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.

Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.

BACKGROUND: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here. PATIENTS AND METHODS: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK). RESULTS: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively. CONCLUSIONS: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

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.

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.

Prospective study comparing different echocardiographic measurements of pulmonary capillary wedge pressure in patients with organic heart disease other than mitral stenosis.

In 25 patients with cardiac disease, but free of left ventricular inflow obstruction, the electrocardiogram and M-mode echocardiogram of the aortic root, left atrium and both the mitral and the aortic valves were obtained simultaneously with the pulmonary artery wedge pressure (PAWP) during right heart catheterization. The echocardiographic measurements of the left atrial size, PR-AC interval, left atrial emptying index and the ratio between the electrocardiographic Q wave to mitral valve closure (Q-MVC) and between aortic valve closure to the mitral E point (AVC-E) were correlated to the pulmonary artery wedge pressure by means of linear regression analysis. A formula in which PAWP = 36.6 (Q-MVC/AVC-E)-- 2 was prospectively used to study the measured pressure in the current group of patients. The pulmonary artery wedge pressure derived from these latter measurements correlated well with the invasive measurement of this pressure (r = 0.91). The pulmonary artery wedge pressure calculated by echocardiography differed from the pulmonary artery wedge pressure measured by catheterization by 3 mm Hg or less in 19 of the 25 patients, by 4 mm Hg or less in 22 patients and by 6 mm Hg or less in 24 patients. Although the correlation between the (Q-MVC/AVC-E) ratio and measured pulmonary artery wedge pressure was highly significant (r = 0.91, probability [p] less than 0.001, n = 25), the left atrial emptying index, PR-AC and left atrial size revealed poor correlation coefficients (r = 0.45, r = 0.45 and r = 0.56 [p less than 0.05]), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The crossed paralyses. The original brain-stem syndromes of Millard-Gubler, Foville, Weber, and Raymond-Cestan.

In this article, the crossed syndromes of Millard-Gubler (facial palsy and contralateral hemiparesis), Foville (facial palsy, conjugate gaze paralysis, and contralateral hemiparesis), Weber (oculomotor palsy and contralateral hemiparesis), and Raymond-Cestan (internuclear ophthalmoplegia and contralateral hemiparesis) are detailed from the original reports. These and other related syndromes were instrumental in establishing important principles in brain-stem localization: the occurrence of cranial nerve palsies contralateral to hemibody motor or sensory disturbances, the concepts of the medial longitudinal fasciculus and conjugate gaze, and the corticobulbar innervation of the facial nerve nucleus.

SPECT in patients with cortical visual loss.

Single-photon emission computed tomography (SPECT) with 99mTc-hexamethylpropyleneamine oxime (HMPAO) was used to investigate changes in cerebral blood flow in seven patients with cortical visual impairment. Traumatic brain injury (TBI) was the cause of cortical damage in two patients, cerebral ischemia in two patients and carbon monoxide (CO) poisoning, status epilepticus and Alzheimer's Disease (AD) each in three separate patients. The SPECT scans of the seven patients were compared to T2-weighted magnetic resonance image (MRI) scans of the brain to determine the correlation between functional and anatomical findings. In six of the seven patients, the qualitative interpretation of the SPECT studies supported the clinical findings (i.e., the visual field defect) by revealing altered regional cerebral blood flow (rCBF) in the appropriate regions of the visual pathway. MR scans in all of the patients, on the other hand, were either normal or disclosed smaller lesions than those detected by SPECT. We conclude that SPECT may reveal altered rCBF in patients with cortical visual impairment of various etiologies, even when MRI studies are normal or nondiagnostic.

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.

Myocardial infarction with angiographically normal coronary arteries.

To determine the prevalence rate and clinical and hemodynamic profile of patients with myocardial infarction (MI) with angiographically normal coronary arteries, we analyzed 3,403 consecutive angiograms performed within a 4.5-year period. Of these studies, 1,124 were performed following an acute MI. Through a computerized search, 12 patients were identified who had documented MI with normal or insignificant (< 30% stenosis in one epicardial vessel only) coronary disease. Q-wave MI developed in five patients (group A) and non-Q-wave MI developed in seven patients (group B). Group A patients were all men whereas group B patients were all women. Overall, group A patients were younger (p = 0.003), had a longer smoking history (p = 0.008), and a higher cardiac index (p = 0.005). In ten patients, areas of localized dyskinesia or hypokinesia were shown on left ventricular cineangiography. Mitral valve prolapse was present in four of the patients and varying degrees of mitral regurgitation were identified in another six. The prevalence rate of MI with angiographically normal coronary arteries was 1% in this study. This entity had a bimodal age and sex distribution: a younger age group, all men, with a stronger cigarette smoking history who had Q-wave MI vs an older age group, all women, and no significant association with cigarette smoking who developed non-Q-wave MI. A mean follow-up of 4 years demonstrated a favorable prognosis in both groups.

Retropubic vaginopexy for correction of urinary stress incontinence.

One of the most important principles of surgical correction of urinary stress incontinence is the restoration of the urethrovesical angle to its original anatomic position. A new variant of urethropexy, suspending the vaginal wall from the anterior rectus fascia, is presented. To accomplish this goal, a special ligature carrier needle was designed. The ligatures are carried with this needle from the vaginal wall, through the space of Retzius, and upward above the rectus fascia where they are tied across the midline, one side to the other. This report describes the new method in detail. Using this technique, urethropexy was performed on 98 patients at the UCLA Olive View Medical Center. The overall cure rate for urinary stress incontinence was over 95% at 6-months to 3-year follow-up. The most common complications were postoperative urinary retention and urinary tract infection. The average length of hospitalization was 5 days.

Streptococcus milleri pyomyoma simulating infective endocarditis.

A 37-year-old woman with clinically occult, abscessed uterine myomas presented with fever, anemia, splenomegaly, and viridans streptococcal bacteremia. An initial diagnosis of endocarditis was made, but fever persisted despite appropriate antibiotics. Pelvic pain evolved and laparotomy revealed an infected myoma. Streptococcus milleri was isolated from both the blood and the uterine abscess. Infected uterine myomata may be clinically silent despite producing sustained bacteremia. The occurrence of suppurating myomas and the significance of S milleri isolates are briefly reviewed.

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.

Improved clinical outcomes for in vitro fertilization with delay of embryo transfer from 48 to 72 hours after oocyte retrieval: use of glucose- and phosphate-free media.

OBJECTIVE: To evaluate clinical outcomes of day 2 versus day 3 ET using a culture media with no glucose or phosphate. DESIGN: Retrospective clinical study. SETTING: Hospital-based fertility clinic. PATIENT(S): One hundred seventy-six IVF-ET patients undergoing controlled ovarian supraovulation. INTERVENTION(S): IVF and delaying the ET by 1 day. MAIN OUTCOME MEASURE(S): Number of blastomeres per embryo, implantation and pregnancy rates. RESULT(S): Delaying the ET from day 2 to day 3 after oocyte retrieval significantly increased implantation rates (13% versus 24%) and ongoing/delivered pregnancy rates per retrieval (26% versus 44%). Day 3 embryos with > or = 8 blastomeres resulted in a significantly higher pregnancy rate (53%) than day 3 embryos with < 8 cells (23%) and day 2 embryos with > or = 4 cells (31%) or < 4 cells (11%). CONCLUSION(S): Day 3 ET was associated with a significant increase in implantation and pregnancy rates. Delaying the ET until day 3 may permit the selection of more viable embryos than on day 2. The absence of glucose and phosphate from the culture media is compatible with good IVF outcomes.

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.

Tuberculous meningitis with blindness and perichiasmal involvement on MRI.

An 11-year-old boy with tuberculous meningitis developed blindness, a rare complication of this disease in the United States. Magnetic resonance imaging demonstrated perichiasmal enhancement, suggesting that arachnoiditis caused the visual loss. Serial neuroimaging over 7 months revealed a persistent inflammatory process in the chiasmatic cistern, hydrocephalus, and progressive cerebral infarctions.

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.

Cerebellar top-of-the-basilar syndrome.

We present a patient with unusual cerebrovasculature due to the absence of anastomosis between anterior and posterior circulations and bilateral fetal posterior cerebral arteries. This resulted in an atypical 'cerebellar' top-of-the-basilar syndrome, with bilateral superior cerebellar artery infarctions. We review the clinical presentation and radiologic findings and explain the embryologic origin of this vascular anatomy.