Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer

PURPOSE The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)–positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN). PATIENTS AND METHODS In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m2) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer–specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN. RESULTS A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%). CONCLUSION With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors

The immune microenvironment in hormone receptor-positive breast cancer before and after preoperative chemotherapy

Purpose: Hormone receptor-positive/HER2-negative (HR+/HER2_) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR+/HER2_ breast tumors. Experimental Design: HR+/HER2_ breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8+ cells, CD68+ cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: Ninety-six patients were analyzed from two cohorts (n = 55, Dana-Farber cohort; n = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissuebased lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset (N = 302). In paired pre-/postchemotherapy samples, sTIL and CD8+ cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy. Conclusions: The immune microenvironment of HR+/ HER2_ tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophagetargeting therapy is warranted

The economic well-being of nations is associated with positive daily situational experiences

People in economically advantaged nations tend to evaluate their life as more positive overall and report greater well-being than people in less advantaged nations. But how does positivity manifest in the daily life experiences of individuals around the world? The present study asked 15,244 college students from 62 nations, in 42 languages, to describe a situation they experienced the previous day using the Riverside Situational Q-sort (RSQ). Using expert ratings, the overall positivity of each situation was calculated for both nations and individuals. The positivity of the average situation in each nation was strongly related to the economic development of the nation as measured by the Human Development Index (HDI). For individuals’ daily experiences, the economic status of their nation also predicted the positivity of their experience, even more than their family socioeconomic status. Further analyses revealed the specific characteristics of the average situations for higher HDI nations that make their experiences more positive. Higher HDI was associated with situational experiences involving humor, socializing with others, and the potential to express emotions and fantasies. Lower HDI was associated with an increase in the presence of threats, blame, and hostility, as well as situational experiences consisting of family, religion, and money. Despite the increase in a few negative situational characteristics in lower HDI countries, the overall average experience still ranged from neutral to slightly positive, rather than negative, suggesting that greater HDI may not necessarily increase positive experiences but rather decrease negative experiences. The results illustrate how national economic status influences the lives of individuals even within a single instance of daily life, with large and powerful consequences when accumulated across individuals within each nation

Microstructuring of lithium niobate

This thesis presents the results from an investigation into methods for micron-scale relief structuring of lithium niobate. A wet etch consisting of HF and HNO3 was applied, and directed by 1) patterning the ferroelectric domain structure of the samples and 2) illuminating the crystals with patterned 488nm light. Post-etch treatment of the structures resulted in ridge waveguides and alignment grooves, while pre-etch manipulation achieved an etch-stop. Ablation was investigated as a method of directly structuring the crystal and for patterning photoresist. The etch was found to leave the +z face untouched. The -z face was etched at a rate, k, in µm/hour given by k = e 20.37 - 6300/T where T is the absolute temperature. This differential etch rate reveals a pattern induced in the ferroelectric domain structure by the technique of electric field patterning. The structures had walls with roughness &lt; 5nm. Straight walls were easily achieved aligned along the y-direction at 120o to this. Other directions can result in facetted walls. Ridge waveguide losses &lt;1dBcm-1, fibre alignment grooves and an etch stop were demonstrated using appropriate pre- and post-etch treatments. The etch was found to be affected by illumination with 488nm radiation. In Fe:LiNbO3 complete and partial frustration of the etch was induced on the -z face. Characteristic features of the partial frustration were sub-micron ridges and triangular pillars, separated by gaps as small as 500nm. In LiNbO3 the etch rate was found to increase on the -z face. The etch rate on the +z face was unaffected in both. Direct ablation with an excimer laser produced relief structures. Aspect ratios &gt; 1:1 resulted in a dendritic structure in the ablated area. Direct ablation was suitable for patterning the photoresist. Surface damage was intentionally induced when producing large (&gt;100µm) openings, however, the effect of surface damage on electric field poling could not be conclusively tested. Submicron openings were also created and subsequent poling produced sub-micron domains, revealed by etching. <br/

Microstructuring in LiNbO₃: a route to MEMS devices in piezoelectric crystal media

Ferroelectric materials such as LiNbO3 and LiTaO3 offer many potential advantages over silicon for MEMS structures and self-actuating miniature devices. These materials possess numerous useful intrinsic properties such as piezoelectricity, pyroelectric and electro-optic coefficients, enabling the construction of micron-scale cantilevers, membranes, tips and switches. So far however, reliable and accurate methods for machining and microstructuring LiNbO3 single crystals have been lacking. We have recently been exploring several such methods, which are sensitive to ferroelectric domain orientation. A sample that has been domain-engineered shows a large difference in etch characteristics: the +z face does not etch at all, whereas the -z face etches normally. Microstructured devices can be fabricated therefore, via spatially selective domain poling followed by etching. The extreme sensitivity of the etch process to domain orientation has enabled us to fabricate ridge waveguides for electro-optic modulator applications, alignment grooves for efficient fibre-pigtailing to LiNbO3 modulators, and micro-cantilevers using a novel technique of contact bonding of dissimilar ferroelectric hosts

Prosecuting Dr Strangelove, Goldfinger, and the Joker at the International Criminal Court: closing the loopholes

In this commentary to Matt Halling's paper, the author takes issue with Halling's proposal to amend Article 7(2) of the Rome Statute with regard to the 'policy element'. Halling's view of plugging 'loopholes' in the Rome Statute in abstracto is met with a voice of realism. The author's realism is expressed on different levels and can be summarized in the following questions. As to the need for an amendment of Article 7(2), how realistic are the scenarios presented by Halling? Do they really call for an amendment? As to the function and role of the court, why expand the Court's mandate when it can only prosecute a handful of cases at any one time? As to the Court prosecutorial policy, does the Court need a fine net when it has limited resources and a mandate that requires it to focus on those who bear the greatest responsibility

Fabrication of alignment grooves in LiNbO₃ substrates for simplified optical fibre pigtailing

A technique for lubricating alignment grooves in LiNbO3 substrates. The simplified optical fibre attachment, is reported. The grooves are produced through the etching of material that has been domain inverted via spatially selective electric field poling. The etched grooves are of very high surface quality, and have a profile that is determined by the area of domain inversion produced. The technique lends itself to a method of fibre alignment that is simplified, more reliable, and less labour intensive than existing schemes

Microstructuring lithium niobate: towards new hybrid devices

Lithium niobate is among the most important nonlinear optical materials used today in the photonics industry as it combines a variety of very important properties which, apart from the optical nonlinearity, includes electrooptic, pyroelectric, piezoelectric behaviour and an optical transparency which extends from the UV (350nm) to the infrared (5µm) spectral region. In order to benefit from both the optical and electro-mechanical properties of lithium niobate it is necessary to develop methods for the fabrication of suitable surface and/or bulk structures depending on the application involved. Such methods for surface and bulk microstructuring have been developed and are presented here aiming to show that there is significant scope for the broadening of the utility of this very useful material. &amp; more..

Ridge waveguides in lithium niobate fabricated by differential etching following spatially selective domain inversion

Ridge structures have been fabricated in z-cut LiNbO3 using the technique of differential etching following spatially selective domain inversion. Waveguides within these ridges have been achieved using the techniques of ion beam implantation, proton exchange, and titanium indiffusion. Using this last method, guides with losses &lt;0.8dB/cm have been realised for light at a wavelength of 1.3µm. We briefly discuss applications for these structures

Microstructuring of lithium niobate using differential etch-rate between inverted and non-inverted ferroelectric domains

Single crystal samples of lithium niobate have been spatially patterned with photoresist, and subsequently domain inverted using electric field poling, to produce a range of two dimensional spatial domain structures. Differential etching has subsequently been carried out using mixtures of hydrofluoric and nitric acids, at a range of temperatures between room temperature and the boiling point. The structures produced show very smooth, well defined, deep features, which have a range of applications in optical ridge waveguides, alignment structures, V-grooves, and micro-tips. Details are given of the fabrication procedures, and examples of structures are shown