Impact of the Spinal Instability Neoplastic Score on Surgical Referral Patterns and Outcomes.

BACKGROUND: The Spinal Instability Neoplastic Score (sins) was developed to identify patients with spinal metastases who may benefit from surgical consultation. We aimed to assess the distribution of sins in a population-based cohort of patients undergoing palliative spine radiotherapy (rt) and referral rates to spinal surgery pre-rt. Secondary outcomes included referral to a spine surgeon post-rt, overall survival, maintenance of ambulation, need for re-intervention, and presence of spinal adverse events. METHODS: We retrospectively reviewed ct simulation scans and charts of consecutive patients receiving palliative spine rt between 2012 and 2013. Data were analyzed using Student's t-test, Chi-squared, Fisher's exact, and Kaplan-Meier log-rank tests. Patients were stratified into low (<7) and high (≥7) sins groups. RESULTS: We included 195 patients with a follow-up of 6.1 months. The median sins was 7. The score was 0 to 6 (low, no referral recommended), 7 to 12 (intermediate, consider referral), and 13 to 18 (high, referral suggested) in 34%, 59%, and 7% of patients, respectively. Eleven patients had pre-rt referral to spine surgery, with a surgery performed in 0 of 1 patient with sins 0 to 6, 1 of 7 with sins 7 to 12, and 1 of 3 with sins 13 to 18. Seven patients were referred to a surgeon post-rt with salvage surgery performed in two of those patients. Primary and secondary outcomes did not differ between low and high sins groups. CONCLUSION: Higher sins was associated with pre-rt referral to a spine surgeon, but most patients with high sins were not referred. Higher sins was not associated with shorter survival or worse outcome following rt.

Phyllodes tumors of the breast: The British Columbia Cancer Agency experience.

PURPOSE: Phyllodes tumors of the breast are uncommon fibroepithelial lesions for which optimal management remains unclear. This retrospective population-based study reports treatment and outcomes for patients with phyllodes tumors and evaluates characteristics that influence outcome. MATERIALS AND METHODS: Data were analysed on 183 patients with newly diagnosed phyllodes tumors from 1999 to 2014. Five-year Kaplan-Meier local recurrence and survival were compared between cohorts with benign (n=83), borderline (n=50) and malignant phyllodes tumor (n=49) histology. RESULTS: Median (range) follow-up was 65 (0.5-197) months. Local excision was performed in 163 and mastectomy in 19 patients. Eleven patients with malignant phyllodes tumors received radiation therapy. Overall, local recurrence occurred in 8.7%, distant metastases in 4.4%, and cause specific deaths in 3.8%. Five-year Kaplan-Meier outcomes among women with benign, borderline, and malignant phyllodes tumors were: local recurrence 6% vs 9% vs 21%, P=0.131; overall survival 96% vs 100% vs 82%, P=0.002; and disease-free survival 94% vs 91% vs 67%, P<0.001. Five-year Kaplan-Meier local recurrence among women with negative vs close vs positive margins were 8% vs 6% vs 37%, P<0.001. Corresponding rates for intermediate vs pushing vs infiltrative borders were 6% vs 6% vs 33%, P=0.006. Positive margins and infiltrative tumor borders were associated with increased local recurrence (all P≤0.006), and the latter remained significant in exploratory analyses after adjusting for margin status and phyllodes tumor classification. CONCLUSIONS: Five-year outcomes among women with phyllodes tumors were comparable to those reported in the literature. Exploratory analysis has suggested that infiltrative tumor borders may be used in conjunction with margin status to assess local recurrence risk.

Health literacy, literacy, numeracy and nutrition label understanding and use: a scoping review of the literature.

BACKGROUND: Low health literacy, literacy and numeracy have been identified as barriers to consumer understanding and the interpretation of nutrition-related information. To inform policy and dietetic practice, we examined the extent, range and nature of research on empirical relationships between health literacy, literacy or numeracy and the understanding and use of nutrition labels. METHODS: A scoping review of the literature was conducted. A search of eight databases on 15 April 2014 and 26 May 2016 returned 651 and 173 records, respectively. After de-duplication and two levels of relevance screening, 16 studies were deemed eligible for inclusion in the present review. RESULTS: The majority of studies were conducted in the USA and focused primarily on the use of back-of-pack nutrition labels. Empirical relationships reported between health literacy and nutrition label use were inconsistent and, in some cases, contradictory. The findings from studies examining empirical relationships between literacy, numeracy and nutrition label use suggest that consumers with lower literacy and numeracy: (i) differ from those with higher levels in some of the judgements that they make about food and (ii) may benefit from interventions designed to improve their understanding and use of nutrition label information. Measurement-related issues were identified, such as a reliance on self-reports of nutrition label use, as well as a lack of independence between some measures of health literacy and nutrition label understanding and use. CONCLUSIONS: The empirical relationships between health literacy, literacy, numeracy and nutrition label understanding and use have not been well-studied. Additional attention is needed regarding the measurement-related issues identified in the present review.

Population-based analysis of the impact and generalizability of the NSABP-B24 study on endocrine therapy for patients with ductal carcinoma in situ of the breast.

BACKGROUND: In 1999, the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B24 trial demonstrated that tamoxifen reduced relapse risk in women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) and radiotherapy (RT). In 2002, Allred's subgroup analysis showed that tamoxifen mainly benefitted estrogen receptor (ER)-positive disease. This study evaluates the impact and generalizability of these trial findings at the population level. PATIENTS AND METHODS: From 1989 to 2009, 2061 women with DCIS underwent BCS + RT in British Columbia. The following cohorts were analyzed: (1) pre-NSABP-B24 era (1989-1998, N = 417); (2) post-NSABP-B24 era (2000-2009, N = 1548). Cohort 2 was further divided into pre- and post-Allred eras. RESULTS: Endocrine therapy (ET) was used in 404/2061 (20%) patients. Median age of patients treated with compared with without ET, was 53 versus 57 years, (P < 0.0005). One of 417 (0.2%) versus 399/1548 (26%) patients took ET before versus after NSABP-B24. Among the post-Allred era cohort treated with ET (N = 227), tumors were ER-positive in 65%, ER-negative in 1%, and ER-unknown in 33%; whereas of those treated without ET (N = 801), ER was positive in 43%, negative in 15%, and unknown in 42% (P < 0.0005). On multivariable analysis of the post-NSABP-B24 era, ET was associated with improved event-free survival (EFS) (hazard ratio 0.6; P = 0.02); 5-year EFS were 96.9% with ET versus 94.5% without ET. CONCLUSIONS: ET use in DCIS patients treated with BCS + RT increased significantly after the NSABP-B24 study. ER+ disease and younger age were associated with increased ET use. ET was associated with improved EFS, confirming the generalizability of trial data at a population level.

Does a 'code stroke' rapid access protocol decrease door-to-needle time for thrombolysis?

BACKGROUND: Timely administration of intravenous tissue plasminogen activator (IVtPA) for acute ischaemic stroke is associated with better clinical outcomes. Therefore, a coordinated hospital system of acute clinical assessment and neuroimaging will likely avoid delays in IV-tPA administration. AIM: In July 2007, we implemented a 'code stroke' rapid access protocol at the Royal Melbourne Hospital with the aim of achieving rapid stroke assessment and treatment. This study investigates the quality of our 'code stroke' protocol and its impact on door-to-needle time and IV-tPA usage. METHODS: We included patients thrombolysed with IV-tPA from January 2003 to June 2007 (pre-code stroke era) and patients thrombolysed from July 2007 to December 2010 (code stroke era). Data collected were demographics, time points (stroke symptom onset, presentation to emergency department, neuroimaging and thrombolysis) and clinical outcomes (modified Rankin Scale) at discharge, symptomatic, intracerebral haemorrhage and death during admission). We compared the door-to-needle time and usage of IV-tPA between the two eras. RESULTS: Patient data on 98 'pre-code stroke' thrombolysed patients and 189 'code stroke' thrombolysed patients were collected. The median age was 71 (60-79), 56% were males, and the median baseline National Institute of Health Stroke Scale score was 13 ± 6.3. There was an 18-min reduction in the median door-to-needle time (90 min in 'pre-code stroke era' vs 72 min in 'code stroke era', P < 0.001). The rate of IV-tPA usage increased from 3.9% in 2004 to 17.3% in 2010. CONCLUSION: Our study showed that 'code stroke' rapid access protocol decreased door-to-needle time and possibly contributed to the increased IV-tPA usage.

Age over 80 years is not associated with increased hemorrhagic transformation after stroke thrombolysis.

Thrombolysis trials have recruited few patients aged ≥80 years, which has led to uncertainty about the likely risk-to-benefit profile in the elderly. Leukoaraiosis (LA) has been associated with hemorrhagic transformation (HT) and increases with advanced age. We tested whether there were any independent associations between age, LA and HT. Consecutive patients treated with intravenous (IV) tissue plasminogen activator (tPA) were identified from a prospective database. LA on baseline CT scans was assessed by two independent raters using the modified Van Swieten Score (mVSS) (maximum score 8, severe >4). HT was assessed on routine 24 hour to 48 hour CT /MRI scans using the European Cooperative Acute Stroke Study criteria for hemorrhagic infarct (HI) or parenchymal hematoma (PH) and judged symptomatic by the treating neurologist as per Safe Implementation of Thrombolysis in Stroke criteria. There were 206 patients treated with IV tPA (mean age: 71.0 years; range: 24-92 years), of whom 65/206 (32%) were aged ≥80 years. Overall, HT occurred in 41/206 patients (20%), HI in 31, PH1 in four (one symptomatic) and PH2 in six (three symptomatic). Age was not associated with HT (any HT: odds ratio [OR]=1.01; 95% confidence interval [CI]=0.5-2.08; p=0.99; PH: OR=0.53; 95% CI=0.12-2.3; p=0.51). There was one patient with PH1 and one patient with PH2 in 65 patients ≥80 years, both asymptomatic. LA was present in 112/208 (54%), and severe in 16.5%. LA increased with age (p<0.001) but was not associated with PH (any LA: OR=0.83; 95% CI=0.25-2.8; p=0.99; severe LA: OR=0.54, 95% CI=0.09-3.5; p=0.99). Age ≥80 years or LA did not increase the risk of HT (including PH) after thrombolysis, although LA increased with age. Neither factor should exclude otherwise eligible patients from tPA treatment.

Extent and scale of local adaptation in salmonid fishes: review and meta-analysis.

What is the extent and scale of local adaptation (LA)? How quickly does LA arise? And what is its underlying molecular basis? Our review and meta-analysis on salmonid fishes estimates the frequency of LA to be ∼55-70%, with local populations having a 1.2 times average fitness advantage relative to foreign populations or to their performance in new environments. Salmonid LA is evident at a variety of spatial scales (for example, few km to>1000 km) and can manifest itself quickly (6-30 generations). As the geographic scale between populations increases, LA is generally more frequent and stronger. Yet the extent of LA in salmonids does not appear to differ from that in other assessed taxa. Moreover, the frequency with which foreign salmonid populations outperform local populations (∼23-35%) suggests that drift, gene flow and plasticity often limit or mediate LA. The relatively few studies based on candidate gene and genomewide analyses have identified footprints of selection at both small and large geographical scales, likely reflecting the specific functional properties of loci and the associated selection regimes (for example, local niche partitioning, pathogens, parasites, photoperiodicity and seasonal timing). The molecular basis of LA in salmonids is still largely unknown, but differential expression at the same few genes is implicated in the convergent evolution of certain phenotypes. Collectively, future research will benefit from an integration of classical and molecular approaches to understand: (i) species differences and how they originate, (ii) variation in adaptation across scales, life stages, population sizes and environmental gradients, and (iii) evolutionary responses to human activities.

Multiple paternity and variance in male fertilization success within Atlantic salmon Salmo salar redds in a naturally spawning population.

The incidence and magnitude of multiple paternity were estimated for a natural, unmanipulated spawning population of Atlantic salmon Salmo salar. Egg nests were surveyed in the autumn and sub-samples were excavated the following spring. Parentage data derived from microsatellite DNA revealed an unexpectedly high level of multiple paternity. Within a single redd, females may mate with as many as 16 different males, including small mature male parr and large anadromous males. Multiple paternity was most pronounced in areas of highest redd density, corresponding with increased abundances of mature male parr. In addition, there was considerable variation in success among males, although this variability did not depend upon the number of males participating in spawning. This work underscores the value of undertaking genetic studies on the mating systems of fishes in unmanipulated, natural environments.

Biological control of Diatraea spp. (Lepidoptera: Pyralidae) in sugarcane crops in Central Venezuela

Entre los años 1990-1996, se evaluó la importancia de la mosca amazónica (Melagonystilum minense) y de la avispa (Cotesia flavipes) como controles biológicos de los perforadores de la caña de azúcar (Diatraea saccharalis y Diatraea rosa) en el centro de Venezuela. Durante el período de la zafra, seleccionamos aleatoriamente tallos de caña de azúcar que fueron abiertos para observar el número de perforaciones, hospedadores, proporción de hospedadores parasitados, proporción de hospedadores parasitados por la mosca amazónica o por la avispa. Como consecuencia de las periódicas liberaciones de las moscas y las avispas criadas en el laboratorio, observamos una disminución pronunciada de la abundancia relativa de Diatraea spp., pero no se obtuvo un efecto evidente de utilizar ambos parasitoides. La abundancia de Diatraea spp. en presencia de ambos parasitoides fue similar a la observada durante los 45 años en que se utilizó únicamente M. minense como control biológico. Sin embargo, M. minense probablemente sea el principal control biológico de esta plaga por ser más eficiente en la búsqueda de la misma y por ser un competidor más fuerte que C. flavipes.

Prognostic significance of the number of axillary lymph nodes removed in patients with node-negative breast cancer.

PURPOSE: The objective of the study was to evaluate the association between the number of lymph nodes removed at axillary dissection and recurrence and survival for patients with node-negative invasive breast cancer. PATIENTS AND METHODS: Subjects were 2,278 women with pathologically node-negative invasive breast cancer, diagnosed from 1989 to 1993 in British Columbia, Canada. Women aged > or = 90 years, with pure in-situ, bilateral invasive breast cancer or T4, N1, N2, or M1 stage, or who had axillary radiation were excluded. Two groups were defined for analysis: node-negative with no systemic therapy (n = 1,468) and node-negative with systemic therapy (n = 810). Median follow-up was 7.5 years. Prognostic variables assessed were age at diagnosis, tumor size, tumor grade, invasion of lymphatics, veins, or nerves, estrogen receptor status, and number of nodes removed. RESULTS: For patients not receiving systemic therapy, regional relapse was significantly increased with smaller numbers of nodes removed (P =.03). There was a trend toward shorter overall survival with fewer nodes removed (P =.06). Node-negative patients who received systemic therapy did not have a higher regional relapse rate or shorter overall survival when fewer nodes were recovered. CONCLUSION: Recovery of a small number of negative lymph nodes at axillary dissection likely understages patients and leads to undertreatment, resulting in an increased regional relapse rate and poorer survival. The use of systemic therapy may overcome this effect. The number of nodes removed, in conjunction with other prognostic factors, may be useful in selecting node-negative patients for systemic therapy.

Differences detected in vivo between samples of aflatoxin-contaminated peanut meal, following decontamination by two ammonia-based processes.

A sample of peanut meal, highly contaminated with aflatoxins, has been subjected to decontamination by two commercial ammonia-based processes. The original contaminated and the two decontaminated meals were fed to rats for 90 days. No lesions associated with aflatoxin-induced hepatocarcinogenesis were detected histologically following feeding with the two detoxified meals. There were, however, clear differences between the two meals in respect of growth rates of the rats. In addition, feeding one of the detoxified meals resulted in hepatic abnormalities detected using novel immunohistochemical reagents. Differences between the two detoxified meals were also indicated by the results of studies using meals 'spiked' with [14C]-aflatoxin B1 prior to being subjected to the detoxification processes. The meals differed in the bioavailability of the label. It was concluded that peanut meal where an initial, unacceptable level of contamination with aflatoxins had been reduced by two ammonia-based processes to comparable, acceptable levels, may still have different effects in vivo when incorporated into animal diets.

1,2-Dibenzamidobenzene inhibitors of human factor Xa.

High-throughput screening of a combinatorial library of diamidophenols yielded lead compounds with the ability to inhibit human factor Xa (fXa) at micromolar concentrations (e.g. compound 4, fXa apparent K(ass) = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showed that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phenyl group of one benzoyl group (A-ring) was substituted in the 4-position with relatively small lipophilic or polarizable groups such as methoxy, vinyl, or chloro and the phenyl group of the other benzoyl group (B-ring) was substituted in the 4-position with larger lipophilic groups such as tert-butyl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide variety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxyl substitution produced slightly higher levels of activity than other substituents when present in combination with favorable B-ring substitution. Methylation of the amide nitrogen atoms was found to greatly decrease activity. Compound 12 is the highest affinity fXa inhibitor in this group of compounds, having fXa apparent K(ass) = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can serve to guide future SAR studies.

N(2)-Aroylanthranilamide inhibitors of human factor Xa.

Reversal of the A-ring amide link in 1,2-dibenzamidobenzene 1 (fXa K(ass) = 0.81 x 10(6) L/mol) led to a series of human factor Xa (hfXa) inhibitors based on N(2)-aroylanthranilamide 4. Expansion of the SAR around 4 showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of hfXa. Bulky groups such as 4-isopropyl, 4-tert-butyl, and 4-dimethylamino were favored in the B-ring to interact with the S4 site of hfXa. The central (C) ring containing a 5-methanesulfonamido group yielded greater activity than carbamoyl groups. Combining the beneficial features from the B- and C-ring SAR, compound 55 represents the most potent hfXa inhibitor in the N(2)-aroylanthranilamide 4 series with hfXa K(ass) = 58 x 10(6) L/mol (K(i) = 11.5 nM).

Structure-based design of potent, amidine-derived inhibitors of factor Xa: evaluation of selectivity, anticoagulant activity, and antithrombotic activity.

To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

Local excision without radiation for high-grade soft-tissue sarcoma of the extremity and superficial trunk.

Purpose. Limb-sparing surgery combined with radiation treatment has become the accepted treatment for patients with high-grade soft-tissue sarcoma. Adjuvant radiation was not routinely used at this institution for patients with clear margins after surgery.This retrospective review analyses the outcome of this group of patients.Patients and methods. Patients studied were referred from 1984 to 1995, were over 16 years of age, were diagnosed with primary high-grade soft-tissue sarcoma of the extremity or superficial trunk, had clear margins after excision and did not receive radiation as a part of their initial treatment. A total of 46 patients were identified.Results. At 5 years, the local control rate was 87%, disease-specific survival was 75% and overall survival was 68%. Of the 6 local recurrences, 3 were located in the buttock (from a total of 7 patients with primary tumours of the buttock), 3 had a primary size of >/= 10 cm (from a total of 8 primary tumours of that size) and all were deep tumours.Discussion. Our data, and those from other reports, suggest that in carefully selected patients appropriate surgery alone results in acceptable local control and survival, and that the morbidity of radiation can be avoided.

The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element.

Modeling of neutral or mildly basic functional groups in the S1 site of thrombin led to the targeting of imidazole as a S1 binding element and correctly predicted the optimal chain length for connecting this group with the S2 and S3 binding elements. Derivatives of 4-(3-aminopropyl)-imidazole can be selective inhibitors of thrombin demonstrating potent anticoagulant activity.

Cancer of the tonsil: the results of ipsilateral radiation treatment.

BACKGROUND AND PURPOSE: The use of ipsilateral irradiation techniques to treat patients with carcinoma of the tonsil reduces the acute radiation reaction in the contralateral pharynx and late damage to the contralateral salivary tissue. However, this may also spare microscopic disease in apparently uninvolved contralateral lymph nodes. The purpose of this study was to analyse the survival and recurrence rates and sites of recurrance in a group of patients with carcinoma of the tonsil treated with ipsilateral techniques. MATERIALS AND METHODS: Between 1975 and 1993, 271 patients with invasive squamous cell cancer of the tonsil were referred to the Vancouver Cancer Centre (VCC). One hundred and seventy-eight received ipsilateral radiation treatment. Three received surgery only, six post-operative radiation, 12 supportive treatment only and 72 bilateral radiation treatment. In the absence of bilateral neck nodes and extensive lymphodenopathy, field sizes were generally kept small to include the primary tumour and the first echelon of nodes. The most common dose was 60 Gy in 25 daily fractions in 5 weeks (2.4 Gy per day). RESULTS AND DISCUSSION: The disease specific survival for all patients treated by radical radiation treatment was 61% at 5 years. For the 178 patients who received ipsilateral radiation treatment the overall primary tumour control rate by ipsilateral radiation treatment alone was 75% and for T1 and T2 tumours 84%. Eight (7.5%) of 101 of these patients with N0 nodes at presentation and without prior failure at the primary site, developed nodal recurrence (four within the initially radiated high dose volume). Two developed contralateral nodes, and two developed field edge nodal recurrence, one cured by surgery. In 54 patients with N1 disease, five developed nodal recurrence, two within field, two contralateral, one of whom was cured by surgery, and one at field edge. In 23 patients with N2a, N2b or N3 disease node control was achieved from radiation treatment in 11 and two more were cured by surgery. All nodal failures were within the radiated volume. Overall, 10 of the 25 patients with nodal failure were cured by subsequent surgery. CONCLUSIONS: Ipsilateral treatment of patients with carcinoma of the tonsil gives survival results that are at least as good as those reported with bilateral treatment with fewer side effects and a very low risk of failure in the contralateral neck.

Restenosis in human vein bypass grafts.

The restenosis rate in vein bypass grafts is higher than in native coronary arteries, and both the cascade of regulatory factors and the vessel reaction may be altered. In this study, vein bypass atherectomy specimens were classified as primary (n = 10) or restenotic (n = 12). Immunohistochemistry with 11 primary antibodies showed low levels of proliferation in both tissues and similar amounts of extracellular matrix components in both primary and restenotic specimens at the time points at which tissue was removed for clinical reasons. Inflammation appeared increased in restenotic specimens. Using in situ hybridization, transforming growth factor-beta1 messenger RNA was detected in both primary and restenotic tissue, with a trend to higher expression in restenosis (8.4 +/- 5.3 vs. 9.4 +/- 7.4 grains/nucleus) and further increased expression in multiple compared with single restenoses (15.1 +/- 6.1 vs. 5.6 +/- 5.1 grains/nucleus, P < 0.05). Hence, there were no great differences in cell proliferation or extracellular matrix formation between primary and restenosis vein graft tissue, in contrast to previously described findings in arterial tissue. This suggests that primary vein graft tissue is already in a chronic 'restenosis-like' state and subsequent injury creates minimal additional upregulation.