Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆.

BACKGROUND: Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). PATIENTS AND METHODS: We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. RESULTS: After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. CONCLUSIONS: The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

The 67P/Churyumov-Gerasimenko observation campaign in support of the Rosetta mission.

We present a summary of the campaign of remote observations that supported the European Space Agency's Rosetta mission. Telescopes across the globe (and in space) followed comet 67P/Churyumov-Gerasimenko from before Rosetta's arrival until nearly the end of the mission in September 2016. These provided essential data for mission planning, large-scale context information for the coma and tails beyond the spacecraft and a way to directly compare 67P with other comets. The observations revealed 67P to be a relatively 'well-behaved' comet, typical of Jupiter family comets and with activity patterns that repeat from orbit to orbit. Comparison between this large collection of telescopic observations and the in situ results from Rosetta will allow us to better understand comet coma chemistry and structure. This work is just beginning as the mission ends-in this paper, we present a summary of the ground-based observations and early results, and point to many questions that will be addressed in future studies.This article is part of the themed issue 'Cometary science after Rosetta'.

Measuring the development of insight by dental health professionals in training using workplace-based assessment.

INTRODUCTION: For health professionals, the development of insight into their performance is vital for safe practice, professional development and self-regulation. This study investigates whether the development of dental trainees' insight, when provided with external feedback on performance, can be assessed using a single criterion on a simple global ratings form such as the Longitudinal Evaluation of Performance or Mini Clinical Evaluation Exercise. METHODS: Postgraduate dental trainees (N = 139) were assessed using this tool on a weekly basis for 6 months. Regression analysis of the data was carried out using SPSS, and a short trainer questionnaire was implemented to investigate feasibility. RESULTS: Ratings for insight were shown to increase with time in a similar manner to the growth observed in other essential skills. The gradient of the slope for growth of insight was slightly less than that of the other observed skills. Trainers were mostly positive about the new criterion assessing trainees' insight, although the importance of training for trainers in this process was highlighted. DISCUSSION: Our data suggest that practitioners' insight into their performance can be developed with experience and regular feedback. However, this is most likely a complex skill dependent on a number of intrinsic and external factors. CONCLUSION: The development of trainees' insight into their performance can be assessed using a single criterion on a simple global ratings form. The process involves no additional burden on evaluators in terms of their time or cost, and promotes best practice in the provision of feedback for trainees.

Interstellar ices as a source of CN-bearing molecules in protoplanetary disks.

A reliable model for the composition and evolution of interstellar ices in regions of active star formation is fundamental to our quest to determine the organic inventory of planetesimals in the early Solar System. This has become a realistic goal since the launch of the Infrared Space Observatory, which provides a facility for infrared spectroscopy unhindered by telluric absorption over the entire spectral range of vibrational modes in solids of exobiological interest. Interstellar molecules detected in the solid phase to date include H2O, NH3, CO, CO2, CH3OH, CH4, H2CO, OCS and HCOOH, together with a C identical to N-bonded absorber generically termed 'XCN'. In this article, we focus on cosmic synthesis of CN-bearing species, as this important class of prebiotic molecules may not have formed endogenously in significant quantities on early Earth if conditions were not highly reducing. Experiments in which interstellar ice analogs are subject to UV photolysis or energetic ion bombardment yield CN-rich residues with a spectral signature that matches a corresponding feature observed in young protostars enshrouded in dust and gas. CN-bearing species are also present in cometary ices, with a combined abundance comparable to the lower end of the range observed in protostars. Energetic processing of interstellar ices is thus a viable and potentially significant source of CN compounds in protoplanetary disks.

Chemistry of the organic-rich hot core G327.3-0.6.

We present gas-phase abundances of species found in the organic-rich hot core G327.3-0.6. The data were taken with the Swedish-ESO Submillimetre Telescope (SEST). The 1-3 mm spectrum of this source is dominated by emission features of nitrile species and saturated organics, with abundances greater than those found in many other hot cores, including Sgr B2 and OMC-1. Population diagram analysis indicates that many species (CH3CN, C2H3CN, C2H5CN, CH3OH, etc.) have hot components that originate in a compact (~2") region. Gas-phase chemical models cannot reproduce the high abundances of these molecules found in hot cores, and we suggest that they originate from processing and evaporation of icy grain mantle material. In addition, we report the first detection of vibrationally excited ethyl cyanide and the first detection of methyl mercaptan (CH3SH) outside the Galactic center.

The role of zinc in senile dementia.

Zinc deficiency has been reported in association with dementia and linked with its pathogenesis. A group of 45 elderly patients admitted to a mental hospital were given diagnoses in accordance with ICD-9, and their fasting plasma zinc levels were recorded. No difference was found in zinc levels between patients with diagnoses of senile dementia and those with other diagnoses.

A comparison of the kinetic properties of phosphoenolpyruvate carboxylase from guard-cell and mesophyll-cell protoplasts of Commelina communis.

Some kinetic properties of partially purified phosphoenolpyruvate carboxylase (PEPCase) from guard-cell and mesophyll-cell protoplasts of Commelina communis are described. The PEPCase activity inherent to each cell type was determined and the apparent K m (phosphoenolpyruvate) and K i (malate) were compared. Malate sensitivity was much higher (K i malate 0.4 mol m(-3)) in the extract of guard-cell protoplasts than in that of mesophyllcell protoplasts (K i malate 4.2 mol m(-3)). The stimulation of activity by glucose-6-phosphate in the presence of malate ('deinhibition') was also investigated in extracts from both cell types and was found to be similar to previously reported results with epidermal tissue. The effect of contamination of an extract of guard-cell protoplasts with mesophyll-cell protoplasts was measured in the presence and absence of malate. It was found that a small amount to mesophyll-cell contaminant appears to desensitize the malate inhibition of PEPCase from guard-cell protoplasts. It is concluded that experiments which use epidermal tissue to study guardcell PEPCase may give misleading information as a consequence of mesophyll contamination.

Tracts of high or low sequence divergence in the mouse major histocompatibility complex.

The K, I and S regions of the mouse major histocompatibility complex (MHC) are composed of long tracts of DNA which differ in sequence divergence. A correlation exists between the location of an MHC gene in a variable or conserved chromosomal tract and the degree of polymorphism and diversity of the proteins encoded by its alleles. Variable tracts appear to be the result of mechanisms which mutate certain coding and non-coding sequences to the same extent and selective pressures operating on the genes.

Evaluation of nine different types of enuresis alarms.

One hundred enuretic children were treated in closely supervised trial conditions with nine commonly used enuresis alarm systems available commercially in the United Kingdom. Although there was little difference between the systems in terms of their effectiveness in stopping bed wetting, parents preferred the Eastleigh and Urilarm De-Luxe models which had distinct advantages in respect of false alarms, breakdowns, and durability of pads. Enuresis alarms that perform poorly in these respects may lead to loss of enthusiasm and non-compliance. The systems vary widely in price, but a private buyer may find a cheaper alarm just as effective.

Comparison of the growth of virulent and attenuated strains of Candida albicans in the kidneys of normal and cortison-treated mice by chitin assay.

Candida albicans strain 22114 was avirulent for mice compared with strain 19321 in that, administered intravenously, 10(6) blastospores of 22114 failed to kill whereas 10(6) blastospores of 19321 produced 100% mortality. Cortisone treatment rendered mice susceptible to killing by 22114. Chitin assay showed that cortisone stimulated the growth of both strains in the mouse kidney. Growth of 19321 was increased up to five-fold and 22114 up to forty-fold. The strains may have differential susceptibility to cortisone-sensitive host defences which control fungal growth in vivo.