Influence of noninjecting and injecting drug use on mortality, retention in the cohort, and antiretroviral therapy, in participants in the Swiss HIV Cohort Study.

OBJECTIVES: We studied the influence of noninjecting and injecting drug use on mortality, dropout rate, and the course of antiretroviral therapy (ART), in the Swiss HIV Cohort Study (SHCS). METHODS: Cohort participants, registered prior to April 2007 and with at least one drug use questionnaire completed until May 2013, were categorized according to their self-reported drug use behaviour. The probabilities of death and dropout were separately analysed using multivariable competing risks proportional hazards regression models with mutual correction for the other endpoint. Furthermore, we describe the influence of drug use on the course of ART. RESULTS: A total of 6529 participants (including 31% women) were followed during 31 215 person-years; 5.1% participants died; 10.5% were lost to follow-up. Among persons with homosexual or heterosexual HIV transmission, noninjecting drug use was associated with higher all-cause mortality [subhazard rate (SHR) 1.73; 95% confidence interval (CI) 1.07-2.83], compared with no drug use. Also, mortality was increased among former injecting drug users (IDUs) who reported noninjecting drug use (SHR 2.34; 95% CI 1.49-3.69). Noninjecting drug use was associated with higher dropout rates. The mean proportion of time with suppressed viral replication was 82.2% in all participants, irrespective of ART status, and 91.2% in those on ART. Drug use lowered adherence, and increased rates of ART change and ART interruptions. Virological failure on ART was more frequent in participants who reported concomitant drug injections while on opiate substitution, and in current IDUs, but not among noninjecting drug users. CONCLUSIONS: Noninjecting drug use and injecting drug use are modifiable risks for death, and they lower retention in a cohort and complicate ART.

Development of a multi-gene PCR assay for the prediction of the response to hormone therapy in breast cancer

Deux tiers des cancers du sein expriment des récepteurs hormonaux ostrogéniques (tumeur ER-positive) et la croissance de ces tumeurs est stimulée par l’estrogène. Des traitements adjuvant avec des anti-estrogènes, tel que le Tamoxifen et les Inhibiteurs de l’Aromatase peuvent améliorer la survie des patientes atteinte de cancer du sein. Toutefois la thérapie hormonale n’est pas efficace dans toutes les tumeurs mammaires ER-positives. Les tumeurs peuvent présenter avec une résistance intrinsèque ou acquise au Tamoxifen. Présentement, c’est impossible de prédire quelle patiente va bénéficier ou non du Tamoxifen. Des études préliminaires du laboratoire de Dr. Mader, ont identifié le niveau d’expression de 20 gènes, qui peuvent prédire la réponse thérapeutique au Tamoxifen (survie sans récidive). Ces marqueurs, identifié en utilisant une analyse bioinformatique de bases de données publiques de profils d’expression des gènes, sont capables de discriminer quelles patientes vont mieux répondre au Tamoxifen. Le but principal de cette étude est de développer un outil de PCR qui peut évaluer le niveau d’expression de ces 20 gènes prédictif et de tester cette signature de 20 gènes dans une étude rétrospective, en utilisant des tumeurs de cancer du sein en bloc de paraffine, de patients avec une histoire médicale connue. Cet outil aurait donc un impact direct dans la pratique clinique. Des traitements futiles pourraient être éviter et l’indentification de tumeurs ER+ avec peu de chance de répondre à un traitement anti-estrogène amélioré. En conséquence, de la recherche plus appropriée pour les tumeurs résistantes au Tamoxifen, pourront se faire.

A "Trojan horse" strategy to reverse drug-resistance in brain tumors

Los gliomas malignos representan una de las formas más agresivas de los tumores del sistema nervioso central (SNC). De acuerdo con la clasificación de los tumores cerebrales de la Organización Mundial de la Salud (OMS), los astrocitomas han sido categorizados en cuatro grados, determinados por la patología subyacente. Es así como los gliomas malignos (o de alto grado) incluyen el glioma anaplásico (grado III) así como el glioblastoma multiforme (GBM, grado IV),estos últimos los más agresivos con el peor pronóstico (1). El manejo terapéutico de los tumores del SNC se basa en la cirugía, la radioterapia y la quimioterapia, dependiendo de las características del tumor, el estadio clínico y la edad (2),(3), sin embargo ninguno de los tratamientos estándar es completamente seguro y compatible con una calidad de vida aceptable (3), (4). En general, la quimioterapia es la primera opción en los tumores diseminados, como el glioblastoma invasivo y el meduloblastoma de alto riesgo o con metástasis múltiple, pero el pronóstico en estos pacientes es muy pobre (2),(3). Solamente nuevas terapias dirigidas (2) como las terapias anti-angiogénicas (4); o terapias génicas muestran un beneficio real en grupos limitados de pacientes con defectos moleculares específicos conocidos (4). De este modo, se hace necesario el desarrollo de nuevas terapias farmacológicas para atacar los tumores cerebrales. Frente a las terapias los gliomas malignos son con frecuencia quimioresistentes, y esta resistencia parece depender de al menos dos mecanismos: en primer lugar, la pobre penetración de muchas drogas anticáncer a través de la barrera hematoencefálica (BBB: Blood Brain Barrier), la barrera del fluido sangre-cerebroespinal (BCSFB: Blood-cerebrospinal fluid barrier) y la barrera sangre-tumor (BTB: blood-tumor barrier). Dicha resistencia se debe a la interacción de la droga con varios transportadores o bombas de eflujo de droga ABC (ABC: ATP-binding cassette) que se sobre expresan en las células endoteliales o epiteliales de estas barreras. En segundo lugar, estos transportadores de eflujo de drogas ABC propios de las células tumorales confieren un fenotipo conocido como resistencia a multidrogas (MDR: multidrug resistance), el cual es característico de varios tumores sólidos. Este fenotipo también está presente en los tumores del SNC y su papel en gliomas es objeto de investigación (5). Por consiguiente el suministro de medicamentos a través de la BBB es uno de los problemas vitales en los tratamientos de terapia dirigida. Estudios recientes han demostrado que algunas moléculas pequeñas utilizadas en estas terapias son sustratos de la glicoproteína P (Pgp: P-gycoprotein), así como también de otras bombas de eflujo como las proteínas relacionadas con la resistencia a multidrogas (MRPs: multidrug resistance-related proteins (MRPs) o la proteína relacionada con cáncer de seno (BCRP: breast-cancer resistance related protein)) que no permiten que las drogas de este tipo alcancen el tumor (1). Un sustrato de Pgp y BCRP es la DOXOrubicina (DOXO), un fármaco utilizado en la terapia anti cáncer, el cual es muy eficaz para atacar las células del tumor cerebral in vitro, pero con un uso clínico limitado por la poca entrega a través de la barrera hematoencefálica (BBB) y por la resistencia propia de los tumores. Por otra parte las células de BBB y las células del tumor cerebral tienen también proteínas superficiales, como el receptor de la lipoproteína de baja densidad (LDLR), que podría utilizarse como blanco terapéutico en BBB y tumores cerebrales. Es asi como la importancia de este estudio se basa en la generación de estrategias terapéuticas que promuevan el paso de las drogas a través de la barrera hematoencefalica y tumoral, y a su vez, se reconozcan mecanismos celulares que induzcan el incremento en la expresión de los transportadores ABC, de manera que puedan ser utilizados como blancos terapéuticos.Este estudio demostró que el uso de una nueva estrategia basada en el “Caballo de Troya”, donde se combina la droga DOXOrubicina, la cual es introducida dentro de un liposoma, salvaguarda la droga de manera que se evita su reconocimiento por parte de los transportadores ABC tanto de la BBB como de las células del tumor. La construcción del liposoma permitió utilizar el receptor LDLR de las células asegurando la entrada a través de la BBB y hacia las células tumorales a través de un proceso de endocitosis. Este mecanismo fue asociado al uso de estatinas o drogas anticolesterol las cuales favorecieron la expresión de LDLR y disminuyeron la actividad de los transportadores ABC por nitración de los mismos, incrementando la eficiencia de nuestro Caballo de Troya. Por consiguiente demostramos que el uso de una nueva estrategia o formulación denominada ApolipoDOXO más el uso de estatinas favorece la administración de fármacos a través de la BBB, venciendo la resistencia del tumor y reduciendo los efectos colaterales dosis dependiente de la DOXOrubicina. Además esta estrategia del "Caballo de Troya", es un nuevo enfoque terapéutico que puede ser considerado como una nueva estrategia para aumentar la eficacia de diferentes fármacos en varios tumores cerebrales y garantiza una alta eficiencia incluso en un medio hipóxico,característico de las células cancerosas, donde la expresión del transportador Pgp se vió aumentada. Teniendo en cuenta la relación entre algunas vías de señalización reconocidas como moduladores de la actividad de Pgp, este estudio presenta no solo la estrategia del Caballo de Troya, sino también otra propuesta terapéutica relacionada con el uso de Temozolomide más DOXOrubicina. Esta estrategia demostró que el temozolomide logra penetrar la BBB por que interviene en la via de señalización de la Wnt/GSK3/β-catenina, la cual modula la expresión del transportador Pgp. Se demostró que el TMZ disminuye la proteína y el mRNA de Wnt3 permitiendo plantear la hipótesis de que la droga al disminuir la transcripción del gen Wnt3 en células de BBB, incrementa la activación de la vía fosforilando la β-catenina y conduciendo a disminuir la β-catenina nuclear y por tanto su unión al promotor del gen mdr1. Con base en los resultados este estudio permitió el reconocimiento de tres mecanismos básicos relacionados con la expresión de los transportadores ABC y asociados a las estrategias empleadas: el primero fue el uso de las estatinas, el cual condujo a la nitración de los transportadores disminuyendo su actividad por la via del factor de transcripción NFκB; el segundo a partir del uso del temozolomide, el cual metila el gen de Wnt3 reduciendo la actividad de la via de señalización de la la β-catenina, disminuyendo la expresión del transportador Pgp. El tercero consistió en la determinación de la relación entre el eje RhoA/RhoA quinasa como un modulador de la via (no canónica) GSK3/β-catenina. Se demostró que la proteína quinasa RhoA promovió la activación de la proteína PTB1, la cual al fosforilar a GSK3 indujo la fosforilación de la β-catenina, lo cual dio lugar a su destrucción por el proteosoma, evitando su unión al promotor del gen mdr1 y por tanto reduciendo su expresión. En conclusión las estrategias propuestas en este trabajo incrementaron la citotoxicidad de las células tumorales al aumentar la permeabilidad no solo de la barrera hematoencefálica, sino también de la propia barrera tumoral. Igualmente, la estrategia del “Caballo de Troya” podría ser útil para la terapia de otras enfermedades asociadas al sistema nervioso central. Por otra parte estos estudios indican que el reconocimiento de mecanismos asociados a la expresión de los transportadores ABC podría constituir una herramienta clave en el desarrollo de nuevas terapias anticáncer.

Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines.

The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer-drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications.

Polymer-drug conjugates for combination anticancer therapy: investigating the mechanism of action.

We developed a family of polymer-drug conjugates carrying the combination of the anticancer agent epirubicin (EPI) and nitric oxide (NO). EPI-PEG-(NO)8, carrying the highest content of NO, displayed greater activity in Caco-2 cells while it decreased toxicity against endothelium cells and cardiomyocytes with respect to free EPI. FACS and confocal microscopy confirmed conjugates internalization. Light scattering showed formation of micelle whose size correlated with internalization rate. EPI-PEG-(NO)8 showed increased bioavailability in mice compared to free EPI.

Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells

Recently we have described an HPMA copolymer conjugate carrying both the aromatase inhibitor aminoglutethimide (AGM) and doxorubicin (Dox) as combination therapy. This showed markedly enhanced in vitro cytotoxicity compared to the HPMA copolymer-Dox (FCE28068), a conjugate that demonstrated activity in chemotherapy refractory breast cancer patients during early clinical trials. To better understand the superior activity of HPMA copolymer-Dox-AGM, here experiments were undertaken using MCF-7 and MCF-7ca (aromatase-transfected) breast cancer cell lines to: further probe the synergistic cytotoxic effects of AGM and Dox in free and conjugated form; to compare the endocytic properties of HPMA copolymer-Dox-AGM and HPMA copolymer-Dox (binding, rate and mechanism of cellular uptake); the rate of drug liberation by lysosomal thiol-dependant proteases (i.e. conjugate activation), and also, using immunocytochemistry, to compare their molecular mechanism of action. It was clearly shown that attachment of both drugs to the same polymer backbone was a requirement for enhanced cytotoxicity. FACS studies indicated both conjugates have a similar pattern of cell binding and endocytic uptake (at least partially via a cholesterol-dependent pathway), however, the pattern of enzyme-mediated drug liberation was distinctly different. Dox release from PK1 was linear with time, whereas the release of both Dox and AGM from HPMA copolymer-Dox-AGM was not, and the initial rate of AGM release was much faster than that seen for the anthracycline. Immunocytochemistry showed that both conjugates decreased the expression of ki67. However, this effect was more marked for HPMA copolymer-Dox-AGM and, moreover, only this conjugate decreased the expression of the anti-apoptotic protein bcl-2. In conclusion, the superior in vitro activity of HPMA copolymer-Dox-AGM cannot be attributed to differences in endocytic uptake, and it seems likely that the synergistic effect of Dox and AGM is due to the kinetics of intracellular drug liberation which leads to enhanced activity. (c) 2006 Elsevier B.V All rights reserved.

Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA)

As the mean age of the global population increases, breast cancer in older individuals will be increasingly encountered in clinical practice. Management decisions should not be based on age alone. Establishing recommendations for management of older individuals with breast cancer is challenging because of very limited level 1 evidence in this heterogeneous population. In 2007, the International Society of Geriatric Oncology (SIOG) created a task force to provide evidence-based recommendations for the management of breast cancer in elderly individuals. In 2010, a multidisciplinary SIOG and European Society of Breast Cancer Specialists (EUSOMA) task force gathered to expand and update the 2007 recommendations. The recommendations were expanded to include geriatric assessment, competing causes of mortality, ductal carcinoma in situ, drug safety and compliance, patient preferences, barriers to treatment, and male breast cancer. Recommendations were updated for screening, primary endocrine therapy, surgery, radiotherapy, neoadjuvant and adjuvant systemic therapy, and metastatic breast cancer.

Janus PEG-based dendrimers for use in combination therapy: controlled multi-drug loading and sequential release

The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different “model drugs”, benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)2-G1-G1-(PPA)2, (BA)4-G2-G1-(PPA)2, (BA)2-G1-G2-(PPA)4, and (BA)4-G2-G2-(PPA)4. Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15–0.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.

Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

Polymer therapeutics designed for a combination therapy of hormone-dependent cancer

Designer drug: A polymer therapeutic was designed for a combination therapy of breast cancer. N-(2-Hydroxypropyl)methacrylamide was used as the model polymer platform to prepare a unimolecular polymer conjugate (see picture, radius of gyration: 12.8 nm) that combines an endocrine (the aromatase inhibitor aminoglutethimide, blue) and a chemotherapeutic agent (the anthraxcycline antibiotic doxorubicin, red).

Impact of the enhanced permeability and retention (EPR) effect and cathepsins levels on the activity of polymer-drug conjugates

Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i) the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR) effect) and (ii) the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B). Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates). An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer), although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

Immediate reconstruction following breast-conserving surgery: Management of the positive surgical margins and influence on secondary reconstruction

The efficacy of breast-conserving Surgery for the local control of early breast cancer has been repeatedly evidenced. Although immediate reconstruction following breast-conserving Surgery has been described, little information is available regarding surgical management in reoperative settings due to positive margins. We studied the influence of intraoperatively assessed and postoperatively controlled Surgical margin status on the type of breast-conserving Surgery and report our results regarding complications in a reoperative breast reconstruction scenario. All patients were seen by a multidisciplinary team who recommended breast-conserving surgery. According to the breast volume, ptosis and tumor size/location, the patients were also evaluated by a plastic Surgeon, who recommended reconstruction with the appropriate technique. Intraoperative assessment Of Surgical margins was determined by histological examination of frozen sections. The mean follow-up time was 48 months. Two hundred and eighteen patients (88.5%) underwent breast-conserving Surgery and immediate reconstruction. Twelve (5.5%) patients had a positive tumor margin after review of the permanent section. All patients underwent re-exploration. In 1.3%, a second reconstructive technique was indicated and in 2.2% a skin-sparing mastectomy with total reconstruction was performed. Our findings support the important role of the intraoperative assessment of surgical margins and its interference in the selection of reconstruction techniques and negative margins: however, it will not guarantee complete excision of the tumor. Success depends on coordinated planning with the oncologic Surgeon and careful intraoperative management, (C) 2008 Elsevier Ltd. All rights reserved.

Colloidal carriers for ophthalmic drug delivery

To achieve effective drug concentration at the intended site for a sufficient period of time is a requisite desired for many drug formulations. For drugs intended to ocular delivery, its poor bioavailability is due to pre-corneal factors. Most ocular diseases are treated by topical drug application in the form of solution, suspension and ointment. However, such dosage forms are no longer sufficient to combat some ocular diseases. Intravitreal drug injection is the current therapy for disorders in posterior segment. The procedure is associated with a high risk of complications, particularly when frequent, repeated injections are required. Thus, sustained-release technologies are being proposed, and the benefits of using colloidal carriers in intravitreal injections are currently under investigation for posterior drug delivery. This review will discuss recent progress and specific development issues relating to colloidal drug delivery systems, such as liposomes, niosomes, nanoparticles, and microemulsions in ocular drug delivery.

Adjuvant therapy with GnRH agonists/tamoxifen in breast cancer should be a good council for patients with hormone receptor-positive tumours and wish to preserve fertility

Infertility represents one of the main long-term consequences of the chemotherapy used for the adjuvant treatment of breast cancer. Approximately 60-65% of breast cancers express the nuclear hormone receptor in premenopausal women. Adjuvant endocrine therapy is an integral component of care for patients with hormone receptor-positive (HR+) tumours. The GnRH agonist (GnRHa) alone or in combination with tamoxifen produces results at least similar to those obtained with the different chemotherapy protocols in patients with HR+ breast cancer with respect to recurrence-free survival and overall survival. It is time to indicate adjuvant therapy with GnRHa associated with tamoxifen for patients with breast cancer (HR+ tumours) if they want to preserve their reproductive function. The evaluation of ovarian reserve tests: follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume 6 months, and 1 year after the end of therapy with GnRHa/tamoxifen must be realised. The recurrence-free survival and overall survival should be analysed. The major implication of this hypothesis will be to avoid adjuvant chemotherapy for patients with breast cancer (HR+ tumours) that request fertility preservation. It is expected that ovarian function should not be altered in almost all cases and subsequent pregnancy a real possibility. (C) 2012 Elsevier Ltd. All rights reserved.