Radioterapia intraoperatoria en cáncer de mama en estadio precoz frente a Radioterapia externa: Análisis observacional de resultados clínicos, tumorales, quirúrgicos, oncológicos y complicaciones.

El cáncer de mama es la neoplasia más prevalente en España, además de la principal causa de muerte por tumor en mujeres. El tratamiento en estadios precoces ha evolucionado, siguiendo el axioma “Menos es más”. La mastectomía ha sido sustituida por cirugías conservadoras, menos agresivas, acompañadas de radioterapia externa de toda la mama (RTE).Se ha demostrado que, aproximadamente, el 90% de las recurrencias del cáncer de mama se localizan a 1-2cm del lecho quirúrgico. Es por ello que, en concordancia de esta corriente, se desarrollaron técnicas para irradiar específicamente esa zona de mayor riesgo, lo que se conoce como Irradiación parcial acelerada.La Radioterapia intraoperatoria (RIO) es una de esas técnicas. Durante el mismo acto quirúrgico, se aplica en una única dosis la terapia que puede resultar equivalente a varias sesiones de radioterapia externa en pacientes seleccionadas.Existen diversos aparatos para aplicar la RIO. Entre ellos se encuentra el dispositivo Axxent Xoft, del que, hasta el momento actual, sólo se han descrito sus resultados en series de casos, mayoritariamente unicéntricas. Con este trabajo, se pretende emitir el primer estudio comparativo entre la RIO con este dispositivo y el tratamiento convencional con RTE.La hipótesis de trabajo es que “el tratamiento de Radioterapia intraoperatoria con el dispositivo Axxent Xoft no presenta diferencias en resultados oncológicos, de morbilidad o de mortalidad frente al tratamiento convencional con radioterapia externa en cáncer de mama en estadio precoz”. Los objetivos planteados son, por un lado, describir las características clínicas, tumorales, operatorias, tratamientos adyuvantes, complicaciones y resultados oncológicos de una cohorte de pacientes con cáncer de mama seleccionadas para tratamiento con cirugía conservadora y RIO como monoterapia. Por otro, describir las mismas características de una cohorte retrospectiva de pacientes con cáncer de mama tratadas con cirugía conservadora y RTE, aplicando para su selección los criterios de inclusión de cirugía conservadora y RIO. Se pretende analizar si la cirugía conservadora con RIO empleando el dispositivo Axxent Xoft, presenta unos resultados oncológicos y de morbilidad equiparables a los presentados con cirugía conservadora y RTE en un mismo centro; además de reconocer qué factores pronósticos perioperatorios clínicos, tumorales o terapéuticos han influido en los resultados oncológicos y en la morbilidad a corto y a largo plazo.Para ello, se ha realizado un estudio analítico observacional empleando una cohorte prospectiva de pacientes tratadas con cirugía conservadora y RIO durante el periodo 2015-2017, y una cohorte retrospectiva de pacientes tratadas con cirugía conservadora y RTE durante el periodo 2012-2017. Las pacientes de ambas cohortes fueron evaluadas y tratadas en el Proceso Asistencial de la Mama del Hospital Universitario Miguel Servet (Zaragoza), seleccionadas siguiendo los mismos criterios: edad ≥45 años, biopsia preoperatoria de carcinoma ductal infiltrante o variantes, tamaño tumoral radiológico preoperatorio ≤3cm, presencia de receptores estrogénicos positivos, HER2 negativo y ausencia de afectación ganglionar clínica y radiológica. Se excluyeron aquellas pacientes que, de forma preoperatoria, presentaron invasión linfovascular en la biopsia, multicentricidad/multifocalidad, mutaciones BRCA y tratamiento neoadyuvante.El estudio fue aprobado por el Comité Ético de Investigación Clínica de Aragón (CEICA) en su resolución del 26 de julio de 2017 (Acta Nº14/2017).Se incluyeron 425 casos: 217 tratados con RIO y 208 con radioterapia externa. La edad media en las cohortes RIO y RTE fue de 67±9.5 y 64.8±9.9 años respectivamente (p=0.01). El 17.7% de las pacientes RIO presentó riesgo anestésico ASA 3, frente al 11.5% de RTE (p=0.027). En los resultados anatomopatológicos definitivos, no se registraron diferencias en tipo histológico, focalidad, presencia de receptores hormonales o estadiaje. Las cirugías oncoplásticas alcanzaron el 6.5% en la cohorte RIO frente al 1.9% en RTE (pLas principales conclusiones de este trabajo son: - El uso de Radioterapia intraoperatoria en pacientes con cáncer de mama en estadio precoz no ha presentado diferencias en los resultados oncológicos de recurrencia local, metástasis, mortalidad o supervivencia, en comparación con el tratamiento convencional empleando radioterapia externa. Sin embargo, estos resultados deben ser interpretados con cautela por el menor tiempo de seguimiento de las pacientes tratadas con radioterapia intraoperatoria y el escaso número de eventos ocurridos.- Las pacientes con un menor “ofrecimiento” de radiación adyuvante por mayor edad y mayor número de comorbilidades asociadas, representan un grupo de especial interés en el que la radioterapia intraoperatoria puede jugar un papel fundamental.- Se ha identificado un mayor número de cirugías oncoplásticas en la cohorte radioterapia intraoperatoria, reflejando los beneficios de la combinación de ambas técnicas. - En cuanto a la morbilidad, la radioterapia intraoperatoria ha demostrado ser una técnica segura, sin diferencias en complicaciones graves que requiriesen tratamiento quirúrgico o intravenoso, asociando además menor radiodermitis grave precoz.- La mayor distancia mínima entre balón aplicador y piel, además de un IMC elevado, se relacionaron con menor radiodermitis.- El antibiótico profiláctico no representó una protección frente a la aparición de complicaciones. Su uso sistemático podría no estar indicado.<br /

Minimally-invasive breast interventions : methods for high yield, low risk, precision biopsy and curative thermal ablation

Advances in medical imaging and the introduction of population-based screening programs have increased the detection rate and overall proportion of small breast tumors. In addition, progress in technology and medical science, in combination with efforts to minimize morbidity, have resulted in the emergence of minimally invasive image-guided interventional procedures for both diagnosis and treatment of breast cancer. The aim of this thesis was to develop and validate new technologies for minimally-invasive diagnosis and treatment of breast cancer. Specifically, to develop and validate a new biopsy system incorporating novel mechanisms for needle insertion and tissue acquisition designed for accurate lesion targeting and high yield tissue sampling; to clinically validate a biopsy enhancement technology using radiofrequency (RF) pulses to counteract dissemination of tumor cells; and to improve and validate radiofrequency ablation (RFA) for the treatment of small carcinoma and demonstrate feasibility in non-operable elderly patients. During the course of this work a new biopsy device has been developed which incorporates a pneumatic insertion mechanism combined with a novel needle design. Paper I presented the device, compared sampling performance to a standard core needle biopsy (CNB) device in three representative bench models, measured needle dynamics on a specially designed needle trajectory test and evaluated ex vivo sample quality. Mean weight of samples were 3.5, 4.6, and 4.3 times higher (p <0.01) than standard CNB device in turkey breast, calf thymus and swine pancreas. The method of tissue acquisition had no negative impact on the histopathologic quality of samples obtained from resected specimens. Maximum measured needle velocity was 21.2 ±2.5 m/s on a stroke length of 2.5 mm. Paper II investigated whether a technology incorporating the application of RF pulses to the biopsy needle could counteract dissemination of tumor cells. In this proof-of-principle setting the technology was adapted to fine needle aspiration (FNA) and prospectively used in 31 patients. Eighty-eight patients underwent routine FNA. Blood emerging from the skin orifice was analyzed for the presence of tumor cells. Viable tumor cells were found in 74% (65/88) of cases for routine FNA and in 0% (0/31) of cases (p <0.001) when RF pulses where applied. It was observed that application of RF pulses had a hemostatic effect, did not degrade the cytological sample inside the needle and caused no additional pain compared with standard FNA. In Papers III, IV & V, the technology, method and protocol for RFA in breast cancer were successively developed and evaluated in a total of 55 patients. Specifically, in Paper III the feasibility of a newly developed RF device for ablation of unifocal breast carcinoma <16 mm immediately prior to partial mastectomy was assessed. In 84% (26/31) of cases complete ablation was achieved as assessed by Hematoxylin and Eosin (H&E) staining. Non-complete ablation was associated with incorrect electrode positioning within the lesion and underestimation of lesion extent due to inaccurate preoperative imaging. In Paper IV, tumors ≤20 mm were included and the feasibility under local anesthesia three weeks prior to planned resection using improved technology and protocol was assessed. Magnetic resonance imaging (MRI) was utilized for patient selection. Exclusion criteria included multifocality, diffuse growth patterns, >25% intraductal components and lobular histology. Magnetic resonance imaging, H&E staining and cytokeratine 8 (CK8) immunostaining were used to determine complete ablation. A pneumatic–mechanical insertion mechanism was developed to improve electrode insertion and positioning. Pain was assessed using the Visual Analogue Scale (VAS). In 100% (18/18) of cases MRI showed no residual tumor growth and devitalization of the entire tumor was shown by at least one histologic method. Pain was reported to be a median of 2 and 2.5 for injection of anesthetics and during ablation, respectively, and the difference was not significant (p =0.512). In Paper V the feasibility of RFA as an alternative to surgical resection in elderly breast cancer patients with severe comorbidities that were unfit for or refused surgery was assessed. Six patients aged ≥85 years were included. In all cases, complete ablation was confirmed using MRI and contrast enhanced ultrasound (CEUS) at 1 month as well as staining assays for H&E and CK8 in tissue samples at 6 months. The procedure was well tolerated with mild to moderate pain during the ablation procedure. Follow-up was a median (range) of 54 months (11 to 94 months). Three patients died of non-cancer related causes. Three patients remained alive at 74, 86 and 94 months of which one experienced a loco-regional recurrence at 59 months. In conclusion, this thesis demonstrates that the newly developed biopsy system enables for a novel method of precision needle insertion and achieves high yield tissue sampling. Furthermore, this thesis demonstrates that the presented biopsy enhancement technology can prevent dissemination of tumor cells. Finally, it demonstrates that RF ablation of small breast carcinoma has a high rate of complete ablation, can be performed under local anesthesia with mild to moderate pain, and is feasible as an individualized treatment option in elderly patients with severe co-morbidity who are refusing, or are unfit for surgery

Diagnostic Significance of Exosomal miRNAs in the Plasma of Breast Cancer Patients

Poster Session AbstractsBackground and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for 25% (up-regulation) and 15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis.link_to_OA_fulltex

Développement de nouvelles sondes per-opératoires positon pour guider la chirurgie des tumeurs solides

L exérèse des tumeurs cancéreuses est une procédure courante pour le traitement de nombreux cancers. L enjeu est de réaliser une excision la plus complète possible pour éviter les récidives tout en épargnant le plus possible les tissus sains bordant la tumeur. La détection de positons est une modalité d imagerie particulièrement adaptée au repérage de résidus tumoraux lors de l'éxerèse car sa forte sélectivité spatiale permet de s'affranchir du bruit provenant de la fixation non spécifique du radiotraceur dans les tissus situés en profondeur, offrant ainsi une meilleur sensibilité et un meilleur rapport signal sur bruit que la détection de photons gamma. L utilisation pour le contrôle d exérèse impose cependant une contrainte forte sur les dimensions du détecteur qui doit être manipulable facilement par le chirurgien et pouvoir être inséré dans des plaies opératoires potentiellement étroites. Une nouvelle génération de photodétecteurs appelés photomultiplicateurs silicium (SiPM) est particulièrement adaptée à cette application car ceux-ci allient la compacité et la robustesse des technologies silicium avec d'excellentes performances de détection. Mon travail de thèse porte sur le développement et la caractérisation de nouvelles sondes positon basées sur ces photodétecteurs. Dans un premier temps, un travail de caractérisation des SiPMs a été réalisé pour évaluer leurs performances pour la détection de positons. Deux prototypes de prototypes de détecteurs aux rôles complémentaires ont ensuite été réalisé: le premier est un imageur, basé sur l assemblage de deux scintillateurs avec une ou deux matrices de SiPMs, qui permet de réaliser rapidement l'image de la distribution de traceur sur une large surface de tissus. Le second détecteur est une sonde de comptage, constituée de fibres scintillantes couplées à des SiPMs individuels via des fibres claires et capable d'être couplée à l'outil d'exérèse. Elle permet de guider l'outil du chirurgien vers les tissus repérés préalablement avec l'imageur. La caractérisation de l imageur a montré sa capacité à détecter des résidus tumoraux de petite taille (15mg) avec une résolution submillimétrique. La sonde de comptage présente quant à elle, une efficacité de détection de 80%.Excision of cancerous tumors is a common procedure for the treatment of numerous cancers. The stake is to perform the most complete excision to prevent recurrences while preserving as much as possible surrounding healthy tissues. Positron detection is a well suited imaging modality for detection of tumor remains during excision because its strong spatial selectivity makes it insensitive to the noise coming from the non-specific accumulation of the radiotracer in healthy tissues located far from the detector, leading to a better sensitivity and a better signal-to-noise ratio than gamma photon detection. Its use for the control of excision implies however strong constraints on detector dimensions which must be easy to handle by the surgeon and easy to insert in tight surgical wound. A new generation of photodetectors called Silicon Photmultipliers (SiPMs) is particularly suited for this application because they present the compactness and robustness of silicon technologies and very good detection performances. My thesis aims to develop and characterize a new generation of new positron probes based on these photodetectors. Two prototypes of detectors with complementary roles were realized: the first one is an imaging device based on the assembly of two scintillators with one or two SiPMs arrays which allows to quickly make an image of tracer distribution along a wide surface of tissues. The second detector is a counting probe made of scintillating fibers associated with individual SiPMs through clear optical fibers and can be associated to the excision tool. It guides the surgeon tool to the tissues previously localized with the imaging probe. Characterization of the imaging probe showed its ability to detect small tumor remains (15mg) with a submillimetric resolution. The counting probe showed a detection efficiency of 80%.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Medical-Data-Models.org:A collection of freely available forms (September 2016)

MDM-Portal (Medical Data-Models) is a meta-data repository for creating, analysing, sharing and reusing medical forms, developed by the Institute of Medical Informatics, University of Muenster in Germany. Electronic forms for documentation of patient data are an integral part within the workflow of physicians. A huge amount of data is collected either through routine documentation forms (EHRs) for electronic health records or as case report forms (CRFs) for clinical trials. This raises major scientific challenges for health care, since different health information systems are not necessarily compatible with each other and thus information exchange of structured data is hampered. Software vendors provide a variety of individual documentation forms according to their standard contracts, which function as isolated applications. Furthermore, free availability of those forms is rarely the case. Currently less than 5 % of medical forms are freely accessible. Based on this lack of transparency harmonization of data models in health care is extremely cumbersome, thus work and know-how of completed clinical trials and routine documentation in hospitals are hard to be re-used. The MDM-Portal serves as an infrastructure for academic (non-commercial) medical research to contribute a solution to this problem. It already contains more than 4,000 system-independent forms (CDISC ODM Format, www.cdisc.org, Operational Data Model) with more than 380,000 dataelements. This enables researchers to view, discuss, download and export forms in most common technical formats such as PDF, CSV, Excel, SQL, SPSS, R, etc. A growing user community will lead to a growing database of medical forms. In this matter, we would like to encourage all medical researchers to register and add forms and discuss existing forms

Using Sentinel Technology in the TARGIT BI Suite

This paper demonstrates so-called sentinels in the TARGIT BI Suite. Sentinels are a novel type of rules that can warn a user if one or more measure changes in a multi-dimensional data cube are expected to cause a change to another measure critical to the user. We present the concept of sentinels, and we explain how sentinels represent stronger and more specific rules than sequential patterns and correlation techniques. In addition, we present the algorithm, implementation, and data warehouse setup that are prerequisites for our demo. In the demo we present a dialogue where users, without any prior technical knowledge, are able to select a critical measure, a number of cubes, and a time dimension, and subsequently mine and schedule sentinels for early warnings. 1