A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.

BACKGROUND: Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS: Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS: A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION: Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION: ClinicalTrials.govNCT02023697.

Tablet-based electroencephalography diagnostics for patients with epilepsy in the West African Republic of Guinea.

BACKGROUND AND PURPOSE: Epilepsy is most common in lower-income settings where access to electroencephalography (EEG) is generally poor. A low-cost tablet-based EEG device may be valuable, but the quality and reproducibility of the EEG output are not established. METHODS: Tablet-based EEG was deployed in a heterogeneous epilepsy cohort in the Republic of Guinea (2018-2019), consisting of a tablet wirelessly connected to a 14-electrode cap. Participants underwent EEG twice (EEG1 and EEG2), separated by a variable time interval. Recordings were scored remotely by experts in clinical neurophysiology as to data quality and clinical utility. RESULTS: There were 149 participants (41% female; median age 17.9 years; 66.6% ≤21 years of age; mean seizures per month 5.7 ± SD 15.5). The mean duration of EEG1 was 53 ± 12.3 min and that of EEG2 was 29.6 ± 12.8 min. The mean quality scores of EEG1 and EEG2 were 6.4 [range, 1 (low) to 10 (high); both medians 7.0]. A total of 44 (29.5%) participants had epileptiform discharges (EDs) at EEG1 and 25 (16.8%) had EDs at EEG2. EDs were focal/multifocal (rather than generalized) in 70.1% of EEG1 and 72.5% of EEG2 interpretations. A total of 39 (26.2%) were recommended for neuroimaging after EEG1 and 22 (14.8%) after EEG2. Of participants without EDs at EEG1 (n = 53, 55.8%), seven (13.2%) had EDs at EEG2. Of participants with detectable EDs on EEG1 (n = 23, 24.2%), 12 (52.1%) did not have EDs at EEG2. CONCLUSIONS: Tablet-based EEG had a reproducible quality level on repeat testing and was useful for the detection of EDs. The incremental yield of a second EEG in this setting was ~13%. The need for neuroimaging access was evident.

Contemporary endovascular management of splenic vascular pathologies.

The spleen is a commonly injured organ and the splenic vasculature is also susceptible to inflammation and trauma, often resulting in aneurysm formation. Splenic artery aneurysms carry a high risk of rupture and are associated with high mortality and morbidity. Due to the advances in endovascular techniques and devices, endovascular management of splenic vascular pathologies is now considered a first-line strategy. Endovascular embolisation and advance techniques including balloon- or stent-assisted coil embolisation enables minimally invasive management option while preserving splenic function.

Hip fractures are preventable: a proposal for osteoporosis screening and fall prevention in older people.

Osteoporosis is highly prevalent but underdiagnosed and undertreated in Hong Kong. Fragility fractures associated with osteoporosis often result in loss of independence and increased mortality for home-dwelling patients, imposing a high socio-economic burden on society. This issue requires urgent attention given the rapid growth of the elderly population in Hong Kong by approximately 4.3% each year. To address this situation, a group of experts convened to discuss practical ways to reduce the burden of fractures and formulated three recommendations: first, all men (aged ≥70 years) and women (aged ≥65 years) should receive universal dual-energy X-ray absorptiometry assessment for osteoporosis. Second, all men (aged ≥70 years) and women (aged ≥65 years) with a fracture-risk assessment-derived 10-year risk (hip fracture with bone mineral density) ≥3% should receive ≥3 years of anti-osteoporotic treatment. Third, comprehensive structured assessment (including dual-energy X-ray absorptiometry) should be conducted in older patients with a history of falling. By implementing these recommendations, we estimate that we could prevent 5234 hip fractures in 10 years, an annual incidence reduction of approximately 7%, and save HK$425 million in direct medical costs plus substantial indirect savings. Ample clinical and cost-effectiveness data support these recommendations, and studies in Hong Kong and abroad could serve as models on how to implement them. We are confident that by applying these recommendations rigorously and systematically, a significant reduction in hip fractures in Hong Kong is achievable.

R0 Resection Margin, A New Quality Measure in the Era of National Bowel Screening?

Aims To determine the completeness of polyp resection (i.e. achieving an R0 margin) and its relation with Endoscopists, histopathologist, size, location and technique of polypectomy in an NSS cohort. The definition of R0 margin is complete macroscopic resection with a negative microscopic margin at polypectomy. Method NCCS (National Colon Cancer Screening) colonoscopies are offered to bowel cancer screening patients after a positive faecal immunochemical test (FIT) test in a Joint Advisory Group (JAG) accredited Gastrointestinal Endoscopy centre. We histologically evaluated the polyp margins for complete resection, which was defined as the absence of adenomatous or hyperplastic tissue in the resected polyp margins in a cohort of faecal immunochemical test positive patients. Results A total of 186 consecutive NCCS colonoscopies out of a total of 542 performed between 2013 and 2017 were included in this study. Of the polyps excised 152(27%) had a R0 margin histologically, and 30(5%) had involvement of the margin. Surprisingly in 373(67%) of polyps pathologists were unable to assess the margin. Conclusion Achieving an R0 margin should be a key performance indicator for endoscopists performing polypectomy. At the same time more studies on polyp margins are recommended.

Risk factors associated with 1-year mortality among patients with HIV-associated tuberculosis in areas with intermediate tuberculosis burden and low HIV prevalence.

INTRODUCTION: Data are limited regarding risk factors for mortality among patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB) in areas with low HIV prevalence and intermediate TB burden, such as the Western Pacific region. This study aimed to assess such risk factors in Hong Kong, which has an intermediate TB burden and low HIV prevalence. METHODS: We conducted a retrospective cohort analysis of adult patients reported to the Hong Kong TB-HIV Registry between 2006 and 2015. Baseline characteristics were compared with Kaplan-Meier estimates. Cox proportional hazards regression modelling was used to identify factors associated with mortality. RESULTS: Of 299 patients studied, 21 (7.0%) died within 12 months of anti-TB treatment (median [interquartile range], 7.5 [3.8-10] months). The median age of death was 54 (interquartile range, 40.5-75.0) years. The cause of death was TB in five and unrelated to TB in the remaining 16. Cox proportional hazards regression showed that older age (adjusted hazard ratio=4.5; 95% confidence interval [CI]=1.4-14.9), history of drug addiction (4.6; 95% CI=1.6-13.0), and low baseline CD4 cell count of <50/µL (2.9; 95% CI=1.1-7.7) were independent risk factors for death within 12 months. CONCLUSION: This study complements previous studies by providing information regarding risk factors associated with mortality among patients with HIV-associated TB in areas with intermediate TB burden and low HIV prevalence. The results from our study may guide targeted measures to improve survival in other areas with intermediate TB burden and low HIV prevalence, such as the Western Pacific region.

Delayed diagnosis of tuberculosis: risk factors and effect on mortality among older adults in Hong Kong.

OBJECTIVE: To assess the risk factors and effects of delayed diagnosis on tuberculosis (TB) mortality in Hong Kong. METHODS: All consecutive patients with TB notified in 2010 were tracked through their clinical records for treatment outcome until 2012. All TB cases notified or confirmed after death were identified for a mortality survey on the timing and causes of death. RESULTS: Of 5092 TB cases notified, 1061 (20.9%) died within 2 years of notification; 211 (4.1%) patients died before notification, 683 (13.4%) died within the first year, and 167 (3.3%) died within the second year after notification. Among the 211 cases with TB notified after death, only 30 were certified to have died from TB. However, 52 (24.6%) died from unspecified pneumonia/sepsis possibly related to pulmonary TB. If these cases are counted, the total TB-related deaths increases from 191 to 243. In 82 (33.7%) of these, TB was notified after death. Over 60% of cases in which TB diagnosed after death involved patients aged ≥80 years and a similar proportion had an advance care directive against resuscitation or investigation. Independent factors for TB notified after death included female sex, living in an old age home, drug abuse, malignancy other than lung cancer, sputum TB smear negative, sputum TB culture positive, and chest X-ray not done. CONCLUSIONS: High mortality was observed among patients with TB aged ≥80 years. Increased vigilance is warranted to avoid delayed diagnosis and reduce the transmission risk, especially among elderly patients with co-morbidities living in old age homes.

Impact of the United kingdom national bowel cancer awareness campaign on colorectal services.

BACKGROUND: Poor public awareness may account for the advanced stage at diagnosis, hence, poorer survival. With the aim of reducing colorectal cancer deaths, the United Kingdom National Bowel Cancer Awareness Campaign was rolled out from January 2012. Currently, the United Kingdom government target is to have all patients suspected to have cancer seen within 2 weeks of referral from general practitioners. This has significant impact on the workload for endoscopists. OBJECTIVE: The study aimed to measure the impact on colorectal services following the National Bowel Cancer Awareness Campaign. DESIGN: The data between February and July 2012 (onset of campaign) were prospectively collected and compared with data retrospectively collected between February and July 2011 inclusive (before campaign). SETTINGS: This study was conducted at a single center, university hospital. PATIENTS: The number of 2-week wait referrals, investigations, and colorectal cancers detected were assessed. MAIN OUTCOME MEASURES: Demographics, staging, and treatment of cancers were compared between groups along with the uptake of colorectal cancer screening. RESULTS: The total number of 2-week wait referrals increased by 47% with a resultant 38% increase in colonic investigations (p = 0.034) and a 23% increase in cancers detected (p = 0.0157). There was a 6.5% increase in the uptake of screening (p = 0.001) and a 62.5% decrease in the number of patients with colorectal cancer presenting as an emergency. LIMITATIONS: This short period of study is a major limitation. Although the data were from prospectively maintained databases, some data were analyzed retrospectively. Because only a single unit was assessed, results across a wider population may be more pronounced. There was also a referral bias in the compliance of primary care in the adherence to the 2-week wait referral criteria, because these criteria can be abused to get anxious patients into secondary care quickly. CONCLUSIONS: The National Bowel Cancer Awareness Campaign significantly increased the demand for colorectal services. With a potentially more favorable oncological outcome, further evaluation of supporting this greater workload demand is warranted.

Distinct and opposing roles for the phosphatidylinositol 3-OH kinase catalytic subunits p110α and p110ß in the regulation of insulin secretion from rodent and human beta cells.

AIMS/HYPOTHESIS: Phosphatidylinositol 3-OH kinases (PI3Ks) regulate beta cell mass, gene transcription, and function, although the contribution of the specific isoforms is unknown. As reduced type 1A PI3K signalling is thought to contribute to impaired insulin secretion, we investigated the role of the type 1A PI3K catalytic subunits α and ß (p110α and -ß) in insulin granule recruitment and exocytosis in rodent and human islets. METHODS: The p110α and p110ß subunits were inhibited pharmacologically or by small hairpin (sh)RNA-mediated knockdown, and were directly infused or overexpressed in mouse and human islets, beta cells and INS-1 832/13 cells. Glucose-stimulated insulin secretion (GSIS), single-cell exocytosis, Ca(2+) signalling, plasma membrane granule localisation, and actin density were monitored. RESULTS: Inhibition or knockdown of p110α increased GSIS. This was not due to altered Ca(2+) responses, depolymerisation of cortical actin or increased cortical granule density, but to enhanced Ca(2+)-dependent exocytosis. Intracellular infusion of recombinant PI3Kα (p110α/p85ß) blocked exocytosis. Conversely, knockdown (but not pharmacological inhibition) of p110ß blunted GSIS, reduced cortical granule density and impaired exocytosis. Exocytosis was rescued by direct intracellular infusion of recombinant PI3Kß (p110ß/p85ß) even when p110ß catalytic activity was inhibited. Conversely, both the wild-type p110ß and a catalytically inactive mutant directly facilitated exocytosis. CONCLUSIONS/INTERPRETATION: Type 1A PI3K isoforms have distinct and opposing roles in the acute regulation of insulin secretion. While p110α acts as a negative regulator of beta cell exocytosis and insulin secretion, p110ß is a positive regulator of insulin secretion through a mechanism separate from its catalytic activity.

The role of F(18)-fluorodeoxyglucose positron emission tomography in guiding diagnosis and management in patients with known or suspected cardiac sarcoidosis.

Cardiac sarcoidosis (CS) has gained significant interest in recent years with the emergence of advanced imaging modalities such as MRI and F(18)-fluorodeoxyglucose-positron emission tomography (FDG-PET) as modalities to aid in the diagnosis of this condition. CS remains a difficult condition to diagnose, particularly in cases of isolated cardiac involvement and it can present with a broad spectrum of clinical syndromes. Furthermore, the appropriate management of these patients remains controversial. FDG-PET has a potential role not only in diagnosis of CS but also in directing further therapies, facilitating the decision to start immunosuppression and monitoring the response to it. In this article, we discuss when to consider FDG-PET, outline the current optimal patient preparation and scanning protocols and then, using case examples, discuss the use of FDG-PET in follow-up of patients with known or suspected CS. We also outline how PET can influence management decisions in these patients.

Metastasis-induced pancreatitis: case report.

This report aims to highlight the importance of malignancy exclusion in the absence of common aetiology in acute pancreatitis. An 83-year-old woman presented acutely with pancreatitis. There had been no history suggestive of gallstones disease and she rarely consumed alcohol. Subsequent ultrasound scan revealed no gallstones but multiple liver metastatic lesions. Further carcinomatosis involving the pancreas, right ovary, pelvic lymphatics and nodular disease of the lungs was demonstrated on computed tomography. Immuno-histochemistry of liver biopsy showed positivity for markers suggestive of metastasis arising from lung small cell carcinoma. The case was discussed at the lung multidisciplinary meeting and the patient was referred for community palliative care. Early diagnosis of metastasis induced pancreatitis allows immediate institution of palliative care, if not suitable for aggressive pharmaco-surgical intervention.

The Ideal Physical Therapist from the Perspective of Individuals With Limb Loss.

BACKGROUND: Effective rehabilitation after limb loss is necessary to maximize function and promote independence. Physical therapists (PT) are one of the primary drivers of the rehabilitation process. While general physical therapy knowledge and abilities have been shown to be important to the rehabilitation process, it is unclear what individuals with limb loss value in their PT's. OBJECTIVE: The purpose of this study was to understand the elements that define an ideal PT from the perspective of individuals with limb loss. METHODOLOGY: Mixed-method design consisting of a 20-item web-based survey and semi-structured interviews that were administered to individuals 18 years or older, who spoke English, and had a history of lower limb loss. FINDINGS: Individuals with limb loss describe an ideal PT as promoting a therapeutic alliance, having specialized knowledge, and collaborating with a prosthetist. Knowledge of the PT as it relates to limb loss was found to be both the greatest facilitator and barrier to the rehabilitation process. CONCLUSION: From the perspective of those with limb loss, an ideal PT promotes a strong therapeutic alliance through communication, has specialized knowledge when it comes to the limb loss rehabilitation process, and collaborates with the prosthetist to problem-solve throughout the rehabilitation process.

Effects of heparin and related drugs on neutrophil function.

We have previously demonstrated that heparin inhibits neutrophil activation, but the precise mechanism of action remains to be elucidated. The current aim was to further investigate the effects of heparin at inducing apoptosis of neutrophils and whether this was related to antagonism at IP(3) receptors. Furthermore, we investigated the ability of heparin and related molecules to inhibit acute neutrophil-induced injury to human bronchial epithelial cells (HBECs) in vitro. Neutrophils were isolated from human peripheral venous blood. Expression of annexin-V was determined in neutrophils following incubation with LMWH. The effects of LMWH and related molecules upon thapsigargin or m-3M3FBS (phospholipase C activator) induced neutrophil elastase (NE) release were also investigated. The cytotoxic effects of fMLP-activated neutrophils following co-incubation with HBECs were quantified through counting adherent cells before and after incubation. There was no detectable increase in annexin-V positive neutrophils following pre-incubation with LMWH at 30 min, 60 min or 16 h, but an increase was observed with Fas-activating antibody at 16 h. LMWH significantly inhibited NE release induced by either m-3M3FBS (73.4 ± 6.1%, 100 IU ml(-1), P < 0.01) or thapsigargin (62.4 ± 6.9%, 100 IU ml(-1), P < 0.01) in a sulphate-dependent manner. LMWH and related sulphated molecules all abrogated the cytotoxic effects of fMLP-activated neutrophils upon HBECs. In conclusion we were not able to demonstrate that heparin induces apoptosis and we did not find any evidence for heparin acting as an IP(3) receptor antagonist in neutrophils. Nonetheless, the potent inhibitory effects of heparin and related molecules upon neutrophil-induced injury to HBECs provide further evidence of the therapeutic potential of heparin and related molecules in the treatment of chronic inflammatory diseases.

Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis.

Lipoarabinomannan (LAM) is a potential marker of active tuberculosis (TB). We performed a systematic review and meta-analysis regarding use of urinary LAM assays for diagnosing active TB. We systematically searched for published and unpublished studies that evaluated urinary LAM for active TB diagnosis. Extracted data were pooled using bivariate random effects models and hierarchical summary receiver operating characteristic curves. Heterogeneity was explored through subgroup analysis and meta-regression. Quality was assessed according to standardised QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. In seven studies that assessed test accuracy in microbiologically confirmed cases only, estimates of sensitivity ranged from 13% to 93%, while specificity ranged from 87% to 99%. In five studies that assessed accuracy in clinical and confirmed TB cases, sensitivity ranged from 8% to 80%, while specificity ranged from 88% to 99%. In five studies with results stratified by HIV status, sensitivity was 3-53% higher in HIV-positive than HIV-negative subgroups; sensitivity was highest with advanced immunosuppression. The LAM urinary assay has several characteristics that make it attractive for diagnosing active TB, but has suboptimal sensitivity for routine clinical use. Further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV or for diagnosis of paediatric TB.