Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52–1.89; OS: HR, 0.95; 95% CI 0.37–2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.     

Bioreplicated visual features of nanofabricated buprestid beetle decoys evoke stereotypical male mating flights

Recent advances in nanoscale bioreplication processes present the potential for novel basic and applied research into organismal behavioral processes. Insect behavior potentially could be affected by physical features existing at the nanoscale level. We used nano-bioreplicated visual decoys of female emerald ash borer beetles (Agrilus planipennis) to evoke stereotypical mate-finding behavior, whereby males fly to and alight on the decoys as they would on real females. Using an industrially scalable nanomolding process, we replicated and evaluated the importance of two features of the outer cuticular surface of the beetle’s wings: structural interference coloration of the elytra by multilayering of the epicuticle and fine-scale surface features consisting of spicules and spines that scatter light into intense strands. Two types of decoys that lacked one or both of these elements were fabricated, one type nano-bioreplicated and the other 3D-printed with no bioreplicated surface nanostructural elements. Both types were colored with green paint. The light-scattering properties of the nano-bioreplicated surfaces were verified by shining a white laser on the decoys in a dark room and projecting the scattering pattern onto a white surface. Regardless of the coloration mechanism, the nano-bioreplicated decoys evoked the complete attraction and landing sequence of Agrilus males. In contrast, males made brief flying approaches toward the decoys without nanostructured features, but diverted away before alighting on them. The nano-bioreplicated decoys were also electroconductive, a feature used on traps such that beetles alighting onto them were stunned, killed, and collected.Biomimicry of insect visual communication signals has received much recent attention, with growing interest in nanofabrication processes that result in artificially produced structural colors (1) such as those emanating from the ridges on butterfly wing scales (2). The fidelity of the nanoreplication of visual signals with communication value to such organisms has been underexplored, however. Visually induced behavior in arthropods often integrates color and edge-motion detection, with interactions often involving a variety of biotic and abiotic entities, making it difficult to reproduce experimentally (3).Bioreplication of visual signaling structures might be manipulated so as to provide insight into the mechanisms of such signaling processes; however, all currently known examples of bioreplicated nanostructures that have been created to affect behavior involve unicellular movements across particular textured environments (4–7), rather than directed to evoke responses of specialized sensory organs of more complex multicellular organisms. Bioreplicated structures emitting behaviorally effective visual cues also may be useful for such practical purposes as the monitoring and detection of pest species, but the communication efficacy of the bioreplica needs to be validated under field conditions using naturally occurring (i.e., wild) populations.In contrast, biomimicry of chemical signals, such as insect pheromones, has been a burgeoning field for more than half a century. Synthetically reproduced pheromones have been successfully applied under field conditions to manipulate insect behavior for invasive species pest detection, population monitoring of endemic species, and disruption of mating. Thousands of studies have described the essential components of nanoscale levels (nanograms) of semiochemical signals that trigger behavioral responses, such as upwind flight for mating (8), alarm responses (9), and trail following (10). Furthermore, neurophysiological techniques have elucidated how these signals are transduced by peripheral sensory organs (11) and integrated into odor sensations in the higher processing centers of the insect brain (12). In the realm of applied science, these insights have led to trapping protocols for pest population detection, attract-and-kill protocols, and mating disruption (13). Visually attractive features of trapping technologies generally have not been approached with such rigor, however, and are usually optimized by simple manipulations of trap colors without efforts to understand the underlying mechanisms of visual attraction.In an effort to initiate such an approach to manipulation of visual signaling systems, we used an industrially scalable nano-bioreplication technique (14) to produce high-fidelity replicas of the structural features of the cuticle of the hard wing covers (elytra) of an invasive buprestid beetle pest, the emerald ash borer (Agrilus planipennis). This species is a tree-killing pest of Asian origin whose visual signal is emitted by the elytra of a female at rest on an ash leaf in direct sunlight, which triggers attraction of flying males that are patrolling the canopy. Male responses unfold as rapid flights toward the females from heights of up to 2 m, usually terminating with the males alighting directly on the females and attempting to copulate (15). This “paratrooper” descent behavior by flying A. planipennis males in the field can be repeatedly evoked by affixing dead A. planipennis females to ash leaves (15, 16). Furthermore, various other potentially invasive European and North American tree-feeding Agrilus species have been observed performing similar stereotypical inflight descents onto dead beetle decoys affixed to the leaves of preferred host trees (17, 18). Such approaches are often seen to congeneric, heterospecific targets. One such species, the two-spotted oak borer, Agrilus biguttatus, that is similar in size and habits to A. planipennis is known to kill oak trees within its native range in Europe (19), particularly after drought (20) or defoliation events (21).The base colors of many metallic-colored beetles, including buprestid beetles (Fig. 1A), are known to be structurally produced by the repeated alternation of cuticle layers (Fig. 1D) with different refractive indices (22, 23). This periodically multilayered assemblage functions as a quarter-wave Bragg stack reflector in a particular spectral regime (2) and is thus highly effective for creating a color of narrow specificity in sunlight, unlike many naturally occurring pigments. The reflected light is also affected by regular fine-scale topographic features of the surface, including thousands of sharp spicules each emitting green to yellow colors, which are further scattered by numerous spines (Fig. 1 B and C). Many of the physical attributes of the A. planipennis cuticle that produce its attractive visual signal have been replicated by a process that involves the stamping of a polymer quarter-wave Bragg stack reflector with a set of dies cast from the actual elytra of a female A. planipennis (Fig. 2) (14).Open in a separate windowFig. 1.Structural color and surface topography of A. planipennis wings. (A) Optical microscopy showing a dorsal view of the beetle elytron. (B) Higher-magnification optical microscopy showing spines and cilia. (C) Scanning electron micrograph showing a higher-resolution image of the surface topography. (D) Transmission electron micrograph of a cross-section of an elytron, showing four alternating layers of differing refractive indices. (C and D are reprinted with permission from ref. 14.)Open in a separate windowFig. 2.Nano-bioreplicated decoy characteristics. (A) Optical microscopy of the nickel die. (B) Scanning electron micrograph of a nickel die used for bioreplication, showing a similar structure as the A. planipennis surface (Fig. 1), but without the cilia. (C) Optical microscopy of the dorsal view of a nano-bioreplicated A. planipennis decoy that reproduces the surface structure of the beetle and is colored by metallic paint. (A and B are reprinted with permission from ref. 14.)Here we report on direct field observations of A. planipennis and A. biguttatus male behavior toward natural beetle decoys versus three types of synthetic decoys with varying degrees of verisimilitude with respect to the fidelity of bioreplication. These synthetic decoys included: (i) a bioreplicated decoy created by a nanomolding process and colored with a polymer functioning as a Bragg reflector; (ii) another bioreplicated decoy created by a nanomolding process and colored with a metallic green paint; and (iii) a 3D-printed decoy consisting of a smooth polymer surface without a nanomolded bioreplicated surface structure, also colored with green metallic paint. We investigated whether the nanomolding process could create light-scattering patterns similar to those of real decoys by observing light emissions resulting from the application of a white laser to the surfaces of real and synthetic decoys in a dark room. We hypothesized that a sufficient degree of verisimilitude with respect to color and fine-scale topological features of the elytra could be achieved through the bioreplication process to elicit inflight mating approaches and landings similar to those evoked by real beetles. We also incorporated the bioreplicated decoys into a trapping system in which the electroconductive properties of the decoy are used to electrocute male beetles when they approach and alight on the decoys.     

Long term treatment with acebutolol in hypertension (author's transl)]

Acebutolol, a new cardioselective beta-adrenoceptor antagonist, has been studied in 40 hypertensive patients (pts.) for a period of 6 months, 25 patients (group A) had never taken any antihypertensive agent, 15 pts. (group B) were previously treated with antihypertensives. This two groups are statistically different for the age (39.8 y. group A; 49.6 y. group B) for the values of basal blood pressure (BP) (175/105 mmHg group A; 197/114 mmHg group B) and for disease duration (9.9 months group A; 39.0 months group B). A significant antihypertensive response was obtained already at the 15th therapy day for the two groups, treated with acebutolol. Further, a little reduction of BP was obtained at the 3rd month going on with therapy; then the BP values showed non significant variation till the end of the study. Orthostatic hypotension were not remarked. After 3 months, acebutolol treatment 41% pts. rised diastolic BP (DBP) below 90 mmHg and 35% pts. had a DBP between 90 and 100 mmHg. The average values of heart rate have been significantly reduced after 15 days of therapy with sligh variations during the following month. The optimal mean daily dosages of the drug were obtained with titration in three months (540 mg/day group A and 740 mg/day group B). Regarding side effects rised during therapy, one patient showed "paradox hypertension" and another bradycardia which justified the interruption of the treatment. In our opinion, on the basis of the results obtained acebutolol shows a good efficacy in the treatment of hypertension and a very high tollerability.     

Risk of Mycobacterium tuberculosis infection and disease among health care workers, Chiang Rai, Thailand.

SETTING: A provincial referral hospital in northern Thailand, where a cross-sectional study during 1995-1996 reported on the occupational risk of Mycobacterium tuberculosis transmission. OBJECTIVE: To describe the effectiveness of prevention strategies for nosocomial tuberculosis (TB). DESIGN: A prospective study among health care workers (HCW) including annual tuberculin skin test (TST) screening and active TB surveillance. Following a comprehensive risk assessment, preventive interventions were implemented targeting HCWs, hospitalised patients, and the hospital environment. RESULTS: The number of pulmonary TB cases diagnosed increased steadily from 102 in 1990 to 356 in 1999. The TST conversion rate was 9.3 (95% CI 3.3-15) per 100 person-years (py) in 1995-1997, but declined steadily to 2.2 (95% CI 0.0-5.1) in 1999. HCWs first screened within 12 months of employment had higher TST conversion rates (adjusted RR = 9.5, 95% CI 1.8-49.5) compared to those employed for longer than 12 months. The annual rate of active TB per 100 000 HCWs was 536 in 1995-1999. CONCLUSION: These HCWs were exposed to active TB patients and were at risk for M. tuberculosis infection, particularly during their first 12 months of employment. Implementation of nosocomial TB control measures in 1996 was followed by declining TST conversion rates, despite increasing exposure to active TB patients.     

New HIV type 1 CRF01_AE/B recombinants displaying unique distribution of breakpoints from incident infections among injecting drug users in Thailand

The goals of this study were to identify and characterize recombinant human immunodeficiency virus type 1 (HIV-1) genomes among incident infections in a prospective cohort study of injecting drug users (IDUs) in Bangkok, Thailand. Through cross-sectional, comparative phylogenetic analysis of the protease and env (C2-V4) gene regions, subtype discordance was observed in HIV-1 sequences from 4 of 111 IDUs (3.5%). Near-full-length HIV-1 genome sequences of the four strains revealed that in all four, the gp120 sequences clustered with a CRF01_AE prototype, while the remainder of the genomes displayed distinct mosaic patterns, with multiple breakpoints between HIV-1 CRF01_AE and subtype B-like regions. Two of the four HIV-1 recombinant strains displayed a nearly identical mosaic structure, suggesting the possible emergence and spread of a potentially new circulating recombinant form of HIV-1. Further characterization of these and other recombinant genomes through long-term follow-up will be important in understanding the generation of viral diversity and escape from the hosts immune responses. This information will be especially important for vaccine development.     

A comparison of full-length glycoprotein 120 from incident HIV type 1 subtype E and B infections in Bangkok injecting drug users with prototype E and B strains that are components of a candidate vaccine

Complete gp120 sequence information was obtained from eight persons with incident HIV-1 infections (four subtype E and four subtype B) who were part of a prospective injecting drug user (IDU) cohort in Bangkok, Thailand, during 1996-1998. The incident subtype E strains were similar to the prototype subtype E strain CM244 isolated in 1992 in northern Thailand. The incident subtype B strains displayed divergence, in both overall genetic distance and other significant gp120 characteristics, from the prototype North American subtype B strain HIV-MN. Recombinant gp120s derived from CM244 and HIV-MN strains are components of a vaccine that is undergoing phase III efficacy testing, begun in March 1999, among Bangkok area IDUs. The information presented here will be important in the evaluation of any breakthrough HIV-1 infections occurring among vaccinees during the vaccine trial and in ongoing vaccine development efforts in Thailand.     

Frequency of HIV-1 dual subtype infections, including intersubtype superinfections, among injection drug users in Bangkok, Thailand

OBJECTIVES: To estimate the frequency and incidence of dual HIV-1 subtype infections, including superinfections, among recent seroconvertors from a cohort of injection drug users (IDUs). METHODS: A total of 1209 HIV-negative IDUs were followed in a prospective cohort study at 15 methadone clinics in Bangkok, Thailand. After 2308 person-years (PY) of follow-up, 133 seroconverted to HIV-1, of which approximately 20% were subtype B and 80% were CRF01_AE (formerly called subtype E). Specimens from 126 individuals were available at time of first seropositive test and specimens from 80 of these 126 individuals were also available more than 12 months later. For each infected participant, we calculated the amount of time to superinfection, loss to follow-up, or to the closest visit more than 12 months after the time of initial seropositivity. RESULTS: Of all 126 seroconverters seen at the time of the first seropositive test result, there was no apparent case of concurrent dual subtype infection detected despite 2301 PY of observation. Overall, the incidence of superinfection was 2.2 per 100 PY [95% confidence interval (CI), 0.3-7.8]. The 1-year incidence of CRF01_AE superinfection following subtype B primary infection was 3.9 per 100 PY (95% CI, 0.1-21.9) and the incidence of subtype B superinfection following CRF01_AE primary infection was 1.5 per 100 PY (95% CI, 0.04-8.3). CONCLUSIONS: Determination of the frequency and incidence of dual HIV-1 subtype infection demonstrates that HIV-1 superinfection is not uncommon in a population with high HIV-1 incidence with more than one circulating strain.     

A multicentre Phase II study of non-pegylated liposomal doxorubicin in combination with trastuzumab and docetaxel as first-line therapy in metastatic breast cancer

To evaluate the cardiotoxicity, general toxicity, and activity of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first-line therapy in metastatic breast cancer.Thirty-one patients with metastatic human epidermal growth factor receptor 2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m²), docetaxel (75 mg/m²) and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) to below 45%, or a decrease in LVEF of at least 20% from baseline.Mean LVEF was maintained at baseline level also in the subset of patients who had received anthracycline previously. Cardiotoxicity developed in three patients during the treatment cycles, and in two further patients after the end of the study. The most common adverse events were haematological toxicity, alopecia, asthenia and fever. The best overall response rate was 65.5%. Median time to progression was 13.0 months.The combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab combines acceptable cardiac and general toxicity and promising activity as first-line therapy in metastatic breast cancer.