Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia.

A pilot screening study for low bone mass in Singaporean women using years since menopause and BMI.

OBJECTIVE: Current risk assessment tools for osteoporosis have inconsistent performance across different cohorts, making them difficult for clinical practice. This study aimed to evaluate a simple screening index comprising years since menopause (YSM) and body mass index (BMI) that identifies postmenopausal Singaporean women with a greater likelihood of low bone mass. METHODS: The study used data from 188 treatment-naïve postmenopausal women. The associations between low bone mass and different demographic variables, including age, YSM and BMI, were assessed using multivariable logistic regression. Diagnostic performance of the calculated screening index was compared to the Osteoporosis Self-Assessment Tool for Asians (OSTA) and the Fracture Risk Assessment Tool (FRAX®). RESULTS: YSM and BMI were significantly associated with low bone mass. The area under the receiver operating characteristic curves was 0.803 for the screening index, 0.759 for the OSTA, 0.683 for the FRAX® (major osteoporotic fracture probability [MOFP]) and 0.647 for the FRAX® (hip fracture probability [HFP]). Non-parametric Spearman's correlation between the screening index and the other models was 0.857 with the OSTA score, 0.694 with the FRAX® (HFP) and 0.565 with the FRAX® (MOFP) (p < 0.0005). CONCLUSIONS: The diagnostic performance of the screening index comprising YSM and BMI was equivalent to the OSTA and the FRAX®. A risk chart was developed for clinicians to identify and recommend subjects for a further dual-energy X-ray absorptiometry scan. Validation of this model in larger and more diverse cohorts is required.

Repurposing Proton Beam Therapy through Novel Insights into Tumour Radioresistance.

Despite improvements in radiotherapy, radioresistance remains an important clinical challenge. Radioresistance can be mediated through enhanced DNA damage response mechanisms within the tumour or through selective pressures exerted by the tumour microenvironment (TME). The effects of the TME have in recent times gained increased attention, in part due to the success of immune modulating strategies, but also through improved understanding of the downstream effects of hypoxia and dysregulated wound healing processes on mediating radioresistance. Although we have a better appreciation of these molecular mechanisms, efforts to address them through novel combination approaches have been scarce, owing to limitations of photon therapy and concerns over toxicity. At the same time, proton beam therapy (PBT) represents an advancement in radiotherapy technologies. However, early clinical results have been mixed and the clinical strategies around optimal use and patient selection for PBT remain unclear. Here we highlight the role that PBT can play in addressing radioresistance, through better patient selection, and by providing an improved toxicity profile for integration with novel agents. We will also describe the developments around FLASH PBT. Through close examination of its normal tissue-sparing effects, we will highlight how FLASH PBT can facilitate combination strategies to tackle radioresistance by further improving toxicity profiles and by directly mediating the mechanisms of radioresistance.

Real-time kidney graft perfusion monitoring using infrared imaging during pediatric kidney transplantation.

INTRODUCTION: Ischemia times in kidney transplantation have shown to be predictive for future graft function. Preservation solutions and anticoagulation protocols have improved the management of pediatric kidney transplantation. Nonetheless, there is no current tool for intra-operative graft monitoring. The aim of this project is to present a novel technique for intra-operative real-time assessment of graft perfusion using a non-invasive infrared camera. METHODS: Prospectively, the authors included 10 pediatric patients. Surgical procedure followed their institutional protocol. Infrared imaging was captured at graft preparation, vascular anastomosis, unclamping, and at 30 s, 1, 5, and 10 min after unclamping. Analyzed variables included type of transplant, ischemia and procedure times, type of anastomosis, and results of doppler/ultrasound. Postoperative variables included creatinine levels during first 72 h. Any complications were also recorded. Delta analysis was calculated to establish the variation of temperature after unclamping. RESULTS: Average age at transplant was 9.9 years. Five cases were living donor transplants. Mean overall ischemia time was 395.6 (SD 64.4 min). Two patients had poor graft perfusion after unclamping. Of those, one had torsion of the arterial anastomosis and the other was a graft from a donor that required cardiopulmonary resuscitation for 45 min. Thermal imaging showed a correlation of 0.318 between graft temperature change and creatinine decrease. Cut-off delta for temperature for good reperfusion was above 0.2 at 1 min CONCLUSION: Real-time infrared imaging shows to be a promising option for non-invasive graft perfusion monitoring. Initial results show good correlation between intra-operative temperature changes, graft perfusion, and postoperative graft function.

Population-based trend analysis of voiding cystourethrogram ordering practices in a single-payer healthcare system before and after the release of evaluation guidelines.

INTRODUCTION: While voiding cystourethrogram (VCUG) is a widely-accepted test, it is invasive and associated with radiation exposure. Most cases of primary vesicoureteral reflux (VUR) are low-grade and unlikely to be associated with acquired renal scarring. To select patients at greatest risk, in 2011 the American Academy of Pediatrics (AAP) published guidelines for evaluation of children ages 2 - 24 months with urinary tract infections (UTIs). Similarly, in 2010 the Society for Fetal Urology (SFU) published guidelines for patients with hydronephrosis. Herein a prospectively-collected database was queried through the Institute of Clinical Evaluative Sciences (ICES), exploring trends in VCUG ordering within the Ontario Health Insurance Program (OHIP), which guarantees universal access to care. MATERIAL AND METHODS: A dedicated ICES analyst extracted data on all patients younger than 18 years in Ontario, Canada, with billing codes for VCUG and ICD-9 codes for VUR, from 2004-2014. The baseline characteristics included patient age, gender, geographic region, specialty of ordering provider and previous diagnoses of UTI and/or antenatal hydronephrosis to determine the indication for ordering the test. Of these, patients were subsequently incurred OHIP procedure codes for endoscopic injection or ureteral reimplantation. Patients who had a VCUG in the setting of urethral trauma, posterior urethral valves, and neurogenic bladder were excluded. RESULTS AND DISCUSSION: Trend analysis demonstrated that the total number of VCUGs ordered in the province has decreased over a decade (Figure 1), with a concurrent decrease in VUR diagnosis. On multivariate regression analysis, the decrease in VCUG ordering could not be explained by changes in population demographics or other baseline patient variables. Most VCUGs obtained per year were ordered by pediatricians or family physicians (mean 2,022+523.8), compared with urologists and nephrologists (mean 616+358.3). Interestingly, while the rate of VCUG requests decreased, the annual number of surgeries performed for VUR (endoscopic or open) did not show a significant reduction over time. CONCLUSIONS: We present a large population-based analysis in a universal access to care system, reporting a decreasing trend in the number of cystograms and differences by primary care versus specialist providers. While it is reassuring to see practice patterns favorably impacted by guidelines, it is also encouraging to note that the number of surgeries has remained stable. This suggests that patients at risk continue to be detected and offered surgical correction. These data confirm previous institution-based assessments and affirm changes in VCUG ordering independent of variables not relevant to the healthcare system, such as the insurance status.

The evaluation of vesicoureteral reflux among children using contrast-enhanced ultrasound: a literature review.

INTRODUCTION: Voiding cystourethrogram (VCUG) with fluoroscopy remains the gold standard for detection and evaluation of vesicoureteral reflux (VUR) among children. However, the ionizing radiation exposure remains a concern for this diagnostic modality. Recent studies have proposed using contrast-enhanced ultrasound as an alternative option for VUR screening and follow-up in children. The aim of the study was to review the literature of comparative studies that assessed the diagnostic accuracy of contrast-enhanced ultrasound compared with VCUG. METHODOLOGY: A systematic literature search was performed on electronic medical literature databases in July 2017. Literature identification, screening, and assessment of eligibility were performed by five reviewers with a pediatric radiologist. Literature was summarized for the study population, contrast used, and ultrasound mode as well as the timing of comparative reference study being performed. The studies were clustered according to the kind of contrast used. Reported diagnostic accuracy was extracted from individual studies and summarized across the included studies using descriptive statistics of median and interquartile range (IQR). RESULT: A total of 45 comparative studies were identified as eligible for the summary of the literature. Two generations of ultrasound contrast were identified in the available studies (first generation, Levovist and second generation, SonoVue). For the ultrasound studies using the first-generation contrast, the median sensitivity, regardless of the ultrasound mode, was 90.25 (IQR 83.25-97), and the median specificity was 93 (IQR 91.3-95.25). Among studies using the second-generation contrast, the median sensitivity was 86.26 (IQR 81.13-97), and the median specificity was 90.99 (IQR 84-98). No serious adverse events were reported in any of the studies. CONCLUSION: Overall, this review highlights the application of contrast-enhanced ultrasound for its advantage of no exposure to ionizing radiation and diagnostic accuracy relatively comparable to VCUG in the evaluation of VUR. In addition to the functional evaluation of the VUR, it also provides an anatomic evaluation of the kidneys and bladder with ultrasound imaging. However, one should also note that this alternate procedure is highly operator dependent where diagnostic accuracy is excellent when the expertise is available.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with cisplatin and 5-fluorouracil in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: a multicentre, open-label, phase II clinical trial.

BACKGROUND: We conducted a single-arm phase II trial to evaluate the efficacy and adverse effects (AEs) of an anti-epidermal growth factor receptor monoclonal antibody, nimotuzumab, combined with cisplatin and 5-fluorouracil (PF) as first-line treatment in recurrent metastatic nasopharyngeal carcinoma after radical radiotherapy. METHODS: Patients who met the eligibility criteria were recruited from ten institutions (ClinicalTrials.gov; NCT01616849). A Simon optimal two-stage design was used to calculate the sample size. All patients received weekly nimotuzumab (200 mg) added to cisplatin (100 mg/m2 D1) and 5-fluorouracil (4 g/m2 continuous infusion D1-4) every 3-weekly for a maximum of six cycles. Primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs. RESULTS: A total of 35 patients were enrolled (13 in stage 1 and 22 in stage 2). Overall ORR and DCR were 71.4% (25/35) and 85.7% (30/35), respectively. Median PFS and OS were 7.0 (95% CI 5.8-8.2) months and 16.3 (95% CI 11.4-21.3) months, respectively. Unplanned exploratory analyses suggest that patients who received ≥2400 mg nimotuzumab and ≥4 cycles of PF had superior ORR, PFS and OS than those who did not (88.9% versus 12.5%, P < 0.001; 7.4 versus 2.7 months, P = 0.081; 17.0 versus 8.0 months, P = 0.202). Favourable subgroups included patients with lung metastasis [HROS 0.324 (95% CI 0.146-0.717), P = 0.008] and disease-free interval of >12 months [HROS 0.307 (95% CI 0.131-0.724), P = 0.004], but no difference was observed for metastatic burden. The only major grade 3/4 AE was leukopenia (62.9%). CONCLUSION: Combination nimotuzumab-PF chemotherapy demonstrates potential efficacy, and is well tolerated as first-line chemotherapy regimen in recurrent metastatic nasopharyngeal carcinoma.

Return to emergency department after pediatric urology procedures.

BACKGROUND: Unplanned postoperative return visits to the emergency department (ED) and readmission represent a quality bench outcome and pose a considerable cost burden to health-care systems. OBJECTIVE: The aim of this study is to evaluate ED return visits after pediatric urology procedures in a tertiary care children's hospital, trying to identify potential causes. This may constitute a platform for future improvement areas. MATERIALS AND METHODS: A Quality Board-approved retrospective study was performed identifying all urologic cases completed between October 2012 and September 2015. Baseline demographics, American Society of Anesthesia class, operating surgeon, type of admission, type and duration of surgical procedure, and type of anesthesia given were evaluated. Patients who returned to the ED within 30 days of the surgery date were identified. The ED records were reviewed for time of return, etiology for visit, and management received. Univariate and subsequent multivariate logistic regression statistical analyses were performed to identify variables associated with ED return. Odds ratio (OR) and 95% confidence intervals (95% CIs) were generated to determine the significance of relationships. RESULTS: Total of 4125 cases was identified. Median age was 32.9 months, with 85.1% of them being male. 349 (8.5%) cases returned to the ED within 30 days of the surgery. The majority of the returned patients, 295 (84.5%), managed conservatively with medications or reassurance, whereas 54 (15.5%) required readmission, and of those readmitted, 15 (4.3%) cases needed further surgical interventions, mainly urinary tract drainage procedures. Multivariate logistic regression analysis identified that the age, residence, admission type, inguinoscrotal surgery, and duration of surgical procedure were significantly associated with ED return (Table). The most common reason for the ED visit was UTI in 17.2%, followed by stent and catheter issues in 14.3%, wound-related in 14.3%, and bleeding in 11.7%. DISCUSSION: Pediatric literature show varying rates of ED return ranging from 2.4% to 2.6% after urologic procedures. Our return to ED rate exceeds that found in US studies, which can perhaps be attributed to the differences between the Canadian and US health-care systems. As found with other studies, age, inpatient admission, procedure type, and increased operative time were related to ED returns, possibly because of the difficulty of young children expressing themselves and the presumed complex nature of longer operations that mostly need inpatient admission. The most common reason for ED return in this study as in others was presumptive UTI. A known limitation of this study is its retrospective nature, along with the possible missed visits of patients who presented to outside hospitals. CONCLUSION: We present an account of the status of ED return visits after pediatric urology procedures in our institute. The majority of ED returns can be managed conservatively and are probably preventable.

The use of postoperative prophylactic antibiotics in stented distal hypospadias repair: a systematic review and meta-analysis.

INTRODUCTION: The current literature on the use of antibiotics perioperatively for many pediatric procedures, including hypospadias, is inconsistent. There is currently no clear evidence for the use of postoperative antibiotic prophylaxis for stented distal hypospadias repair. OBJECTIVE: This study aims to synthesize and assess the available literature on the use versus non-use of postoperative antibiotic prophylaxis for stented distal hypospadias repair. METHODOLOGY: Systematic literature search was performed on March 2018 for evaluation of trials that assessed the use and non-use of postoperative prophylactic antibiotics among stented distal hypospadias repair in children. Methodological quality of the studies was assessed according to the study design as recommended by the Cochrane Collaboration. The outcome assessed includes composite overall posthypospadias repair complications of infection and wound healing complications. The event rate for each treatment group was extracted to extrapolate intervention relative risk (RR) and corresponding 95% confidence interval (CI). Mantel-Haenszel method with random effect model was used in pooling of effect estimates from the included studies. Heterogeneity was assessed with subgroup analysis performed according to the study design. Publication bias was likewise determined. The protocol of this review was registered in PROSPERO (CRD42018087301) and reported in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULT: A total of seven studies (four cohorts, three randomized controlled trials) with 986 stented distal hypospadias repairs (408 with no post-operative prophylactic antibiotics and 578 given postoperative prophylactic antibiotics) were included for the meta-analysis. Moderate to serious risk of bias was noted among the cohort studies, while the included randomized controlled trials (RCT) were of high risk of bias. Inconsistencies of effect estimates between subgroups and publication bias with small study effect were likely present. The overall pooled effect estimates comparing treatment groups showed no significant difference for outcomes of overall composite postoperative complication (RR 0.93, 95% CI 0.45, 1.93). Assessment of composite infection related complications and wound healing complications likewise did not show any significant between-group differences (RR 1.28, 95% CI 0.49, 3.35 and RR 1.01, 95% CI 0.48, 2.12; respectively) (Table). Asymptomatic bacteriuria was noted to be significantly higher among the intervention group with no postoperative prophylactic antibiotics (RR 4.01, 95% CI 1.11, 14.54). CONCLUSION: The available evidence to date was assessed to be of high risk. The low level of evidence generated suggests that there is limited utility in the use of postoperative prophylactic antibiotics to prevent clinically significant posthypospadias repair complications.

Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy.

Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-ß signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.

Adaptive radiotherapy for head and neck cancers: Fact or fallacy to improve therapeutic ratio?

Modern standards of precision radiotherapy, primarily driven by the technological advances of intensity modulation and image guidance, have led to increased versatility in radiotherapy planning and delivery. The ability to shape doses around critical normal organs, while simultaneously "painting" boost doses to the tumor have translated to substantial therapeutic gains in head and neck cancer patients. Recently, dose adaptation (or adaptive radiotherapy) has been proposed as a novel concept to enhance the therapeutic ratio of head and neck radiotherapy, facilitated in part by the onset of molecular and functional imaging. These contemporary imaging techniques have enabled visualisation of the spatial molecular architecture of the tumor. Daily cone-beam imaging, besides improving treatment accuracy, offers another unique angle to explore radiomics - a novel high throughput feature extraction and selection workflow, for adapting radiotherapy based on real-time tumor changes. Here, we review the existing evidence of molecular and functional imaging in head and neck cancers, as well as the current application of adaptive radiotherapy in the treatment of this tumor type. We propose that adaptive radiotherapy can be further exploited through a systematic application of molecular and functional imaging, including radiomics, at the different phases of planning and treatment.

Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma.

Background: As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods: From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results: One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions: Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Recent advances and anaesthetic considerations in corneal transplantation.

Significant surgical advances have been made recently in corneal transplantation. Penetrating keratoplasty was the dominant method from 1905, until selective lamellar keratoplasty emerged as the preferred technique over the last 20 years. Advanced techniques such as corneal limbal stem cell transplant and keratoprosthesis are also available. The major surgical complications of corneal transplantation are extrusion of ocular content and expulsive choroidal haemorrhage. It is essential for an ophthalmic anaesthetist to have a good understanding of these new surgical procedures so as to provide optimal surgical conditions. This article aims to inform anaesthetists about the recent surgical advances in corneal transplantation and explore the anaesthetic considerations of these new techniques. General anaesthesia remains suitable for a wide range of these procedures especially in repeat surgery, difficult, or prolonged procedures. Regional ophthalmic blocks are ideal for endothelial keratoplasty but can be used in penetrating keratoplasty based on individual risk-benefit assessment, and as a supplement to general anaesthesia. Topical anaesthesia provides an alternative when general anaesthesia and ophthalmic regional blocks are less desirable but overall its use is limited.

Risk factors for hospital and long-term mortality of critically ill elderly patients admitted to an intensive care unit.

BACKGROUND: Data on long-term outcomes of elderly (≥65 years) patients in ICU are sparse. MATERIALS AND METHODS: Adult patients (n = 1563, 45.4% elderly) admitted over 28 months were analyzed by competing risks regression model to determine independent factors related to in-hospital and long-term mortality. RESULTS: 414 (26.5%) and 337 (21.6%) patients died in-hospital and during the 52 months following discharge, respectively; the elderly group had higher mortality during both periods. After discharge, elderly patients had 2.3 times higher mortality compared to the general population of the same age-group. In-hospital mortality was independently associated with mechanical ventilation (subdistribution hazard ratio (SHR) 2.74), vasopressors (SHR 2.56), neurological disease (SHR 1.77), and Mortality Prediction Model II score (SHR 1.01) regardless of age and with malignancy (SHR, hematological 3.65, nonhematological 3.4) and prior renal replacement therapy (RRT, SHR 2.21) only in the elderly. Long-term mortality was associated with low hemoglobin concentration (SHR 0.94), airway disease (SHR 2.23), and malignancy (SHR hematological 1.11, nonhematological 2.31) regardless of age and with comorbidities especially among the nonelderly. CONCLUSIONS: Following discharge, elderly ICU patients have higher mortality compared to the nonelderly and general population. In the elderly group, prior RRT and malignancy contribute additionally to in-hospital mortality risk. In the long-term, comorbidities (age-related), anemia, airway disease, and malignancy were significantly associated with mortality.

MSC-seeded dense collagen scaffolds with a bolus dose of VEGF promote healing of large bone defects.

The functional repair of large skeletal defects remains a significant challenge to orthopaedic surgeons due to the lack of effective strategies to promote bone regeneration, particularly in the elderly. This study investigated the potential use of bone marrow derived mesenchymal stromal cells (MSC) in a dense collagen scaffold with a bolus dose of vascular endothelial growth factor (VEGF) to repair a defect in the femoral diaphysis of mice. MSC isolated from bone marrow of 4-month-old donor mice were seeded in type I collagen gels that were then compressed to form scaffolds with a fibrillar density similar to osteoid. The cells remained metabolically active in scaffolds incubated in vitro for up to 15 days and differentiated into osteoblasts that deposited calcium-phosphate mineral into the scaffold, which was quantified using micro-computed tomographic (micro-CT) imaging. When implanted in a 1 mm x 3 mm unicortical defect the MSC-loaded scaffolds were rapidly mineralised and integrated into host bone with administration of 10 ng of recombinant VEGF injected into the femoral canal at 4 days postoperative. Empty scaffolds and MSC-seeded scaffolds implanted in defects that did not receive a bolus dose of VEGF did not mineralise or integrate with native bone. The approach with MSC, hydrogels and a biologic factor already approved for human use warrants further pre-clinical investigation with a large animal model.

Biomarkers of radiation exposure: can they predict normal tissue radiosensitivity?

Late adverse tissue reactions affect up to a fifth of cancer patients receiving radiotherapy, with several clinical parameters known to influence normal tissue responses. Despite careful control of treatment-related parameters, a significant component of inter-individual variability in normal tissue responses remains unaccounted for, suggesting that perhaps intrinsic genetic and epigenetic factors are the major determinants of normal tissue effects. Against this background, research was initiated into cellular markers predictive of clinical radiosensitivity, focusing first on colony-forming assays, before the advent of reliable surrogate end points, such as chromosomal radiosensitivity and DNA damage repair. More recently, collaborative efforts have focused on genotyping analysis at a target gene or whole genome level. Despite early positive reports from several small-scale pilot studies testing these assays, subsequent attempts to reproduce comparable levels of association between the cellular markers and clinical phenotype in larger cohorts have frequently been inconclusive, although the first well-replicated studies are beginning to emerge. Here, we discuss the underlying rationale, consider aspects pertaining to patient recruitment and study design, review some of the reported findings for DNA damage-related markers, and highlight some of the limitations and confounding factors affecting tests of association between predictive markers and clinical radiosensitivity. We propose that an integrative approach incorporating multiple assays involving collaborations across centres, together with prospective meticulous recruitment of patients taking into account modifying clinical factors of normal tissue responses, enhances the chance of finding the long sought after markers of individual radiosensitivity.

Environmental nicotine contamination in latent fingermarks from smoker contacts and passive smoking.

Hydrophobic silica nanopowder has been used as an effective latent fingermark development agent and subsequently as an enhancement agent in the surface-assisted laser desorption/ionisation-time of flight (SALDI-TOF) mass spectrometry for analysis of fingermark components. The technique has been used in the detection of nicotine and cotinine in the fingermarks of smokers. In order to have confidence in concluding that the nicotine in such samples is indicative of cigarette usage, it is necessary to establish that contamination by environmental contact or from hand to hand contact with smokers or from passive smoking does not lead to false identification of non-smokers as smokers. To investigate this possibility, the background level of nicotine in fingermark material from a number of commonly used places was determined. In addition, a series of experiments was carried out to assess the extent to which nicotine can be transferred through handshakes and finger transfer as well as touching of door handles. The rate of loss of nicotine from latent fingermarks was also assessed over a 24-h period under ambient laboratory conditions. Finally, a laboratory-based model system was evaluated to ascertain the possible transport of nicotine in cigarette smoke from a source to adjacent areas to simulate cross-contamination of a non-smoker by passive exposure. It was observed that person-to-person transfer from a smoker to a non-smoker can occur following handshakes but at low levels and that passive cross-contamination from contact with surfaces is possible under simulated conditions. However, levels of nicotine in the wider environment were found to be too low for detection using this technique which may reflect the half-life of nicotine in latent fingermarks which was about 11h. Likewise, transfer via smoke is possible to objects within about 0.1m of the cigarette but it is unlikely that significant secondary nicotine contamination will occur on the faces and hands of adjacent non-smokers.

Thawed cryoprecipitate stored for 6 h at room temperature: a potential alternative to factor VIII concentrate for continuous infusion.

Continuous infusion (CI) of factor VIII concentrates has been demonstrated to be cost-effective method in maintaining stable levels of FVIII activity in haemophilia A patients with major bleeding or undergoing major surgery. Cryoprecipitates remain the major source of FVIII in developing countries-like the Philippines because of limited availability and high cost of concentrates. To support the use of cryoprecipitate as alternative to FVIII concentrate for CI in centres with no factor concentrates, FVIII levels in 37 bags of random cryoprecipitate were measured at 0, 2, 4 and 6 h after thawing, kept at room temperature with bacteriological culture studies performed on the sixth hour. The mean FVIII content at hour 0 was 108.10 U per bag. Type ORh+ blood had lower FVIII content (+/-78.91 U per bag) compared with blood types ARh+ (+/-121.64 U per bag) and BRh+ (+/-117.04 U per bag). The units stored <6 months had higher FVIII content (+/-117.74 U per bag) compared with those stored for over 6- but <12-months (+/-66.77 U per bag). The mean rate of decline of FVIII activity at 2, 4 and 6 h was statistically significant at 10.35% (P = 0.000), 21.49% (P = 0.000) and 29.41% (P = 0.000) from baseline, respectively, using the paired t-test. Similar finding was found across different blood types and storage duration. Only one of 37 bags grew Staphylococcus aureus on day 10 of incubation.