HER-2/neu Testing and Therapy in Gastroesophageal Adenocarcinoma

Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy

25 kHz narrow spectral bandwidth of a wavelength tunable diode laser with a short waveguide-based external cavity

We report on the spectral properties of a diode laser with a tunable external cavity in integrated optics. Even though the external cavity is short compared to other small-bandwidth external cavity lasers, the spectral bandwidth of this tunable laser is as small as 25 kHz (FWHM), at a side-mode suppression ratio (SMSR) of 50 dB. Our laser is also able to access preset wavelengths in as little as 200 us and able to tune over the full telecom C-band (1530 nm - 1565 nm).Comment: 8 pages, 7 figure

Low frequency of HER2 amplification and overexpression in early onset gastric cancer

BACKGROUND: The recent ToGA trial results indicated that trastuzumab is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer (GC). Although GC mainly affects older patients, fewer than 10% of GC patients are considered early-onset (EOGC) (presenting at the age of 45 years or younger). These EOGC show different clinicopathological and molecular profiles compared to late onset GC suggesting that they represent a separate entity within gastric carcinogenesis. In light of potential trastuzumab benefit, subpopulations of GC such as EOGC (versus late onset) should be evaluated for their frequency of amplification and overexpression using currently available techniques. METHODS: Tissue microarray (TMA) blocks of 108 early onset GC and 91 late onset GC were stained by immunohistochemistry (IHC, Hercep test, DAKO) and chromogenic in situ hybridization (CISH, SPoT-Light, Invitrogen). RESULTS: Overall, we found only 5% HER2 high level amplification and 3% HER2 3+ overexpression (6/199). In addition, 8 patients (4%) showed a low level CISH amplification and 9 patients (4.5%) showed a 2+ IHC score. IHC and CISH showed 92% concordance and CISH showed less heterogeneity than IHC. In 2/199 cases (1%), IHC showed clinically relevant heterogeneity between TMA cores, but all cases with focal IHC 3+ expression were uniformly CISH high level amplified. Early onset GCs showed a significantly lower frequency of HER2 amplification (2%) and overexpression (0%) than late onset GCs (8% and 7% respectively) (p = 0.085 and p = 0.008 respectively). Proximal GC had more HER2 amplification (9% versus 3%) and overexpression (7% versus 2%) than distal tumours although this difference was not significant (p = 0.181 and p = 0.182 respectively). HER2 CISH showed more high level amplification in the intestinal type (7%, 16% if low-level included) compared to the mixed (5%, 5% if low-level included) and diffuse type (3%, 4% if low-level included) GCs (p = 0.029). A similar association was seen for HER2 IHC and histologic type (p = 0.008). Logistic regression indicated a significant association between HER2 expression and age, which remained significant when adjusted for both location and histological type. CONCLUSIONS: Even focal HER2 overexpression in GC points to uniform HER2 amplification by CISH. We show for the first time that early onset GC has a lower frequency of HER2 amplification and overexpression than late onset GC, and confirm that intestinal type GC shows the highest rate of HER2 amplification and overexpression

Analysis and modeling of CLBG using the transfer matrix

Gratings in optical fibers have been increasingly used in a variety of applications such as sensors and Telecomm. Depending on perturbation separation, they are classified as: fiber Bragg gratings (FBG), and long period gratings (LPG), whose each spectral output offer advantages for certain applications. Nowadays there is a great interest in the study of arrays formed by the combination of long period gratings and Bragg gratings in cascade (CLBG), where the propagation modes of the core and the cladding propagate in the Bragg grating after they propagate in the LPG. In this work, analysis and modeling of Cascaded Long Bragg Gratings using the Transfer Matrix method was performed for the case of two gratings in series along one fiber. We analyzed the variation of the FWHM of the reflectance and transmittance spectra for different values of the difference of the refractive indexes of the core and the perturbation of the grating, using the typical core refractive index of an SMF-28 as reference value. For smaller index difference a narrow intensity peak was observed. After the number of perturbations was varied, when there is a greater number of perturbations in the grating, there is greater intensity in reflectance. However, as our results show, this dependence is not a linear function. The results were obtained under the maximum-reflectivity condition (tuned) for each single grating. The development of the mathematical model, the results of the simulation and the analysis of results are part of the development of the present work11103SPIE Optical engineering + applications - Optical modeling and system alignmentAuthors are grateful to UAM-Azcapotzalco, CONACYT, University of Twente and UNICAMP for their suppor

On the Influence of Pulse Shapes on Ionization Probability

We investigate analytical expressions for the upper and lower bounds for the ionization probability through ultra-intense shortly pulsed laser radiation. We take several different pulse shapes into account, including in particular those with a smooth adiabatic turn-on and turn-off. For all situations for which our bounds are applicable we do not find any evidence for bound-state stabilization.Comment: 21 pages LateX, 10 figure

Dilemmas for the pathologist in the oncologic assessment of pancreatoduodenectomy specimens

A pancreatoduodenectomy specimen is complex, and there is much debate on how it is best approached by the pathologist. In this review, we provide an overview of topics relevant for current clinical practice in terms of gross dissection, and macro- and microscopic assessment of the pancreatoduodenectomy specimen with a suspicion of suspected pancreatic cancer. Tumor origin, tumor size, degree of differentiation, lymph node status, and resection margin status are universally accepted as prognostic for survival. However, different guidelines diverge on important issues, such as the diagnostic criteria for evaluating the completeness of resection. The macroscopic assessment of the site of origin in periampullary tumors and cystic lesions is influenced by the grossing method. Bi-sectioning of the head of the pancreas may offer an advantage in this respect, as this method allows for optimal visualization of the periampullary area. However, a head-to-head comparison of the assessment of clinically relevant parameters, using axial slicing versus bi-sectioning, is not available yet and the gold standard to compare both techniques prospectively might be subject of debate. Further studies are required to validate the various dissection protocols used for pancreatoduodenectomy specimens and their specific value in the assessment of pathological parameters relevant for prognosis

On the absence of bound-state stabilization through short ultra-intense fields

We address the question of whether atomic bound states begin to stabilize in the short ultra-intense field limit. We provide a general theory of ionization probability and investigate its gauge invariance. For a wide range of potentials we find an upper and lower bound by non-perturbative methods, which clearly exclude the possibility that the ultra intense field might have a stabilizing effect on the atom. For short pulses we find almost complete ionization as the field strength increases.Comment: 34 pages Late

Significant variation in histopathological assessment of endoscopic resections for Barrett's neoplasia suggests need for consensus reporting:propositions for improvement

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett's esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria

Ionization Probabilities through ultra-intense Fields in the extreme Limit

We continue our investigation concerning the question of whether atomic bound states begin to stabilize in the ultra-intense field limit. The pulses considered are essentially arbitrary, but we distinguish between three situations. First the total classical momentum transfer is non-vanishing, second not both the total classical momentum transfer and the total classical displacement are vanishing together with the requirement that the potential has a finite number of bound states and third both the total classical momentum transfer and the total classical displacement are vanishing. For the first two cases we rigorously prove, that the ionization probability tends to one when the amplitude of the pulse tends to infinity and the pulse shape remains fixed. In the third case the limit is strictly smaller than one. This case is also related to the high frequency limit considered by Gavrila et al.Comment: 16 pages LateX, 2 figure

Tethering Cells via Enzymatic Oxidative Crosslinking Enables Mechanotransduction in Non-Cell-Adhesive Materials

Cell–matrix interactions govern cell behavior and tissue function by facilitating transduction of biomechanical cues. Engineered tissues often incorporate these interactions by employing cell-adhesive materials. However, using constitutively active cell-adhesive materials impedes control over cell fate and elicits inflammatory responses upon implantation. Here, an alternative cell–material interaction strategy that provides mechanotransducive properties via discrete inducible on-cell crosslinking (DOCKING) of materials, including those that are inherently non-cell-adhesive, is introduced. Specifically, tyramine-functionalized materials are tethered to tyrosines that are naturally present in extracellular protein domains via enzyme-mediated oxidative crosslinking. Temporal control over the stiffness of on-cell tethered 3D microniches reveals that DOCKING uniquely enables lineage programming of stem cells by targeting adhesome-related mechanotransduction pathways acting independently of cell volume changes and spreading. In short, DOCKING represents a bioinspired and cytocompatible cell-tethering strategy that offers new routes to study and engineer cell–material interactions, thereby advancing applications ranging from drug delivery, to cell-based therapy, and cultured meat