A stable relativistic ion acceleration regime for thin foils irradiated by circularly polarized laser pulses is suggested. In this regime, the "light-sail" stage of radiation pressure acceleration ...for ions is smoothly connected with the initial relativistic "hole-boring" stage, and a defined relationship between laser intensity I0, foil density n{0}, and thickness l{0} should be satisfied. For foils with a wide range of n{0}, the required I0 and l{0} for the regime are theoretically estimated and verified with the particle-in-cell code ILLUMINATION. It is shown for the first time by 2D simulations that high-density monoenergetic ion beams with energy above GeV/u and divergence of 10 degrees are produced by circularly polarized lasers at intensities of 10;{22} W/cm;{2}, which are within reach of current laser systems.
We report the generation of stable and tunable electron bunches with very low absolute energy spread (ΔE ≈ 5 MeV) accelerated in laser wakefields via injection and trapping at a sharp downward ...density jump produced by a shock front in a supersonic gas flow. The peak of the highly stable and reproducible electron energy spectrum was tuned over more than 1 order of magnitude, containing a charge of 1-100 pC and a charge per energy interval of more than 10 pC/MeV. Laser-plasma electron acceleration with Ti:sapphire lasers using this novel injection mechanism provides high-quality electron bunches tailored for applications.
The acceleration of ions from ultrathin foils has been investigated by using 250 TW, subpicosecond laser pulses, focused to intensities of up to 3 × 10(20) W cm(-2). The ion spectra show the ...appearance of narrow-band features for protons and carbon ions peaked at higher energies (in the 5-10 MeV/nucleon range) and with significantly higher flux than previously reported. The spectral features and their scaling with laser and target parameters provide evidence of a multispecies scenario of radiation pressure acceleration in the light sail mode, as confirmed by analytical estimates and 2D particle-in-cell simulations. The scaling indicates that monoenergetic peaks with more than 100 MeV/nucleon are obtainable with moderate improvements of the target and laser characteristics, which are within reach of ongoing technical developments.
Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no ...consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations. We believe this undermines the effectiveness of strategies that target specific ranges for drug parameters for which lipophilicity plays such a dominant role. As a result, our research organization no longer leverages the common approach of screening for low intrinsic clearance in vitro to target high unbound exposure in vivo. Instead, we advocate for approaches less biased to lipophilicity through optimization of key parameter ratios controlling dose. We believe this improves efficiency in drug discovery by enabling exploration of broad physicochemical space.
Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned ...analyses of the influence of tumor biomarkers on treatment outcome were carried out.
Patients received weekly cetuximab (400 mg/m2 on day 1, subsequently 250 mg/m2) plus irinotecan (80 mg/m2) and a 24-hour continuous infusion of folinic acid (200 mg/m2) and 5-FU (1500 mg/m2) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD).
The most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months 95% confidence interval (CI) 7.1–15.6 and 16.5 months (95% CI 11.7–30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression.
Cetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.
This article provides an overview of various patterning methodologies, and it is organized into three major sections: generation of patterns, replication of patterns, and three‐dimensional ...patterning. Generation of patterns from scratch is usually accomplished by serial techniques that are able to provide arbitrary features. The writing process can be carried out in many different ways. It can be achieved using a rigid stylus; or a focused beam of photons, electrons, and other energetic particles. It can also be accomplished using an electrical or magnetic field; or through localized add‐on of materials such as a liquid‐like ink from an external source. In addition, some ordered but relatively simple patterns can be formed by means of self‐assembly. In replication of patterns, structural information from a mask, master, or stamp is transferred to multiple copies with the use of an appropriate material. The patterned features on a mask are mainly used to direct a flux of radiation or physical matter from a source onto a substrate, whereas a master/stamp serves as the original for replication based on embossing, molding, or printing. The last section of this article deals with three‐dimensional patterning, where both vertical and lateral dimensions of a structure need to be precisely controlled to generate well‐defined shapes and profiles. The article is illustrated with various examples derived from recent developments in this field.
Patterning is of paramount importance in many areas of modern science and technology. In this review, three broad aspects are discussed: strategies for generating patterns from scratch; duplication and transfer of patterns from the surface of a mask or master into other functional materials (see Figure); and, briefly, methods for generating (and replicating) certain types of three‐dimensional structures.
This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as ...first-line therapy in patients with metastatic colorectal cancer (mCRC).
Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m2/day 1 plus capecitabine 1000 mg/m2 bid/days 1–14 or with irinotecan 200 mg/m2/day 1 plus capecitabine 800 mg/m2 bid/days 1–14 both every 21 days. The primary end point was 6 months progression-free survival (PFS).
A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx–bevacizumab: n = 127; mCapIri–bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%–84%) and 84% (95% CI, 77%–90%). Median PFS and OS were 10.4 months (95% CI, 9.0–12.0) and 24.4 months (95% CI, 19.3–30.7) with CapOx–bevacizumab, and 12.1 months (95% CI, 10.8–13.2) and 25.5 months (95% CI, 21.0–31.0) with mCapIri–bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx–bevacizumab and in 16% with mCapIri–bevacizumab.
Both, CapOx–bevacizumab and mCapIri–bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.
We demonstrate a laser wakefield accelerator with a novel electron injection scheme resulting in enhanced stability, reproducibility, and ease of use. In order to inject electrons into the ...accelerating phase of the plasma wave, a sharp downward density transition is employed. Prior to ionization by the laser pulse this transition is formed by a shock front induced by a knife edge inserted into a supersonic gas jet. With laser pulses of 8 fs duration and with only 65 mJ energy on target, the accelerator produces a monoenergetic electron beam with tunable energy between 15 and 25 MeV and on average 3.3 pC charge per electron bunch. The shock-front injector is a simple and powerful new tool to enhance the reproducibility of laser-driven electron accelerators, is easily adapted to different laser parameters, and should therefore allow scaling to the energy range of several hundred MeV.
A novel regime is proposed where, by employing linearly polarized laser pulses at intensities 10(21) W cm(-2) (2 orders of magnitude lower than discussed in previous work T. Esirkepov et al., Phys. ...Rev. Lett. 92, 175003 (2004)), ions are dominantly accelerated from ultrathin foils by the radiation pressure and have monoenergetic spectra. In this regime, ions accelerated from the hole-boring process quickly catch up with the ions accelerated by target normal sheath acceleration, and they then join in a single bunch, undergoing a hybrid light-sail-target normal sheath acceleration. Under an appropriate coupling condition between foil thickness, laser intensity, and pulse duration, laser radiation pressure can be dominant in this hybrid acceleration. Two-dimensional particle-in-cell simulations show that 1.26 GeV quasimonoenergetic C(6+) beams are obtained by linearly polarized laser pulses at intensities of 10(21) W cm(-2).
Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in ...rPDAC (National Comprehensive Cancer Network criteria).
NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle.
The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B). The pre-defined DFS rate of 55% at 18 months was not reached in both arms A: 33.3% (95% confidence interval CI 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%). Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms.
The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A 25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months). There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined.
The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013–005559-34).
Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer:•Did not meet its primary endpoint in either arm of the study (DFS rate at 18 months of 55% in the mITT population).•Showed that pre-operative chemotherapy can be completed by the majority of patients (90%).•Showed an mOS as a secondary endpoint of 25.5 months in arm A (perioperative) and 16.7 months in arm B (upfront surgery).•Gemcitabine and nab-paclitaxel were safe and well tolerated both in the perioperative as well as the adjuvant setting.
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