Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study.

BACKGROUND: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

Sodium transport by rat cortical collecting tubule. Effects of vasopressin and desoxycorticosterone.

We have used rat cortical collecting tubules perfused in vitro to study the effects of antidiuretic hormone (ADH) and desoxycorticosterone (DOCA) on the unidirectional fluxes of sodium. We found that in the basal state, lumen-to-bath flux (Jlb) and bath-to-lumen flux (Jbl) of 22Na were approximately equal, 39.5 +/- 3.9 and 41.8 +/- 11.0 pmol X min-1 X min-1, respectively, resulting in no net flux. Addition of 100 microU/ml ADH to the bath produced a stable increase in Jlb to 58.3 +/- 4.7 pmol X min-1 X mm-1. Pretreatment of the animal with DOCA for 4 to 7 d (20 mg/kg per d) increased baseline Jlb to 81.6 +/- 8.7 pmol X min-1 X mm-1. Addition of ADH to a tubule from a DOCA-pretreated rat caused an increase in Jlb to 144.1 +/- 12.0 pmol X min-1 X mm-1 X Neither hormone had an effect on Jbl X Thus ADH produced a greater absolute and fractional increase in Jlb when the animal was pretreated with DOCA, and the ADH-induced increase over baseline was greater than the DOCA-induced increase. Both the ADH-and DOCA-induced stimulation of Jlb were completely abolished by 10(-5) M luminal amiloride, suggesting that the route of sodium transport stimulated by both hormones involves apical sodium channels. However, ADH and DOCA have very different time courses of action; ADH acted within minutes, while aldosterone and DOCA are known to require 90-180 min. The facilitating action of ADH on DOCA-induced stimulation of sodium transport may be important for maximal sodium reabsorption and for the ability to achieve a maximally concentrated urine.

An analysis of unstirred layers in series with "tight" and "porous" lipid bilayer membranes.

The present experiments were designed to evaluate the effective thickness of the unstirred layers in series with native and porous (i.e., in the presence of amphotericin B) lipid bilayer membranes and, concomitantly, the respective contributions of membranes and unstirred layers to the observed resistances to the diffusion of water and nonelectrolytes between aqueous phases. The method depended on measuring the tracer permeability coefficients for the diffusion of water and nonelectrolytes (P(DDi), cm sec(-1)) when the aqueous phase viscosity (eta) was increased with solutes having a unity reflection coefficient, such as sucrose or dextran. The effective thickness of the unstirred layers (alpha(t), cm) and the true, or membrane, permeability coefficients for diffusion of water and nonelectrolytes (P(mmi), cm sec(-1)) were computed from, respectively, the slope and intercept of the linear regression of 1/P(DDi) on eta. In both the native and porous membranes, alpha(t) was approximately 110 x 10(-4) cm. The ratio of P(f), the osmotic water permeability coefficient (cm sec(-1)) to P(mmH2O) was 1.22 in the native membranes and 3.75 in the porous membranes. For the latter, the effective pore radius, computed from Poiseuille's law, was approximately 5.6 A. A comparison of P(mmi) and P(DDi), indicated that the porous membranes accounted for 16, 25, and 66% of the total resistance to the diffusion of, respectively, H(2)O, urea, and glycerol, while the remainder was referable to the unstirred layers.

Volume reabsorption, transepithelial potential differences, and ionic permeability properties in mammalian superficial proximal straight tubules.

This paper describes experiments designed to evaluate Na(+) and Cl(-) transport in isolated proximal straight tubules from rabbit kidneys. When the perfusing solution was Krebs-Ringer buffer with 25 mM HCO(3) (-) (KRB) and the bath contained KRB plus 6% albumin, net volume reabsorption (J(v), nl min(-1) mm(-1) was -0.46 +/- 0.03 (SEM); V(e), the spontaneous transepithelial potential difference, was -1.13 +/- 0.05 mV, lumen negative. Both J(v), and V(e), were reduced to zero at 21 degrees C or with 10(-4) M ouabain, but J(v), was not HCO(3) (-) dependent. Net Na(+) reabsorption, measured as the difference between (22)Na(+) fluxes, lumen to bath and bath to lumen, accounted quantitatively for volume reabsorption, assuming the latter to be an isotonic process, and was in agreement with the difference between lumen to bath (22)Na(+) fluxes during volume reabsorption and at zero volume flow. The observed flux ratio for Na(+) was 1.46, and that predicted for a passive process was 0.99; thus, Na(+) reabsorption was rationalized in terms of an active transport process. The Cl(-) concentration of tubular fluid rose from 113.6 to 132.3 mM during volume reabsorption. Since V(e), rose to +0.82 mV when tubules were perfused with 138.6 mM Cl(-) solutions, V(e) may become positive when tubular fluid Cl(-) concentrations rise during volume reabsorption. The permeability coefficients P(Na) and P(Cl) computed from tracer fluxes were, respectively, 0.23 x 10(-4) and 0.73 x 10(-4) cm s(-1). A P(Na)/P(Cl) ratio of 0.3 described NaCl dilution potentials at zero volume flow. The magnitudes of the potentials were the same for a given NaCl gradient in either direction and P(Na)/P(Cl) was constant in the range 32-139 mM NaCl. We infer that the route of passive ion permeation was through symmetrical extracellular interfaces, presumably tight junctions, characterized by neutral polar sites in which electroneutrality is maintained by mobile counterions.

Coupling of solute and solvent flows in porous lipid bilayer membranes.

The present experiments were designed to evaluate coupling of water and nonelectrolyte flows in porous lipid bilayer membranes (i.e., in the presence of amphotericin B) in series with unstirred layers. Alterations in solute flux during osmosis, with respect to the flux in the absence of net water flow, could be related to two factors: first, changes in the diffusional component of solute flux referable to variations in solute concentrations at the membrane interfaces produced by osmotic flow through the unstirred layers; and second, coupling of solute and solvent flows within the membrane phase. Osmotic water flow in the same direction as solute flow increased substantially the net fluxes of glycerol and erythritol through the membranes, while osmotic flow in the opposite direction to glycerol flow reduced the net flux of that solute. The observed effects of osmotic water flow on the fluxes of these solutes were in reasonable agreement with predictions based on a model for coupling of solute and solvent flows within the membrane phase, and considerably in excess of the prediction for a diffusion process alone.

Osmosis in cortical collecting tubules. ADH-independent osmotic flow rectification.

The present experiments were designed to evaluate the effects of varying the osmolality of luminal solutions on the antidiuretic hormone (ADH)-independent water and solute permeability properties of isolated rabbit cortical collecting tubules. In the absence of ADH, the osmotic water permeability coefficient (cm s(-1)) P(f) (l-->b), computed from volume flows from hypotonic lumen to isotonic bath, was 20 +/- 4 x 10(-4) (SEM); the value of P(f) (b-->l) in the absence of ADH, computed from volume flows from isotonic bath to hypertonic lumen, was 88 +/- 15 x 10(-4) cm s(-1). We also measured apparent urea permeability coefficients (cm s(-1)) from (14)C-urea fluxes from lumen to bath (P(DDurea) (l-->b)) and from bath to lumen (P(DDurea) (b-->l)). For hypotonic luminal solutions and isotonic bathing solutions, P(DDurea) (l-->b) was 0.045 +/- 0.004 x 10(-4) and was unaffected by ADH. The ADH-independent values of P(DDurea) (l-->b) and P(urea) (b-->l) were, respectively, 0.216 +/- 0.022 x 10(-4) cm s(-1) and 0.033 +/- 0.002 x 10(-4) cm s(-1) for isotonic bathing solutions and luminal solutions made hypertonic with urea, i.e., there was an absolute increase in urea permeability and asymmetry of urea fluxes. Significantly, P(DDurea) (l-->b) did not rise when luminal hypertonicity was produced by sucrose; and, bathing fluid hypertonicity did not alter tubular permeability to water or to urea. We interpret these data to indicate that luminal hypertonicity increased the leakiness of tight junctions to water and urea but not sucrose. Since the value of P(f) (b-->l) in the absence of ADH, when tight junctions were open to urea, was approximately half of the value of P(f) (l-->b) in the presence of ADH, when tight junctions were closed to urea, we conclude that tight junctions are negligible paracellular shunts for lumen to bath osmosis with ADH. These findings, together with those in the preceding paper, are discussed in terms of a solubility-diffusion model for water permeation in which ADH increases water solubility in luminal plasma membranes.

Energy balance in man measured by direct and indirect calorimetry.

In six 24-hr measurements of energy balance, direct and indirect calorimetry agreed within +/-3%, which is probably the range of experimental error. But in seven other 24-hr periods there was disagreement in the range of 8 to 23%, and these were usually days when the subjects ate much less than they spent metabolically. Our direct calorimeter is an insulated, water cooled suit. Continous measurements of O2 consumption and CO2 production provided data on metabolic expenditure (M) by indirect calorimetry. The 24-hr values for M matched the energy losses within +/-60 kcal (+/-3% of M) in four men who rested all day and lay down to sleep at night. Similar agreement was seen in one of the four who worked on a treadmill for 4 hr and stayed busy all day. but in another energy losses were 342 kcal greater than M (10% of M). When the experiments gave values for M minus the losses greater than +/-60 kcal, this is called "unmeasured energy". In further experiments, two subjects stayed awake for 24 hr, and their unmeasured energies were 279 and 393 kcal. The same two men, eating sparingly, also worked for 24 hr so as to double their resting metabolic expenditures; the unmeasured energies were even larger, 380 and 958 kcal. When they repeated the 24 hr of mild work, but ate nearly as much as they spent metabolically, one man was near energy balance, while the other showed an unmeasured energy of -363 kcal. Little heat storage was evident in these experiments; therefore, heat balance was present and energy balance should have been present. In the group of 13 experiments, it appeared that the greater the food deficit, the larger was the unmeasured energy (excess of metabolic expenditure over loss of energy).

Nonsurgical management of binocular diplopia induced by macular pathology.

OBJECTIVE: To treat binocular diplopia secondary to macular pathology. METHODS: Seven patients underwent evaluation and treatment. All had constant vertical diplopia caused by various maculopathies, including subretinal neovascularization, epiretinal membrane, and central serous retinopathy. Visual acuity ranged from 20/20 to 20/30 in the affected eye. All except 1 patient had a small-angle, comitant hyperdeviation with no muscle paresis. Sensory evaluation demonstrated peripheral fusion and reduced stereoacuity. Neither prism correction nor manipulation of the refractive errors corrected the diplopia. A partially occlusive foil (Bangerter) of density ranging from 0.4 to 1.0 was placed in front of the affected eye to restore stable, single vision. RESULTS: The Bangerter foil eliminated the diplopia in all patients. Two patients elected not to wear the foil; 1 patient was afraid of becoming dependent, and the other was bothered by the visual blur. Visual acuity in the affected eye was reduced on average by 3 lines. All patients maintained the same level of sensory fusion, with only 2 having reduced stereoacuity. Symptoms returned when the foil was removed or its density was reduced. CONCLUSION: Low-density Bangerter foils provide an effective, inexpensive, and aesthetically acceptable management for refractory binocular diplopia induced by macular pathology, allowing peripheral fusion to be maintained.

Large-angle exotropia corrected by intraoperative botulinum toxin A and monocular recession resection surgery.

PURPOSE: Surgical correction of large-angle exotropia, greater than 70 PD, traditionally requires operating on three or four horizontal muscles. However, in secondary exotropia from monocular visual loss, it is advisable to operate only on the eye with poor vision. We used intraoperative botulinum toxin as an adjunct to the monocular recession-resection procedure for large-angle sensory exotropia, therefore operating only on the visually impaired eye. METHODS: Three patients underwent monocular recession (10 mm) and resection (10 mm) along with intraoperative botulinum toxin A injection of 10 units into the recessed muscle. All had desired cosmetic repair of long-standing large-angle exotropia (range 100 to 110 PD) with amblyopia and vision worse than 20/200 in the deviated eye. RESULTS: Within 4 days after operation all patients demonstrated maximal paresis of the lateral rectus muscle. This lasted 8 to 12 weeks and resulted in stable orthotropia at 2.5 years in case 1 and stable 8 PD exotropia at 4 years in case 2. The third case demonstrated a stable 18 PD exotropia by 7 months with a satisfactory cosmetic result. CONCLUSION: This technique provides an alternative for the surgical correction of large-angle exotropia by operating only on two horizontal muscles. In sensory exotropia it also avoids subjecting a normal eye to an operative risk.

A new optical modality to overcome diplopia.

The author has presented a new method to correct vertical diplopia using a prism contact lens. To the present time, its application has been limited to contact lenses correcting refractive errors of less than 3D and to ground-in prisms of not more than 6 delta. The field is new. Technical, mathematical, and clinical advances should eventually allow the use of stronger prisms over a wider range of refractive corrections.

Fresnel prisms and their effects on visual acuity and binocularity.

1. The visual acuity with the Fresnel membrane prism is significantly less than that with the conventional prism of the same power for all prism powers from 12 delta through 30 delata at distance and from 15 delta through 30 delta at near. 2. The difference in the visual acuity between base up and base down, and between base in and base out, is not significantly different for either the Fresnel membrane prism or for the conventional prism. 3. For both Fresnel membrane prism and the conventional prism, the visual acuity when looking straight ahead. 4. Using Fresnel membrane prisms of the same power from different lots, the visual acuity varied significantly. The 30 delta prism caused the widest range in visual acuity. 5. When normal subjects are fitted with the higher powers of the Fresnel membrane prism, fusion and stereopsis are disrupted to such an extent that the use of this device to restore or to improve binocular vision in cases with large-angle deviations is seriously questioned. 6. Moreover, the disruption of fusion and stereopsis is abrupt and severe and does not parallel the decrease in visual acuity. The severely reduced ability to maintain fusion may be related to the optical aberrations, which, in turn, may be due to the molding process and the polyvinyl chloride molding material. 7. Through the flexibility of the membrane prism is a definite advantage, because of its proclivity to reduce visual acuity and increase aberrations its prescription for adults often must be limited to only one eye. 8. For the same reasons in the young child with binocular vision problems, the membrane prism presently available should be prescribed over both eyes only in powers less than 20 delta. When the membrane prism is to be used as a partial occluder (over one eye only), any power can be used. 9. The new Fresnel "hard" prism reduces visual acuity minimally and rarely disrupts binocularity, thus increasing the potential for prismotherapy to establish binocularity. This prism is currently available only for use as a trial set. Since the cosmetic appearance of the Fresnel "hard" prism is similar to that of the Fresnel membrane prism and it is easier to maintain, it would be the prism of choice (over all other types) for bilateral prescriptions in the young patient with emmetropia. The manufacturer is urged to make these prisms available to fit a special round adjustable frame, such as that developed in Europe for use with the wafer prism.

A new laser for collagen wounding in corneal and strabismus surgery: a preliminary report.

It has been shown that using a small spot size 2 to 5 mu, a dye modified excimer laser emitting at 595 nm can produce laser ablation of tissue in corneal stroma without compromising anterior and posterior limiting membranes. The surface of extraocular muscle tendon sheath has been similarly laser modified. An instrument, under prototype construction, designed for clinical application of this laser energy is described as well as clinical implications of such surgical interventions in corneal and extraocular muscle surgery.

The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis.

Rac1b, an alternative splice form of Rac1, has been previously shown to be upregulated in colon and breast cancer cells, suggesting an oncogenic role for Rac1b in these cancers. Our analysis of NSCLC tumor and matched normal tissue samples indicates Rac1b is upregulated in a significant fraction of lung tumors in correlation with mutational status of K-ras. To directly assess the oncogenic potential of Rac1b in vivo, we employed a mouse model of lung adenocarcinoma, in which the expression of Rac1b can be conditionally activated specifically in the lung. Although expression of Rac1b alone is insufficient to drive tumor initiation, the expression of Rac1b synergizes with an oncogenic allele of K-ras resulting in increased cellular proliferation and accelerated tumor growth. Finally, we show that in contrast to our previous findings demonstrating a requirement for Rac1 in K-ras-driven cell proliferation, Rac1b is not required in this context. Given the partially overlapping spectrum of downstream effectors regulated by Rac1 and Rac1b, our findings further delineate the signaling pathways downstream of Rac1 that are required for K-ras driven tumorigenesis.