SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers

Background: Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Gemcitabine-based regimens are the standard of care in advanced disease, but median overall survival (OS) is roughly 12 months. The addition of albumin-bound paclitaxel to gemcitabine and cisplatin (GAP) demonstrated promising efficacy in a 60 patient, single-arm phase II study (Shroff et al, JAMA Oncol 2019), with observed median OS of 19.2 months. Methods: SWOG 1815 is a randomized, open-label, phase III trial comparing GAP to gemcitabine/cisplatin (GC). The study included newly diagnosed advanced BTC patients (pts), randomized 2:1 to GAP vs. GC. GAP included gemcitabine at 800 mg/m2, cisplatin at 25 mg/m2 and albumin-bound paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. GC included standard dosing of gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of a 21-day cycle. Pts were treated until progression. The primary endpoint was overall survival (OS) with a target hazard ratio of 0.7 with 90% power and a 1-sided alpha of 0.025; randomization was stratified by disease site (intrahepatic cholangiocarcinoma [CCA] vs gallbladder adenocarcinoma [GBC] vs extrahepatic CCA), disease stage (locally advanced vs metastatic), and Zubrod PS 0 vs 1. Results: Of 441 eligible pts randomized, 55% were female. 67% of patients had intrahepatic CCA, 16% had GBC and 17% had extrahepatic CCA. Most pts had metastases (73%). Median OS with GAP vs. GC was 14 vs. 12.7 mo respectively (HR 0.93, 95% CI 0.74-1.19, p=0.58), ORR (confirmed and unconfirmed) 34% vs25% (p=0.11) and median PFS 8.2 vs 6.4 mo (HR 0.92, 95% CI 0.72-1.16, p=0.47), respectively. Grade 3 and 4 treatment related adverse events (TRAEs) in ≥10% of pts for GAP and GC were anemia, neutropenia, and thrombocytopenia. GAP had more ≥ grade 3 hematologic AEs compared to the GC arm (60% vs. 45%, p=0.003). Discontinuation due to toxicity was at 24% vs 19% (p=0.26) with GAP vs GC. In exploratory subset analyses, GAP vs GC improved OS in pts with locally advanced disease (medians 19.2 vs 13.7 mo; HR 0.67, 95% CI 0.42- 1.06, p=0.09) and in GBC pts (medians 17.0 vs 9.3 mo; HR 0.74, 95% CI 0.41-1.35, p=0.33). ORR for GAP vs GC in GBC was 50% vs 24% (p=0.09) and for locally advanced disease 28 vs 21% p=0.74. Conclusions: SWOG 1815 did not result in a statistically significant improvement in median OS with GAP vs. GC. The GAP regimen had higher rates of TRAEs without a statistically significant difference in discontinuation rates. Pts with locally advanced disease and GBC may benefit from the use of GAP. Further analyses are ongoing to understand potential benefit of GAP in subsets of BTC pts. Funding: NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, and CA180868; and in part by Celgene Corporation, Summit, NJ (subsidiary of Bristol Myer Squibb)

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1.Purpose WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.Estonian Research CouncilNational Natural Science Foundation of ChinaRoyal SocietySouth Carolina Department of Disabilities and Special Needs (SCDDSN)National Institute of Neurological Disorders and Stroke (NINDS

Acoustic methods for characterisation of microstructures and deformation processes in Nimonic alloy PE 16 and Zircaloy-2

This paper discusses the experience of the authors in using ultrasonic attenuation and velocity measurements and acoustic emission technique for characterisation of micro-structures and deformation processes in Nimonic alloy PE 16 and Zircaloy-2. It is possible to assess the volume fraction of γ' in Nimonic alloy PE 16 using ultrasonic velocity measurements. Acoustic emission technique is useful to monitor the influence of presence of secondary phases γ' and MC independently and also their conjoint presence on tensile deformation. In Zircaloy-2. low frequency ultrasonic velocity measurements are useful for detecting presence of hard intermetallics and high frequency velocity measurements are useful for revealing the early stage dissociation of β quenched microstructure to α phase. Also, assessment of hydrogen concentration in the range 25 to1100 mg/kg in Zircaloy-2 is possible using ultrasonic velocity ratio (longitudinal to shear) obtained from the precise ultrasonic transit time measurements

A tunable optical filter

We present the details of a new tunable optical filter, suitable for selecting different bands of wavelength in the UV, visible and IR regions. The filter comprises a ferrofluid-based emulsion cell (emulsion sandwiched between two transparent sheets), a miniature solenoid and a variable direct current source for changing the magnetic field inside the solenoid. By varying the magnetic field, one can tune the filter and select the desired wavelength. We discuss the working principle of the new tunable optical filter with a few examples

Effect of polymer-surfactant association on colloidal force

We investigate the forces between emulsion droplets in the presence of neutral polymer-surfactant complexes. The polymer used in our experiment was statistical copolymer of polyvinyl alcohol. The anionic surfactant used is sodiumdodecyl sulphate, the cationic surfactants are cetyltrimethylammonium bromide and tetradecyltrimethylammonium bromide, and the nonionic surfactant is nonylphenol ethoxylate (NP10). It has been found that the force profiles in the presence of surfactant-polymer complexes follow an exponential scaling with a characteristic decay length, close to the radius of gyration of the polymer alone. A continuous increase in the onset of repulsion is observed in the case of all three ionic surfactants, whereas no such variation was noticed in the case of nonionic surfactant, NP10. The experimental observations suggest that in the presence of charged surfactant molecules or micelles, the neutral polymer chain at the interface is converted into partial polyelectrolytes, where the charges on the chain repel each other and the electrostatic repulsion collectively leads to chain stretching. These results suggest that the associative polymers can be potential candidates for making the emulsions stable for a sufficiently long period

Stretching and collapse of neutral polymer layers under association with ionic surfactants

We provide experimental evidence for stretching and collapse of neutral polymer layers, already adsorbed at an oil-in-water interface, due to its interaction with surfactants. Upon stretching, the first interaction length (2L0) follows a power law dependence on surfactant concentration (∝Csx, where x ≈ 0.5 for cationic surfactants) and collapses in the presence of salt, as a relatively weak power law (Cs−y, where y=0.17), in good agreement with brush length decay for polyelectrolyte brushes