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Aims Ablative therapy, such as focal therapy, cryotherapy or electroporation, aims to treat clinically significant prostate cancer with reduced treatment-related toxicity. Up to a third of patients may require further local salvage treatment after ablative therapy failure. Limited descriptive, but no comparative, evidence exists between different salvage treatment outcomes. The aim of this study was to compare oncological and functional outcomes after salvage robot-assisted radical prostatectomy (SRARP) and salvage radiotherapy (SRT). Materials and methods Data were collected prospectively and retrospectively on 100 consecutive SRARP cases and 100 consecutive SRT cases after ablative therapy failure in a high-volume tertiary centre. Results High-risk patients were over-represented in the SRARP group (66.0%) compared with the SRT group (48.0%) (P = 0.013). The median (interquartile range) follow-up after SRARP was 16.5 (10.0–30.0) months and 37.0 (18.5–64.0) months after SRT. SRT appeared to confer greater biochemical recurrence-free survival at 1, 2 and 3 years compared with SRARP in high-risk patients (year 3: 86.3% versus 66.0%), but biochemical recurrence-free survival was similar for intermediate-risk patients (year 3: 90.0% versus 75.6%). There was no statistical difference in pad-free continence at 12 and 24 months between SRARP (77.2 and 84.7%) and SRT (75.0 and 74.0%) (P = 0.724, 0.114). Erectile function was more likely to be preserved in men who underwent SRT. After SRT, cumulative bowel and urinary Radiation Therapy Oncology Group toxicity grade I were 25.0 and 45.0%, grade II were 11.0 and 11.0% and grade III or IV complications were 4.0 and 5.0%, respectively. Conclusion We report the first comparative analyses of salvage prostatectomy and radiotherapy following ablative therapy. Men with high-risk disease appear to have superior oncological outcomes after SRT; however, treatment allocation does not appear to influence oncological outcomes for men with intermediate-risk disease. Treatment allocation was associated with a different spectrum of toxicity profile. Our data may inform shared decision-making when considering salvage treatment following focal or whole-gland ablative therapy.

Background The first-in-human, ongoing phase I study of PF-06801591, a humanized IgG4 antibody to programmed cell death 1 (PD-1) receptor, consisted of a Part 1 dose escalation and Part 2 dose expansion. In Part 1, PF-06801591 was administered intravenously or SC with an acceptable safety profile and antitumor activity in several solid tumor types. Herein, we report on Part 2 where we further evaluated SC PF-06801591 in patients (pts) with NSCLC and UC. Methods Anti-PD-1/L1-naive pts with NSCLC (n = 68) and UC (n = 38) received SC PF-06801591 300 mg q4w. NSCLC pts had ≤1 prior line of chemotherapy (CT) ± ≥1 ALK/EGFR mutation-directed therapies (if applicable) and UC pts had ≤2 lines of prior CT. Tumors were evaluated q8w by RECIST 1.1. Blood samples were collected for pharmacokinetic (PK) and immunogenicity assessments. Archival or baseline biopsies were evaluated by immunohistochemistry for PD-L1, RNA-seq, and whole exome sequencing. Results As of 27Dec2018, with median duration of treatment of 2.8 mos. in all 106 treated pts (55 still receiving treatment), 50.9% had treatment-related AEs (TRAEs) with 8.5% grade 3 or higher. Most common TRAEs were hyperthyroidism (9.4%), pruritus (6.6%), and increased amylase/lipase, anemia, hypothyroidism, pneumonitis, and rash (4.7% each). Treatment-emergent anti-drug antibodies were detected in 3 pts. With median follow-up of 5.1 mos. in 67 modified intent to treat (mITT) NSCLC pts, 11 (16.4%) pts achieved a partial response (PR) and 26 (38.8%) had stable disease (SD); the objective response rate (ORR) was 16.4% with 95% confidence interval (CI) 8.5-27.5% (25% in pts with ≥1% tumor cell PD-L1 expression). With median follow-up of 3.0 mos. in 37 mITT UC pts, 6 (16.2%) pts had a PR and 13 (35.1%) had SD; ORR was 16.2% (95% CI 6.2-32.0%). PK and biomarker data will be presented. Conclusions SC PF-06801591 given monthly was well tolerated, with minimal rates of injection site reactions and low incidence of immunogenicity. SC PF-06801591 demonstrated antitumor activity in NSCLC and UC pts at an early time point. The study is ongoing to further assess the durability of responses and long-term safety profile. Clinical trial identification NCT02573259. Editorial acknowledgement S. Mariani MD PhD of Engage Scientific Solutions, Southport, CT, funded by Pfizer and L. Chen. Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure B.C. Cho: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MOGAM Institute; Research grant / Funding (institution): Dong-A ST; Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Advisory / Consultancy, Research grant / Funding (institution): Ono; Research grant / Funding (institution): Dizal Pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Gencurix Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics. K. Penkov: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Prestige Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Tanvex. M. Korozan: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Regeneron. Y. Kulyaba: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Azaya Therapeutics; Research grant / Funding (institution): Celltrion; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Synta Pharmaceuticals; Research grant / Funding (institution): Tanvex. H.K. Ahn: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Eisai; Honoraria (self): Ono; Honoraria (self): Roche. S. Odintsova: Full / Part-time employment: Complete Medical Technologies. J. Davda: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. A. Forgie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. X. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. R. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. I.A. Jacobs: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. F. Kazazi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. J. Chou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. M.L. Johnson: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Genentech/Roche; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): Loxo; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution), Research grant / Funding (institution): Mirati; Honoraria (institution), Research grant / Funding (institution): Sanofi; Honoraria (institution): Calithera; Honoraria (institution): Celgene; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): GenMab; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): StemCentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Daiichi–Sankyo; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Gritstone; Research grant / Funding (institution): Hengrui Therapeutics; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Neovia; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Tarveda; Spouse / Financial dependant, contract lobbyist : Astellas; Spouse / Financial dependant, contract lobbyist : Otsuka Pharmaceuticals. All other authors have declared no conflicts of interest.

Introduced in 2012, the Tuition Fee Free (TFF) policy has become a flagship policy of the Papua New Guinea (PNG) government. Since 2012, further changes to this policy have been introduced; these changes continue to reduce financial barriers to school attendance and attempt to recentralise control of education funding. What have these policy changes meant for schools, administrators, non-governmental service providers (such as the church), and other key stakeholders? This paper draws on qualitative and quantitative research conducted in 2012 and 2016 in East New Britain and Gulf provinces – the former performs relatively well in delivering services, the latter relatively poorly. Interviews were conducted with education representatives, community members, government and church officials and other stakeholders to assess the impact of PNG’s fourth and most enduring attempt at providing free education. Researchers visited 10 schools, four district administrations and two provincial administrations. The research approach allows for a comparison of progress and regress in these schools between 2012 and 2016. It is argued that while the TFF policy has helped improve access and strengthened school autonomy, recent policy reforms have threatened school-community relations, undermined school quality and weakened conditions for effective service provision. The paper will provide recommendations about how PNG policy makers and others might address some of the challenges.

This article will outline the clinical presentation and management of patellar instability and fracture. Patellar instability is a generic term that describes anything from symptomatic apprehension to patellar subluxation and through to patellar dislocation. It can result from osseous abnormalities such as patella alta or patellofemoral dysplasia or it can arise secondary to soft tissue abnormalities such as a torn medial patellofemoral ligament. Failing conservative management, surgical treatment is directed to the underlying cause(s) of the instability, and can include medial patellofemoral ligament reconstruction or a bony realignment procedure. Patellar fracture is a common injury caused by excessive tension through the extensor mechanism or a direct blow. Such injury can lead to stiffness, extension weakness and patellofemoral arthritis. Non-surgical management is indicated for non-displaced fractures with an intact extensor mechanism. Surgical fixation is recommended for fractures that either disrupt the extensor mechanism or that demonstrate over 2–3 mm of step-off and/or over 1–4 mm of displacement. Anatomic reduction and fixation with a tension-band technique is associated with the best outcomes; however, symptomatic hardware is a frequent complication.

Uterine sarcomas are a group of rare tumours that provide considerable challenges in their treatment. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made post-operatively. Current staging systems have been unsatisfactory, although a new FIGO staging system specifically for uterine sarcomas has now been introduced, and may allow better grouping of patients according to expected prognosis. While the mainstay of treatment of early disease is a total abdominal hysterectomy, it is less clear whether routine oophorectomy or lymphadenectomy is necessary. Adjuvant pelvic radiotherapy may improve local tumour control in high risk patients, but is not associated with an overall survival benefit. Similarly there is no good evidence for the routine use of adjuvant chemotherapy. For advanced leiomyosarcoma, newer chemotherapy agents including gemcitabine and docetaxel, and trabectedin, offer some promise, while hormonal therapies appear to be more useful in endometrial stromal sarcoma. Novel targeted agents are now being introduced for sarcomas, and uterine sarcomas, and show some indications of activity. Non-pharmacological treatments, including surgical metastatectomy, radiofrequency ablation, and CyberKnife(®) radiotherapy, are important additions to systemic therapy for advanced metastatic disease.

Optimization of the use of monoclonal antibodies (MAbs) as diagnostic tools and therapeutic agents in the treatment of cancer is aided by quantitative characterization of the transport and tissue disposition of these agents in whole animals. This characterization may be effectively achieved by the application of physiologically based pharmacokinetic (PBPK) models. The purpose of this study was to develop a PBPK model to characterize the biodistribution of the pancarcinoma MAb CC49 IgG in normal and neoplastic tissues of nude mice, and to further apply the model to predict the disposition of multivalent single chain Fv (scFv) constructs in mice. Since MAbs are macromolecules, their transport is membrane-limited and a two-pore formalism is employed to describe their extravasation. The influence of binding of IgG to the protective neonatal Fc receptor (FcRn) on its disposition is also accounted for in the model. The model successfully described (131)I-CC49 IgG concentrations in blood, tumor and various organs/tissues in mice. Sensitivity analysis revealed the rate of transcapillary transport to be a critical determinant of antibody penetration and localization in the tumor. The applicability of the model was tested by predicting the disposition of di- and tetravalent scFv constructs of CC49 in mice. The model gave reasonably good predictions of the disposition of the scFv constructs. Since the model employs physiological parameters, it can be used to scale-up mouse biodistribution data to predict antibody distribution in humans. Therefore, the clinical utility of the model was tested with data for (131)I-CC49 obtained in patients, by scaling up murine parameter values according to known empirical relationships. The model gave satisfactory predictions of CC49 disposition and tumor uptake in man.

Serotonin is suggested to regulate adult hippocampal neurogenesis, and previous studies with serotonin depletion reported either a decrease or no change in adult hippocampal progenitor proliferation. We have addressed the effects of serotonin depletion on distinct aspects of adult hippocampal neurogenesis, namely the proliferation, survival and terminal differentiation of hippocampal progenitors. We used the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) to deplete serotonin levels. 5,7-DHT selectively decreased hippocampal serotonin levels, while PCPA resulted in a significant decline in both serotonin and norepinephrine levels. We observed a robust decline in the proliferation and survival of adult hippocampal progenitors following PCPA treatment. This was supported by a decrease in the number of doublecortin-positive cells in the neurogenic niche in the hippocampus. In striking contrast, 5,7-DHT did not alter the proliferation or survival of adult hippocampal progenitors and did not alter the number of doublecortin-positive cells. The terminal differentiation of adult hippocampal progenitors was not altered by either PCPA or 5,7-DHT treatment. An acute increase in serotonin levels also did not influence adult hippocampal progenitor proliferation. These results suggest that selective serotonin depletion or an acute induction in serotonin levels does not regulate adult hippocampal neurogenesis, whereas treatment with PCPA that induces a decline in both serotonin and norepinephrine levels results in a significant decrease in adult hippocampal neurogenesis. Our results highlight the need for future studies to examine the role of other monoamines in both the effects of stress and antidepressants on adult hippocampal neurogenesis.

We have recently developed a single-step, low-temperature process for the catalytic production of fuels, such as hydrogen and/or alkanes, from renewable biomass-derived oxygenated hydrocarbons. This paper reviews our work in the development of this aqueous-phase reforming (APR) process to produce hydrogen or alkanes in high yields. First, the thermodynamic and kinetic considerations that form the basis of the process are discussed, after which reaction kinetics results for ethylene glycol APR over different metals and supports are presented. These studies indicate Pt-based catalysts are effective for producing hydrogen via APR. Various reaction pathways may occur, depending on the nature of the catalyst, support, feed and process conditions. The effects of these various factors on the selectivity of the process to make hydrogen versus alkanes are discussed, and it is shown how process conditions can be manipulated to control the molecular weight distribution of the product alkane stream. In addition, process improvements that lead to hydrogen containing low concentrations of CO are discussed, and a dual-reactor strategy for processing high concentrations of glucose feeds is demonstrated. Finally, various strategies are assembled in the form of a composite process that can be used to produce renewable alkanes or fuel-cell grade hydrogen with high selectivity from concentrated feedstocks of oxygenated hydrocarbons. # 2004 Elsevier B.V. All rights reserved.

The rates of aqueous-phase reforming of methanol and ethylene glycol to form H2 and CO2 were measured under kinetically controlled reaction conditions at temperatures of 483 and 498 K over alumina-supported platinum catalysts. Results show that the rates of formation of H2 from aqueous solutions of methanol (from 1 to 10 wt%) are similar to the rates of conversion of ethylene glycol, suggesting that CC bond cleavage is not rate limiting for ethylene glycol reforming. Aqueous-phase reforming of both oxygenated hydrocarbons over Pt/Al2O3 leads to nearly 100% selectivity for the formation of H2 (compared to the formation of alkanes), suggesting that methanation or Fischer–Tropsch reactions involving CO/CO2 and H2 do not appear to be important over platinum-based catalysts under the conditions of the present study. The rate of production of hydrogen is higher order in methanol (0.8) compared to ethylene glycol (0.3–0.5), and the reaction is weakly inhibited by hydrogen (−0.5 order) for both feedstocks. The rates of aqueous-phase reforming of methanol and ethylene glycol show apparent activation barriers of 140 and 100 kJ/mol, respectively, from 483 K and 22.4 bar total pressure to 498 K and 29.3 bar total pressure. Low levels of CO (