Personalized medicine for metastatic breast cancer

Cel przeglądu. Dzięki nowym technikom sekwencjonowania DNA można identyfikować w materiale biopsyjnymu chorych na raka piersi z przerzutami powtarzające się zmiany w genomie, co może prowadzić do molekularnego selekcjonowania przypadków do badań klinicznych nad lekami ukierunkowanymi. W niniejszym przeglądzie przedstawiano aktualne dane dotyczące powtarzających się zmian w genomie w raku piersi z przerzutami, a także podsumowano wyniki badań klinicznych wczesnej fazy dotyczących nowych leków ukierunkowanych.Najnowsze odkrycia. Postęp kliniczny w zakresie personalizacji leczenia obejmuje zastosowanie leków ukierunkowanych na szlak PI3K/mTOR, receptor czynnika wzrostu fibroblastów, receptor typu drugiego ludzkiego naskórkowego czynnika wzrostu, szlaki naprawy DNA oraz szlaki regulujące cykl komórkowy. Leki ukierunkowane na szlak PI3K/mTOR wykazują aktywność w raku piersi opornym na leczenie hormonalne i trastuzumab. W podgrupie chorych na raka piersi z przerzutami, po preselekcji w kierunku aberracji w zakresie wymienionych szlaków, wykazano potencjalną aktywność leków ukierunkowanych na szlak PI3K/mTOR, FGFR i polimerazę poli(ADP-rybozy). Prowadzone są również badania oceniające skuteczność leczenia skojarzonego z udziałem leków ukierunkowanych, hormonoterapii, leków przeciw HER-2 lub też chemioterapii w grupach chorych z określonymi zmianami genomu w zakresie genów receptorów hormonalnych, szlaku HER-2 czy też pozostałych istotnych szlaków sygnałowych.Podsumowanie. Obecnie wdrażane jest nowe podejście do spersonalizowanego leczenia chorych na raka piersi z przerzutami. Uwzględnia ono selekcję molekularną mającą na celu identyfikację istotnych klinicznie zmian w genomie oraz leczenie ukierunkowane molekularnie. Konieczne jest prowadzenie badań klinicznych, które pozwolą wykazać, czy dane subpopulacje chorych na raka piersi z przerzutami mogą odnieść rzeczywistą korzyść z leczenia dobranego według zmian w genomie.Purpose of review. With recent advances in DNA sequencing technology, recurrent genomic alterations can be identified in tumor samples from patients with metastatic breast cancer (MBC) to enrich clinical trials testing targeted therapies. This review provides an overview of clinically relevant genomic alterations in MBC and summarizes the recent clinical data from early phase trials of novel targeted treatments.Recent findings. The clinical development of personalized treatment includes targeted agents directed against PI3K/mTOR, fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), DNA repair, and cell cycle pathways. PI3K/mTOR pathway drugs are active in endocrine and trastuzumab-resistant disease. Drugs targeted at PI3K/mTOR, FGFR, and poly(ADP-ribose) polymerase show early signs of efficacy in MBC subpopulations enriched with relevant pathway aberrancies. Regimens combining targeted agents with either endocrine, anti-HER2, or chemotherapy treatments are also being studied in hormone receptor-definedand HER2-defined or pathway-enriched subgroups.Summary. A new approach to personalized medicine for MBC that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging. Clinical trials are needed to determine whether rare subpopulations of MBC benefit from genotype-targeted treatments

Coexistence of Ferroelectric Triclinic Phases and Origin of Large Piezoelectric Responses in Highly Strained BiFeO3 films

The structural evolution of the strain-driven morphotropic phase boundary (MPB) in BiFeO3 films has been investigated using synchrotron x-ray diffractometry in conjunction with scanning probe microscopy. Our results demonstrate the existence of mixed-phase regions that are mainly made up of two heavily tilted ferroelectric triclinic phases. Analysis of first-principles computations suggests that these two triclinic phases originate from a phase separation of a single monoclinic state accompanied by elastic matching between the phase-separated states. These first-principle calculations further reveal that the intrinsic piezoelectric response of these two low-symmetry triclinic phases is not significantly large, which thus implies that the ease of phase transition between these two energetically close triclinic phases is likely responsible for the large piezoelectric response found in the BiFeO3 films near its MPB. These findings not only enrich the understandings of the lattice and domain structure of epitaxial BiFeO3 films but may also shed some light on the origin of enhanced piezoelectric response near MPB.Comment: 19 pages, 3 figures and 1 tabl

Mass and Hot Baryons in Massive Galaxy Clusters from Subaru Weak Lensing and AMiBA SZE Observations

We present a multiwavelength analysis of a sample of four hot (T_X>8keV) X-ray galaxy clusters (A1689, A2261, A2142, and A2390) using joint AMiBA Sunyaev-Zel'dovich effect (SZE) and Subaru weak lensing observations, combined with published X-ray temperatures, to examine the distribution of mass and the intracluster medium (ICM) in massive cluster environments. Our observations show that A2261 is very similar to A1689 in terms of lensing properties. Many tangential arcs are visible around A2261, with an effective Einstein radius \sim 40 arcsec (at z \sim 1.5), which when combined with our weak lensing measurements implies a mass profile well fitted by an NFW model with a high concentration c_{vir} \sim 10, similar to A1689 and to other massive clusters. The cluster A2142 shows complex mass substructure, and displays a shallower profile (c_{vir} \sim 5), consistent with detailed X-ray observations which imply recent interaction. The AMiBA map of A2142 exhibits an SZE feature associated with mass substructure lying ahead of the sharp north-west edge of the X-ray core suggesting a pressure increase in the ICM. For A2390 we obtain highly elliptical mass and ICM distributions at all radii, consistent with other X-ray and strong lensing work. Our cluster gas fraction measurements, free from the hydrostatic equilibrium assumption, are overall in good agreement with published X-ray and SZE observations, with the sample-averaged gas fraction of = 0.133 \pm 0.027, for our sample = (1.2 \pm 0.1) \times 10^{15} M_{sun} h^{-1}. When compared to the cosmic baryon fraction f_b = \Omega_b/\Omega_m constrained by the WMAP 5-year data, this indicates /f_b = 0.78 \pm 0.16, i.e., (22 \pm 16)% of the baryons are missing from the hot phase of clusters.Comment: accepted for publication in ApJ; high resolution figures available at http://www.asiaa.sinica.edu.tw/~keiichi/upfiles/AMiBA7/ms_highreso.pd

Penile prosthesis implantation in Chinese patients with severe erectile dysfunction: 10-year experience

We retrospectively evaluated the clinical outcome of penile prosthesis implantation (PPI) in Chinese patients with severe erectile dysfunction (SED). From July 2000 to December 2011, 224 patients (mean age: 35.9±11.8 years, range: 20–75 years) with SED underwent PPI by experienced surgeon according to standard PPI procedure at our centre. A malleable prosthesis (AMS 650) was implanted in 45 cases (20.1%), and a three-piece inflatable prosthesis (AMS 700 CXM or AMS 700 CXR) was implanted in 179 cases (79.9%). Surgical outcomes, including postoperative complications, clinical efficacy and couple satisfaction, were evaluated over than 6 months postoperatively using medical record abstraction, IIEF-5, quality of life (QoL) scores, and the patient/partner sexual satisfaction score proposed by Bhojwani et al. Of the 224 patients eligible for the study, 201 subjects (89.7%) completed follow-up. All of patients could perform sexual intercourse post PPI with the mean postoperative IIEF-5 and QoL scores were 20.02±2.32 and 5.28±0.76, respectively, which were significantly improved compared with the preoperative scores (6.29±1.5 and 2.13±0.84, P<0.01). Of the 201 men, mechanical malfunction occurred in four cases (2.0%) and three cases were re-implanted new device, and two cases (1.0%) developed a mild curvature of the penis. Scrotal erosion with infection occurred in one case with diabetes mellitus (0.5%) and required complete removal of the implanted AMS 700 CXM. Satisfactory sexual intercourse at least twice per month was reported by 178 men (88.6%), and overall satisfaction with the PPI surgery was reported by 89.0% of men and 82.5% of partners. Patient satisfaction in the three-piece inflatable prosthesis group was higher than in the malleable prosthesis group (P<0.05). Satisfaction, however, between the types of prostheses, did not differ in the partner survey. PPI is a safe and effective treatment option for Chinese patients with SED and experienced surgeon perform PPI according to standard PPI procedure could reduce the postoperative complications of PPI and could improve patient satisfaction ratio and QoL

Ultrahigh Carrier Mobility Achieved in Photoresponsive Hybrid Perovskite Films via Coupling with Single-Walled Carbon Nanotubes

Organolead trihalide perovskites have drawn substantial interest for photovoltaic and optoelectronic applications due to their remarkable physical properties and low processing cost. However, perovskite thin films suffer from low carrier mobility as a result of their structural imperfections such as grain boundaries and pinholes, limiting their device performance and application potential. Here we demonstrate a simple and straightforward synthetic strategy based on coupling perovskite films with embedded single-walled carbon nanotubes. We are able to significantly enhance the hole and electron mobilities of the perovskite film to record-high values of 595.3 and 108.7 cm2 V−1 s−1, respectively. Such a synergistic effect can be harnessed to construct ambipolar phototransistors with an ultrahigh detectivity of 3.7 × 1014 Jones and a responsivity of 1 × 104 A W−1, on a par with the best devices available to date. The perovskite/carbon nanotube hybrids should provide a platform that is highly desirable for fields as diverse as optoelectronics, solar energy conversion, and molecular sensing

Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature

[Background] This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions.[Methods] Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method.[Results] Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported.[Conclusion] Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.Peer reviewe