Metastatic small bowel adenocarcinoma: role of metastasectomy and systemic chemotherapy.

BACKGROUND: Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. PATIENTS AND METHODS: In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. RESULTS: The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. CONCLUSIONS: In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited.

Image-plate sensitivity to x rays at 2 to 60 keV.

The sensitivity of Fuji SR and MS image plates (IPs) used in x-ray spectrometers on OMEGA and the National Ignition Facility has been measured using two techniques. A set of radioisotopes has been used to constrain image-plate sensitivity between 6 and 60 keV, while a Manson source has been used to expose image plates to x rays at energies between 1.5 and 8 keV. These data have shown variation in sensitivity on the order of 5% for a given IP type and scanner settings. The radioisotope technique has also been used to assess IP fading properties for MS-type plates over long times. IP sensitivity as a function of scanner settings and pixel size has been systematically examined, showing variations of up to a factor of 2 depending on the IP type. Cross-calibration of IP scanners at different facilities is necessary to produce a consistent absolute sensitivity curve spanning the energy range of 2-60 keV.

Imaging at an x-ray absorption edge using free electron laser pulses for interface dynamics in high energy density systems.

Tuning the energy of an x-ray probe to an absorption line or edge can provide material-specific measurements that are particularly useful for interfaces. Simulated hard x-ray images above the Fe K-edge are presented to examine ion diffusion across an interface between Fe2O3 and SiO2 aerogel foam materials. The simulations demonstrate the feasibility of such a technique for measurements of density scale lengths near the interface with submicron spatial resolution. A proof-of-principle experiment is designed and performed at the Linac coherent light source facility. Preliminary data show the change of the interface after shock compression and heating with simultaneous fluorescence spectra for temperature determination. The results provide the first demonstration of using x-ray imaging at an absorption edge as a diagnostic to detect ultrafast phenomena for interface physics in high-energy-density systems.

X-ray transport and radiation response assessment (XTRRA) experiments at the National Ignition Facility.

Our team has developed an experimental platform to evaluate the x-ray-generated stress and impulse in materials. Experimental activities include x-ray source development, design of the sample mounting hardware and sensors interfaced to the National Ignition Facility's diagnostics insertion system, and system integration into the facility. This paper focuses on the X-ray Transport and Radiation Response Assessment (XTRRA) test cassettes built for these experiments. The test cassette is designed to position six samples at three predetermined distances from the source, each known to within ±1% accuracy. Built-in calorimeters give in situ measurements of the x-ray environment along the sample lines of sight. The measured accuracy of sample responses as well as planned modifications to the XTRRA cassette is discussed.

Multiple exposures to indoor contaminants: Derivation of benchmark doses and relative potency factors based on male reprotoxic effects.

Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10 = 7.72E-07 mg/kg bw/d; RPF10 = 7,033,679); for 50%, benzo[a]pyrene (BMD50 = 0.030 mg/kg bw/d; RPF50 = 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50 = 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data.

Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms.

BACKGROUND: Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. METHODS: The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. RESULTS: A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42 months vs. 76 months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P = 0.03) and PFS (4 months vs. 9 months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P = 0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9 months versus 3 months (P = 0.05). CONCLUSIONS: Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.

X-ray area backlighter development at the National Ignition Facility (invited).

1D spectral imaging was used to characterize the K-shell emission of Z ≈ 30-35 and Z ≈ 40-42 laser-irradiated foils at the National Ignition Facility. Foils were driven with up to 60 kJ of 3ω light, reaching laser irradiances on target between 0.5 and 20 × 10(15) W/cm(2). Laser-to-X-ray conversion efficiency (CE) into the Heα line (plus satellite emission) of 1.0%-1.5% and 0.15%-0.2% was measured for Z ≈ 30-32 and Z ≈ 40-42, respectively. Measured CE into Heα (plus satellite emission) of Br (Z = 35) compound foils (either KBr or RbBr) ranged between 0.16% and 0.29%. Measured spectra are compared with 1D non-local thermodynamic equilibrium atomic kinetic and radiation transport simulations, providing a fast and accurate predictive capability.

The NIF x-ray spectrometer calibration campaign at Omega.

The calibration campaign of the National Ignition Facility X-ray Spectrometer (NXS) was carried out at the Omega laser facility. Spherically symmetric, laser-driven, millimeter-scale x-ray sources of K-shell and L-shell emission from various mid-Z elements were designed for the 2-18 keV energy range of the NXS. The absolute spectral brightness was measured by two calibrated spectrometers. We compare the measured performance of the target design to radiation hydrodynamics simulations.

Demonstration of x-ray fluorescence imaging of a high-energy-density plasma.

Experiments at the Trident Laser Facility have successfully demonstrated the use of x-ray fluorescence imaging (XRFI) to diagnose shocked carbonized resorcinol formaldehyde (CRF) foams doped with Ti. One laser beam created a shock wave in the doped foam. A second laser beam produced a flux of vanadium He-α x-rays, which in turn induced Ti K-shell fluorescence within the foam. Spectrally resolved 1D imaging of the x-ray fluorescence provided shock location and compression measurements. Additionally, experiments using a collimator demonstrated that one can probe specific regions within a target. These results show that XRFI is a capable alternative to path-integrated measurements for diagnosing hydrodynamic experiments at high energy density.

Development of a Big Area BackLighter for high energy density experiments.

A very large area (7.5 mm(2)) laser-driven x-ray backlighter, termed the Big Area BackLighter (BABL) has been developed for the National Ignition Facility (NIF) to support high energy density experiments. The BABL provides an alternative to Pinhole-Apertured point-projection Backlighting (PABL) for a large field of view. This bypasses the challenges for PABL in the equatorial plane of the NIF target chamber where space is limited because of the unconverted laser light that threatens the diagnostic aperture, the backlighter foil, and the pinhole substrate. A transmission experiment using 132 kJ of NIF laser energy at a maximum intensity of 8.52 × 10(14) W/cm(2) illuminating the BABL demonstrated good conversion efficiency of >3.5% into K-shell emission producing ~4.6 kJ of high energy x rays, while yielding high contrast images with a highly uniform background that agree well with 2D simulated spectra and spatial profiles.

A geophysical shock and air blast simulator at the National Ignition Facility.

The energy partitioning energy coupling experiments at the National Ignition Facility (NIF) have been designed to measure simultaneously the coupling of energy from a laser-driven target into both ground shock and air blast overpressure to nearby media. The source target for the experiment is positioned at a known height above the ground-surface simulant and is heated by four beams from the NIF. The resulting target energy density and specific energy are equal to those of a low-yield nuclear device. The ground-shock stress waves and atmospheric overpressure waveforms that result in our test system are hydrodynamically scaled analogs of full-scale seismic and air blast phenomena. This report summarizes the development of the platform, the simulations, and calculations that underpin the physics measurements that are being made, and finally the data that were measured. Agreement between the data and simulation of the order of a factor of two to three is seen for air blast quantities such as peak overpressure. Historical underground test data for seismic phenomena measured sensor displacements; we measure the stresses generated in our ground-surrogate medium. We find factors-of-a-few agreement between our measured peak stresses and predictions with modern geophysical computer codes.

Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Demonstration of a 13-keV Kr K-shell x-ray source at the National Ignition Facility.

We report 3% conversion efficiency of laser energy into Kr K-shell (≈13 keV) radiation, consistent with theoretical predictions. This is ≈10× greater than previous work. The emission was produced from a 4.1-mm-diameter, 4-mm-tall gas pipe target filled with 1.2 or 1.5 atm of Kr gas. 160 of the National Ignition Facility laser beams deposited ≈700 kJ of 3ω light into the target in an ≈140 TW, 5.0-ns-duration square pulse. The Dante diagnostics measured ≈5 TW into 4π solid angle of ≥12 keV x rays for ≈4 ns, which includes both continuum emission and flux in the Kr He_{α} line at 13 keV.

Hot-spot mix in ignition-scale inertial confinement fusion targets.

Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation-front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed.

Relationship between postural control and restricted, repetitive behaviors in autism spectrum disorders.

Restricted, repetitive behaviors (RRBs) are one of the core diagnostic criteria of autism spectrum disorders (ASD), and include simple repetitive motor behaviors and more complex cognitive behaviors, such as compulsions and restricted interests. In addition to the core symptoms, impaired movement is often observed in ASD. Research suggests that the postural system in individuals with ASD is immature and may never reach adult levels. RRBs have been related to postural sway in individuals with mental retardation. Our goals were to determine whether subjects with ASD had greater postural sway and whether RBS-R scores were related to the magnitude of postural sway. We compared the center of pressure (COP) sway area during quiet stance with scores on the Repetitive Behavior Scale-Revised (RBS-R) in children with ASD and typically developing (TD) controls ages 3-16. All subjects had Non-verbal IQ > 70. Subjects performed four quiet stance trials at a self-selected stance width for 20 s. Subjects with ASD had greater postural sway area compared to controls. Not surprisingly, subjects with ASD exhibited greater frequencies and intensities of RRBs overall and on all six subscales. Further, there was a positive correlation between postural sway area and presence of RRBs. Interestingly, results of the postural sway area for the ASD group suggests that roughly half of the ASD subjects scored comparable to TD controls, whereas the other half scored >2 SD worse. Motor impaired children did not have significantly worse IQ scores, but were younger and had more RRBs. Results support previous findings of relationships between RRBs and postural control. It appears that motor control impairments may characterize a subset of individuals with ASD. Better delineation of motor control abilities in individuals with ASD will be important to help explain variations of abilities in ASD, inform treatment, and guide examination of underlying neural involvement in this very diverse disorder.

A Langmuir probe diagnostic for time-of-flight measurements of transient plasmas produced by high-energy laser ablation.

We discuss here the development of a Langmuir probe (LP) diagnostic to examine high-density, high-temperature inhomogeneous plasmas such as those that can be created at the University of Rochester's Laboratory for Laser Energetics OMEGA facility. We have configured our diagnostic to examine the velocity of the plasma expanding from the target. We observe velocities of approximately 16-17 cm/µs, with individual LP currents displaying complex structures, perhaps due to the multiple atomic species and ionization states that exist.

Source geometric considerations for OMEGA Dante measurements.

The Dante is a 15 channel filtered diode array which is installed on the OMEGA laser facility at the Laboratory for Laser Energetics, University of Rochester. The system yields the spectrally and temporally resolved radiation flux from 50 eV to 10 keV from various targets (i.e., Hohlraum, gas pipes, etc.). The absolute flux is determined from the radiometric calibration of the x-ray diodes, filters, and mirrors and an unfold algorithm applied to the recorded voltages from each channel. The unfold algorithm assumes an emitting source that is spatially uniform and has a constant area as a function of photon energy. The emitting x-ray source is usually considered to be the laser entrance hole (LEH) of a given diameter for Hohlraum type targets or the effective wall area of high conversion efficiency K-shell type targets. This assumption can be problematic for several reasons. High intensity regions or "hot spots" in the x-ray are observed where the drive laser beams strike the target. The "hot spots" create non-uniform emission seen by the Dante. Additionally, thinned walled (50 µm) low-Z targets (C(22)H(10)N(2)O(5)) have an energy dependent source size since the target's walls will be fully opaque for low energies (E < 2-3 keV) yet fully transmissive at higher energies. Determining accurate yields can be challenging for these types of targets. Discussion and some analysis will be presented.

Integrated x-ray reflectivity measurements of elliptically curved pentaerythritol crystals.

The elliptically curved pentaerythritol (PET) crystals used in the Supersnout 2 x-ray spectrometer on the National Ignition Facility at Lawrence Livermore National Laboratory have been calibrated photometrically in the range of 5.5-16 keV. The elliptical geometry provides broad spectral coverage and minimizes the degradation of spectral resolution due to the finite source size. The reflectivity curve of the crystals was measured using a x-ray line source. The integrated reflectivity (R(I)) and width of its curve (ΔΘ) were the measurements of major interest. The former gives the spectrometer throughput, and the latter gives the spectrometer resolving power. Both parameters are found to vary considerably with the radius of curvature of the crystal and with spectral energy. The results are attributed to an enhanced mosaic effect due to the increase in curvature. There are also contributions from the crystal cleaving and gluing processes.

The x-ray source application test cassette for radiation exposures at the OMEGA laser.

We have designed a sample cassette that can be used to position up to six samples in the OMEGA laser chamber. The cassette accommodates round samples up to 38.1 mm (1.5(")) in diameter and square samples up to 27 mm on a side, any of which can be up to 12.7 mm thick. Smaller specimens are centered with spacers. The test cassette allows each sample to have a unique filter scheme, with multiple filter regions in front of each sample. This paper will present mechanical design considerations and operational aspects of the x-ray source application cassette.