Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

An optically multiplexed single-shot time-resolved probe of laser-plasma dynamics.

We introduce a new approach to temporally resolve ultrafast micron-scale processes via the use of a multi-channel optical probe. We demonstrate that this technique enables highly precise time-resolved, two-dimensional spatial imaging of intense laser pulse propagation dynamics, plasma formation and laser beam filamentation within a single pulse over four distinct time frames. The design, development and optimization of the optical probe system is presented, as are representative experimental results from the first implementation of the multi-channel probe with a high-power laser pulse interaction with a helium gas jet target.

Enhanced relativistic-electron-beam energy loss in warm dense aluminum.

Energy loss in the transport of a beam of relativistic electrons in warm dense aluminum is measured in the regime of ultrahigh electron beam current density over 2×10^{11} A/cm^{2} (time averaged). The samples are heated by shock compression. Comparing to undriven cold solid targets, the roles of the different initial resistivity and of the transient resistivity (upon target heating during electron transport) are directly observable in the experimental data, and are reproduced by a comprehensive set of simulations describing the hydrodynamics of the shock compression and electron beam generation and transport. We measured a 19% increase in electron resistive energy loss in warm dense compared to cold solid samples of identical areal mass.

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.

BACKGROUND: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. METHODS: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. RESULTS: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). CONCLUSIONS: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.

Tunable mega-ampere electron current propagation in solids by dynamic control of lattice melt.

The influence of lattice-melt-induced resistivity gradients on the transport of mega-ampere currents of fast electrons in solids is investigated numerically and experimentally using laser-accelerated protons to induce isochoric heating. Tailoring the heating profile enables the resistive magnetic fields which strongly influence the current propagation to be manipulated. This tunable laser-driven process enables important fast electron beam properties, including the beam divergence, profile, and symmetry to be actively tailored, and without recourse to complex target manufacture.

Adherence therapy improves medication adherence and quality of life in people with Parkinson's disease: a randomised controlled trial.

BACKGROUND: Many factors are associated with medication non-adherence in Parkinson's disease (PD), including complex treatment regimens, mood disorders and impaired cognition. However, interventions to improve adherence which acknowledge such factors are lacking. A phase II randomised controlled trial was conducted investigating whether Adherence Therapy (AT) improves medication adherence and quality of life (QoL) compared with routine care (RC) in PD. METHODS: Eligible PD patients and their spouse/carers were randomised to intervention (RC plus AT) or control (RC alone). Primary outcomes were change in adherence (Morisky Medication Adherence Scale) and QoL (Parkinson's Disease Questionnaire-39) from baseline to week-12 follow up. Secondary outcomes were MDS-UPDRS (part I, II, IV), Beliefs about Medication Questionnaire (BMQ), EuroQol (EQ-5D) and the Caregiving Distress Scale. Blinded data were analysed using logistic and linear regression models based on the intention-to-treat principle. RESULTS: Seventy-six patients and 46 spouse/carers completed the study (intervention: n = 38 patients, n = 24 spouse/carers). At week-12 AT significantly improved adherence compared with RC (OR 8.2; 95% CI: 2.8, 24.3). Numbers needed to treat (NNT) were 2.2 (CI: 1.6, 3.9). Compared with RC, AT significantly improved PDQ-39 (-9.0 CI: -12.2, -5.8), BMQ general harm (-1.0 CI: -1.9, -0.2) and MDS-UPDRS part II (-4.8 CI: -8.1, -1.4). No significant interaction was observed between the presence of a spouse/carer and the effect of AT. CONCLUSION: Adherence Therapy improved self-reported adherence and QoL in a PD sample. The small NNT suggests AT may be cost-effective. A larger pragmatic trial to test the efficacy and cost-effectiveness of AT by multiple therapists is required.

Annular fast electron transport in silicon arising from low-temperature resistivity.

Fast electron transport in Si, driven by ultraintense laser pulses, is investigated experimentally and via 3D hybrid particle-in-cell simulations. A transition from a Gaussian-like to an annular fast electron beam profile is demonstrated and explained by resistively generated magnetic fields. The results highlight the potential to completely transform the beam transport pattern by tailoring the resistivity-temperature profile at temperatures as low as a few eV.

Exotic dense-matter states pumped by a relativistic laser plasma in the radiation-dominated regime.

In high-spectral resolution experiments with the petawatt Vulcan laser, strong x-ray radiation of KK hollow atoms (atoms without n = 1 electrons) from thin Al foils was observed at pulse intensities of 3 × 10(20) W/cm(2). The observations of spectra from these exotic states of matter are supported by detailed kinetics calculations, and are consistent with a picture in which an intense polychromatic x-ray field, formed from Thomson scattering and bremsstrahlung in the electrostatic fields at the target surface, drives the KK hollow atom production. We estimate that this x-ray field has an intensity of >5 × 10(18) W/cm(2) and is in the 3 keV range.

Controlling fast-electron-beam divergence using two laser pulses.

This Letter describes the first experimental demonstration of the guiding of a relativistic electron beam in a solid target using two colinear, relativistically intense, picosecond laser pulses. The first pulse creates a magnetic field that guides the higher-current, fast-electron beam generated by the second pulse. The effects of intensity ratio, delay, total energy, and intrinsic prepulse are examined. Thermal and Kα imaging show reduced emission size, increased peak emission, and increased total emission at delays of 4-6 ps, an intensity ratio of 10∶1 (second:first) and a total energy of 186 J. In comparison to a single, high-contrast shot, the inferred fast-electron divergence is reduced by 2.7 times, while the fast-electron current density is increased by a factor of 1.8. The enhancements are reproduced with modeling and are shown to be due to the self-generation of magnetic fields. Such a scheme could be of considerable benefit to fast-ignition inertial fusion.

The changing landscape of axillary surgery: which breast cancer patients may still benefit from complete axillary lymph node dissection?

BACKGROUND AND OBJECTIVES: Many breast cancer patients undergoing completion axillary lymph node dissection (CALND) for sentinel lymph node (SLN) metastases have no further disease. Predicting patients at high risk of non-sentinel lymph node (NSLN) metastasis may help guide effective utilization of CALND. METHODS: SLN+ breast cancer patients undergoing frozen section (FS) analysis at a single institution (2004-2010) were studied retrospectively. Factors associated with NSLN metastases were identified. RESULTS: Two-hundred forty SLN+ patients were identified. The incidence of NSLN metastases was 45% in FS(+) patients undergoing CALND, compared to 10% of FS(-) patients following CALND (P < 0.001). Multivariate analysis revealed that FS positivity, tumor size, and the presence of angiolymphatic invasion were significant factors associated with NSLN metastases (all P < 0.05). Further analysis of FS(+) patients revealed that tumor size, ER(-) status, and lymph node metastasis size were also associated with risk of NSLN metastases. An algorithm for the management of the axilla in SLN+ breast cancer patients was devised, based on clinic-pathologic predictors of NSLN metastases. CONCLUSION: A SLN+ biopsy by FS predicts the presence of NSLN metastases and, in combination with other factors, may justify immediate CALND. CALND may, however, be avoided in selected low-risk SLN+ patients.

Influence of spatial-intensity contrast in ultraintense laser-plasma interactions.

Increasing the intensity to which high power laser pulses are focused has opened up new research possibilities, including promising new approaches to particle acceleration and phenomena such as high field quantum electrodynamics. Whilst the intensity achievable with a laser pulse of a given power can be increased via tighter focusing, the focal spot profile also plays an important role in the interaction physics. Here we show that the spatial-intensity distribution, and specifically the ratio of the intensity in the peak of the laser focal spot to the halo surrounding it, is important in the interaction of ultraintense laser pulses with solid targets. By comparing proton acceleration measurements from foil targets irradiated with by a near-diffraction-limited wavelength scale focal spot and larger F-number focusing, we find that this spatial-intensity contrast parameter strongly influences laser energy coupling to fast electrons. We find that for multi-petawatt pulses, spatial-intensity contrast is potentially as important as temporal-intensity contrast.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Effect of lattice structure on energetic electron transport in solids irradiated by ultraintense laser pulses.

The effect of lattice structure on the transport of energetic (MeV) electrons in solids irradiated by ultraintense laser pulses is investigated using various allotropes of carbon. We observe smooth electron transport in diamond, whereas beam filamentation is observed with less ordered forms of carbon. The highly ordered lattice structure of diamond is shown to result in a transient state of warm dense carbon with metalliclike conductivity, at temperatures of the order of 1-100 eV, leading to suppression of electron beam filamentation.

Deconvolution of multi-Boltzmann x-ray distribution from linear absorption spectrometer via analytical parameter reduction.

Accurate characterization of incident radiation is a fundamental challenge for diagnostic design. Herein, we present an efficient spectral analysis routine that is able to characterize multiple components within the spectral emission by analytically reducing the number of parameters. The technique is presented alongside the design of a hard x-ray linear absorption spectrometer using the example of multiple Boltzmann-like spectral distributions; however, it is generally applicable to all absorption based spectrometer designs and can be adapted to any incident spectral shape. This routine is demonstrated to be tolerable to experimental noise and suitable for real-time data processing at multi-Hz repetition rates.

Interaction of ethanol and water with the {1014} surface of calcite.

Molecular dynamics simulations have been used to model the interaction between ethanol, water, and the {1014} surface of calcite. Our results demonstrate that a single ethanol molecule is able to form two interactions with the mineral surface (both Ca-O and O-H), resulting in a highly ordered, stable adsorption layer. In contrast, a single water molecule can only form one or other of these interactions and is thus less well bound, resulting in a more unstable adsorption layer. Consequently, when competitive adsorption is considered, ethanol dominates the adsorption layer that forms even when the starting configuration consists of a complete monolayer of water at the surface. The computational results are in good agreement with the results from atomic force microscopy experiments where it is observed that a layer of ethanol remains attached to the calcite surface, decreasing its ability to interact with water and for growth at the {1014} surface to occur. This observation, and its corresponding molecular explanation, may give some insight into the ability to control crystal form using mixtures of different organic solvents.

High order mode structure of intense light fields generated via a laser-driven relativistic plasma aperture.

The spatio-temporal and polarisation properties of intense light is important in wide-ranging topics at the forefront of extreme light-matter interactions, including ultrafast laser-driven particle acceleration, attosecond pulse generation, plasma photonics, high-field physics and laboratory astrophysics. Here, we experimentally demonstrate modifications to the polarisation and temporal properties of intense light measured at the rear of an ultrathin target foil irradiated by a relativistically intense laser pulse. The changes are shown to result from a superposition of coherent radiation, generated by a directly accelerated bipolar electron distribution, and the light transmitted due to the onset of relativistic self-induced transparency. Simulations show that the generated light has a high-order transverse electromagnetic mode structure in both the first and second laser harmonics that can evolve on intra-pulse time-scales. The mode structure and polarisation state vary with the interaction parameters, opening up the possibility of developing this approach to achieve dynamic control of structured light fields at ultrahigh intensities.

Predictive factors of upstaging DCIS to invasive carcinoma in BCT vs mastectomy.

BACKGROUND: Upstaging from DCIS to invasive ductal carcinoma varies widely from 0 to 59%. We aim to identify risk factors associated with upstaging in all DCIS patients and based on specific surgical intervention. METHODS: Patients with a pre-operative diagnosis of DCIS undergoing BCT or mastectomy were reviewed. Multivariable analysis was performed to identify risk factors for upstaging. RESULTS: In total, 623 patients had a preoperative diagnosis of DCIS. Upstaging occurred in 74 patients (12%) overall. There was no difference in upstaging rates between mastectomy and BCT (11% v 14% p = 0.27). Sentinel lymph node biopsy was positive in 4/212 patients (1%). Multivariable analysis revealed suspicion of microinvasion (OR 5.7 95%CI2.2-14.9), surgeon suspicion of invasive disease (OR 2.7, 95% CI 1.2-6.4) and larger size/multicentric/extensive tumor (OR 1.9 95% CI 1.1-3.4) increase risk of upstaging. CONCLUSIONS: Suspicion of microinvasion, surgeon suspicion, and tumor size can be used to help guide the use of sentinel lymph node biopsy. For patients without these high risk characteristics, it is hard to justify the use of concurrent SLN biopsy for patients who undergo BCT.

Time-resolved measurements of fast electron recirculation for relativistically intense femtosecond scale laser-plasma interactions.

A key issue in realising the development of a number of applications of high-intensity lasers is the dynamics of the fast electrons produced and how to diagnose them. We report on measurements of fast electron transport in aluminium targets in the ultra-intense, short-pulse (<50 fs) regime using a high resolution temporally and spatially resolved optical probe. The measurements show a rapidly (≈0.5c) expanding region of Ohmic heating at the rear of the target, driven by lateral transport of the fast electron population inside the target. Simulations demonstrate that a broad angular distribution of fast electrons on the order of 60° is required, in conjunction with extensive recirculation of the electron population, in order to drive such lateral transport. These results provide fundamental new insight into fast electron dynamics driven by ultra-short laser pulses, which is an important regime for the development of laser-based radiation and particle sources.

Near-100 MeV protons via a laser-driven transparency-enhanced hybrid acceleration scheme.

The range of potential applications of compact laser-plasma ion sources motivates the development of new acceleration schemes to increase achievable ion energies and conversion efficiencies. Whilst the evolving nature of laser-plasma interactions can limit the effectiveness of individual acceleration mechanisms, it can also enable the development of hybrid schemes, allowing additional degrees of control on the properties of the resulting ion beam. Here we report on an experimental demonstration of efficient proton acceleration to energies exceeding 94 MeV via a hybrid scheme of radiation pressure-sheath acceleration in an ultrathin foil irradiated by a linearly polarised laser pulse. This occurs via a double-peaked electrostatic field structure, which, at an optimum foil thickness, is significantly enhanced by relativistic transparency and an associated jet of super-thermal electrons. The range of parameters over which this hybrid scenario occurs is discussed and implications for ion acceleration driven by next-generation, multi-petawatt laser facilities are explored.