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Arden L Corter,1 Brittany Speller,1 Kristin McBain,2 Frances C Wright,3,4 May Lynn Quan,5 Erin Kennedy,6 Selina Schmocker,6 Nancy N Baxter1,4,7On behalf of the RUBY Cohort Investigators1Department of Surgery, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada; 2Applied Health Research Centre, St Michael’s Hospital, Toronto, Canada; 3Department of Surgery, Sunnybrook Hospital, Toronto, ON M4N 3M5, Canada; 4Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Canada; 5Department of Surgery, University of Calgary, Foothills Medical Centre, Calgary, AB T2N 2T9, Canada; 6Division of General Surgery, Mount Sinai Hospital, Toronto, Canada; 7Dalla Lana School of Public Health, University of Toronto, Toronto, CanadaCorrespondence: Nancy N BaxterDepartment of Surgery, St. Michael’s Hospital, 16-040 Cardinal Carter Wing, 30 Bond Street, Toronto, Ontario M5B1W8, CanadaTel +1416 864-5168Fax +1416 360-0637Email nancy.baxter@unityhealth.toBackground: Presentation to multidisciplinary cancer conferences (MCCs) supports optimal treatment of young women with breast cancer (YWBC). However, research shows barriers to MCC practice, and variation in professional attendance and referral patterns. A checklist may help overcome these barriers and support MCC practice with YWBC.Methods: We developed, piloted and evaluated an MCC checklist in sites participating in a pan-Canadian study (RUBY; Reducing the bUrden of Breast cancer in Young women). A survey assessed checklist processes and impacts, and checklist data were analysed for checklist uptake, MCC presentation rates and MCC processes including staff attendance.Results: Fifteen RUBY sites used the checklist (∼50%), mostly for data collection/tracking. Some positive effects on clinical practice such as increased presentation of YWBC at MCC were reported, but most survey participants indicated that MCC processes were sufficient without the checklist. Conversely, checklist data show that only 31% of patients were presented at MCC. Of those, 41% were recommended treatment change.Conclusion: Despite limited checklist uptake, there was evidence of its clinical practice benefit. Furthermore, it supported data collection/quality monitoring. Critically, checklist data showed gaps in MCC practice and low MCC presentation rates for YWBC. This contrasts with overall provider perceptions that MCCs are working well. Findings suggest that supports for MCC are needed but may best take the form of clear national practice recommendations and audit and feedback cycles to inform awareness of good MCC practice and outcomes. In this setting, tools like the MCC checklist may become helpful in supporting MCC practice.Keywords: breast neoplasm, multidisciplinary, cancer conference, implementation, evaluation, checklist

Arden L Corter,1 May Lynn Quan,2 Frances L Wright,3 Erin D Kennedy,4 Marko RI Simunovic,5 Juliet Shao,1 Nancy N Baxter1,6 1Department of Surgery, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada; 2Department of Surgery and Oncology, University of Calgary, Calgary, Canada; 3Department of Surgery, University of Toronto, Toronto, Canada; 4Division of General Surgery, University Health Network, Mount Sinai Hospital, Toronto, Canada; 5Department of Surgery, McMaster University, Hamilton, Canada; 6Dalla Lana School of Public Health, University of Toronto, Toronto, Canada Background: Young women with breast cancer (YWBC) experience worse medical and psychosocial outcomes than their older counterparts. Early input from a multidisciplinary team via pre-treatment multidisciplinary cancer conferences (pMCCs) may be important for addressing the complex needs of YWBC. However, pMCCs are not common. This study has two parts: a survey and workshop aimed at assessing clinicians’ perspectives on pMCCs, including the importance of pMCCs in the care of YWBC, as well as barriers to, and strategies for supporting their implementation.Methods: Survey results highlight variability across sites in the delivery of multidisciplinary care in general. However, both survey and workshop results emphasize clinicians’ agreement on the importance of pMCCs and suggest that numerous practical and systems levels barriers be addressed before pMCCs can be implemented.Conclusions: pMCCs have the potential to improve surgical treatment and psychosocial outcomes for YWBC. A combined practical and policy approach to their implementation, which sees extension of existing standards to include pMCCs, may support their adoption and subsequent audit practices to assess the effect of pMCCs on outcomes for YWBC. Keywords: multidisciplinary care, pre-treatment, cancer conference, breast cancer, young women

Increasing numbers of women are seeking evaluation of screen-detected breast abnormalities, and more women with breast cancer are living with the consequences of treatment. Improved technologies have helped to individualize diagnostic evaluation and treatment, improve efficacy and minimize morbidity. This article highlights some of these technologies. Superior imaging techniques have improved breast cancer screening and show promise for intraoperative surgical guidance and postoperative specimen evaluation. Digital mammography improves the sensitivity of mammography for women younger than 50 years with dense breasts, and tomosynthesis may improve specificity. Magnetic resonance imaging provides sensitive delineation of the extent of the disease and superior screening for women with a greater than 25% lifetime risk of breast cancer Minimally invasive techniques have been developed for the assessment of intraductal lesions, biopsy of imaging abnormalities, staging of the axilla and breast radiotherapy. Ductoscopy facilitates intraductal biopsy and localization of lesions for excision, sentinel lymph node biopsy is becoming standard for axillary staging, and intraoperative radiotherapy has the potential to reduce treatment time and morbidity. Three-dimensional imaging allows correlation of final histology with preoperative imaging for superior margin assessment. Related techniques show promise for translation to the intraoperative setting for surgical guidance. New classifications of breast cancers based on gene expression, rather than morphology, describe subtypes with different prognoses and treatment implications, and new targeted therapies are emerging. Genetic fingerprints that predict treatment response and outcomes are being developed to assign targeted treatments to individual patients likely to benefit. Surgeons play a vital role in the successful integration of new technologies into practice. [ABSTRACT FROM AUTHOR]

Background: We sought to identify criteria for the intraoperative assessment of sentinel lymph node (SLN) involvement in women with early breast cancer. We also sought to determine whether the SLN nomogram developed by the Memorial Sloan-Kettering Cancer Center (MSKCC) to predict nonsentinel lymph node (NSLN) involvement when the SLN is positive would accurately predict NSLN involvement in our patient population.Methods: We performed 405 SLN biopsies in 397 women between January 1998 and June 2005. We determined factors associated with SLN metastases using univariate and multivariate logistic regression. Ninety women who had 1 positive SLN or more and underwent axillary lymph node dissection (ALND) had complete data for analysis. We applied the MSKCC nomogram retrospectively to this subset of women, and we calculated the probability of NSLN involvement and compared it with the observed rate.Results: Multifocality and the presence of lymphovascular invasion were predictive of SLN involvement. Ductal carcinoma in situ was negatively associated with SLN involvement. Intraoperative evaluation identified 57 (63%) of the 90 women with involved SLN, of which 26 (29%) had involved NSLN. Application of the MSKCC nomogram to our data set produced an area under the receiver operator characteristic curve of 0.71. The nomogram tended to overestimate the probability of NSLN involvement in our population.Conclusion: Lymphovascular invasion and multifocality were associated with SLN involvement. Women with small low-grade tumours may not require routine intraoperative evaluation of SLNs. The MSKCC nomogram appears to be most useful as a decision aid in selecting those women with an involved SLN in whom ALND may be omitted. [ABSTRACT FROM AUTHOR]

Aims: The primary goal of this study is to evaluate the capabilities of Large Language Models (LLMs) in understanding and processing complex medical documentation. We chose to focus on the identification of pathologic complete response (pCR) in narrative pathology reports. This approach aims to contribute to the advancement of comprehensive reporting, health research, and public health surveillance, thereby enhancing patient care and breast cancer management strategies., Methods: The study utilized two analytical pipelines, developed with open-source LLMs within the healthcare system's computing environment. First, we extracted embeddings from pathology reports using 15 different transformer-based models and then employed logistic regression on these embeddings to classify the presence or absence of pCR. Secondly, we fine-tuned the Generative Pre-trained Transformer-2 (GPT-2) model by attaching a simple feed-forward neural network (FFNN) layer to improve the detection performance of pCR from pathology reports., Results: In a cohort of 351 female breast cancer patients who underwent neoadjuvant chemotherapy (NAC) and subsequent surgery between 2010 and 2017 in Calgary, the optimized method displayed a sensitivity of 95.3% (95%CI: 84.0-100.0%), a positive predictive value of 90.9% (95%CI: 76.5-100.0%), and an F1 score of 93.0% (95%CI: 83.7-100.0%). The results, achieved through diverse LLM integration, surpassed traditional machine learning models, underscoring the potential of LLMs in clinical pathology information extraction., Conclusions: The study successfully demonstrates the efficacy of LLMs in interpreting and processing digital pathology data, particularly for determining pCR in breast cancer patients post-NAC. The superior performance of LLM-based pipelines over traditional models highlights their significant potential in extracting and analyzing key clinical data from narrative reports. While promising, these findings highlight the need for future external validation to confirm the reliability and broader applicability of these methods., (© 2024. The Author(s).)

Background: Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery., Methods: PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1-3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness., Discussion: This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients., Trial Registration: This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021)., (© 2024. The Author(s).)

Early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, is associated with poor prognosis. This study investigated the mutational landscape of non-metastatic EoBC and the prognostic relevance of mutational signatures using 100 tumour samples from Alberta, Canada. The MutationalPatterns package in R/Bioconductor was used to extract de novo single-base substitution (SBS) and insertion-deletion (indel) mutational signatures and to fit COSMIC SBS and indel signatures. We assessed associations between these signatures and clinical characteristics of disease, in addition to recurrence-free (RFS) and overall survival (OS). Five SBS and two indel signatures were extracted. The SBS13-like signature had higher relative contributions in the HER2-enriched subtype. Patients with higher than median contribution tended to have better RFS after adjustment for other prognostic factors (HR = 0.29; 95% CI: 0.08-1.06). An unsupervised clustering algorithm based on absolute contribution revealed three clusters of fitted COSMIC SBS signatures, but cluster membership was not associated with clinical variables or survival outcomes. The results of this exploratory study reveal various SBS and indel signatures may be associated with clinical features of disease and prognosis. Future studies with larger samples are required to better understand the mechanistic underpinnings of disease progression and treatment response in EoBC.

Importance: Few oncology studies have assessed the effectiveness of adjuvant ovarian function suppression (OFS) in observational settings for premenopausal hormone receptor-positive breast cancer. Target trial emulation is increasingly used for estimating treatment outcomes in observational cohorts., Objectives: To describe hormone therapy and OFS treatment patterns (aim 1), examine the association between adding OFS to tamoxifen (TAM) or aromatase inhibitor (AI) and survival (aim 2), and examine the association between duration of hormone treatment (TAM or AI) plus OFS (H-OFS) and survival (aim 3)., Design, Setting, and Participants: This population-based cohort study included all premenopausal, early-stage breast cancer diagnoses between 2010 and 2020 in Alberta, Canada. Target trial emulation was conducted. Eligibility criteria were directly modeled after the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Participants were followed up for a maximum of 5 years. Data were analyzed from July 2022 through March 2023., Exposures: For aim 2, exposures were receiving the following baseline treatments for 2 years: AI + OFS (AI-OFS), TAM + OFS (T-OFS), and TAM alone. For aim 3, exposures were a 2-year or greater and a less than 2-year duration of H-OFS., Main Outcomes and Measures: Recurrence-free survival was the primary outcome of interest. Marginal structural Cox models with inverse probability treatment and censoring weights were used to estimate hazard ratios (HRs), adjusted for baseline and time-varying confounding variables., Results: Among 3434 female patients with premenopausal, early-stage breast cancer diagnoses (median [IQR] age, 45 [40-48] years), 2647 individuals satisfied SOFT and TEXT eligibility criteria. There were 2260 patients who initiated TAM, 232 patients who initiated T-OFS, and 155 patients who initiated AI-OFS; 192 patients received H-OFS for 2 or more years, and 195 patients received H-OFS for less than 2 years. The 5-year recurrence risks were not significantly lower in AI-OFS vs TAM (HR, 0.76; 95% CI, 0.38-1.33) or T-OFS vs TAM (HR, 0.87; 95% CI, 0.50-1.45) groups. Patients receiving H-OFS for 2 or more years had significantly better 5-year recurrence-free survival compared with those receiving H-OFS for less than 2 years (HR, 0.69; 95% CI, 0.54-0.90)., Conclusions and Relevance: This study found no significant reductions in recurrence risk for AI-OFS and T-OFS compared with TAM alone. H-OFS duration for at least 2 years was associated with significantly improved recurrence-free survival.

Background: In 2016, a multi-pronged pathway was implemented across 13 hospitals to improve the mastectomy perioperative care experience with one objective being to safely allow same day surgery mastectomy. While the pathway successfully increased same day mastectomy rates from 1.7 to 73.0%, the rate of postoperative emergency department (ED) visits remained high at > 20%, despite focused interventions to enhance perioperative support., Aim: To investigate potential factors associated with high postoperative ED visits following mastectomies in Alberta, Canada., Methods: Data was collected using the Discharge Abstract Database and the National Ambulatory Care Reporting System database. Eligible patients included all women over 18 years old who underwent a mastectomy province-wide between 2004 and 2020. Patient demographics were collected. Primary outcome of interest was ED visit within 30 days of mastectomy. Univariate and multivariable analyses were performed to identify independent predictors for post-operative ED visits., Results: A total of 19,974 patients had mastectomy during the study period, of which 4590 (23%) had an ED visit within 30 days of surgery. Independent factors associated with ED visits were increasing age, overnight stay mastectomy, reconstruction, certain comorbidities, and living rurally., Conclusions: Post-operative ED visits remain high despite initiating a province-wide surgical pathway in 2016 which emphasizes patient education and improved perioperative care and supports. Currently, the majority of ED visits are manageable in non-emergent settings. Patient populations at higher risk for ED visits groups may benefit from additional targeted support and resources to reduce unplanned ED visits., (© 2023. Society of Surgical Oncology.)

Background: The risk of breast cancer may be decreased in women who undergo reduction mammoplasty. The purpose of this study was to describe the incidence and treatment of breast cancer after reduction mammoplasty and to better understand the use of breast cancer screening modalities in these patients., Methods: This population-based retrospective analysis utilized the Discharge Abstract Database held by the Canadian Institute for Health Information and the National Ambulatory Care Reporting System to identify all women aged 20 years or older who underwent reduction mammoplasty in Alberta, Canada. The incidence and treatment of breast cancer were compared among patients who underwent reduction mammoplasty and age-sex-matched controls. Imaging utilization, including the use of mammography, ultrasound, and breast biopsy, was also compared., Results: Between 2003 and 2007, 8021 patients over 20 years old underwent reduction mammoplasty in Alberta. Patients were followed for an average of 12.6 years. Eighty-nine (1.1%) patients who underwent reduction mammoplasty developed breast cancer after surgery, compared to 453 (1.9%) controls ( P < 0.0001). Among patients diagnosed with breast cancer, there was no difference in patient and tumor characteristics. Women who underwent reduction mammoplasty were more likely to undergo mastectomy for cancer (41.6% vs 1.5%; P < 0.0001) and were more likely to undergo mammography (66.7% vs 58.7%; P < 0.0001), ultrasound (29.2% vs 26.2%; P < 0.0001) and biopsy for benign disease (7.2% vs 6%, P < 0.0001) compared to controls., Conclusions: Despite an increased frequency of breast cancer screening, the incidence of breast cancer is lower after reduction mammoplasty compared with women who did not undergo breast reduction. After a diagnosis of breast cancer, surgical treatment patterns differ between groups, whereby mastectomy is more common after reduction mammoplasty., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Opioids are a mainstay of cancer pain management; however, patients with metastatic cancer are often excluded from studies, leading to a lack of evidence on whether increased prescribing (dosage and/or duration) results in improved outcomes for this population. This study aimed to investigate whether increased opioid prescribing is associated with an improvement in patient-reported pain among patients with metastatic cancer., Patients and Methods: A retrospective cohort of all adult patients diagnosed with stage IV cancers, who completed at least two patient-reported outcomes (PROs) within 30 days of each other, was identified from administrative data. Opioid prescriptions were categorized by dosage level and number of prescription days. Multivariable logistic regression was used to investigate the association between opioid prescribing and clinically important improvement in pain score (≥ 1 point change on the Edmonton Symptom Assessment System)., Results: A total of 2169 patients were included, 770 (35.5%) of whom had active opioid prescription between PROs, with an average daily dosage of 86.1 mg of oral morphine equivalent. Active prescription was associated with improvement in pain (OR = 2.17, P < 0.001). However, among patients with active prescription, neither dosage nor number of prescription days was significantly associated with pain improvement., Conclusion: Opioid prescription is important for treating cancer-related pain; however, increased dosage or duration may not be leading to greater improvements in pain. Patients with metastatic cancer who are receiving increased opioid prescribing may have difficult-to-treat pain and may benefit from multidisciplinary pain management strategies to supplement opioid prescription and improve outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Derivatives of lactam, cyclic urea and carbamate were explored as aniline amide replacements in a series of phthalazinone-based ROCK inhibitors. Potent ROCK2 inhibitors such as 22 were identified with excellent overall kinase selectivity as well as good isoform selectivity over ROCK1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Lymphedema remains a risk for 13-34% of breast cancer patients who require an axillary dissection (ALND) and radiation. Immediate lymphovenous anastomosis (LVA) may mitigate lymphedema by up to 30% by restoring the physiologic lymphatic drainage immediately after ALND. Currently, completion of ALND (cALND) versus radiation after neoadjuvant therapy (NAC) is being addressed by the Alliance A11202 trial, leaving a paucity of data to guide practice. Our study describes the implementation process of LVA into clinical practice after NAC for node-positive breast cancer in the current clinical context., Methods: We reviewed a prospective database of LVA in node-positive patients (cT1-4,Nany) who received NAC followed by axillary surgery ± immediate LVA from October 2021 to 2022. The evolution of the surgical approach is described. Specifically, patients who downstaged to clinically negative nodes post-NAC were offered targeted SLNB with dual-tracer and intraoperative frozen section (FS). Patients were reminded that the standard of care for any node positive is cALND. Immediate cALND with LVA was performed for grossly positive nodes or all positive SLNs; cALND was omitted for those with negative SLNs. For a microscopic disease on a frozen section, a shared decision was made pre-operatively, given each patient's differing valuations of the benefit and risks of cALND ± LVA versus no cALND with planned regional radiation postoperatively. LVA was offered as an option as part of our institutional evaluation of the procedure., Results: A total of 15 patients were included; the mean age was 49.9 (range 32-75) with stage IIA to IIIB breast cancer. Of these, 6 (40%) were triple negative, 5 (33.3%) HER-2 positive, and 4 (26.7%) ER/PR+ HER-2 negative. There were 13 women (86.7%) who had persistent axillary adenopathy based on clinical and/or ultrasound assessment, with 8 patients proceeding directly to ALND with LVA. Among these patients, 3 (37.5%) had pathologic nodal disease, and 5 (62.5%) were node negative, confirming the limitations of pre-operative imaging. As a result, the subsequent 7 (46.7%) underwent targeted SLNB with FS, with 3 patients (42.9%) avoiding an ALND as a result of a negative FS. A total of 4 patients (57.1%) had 1 or more positive lymph nodes on FS: 3 proceeded with a cALND and LVA, and 1 patient (14.2%) opted for no cALND based on a pre-operative discussion and received adjuvant radiation and chemotherapy. Of the 11 patients who underwent ALND and LVA, 1 patient (9.1%) developed lymphedema at 6.9 months following their surgery. The accuracy, sensitivity, and specificity of pre-operative US were 46.7%, 85.7%, and 12.5% and intraoperative FS were 88.0%, 72.7%, and 100%, respectively., Conclusions: As adjuvant nodal radiation and systemic therapy continue to improve, the benefit of a cALND in patients with the limited residual disease remains unclear as we await the outcomes from clinical trials. In the era of clinical uncertainty, we propose a nuanced approach to the axilla by utilizing a shared decision model with patients, incorporating targeted SLNB with FS and completion node dissection when required and desired by the patient, coupled with LVA in a simple stepwise treatment pathway.

Objective: The aim of the study was to compare the health outcomes and resource use of cancer patients who were new persistent opioid users with those who were not, after undergoing curative intent surgery for cancer., Background: Little is known about long-term health outcomes (overdose, mortality) and resource utilization of new persistent opioid users among cancer patients undergoing curative-intent surgery., Methods: This retrospective cohort study included all adults with a diagnosis of solid cancers who underwent curative-intent surgery during the study period (2011-2015) in Alberta, Canada and were opioid-naïve before surgery, with a follow-up period until December 31, 2019. The key exposure, "new persistent opioid user," was defined as a patient who was opioid-naive before surgery and subsequently filled at least 1 opioid prescription between 60 and 180 days after surgery. The primary outcome was opioid overdose that occurred within 3 years of surgery. All-cause death, noncancer caused death, and department visit (yes vs. no), and hospitalization (yes vs. no) in the follow-up periods were also included as outcomes., Results: In total, 19,219 patients underwent curative intent surgery with a median follow-up of 47 months, of whom 1530 (8.0%) were identified as postoperative new persistent opioid users. In total, 101 (0.5%) patients experienced opioid overdose within 3 years of surgery. Compared with nonopioid users, new persistent opioid users experienced a higher rate of opioid overdose (OR = 2.37, 95% CI: 1.44-3.9) within 3 years of surgery. New persistent opioid use was also associated with a greater likelihood of being hospitalized (OR = 2.03, 95% CI: 1.76-2.33) and visiting an emergency room (OR = 1.83, 95% CI: 1.62-2.06) in the first year after surgery, and a higher overall (HR = 1.28, 95% CI: 1.1-1.49) and noncancer caused mortality (HR = 1.33, 95% CI: 1.12-1.58), when compared with nonopioid users., Conclusion: Postoperative new persistent opioid use among cancer patients undergoing curative-intent surgery is associated with subsequent opioid overdose, worse survival, and more health resource utilization., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Accurate identification of pathologic complete response (pCR) from population-based electronic narrative data in a timely and cost-efficient manner is critical. This study aimed to derive and validate a set of natural language processing (NLP)-based machine-learning algorithms to capture pCR from surgical pathology reports of breast cancer patients who underwent neoadjuvant chemotherapy (NAC)., Methods: This retrospective cohort study included all invasive breast cancer patients who underwent NAC and subsequent curative-intent surgery during their admission at all four tertiary acute care hospitals in Calgary, Alberta, Canada, between 1 January 2010 and 31 December 2017. Surgical pathology reports were extracted and processed with NLP. Decision tree classifiers were constructed and validated against chart review results. Machine-learning algorithms were evaluated with a performance matrix including sensitivity, specificity, positive predictive value (PPV), negative predictive value [NPV], accuracy, area under the receiver operating characteristic curve [AUC], and F1 score., Results: The study included 351 female patients. Of these patients, 102 (29%) achieved pCR after NAC. The high-sensitivity model achieved a sensitivity of 90.5% (95% confidence interval [CI], 69.6-98.9%), a PPV of 76% (95% CI, 59.6-87.2), an accuracy of 88.6% (95% CI, 78.7-94.9%), an AUC of 0.891 (95% CI, 0.795-0.987), and an F1 score of 82.61. The high-PPV algorithm reached a sensitivity of 85.7% (95% CI, 63.7-97%), a PPV of 81.8% (95% CI, 63.4-92.1%), an accuracy of 90% (95% CI, 80.5-95.9%), an AUC of 0.888 (95% CI, 0.790-0.985), and an F1 score of 83.72. The high-F1 score algorithm obtained a performance equivalent to that of the high-PPV algorithm., Conclusion: The developed algorithms demonstrated excellent accuracy in identifying pCR from surgical pathology reports of breast cancer patients who received NAC treatment., (© 2022. Society of Surgical Oncology.)

Early-onset diagnosis, defined by age <40 years, has historically been associated with inferior outcomes in breast cancer. Recent evidence suggests that this association is modified by molecular subtype. We performed a systematic review and meta-analysis of the literature to synthesize evidence on the association between early-onset diagnosis and clinical outcomes in triple-negative breast cancer (TNBC). Studies comparing the risk of clinical outcomes in non-metastatic TNBC between early-onset patients and later-onset patients (≥40 years) were queried in Medline and EMBASE from inception to February 2023. Separate meta-analyses were performed for breast cancer specific survival (BCSS), overall survival (OS), and disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and pathological complete response (pCR). In total, 7581 unique records were identified, and 36 studies satisfied inclusion criteria. The pooled risk of any recurrence was significantly greater in early-onset patients compared to later-onset patients. Better BCSS and OS were observed in early-onset patients relative to later-onset patients aged >60 years. The pooled odds of achieving pCR were significantly higher in early-onset patients. Future studies should evaluate the role of locoregional management of TNBC and the implementation of novel therapies such as PARP inhibitors in real-world settings, and whether they improve outcomes.

Background: The incidence of colorectal cancer (CRC) is increasing among young adults. We sought to report on patient and disease characteristics, treatment practice patterns and outcomes in this population., Methods: We conducted a retrospective cohort study using administrative health data from the Alberta Cancer Registry (2004-2015), including demographic and tumour characteristics, and treatment received. Outcome measures included overall and cancer-specific deaths. We used Cox regression and Kaplan-Meier curves to assess for factors associated with survival., Results: We included 18 070 patients with CRC ( n = 1583 [8.8%] < 50 yr, n = 16 487 [91.2 %] ≥ 50 yr). Younger patients were more likely to present with locally advanced disease (21.0% v. 18.0%, p < 0.0001), stage III (16.4 % v. 14.6%, p < 0.0001) or metastatic (16.7% v. 13.8%, p < 0.0001) involvement. Younger patients were more likely to receive surgery (87.2% v. 80.9%, p < 0.0001), chemotherapy (59.6% v. 34.1%, p < 0.0001) or radiation therapy (49.5% v. 37.2%, p < 0.001). At 5 years, overall and cancer-specific survival was better among younger patients than older patients (30.6% v. 51.5% overall deaths, 27.5% v. 38.4% cancer-specific deaths, p < 0.0001)., Conclusion: Despite higher stage and higher grade disease, young patients with CRC had more favourable oncologic outcomes than stage-matched older patients, which may be related to younger patients receiving more aggressive treatment. Further investigation should focus on optimal treatment patterns for young patients with CRC., Competing Interests: Competing interests: Ameer Farooq is the associate digital editor for CJS; he was not involved in the review or decision to accept this manuscript for publication. He is also codirector of social media for Evidence Based Reviews in Surgery. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: Consideration of sentinel lymph node biopsy (SLNB) is recommended for patients with T1b melanomas and T1a melanomas with high-risk features; however, the proportion of patients with actionable results is low. We aimed to identify factors predicting SLNB positivity in T1 melanomas by examining a multi-institutional international population., Methods: Data were extracted on patients with T1 cutaneous melanoma who underwent SLNB between 2005 and 2018 at five tertiary centers in Europe and Canada. Univariable and multivariable logistic regression analyses were performed to identify predictors of SLNB positivity., Results: Overall, 676 patients were analyzed. Most patients had one or more high-risk features: Breslow thickness 0.8-1 mm in 78.1% of patients, ulceration in 8.3%, mitotic rate > 1/mm 2 in 42.5%, Clark's level ≥ 4 in 34.3%, lymphovascular invasion in 1.4%, nodular histology in 2.9%, and absence of tumor-infiltrating lymphocytes in 14.4%. Fifty-three patients (7.8%) had a positive SLNB. Breslow thickness and mitotic rate independently predicted SLNB positivity. The odds of positive SLNB increased by 50% for each 0.1 mm increase in thickness past 0.7 mm (95% confidence interval [CI] 1.05-2.13) and by 22% for each mitosis per mm 2 (95% CI 1.06-1.41). Patients who had one excised node (vs. two or more) were three times less likely to have a positive SLNB (3.6% vs. 9.6%; odds ratio 2.9 [1.3-7.7])., Conclusions: Our international multi-institutional data confirm that Breslow thickness and mitotic rate independently predict SLNB positivity in patients with T1 melanoma. Even within this highly selected population, the number needed to diagnose is 13:1 (7.8%), indicating that more work is required to identify additional predictors of sentinel node positivity., (© 2022. Society of Surgical Oncology.)

Background: Understanding occurrence and timing of second events (recurrence and second primary cancer) is essential for cancer specific survival analysis. However, this information is not readily available in administrative data., Methods: Alberta Cancer Registry, physician claims, and other administrative data were used. Timing of second event was estimated based on our developed algorithm. For validation, the difference, in days between the algorithm estimated and the chart-reviewed timing of second event. Further, the result of Cox-regression modeling cancer-free survival was compared to chart review data., Results: Majority (74.3%) of the patients had a difference between the chart-reviewed and algorithm-estimated timing of second event falling within the 0-60 days window. Kaplan-Meier curves generated from the estimated data and chart review data were comparable with a 5-year second-event-free survival rate of 75.4% versus 72.5%., Conclusion: The algorithm provided an estimated timing of second event similar to that of the chart review., (© 2022 Wiley Periodicals LLC.)

Locoregional management of breast cancer is founded on evidence generated over a vast time period, much longer than the career span of many practicing physicians. Oncologists rely on specific patient and tumour characteristics to recommend modern-day treatments. However, some of this information may not have been available during prior periods in which the evidence was generated. For example, the comprehensive Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analyses published in the 2000s typically included older trials accruing patients between the 1960s and 1980s. This raises some uncertainty about whether conclusions from studies conducted in prior eras are as relevant or applicable to modern-day patients and treatments. Reviewing the chronological order and details of the evidence can be beneficial to understanding these nuances. This review discusses the evolution of locoregional management through some key clinical trials. We aim to highlight the time period in which the evidence was generated and emphasize the 10-year outcomes for the comparability of results. Evidence supporting surgical management of the breast and axilla, as well as details of radiotherapy are discussed briefly for all stages of breast cancer.

Purpose: Young women with breast cancer (YWBC) are an understudied population and there are limited data on risk factors for psychological morbidity early in diagnosis. We examined psychological morbidity (anxiety, depression, stress symptoms), well-being and associated risk factors., Methods: A total of 845 women from a pan-Canadian, multicentre inception cohort study of YWBC (age ≤ 40) who completed Patient Reported Outcome Measures (PROMs) after their initial surgical consultation and prior to surgical or other treatments were included. Multivariate regression analyses identified risk factors (i.e. parenting young children) associated with psychological morbidity and whether coping self-efficacy was protective., Results: Rates of clinically significant anxiety (n = 683, 69.1%) and depression (n = 422, 42.7%) were high but lower for stress symptoms (n = 67, 6.8%). Probability of anxiety was high for women with a previous history of depression (OR 2.02, P = 0.03, CI 1.09-3.74) and working full-time (OR 1.76, P = 0.05 CI 1.02-2.77). Whereas, pre-existing depression (OR 2.91, P = 0.01, CI 1.36-6.01), younger children (age ≤ 10) (OR 1.69, P = 0.05, CI 1.01-2.93), and income > $100,000 (OR 2.06, P = 0.02, CI 1.18-3.64) were risk factors for depression. Coping self-efficacy was protective with a decreased risk of anxiety (OR 0.11, P ≤ 0.01 CI 0.04-0.28), depression (OR 0.03, P ≤ .01, CI 0.01-0.16), stress symptoms (OR 0.17, P ≤ .01, CI 0.04-0.65) and higher psychosocial well-being with a gain of 19.68 points (P < 0.01) for high levels of CSE (> mean plus 1 SD). Those with lower levels of neurosis had less negative outcomes., Conclusion: Young women with breast cancer are vulnerable to psychological morbidity early in diagnosis, particularly those with low coping self-efficacy and may benefit from earlier supportive care., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Prompt referral by their surgeon enables fertility preservation (FP) by young women with breast cancer (YWBC) without treatment delay. Following a FP knowledge intervention, we evaluated surgeon and patient reports of fertility discussion, FP referral offer and uptake, and FP choices and reasons for declining FP among patients enrolled in the Reducing Breast Cancer in Young Women, prospective pan-Canadian study., Methods: Between September 2015 and December 2020, 1271 patients were enrolled at 31 sites. For each patient, surgeons were sent a questionnaire inquiring whether: (1) fertility discussion was initiated by the surgical team; (2) FP referral was offered; (3) referral was accepted; a reason was requested for any "no" response. Patients were surveyed about prediagnosis fertility plans and postdiagnosis oncofertility management., Results: Surgeon questionnaires were completed for 1068 (84%) cases. Fertility was discussed with 828 (84%) and FP consultation offered to 461 (47%) of the 990 YWBC with invasive disease. Among the 906 responding YWBC, referral was offered to 220 (82%) of the 283 (33%) with invasive disease who stated that they had definitely/probably not completed childbearing prediagnosis. Of these, 133 (47%) underwent FP. The two most common reasons for not choosing FP were cost and unwillingness to delay treatment., Conclusions: Although the rates of surgeon fertility discussion and FP referral was higher than most reports, likely due to our previous intervention, further improvement is desirable. FP should be offered to all YWBC at diagnosis, regardless of perceived childbearing intent. Cost remains an important barrier to FP uptake., (© 2022. Society of Surgical Oncology.)

Background: In cancer survival analyses using population-based data, researchers face the challenge of ascertaining the timing of recurrence. We previously developed algorithms to identify recurrence of breast cancer. This is a follow-up study to detect the timing of recurrence., Methods: Health events that signified recurrence and timing were obtained from routinely collected administrative data. The timing of recurrence was estimated by finding the timing of key indicator events using three different algorithms, respectively. For validation, we compared algorithm-estimated timing of recurrence with that obtained from chart-reviewed data. We further compared the results of cox regressions models (modeling recurrence-free survival) based on the algorithms versus chart review., Results: In total, 598 breast cancer patients were included. 121 (20.2%) had recurrence after a median follow-up of 4 years. Based on the high accuracy algorithm for identifying the presence of recurrence (with 94.2% sensitivity and 79.2% positive predictive value), the majority (64.5%) of the algorithm-estimated recurrence dates fell within 3 months of the corresponding chart review determined recurrence dates. The algorithm estimated and chart-reviewed data generated Kaplan-Meier (K-M) curves and Cox regression results for recurrence-free survival (hazard ratios and P-values) were very similar., Conclusion: The proposed algorithms for identifying the timing of breast cancer recurrence achieved similar results to the chart review data and were potentially useful in survival analysis., (© 2022. The Author(s).)

Purpose: The optimal characteristics among patients with breast cancer to recommend neoadjuvant chemotherapy is an active area of clinical research. We developed and compared several approaches to developing prediction models for pathologic complete response (pCR) among patients with breast cancer in Alberta., Methods: The study included all patients with breast cancer who received neoadjuvant chemotherapy in Alberta between 2012 and 2014 identified from the Alberta Cancer Registry. Patient, tumor, and treatment data were obtained through primary chart review. pCR was defined as no residual invasive tumor at surgical excision in breast or axilla. Two types of prediction models for pCR were built: (1) expert model: variables selected on the basis of oncologists' opinions and (2) data-driven model: variables selected by trained machine. These model types were fit using logistic regression (LR), random forests (RF), and gradient-boosted trees (GBT). We compared the models using area under the receiver operating characteristic curve and integrated calibration index, and internally validated using bootstrap resampling., Results: A total of 363 cases were included in the analyses, of which 86 experienced pCR. The RF and GBT fits yielded higher optimism-corrected area under the receiver operating characteristic curves compared with LR for the expert (RF: 0.70; GBT: 0.69; LR: 0.65) and data-driven models (RF: 0.71; GBT: 0.68; LR: 0.64). The LR fit yielded the lowest integrated calibration indices for the expert (LR: 0.037; GBT: 0.05; RF: 0.10) and data-driven models (LR: 0.026; GBT: 0.06; RF: 0.099)., Conclusion: Our models demonstrated predictive ability for pCR using routinely collected clinical and demographic variables. We show that machine learning fit methods can be used to optimize models for pCR prediction. We also show that additional variables beyond clinical expertise do not considerably improve predictive ability and may not be of value on the basis of the burden of data collection., Competing Interests: Devon BoyneEmployment: Cytel Darren BrennerEmployment: CytelNo other potential conflicts of interest were reported.

Objective: This study aimed to evaluate the association between prescribers' opioid prescribing history and persistent postoperative opioid use in cancer patients undergoing curative-intent surgery., Background: Study has shown that patients may be over-prescribed analgesics after surgery. However, whether and how the prescriber's opioid prescribing behavior impacts persistent opioid use is unclear., Methods: All adults with a diagnosis of solid cancers who underwent surgery during the study period (2009-2015) in Alberta, Canada and were opioid-naïve were included. The key exposure was the historical opioid-prescribing pattern of a patient's most responsible prescriber. The primary outcome was "new persistent postoperative opioid user," was defined as a patient who was opioid-naïve before surgery and subsequently filled at least 1 opioid prescription between 60 and 180 days after surgery., Results: We identified 24,500 patients. Of these, 2106 (8.6%) patients became a new persistent opioid user after surgery. Multivariate analysis demonstrated that patients with most responsible prescribers that historically prescribed higher daily doses of opioids (≥50 vs <50 mg oral morphine equivalent) had an increased risk of new persistent opioid use after surgery (odds ratio = 2.41, P < 0.0001). In addition to the provider's prescribing pattern, other factors including younger age, comorbidities, presurgical opioid use, chemotherapy, type of tumor/surgical procedure were also found to be independently associated with new persistent postoperative opioid use., Conclusions: Our results suggest that prescriber with a history of prescribing a higher opioid dose is an important predictor of persistent postoperative opioid use among cancer patients undergoing curative-intent surgery., Competing Interests: All the authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Melanoma metastases to the groin are frequently managed by therapeutic lymph node dissection. Evidence is lacking regarding the extent of dissection required. Thus, we sought to describe practice patterns for the use of inguinal vs. ilioinguinal dissection, as well as the perioperative/oncologic outcomes of each procedure. A mixed-methods approach was employed to evaluate surgical practice patterns. A retrospective review of three multi-site databases was carried out, together with semi-structured interviews of melanoma surgeons. A total of 347 patients who underwent dissection were reviewed. The main indications stated for adding a "deep" ilioinguinal dissection were palpable or radiologically positive disease. There was no significant difference in complications, length of stay or lymphedema between patients having inguinal vs. ilioinguinal dissection, irrespective of method of diagnosis. There was also no significant difference in recurrence, cancer-specific survival or overall survival between groups. In conclusion, ilioinguinal dissection is a safe and well-tolerated procedure, with no significant added morbidity relative to an inguinal dissection. The indications for ilioinguinal dissection currently in use produce an appropriate deep node positivity rate and ilioinguinal dissection should continue to be used selectively. Randomized data are needed to clarify the impact of ilioinguinal dissection on regional control and survival.

Breast cancer patients receiving adjuvant chemotherapy are at increased risk of acute care use. The incidence of emergency department (ED) visits and hospitalizations (H) have been characterized in other provinces but never in Alberta. We conducted a retrospective population-based cohort study using administrative data of women with stage I-III breast cancer receiving adjuvant chemotherapy. Rates of ED and H use in the 180 days following chemotherapy initiation were determined, and logistic regression was performed to identify risk factors. We found that 47% of women receiving adjuvant chemotherapy experienced ED or H, which compared favourably to other provinces. However, Alberta had the highest rate of febrile neutropenia-related ED visits, and among the highest chemotherapy-related ED visits. The incidence of acute care use increased over time, and there were significant institutional differences despite operating under a single provincial healthcare system. Our study demonstrates the need for systematic measurement and the importance of quality improvement programs to address this gap.

Background: We hypothesized that there are geographic areas of increased cancer incidence in Alberta, and that these are associated with high densities of oil and gas(O+G) infrastructure. Our objective was to describe the relationship between O+G infrastructure and incidence of solid tumours on a population level., Methods: We analyzed all patients >=18 years old with urological, breast, upper GI, colorectal, head and neck, hepatobiliary, lung, melanoma, and prostate cancers identified from the Alberta Cancer Registry from 2004-2016. Locations of active and orphan O+G sites were obtained from the Alberta Energy Regulator and Orphan Well Association. Orphan sites have no entity responsible for their maintenance. ArcGIS (ESRI, Toronto, Ontario) was used to calculate the distribution of O+G sites in each census distribution area (DA). Patient residence at diagnosis was defined by postal code. Incidence of cancer per DA was calculated and standardized. Negative binomial regression was done on O+G site density as a categorical variable with cutoffs of 1 and 30 wells/100km 2 , compared to areas with 0 sites., Results: 125,316 patients were identified in the study timeframe;58,243 (46.5%) were female, mean age 65.6 years. Breast (22%) and prostate (19.8%) cancers were most common. Mortality was 36.5% after a median of 30 months follow up (IQR 8.4 - 68.4). For categorical density of active O+G sites, RR was 1.02 for 1-30 sites/100km 2 (95% CI=0.95-1.11) and 1.15 for >30 sites/100km2 (p<0.0001, 95%CI=1.11-1.2). For orphan sites, 1-30 sites RR was 1.25 (p<0.0001, 95%CI=1.16-1.36) and 1.01 (p=0.97, 95%CI=0.7-1.45) for >30 sites. For all O+G sites, RR for 1-30 sites was 1.03 (p=0.4328, 95%CI=0.95-1.11) and 1.15 (p<0.0001, 95%CI=1.11-1.2) for >30 sites., Conclusion: We report a statistically significant correlation between O+G infrastructure density and solid tumour incidence in Alberta. To our knowledge this is the first population-level study to observe that active and orphan O+G sites are associated with increased risk of solid tumours. This finding may inform policy on remediation and cancer prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jost, Dingley, Jost, Cheung, Quan, Bouchard-Fortier, Kong and Xu.)

Background: To understand the association between various treatments and survival for older women with higher-risk breast cancer when controlling for patient and tumor factors., Materials and Methods: We conducted a retrospective, population-based study. Women aged 80 years or older and diagnosed between 2004 and 2017 with non-metastatic, higher-risk breast cancer were identified form the provincial cancer registry in Alberta, Canada. Higher-risk was defined as any of following: T3/4, node positive, human epidermal factor receptor-2 (Her2) positive or triple negative disease. Treatments were surgery, radiotherapy and systemic therapy (hormonal therapy, and/or chemotherapy and/or trastuzumab) or a combination of the previous. Cox regression models were used to examine the association between treatments and breast cancer specific survival (BCSS) and overall survival (OS)., Results: 1369 patients were included. The median age was 84 years. 332 (24%) of women had T3-T4 tumors, 792 (58%) had nodal involvement, 130 (10%) had Her2 positive tumors, 124 (9%) had triple negative tumors. After a median follow-up of 35 months, 29.5% of patients died of breast cancer whereas 34.2% died from other causes. Patients had a lower adjusted hazard for BCSS if they had surgery (hazard ratio [HR] = 0.37 95% confidence interval [CI]: 0.27, 0.51), or systemic therapy (HR = 0.75, 95%CI: 0.58, 0.98). Patients had an increased probability of breast cancer death in the first 5 years after diagnosis compared to death from other causes., Conclusions: Surgery and systemic therapy were associated with longer BCSS and OS. This suggests that maximizing treatments might benefit higher-risk patients., Competing Interests: Declarations of competing interest LB has received an honorarium from Genentech and travel support from Elekta. Other authors, none., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Breast cancer incidence among younger women (under age 50) has increased over the past 25 years, yet little is known about the etiology among this age group. The objective of this study was to investigate relationships between modifiable and non-modifiable risk factors and early-onset breast cancer among three prospective Canadian cohorts., Methods: A matched case-control study was conducted using data from Alberta's Tomorrow Project, BC Generations Project, and the Ontario Health Study. Participants diagnosed with breast cancer before age 50 were identified through provincial registries and matched to three control participants of similar age and follow-up. Conditional logistic regression was used to examine the association between factors and risk of early-onset breast cancer., Results: In total, 609 cases and 1,827 controls were included. A body mass index ≥ 30 kg/m 2 was associated with a lower risk of early-onset breast cancer (OR 0.65; 95% CI 0.47-0.90), while a waist circumference ≥ 88 cm was associated with an increased risk (OR 1.58; 95% CI 1.18-2.11). A reduced risk was found for women with ≥ 2 pregnancies (OR 0.76; 95% CI 0.59-0.99) and a first-degree family history of breast cancer was associated with an increased risk (OR 1.95; 95% CI 1.47-2.57)., Conclusions: In this study, measures of adiposity, pregnancy history, and familial history of breast cancer are important risk factors for early-onset breast cancer. Evidence was insufficient to conclude if smoking, alcohol intake, fruit and vegetable consumption, and physical activity are meaningful risk factors. The results of this study could inform targeted primary and secondary prevention for early-onset breast cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Triple-negative breast cancer (TNBC) is more common among young women, although it frequently presents in older patients. Despite an aging population, there remains a paucity of data on the treatment of TNBC in elderly women. We conducted a systematic review of the peer-reviewed and unpublished literature that captures the management and breast-cancer-specific survival (BCSS) of women ≥70 years old with TNBC. Out of 739 papers, five studies met our inclusion criteria. In total, 2037 patients with TNBC treated between 1973 and 2014 were captured in the analysis. Women ≥70 years old were less likely to undergo surgical resection compared to those <70 (92.8% vs. 94.6%, p = 0.002). Adjuvant therapy, including radiation and chemotherapy, was also less likely to be utilized in women ≥70 years of age. These treatment differences were associated with more than a doubling of cancer-specific mortality in the elderly cohort (5.9% vs. 2.7% in ≤70 years old, p < 0.0001). Two of the five studies showed improved BCSS with adjuvant treatment while others showed no difference. Our systemic review questions the appropriateness of therapeutic de-escalation in this cohort and highlights the significant gap in our understanding of the optimal management for elderly patients with TNBC. Until more data are available, multidisciplinary treatment decision-making should carefully balance the available clinical evidence as well as the patient's predicted life expectancy and goals-of-care preferences.

Background: Inhibition of activated factor XI (FXIa) is a promising antithrombotic drug target. BMS-724296 is a selective, reversible, small-molecule inhibitor of human FXIa (K i 0.3 nM)., Objectives: This study assessed effects of BMS-724296 versus standard-of-care oral anticoagulants apixaban (activated factor X inhibitor) and dabigatran (thrombin inhibitor) on arterial thrombosis, kidney bleeding time (KBT), and clotting time (CT) in nonhuman primate (NHP) cynomolgus monkey models., Methods: Carotid artery thrombosis was produced by electrical stimulation in anesthetized NHPs. Hemostasis was assessed with a provoked KBT model. Thrombosis, KBT, and CT were monitored. Vehicle and various doses of BMS-724296, apixaban, and dabigatran were administered as bolus (intravenous [i.v.]) followed by infusion starting 30 minutes before initiation of thrombosis and continued until the experiment's end (n = 3-8/group). Primary end points included thrombus weight reduction (TWR), KBT, and CT (activated partial thromboplastin time [aPTT], prothrombin time [PT], and thrombin time [TT])., Results: BMS-724296 at 0.025 + 0.05, 0.05 + 0.1, 0.102 + 0.2, and 0.4 + 0.8 mg/kg+mg/kg/h i.v. (bolus + infusion) reduced thrombus weight by 0 ± 0, 35 ± 7*, 72 ± 4*, and 86 ± 4%*, respectively (* P  < .05 vs vehicle; n = 5-6/group). BMS-724296 at the highest dose (0.4 + 0.8 mg/kg+mg/kg/h) did not increase KBT compared to vehicle (109 ± 6 vs 113 ± 20 seconds, respectively) and increased ex vivo aPTT by 2.9 ± 0.1-fold without changing PT and TT. In companion NHP studies, high doses of apixaban and dabigatran produced similar TWR as BMS-724296, but increased KBT 4.3 ± 0.5-fold and 5.8 ± 0.5-fold, respectively (n = 3-4/group)., Conclusions: BMS-724296 produced similar antithrombotic efficacy as apixaban and dabigatran but with no increase in KBT in NHPs. These findings suggest that FXIa inhibitors may provide safe and effective antithrombotic therapy., (© 2021 Bristol Myers Squibb. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: The majority of women in Nigeria present with advanced-stage breast cancer. To address the role of geospatial access, we constructed a geographic information-system-based model to evaluate the relationship between modeled travel time, stage at presentation, and overall survival among patients with breast cancer in Nigeria., Methods: Consecutive patients were identified from a single-institution, prospective breast cancer database (May 2009-January 2019). Patients were geographically located, and travel time to the hospital was generated using a cost-distance model that utilized open-source data. The relationships between travel time, stage at presentation, and overall survival were evaluated with logistic regression and survival analyses. Models were adjusted for age, level of education, and socioeconomic status., Results: From 635 patients, 609 were successfully geographically located. The median age of the cohort was 49 years (interquartile range [IQR], 40-58 years); 84% presented with ≥stage III disease. Overall, 46.5% underwent surgery; 70.8% received systemic chemotherapy. The median estimated travel time for the cohort was 45 minutes (IQR, 7.9-79.3 minutes). Patients in the highest travel-time quintile had a 2.8-fold increase in the odds of presenting with stage III or IV disease relative to patients in the lowest travel-time quintile (P = .006). Travel time ≥30 minutes was associated with an increased risk of death (HR, 1.65; P = .004)., Conclusions: Geospatial access to a tertiary care facility is independently associated with stage at presentation and overall survival among patients with breast cancer in Nigeria. Addressing disparities in access will be essential to ensure the development of an equitable health policy., (© 2020 American Cancer Society.)

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1 and ROCK2 inhibitors is described. Optimization led to compounds with sub-nanomolar inhibitory affinity for both kinases and excellent kinome selectivity. Compound 19 exhibited ROCK1 and ROCK2 IC 50 of 0.67 nM and 0.18 nM respectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The understanding of the biology and epidemiology of, and the optimal therapeutic strategies for, breast cancer (bca) in younger women is limited. We present the rationale, design, and initial recruitment of Reducing the Burden of Breast Cancer in Young Women (ruby), a unique national prospective cohort study designed to examine the diagnosis, treatment, quality of life, and outcomes from the time of diagnosis for young women with bca., Methods: Over a 4-year period at 33 sites across Canada, the ruby study will use a local and virtual recruitment model to enrol 1200 women with bca who are 40 years of age or younger at the time of diagnosis, before initiation of any treatment. At a minimum, comprehensive patient, tumour, and treatment data will be collected to evaluate recurrence and survival. Patients may opt to complete patient-reported questionnaires, to provide blood and tumour samples, and to be contacted for future research, forming the core dataset from which 4 subprojects evaluating genetics, lifestyle factors, fertility, and local management or delivery of care will be performed., Summary: The ruby study will be the most comprehensive repository of data, biospecimens, and patient-reported outcomes ever collected with respect to young women with bca from the time of diagnosis, enabling research unique to that population now and into the future. This research model could be used for other oncology settings in Canada., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Background: In response to Choosing Wisely recommendations that sentinel lymph node biopsy (slnb) should not be routinely performed in elderly patients with node-negative (cN0), estrogen receptor-positive (er+) breast cancer, we sought to evaluate how nodal staging affects adjuvant treatment in this population., Methods: From a prospective database, we identified patients 70 or more years of age with cN0 breast cancer treated with surgery for er+ her2-negative invasive disease during 2012-2016. We determined rates of, and factors associated with, nodal positivity (pN+), and compared the use of adjuvant radiation (rt) and systemic therapy by nodal status., Results: Of 364 patients who met the inclusion criteria, 331 (91%) underwent slnb, with 75 (23%) being pN+. Axillary node dissection was performed in 11 patients (3%). On multivariate analysis, tumour size was the only factor associated with pN+ ( p = 0.007). Nodal positivity rates were 0%, 13%, 23%, 33%, and 27% for lesions preoperatively sized at 0-0.5 cm, 0.5-1 cm, 1.1-2.0 cm, 2.1-5.0 cm, and more than 5.0 cm. Compared with patients assessed as node-negative, those who were pN+ were more likely to receive axillary rt (lumpectomy: 53% vs. 1%, p < 0.001; mastectomy: 43% vs. 2%, p < 0.001), and adjuvant systemic therapy (endocrine: 82% vs. 69%; chemotherapy plus endocrine: 7% vs. 2%, p = 0.002)., Conclusions: Of elderly patients with cN0 er+ breast cancer, 23% were pN+ on slnb. Size was the primary predictor of nodal status, and yet significant rates of nodal positivity were observed even in tumours preoperatively sized at 1 cm or less. The use of rt and systemic adjuvant therapies differed by nodal status, although the long-term oncologic implications require further investigation. Multidisciplinary input on a case-by-case basis should be considered before omission of slnb., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Objectives: Breast cancer incidence has fluctuated considerably in Canada, with recent reductions in rates among screening-eligible women. However, incidence of early-onset and pre-menopausal breast cancer is understudied. We examined age-specific trends in breast cancer incidence between 1971 and 2015, as well as possible trends by birth cohort., Methods: Incidence data were collected from the National Cancer Incidence Reporting System and the Canadian Cancer Registry, and annual percent changes were estimated using the Joinpoint Regression Program. Five-year birth cohort models were fit using the National Cancer Institute's web tool., Results: Breast cancer incidence among women under age 40 has increased since 2000, while incidence under 50 has remained stable. Rates of post-menopausal breast cancer declined sharply and have recently plateaued. More recent birth cohorts are at a non-significantly increased risk of breast cancer compared with the reference, with an increasing upward trend., Conclusions: Rates of breast cancer may be increasing among younger women, and there is suggestive evidence that more recent birth cohorts are at increased risk of the disease. More research is needed into the risk factors for pre-menopausal breast cancer to support primary prevention efforts in this area.

Background: The incidence of breast biopsy following treatment for breast cancer is not well-characterized. We sought to determine the frequency and outcomes of breast biopsy and the need for subsequent surgery in patients treated with breast-conserving surgery (BCS)., Methods: Using a prospective database, we identified patients in Alberta, Canada, treated with BCS for screen-detected breast cancer or ductal carcinoma in situ (DCIS) from 2010 to 2014. Post-treatment breast procedures were identified from physician claims data. Multivariable analysis was performed to identify factors associated with biopsy., Results: We included 2065 patients with a median of 6.4 years of follow-up; most had DCIS (n = 426, 20.6%) or stage I disease (n = 1385, 67.1%). Post-treatment core biopsy was performed in 389 (18.8%, 95% confidence interval [CI] 17.2-20.6%) patients, and excisional biopsy was performed in 19 (0.9%, 95% CI 0.6-1.4%) patients. The per-patient benign-to-malignant biopsy ratio was 3.2 to 1, and the overall malignancy rate was 6.1% (95% CI 5.1-7.2%). Younger age, proximity to a cancer center, positive margins, and the use of magnetic resonance imaging were associated with biopsy (p < 0.05). Additional surgery was performed in 150 (7.3%, 95% CI 6.2-8.5%) patients; 93 (4.5%, 95% CI 3.6-5.4%) patients underwent mastectomy. Surgery was performed for local recurrence/ipsilateral cancer in 62 (3.0%) patients, contralateral breast cancer in 60 (2.9%) patients, bilateral breast cancer in 3 (0.1%) patients, and benign indications/prophylaxis in 25 (1.2%) patients., Conclusions: One in five patients required breast biopsy during post-treatment surveillance following BCS and most revealed benign findings. Rates of additional surgery, especially subsequent mastectomy due to ipsilateral or contralateral malignancy, were low. Patients can be reassured of these findings during pre-treatment counseling and post-treatment surveillance.