Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

Observation of the Exotic Isotope

A ^{13}F resonance was observed following a charge-exchange reaction between a fast ^{13}O beam and a ^{9}Be target. The resonance was found in the invariant-mass distribution of 3p+^{10}C events and probably corresponds to a 5/2^{+} excited state. The ground state was also expected to be populated, but was not resolved from the background. The observed level decays via initial proton emissions to both the ground and first 2^{+} state of ^{12}O, which subsequently undergo 2p decay. In addition, there may also be a significant proton decay branch to the second 2^{+} level in ^{12}O. The wave function associated with the observed level may be collectivized due to coupling to the continuum as is it located just above the threshold for proton decay to the 2_{2}^{+} state of ^{12}O.

First Observation of the Four-Proton Unbound Nucleus

^{18}Mg was observed, for the first time, by the invariant-mass reconstruction of ^{14}O+4p events. The ground-state decay energy and width are E_{T}=4.865(34) MeV and Γ=115(100) keV, respectively. The observed momentum correlations between the five particles are consistent with two sequential steps of prompt 2p decay passing through the ground state of ^{16}Ne. The invariant-mass spectrum also provides evidence for an excited state at an excitation energy of 1.84(14) MeV, which is likely the first excited 2^{+} state. As this energy exceeds that for the 2^{+} state in ^{20}Mg, this observation provides an argument for the demise of the N=8 shell closure in nuclei far from stability. However, in open systems this classical argument for shell strength is compromised by Thomas-Ehrman shifts.

Probing the Symmetry Energy with the Spectral Pion Ratio.

Many neutron star properties, such as the proton fraction, reflect the symmetry energy contributions to the equation of state that dominate when neutron and proton densities differ strongly. To constrain these contributions at suprasaturation densities, we measure the spectra of charged pions produced by colliding rare isotope tin (Sn) beams with isotopically enriched Sn targets. Using ratios of the charged pion spectra measured at high transverse momenta, we deduce the slope of the symmetry energy to be 42

Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

Optimizing the design of invasive placebo interventions in randomized controlled trials.

BACKGROUND: Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs. METHODS: A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics. RESULTS: The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel. CONCLUSION: DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.

ANTECEDENTES: Los ensayos controlados con placebo juegan un papel importante en la evaluación de las intervenciones sanitarias. Sin embargo, pueden ser difíciles de diseñar e implementar en el caso de intervenciones invasivas, incluida la cirugía. Se necesita un conocimiento profundo de los componentes de la intervención terapéutica (para determinar qué se debe y qué no se debe administrar como parte del placebo). También se precisa de una evaluación del riesgo para los pacientes y de las estrategias para garantizar que el placebo imite el tratamiento de forma efectiva. Hasta la fecha no existen guías para el diseño de intervenciones invasivas con placebo. Este estudio tuvo como objetivo desarrollar un marco para optimizar el diseño y la práctica de intervenciones invasivas con placebo dentro en los ensayos clínicos aleatorizados (ECA). MÉTODOS: Utilizando la literatura publicada, se desarrolló un marco preliminar para i) ampliar el alcance de los modelos existentes para facilitar la deconstrucción de las actuaciones invasivas, y ii) identificar estrategias para optimizar el placebo. El marco se perfeccionó tras consultar con partes interesadas ​​en ensayos quirúrgicos, metodología de consenso y ética médica. RESULTADOS: El marco DITTO resultantes consiste en cinco etapas: Etapa 1: deconstrucción de la intervención de tratamiento en sus componentes esenciales y co-intervenciones; Etapa 2: identificar el(los) elemento(s) quirúrgico(s) básico(s); Etapa 3: eliminar el(los) elemento(s) básico(s); Etapa 4: considerar el riesgo, la viabilidad y el papel del placebo en el ensayo al tener en cuenta los demás componentes; y Etapa 5: optimizar el placebo para garantizar el cegamiento efectivo de los pacientes y del personal del ensayo. CONCLUSIÓN: DITTO considera de forma sistemática la naturaleza invasiva del placebo, teniendo en cuenta el riesgo, la viabilidad y la optimización del placebo. El uso de este marco de referencia puede ayudar al diseño de ECAs de alta calidad, necesarios para afianzar la implementación de intervenciones sanitarias.

First Observation of Unbound

The structure of the extremely proton-rich nucleus _{8}^{11}O_{3}, the mirror of the two-neutron halo nucleus _{3}^{11}Li_{8}, has been studied experimentally for the first time. Following two-neutron knockout reactions with a ^{13}O beam, the ^{11}O decay products were detected after two-proton emission and used to construct an invariant-mass spectrum. A broad peak of width ∼3.4 MeV was observed. Within the Gamow coupled-channel approach, it was concluded that this peak is a multiplet with contributions from the four lowest ^{11}O resonant states: J^{π}=3/2_{1}^{-}, 3/2_{2}^{-}, 5/2_{1}^{+}, and 5/2_{2}^{+}. The widths and configurations of these states show strong, nonmonotonic dependencies on the depth of the p-^{9}C potential. This unusual behavior is due to the presence of a broad threshold resonant state in ^{10}N, which is an analog of the virtual state in ^{10}Li in the presence of the Coulomb potential. After optimizing the model to the data, only a moderate isospin asymmetry between ground states of ^{11}O and ^{11}Li was found.

Update on the Hong Kong Reference Framework for Hypertension Care for Adults in Primary Care Settings-review of evidence on the definition of high blood pressure and goal of therapy.

The Hong Kong Reference Framework for Hypertension Care for Adults in Primary Care Settings is updated regularly to ensure it reflects the latest medical development and best practice. In 2017, guidelines from the United States included a major change, adopting the lower blood pressure values of 130/80 mm Hg in defining hypertension, in contrast to the prevailing international consensus of 140/90 mm Hg. After thorough review of the literature and international guidelines, the Advisory Group on Hong Kong Reference Framework for Care of Diabetes and Hypertension in Primary Care Settings (Advisory Group) recommends that the definition of hypertension adopted in the Reference Framework should remain unchanged as a blood pressure of ≥140/90 mm Hg, as there is currently inadequate evidence and lack of general consensus to support such change in Hong Kong. The Advisory Group agrees on individualised treatment goals, and recommends that the initial blood pressure goal for individuals with uncomplicated hypertension should be <140/90 mm Hg; for those who can tolerate it, the goal should be ≤130/80 mm Hg. A lower blood pressure is advisable for young or overweight/obese patients, smokers, and patients with other cardiovascular risk factors.

Antioxidant Rich Potato Improves Arterial Stiffness in Healthy Adults.

Arterial stiffness is an emerging risk factor for cardiovascular disease and dietary anthocyanins may be important in mediating vascular tone. The present study investigated the effect of consumption of an anthocyanin-rich potato, Purple Majesty on arterial stiffness measured as pulse wave velocity in 14 healthy male and female adults. Participants consumed 200 g/day of cooked purple potato containing 288 mg anthocyanins, or a white potato containing negligible anthocyanins for 14 days, separated by a 7-day washout period. Non-invasive assessment of vascular tone by pulse wave velocity was determined in addition to systolic and diastolic blood pressure, high-density lipoproteins, low-density lipoproteins, triglycerides, glucose, insulin and C-reactive protein. Pulse wave velocity was significantly reduced (p = 0.001) following Purple Majesty consumption for 14-days. There were no significant changes with any other clinical parameter measured, and no changes following white potato consumption. The findings from this short-term study indicate a potential effect of Purple Majesty consumption on arterial stiffness.

Understanding mortality rates after hip fracture repair using ASA physical status in the National Hip Fracture Database.

Hip fracture is the most common reason for older patients to need emergency anaesthesia and surgery. Up to one-third of patients die in the year after hip fracture, but this view of outcome may encourage therapeutic nihilism in peri-operative decisions and discussions. We used a multicentre national dataset to examine relative and absolute mortality rates for patients presenting with hip fracture, stratified by ASA physical status. We analysed ASA physical status, dates of surgery, death and hospital discharge for 59,369 out of 64,864 patients in the 2015 National Hip Fracture Database; 3914 (6.6%) of whom died in hospital. Rates of death in hospital were 1.8% in ASA 1-2 patients compared with 16.5% in ASA 4 patients. Survival rates for ASA 4 patients on each of the first three postoperative days were: 98.8%, 99.1% and 99.1% (compared with figures of > 99.9% in ASA 1-2 patients over these days). Survival on postoperative day 6 was 99.4% for ASA 4 patients. Nearly half (48.6%) of the 1427 patients who did not have surgery died in hospital. Although technically sound, a focus on cumulative and relative risk of mortality may frame discussions in an unduly negative fashion, discouraging surgeons and anaesthetists from offering an operation, and deterring patients and their loved ones from agreeing to it. A more optimistic and pragmatic explanation that over 98% of ASA 4 patients survive both the day of surgery and the day after it, may be more appropriate.

Pathological outcome for Chinese patients with low-risk prostate cancer eligible for active surveillance and undergoing radical prostatectomy: comparison of six different active surveillance protocols.

INTRODUCTION: Active surveillance is one of the therapeutic options for the management of patients with low-risk prostate cancer. This study compared the performance of six different active surveillance protocols for prostate cancer in the Chinese population. METHODS: Patients who underwent radical prostatectomy for prostate cancer from January 1998 to December 2012 at a university teaching hospital in Hong Kong were reviewed. Six active surveillance protocols were applied to the cohort. Statistical analyses were performed to compare the probabilities of missing unfavourable pathological outcome. The sensitivity and specificity of each protocol in identifying low-risk disease were compared. RESULTS: During the study period, 287 patients were included in the cohort. Depending on different active surveillance protocols used, extracapsular extension, seminal vesicle invasion, pathological T3 disease, and upgrading of Gleason score were present on final pathology in 3.3%-17.1%, 0%-3.3%, 3.3%-19.1%, and 20.6%-34.5% of the patients, respectively. The University of Toronto protocol had a higher rate of extracapsular extension at 17.1% and pathological T3 disease at 19.1% on final pathology than the more stringent protocols from John Hopkins (3.3% extracapsular extension, P=0.05 and 3.3% pathological T3 disease, P=0.03) and Prostate Cancer Research International: Active Surveillance (PRIAS; 8.0% pathological T3 disease, P=0.04). The Royal Marsden protocol had a higher rate of upgrading of Gleason score at 34.5% compared with the more stringent protocol of PRIAS at 20.6% (P=0.04). The specificities in identifying localised disease and low-risk histology among different active surveillance protocols were 59%-98% and 58%-94%, respectively. The John Hopkins active surveillance protocol had the highest specificity in both selecting localised disease (98%) and low-risk histology (94%). CONCLUSIONS: Active surveillance protocols based on prostate-specific antigen and Gleason score alone or including Gleason score of 3+4 may miss high-risk disease and should be used cautiously. The John Hopkins and PRIAS protocols are highly specific in identifying localised disease and low-risk histology.

Are we making good use of our public resources? The false-positive rate of screening by fundus photography for diabetic macular oedema.

INTRODUCTION: A large proportion of patients diagnosed with diabetic maculopathy using fundus photography and hence referred to specialist clinics following the current screening guidelines adopted in Hong Kong and United Kingdom are found to be false-positive, implying that they did not have macular oedema. This study aimed to evaluate the false-positive rate of diabetic maculopathy screening using the objective optical coherence tomography scan. METHODS: This was a cross-sectional observational study. Consecutive diabetic patients from the Hong Kong West Cluster Diabetic Retinopathy Screening Programme with fundus photographs graded R1M1 were recruited between October 2011 and June 2013. Spectral-domain optical coherence tomography imaging was performed. Central macular thickness of ≥300 µm and/or the presence of optical coherence tomography signs of diabetic macular oedema were used to define the presence of diabetic macular oedema. Patients with conditions other than diabetes that might affect macular thickness were excluded. The mean central macular thickness in various subgroups of R1M1 patients was calculated and the proportion of subjects with central macular thickness of ≥300 µm was used to assess the false-positive rate of this screening strategy. RESULTS: A total of 491 patients were recruited during the study period. Of the 352 who were eligible for analysis, 44.0%, 17.0%, and 38.9% were graded as M1 due to the presence of foveal 'haemorrhages', 'exudates', or 'haemorrhages and exudates', respectively. The mean (±standard deviation) central macular thickness was 265.1±55.4 µm. Only 13.4% (95% confidence interval, 9.8%-17.0%) of eyes had a central macular thickness of ≥300 µm, and 42.9% (95% confidence interval, 37.7%-48.1%) of eyes had at least one optical coherence tomography sign of diabetic macular oedema. For patients with retinal haemorrhages only, 9.0% (95% confidence interval, 4.5%-13.5%) had a central macular thickness of ≥300 µm; 23.2% (95% confidence interval, 16.6%-29.9%) had at least one optical coherence tomography sign of diabetic macular oedema. The false-positive rate of the current screening strategy for diabetic macular oedema was 86.6%. CONCLUSION: The high false-positive rate of the current diabetic macular oedema screening adopted by the United Kingdom and Hong Kong may lead to unnecessary psychological stress for patients and place a financial burden on the health care system. A better way of screening is urgently needed. Performing additional spectral-domain optical coherence tomography scans on selected patients fulfils this need.

Quality of care in patients with diabetic kidney disease in Asia: The Joint Asia Diabetes Evaluation (JADE) Registry.

AIMS: Diabetic kidney disease independently predicts cardiovascular disease and premature death. We examined the burden of chronic kidney disease (CKD, defined as an estimated GFR < 60 ml/min/1.73 m(2) ) and quality of care in a cross-sectional survey of adults (age ≥ 18 years) with Type 2 diabetes across Asia. METHODS: The Joint Asia Diabetes Evaluation programme is a disease-management programme implemented using an electronic portal that systematically captures clinical characteristics of all patients enrolled. Between July 2007 and December 2012, data on 28 110 consecutively enrolled patients (China: 3415, Hong Kong: 15 196, India: 3714, Korea: 1651, Philippines: 3364, Vietnam: 692, Taiwan: 78) were analysed. RESULTS: In this survey, 15.9% of patients had CKD, 25.0% had microalbuminuria and 12.5% had macroalbuminuria. Patients with CKD were less likely to achieve HbA1c < 53 mmol/mol (7.0%) (36.0% vs. 42.3%) and blood pressure < 130/80 mmHg (20.8% vs. 35.3%), and were more likely to have retinopathy (26.2% vs. 8.7%), sensory neuropathy (29.0% vs. 7.7%), cardiovascular disease (26.6% vs. 8.7%) and self-reported hypoglycaemia (18.9% vs. 8.2%). Despite high frequencies of albuminuria (74.8%) and dyslipidaemia (93.0%) among CKD patients, only 49.0% were using renin-angiotensin system inhibitors and 53.6% were on statins. On logistic regression, old age, male gender, tobacco use, long disease duration, high HbA1c , blood pressure and BMI, and low LDL cholesterol were independently associated with CKD (all P < 0.05). CONCLUSIONS: The poor control of risk factors, suboptimal use of organ-protective drugs and high frequencies of hypoglycaemia highlight major treatment gaps in patients with diabetic kidney disease in Asia.

Impact of skeletal-related events on survival in patients with metastatic prostate cancer prescribed androgen deprivation therapy.

OBJECTIVE: To investigate the impact of skeletal-related events on survival in patients with metastatic prostate cancer prescribed long-term androgen deprivation therapy. METHODS: This historical cohort study was conducted in two hospitals in Hong Kong. Patients who were diagnosed with metastatic prostate cancer and prescribed androgen deprivation therapy between January 2006 and December 2011 were included. Details of skeletal-related events and mortality were examined. RESULTS: The median follow-up was 28 (range, 1-97) months. Of 119 patients, 52 (43.7%) developed skeletal-related events throughout the study, and the majority received bone irradiation for pain control. The median actuarial overall survival and cancer-specific survival for patients with skeletal-related events were significantly shorter than those without skeletal-related events (23 vs 48 months, P=0.003 and 26 vs 97 months, P<0.001, respectively). Multivariate analysis revealed that the adjusted hazard ratio of presence of skeletal-related events on overall and cancer-specific survival was 2.73 (95% confidence interval, 1.46-5.10; P=0.002) and 3.92 (95% confidence interval, 1.87-8.23; P<0.001), respectively. A prostate-specific antigen nadir of >4 ng/mL was an independent poor prognostic factor for overall and cancer-specific survival after development of skeletal-related events (hazard ratio=10.42; 95% confidence interval, 2.10-51.66 and hazard ratio=10.54; 95% confidence interval, 1.94-57.28, respectively). CONCLUSIONS: Skeletal-related events were common in men with metastatic prostate cancer. This is the first reported study to show that a skeletal-related event is an independent prognostic factor in overall and cancer-specific survival in patients with metastatic prostate cancer prescribed androgen deprivation therapy. A prostate-specific antigen nadir of >4 ng/mL is an independent poor prognostic factor for overall and cancer-specific survival following development of skeletal-related events.

Peritoneal implantation of ureter in cadaveric renal transplant.

We report here a case of complication of peritoneal implantation of ureter in cadaveric renal transplant. The patient presented with anuria and delayed graft function. The diagnosis was suspected upon physical examination and radiological investigation. The complication was managed with reimplantation of the ureter into the bladder and the patient recovered with good graft function. We discuss this case, review the literature on this rare complication, and share our suggestions on how it can be prevented.

Patient information leaflets for placebo-controlled surgical trials: a review of current practice and recommendations for developers.

INTRODUCTION: Informed consent for participation in an RCT is an important ethical and legal requirement. In placebo surgical trials, further issues are raised, and to date, this has not been explored. Patient information leaflets (PILs) are a core component of the informed consent process. This study aimed to investigate the key content of PILs for recently completed placebo-controlled trials of invasive procedures, including surgery, to highlight areas of good practice, identify gaps in information provision for trials of this type and provide recommendations for practice. METHODS: PILs were sought from trials included in a recent systematic review of placebo-controlled trials of invasive procedures, including surgery. Trial characteristics and data on surgical and placebo interventions under evaluation were extracted. Directed content analysis was applied, informed by published regulatory and good practice guidance on PIL content and existing research on placebo-controlled surgical trials. Results were analysed using descriptive statistics and presented as a narrative summary. RESULTS: Of the 62 eligible RCTs, authors of 59 trials were contactable and 14 PILs were received for analysis. At least 50% of all PILs included content on general trial design. Explanations of how the placebo differs or is similar to the surgical intervention (i.e. fidelity) were reported in 6 (43%) of the included PILs. Over half (57%) of the PILs included information on the potential therapeutic benefits of the surgical intervention. One (7%) included information on potential indirect therapeutic benefits from invasive components of the placebo. Five (36%) presented the known risks of the placebo intervention, whilst 8 (57%) presented information on the known risks of the surgical intervention. A range of terms was used across the PILs to describe the placebo component, including 'control', 'mock' and 'sham'. CONCLUSION: Developers of PILs for placebo-controlled surgical trials should carefully consider the use of language (e.g. sham, mock), be explicit about how the placebo differs (or is similar) to the surgical intervention and provide balanced presentations of potential benefits and risks of the surgical intervention separately from the placebo. Further research is required to determine optimal approaches to design and deliver this information for these trials.