Patients not taking a previously prescribed bone active medication now prescribed medication through Ontario FLS.

In an Ontario fracture liaison service (FLS), we compared medication prescription rates among patients not taking a previously prescribed bone active medication to those with no previous prescription. Prescription rates were similar between these two groups of patients. The FLS provided a secondary opportunity for patients to initiate bone active medication. PURPOSE: We compared bone active medication prescription rates among patients presenting to an Ontario fracture liaison service (FLS) who reported not taking a previously prescribed bone active medication to those with no history of prescription. METHODS: Eligible patients were those screened in 39 fracture clinics between July 1, 2017, and September 15, 2019, who were not taking bone active medication at the time of screening and classified as high risk for future fracture based on CAROC or FRAX. Sociodemographic and clinical risk factor variables were assessed at screening. Bone active medication prescription rate was assessed within 6 months of screening and defined as having received a prescription for the medication from either a specialist or primary care provider. In cases where a specialist report was not available, patient self-reported data were collected. The chi-square test of independence was used to assess differences in prescription rates. RESULTS: Of 17,575 patients screened, eligible patients were 350 with a previous prescription and 2644 without a previous prescription. Compared with patients who reported no previous prescription, those who had a previous prescription were older, more likely to be female and to report a previous fracture, and less likely to smoke. There was no statistically significant difference between the medication prescription rate of patients with a previous prescription (73.7%) compared to patients with no previous prescription (70.7%) (p = 0.157). CONCLUSION: A large jurisdiction-wide FLS approach provided a secondary opportunity to patients who were not taking a previously prescribed bone active medication to initiate that medication.

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.

Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: a 5-year longitudinal study.

BACKGROUND: Cardiovascular diseases (CVDs) are more frequent in multiple sclerosis (MS) patients when compared to controls. In particular, CVDs are linked with higher accumulation of lesions and advanced brain atrophy. OBJECTIVE: To investigate whether CVDs contribute to accelerated lesion accumulation and brain atrophy over 5 years in patients with MS. METHODS: 194 MS patients and 43 controls without neurologic disease were followed for 5 years. Full physical, neurological evaluation, and structured questionnaire investigating CVD and risk factors (hypertension, hyperlipidemia, heart disease, smoking, diabetes, obesity/overweight) were collected using interview-based questionnaire and further cross-reference with electronic medical records. Lesion and brain atrophy outcomes were assessed with 3T MRI. ANCOVA adjusted for age, gender, and disease duration were used accordingly. False discovery rate correction was performed using Benjamini-Hochberg correction. RESULTS: Patients with diagnosis of heart disease showed higher white matter and whole brain volume loss compared to those without (-4.2% vs. -0.7%, P = 0.01 and -3.4% vs. -1.6%, P = 0.01, respectively). The percentage lateral ventricle volume change in MS patients with hypertension was higher compared to non-hypertensive patients (24.5% vs. 14.1%, P = 0.05). Hyperlipidemia, smoking, and obesity/overweight were not associated with progression of MRI-derived outcomes. CVDs did not contribute to larger lesion volume accrual over the 5-year period. The presence of CVDs was not associated with MRI-derived changes in the controls. CONCLUSIONS: Hypertension and heart disease contribute to advanced brain atrophy in MS patients. CVDs did not contribute to additional lesion accrual. CVD comorbidities in MS patients may contribute to neurodegenerative tissue injury that can be detected with brain MRI.

Cost Savings Analysis of Early Extubation Following Congenital Heart Surgery.

The clinical benefit of early extubation following congenital heart surgery has been demonstrated; however, its effect on resource utilization has not been rigorously evaluated. We sought to determine the cost savings of implementing an early extubation pathway for children undergoing surgery for congenital heart disease. We performed a cost savings analysis after implementation of an early extubation strategy among children undergoing congenital heart surgery at British Columbia Children's Hospital (BCCH) over a 2.5-year period. All patients undergoing one of the eight Society of Thoracic Surgeons (STS) benchmark operations, ASD repair, or bidirectional cavopulmonary anastomosis were included in the analysis (n = 370). We compared our data to aggregate STS multi-institutional data from a contemporary cohort. We estimated daily costs for ICU care, ward care, medications, imaging, additional procedures, and allied health care using an administrative database. Direct costs, indirect costs, and cost savings were estimated. Simulation methods, Monte Carlo, and bootstrapping were used to calculate the 95% credible intervals for all estimates. The mean cost savings per procedure was $12,976 and the total estimated cost savings over the study period at BCCH was $4.8 million with direct costs accounting for 91% of cost savings. Sensitivity analysis demonstrated a mean cost savings range of $11,934-$14,059 per procedure. Early extubation is associated with substantial cost savings due to reduced hospital resource utilization. Implementation of an early extubation strategy following congenital heart surgery may contribute to improved resource utilization.

Vitamin D supplementation in primary allergy prevention: Systematic review of randomized and non-randomized studies.

BACKGROUND: To date, a systematic review of the evidence regarding the association between vitamin D and allergic diseases development has not yet been undertaken. OBJECTIVE: To review the efficacy and safety of vitamin D supplementation when compared to no supplementation in pregnant women, breastfeeding women, infants, and children for the prevention of allergies. METHODS: Three databases were searched through January 30, 2016, including randomized (RCT) and nonrandomized studies (NRS). Two reviewers independently extracted data and assessed the certainty in the body of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Among the 1932 articles identified, one RCT and four NRS were eligible. Very low certainty in the body of evidence across examined studies suggests that vitamin D supplementation for pregnant women, breastfeeding women, and infants may not decrease the risk of developing allergic diseases such as atopic dermatitis (in pregnant women), allergic rhinitis (in pregnant women and infants), asthma and/or wheezing (in pregnant women, breastfeeding women, and infants), or food allergies (in pregnant women). We found no studies of primary prevention of allergic diseases in children. CONCLUSION: Limited information is available addressing primary prevention of allergic diseases after vitamin D supplementation, and its potential impact remains uncertain.

A comparison of computer-assisted detection (CAD) programs for the identification of colorectal polyps: performance and sensitivity analysis, current limitations and practical tips for radiologists.

AIM: To directly compare the accuracy and speed of analysis of two commercially available computer-assisted detection (CAD) programs in detecting colorectal polyps. MATERIALS AND METHOD: In this retrospective single-centre study, patients who had colorectal polyps identified on computed tomography colonography (CTC) and subsequent lower gastrointestinal endoscopy, were analysed using two commercially available CAD programs (CAD1 and CAD2). Results were compared against endoscopy to ascertain sensitivity and positive predictive value (PPV) for colorectal polyps. Time taken for CAD analysis was also calculated. RESULTS: CAD1 demonstrated a sensitivity of 89.8%, PPV of 17.6% and mean analysis time of 125.8 seconds. CAD2 demonstrated a sensitivity of 75.5%, PPV of 44.0% and mean analysis time of 84.6 seconds. CONCLUSION: The sensitivity and PPV for colorectal polyps and CAD analysis times can vary widely between current commercially available CAD programs. There is still room for improvement. Generally, there is a trade-off between sensitivity and PPV, and so further developments should aim to optimise both. Information on these factors should be made routinely available, so that an informed choice on their use can be made. This information could also potentially influence the radiologist's use of CAD results.

Successful treatment of chronic hepatitis C infection with crushed elbasvir/grazoprevir administered via a percutaneous endoscopic gastrostomy tube.

WHAT IS KNOWN AND OBJECTIVE: Elbasvir/grazoprevir is an all-oral regimen approved for patients with hepatitis C virus (HCV) genotypes 1 and 4, and in renal insufficiency. However, to date, no data exist on the efficacy of this regimen when it is crushed and administered through a percutaneous endoscopic gastrostomy (PEG) tube. Here, we illustrate the case of a 63-year-old man who is the only known patient with HCV infection in the English literature to have successfully achieved a sustained viral response (SVR) when elbasvir/grazoprevir oral combination was administered through a PEG tube. CASE SUMMARY: A 63-year-old man with worsening HCV-associated membranoproliferative glomerulonephritis was referred to the gastroenterology clinic for prompt HCV treatment. He had history of high-grade mucoepidermoid carcinoma of the parotid status post-resection and was expected to develop severe mucositis and dysphagia during radiation precluding typical oral therapy of his HCV. He received a PEG tube for nutrition and underwent a 16 week course of crushed Elbasvir/Grazoprevir for HCV treatment through the PEG. At the end of the therapy he achieved SVR and his kidney function also improved. WHAT IS NEW AND CONCLUSION: We present the first known clinical case of a non-cirrhotic patient with HCV genotype 1A with HCV-related MPGN treated successfully with crushed Elbasvir/Grazoprevir administered through a PEG tube. With the prevalence of PEG tube insertion and HCV on a rise, we expect these 2 population cohorts to intersect in the future. Our report may serve as a guidance in such clinical scenario.

Unusual array of neural communications in the infratemporal fossa: Useful for skull base surgery.

Variations in the branching pattern of the mandibular nerve frequently accounts for failure to obtain adequate local anesthesia in routine oral and dental procedures, and also for unexpected injury to the nerves during surgery. The knowledge of the neurovascular relationships of the infratemporal region is relevant in odontostomatology practice. In this article we present a rare case of atypical communication between the inferior alveolar nerve and lingual nerve and the mylohyoid and lingual nerves. Further, the clinical implications of these communications on the development of the supplementary innervation and their possible role in anesthesia is discussed in detail. The communication between mylohyoid and lingual nerve was found in this case near the submandibular ganglion after the lingual nerve passes in close relation to third molar tooth, which makes it more susceptible to injury during third molar extractions. The communicating branch between the mylohyoid nerve and lingual nerve may also innervate the tongue, and surgeons should be aware of this variation to avoid post- operative complcations after oral surgeries. Thus the precise anatomy of structures of infratemporal region and its variations may prove beneficial to clinicians, especially to oral and maxillofacial surgeons.

Prebiotics for the prevention of allergies: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Prevalence of allergic diseases in infants is approximately 10% reaching 20 to 30% in those with an allergic first-degree relative. Prebiotics are selectively fermented food ingredients that allow specific changes in composition/activity of the gastrointestinal microflora. They modulate immune responses, and their supplementation has been proposed as an intervention to prevent allergies. OBJECTIVE: To assess in pregnant women, breastfeeding mothers, and infants (populations) the effect of supplementing prebiotics (intervention) versus no prebiotics (comparison) on the development of allergic diseases and to inform the World Allergy Organization guidelines. METHODS: We performed a systematic review of studies assessing the effects of prebiotic supplementation with an intention to prevent the development of allergies. RESULTS: Of 446 unique records published until November 2016 in Cochrane, MEDLINE, and EMBASE, 22 studies fulfilled a priori specified criteria. We did not find any studies of prebiotics given to pregnant women or breastfeeding mothers. Prebiotic supplementation in infants, compared to placebo, had the following effects: risk of developing eczema (RR: 0.68, 95% CI: 0.40 to 1.15), wheezing/asthma (RR, 0.37; 95% CI: 0.17 to 0.80), and food allergy (RR: 0.28, 95% CI: 0.08 to 1.00). There was no evidence of an increased risk of any adverse effects (RR: 1.01, 95% CI: 0.92 to 1.10). Prebiotic supplementation had little influence growth rate (MD: 0.92 g per day faster with prebiotics, 95% CI: 0 to 1.84) and the final infant weight (MD: 0.10 kg higher with prebiotics, 95% CI: -0.09 to 0.29). The certainty of these estimates is very low due to risk of bias and imprecision of the results. CONCLUSIONS: Currently available evidence on prebiotic supplementation to reduce the risk of developing allergies is very uncertain.

Exosome-associated AAV vector as a robust and convenient neuroscience tool.

Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill and time-intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when the vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared with standard AAV. Here, we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood-brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV-transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing three-dimensional reconstruction of transduced Purkinje cells in the cerebellum using ex vivo serial two-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable the widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.

Cost trajectories for cancer patients.

BACKGROUND: Health care spending is known to be highly skewed, with a small subset of the population consuming a disproportionate amount of health care resources. Patients with cancer are high-cost users because of high incremental health care costs for treatment and the growing prevalence of cancer. The objectives of the present study included characterizing cancer-patient trajectories by cost, and identifying the patient and health system characteristics associated with high health system costs after cancer treatment. METHODS: This retrospective cohort study identified Ontario adults newly diagnosed with cancer between 1 April 2009 and 30 September 2010. Costs of health care use before, during, and after cancer episodes were used to develop trajectories of care. Descriptive analyses examined differences between the trajectories in terms of clinical and health system characteristics, and a logistic regression approach identified predictors of being a high-cost user after a cancer episode. RESULTS: Ten trajectories were developed based on whether patients were high- or low-cost users before and after their cancer episode. The most common trajectory represented patients who were low-cost in the year before cancer, survived treatment, and continued to be low-cost in the year after cancer (31.4%); stage ii cancer of the male genital system was the most common diagnosis within that trajectory. Regression analyses identified increases in age and in multimorbidity and low continuity of care as the strongest predictors of high-cost status after cancer. CONCLUSIONS: Findings highlight an opportunity to proactively identify patients who might transition to high-cost status after cancer treatment and to remediate that transition.

Enhanced fitness and renal function in Type 2 diabetes.

AIMS: To investigate the renal effects of fitness in people with diabetes with mild renal dysfunction. METHODS: The effect of a 12-week exercise programme on estimated GFR in 128 people with diabetes was evaluated. RESULTS: All cardiometabolic variables improved after 12 weeks of supervised exercise. Although there was a modest 3.9% increase in estimated GFR from baseline in the 128 people who completed the study, those with baseline chronic kidney disease stages 2 and 3 were found to have significant (6 and 12%, respectively; p < 0.01) improvements in post-exercise estimated GFR. Moreover, 42% of the people with chronic kidney disease stage 3 improved to chronic kidney disease stage 2 after the intervention. CONCLUSION: Short-term exercise improves renal function in those with more moderate baseline chronic kidney disease. Thus, renal function appears to be responsive to enhanced physical fitness. Being a strong and modifiable risk factor, enhanced fitness should be considered a non-pharmacological adjunct in the management of diabetic kidney disease.

Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: This systematic review addresses the question "What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer?" METHODS: The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. RESULTS: Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). CONCLUSIONS: Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population.

Optimal systemic therapy for early breast cancer in women: a clinical practice guideline.

The Breast Cancer Disease Site Group of Cancer Care Ontario identified the need for new guidelines for the adjuvant systemic therapy of early-stage breast cancer. The specific question to be addressed was "What is the optimal adjuvant systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered?" A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period January 2008 to March 5, 2012, and updated to May 12, 2014. Guidelines were located from that search, from the Standards and Guidelines Evidence directory of cancer guidelines, and from the Web sites of major guideline organizations. The literature located was subdivided into the broad categories of chemotherapy, hormonal therapy, and therapy targeted to her2 (human epidermal growth factor receptor 2). Although several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting, the review focused on trials with rates of disease-free and overall survival as endpoints and thus excluded several trials that used pathologic complete response as a primary endpoint. Based on the systematic review, the working group drafted recommendations on the use of chemotherapy, hormonal therapy, and targeted therapy; based on their professional experience, they also drafted recommendations on patient and disease characteristics and recurrence risk. The literature review and draft recommendations were circulated to a consensus panel of medical oncologists who had expertise in breast cancer and who represented the regions of Ontario. Items without initial consensus were discussed at an in-person consensus meeting held in Toronto, November 23, 2012. The final recommendations are those for which consensus was reached before or at the meeting. Some of the key evidence was revised after the updated literature search. Evidence reviews for systemic chemotherapy, endocrine therapy, and targeted therapy for her2-positive disease are reported in separate articles in this supplement. The full three-part 1-21 evidence-based series, including complete details of the development and consensus processes, can be found on the Cancer Care Ontario Web site at https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs.

Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: The Program in Evidence-Based Care (pebc) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (her2)-directed therapy. METHODS: For the systematic review, the medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists' Collaborative Group meta-analyses encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite-based regimens (for example, cyclophosphamide-methotrexate-5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline-taxane-based polychemotherapy regimens are, overall, considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work. CONCLUSIONS: The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and her2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement.

Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: Cancer Care Ontario's Program in Evidence-Based Care (pebc) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and her2 (human epidermal growth factor receptor 2)-targeted therapy. METHODS: For the systematic review, the literature in the medline and embase databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists' Collaborative Group encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. SUMMARY: The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here; the evidence for chemotherapy and her2-targeted treatment-and the final clinical practice recommendations-are presented separately in this supplement.

A Canadian national expert consensus on neoadjuvant therapy for breast cancer: linking practice to evidence and beyond.

BACKGROUND: Use of the neoadjuvant approach to treat breast cancer patients has increased since the early 2000s, but the overall pathway of care for such patients can be highly variable. The aim of our project was to establish a multidisciplinary consensus among clinicians with expertise in neoadjuvant therapy (nat) for breast cancer and to determine if that consensus reflects published methods used in randomized controlled trials (rcts) in this area. METHODS: A modified Delphi protocol, which used iterative surveys administered to 85 experts across Canada, was established to obtain expert consensus concerning all aspects of the care pathway for patients undergoing nat for breast cancer. All rcts published between January 1, 1967, and December 1, 2012, were systematically reviewed. Data extracted from the rcts were analyzed to determine if the methods used matched the expert consensus for specific areas of nat management. A scoring system determined the strength of the agreement between the literature and the expert consensus. RESULTS: Consensus was achieved for all areas of the pathway of care for patients undergoing nat for breast cancer, with the exception of the role of magnetic resonance imaging in the pre-treatment or preoperative setting. The levels of agreement between the consensus statements and the published rcts varied, primarily because specific aspects of the pathway of care were not well described in the reviewed literature. CONCLUSIONS: A true consensus of expert opinion concerning the pathway of care appropriate for patients receiving nat for breast cancer has been achieved. A review of the literature illuminated gaps in the evidence about some elements of nat management. Where evidence is available, agreement with expert opinion is strong overall. Our study is unique in its approach to establishing consensus among medical experts in this field and has established a pathway of care that can be applied in practice for patients receiving nat.

Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer.

UNLABELLED: The pi3k/Akt/mtor (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. METHODS: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of pi3k/Akt/mtor inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. RESULTS: Differing toxicities are associated with the various classes of pi3k/Akt/mtor pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. DISCUSSION: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future pi3k/Akt/mtor signalling pathway inhibitors.

A pilot case-cohort study of brain cancer in poultry and control workers.

We conducted an exploratory study to investigate which exposures (including poultry oncogenic viruses) are associated with brain cancer in poultry workers. A total of 46,819 workers in poultry and nonpoultry plants from the same union were initially followed for mortality. Brain cancer was observed to be in excess among poultry workers. Here we report on a pilot case-cohort study with cases consisting of 26 (55%) of the 47 brain cancer deaths recorded in the cohort, and controls consisting of a random sample of the cohort (n = 124). Exposure information was obtained from telephone interviews, and brain cancer mortality risk estimated by odds ratios. Increased risk of brain cancer was associated with killing chickens, odds ratio (OR) = 5.8 (95% confidence interval, 1.2-28.3); working in a shell-fish farm, OR = 13.0 (95% CI, 1.9-84.2); and eating uncooked fish, OR = 8.2 (95% CI, 1.8-37.0). Decreased risks were observed for chicken pox illness, OR = 0.2 (95% CI, 0.1-0.6), and measles vaccination, OR = 0.2 (95% CI, 0.1-0.6). Killing chickens, an activity associated with the highest occupational exposure to poultry oncogenic viruses, was associated with brain cancer mortality, as were occupational and dietary shellfish exposures. These findings are novel.

Ventral hernia repair using bioresorbable poly-4-hydroxybutyrate mesh in clean and contaminated surgical fields: a systematic review and meta-analysis.

PURPOSE: Use of biologic or synthetic mesh in hernia repair shifts is based on evolving evidence. Poly-4-hydroxybutyrate (P4HB) biosynthetic mesh is a potential alternative to biologic and synthetic mesh in ventral hernia repair (VHR). This meta-analysis assesses the efficacy of P4HB mesh in clean and contaminated surgical settings. METHODS: Two authors searched literature on PubMed, reviewing titles and abstracts of all articles to determine inclusion eligibility. Post-operative data were compared via transformation method to convert the proportion of patients with the outcome of interest into a suitable quantity for random-effects synthesis using STATA software. RESULTS: Initial search yielded 287 citations. Six studies were included and categorized on whether hernia repairs were conducted in clean (CDC class I) or contaminated cases (CDC class II-IV). The pooled proportion of surgical site infection (SSI), surgical site occurrence (SSO), hernia recurrence, total surgical complications, and reoperation were calculated in 391 clean and 81 contaminated cases. For clean vs. contaminated cases, the following pooled proportions were noted: SSI (2% (CI 0-7%) vs 9% (CI 0-025) (p = 0.03), SSO: 14% (CI 5-25%) vs 35% (CI 22-50%) (p = 0.006), hernia recurrence (8% (CI 1-19%) vs 4% (CI 0-12%) (p = 0.769); surgical complications (17% (CI 6-32%) vs 50% (CI 27-72%) (p = 0.009). Reoperation data were available in 298 clean cases across four studies: 5% (CI 0-15%). CONCLUSIONS: P4HB biosynthetic mesh may be more effective than previously thought, particularly in clean wounds. P4HB may also be superior to biologic mesh when compared to clinical trial data. Further research is necessary for more direct comparison.