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.

Pneumonitis After Concurrent Chemoradiation and Immune Checkpoint Inhibition in Patients with Locally Advanced Non-small Cell Lung Cancer.

AIMS: Pneumonitis is a common and potentially deadly complication of combined chemoradiation and immune checkpoint inhibition (CRT-ICI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study we sought to identify the risk factors for pneumonitis with CRT-ICI therapy in LA-NSCLC cases and determine its impact on survival. MATERIALS AND METHODS: We conducted a retrospective chart review of 140 patients with LA-NSCLC who underwent curative-intent CRT-ICI with durvalumab between 2018 and 2021. Pneumonitis was diagnosed by a multidisciplinary team of clinical experts. We used multivariable cause-specific hazard models to identify risk factors associated with grade ≥2 pneumonitis. We constructed multivariable Cox proportional hazard models to investigate the impact of pneumonitis on all-cause mortality. RESULTS: The median age of the cohort was 67 years; most patients were current or former smokers (86%). The cumulative incidence of grade ≥2 pneumonitis was 23%. Among survivors, 25/28 patients had persistent parenchymal scarring. In multivariable analyses, the mean lung dose (hazard ratio 1.14 per Gy, 95% confidence interval 1.03-1.25) and interstitial lung disease (hazard ratio 3.8, 95% confidence interval 1.3-11.0) increased the risk for pneumonitis. In adjusted models, grade ≥2 pneumonitis (hazard ratio 2.5, 95% confidence interval 1.0-6.2, P = 0.049) and high-grade (≥3) pneumonitis (hazard ratio 8.3, 95% confidence interval 3.0-23.0, P < 0.001) were associated with higher all-cause mortality. CONCLUSIONS: Risk factors for pneumonitis in LA-NSCLC patients undergoing CRT-ICI include the mean radiation dose to the lung and pre-treatment interstitial lung disease. Although most cases are not fatal, pneumonitis in this setting is associated with markedly increased mortality.

Improving the Accuracy of Corrective Osteotomy for Congenital Radio Ulnar Synostosis using the Axis of Rotation of the Forearm as a Guide.

Introduction: Despite several techniques for corrective osteotomy in congenital radioulnar synostosis (CRUS) the published literature lacks a guide for radiographic planning and rationale for the site and level of the osteotomy. The primary objective of this study is to report a technique of radiographically controlled corrective osteotomy using the axis of rotation of the forearm in CRUS. Materials and methods: Children with CRUS underwent corrective osteotomy based on radiographic planning; the extent of rotational correction and functional outcomes were assessed at a mean of 27 months after the operation. Results: Seven forearms in six children of an average of 6.25 years were assessed for correction and functional outcomes. The average pre-operative pronation deformity was 71.5°. The average correction achieved was 64°. At follow-up, there were five excellent and two good functional outcomes. All children could perform daily tasks besides eating with hand and personal hygiene. Conclusion: Radiographic determination of the osteotomy sites by the method described is effective, consistent, and reproducible in achieving optimal functional outcomes in congenital radioulnar synostosis.

Arytenoid granuloma: a single-institution experience of management of 62 cases.

OBJECTIVE: This retrospective study was undertaken to assess the outcome of the medical and/or surgical management of patients presenting with clinical features of arytenoid granuloma. METHODS: The records of 53 males and 9 females were reviewed for predisposing factors, types of treatment received and recurrence following the treatment. RESULTS: Most of the patients (48 out of 62, 77.4 per cent) were treated conservatively with medical management and voice therapy, which resulted in complete resolution of arytenoid granuloma in over two-thirds of the patients treated (32 out of 48, 66.6 per cent). Overall, 28 patients (out of 62, 45.1 per cent) required surgery (14 failed medical treatment cases and 14 surgery as first-line treatment cases). Of these, five patients (out of 28, 17.9 per cent) had recurrence, and were managed with revision surgery and concurrent local injection of Botox. CONCLUSION: Anti-reflux medication and voice therapy are effective first-line management options. Pre- and post-surgery adjuvant treatment improves the results of surgery. Local injection of Botox was successful in the treatment of failed surgical cases.

A Protocol for Mitotic Metaphase Chromosome Count Using Shoot Meristematic Tissues of Mulberry Tree Species.

Studies on chromosomal status are a fundamental aspect of plant cytogenetics and breeding because changes in number, size, and shape of chromosomes determine plant physiology/performance. Despite its significance, the classical cytogenetic study is now frequently avoided because of its tedious job. In general, root meristems are used to study the mitotic chromosome number, even though the use of root tips was restricted because of sample availability, processing, and lack of standard protocols. Moreover, to date, a protocol using shoot tips to estimate chromosome number has not yet been achieved for tree species' germplasm with a large number of accessions, like mulberry (Morusspp.). Here, we provide a step-by-step, economically feasible protocol for the pretreatment, fixation, enzymatic treatment, staining, and squashing of meristematic shoot tips. The protocol is validated with worldwide collections of 200 core set accessions with a higher level of ploidy variation, namely diploid (2n = 2x = 28), triploid (2n = 3x = 42), tetraploid (2n = 4x = 56), hexaploid (2n = 6x = 84), and decosaploid (2n = 22x = 308) belonging to nine species of Morus spp. Furthermore, accession from each ploidy group was subjected to flow cytometry (FCM) analysis for confirmation. The present protocol will help to optimize metaphase plate preparation and estimation of chromosome number using meristematic shoot tips of tree species regardless of their sex, location, and/or resources.

Late-Onset Posttransplant Lymphoproliferative Disorders after Solid Organ Transplantation in Adults: A Case Series and Review of the Literature.

The posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that have wide variety of clinical and histological presentations. The management of PTLDs is challenging due to variety of involvement sites and histological types. The length and type of immunosuppression are correlated with the emergence of PTLDs, and most of the cases appear within the first two years after transplant. This case series describes five late-onset PTLDs with rare histological features and multiorgan involvement.

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.

Tumor Infiltrating Lymphocytes in Breast Cancer Patients with Progressive Disease during Neoadjuvant Chemotherapy.

A minority of breast cancer (BC) patients progress during neoadjuvant chemotherapy (NCT). The aim of this study was to assess the value of Tumor infiltrating lymphocytes (TILs) in such a high-risk population where valid biomarkers are eagerly needed. A retrospective review identified BC patients who either progressed during NCT or achieved a pathologic complete response (pCR). An experienced BC pathologist semi-quantified stromal TILs in pre-treatment core biopsies using hematoxylin and eosin stained slides. The primary outcome was to compare the levels of TILs between the 2 groups as a continuous and categorical variable using the t-test and X2 test as appropriate. The secondary outcome was to compare survival outcomes between patients with high versus low TILs level using the log-rank test. Fifty patients were successfully identified and assessed for TILs: 21 progressed during NCT and 29 had a pCR. Patients with progressive disease were older with more advanced disease (p = 0.03, p = 0.0001 respectively). A significantly lower mean level of TILs was found in patients with progressive disease compared to patients with pCR: 14.3% (Standard Deviation (SD): 16.9) versus 32.8% (SD: 31), p = 0.01). The level of TILs was neither associated with baseline characteristics nor with survival outcomes. BC patients progressing during NCT have low TILs levels compared to patients with pCR. Prospective studies are needed to establish the utility of TILs as early biomarkers of tumor response, particularly in patients with disease progression who need novel treatment approaches.

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.

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.

Maxillomandibular advancement is a successful treatment for obstructive sleep apnoea: a systematic review and meta-analysis.

The primary objective of this review was to establish the effectiveness of maxillomandibular advancement (MMA) as a successful treatment modality in improving airway patency in patients with obstructive sleep apnoea (OSA). A systematic and detailed search was performed using PubMed Central, covering the period January 2000 to December 2015, with well-defined selection criteria. The authors independently conducted the study selection, data extraction, and assessed the risk of bias of the included studies. Twenty studies met the inclusion criteria. The outcome measures studied were the apnoea-hypopnoea index (AHI), respiratory disturbance index (RDI), Epworth Sleepiness Scale (ESS), lowest oxygen saturation (LSAT), and body mass index (BMI). The random-effects model was adopted for meta-analysis as moderate heterogeneity was identified. The analysis revealed significant changes in the outcome measures after the intervention. The results showed that the preoperative severity of OSA based on AHI and RDI significantly influences the outcome of MMA intervention, with a strong positive correlation between the pre MMA AHI values and the percentage change post intervention. The surgical success of MMA in patients with OSA was found to be 100% with respect to AHI and RDI scores. It is concluded that MMA is a successful treatment for OSA.

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.

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.

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.

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.

A systematic review and quality appraisal of international guidelines for early breast cancer systemic therapy: Are recommendations sensitive to different global resources?

The breast cancer incidence in low and middle income countries (LMCs) is increasing globally, and patient outcomes are generally worse in these nations compared to high income countries (HICs). This is partly due to resource constraints associated with implementing recommended breast cancer therapies. Clinical practice guideline (CPG) adherence can improve breast cancer outcomes, however, many CPGs are created in HICs, and include costly recommendations that may not be feasible in LMCs. In addition, the quality of CPGs can be variable. The aim of this study was to perform a systematic review of CPGs on early breast cancer systemic therapy with potential international impact, to evaluate their content, quality, and resource sensitivity. A MEDLINE and gray literature search was completed for English language CPGs published between 2005 and 2010, and then updated to July 2014. Extracted guidelines were evaluated using the AGREE 2 instrument. Guidelines were specifically analyzed for resource sensitivity. Most of the extracted CPGs had similar recommendations with regards to systemic therapy. However, only one, the Breast Health Global Initiative, made recommendations with consideration of different global resources. Overall, the CPGs were of variable quality, and most scored poorly in the quality domain evaluating implementation barriers such as resources. Published CPGs for early breast cancer are created in HICs, have similar recommendations, and are generally resource-insensitive. Given the visibility and influence of these CPGs on LMCs, efforts to create higher quality, resource-sensitive guidelines with less redundancy are needed.

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.

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.

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.