Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). PATIENTS AND METHODS: Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). CONCLUSIONS: Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

The effect of ethidium bromide on mitochondrial DNA synthesis and mitochondrial DNA structure in HeLa cells.

The synthesis of mitochondrial DNA (mDNA) in HeLa cells is selectively inhibited by relatively low concentrations of ethidium bromide. After exposure of cells to strongly inhibitory concentrations of the drug, the apparent superhelix density of mDNA is rapidly increased, as judged by its buoyant density in CsCl in the presence of ethidium bromide. Mitochondrial DNA synthesized in the presence of partially inhibitory concentrations of ethidium bromide is also altered in its buoyant density in the presence of the dye, but is more heterogeneous in this respect. However, the change in buoyant density of newly synthesized mDNA may be explained by changes in structure other than a change in superhelix density, as indicated by its increased resistance to digestion by pancreatic DNase.

Vitamin C status and other nutritional indices in patients with stroke and other acute illnesses: a case-control study.

Sixty-three patients with acute thrombotic stroke were compared with 47 age and sex-matched patients admitted concurrently with acute ischaemic cardiac pain and a further 44 with acute noncardiovascular illnesses. Overall the stroke patients scored highest on a questionnaire designed to estimate mean daily intake of vitamin C before hospital admission. There were problems with this retrospective dietary assessment, however, and the diet scores of the 27 stroke patients able to answer the questionnaire themselves fell between those of the other two groups. There were no significant differences between the three patient groups in plasma ascorbic acid or uric acid levels, but plasma magnesium and albumin levels were higher in the stroke patients. These findings were similar for patients aged over and under 70 but intergroup differences in magnesium and albumin levels were more marked in the elderly. These results do not support the postulated inverse relationship between vitamin C status and the risk of stroke.

Binding of Alz 50 depends on Phe8 in tau synthetic peptides and varies between native and denatured tau proteins.

Alz 50 is a monoclonal antibody that in Western blotting analysis recognizes both normal tau as well as hyperphosphorylated tau proteins associated with paired helical filaments (PHF-tau) in Alzheimer disease (AD). Within tissue sections of AD brain, however, Alz 50 immunolabels only PHF, which suggests that the antibody recognizes a conformational epitope. Using competitive enzyme-linked immunosorbent assay, we demonstrate that Alz 50 binds to tau synthetic peptides with low affinity (KD between 0.27 to 2.7 x 10(-5) M) and that the binding is specific for the RQEF sequence corresponding to N-terminal residues 5-8 of tau. The Alz 50 epitope appears to be largely dependent on Phe8, a strongly hydrophobic amino acid residue, since the substitution of Phe8 with Ala8 in the synthetic peptide abolishes Alz 50 binding. The effects of tau conformation on Alz 50 binding were studied with various normal tau proteins with either low or high phosphate content (adult vs. fetal) and PHF-tau proteins. The normal tau fractions were isolated from both adult and fetal human brains using affinity chromatography (native form) and heat/perchloric acid treatments (denatured form). PHF-tau was isolated as Sarcosyl-insoluble fraction. With competitive ELISA, the denatured form of normal tau (fetal and adult) bound Alz 50 with the same high affinity as did PHF-tau (KD between 1.3 to 1.8 x 10(-7) M). In contrast, the native form of tau from either brain was unable to fully compete for Alz 50 and at most only 50% of the Alz 50 binding sites in native tau were occupied. These results suggest that native tau may exist either in complexes with other proteins or in a form of dimers/oligomers, in which only some N-termini are available for binding (e.g. head-to-tail assembly). The results also suggest that denaturation rather than phosphorylation of tau has more significant effect on interactions of tau with Alz 50.

Parent vessel occlusion for vertebrobasilar fusiform and dissecting aneurysms.

BACKGROUND AND PURPOSE: Previous reports of outcome with permanent vessel occlusion (PVO) for large, giant, or fusiform aneurysms in the posterior circulation have been limited. We undertook this study to evaluate the perioperative (within 30 days) and follow-up outcomes for patients treated with permanent occlusion of the vertebral artery for vertebrobasilar fusiform and dissecting aneurysms. METHODS: Thirteen consecutive patients were studied. Two groups were defined for the study. Group I patients underwent PVO to achieve complete thrombosis of the aneurysm. Group II patients underwent PVO to reduce flow to the aneurysm where complete thrombosis was not desirable. Modified Rankin scores were obtained at presentation and at follow-up (follow-up range, 1-76 months; mean, 22.0 months). RESULTS: All group I aneurysms were shown to be thrombosed on the angiograms obtained at the immediate follow-up examinations. Improvement in outcome scores was achieved by all group I patients. Improvement in Rankin scores after endovascular treatment was statistically significant (P =.026). All group II patients had complete occlusion of the vertebral artery; however, continued filling of the fusiform aneurysm was still observed. Four patients in group II died during the follow-up period. Two of these deaths were attributable to the aneurysms. Of the remaining three patients, two experienced clinical worsening and one remained stable. CONCLUSION: In this series, PVO for chronic fusiform and acute dissecting aneurysms of the vertebrobasilar system proved to be a useful therapeutic endovascular technique. Long-term outcomes suggest that patients with aneurysms involving only one vertebral artery, where complete thrombosis can be achieved, have better clinical outcomes than those who have aneurysms involving the basilar artery or both vertebral arteries, where complete thrombosis cannot achieved by using PVO.

Near-field visual acuity of pigeons: effects of head location and stimulus luminance.

Two pigeons were trained to discriminate a grating stimulus from a blank stimulus of equivalent luminance in a three-key chamber. The stimuli and blanks were presented behind a transparent center key. The procedure was a conditional discrimination in which pecks on the left key were reinforced if the blank had been present behind the center key and pecks on the right key were reinforced if the grating had been present behind the center key. The spatial frequency of the stimuli was varied in each session from four to 29.5 lines per millimeter in accordance with a variation of the method of constant stimuli. The number of lines per millimeter that the subjects could discriminate at threshold was determined from psychometric functions. Data were collected at five values of stimulus luminance ranging from--0.07 to 3.29 log cd/m2. The distance from the stimulus to the anterior nodal point of the eye, which was determined from measurements taken from high-speed motion-picture photographs of three additional pigeons and published intraocular measurements, was 62.0 mm. This distance and the grating detection thresholds were used to calculate the visual acuity of the birds at each level of luminance. Acuity improved with increasing luminance to a peak value of 0.52, which corresponds to a visual angle of 1.92 min, at a luminance of 2.33 log cd/m2. Further increase in luminance produced a small decline in acuity.

The effect of sodium trimetaphosphate (TMP) as a chewing gum additive on caries increments in children.

A three-year study on school-age children using trimetaphosphate as a chewing gum additive produced significant reductions in proximal surface dental caries increments as compared to an non-chewing gum group. The reductions were 23.3% for the TMP sucrose gum group and 47.6% for the TMP nonsugar group as compared to the no-gum group.

Critical care and tuberculosis.

The scientific literature documents the resurgence of airborne nosocomial transmission of Mycobacterium tuberculosis to patients and health care providers that has occurred in the last decade. Tuberculosis may not be recognized or diagnosed at the time of admission to the intensive care unit, adding to the risk of disease transmission to nurses, other health care providers, and patients. In the critical care setting, compliance with infection control requires the integration of specific policies and procedures into crises-based practices.

HIV infection/AIDS and critical care.

The complications of HIV infection may involve almost any organ system, often resulting in severe dysfunction that may be life threatening. Other disorders not associated with HIV infection may occur in HIV-infected patients and may be severe enough to require critical care. The risk for HIV infection may be unrecognized or undiagnosed at the time of admission to the intensive care unit, placing nurses and other health care providers at risk for the transmission of disease. In the critical care setting, compliance with infection control requires the integration of specific policies and procedures into crises-based practices.

Regulation of protein synthesis in HeLa cells. 3. Inhibition during poliovirus infection.

The mechanism of inhibition of host cell protein synthesis by poliovirus has been studied by examining the behavior of host polyribosomes and polyribosome-associated messenger ribonucleic acid (mRNA). Virus infection appears to result in a specific inhibition of the initiation of translation of host cell mRNA. The site of inhibition does not appear to be mRNA itself. Human cells respond to virus infection by producing a factor antagonistic to the virus inhibition which promotes the initiation of host mRNA translation. The production of the host factor is sensitive to actinomycin; however, the behavior of the host cell factor and that of host mRNA appear distinctly different.

Treatment of localized prostate cancer with intermittent triple androgen blockade: preliminary results in 110 consecutive patients.

OBJECTIVES: To determine the effectiveness of triple androgen blockade as an alternative to watchful waiting, radical prostatectomy or radiation therapy in the management of patients with clinical stage T1 to T3 prostate cancer. METHODS: The records of 110 consecutive patients were retrospectively evaluated. Patients were treated with a three-drug androgen blockade regimen, consisting of a luteinizing hormone-releasing hormone agonist (leuprolide or goserelin) plus an antiandrogen (flutamide or bicalutamide) plus finasteride (a 5-alpha-reductase inhibitor), followed by finasteride maintenance therapy, as the sole intervention. All patients refused local therapy and had their prostates intact. Determinants of efficacy included serum prostate-specific antigen (PSA) levels and disease-specific survival. RESULTS: Patients were treated for a median of 13 months with triple androgen blockade. At baseline, mean PSA level was 13.2 +/- 1.2 ng/ml (range, 0.39-100 ng/ml), and mean Gleason score was 6.6 +/- 0.1 (range, 4-10). During treatment, PSA levels declined to < or =0.1 ng/ml in all patients, with a median time of 3 months. After a median follow-up of 36 months since initiation of treatment, PSA levels have remained stable in 105 of 110 patients (95.5%). At a median follow-up of 55 months (range, 38-125 months), the mean PSA level for the first 57 patients treated in this series is 1.88 +/- 0.1 (range, 0-11.0 ng/ml). Only 9 of 110 (8.1%) patients have a PSA level > or =4.0 ng/ml. To date, no patient has received a second cycle of hormone blockade. CONCLUSIONS: Although median follow-up is short, triple androgen blockade therapy followed by finasteride maintenance appears to be a promising alternative for the management of patients with clinically localized or locally advanced prostate cancer. Further study of this approach is warranted.

The effect of preceding anaerobic exercise on aerobic and anaerobic work.

The effects of exercise-induced elevation of lactic acid concentration in blood [Lab] up to 12-14 mM on the subsequent aerobic (less than or equal to VO2 max) and anaerobic (supramaximal) performance was investigated in a group of trained non-athletic subjects. For submaximal loads ranging from 0.6 VO2 max to VO2 max the VO2 max/external work load (Wext) ratio was unaffected by preceding anaerobic exercise, VO2 max was not significantly different, whereas the maximal performance time of a standard exercise was reduced. The kinetics of the VO2 on- adjustment at the onset of 0.9 VO2 max rectangular loads carried out by the arms and/or by the legs was significantly increased by a preceding supramaximal anaerobic load carried out by the same as well as by the non-exercised limbs. It is concluded that in the presence of high [Lab] (1) the maximal aerobic power (VO2 max) is unchanged; (2) the efficiency of aerobic work is unaffected, which implies that during active recovery most La is used as substrate, provided the metabolic level during the latter exceeds 0.6 VO2 max; (3) the endurance for anaerobic as well as for aerobic exercise is reduced; (4) the kinetics of the VO2 adjustment at the onset of submaximal rectangular loads is faster, both in primed and in non-exercised muscles.

Reduction of plasma cholesterol by lovastatin normalizes erythrocyte membrane fluidity in patients with severe hypercholesterolaemia.

The effect of lovastatin on erythrocyte membrane composition and fluidity was investigated in eight patients with severe hypercholesterolaemia (mean LDL-cholesterol of 7.2 mmol l-1). Lovastatin was administered at a dosage of 40-80 mg for 20 weeks and was discontinued for 5 weeks thereafter. Parallel to a 47% fall in plasma LDL cholesterol, there was a significant reduction (P < 0.01) in erythrocyte membrane cholesterol:phospholipid molar ratio, while erythrocyte membrane fluidity assessed by diphenylhexatriene (DPH) fluorescence polarization increased significantly (P < 0.01). Discontinuation of lovastatin resulted in the reversal of erythrocyte membrane composition and fluidity to pre-treatment values.

Breast self-examination among diagnosed breast cancer patients.

The practice of breast self-examination (BSE) was explored by personal interview in a sample of women with diagnosed breast cancer. Despite physician recommendations to practice BSE, only 43% of those interviewed were examining themselves regularly, a figure that is little different from that of the general population. Predictors of BSE were age (older women were less likely to practice) and practice of BSE before diagnosis. Factors contributing to nonpractice were judged to be: (1) the patients' beliefs that occasional examinations by physicians are a sufficient substitute for BSE; (2) the patients' perceptions that BSE is discretionary and not truly "medical"; and (3) the fact that BSE may raise patients' anxiety over cancer without affecting its likelihood. It was concluded that the practice of BSE among diagnosed patients could be increased if physicians stress its importance and provide systematic instruction or reinstruction in its practice.