Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations.

BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape. PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA). RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations. CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies.

BACKGROUND: The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations. PATIENTS AND METHODS: Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant. RESULTS: Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)]. CONCLUSIONS: Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.

Stellar

The ^{36}Ar(n,γ)^{37}Ar (t_{1/2}=35 d) and ^{38}Ar(n,γ)^{39}Ar (269 yr) reactions were studied for the first time with a quasi-Maxwellian (kT∼47 keV) neutron flux for Maxwellian average cross section (MACS) measurements at stellar energies. Gas samples were irradiated at the high-intensity Soreq applied research accelerator facility-liquid-lithium target neutron source and the ^{37}Ar/^{36}Ar and ^{39}Ar/^{38}Ar ratios in the activated samples were determined by accelerator mass spectrometry at the ATLAS facility (Argonne National Laboratory). The ^{37}Ar activity was also measured by low-level counting at the University of Bern. Experimental MACS of ^{36}Ar and ^{38}Ar, corrected to the standard 30 keV thermal energy, are 1.9(3) and 1.3(2) mb, respectively, differing from the theoretical and evaluated values published to date by up to an order of magnitude. The neutron-capture cross sections of ^{36,38}Ar are relevant to the stellar nucleosynthesis of light neutron-rich nuclides; the two experimental values are shown to affect the calculated mass fraction of nuclides in the region A=36-48 during the weak s process. The new production cross sections have implications also for the use of ^{37}Ar and ^{39}Ar as environmental tracers in the atmosphere and hydrosphere.

Demonstration of a high-intensity neutron source based on a liquid-lithium target for Accelerator based Boron Neutron Capture Therapy.

A free surface liquid-lithium jet target is operating routinely at Soreq Applied Research Accelerator Facility (SARAF), bombarded with a ~1.91 MeV, ~1.2 mA continuous-wave narrow proton beam. The experiments demonstrate the liquid lithium target (LiLiT) capability to constitute an intense source of epithermal neutrons, for Accelerator based Boron Neutron Capture Therapy (BNCT). The target dissipates extremely high ion beam power densities (>3 kW/cm(2), >0.5 MW/cm(3)) for long periods of time, while maintaining stable conditions and localized residual activity. LiLiT generates ~3×10(10) n/s, which is more than one order of magnitude larger than conventional (7)Li(p,n)-based near threshold neutron sources. A shield and moderator assembly for BNCT, with LiLiT irradiated with protons at 1.91 MeV, was designed based on Monte Carlo (MCNP) simulations of BNCT-doses produced in a phantom. According to these simulations it was found that a ~15 mA near threshold proton current will apply the therapeutic doses in ~1h treatment duration. According to our present results, such high current beams can be dissipated in a liquid-lithium target, hence the target design is readily applicable for accelerator-based BNCT.

Note: Proton irradiation at kilowatt-power and neutron production from a free-surface liquid-lithium target.

The free-surface Liquid-Lithium Target, recently developed at Soreq Applied Research Accelerator Facility (SARAF), was successfully used with a 1.9 MeV, 1.2 mA (2.3 kW) continuous-wave proton beam. Neutrons (~2 × 10(10) n/s having a peak energy of ~27 keV) from the (7)Li(p,n)(7)Be reaction were detected with a fission-chamber detector and by gold activation targets positioned in the forward direction. The setup is being used for nuclear astrophysics experiments to study neutron-induced reactions at stellar energies and to demonstrate the feasibility of accelerator-based boron neutron capture therapy.

High-power electron beam tests of a liquid-lithium target and characterization study of (7)Li(p,n) near-threshold neutrons for accelerator-based boron neutron capture therapy.

A compact Liquid-Lithium Target (LiLiT) was built and tested with a high-power electron gun at Soreq Nuclear Research Center (SNRC). The target is intended to demonstrate liquid-lithium target capabilities to constitute an accelerator-based intense neutron source for Boron Neutron Capture Therapy (BNCT) in hospitals. The lithium target will produce neutrons through the (7)Li(p,n)(7)Be reaction and it will overcome the major problem of removing the thermal power >5kW generated by high-intensity proton beams, necessary for sufficient therapeutic neutron flux. In preliminary experiments liquid lithium was flown through the target loop and generated a stable jet on the concave supporting wall. Electron beam irradiation demonstrated that the liquid-lithium target can dissipate electron power densities of more than 4kW/cm(2) and volumetric power density around 2MW/cm(3) at a lithium flow of ~4m/s, while maintaining stable temperature and vacuum conditions. These power densities correspond to a narrow (σ=~2mm) 1.91MeV, 3mA proton beam. A high-intensity proton beam irradiation (1.91-2.5MeV, 2mA) is being commissioned at the SARAF (Soreq Applied Research Accelerator Facility) superconducting linear accelerator. In order to determine the conditions of LiLiT proton irradiation for BNCT and to tailor the neutron energy spectrum, a characterization of near threshold (~1.91MeV) (7)Li(p,n) neutrons is in progress based on Monte-Carlo (MCNP and Geant4) simulation and on low-intensity experiments with solid LiF targets. In-phantom dosimetry measurements are performed using special designed dosimeters based on CR-39 track detectors.

Neurologic safety event rates in the SENTIS trial control population.

BACKGROUND: Adverse event (AE) rates for interventional stroke trials are not well established. AIMS: We prospectively evaluated control arm AEs from a randomized stroke trial to establish expected rates of neurologic AEs. METHODS: Control data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS) Trial were evaluated. Patients were ≥ 18 years with National Institutes of Health Stroke Scale (NIHSS) scores 5-18 within 14 h of stroke onset. Follow-up was 90 days. Neurological AEs and serious AEs (SAEs) were adjudicated and the following defined times used to determine treatment relatedness: 24-h imaging for intracranial hemorrhage (ICnH) including hemorrhagic transformation, 7 days each for cerebral edema and neurologic worsening/stroke progression, and 30 days for new ischemic strokes. RESULTS: The control group included 257 patients, 49.4% female, mean age of 68.3 years, and median NIHSS of 10. Neurologic AEs occurred at the following rates: ICnH 27.6%, cerebral edema 6.6%, neurologic worsening 18.3%, and new stroke 4.7%. Most of these events occurred within the defined times: ICnH 74.6%, cerebral edema 94.1%, neurologic worsening 87.2%, and new stroke 83.3%. CONCLUSIONS: SENTIS Trial control arm neurologic events provide estimates of expected AE rates and defined times that can be used for future stroke trial's safety assessments.

High-power liquid-lithium jet target for neutron production.

A compact liquid-lithium target (LiLiT) was built and tested with a high-power electron gun at the Soreq Nuclear Research Center. The lithium target, to be bombarded by the high-intensity proton beam of the Soreq Applied Research Accelerator Facility (SARAF), will constitute an intense source of neutrons produced by the (7)Li(p,n)(7)Be reaction for nuclear astrophysics research and as a pilot setup for accelerator-based Boron Neutron Capture Therapy. The liquid-lithium jet target acts both as neutron-producing target and beam dump by removing the beam thermal power (>5 kW, >1 MW/cm(3)) with fast transport. The target was designed based on a thermal model, accompanied by a detailed calculation of the (7)Li(p,n) neutron yield, energy distribution, and angular distribution. Liquid lithium is circulated through the target loop at ~200 °C and generates a stable 1.5 mm-thick film flowing at a velocity up to 7 m/s onto a concave supporting wall. Electron beam irradiation demonstrated that the liquid-lithium target can dissipate electron power areal densities of >4 kW/cm(2) and volume power density of ~2 MW/cm(3) at a lithium flow of ~4 m/s while maintaining stable temperature and vacuum conditions. The LiLiT setup is presently in online commissioning stage for high-intensity proton beam irradiation (1.91-2.5 MeV, 1-2 mA) at SARAF.

High-power liquid-lithium target prototype for accelerator-based boron neutron capture therapy.

A prototype of a compact Liquid-Lithium Target (LiLiT), which will possibly constitute an accelerator-based intense neutron source for Boron Neutron Capture Therapy (BNCT) in hospitals, was built. The LiLiT setup is presently being commissioned at Soreq Nuclear Research Center (SNRC). The liquid-lithium target will produce neutrons through the (7)Li(p,n)(7)Be reaction and it will overcome the major problem of removing the thermal power generated using a high-intensity proton beam (>10 kW), necessary for sufficient neutron flux. In off-line circulation tests, the liquid-lithium loop generated a stable lithium jet at high velocity, on a concave supporting wall; the concept will first be tested using a high-power electron beam impinging on the lithium jet. High intensity proton beam irradiation (1.91-2.5 MeV, 2-4 mA) will take place at Soreq Applied Research Accelerator Facility (SARAF) superconducting linear accelerator currently in construction at SNRC. Radiological risks due to the (7)Be produced in the reaction were studied and will be handled through a proper design, including a cold trap and appropriate shielding. A moderator/reflector assembly is planned according to a Monte Carlo simulation, to create a neutron spectrum and intensity maximally effective to the treatment and to reduce prompt gamma radiation dose risks.

Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVES: 1) To evaluate the risk of subsequent stroke or death in patients with a cryptogenic stroke and a patent foramen ovale (PFO), atrial septal aneurysm (ASA), or both. 2) To establish the optimal method of stroke prevention in this population of patients. METHODS: MEDLINE, the Cochrane database of systematic reviews, key meeting abstracts from 1997 to 2002, and relevant reference lists were searched to select studies that prospectively collected outcome data in cryptogenic stroke patients with and without interatrial septal abnormalities. Studies were also selected that prospectively compared at least two treatment options. The quality of each study was graded (class I to IV) using a standard classification-of-evidence scheme for each question. Risk analyses were performed and data were pooled when appropriate. RESULTS: The literature search generated 129 articles of which only four fulfilled the inclusion and exclusion criteria. Two studies were graded class I, one study was graded class II, and one study was graded class IV for prognosis. Pooled results of the two class I and one class II studies demonstrated no increased risk of subsequent stroke or death in patients with PFO compared to those without (RR = 0.95, 95% CI 0.62 to 1.44). One class I study found increased risk of recurrent stroke in patients with PFO and ASA (annual rate = 3.8% versus 1.05%, RR = 2.98, 95% CI 1.17 to 7.58) but not increased risk of a composite of stroke and death (annual rate = 3.8% versus 1.8%, RR = 2.10, 95% CI 0.86 to 5.06). Regarding therapy, one study was graded class II, one study class III, and two studies class IV. Among patients with cryptogenic stroke and PFO or ASA, there was no significant difference in stroke or death rate in warfarin-treated patients relative to aspirin-treated patients and the confidence intervals were unable to rule out a benefit of one drug over the other (annual rate = 4.7% versus 8.9%, RR = 0.53, 95% CI 0.18 to 1.58). Minor bleeding rates were higher in the cohort of patients who received warfarin (22.9/100 patient-years versus 8.66/100 patient-years, rate ratio = 2.64, p < 0.001). No studies compared medical therapy with surgical or endovascular closure. CONCLUSION: PFO is not associated with increased risk of subsequent stroke or death among medically treated patients with cryptogenic stroke. However, both PFO and ASA possibly increase the risk of subsequent stroke (but not death) in medically treated patients younger than 55 years. In patients with a cryptogenic stroke and an atrial septal abnormality the evidence is insufficient to determine if warfarin or aspirin is superior in preventing recurrent stroke or death, but minor bleeding is more frequent with warfarin. There is insufficient evidence to evaluate the efficacy of surgical or endovascular closure.

Early separation and sibling incest. A test of the revised Westermarck theory.

This was a follow-up study of earlier reported findings by the present investigators suggesting, albeit equivocally, that separation during early childhood inhibited later sexual acts of a potentially procreative nature between siblings but did not deter other sexual activity. The present study surveyed 170 subjects, mostly in the Toronto area, by telephone and mail. Respondents reporting potentially procreative, postchildhood sexual acts (attempted or completed genital intercourse) with siblings were compared with those reporting sexual relationships excluding procreative acts, and a third sample reporting no postchildhood sibling sexual behavior. Consonant with expectations from the earlier study, prolonged separation during early childhood was associated with procreative postchildhood sexual activity but not with other postchildhood sexual activity. Contrary to predictions, however, both sexual activity groups reported significantly more nudity and physical contact with siblings during childhood than subjects reporting no sexual activity. The findings are discussed in terms of a revised version of the Westermarck hypothesis, which is consistent with a domain-specific approach to evolved incest avoidance mechanisms.

Evolved mechanisms underlying wayfinding. further studies on the hunter-gatherer theory of spatial sex differences.

Based on Silverman and Eals' hunter-gatherer theory of the origin of sex-specific spatial attributes, the present research sought to identify the evolved mechanisms involved in hunting that contribute to the dimorphism. The focus of these studies was the relationship between three-dimensional mental rotations, the spatial test showing the largest and most reliable sex difference favoring males, and wayfinding in the woods. Space constancy was presumed to be the evolved mechanism fundamental to both of these abilities. Measures of wayfinding were derived by leading subjects individually on a circuitous route through a wooded area, during which they were stopped at prescribed places and required to set an arrow pointing in the direction the walk began. As well, subjects were eventually required to lead the experimenters back to the starting point by the most direct route. In support of the hypotheses, males excelled on the various measures of wayfinding, and wayfinding was significantly related across sexes to mental rotations scores but not to nonrotational spatial abilities or general intelligence.

Vertebrobasilar dolichoectasia associated with Marfan syndrome.

We report a 37-year-old woman with Marfan syndrome (MFS) who presented with acute myelopathy secondary to a subdural spinal hematoma. The patient died of a subarachnoid hemorrhage 4 days later. Autopsy showed a markedly ectatic vertebrobasilar system with fragmentation of the internal elastic lamina. Microscopic examination of the aorta similarly showed a fragmented internal elastic lamina. We discuss the implications of our patient's early onset vertebrobasilar dolichoectasia; this intracranial disease represents a rare cause of subarachnoid hemorrhage in MFS.

Testosterone levels and spatial ability in men.

Testosterone (T) levels were measured by salivary assays in 59 males at times of the day when T was expected to be highest and lowest. Relationships were evaluated for mean hormone levels across the two sessions and hormone level changes between sessions with performance on three-dimensional mental rotations, a spatial test which customarily favours males. An anagrams task and the digit symbol test were used as controls. Mental rotations scores showed a significant positive relationship with mean T levels but not with changes in T. There were no significant relationships between control test scores and mean T levels. Findings are discussed in terms of their contributions to the resolution of ambiguities in prior reported data.

Oolemma rupture inside the intracytoplasmic sperm injection needle significantly improves the fertilization rate and reduces oocyte damage.

OBJECTIVE: To compare the effect on fertilization, oocyte damage, embryo freezing, and pregnancy rates of two different techniques for rupturing the oolemma during intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective study. SETTING: Fertility Center, Alliant Health System Hospital. PATIENT(S): Seventy-nine consecutive IVF-ICSI cases. INTERVENTION(S): Patients in group I had ICSI performed by pushing the needle into the oocyte until the oolemma was observed to break outside the needle. In group II the oolemma was aspirated into the needle until it ruptured inside the needle. MAIN OUTCOME MEASURE(S): In group II ICSI resulted in significantly higher fertilization and lower oocyte damage rates (66% and 13%) than in group 1 (39% and 29%). There were no statistically significant differences in embryo cleavage rates or pregnancy rates per retrieval between the two groups. A greater number of cases had embryos cryopreserved in group II than in group I. RESULT(S): Rupturing the oolemma by aspirating it into the ICSI needle (group II) improved laboratory outcomes compared with the more traditional technique of breaking this membrane by the stabbing action of the needle (group I). This modification of the ICSI technique also increased the number of patients with cryopreserved embryos and therefore could increase the pregnancy rate per patient. CONCLUSION(S): The site and technique used to rupture the oolemma during ICSI has a significant effect on the fertilization and damage rates.

Transient migraine-like symptoms with internal carotid artery dissection.

We report three patients with angiographically confirmed internal carotid artery (ICA) dissection who presented with transient symptoms resembling migraine with aura. Marching impairments from one modality to another preceded recognition of the diagnosis of dissection and were not associated with clinical or radiologic evidence of cerebral infarction. We review the clinical patterns in which ICA dissection may be identified in the setting of migrainous symptoms, given the different therapeutic approaches to migraine and dissection and the non-invasive means to diagnose dissection with magnetic resonance imaging (MRI). We offer mechanisms for recurrent neurologic symptoms in patients with ICA dissection.