Evidence for a role of metformin in preventing olfactory dysfunction among older adults.

BACKGROUND: Olfactory dysfunction (OD) is increasingly recognized as a hallmark of unhealthy aging and is intimately associated with mortality, but therapies remain elusive. Recognizing the increased prevalence of OD in individuals with diabetes, and the potential anti-aging effects of metformin, we studied the association of metformin use with OD. METHODS: Cross-temporal study of participants from Waves 2 (2010-11) and 3 (2015-16) of the National Social Life, Health, and Aging Project (NSHAP), a nationally representative cohort study of community-dwelling older adults. We included participants with diabetes who had complete data on olfaction and relevant covariates at Wave 2 and were not lost to follow-up at Wave 3. Olfactory identification (OI), the ability to identify the odorant, and olfactory sensitivity (OS), the ability to detect the presence of an odorant, were tested. Weighted multivariable logistic regression was used to study the association between metformin use at Wave 2 (baseline) and odds of having impaired OI/OS at Wave 3, adjusted for age, sex, race/ethnicity, education, smoking, BMI, HbA1c, years since diabetes diagnosis, and insulin use. RESULTS: Among 228 participants with diabetes (mean age=70 years, 53% female, 21% Black), 112 (49%) used metformin at baseline. Relative to nonusers, users had 58% lower odds of impaired OI and 67% lower odds of impaired OS at Wave 3. Among participants with normal baseline OS (N=62), users had 97% lower odds of impaired OS at Wave 3. CONCLUSIONS: Metformin use is associated with lower odds of OD among individuals with diabetes, suggesting a potential protective effect on olfaction. Future work including a larger sample and additional information on metformin use is needed to establish whether these findings are independent of diabetic control.

Assessing Bias in Cognitive Testing for Older Adults with Sensory Impairment: An Analysis of Differential Item Functioning in the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

OBJECTIVES: Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition. METHODS: Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5-4 kHz pure-tone average > 25 decibels). RESULTS: We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p = .04) and in BLSA: .62 logits (p = .02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p = .001) and Incidental Learning test in ARIC-NCS: .35 logits (p = .001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement. CONCLUSIONS: DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

The effect of missing data and imputation on the detection of bias in cognitive testing using differential item functioning methods.

BACKGROUND: Item response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies. METHODS: We used data from Visit 6 (2016-2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection. RESULTS: When missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation. CONCLUSIONS: Incorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing.

Lutetium oxodotreotide (177Lu-Dotatate) for the treatment of unresectable or metastatic progressive gastroenteropancreatic neuroendocrine tumors: a cost-effectiveness analysis for Scotland.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland. METHODS: Cost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes. RESULTS: For unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained. In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus. CONCLUSIONS: Cost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903).

BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.

Signal transducer and activator of transcription (STAT) 1 and STAT3 are expressed in the human ovary and have Janus kinase 1-independent functions in the COV434 human granulosa cell line.

Ovarian granulosa cells are fundamental for oocyte maintenance and maturation. Recent studies have demonstrated the importance of members of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway in the granulosa cell population of mouse and horse ovaries, with perturbation of JAK1 signalling in the mouse shown to impair oocyte maintenance and accelerate primordial follicle activation. The presence and role of the JAK/STAT pathway in human granulosa cells has yet to be elucidated. In this study, expression of JAK1, STAT1 and STAT3 was detected in oocytes and granulosa cells of human ovarian sections from fetal (40 weeks gestation) and premenopausal ovaries (34-41 years of age; n=3). To determine the effects of JAK1 signalling in granulosa cells, the human granulosa-like cell line COV434 was used, with JAK1 inhibition using ruxolitinib. Chemical inhibition of JAK1 in COV434 cells with 100nM ruxolitinib for 72h resulted in significant increases in STAT3 mRNA (P=0.034) and p-Y701-STAT1 protein (P=0.0117), demonstrating a role for JAK1 in modulating STAT in granulosa cells. This study implicates a conserved role for JAK/STAT signalling in human ovary development, warranting further investigation of this pathway in human granulosa cell function.

Self-efficacy in non-concussed youth: a normative study.

OBJECTIVE: In pediatric concussion, there has been a shift to consider how pre-injury profiles, such as self-efficacy, affect the recovery trajectory. The aim of this study was to investigate normal ranges of self-efficacy (overall, academic, social, emotional) in youth and to explore its relationship with the effects of daily stressors, operationalized as concussion-like symptoms, demographic factors, pre-injury/learning related factors, and concussion history. METHODS: A cross-sectional study of 1300 uninjured youth 13-18 years old (1111 males, 189 females) was conducted by secondary analysis of clinical pre-injury/baseline concussion data. Demographic information, concussion-like symptoms (Post-concussion Symptom Inventory), and self-efficacy (Self-efficacy Questionnaire for Children) were self-reported. RESULTS: The most reported concussion-like symptoms were common stress symptoms and there was a strong negative relationship with self-efficacy. Males reported higher self-efficacy than females, but no age effects were observed. Pre-injury factors including learning disability, ADHD, special education, IEP, mental health challenges, history of headaches/migraines, and concussion history were associated with significantly lower overall self-efficacy. CONCLUSIONS: These normative ranges and predictive model can be used to provide a benchmark of self-efficacy to indicate how youth may respond to a concussion, and to inform clinical care during recovery.

A novel water-in-oil emulsion with a lecithin-modified bentonite prevents skin damage from urban dust and cedar pollen.

OBJECTIVE: Particulate matter (PM), such as air pollutants and pollens, are known to cause skin ageing through skin inflammation. It is important to develop formulations which protect the skin from PM. We previously developed a conventional water-in-oil emulsion with a synthetic surfactant, distearyldimonium chloride, modified bentonite (C-W/O), which protects skin from allergens. In the present study, we developed a novel water-in-oil emulsion with a natural surfactant, lecithin, modified bentonite (N-W/O). METHODS: The microarray analysis was performed using total RNA extracted from a reconstructed human epidermis (RHE) stimulated with urban aerosols or cedar pollen for 6 h in order to develop an epidermal inflammation model by PM for the evaluation of topical formulations. We then compared the efficacy of N-W/O and C-W/O to prevent epidermal degradation. Tissues and culture media were collected 24 h after the urban aerosol or cedar pollen stimulation for a histological assay, and the quantification of MMP1 and IL-8 secretion. RESULTS: The expression levels of proinflammatory cytokines and chemokines, such as IL1A and CXCL8, and matrix metalloproteinases, including MMP1, MMP3 and MMP9, were significantly up-regulated by the PM stimulation. As a result of ranking based on the pathway enrichment analysis, oxidative stress-related pathways, such as MAPK-mediated signalling, HIF-1 signalling, IL-1 signalling and ROS-induced cellular signalling, were ranked high in the urban dust- and cedar pollen-treated groups. A thickened stratum corneum, thinned vital layer and cleaved E-cadherin were observed by haematoxylin and eosin staining and immunohistochemical staining of E-cadherin in the PM treated groups. The secretion of MMP1 and IL-8 into the media was significantly increased by the PM stimulation. N-W/O prevented the degradation of epidermal integrity and secretion of inflammatory proteins more effectively than C-W/O. CONCLUSION: The present results showed that N-W/O made using natural surfactant is useful at protecting skin from PM, such as urban aerosols and cedar pollen.

OBJECTIF: Les particules en suspensions (PM), telles que les polluants atmosphériques et les pollens, sont connues comme des causes de vieillissement de la peau par inflammation cutanée. Il est essentiel de mettre au point des formules qui protègent la peau contre ces particules. Par le passé, nous avons mis au point une émulsion eau-dans-huile classique composée d'un tensioactif synthétique, de distearyldimonium chloride et de bentonites modifiées (E/H-C), qui protège la peau contre les allergènes. Dans la présente étude, nous avons conçu une nouvelle émulsion eau-dans-huile composée d'un tensioactif naturel, de lécithine et de bentonites modifiées (N-E/H). MÉTHODES: L'analyse des microréseaux a été réalisée à l'aide de l'ARN total extrait d'un épiderme humain reconstitué (EHR) stimulé par les aérosols urbains ou le pollen de cèdre pendant 6 h afin de mettre au point un modèle d'inflammation de l'épiderme par les particules en suspensions en vue de l'évaluation des formulations topiques. Nous avons ensuite comparé l'efficacité de la N-E/H et de l'E/H-C dans le but d'éviter la dégradation de la peau. Les milieux de culture tissulaire ont été collectés 24 h après stimulation par l'aérosol urbain ou par du pollen de cèdre pour un dosage histologique et une quantification de MMP-1 et des sécrétions de l'IL-8. RÉSULTATS: Les niveaux d'expression des cytokines pro-inflammatoires et des chimiokines, à l'instar de l'IL1A et du CXCL8, ainsi que des métalloprotéinases matricielles, notamment les MMP1, les MMP3 et les MMP9, étaient essentiellement régulés positivement par la stimulation des particules en suspensions. En raison du classement basé sur l'analyse d'enrichissement des voies, le stress oxydatif, telles que la signalisation médiée par MAPK, la signalisation HIF-1, la signalisation IL-1 et la signalisation cellulaire induite par les ROS ont été classés en tête pour les groupes traités par la poussière urbaine et par le pollen-de cèdre. Un stratum corneum épaissie, une couche vitale fine et une clivée d'E-cadhérine ont été observées par coloration à l'hématoxyline-éosine et par coloration immunohistochimique de l'E-cadhérine dans les groupes traités aux particules en suspensions. La sécrétion de MMP1 et de l'IL-8 dans les milieux a augmenté de façon significative par stimulation des particules en suspensions. La N-E/H a permis d'éviter une dégradation de l'intégrité de la peau et la sécrétion de protéines inflammatoires de manière plus efficace que l'E/H-C. CONCLUSION: Les résultats actuels ont révélé que la N-E/H produite grâce à l'utilisation d'un tensioactif naturel est utile pour la protection de la peau contre les particules en suspensions telles que les aérosols urbains et le pollen de cèdre.

Routine germline BRCA1 and BRCA2 testing in patients with ovarian carcinoma: analysis of the Scottish real-life experience.

OBJECTIVE: To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy. DESIGN: Retrospective cohort study. SETTING: Four cancer/genetics centres in Scotland. POPULATION: Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria). METHODS: Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. MAIN OUTCOME MEASURES: Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations. RESULTS: Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of <15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged >70 years was 8.2%. CONCLUSIONS: Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate. TWEETABLE ABSTRACT: BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.

A multicenter, open-label, expanded phase 2 study to evaluate the safety and efficacy of etirinotecan pegol, a polymer conjugate of irinotecan, in women with recurrent platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Etirinotecan pegol (EP) is a novel polyethylene glycol conjugated form of irinotecan with documented activity in platinum-resistant ovarian cancer (PROC). We report the results of the expanded portion of a phase II study of EP in patients with PROC who received prior pegylated liposomal doxorubicin (PLD) or who were unable to receive it. METHODS: This multicenter, open-label, phase II study evaluated EP q21d for PROC. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.0. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Patient populations evaluated included a modified intent-to-treat (mITT) group consisting of all patients who received at least one dose and with measurable disease and a primary efficacy (pEFF) group (subset of the mITT population who received prior PLD). RESULTS: One hundred thirty-nine patients were enrolled. Of the 132 patients in the mITT group, 20 achieved an ORR (15.2%; 95% CI 9.5-22.4); median PFS and OS were 4.4 months and 10.2 months, respectively. In the pEFF group (n=104), 15 patients (14.4%; 95% CI 8.3-22.7) achieved an ORR; median PFS and OS were 4.4 months and 10.9 months, respectively. The most common grade 3/4 toxicities were diarrhea (20%), abdominal pain (17%), vomiting (14%), dehydration (13%), and nausea (13%). Severe diarrhea was reduced to 15% with strict adherence to screening and management guidelines. CONCLUSIONS: This study confirms the activity and safety of single-agent EP in patients with PROC, including patients who received prior PLD. Further evaluation earlier in the disease course and in combination is warranted.

A Preliminary Exploration of Concussion and Strength Performance in Youth Ice Hockey Players.

The objective of this study was to describe the effect of concussion on upper and lower body strength in children and youth athletes. The participant group was made up of 178 unique male and female ice hockey players (ages 8-14 years). Using a 3-year prospective longitudinal research design, baseline and post-concussion data on hand grip strength, jump tests, and leg maximal voluntary contraction were collected. Using a linear mixed-effects model, no significant differences were found when comparing the baseline strength performance of individuals who went on to experience a concussion and those who did not. When accounting for sex, multiple concussions, and ongoing changes in strength associated with age, weaker hand grip scores were found following concussion while participants were still symptomatic. Lower squat jump heights were achieved while participants were symptomatic as well as when they were no longer self-reporting symptoms associated with concussion. This study represents an initial step towards better understanding strength performance following concussion that may limit the on and off ice performance of youth ice hockey players, as well as predispose youth to subsequent injuries.

Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer.

BACKGROUND: The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed. METHODS: Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival. RESULTS: We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer. CONCLUSIONS: Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.

Diagnostic findings in sinonasal aspergillosis in dogs in the United Kingdom: 475 cases (2011-2021).

OBJECTIVES: To describe the diagnostic tests used and their comparative performance in dogs diagnosed with sinonasal aspergillosis in the United Kingdom. A secondary objective was to describe the signalment, clinical findings and common clinicopathologic abnormalities in sinonasal aspergillosis. MATERIALS AND METHODS: A multi-centre retrospective survey was performed involving 23 referral centres in the United Kingdom to identify dogs diagnosed with sinonasal aspergillosis from January 2011 to December 2021. Dogs were included if fungal plaques were seen during rhinoscopy or if ancillary testing (via histopathology, culture, cytology, serology or PCR) was positive and other differential diagnoses were excluded. RESULTS: A total of 662 cases were entered into the database across the 23 referral centres. Four hundred and seventy-five cases met the study inclusion criteria. Of these, 419 dogs had fungal plaques and compatible clinical signs. Fungal plaques were not seen in 56 dogs with turbinate destruction that had compatible clinical signs and a positive ancillary test result. Ancillary diagnostics were performed in 312 of 419 (74%) dogs with observed fungal plaques permitting calculation of sensitivity of cytology as 67%, fungal culture 59%, histopathology 47% and PCR 71%. CLINICAL SIGNIFICANCE: The sensitivities of ancillary diagnostics in this study were lower than previously reported challenging the clinical utility of such tests in sinonasal aspergillosis. Treatment and management decisions should be based on a combination of diagnostics including imaging findings, visual inspection, and ancillary testing, rather than ancillary tests alone.

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609.

Recombination-activating gene 1 (Rag1) and Rag2 enzymes are required for T cell receptor assembly and thymocyte development. The mechanisms underlying the transcriptional activation and repression of Rag1 and Rag2 are incompletely understood. The zinc-finger protein, Zfp608, represses Rag1 and Rag2 expression when expressed in thymocytes blocking T-cell maturation. Here we show that the related zinc-finger protein, Zfp609, is necessary for Rag1 and Rag2 expression in developing thymocytes. Zfp608 represses Rag1 and Rag2 expression indirectly by repressing the expression of Zfp609. Thus, the balance of Zfp608 and Zfp609 plays a critical role in regulating Rag1 and Rag2 expression, which may manifest itself not only during development of immature thymocytes into mature T cells but also in generation of the T-cell arm of the adaptive immune system, which does not fully develop until after birth.

Age and competition level on injuries in female ice hockey.

The objective of this study was to describe the number, types and locations of known injuries occurring across different age categories and levels of competition in female ice hockey within the Ontario Women's Hockey Association from 2004/05 to 2007/08. We further examined under which aforementioned factors and combination of factors an unusually high or low number of injuries was recorded. Secondary analysis of anonymized injury data was conducted. The most common known injury type was strain/sprain, followed by concussion while the most frequent injury location was head/face/mouth. Analysis of deviance indicated that a significantly higher than expected number of sprain/strain, concussion and laceration injuries were recorded compared to all other injury types. In addition, there were a higher number of injuries recorded at the AA level compared to all other levels of competition. Finally, the age categories of Peewee, Midget and Intermediate within the AA level of competition, as well as Senior/Adult within the Houseleague level of competition also recorded a significantly higher number of injuries compared to other combinations of descriptive factors. Further research with female youth is needed to better understand the high number of injuries, including concussions, reported overall.

Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).

These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

A systemic review of toxic death in clinical oncology trials: an Achilles' heel in safety reporting revisited.

BACKGROUND: Toxic death is defined as study treatment-related mortality and as such is considered as an iatrogenic death. This belongs to unnatural death where an autopsy is advised. Until now, conventional autopsy is the gold standard to discriminate between pre- and post-mortem discrepancies. METHODS: The consequences of lack of systematically performing an autopsy will be explored in the setting of oncological clinical trials. RESULTS: During more than one decade, 6428 Serious Adverse Events have been registered in the EORTC Safety database on a total of 34 734 subjects. The number of deaths were 764 (mortality rate of 2.2%) whereof 255 (rate of 0.7%) toxic deaths. In 89.8% of these toxic deaths, no autopsy has been done; in 25.1% (64 cases) an inconsistent cause of death was found based on studying of the medical narrative. The autopsy rate was only 10.2% (26 out of 255) and, in 46.2% of the performed autopsies, there was a clinical pathological discrepancy. CONCLUSION: When no autopsy is performed, there is a high risk for a wrong diagnosis in case of suspected toxic death. The high discrepancy rate, possibly due to a low autopsy rate, shows that toxic death is an Achilles' heel in iatrogenic mortality.

Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial.

BACKGROUND: To perform a subset analysis of patients with partially platinum-sensitive recurrent ovarian cancer (ROC) who received either CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) in the CALYPSO trial. PATIENTS AND METHODS: CALYPSO, an international phase III, non-inferiority trial, enrolled women with ROC that relapsed >6 months following first- or second-line therapy. Patients were randomized to CD or CP. Patients with a treatment-free interval of >6 and ≤ 12 months were evaluated for progression-free survival (PFS), the primary end point of CALYPSO trial, and safety. RESULTS: A total of 344 partially platinum-sensitive patients were included (N = 161, CD and N = 183, CP). The hazard ratio for PFS was 0.73 (95% confidence interval: 0.58-0.90; P = 0.004 for superiority) in favor of CD. Median PFS times were 9.4 months (CD) and 8.8 months (CP). Toxicities more common with CP versus CD included grade 3/4 neutropenia (50% versus 39%; P = 0.015), grade 2 alopecia (86% versus 9%; P < 0.001), neuropathy and hypersensitivity reactions. Hand-foot syndrome was more common with CD; however, grade 3/4 reactions were low (one patient in each arm). CONCLUSION: Carboplatin-PLD has a more favorable risk-benefit profile than CP in patients with partially platinum-sensitive ROC and should be considered an effective treatment option for these patients.

Health-related quality of life in recurrent platinum-sensitive ovarian cancer--results from the CALYPSO trial.

BACKGROUND: In the CALYPSO trial, carboplatin-pegylated liposomal doxorubicin (CD) demonstrated superior therapeutic index versus carboplatin-paclitaxel (CP) in patients with recurrent ovarian cancer. This paper reports the health-related quality of life (HRQoL) findings. MATERIALS AND METHODS: HRQoL was measured with the EORTC QoL-QC30 questionnaire and OV28 ovarian cancer module. Mean change scores from baseline in HRQoL subscales (five functional scales and global health status) in each arm and the proportion of patients improved or worsened were calculated every 3 months until 12 months. RESULTS: Compliance was 90% at baseline and 76%, 64%, 57% at 3, 6, and 9 months, respectively. Baseline HRQoL showed already impaired global scores (mean 62/100) and considerable symptom burden (90% of patients reporting nonzero scores). Global QoL and abdominal symptom scores improved over time in both arms; at 6 months, 36% of patients met criteria for improved symptoms. Treatment with CD resulted in less peripheral neuropathy (9.8 versus 24.2), fewer other chemotherapy side-effects (9.5 versus 16.2), and less impact on body image (3.8 versus 10.4) versus CP (all P<0.02) at 6 months. CONCLUSIONS: These patient-reported outcomes confirm the overall lower toxicity of CD versus CP. The improved disease-related outcomes achieved with CD were not at the expense of QoL.