinapant and AT-406 can synergise with BCL-2 inhibitor ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression.

Conclusions

Proposed synergistic rational anticancer combined protocols of IAP antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further exploited in vivo, from precision tumour biology to precision medical oncology.

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Which is better for gastric cancer patients, perioperative or adjuvant chemotherapy: a meta-analysis

Abstract

Background

The preferred chemotherapy method for gastric cancer continues to be matter of debate. We performed a meta-analysis to comparing prognosis and safety between perioperative chemotherapy and adjuvant chemotherapy to identify the better chemotherapy option for gastric cancer.

Methods

We searched the PubMed, EMBASE, Cochrane Library, and Ovid databases for eligible studies until February 2016. The main endpoints were prognostic value (hazard ratio [HR] for overall survival [OS] and 1-, 2-, 3-, and 5-year survival rate), response rate of chemotherapy, radical resection rate, post-operative complication rate, and adverse effects of chemotherapy.

Results

Five randomized controlled trials and six clinical controlled trials involving 1,240 patients were eligible for analysis. Compared with the adjuvant chemotherapy group, the perioperative chemotherapy group had significantly better prognosis (HR, 0.74; 95 % CI, 0.61 to 0.89; P < 0.01). The difference between the two groups remained significant in the studies that used combination chemotherapy as the neoadjuvant chemotherapy regimen (HR, 0.59; 95 % CI, 0.46 to 0.76; P < 0.01) but were not significant in the studies that used fluoropyrimidine monotherapy (HR, 0.93; 95 % CI, 0.56 to 1.55; P = 0.84). Furthermore, the two groups showed no significant differences in the post-operative complication rates (relative risk, 0.98; 95 % CI, 0.63 to 1.51; P = 0.91) or adverse effects of chemotherapy (P > 0.05 for all adverse effects).

Conclusion

Perioperative chemotherapy showed improved survival compared to adjuvant chemotherapy for gastric cancer. In addition, combination chemotherapy resulted in better survival compared to monotherapy in the neoadjuvant chemotherapy regimens.

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PNA clamping-assisted fluorescence melting curve analysis for detecting EGFR and KRAS mutations in the circulating tumor DNA of patients with advanced non-small cell lung cancer

Abstract

Background

Circulating cell-free DNA (cfDNA) is emerging as a surrogate sample type for mutation analyses. To improve the clinical utility of cfDNA, we developed a sensitive peptide nucleic acid (PNA)-based method for analyzing EGFR and KRAS mutations in the plasma cfDNA of patients with advanced non-small cell lung cancer (NSCLC).

Methods

Baseline tissue and plasma samples were collected from treatment-naïve advanced NSCLC patients participated in a randomized phase II study, which was registered with ClinicalTrials.gov at Feb. 2009 (NCT01003964). EGFR and KRAS mutations in the plasma cfDNA were analyzed retrospectively using a PNA clamping-assisted fluorescence melting curve analysis. The results were compared with those obtained from tissue analysis performed using the direct sequencing. Exploratory analyses were performed to determine survival predicted by the plasma and tissue mutation status.

Results

Mutation analyses in matched tissue and plasma samples were available for 194 patients for EGFR and 135 patients for KRAS. The mutation concordance rates were 82.0 % (95 % confidence interval [CI], 76.5–87.4) for EGFR and 85.9 % (95 % CI, 80.1–91.8) for KRAS. The plasma EGFR mutation test sensitivity and specificity were 66.7 % (95 % CI, 60.0–73.3) and 87.4 % (95 % CI, 82.7–92.1), respectively, and the plasma KRAS mutation test sensitivity and specificity were 50.0 % (95 % CI, 41.6–58.4) and 89.4 % (95 % CI, 84.2–94.6), respectively. The predictive value of the plasma EGFR and KRAS mutation status with respect to survival was comparable with that of the tissue mutation status.

Conclusions

These data suggest that plasma EGFR and KRAS mutations can be analyzed using PNA-based real-time PCR methods and used as an alternative to tumor genotyping for NSCLC patients when tumor tissue is not available.

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Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma

Abstract

Background

Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC).

Methods

We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes.

Results

We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS.

Conclusions

PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer.

Trial registration

The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010).

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Free-range apps

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Issue Information

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Gynecologic cytology in Cancer Cytopathology: 20 years of massive change

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In This Issue

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Issue Information

Cover of this issue. Crystal structure of the kinase domain of EGFR. See also Banno, et al. (pages 1134–1140 of this issue).

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The effect of purification of Ga-68-labeled exendin on in vivo distribution

Abstract

Background

Ga-labeled radiotracers are increasingly used for PET imaging. During the labeling procedure, formation of ⁶⁸Ga-colloid may occur. Upon i.v. injection, ⁶⁸Ga-colloid will accumulate rapidly in the liver, spleen, and bone marrow, resulting in reduced target-to-background ratios. In this study, we applied a thin layer chromatography (TLC) method to measure colloid content and we studied the effect of the purification method on the in vivo characteristics of ⁶⁸Ga-labeled DOTA-exendin-3.

DOTA-exendin-3 was labeled with ⁶⁸Ga, and the colloid content was measured by TLC on silica gel ITLC with two mobile phases. The labeling mixture was purified by gel filtration on a 5-ml G25M column, by reversed-phase high-performance liquid chromatography (RP-HPLC) using a C₈ column or by solid phase extraction (SPE) on an HLB cartridge. The in vivo characteristics of the preparations were determined in BALB/c nude mice, and PET images were acquired 1 h p.i. using a microPET scanner. In these studies, unpurified ⁶⁸Ga-DOTA-exendin-3 and ¹¹¹In-DOTA-exendin-3 were used as a reference.

Results

The colloid content of ¹¹¹In-DOTA-exendin-3 and unpurified, gel filtration, RP-HPLC- and SPE-purified ⁶⁸Ga-DOTA exendin-3 was <3, 7, 9, <3, and <3 %, respectively. Unpurified ⁶⁸Ga-DOTA exendin-3 showed high liver and spleen uptake. Gel filtration partly removed ⁶⁸Ga-colloid from the preparation, resulting in moderate liver and spleen SPE-purified ⁶⁸Ga-DOTA exendin-3 showed very low liver and spleen uptake, that was similar to that of RP-HPLC purified ⁶⁸Ga-DOTA exendin-3.

Conclusions

We showed that the colloid content can be measured by TLC and that solid phase extraction and HPLC completely remove ⁶⁸Ga-colloid from ⁶⁸Ga-labeled tracer preparations, resulting in very low liver and spleen uptake. This study clearly shows the importance of removal of ⁶⁸Ga-colloid from preparations.

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Simple Predictive Model for Identifying Patients with Chronic Hepatitis C and Hepatitis C Virus Genotype 4 Infection with a High Probability of Sustained Virologic Response with Peginterferon Alfa-2a/Ribavirin: Pooled Analysis of Data from Two Large, International Cohort Studies

Abstract

Introduction

Wherever access to direct-acting antiviral agents is restricted, dual peginterferon/ribavirin (PegIFN/RBV) therapy remains an option for treatment of hepatitis C virus (HCV) genotype 4 (GT4) infection, which predominates in the Middle East and Sub-Saharan Africa. Our goal was to develop a baseline scoring system to identify GT4-infected patients with a low or high probability of achieving a sustained virologic response (SVR) with PegIFN alfa-2a/RBV using data from two large cohort studies.

Methods

Associations between baseline characteristics and SVR were explored by generalized additive models and multiple logistic regression analysis to develop a predictive model, which was then checked by bootstrapping. The score comprised four factors with points assigned thus: age ≤40, 3 points; >40 but ≤55, 2 points; alanine aminotransferase ≤1 or >3× the upper limit of normal, 1 point; no cirrhosis, 1 point; HCV RNA <50,000 IU/mL, 2 points; 50,000 to <400,000 IU/mL, 1 point. The values for a given patient are summed to produce a score from 0 to 7 where higher scores indicate higher chances of SVR.

Results

Among the 459 patients, 28 (6%), 50 (11%), 92 (20%), 121 (26%), 103 (22%), and 65 (14%) patients had scores of 0–1, 2, 3, 4, 5, and 6–7, respectively, with respective SVR rates of 11%, 28%, 50%, 57%, 63%, and 83%. Relapse rates decreased with increasing prediction score (80%, 39%, 15%, 19%, 5%, and 7%, respectively). SVR rates were consistently higher in Caucasian than Black patients and in patients with a rapid virologic response HCV RNA <50 IU/mL at week 4); however, the trend toward higher SVR rates with increasing score remained apparent in each subgroup.

Conclusion

In conclusion, a simple scoring system can be used to identify GT4-infected patients with a high probability of achieving an SVR with PegIFN alfa-2a/RBV.

Funding

F. Hoffmann-La Roche Ltd.

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Assessment of sites of marrow and extramedullary hematopoiesis by hybrid imaging in primary myelofibrosis patients

Abstract

We investigated noninvasive procedures by hybrid imaging to assess the sites of active or inactive hematopoiesis in patients with primary myelofibrosis (PMF). To this end, we used two radionuclides, technetium 99m (^99mTc) and indium 111-chloride (¹¹¹In-Cl₃), coupled with single-photon emission tomography/computed tomography (SPECT/CT). We studied five patients with PMF and one with secondary myelofibrosis (MF). The classical pattern of lower fixation of both tracers at the axial skeleton where the myelofibrotic process occurs and the reactivation of sites of active hematopoiesis at the distal skeleton were confirmed. Coupling both radionuclides to SPECT/CT imaging allowed for more precise visualization of the sites of extramedullary hematopoiesis as those observed in the spleen and liver. Splenic high uptake of ¹¹¹In-Cl₃ coupled with SPECT/CT represents a pathognomonic feature of PMF. We conclude that, the hybrid imaging procedures that we studied might constitute an alternative noninvasive method for the screening of the whole-body marrow and, by this way, to assess the impact of targeted therapies in PMF patients in whom it is well known that the distribution of the hematopoietic active areas is disturbed. Hybrid imaging could also be useful for diagnostic purposes in cases of early PMF or in suspected cases of myelofibrosis secondary to polycythemia vera or essential thrombocythemia.

Hybrid imaging procedures coupling radionuclides to single-photon emission tomography/computed tomography allow a good evaluation of the extent and intensity of the sites of active/inactive hematopoiesis in primary or secondary myelofibrosis patients. This procedure can also be useful in challenging differential diagnosis cases of myeloproliferative neoplasms or when a myelofibrotic transformation of essential thrombocytemia or polycythemia vera is suspected.

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Prostate cancer outcomes of men with biopsy Gleason score 6 and 7 without cribriform or intraductal carcinoma

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Charlotte F. Kweldam, Intan P. Kümmerlin, Daan Nieboer, Esther I. Verhoef, Ewout W. Steyerberg, Luca Incrocci, Chris H. Bangma, Theodorus H. van der Kwast, Monique J. Roobol, Geert J. van Leenders
Aim of the studyGleason score (GS) 3 + 4 = 7 prostate cancer patients with presence of cribriform or intraductal carcinoma (7⁺) have a worse disease-specific survival than those without. The aim of this study was to compare the clinicopathologic characteristics and patient outcomes of men with biopsy GS 3 + 4 = 7 without cribriform or intraductal carcinoma (7^–) to those with GS 3 + 3 = 6.Materials and methodsWe included all patients from the first screening round of the European Randomized Study of Screening for Prostate Cancer (1993–2000) with a revised GS ≤ 3 + 4 = 7 (n = 796) following the 2014 International Society of Urological Pathology criteria. Relations with biochemical recurrence after radical prostatectomy or radiotherapy were analysed using log-rank testing and multivariable Cox regression analysis.ResultsIn total, 486 patients had GS 6 and 310 had GS 7, 54 of whom had GS 7⁺ (17%). During a median follow-up of 15 years, biochemical recurrence was seen in 61 (20%) GS 6, 54 (21%) GS 7^– and 22 (41%) GS 7⁺ patients (41%). Both biopsy GS 7^– and 7⁺ patients had significantly higher prostate-specific antigen levels, mean tumour percentage, percentage of positive cores and ≥cT3 than those with GS 6 (all P < .001). GS 7^– patients did not have a poorer biochemical recurrence-free survival (BCRFS) after radical prostatectomy than GS 6 patients (log-rank P = .13), whereas those with GS 7⁺ had (log-rank P = .05). In multivariable analyses, biopsy GS 7^– was not associated with poorer BCRFS after radical prostatectomy (hazard ratio [HR], 1.3; 95% confidence interval [CI]: 0.67–2.4; P = .47) or radiotherapy (HR, 0.88; 95% CI: 0.51–1.5; P = .63). GS 7⁺ was independently associated with poorer BCRFS after radical prostatectomy (HR, 3.0; 95% CI: 1.1–7.8; P = .03), but not after radiotherapy (HR, 1.2; 95% CI: 0.58–2.3; P = .67).ConclusionsMen with biopsy GS 7^– prostate cancer have similar BCRFS after radical prostatectomy or radiotherapy to those with GS 6 and may be candidates for active surveillance as long as other inclusion criteria such as on PSA and tumour volume are met.



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Tissue inhibitor of metalloproteinase-3 (TIMP3) expression decreases during melanoma progression and inhibits melanoma cell migration

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Asha M. Das, Michiel Bolkestein, Thom van der Klok, Charlotte M.C. Oude Ophuis, Cindy E. Vermeulen, Joost A.P. Rens, Winand N.M. Dinjens, Peggy N. Atmodimedjo, Cornelis Verhoef, Senada Koljenović, Ron Smits, Timo L.M. ten Hagen, Alexander M.M. Eggermont
AimsMalignant melanoma is the most aggressive form of skin cancer, and metastatic dissemination to regional and visceral sites is responsible for the majority of melanoma-related mortalities. In a recent study by our group, we observed reduced expression of tissue inhibitor of metalloproteinase-3 (TIMP3) in the majority of stage III melanoma samples studied. TIMP3 has been reported as a tumour suppressor in several human malignancies, with reduced expression correlating with poor clinical outcome. In this study, we investigated the changes in TIMP3 expression during melanoma progression.Patients and methodsTIMP3 expression was analysed by immunohistochemistry in sequential archived tumour material from stage I/II, stage III and stage IV samples from melanoma patients (n = 33). Protein expression was investigated for associations with disease-free survival and overall survival. Methylation status of the gene promoter was determined using methylation-specific PCR. In vitro assays were used to investigate the functional consequences of TIMP3 expression on behavioural aspects of melanoma cells.ResultsWe show that TIMP3 expression decreases with melanoma progression although no significant clinical associations were obtained. Analysis of the status of promoter methylation using methylation-specific PCR revealed it to be a low-frequency event in melanoma. Additionally, through gene modulation experiments in melanoma cell lines, we show that TIMP3 negatively regulates cell migration, invasion and anoikis resistance.ConclusionsCollectively, our data suggests that TIMP3 functions as a tumour suppressor in melanoma and negatively regulates several aspects of the metastatic cascade.



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Sunitinib uptake inhibits platelet function in cancer patients

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Siamack Sabrkhany, Arjan W. Griffioen, Sharo Pineda, Linda Sanders, Nadine Mattheij, Johanna P. van Geffen, Maureen J. Aarts, Johan W.M. Heemskerk, Mirjam G.A. oude Egbrink, Marijke J.E. Kuijpers
BackgroundSunitinib is an oral tyrosine kinase inhibitor used for cancer treatment. Patients treated with sunitinib are at higher bleeding risk. As tyrosine kinases are essential for platelet signalling, the effects of sunitinib on platelet function in vitro and in cancer patients on treatment were investigated.Patients and methodsBlood samples were collected from eight healthy volunteers and eight patients diagnosed with metastatic renal cell cancer (RCC) before and 2 weeks on treatment with sunitinib. Platelets from 15 additional healthy individuals were preincubated with sunitinib or vehicle to perform in vitro experiments. Immunofluorescence imaging, western blotting, light transmission aggregometry, whole blood perfusion over collagen, flow cytometry and ELISA were performed.ResultsConfocal microscopy indicated that platelets sequester sunitinib in vitro and in patients. In platelets from healthy controls, tyrosine phosphorylation was inhibited by sunitinib. Also, sunitinib dose dependently reduced collagen- and ADP-induced aggregation, collagen-dependent thrombus formation and collagen-induced secretion of platelet-derived growth factor and β-thromboglobulin. In blood from RCC patients before treatment, thrombus formation and procoagulant activity under flow were 47% and 80% higher than in healthy controls. After 14 d of sunitinib treatment, platelet count was moderately, but significantly decreased (from 243 to 144 × 10⁹/l). At the same time, collagen-induced platelet aggregation as well as thrombus formation and phosphatidylserine exposure under flow were significantly reduced (by 45%, 16% and 61%, respectively).ConclusionsSunitinib uptake by platelets inhibits collagen receptor-induced aggregation and thrombus formation via reduction of protein tyrosine phosphorylation and α-granule secretion. This dysfunction may contribute to the higher bleeding tendency observed in sunitinib-treated patients.



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Publication status of contemporary oncology randomised controlled trials worldwide

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Yu-Pei Chen, Xu Liu, Jia-Wei Lv, Wen-Fei Li, Yuan Zhang, Ying Guo, Ai-Hua Lin, Ying Sun, Yan-Ping Mao, Jun Ma
BackgroundLittle is known about the extent of selective publication in contemporary oncology randomised controlled trials (RCTs) worldwide. This study aimed to evaluate the rates of publication and timely publication (within 24 months) for contemporary oncology RCTs from all over the world. We also investigated the trial characteristics associated with publication and timely publication.Patients and methodsWe identified all phase III oncology RCTs registered on ClinicalTrials.gov with a primary completion date between January 2008 and December 2012. We searched PubMed and EMBASE to identify publications. The final search date was 31 December 2015. Our primary outcome measure was the time to publication from the primary completion date to the date of primary publication in a peer-reviewed journal.ResultsWe identified 598 completed oncology RCTs; overall, 398 (66.6%) had been published. For published trials, the median time to publication was 25 months (interquartile range, 16–37 months). Only 192 trials (32.1%) were published within 24 months. Timely publication was independently associated with trials completed late in 2012. Trials conducted in Asia and other regions were less likely to have timely publication, but trials conducted in different locations were all equally likely to be published. Industry- and NIH-funded trials were equally likely to be published timely or at any time after trial completion. Among 391 published trials with clear primary outcomes, there was a trend for timely publication of positive trials compared with negative trials.ConclusionsDespite the ethical obligations and societal expectations of disclosing findings promptly, oncology RCTs performed poorly.



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Dual-energy compared to single-energy CT in pediatric imaging: a phantom study for DECT clinical guidance

Abstract

Background

Dual-energy CT technology is available on scanners from several vendors and offers significant advantages over classic single-energy CT technology in multiple clinical applications. Many studies have detailed dual-energy CT applications in adults and several have evaluated the relative radiation dose performance of dual-energy CT in adult imaging. However, little has been published on dual-energy CT imaging in the pediatric population, and the relative dose performance of dual-energy CT imaging in the pediatric population is not well described.

Objective

When evaluating dual-energy CT technology for implementation into a routine clinical pediatric imaging practice, the radiation dose implications must be considered, and when comparing relative CT dose performance, image quality must also be evaluated. Therefore the purpose of this study is to develop dual-energy CT scan protocols based on our optimized single-energy scan protocols and compare the dose.

Materials and methods

We scanned the head, chest and abdomen regions of pediatric-size anthropomorphic phantoms with contrast inserts, using our optimized single-energy clinical imaging protocols on a Siemens Flash® CT scanner. We then scanned the phantoms in dual-energy mode using matching image-quality reference settings. The effective CT dose index volume (CTDI_vol) of the scans was used as a surrogate for relative dose in comparing the single- and dual-energy scans. Additionally, we evaluated image quality using visual assessment and contrast-to-noise ratio.

Results

Dual-energy CT scans of the head and abdomen were dose-neutral for all three phantoms. Dual-energy CT scans of the chest showed a relative dose increase over the single-energy scan for 1- and 5-year-old child-based age-equivalent phantoms, ranging 11–20%. Quantitative analysis of image quality showed no statistically significant difference in image quality between the single-energy and dual-energy scans. There was no clinically significant difference in image quality by visual assessment.

Conclusion

Dual-energy CT is dose-neutral in imaging the head and abdomen in children. It is not dose-neutral in chest imaging of very small children. With a better understanding of the dose consequences of converting single-energy protocols to dual-energy protocols we can begin to implement clinical dual-energy CT and utilize its unique capabilities in pediatric imaging.

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The role of MR imaging in investigating isolated pediatric nystagmus

Abstract

Background

The use of MRI in isolated pediatric nystagmus remains a gray area in clinical management. Many clinicians prefer to order an MRI to rule out intracranial pathology despite the lack of clinically significant findings in most cases.

Objective

To assess the yield of MR imaging in isolated pediatric nystagmus and define a management algorithm to minimize avoidable MRI referrals and streamline MRI protocols.

Materials and methods

We reviewed the charts of 148 children who underwent neuro MRI for isolated nystagmus between January 2008 and September 2014. We noted nystagmus onset and clinical characteristics and compared them with the MRI features and visual electrophysiology results.

Results

We included 85 boys and 63 girls (total 148, average age at MRI 4.24 ± 4.19 years). Twenty-three (15.5%) children had abnormal intracranial findings on MRI including abnormal signal lesions (4.1%; n=6), Chiari I malformations (3.4%; n=5) and optic pathway glioma (2.0%; n=3). The time of onset of nystagmus was not associated with an abnormal MRI (P=0.2). Seventy children underwent visual electrophysiology testing but this test could not predict abnormality at MRI, either (P=0.12).

Conclusion

Among children with isolated nystagmus, 15.5% had abnormalities on neuroimaging. Neither clinical characteristics of nystagmus nor the visual electrophysiology results allowed prediction of intracranial pathology. We were unable to formulate a management algorithm for the optimal sequence of investigations (MRI preceding visual electrophysiology or vice versa), but we discuss the use of gadolinium contrast agent and orbital sequences in isolated pediatric nystagmus.

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Economic independence in survivors of cancer diagnosed at a young age: A Norwegian national cohort study

BACKGROUND

The impact of cancer on socioeconomic outcomes is attracting attention as the number of survivors of cancer in young age continues to rise. This study examines economic independence in a national cohort of survivors of cancer at a young age in Norway.

METHODS

Through the linkage of several national registries, the study cohort comprised 1,212,013 individuals born in Norway during 1965 through 1985, of which 5440 had received a cancer diagnosis before age 25 years. Follow-up was through 2007, and the main outcomes were receipt of governmental financial assistance, employment, income, and occupation. Analytic methods included Cox proportional hazard regression, log-binomial regression, and quantile regression models.

RESULTS

Individuals in the cancer survivor group had an increased probability of receiving governmental financial assistance (men: hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.3-1.5; women: HR, 1.5; 95% CI, 1.3-1.6) and of not being employed (men: HR, 1.4; 95% CI, 1.2-1.7; women: HR, 1.4; 95% CI, 1.2-1.6) compared with those in the noncancer group. Income discrepancies were particularly pronounced for survivors of central nervous system tumors. There was no difference in representation in higher skilled occupations.

CONCLUSIONS

Survivors of cancer at a young age in Norway had an increased risk of being economically dependent and unemployed. This was evident in several tumor groups and was most pronounced in female survivors. There were only small differences in income or representation in higher skilled occupations for most employed survivors compared with the noncancer group. The current results are important for understanding the impact of a cancer diagnosis at a young age on subsequent job market outcomes. Cancer 2016. © 2016 American Cancer Society.

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The changing landscape of papillary thyroid cancer: Epidemiology, management, and the implications for patients

The incidence of thyroid cancer has tripled over the past 3 decades, with the vast majority of the increase noted to be among small, indolent papillary thyroid carcinomas. Substantial overdiagnosis and potential overtreatment have led to a shift in clinical practice toward less aggressive approaches and a focus on improved risk stratification. This shift in practice may be associated with recent evidence suggesting that the increase in the incidence of thyroid cancer is slowing. Because patients are often young when they are diagnosed with thyroid cancer and because there is excellent long-term, disease-specific survival, there is an ever-growing population of survivors of thyroid cancer in the United States who accumulate substantial associated health care costs as they undergo surveillance and/or remedial treatment. Survivors of thyroid cancer can experience significant detriments to their quality of life and endure financial hardship. Future research should focus on the appropriateness of treatment as well as the financial and quality-of-life effects of thyroid cancer survivorship. Cancer 2016. © 2016 American Cancer Society.

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Patient function, long-term survival, and use of surgery in patients with kidney cancer

BACKGROUND

Beyond age and comorbidity, functionality can shape the long-term survival potential of patients with cancer. Accordingly, herein the authors compared mortality and receipt of cancer-directed surgery according to patient function among older adults with kidney cancer.

METHODS

Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2000 through 2009, the authors studied 28,326 elderly subjects with primary kidney cancer. Patient function was quantified using function-related indicators, claims indicative of dysfunction and disability. Adjusting for patient and cancer characteristics, competing risk regression was used to assess the relationship between function-related indicator count and cause-specific mortality and then generalized estimating equations were used to quantify the probability of surgery.

RESULTS

A total of 13,619 adult patients (48.1%) with at least 1 function-related indicator were identified. A higher indicator category was associated with older age, greater comorbidity, female sex, unmarried status, lower socioeconomic status, and higher stage of disease (P<.001). Compared with patients with an indicator count of 0, those with an indicator count of 1 (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.04-1.16) and ≥2 (hazard ratio, 1.46; 95% CI, 1.39-1.53) were found to have higher other-cause mortality. Conversely, kidney cancer mortality varied minimally with patient function. Patients with ≥ 2 indicators received cancer-directed surgery less often than those without disability (odds ratio, 0.61; 95% CI, 0.56-0.66), although treatment probabilities remained high for patients with locoregional disease and low for those with metastatic cancer.

CONCLUSIONS

Among older adults with kidney cancer, functional health stands as a significant predictor of long-term survival. However, receipt of cancer-directed surgery appears largely determined by cancer stage. Patient function should be considered more heavily when determining treatment for older adults with kidney cancer. Cancer 2016. © 2016 American Cancer Society.

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Contemporary Trends in Radiation Oncology Resident Research

Publication date: Available online 11 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vivek Verma, Lindsay Burt, Phyllis A. Gimotty, Eric Ojerholm
PurposeMorgan et al established a national benchmark for resident research productivity in the mid-2000s. The present study tested whether contemporary data were significantly different.Methods and MaterialsWe compiled a list of radiation oncology residents from the 2 most recent graduating classes (June 2014 and 2015) using the Association of Residents in Radiation Oncology (ARRO) annual directories. We queried the PubMed database for each resident's first-authored publications from postgraduate years (PGY) 2 through 5, plus a 3-month period after residency completion. We abstracted corresponding historical data for 2002-2007 from the benchmark publication by Morgan et al. We tested the null hypothesis that these two samples had the same distribution for number of publications using the Wilcoxon rank-sum test. We explored the association of demographic factors and publication number using multivariable zero-inflated Poisson regression.ResultsThere were 334 residents publishing 659 eligible first-author publications during residency (range: 0−17; interquartile range: 0−3; mean: 2.0; median: 1). The contemporary and historical distributions were significantly different (P<0.001); contemporary publication rates were higher. Publications accrued late in residency (27% in PGY-4, 59% in PGY-5), and most were original research (75%). In the historical cohort, half of all papers were published in 3 journals; in contrast, the top half of contemporary publications were spread over 10 journals—most commonly International Journal of Radiation Oncology, Biology, Physics (17%), Practical Radiation Oncology (7%), and Radiation Oncology (4%). Male gender, non-PhD status, and larger residency size were associated with higher number of publications in the multivariable analysis.ConclusionWe observed an increase in first-author publications during training compared to historical data from the mid-2000s. These contemporary figures may be useful to medical students considering radiation oncology, current residents, training programs, and prospective employers.

Teaser

We explored contemporary trends in research productivity among U.S. radiation oncology residents. We observed an increase in first-author publications compared to historical data from the mid-2000s. Gender, PhD status, and residency size were associated with number of publications in a multivariable analysis.


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Quality of life and performance status from a sub-study conducted within a prospective phase III randomized trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for locally advanced head and neck carcinoma: NRG Oncology RTOG 0522

Publication date: Available online 12 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Minh Tam Truong, Qiang Zhang, David I. Rosenthal, Marcie List, Rita Axelrod, Eric Sherman, Randal Weber, Phuc Felix Nguyen-Tân, Adel El-Naggar, André Konski, James Galvin, David Schwartz, Andy Trotti, Craig Silverman, Anurag Singh, Karen Godette, James A. Bonner, Christopher U. Jones, Adam S. Garden, George Shenouda, Chance Matthiesen, Quynh-Thu Le, Deborah Bruner
PurposeTo analyze the quality of life (QOL) and performance status (PS) (secondary outcome) of stage III-IV head and neck cancer (HNC) patients enrolled on a prospective randomized phase III trial, comparing radiation-cisplatin without (CIS) or with cetuximab (CET/CIS). The QOL hypothesis proposed a between-arm difference in FACT-H&N-Total score of ≥ 10% of the instrument range from baseline to 1-year.Methods and MaterialsPatients with QOL/PS study consent completed the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), Performance Status Scale for HNC (PSS-HN), and EuroQol (EQ-5D) at baseline through to 5-years. Pretreatment QOL/PS scores were correlated with outcome and p16-status in oropharyngeal cancer (OPC) patients.ResultsOf 818 analyzable patients, the 1-year change from baseline score for FACT-HN-Total was -0.41(CIS arm) and -5.11 (CET/CIS arm) (p=0.016), representing a 3.2% between-arm change of FACT-HN-Total score. Mean EQ-5D-index and PSS-HN scores were not significantly different between arms. P16-positive OPC patients had significantly higher baseline and 1-year scores for PSS-HN, FACT-HN-Total, physical, functional subscales, and 2-years for EQ-5D-index compared to p16-negative OPC patients. Higher pretreatment PSS-HN-diet, PSS-HN-eating, FACT-HN and EQ-5D-index scores were associated with better overall (OS), and progression-free (PFS) survival on multivariate analysis. Higher baseline FACT-HN-Total, functional, physical subscale, and EQ-5D-index scores were associated with improved OS, PFS in p16-positive OPC, but not for p16-negative and non-OPC patients.ConclusionThere was no clinically meaningful difference in QOL/PS between arms. P16-positive OPC patients have significantly higher QOL/PS than p16-negative patients. Pretreatment QOL/PS is a significant independent predictor of outcome in locally advanced HNC.

Teaser

In this prospective randomized study, no differences in quality of life (QOL) and performance status (PS) were found between concurrent accelerated concomitant cisplatin with or without cetuximab. Distinct QOL/PS profiles were found between p16-positive and negative OPC patients. P16-positive OPC patients demonstrated higher baseline and 1-year QOL/PS scores using FACT-HN and PSS-HN, and greater acute PS decline at the end of treatment, compared to p16-negative patients. Pretreatment QOL/PS was independently correlated with survival.


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A comparison of Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) for breast target volume delineation in prone and supine positions

Publication date: Available online 11 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Elise M. Pogson, Geoff P. Delaney, Verity Ahern, Miriam Boxer, Christine Chan, Steven David, Marion Dimigen, Jennifer A. Harvey, Eng-Siew Koh, Karen Lim, George Papadatos, Mei L. Yap, Vikneswary Batumalai, Elizabeth Lazarus, Kylie Dundas, Jesmin Shafiq, Gary Liney, Catherine Moran, Peter Metcalfe, Lois Holloway
Purpose/Objective(s)MRI provides no ionizing radiation dose (allowing inter and intra fraction imaging), improved soft tissue contrast and potentially improved conformity in delineation than CT. This study aimed to determine if T2 weighted magnetic resonance imaging improves seroma cavity (SC) and Whole Breast (WB) inter-observer conformity for radiotherapy purposes compared with the gold standard of CT, both in the prone and supine positions.Methods and MaterialsEleven observers (two Radiologists and nine Radiation Oncologists) delineated SC and WB Clinical Target Volumes (CTVs) on T2-weighted MRI and CT supine and prone scans (4 scans per patient) for 33 patient datasets. Individual observer's volumes were compared using the Dice Similarity Coefficient (DSC), Volume overlap Index (VOI), Centre of Mass (COM) shift and Hausdorff Distances (HD). An average Cavity Visualization Score (CVS) was also determined.ResultsImaging modality did not affect inter-observer variation for WB CTVs. Prone WB CTVs were larger in volume and more conformal than Supine CTVs (on both MRI and CT). SC volumes were larger on CT than MRI. SC volumes proved to be comparable in inter-observer conformity in both modalities (VOI of 0.57±0.03 for CT supine, 0.52±0.04 for MR supine, 0.56±0.03 for CT prone and 0.55±0.04 for MR prone) however after registering modalities together the inter-modality variation (DSC of 0.41±0.05 for supine and 0.38±0.04 for prone) was larger than the inter-observer variability for SC despite the location typically remaining constant.ConclusionsMRI inter-observer variation was comparable to CT for the WB CTV and SC delineation, in both prone and supine positions. Whilst the CVS and inter-observer concordance was not significantly higher for MRI than CT, the SCs were smaller on MRI, potentially due to clearer SC definition, especially on T2-weighted MR images.

Teaser

Inter-observer variation and volume differences in seroma cavity (SC) and Whole Breast (WB) Clinical Target Volumes (CTVs) from MRI and CT images, in prone and supine positions, were compared. Prone WB CTVs were larger and exhibited less inter-observer variation than supine in both imaging modalities. CT SC volumes were significantly larger than MRI in both positions. No clinically significant differences in inter-observer variation were demonstrated between MRI and CT for WB or SC volumes.


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Rapid Development of Omentum Metastasis Following Stereotactic Body Radiotherapy (Sbrt) to Para-Aortic Lymph Nodes from Colon Cancer

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A prognostic model for advanced colorectal neoplasia recurrence

Abstract

Purpose

Following colonoscopic polypectomy, US Multisociety Task Force (USMSTF) guidelines stratify patients based on risk of subsequent advanced neoplasia (AN) using number, size, and histology of resected polyps, but have only moderate sensitivity and specificity. We hypothesized that a state-of-the-art statistical prediction model might improve identification of patients at high risk of future AN and address these challenges.

Methods

Data were pooled from seven prospective studies which had follow-up ascertainment of metachronous AN within 3–5 years of baseline polypectomy (combined n = 8,228). Pooled data were randomly split into training (n = 5,483) and validation (n = 2,745) sets. A prognostic model was developed using best practices. Two risk cut-points were identified in the training data which achieved a 10 percentage point improvement in sensitivity and specificity, respectively, over current USMSTF guidelines. Clinical benefit of USMSTF versus model-based risk stratification was then estimated using validation data.

Results

The final model included polyp location, prior polyp history, patient age, and number, size and histology of resected polyps. The first risk cut-point improved sensitivity but with loss of specificity. The second risk cut-point improved specificity without loss of sensitivity (specificity 46.2 % model vs. 42.1 % guidelines, p < 0.001; sensitivity 75.8 % model vs. 74.0 % guidelines, p = 0.64). Estimated AUC was 65 % (95 % CI: 62–69 %).

Conclusion

This model-based approach allows flexibility in trading sensitivity and specificity, which can optimize colonoscopy over- versus underuse rates. Only modest improvements in prognostic power are possible using currently available clinical data. Research considering additional factors such as adenoma detection rate for risk prediction appears warranted.

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Population mixing and incidence of cancers in adolescents and young adults between 1990 and 2013 in Yorkshire, UK

Abstract

Purpose

Epidemiological evidence suggests a role for an infectious etiology for cancers in teenagers and young adults (TYAs). We investigated this by describing associations between infection transmission using the population mixing (PM) proxy and incidence of cancers in TYAs in Yorkshire, UK.

Methods

We extracted cancer cases from the Yorkshire Specialist Register of Cancer in Children and Young People from 1990 to 2013 (n = 1929). Using multivariable Poisson regression models (adjusting for effects of deprivation and population density), we investigated whether PM was associated with cancer incidence. We included population mixing–population density interaction terms to examine for differences in effects of PM in urban and rural populations.

Results

Nonsignificant IRRs were observed for leukemias (IRR 1.20, 95% CI 0.91–1.59), lymphomas (IRR 1.09, 95% CI 0.90–1.32), central nervous system tumors (IRR 1.06, 95% CI 0.80–1.40) and germ cell tumors (IRR 1.14, 95% CI 0.92–1.41). The association between PM and cancer incidence did not vary in urban and rural areas.

Conclusions

Study results suggest PM is not associated with incidence of cancers among TYAs. This effect does not differ between rural and urban settings.

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Integrating Collaborative Learning and Competition in a Hematology/Oncology Training Program

Abstract

New educational methods and structures to improve medical education are needed to face the challenge of an exponential increase and complexity of medical knowledge. Collaborative learning has been increasingly used in education, but its use in medical training programs is in its infancy, and its impact is still unknown; the role of competition in education is more controversial. We introduced these pedagogical methods to the hematology/oncology fellowship program at the University of Arkansas for Medical Sciences to improve attendance and performance at didactic activities and different educational outcomes. One year after the adoption of these methods, the fellowship program has reached many of the expected goals from this intervention without the negative consequences of competition observed in younger learners. The most important conclusion of this project is that collaboration and cross-generational team work provide a healthy and effective learning environment and competition may not add further benefit. Analysis, interpretation, and discussion of our experience are provided. This study was approved by the University of Arkansas for Medical Sciences IRB as a low risk educational intervention not requiring a consent form.

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Mutated NPM1 in combination with overexpression of Meis1 or Hoxa9 is not sufficient to induce acute myeloid leukemia

Abstract

Background

Acute myeloid leukemia (AML) carrying nucleophosmin 1 (NPM1) mutations (NPMc⁺) is regarded as a separate entity of myeloid neoplasms due to its distinct biological and clinical features. However, NPMc⁺ alone displays low leukemogenic activity and cooperating events appear crucial for AML to develop. Dysregulation of homeobox genes, such as HOXA9 and MEIS1, is a common transcriptional signature of NPMc⁺ AML. Furthermore, the pathogenic role for NPMc⁺ in AML remains incompletely understood.

Aim

To elucidate if NPMc⁺ collaborates with Meis1 or Hoxa9 in the evolvement of AML.

Methods

Murine bone marrow cells were genetically engineered to express mutated NPM1 variant A in combination with overexpression of Meis1 or Hoxa9. The capacity of the transduced cells to transform in vitro and to cause leukemia in vivo was then assessed.

Findings and conclusion

There was no synergy between NPMc⁺ and Meis1 or Hoxa9 in causing leukemogenic transformation of murine bone marrow cells, or in inducing AML in a transplantation model. Hence, overexpression of Meis1 or Hoxa9 in combination with NPMc⁺ expression was not sufficient to generate an NPMc⁺ AML mouse model.

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The use of 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kβ/δ inhibitor

Abstract

Background

The phosphatidylinositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and a promising therapeutic target. AZD8186 (AstraZeneca) is a PI3Kβ/δ inhibitor, currently in phase 1 clinical trials. ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) is often used as a biomarker for inhibitors targeting the PI3K axis because of the association of this pathway with glucose metabolism. In this study, we assessed if ¹⁸F-FDG PET could be used as a pharmacodynamic marker to monitor PI3Kβ inhibition by AZD8186, and hence have potential as a clinical biomarker of PI3Kβ pathway activation, and for patient selection. ¹⁸F-FDG PET scans were performed in nude mice bearing 786-0 renal, U87-MG glioma, and BT474C breast xenograft models. Mice were fasted prior to imaging and static ¹⁸F-FDG PET imaging was performed. Tumour growth was monitored throughout each study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis performed.

Results

Results showed that in PTEN null tumour xenograft models, 786-0 and U87-MG, the PI3Kβ inhibitor AZD8186 reduces ¹⁸F-FDG uptake at a dose of 50 mg/kg, the same dose which causes tumour inhibition, while it has no impact in a PI3Kα mutant tumour xenograft BT474C. Consistent with the change in ¹⁸F-FDG uptake, AZD8186 also modulated AKT and associated glucose pathway biomarkers in the PTEN null tumour xenografts but not in PTEN wild-type tumours.

Conclusions

Our pre-clinical studies support the use of ¹⁸F-FDG PET imaging as a sensitive and non-invasive pharmacodynamic biomarker for use in clinical studies with AZD8186.

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Nephroprotective effects of enalapril after [177Lu]-DOTATATE therapy using serial renal scintigraphies in a murine model of radiation-induced nephropathy

Abstract

Background

Radiation-induced nephropathy is still dose limiting in radionuclide therapy of neuroendocrine tumors. We investigated the nephroprotective potential of the angiotensine converting enzyme inhibiting drug enalpril after [177Lu]-DOTATATE therapy in a murine model of radiation-induced nephropathy by renal scintigraphy.

At first, the appropriate therapy activity to induce nephropathy was identified. Baseline scintigraphy (n = 12) entailed 12-min dynamic acquisitions after injection of 25 MBq [99mTc]-MAG3, which was followed by radionuclide therapy at four escalating activities of [177Lu]-DOTATATE: group (Gp) 1: 10 MBq; Gp 2: 20 MBq; Gp 3: 40 MBq; Gp 4: 65 MBq. Follow-up [99mTc]-MAG3 scintigraphy was carried out at days 9, 23, 44, and 65. The treatment activity for the intervention arm was selected on the basis of histological examination and declining renal function. In the second part, daily administration by gavage of 10 mg/kg/d enalapril or water (control group) was initiated on the day of radionuclide therapy. Follow-up scintigraphy was carried out at days 9, 23, 44, 65, and 86. We also created a non-therapy control group to detect therapy-independent changes of renal function over time. For all scintigraphies, mean renogram curves were analyzed and the "fractional uptake rate" (FUR; %I.D./min ± SEM) of the tracer by the kidneys was calculated as an index of renal clearance.

Results

At day 65 of follow-up, no significant change in the FUR relative to baseline (11.0 ± 0.3) was evident in radionuclide therapy groups 1 (11.2 ± 0.5) and 2 (10.1 ± 0.6), but FUR was significantly reduced in groups 3 (8.93 ± 0.6, p < 0.05) and 4 (6.0 ± 0.8, p < 0.01); we chose 40 MBq [177Lu]-DOTATATE (Gp 3) for the intervention study. Here, at the last day of follow-up (day 86), FUR was unaltered in enalapril-treated mice (11.8 ± 0.5) relative to the baseline group (12.4 ± 0.3) and non-therapy group (11.9 ± 0.8), whereas FUR in the control group had undergone a significant decline (9.3 ± 0.5; p < 0.01). Histological examination revealed prevention of kidney damage by enalapril treatment.

Conclusions

Treatment with enalapril is effective for nephroprotection during radionuclide therapy with [177Lu]-DOTATATE in mice. Although these results are only limitedly transferable to human studies, enalapril might serve as a promising drug in the mitigation of nephropathy following treatment with [177Lu]-DOTATATE.

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