ALDH1A3 promotes invasion and metastasis in triple-negative breast cancer by regulating the plasminogen activation pathway.

Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that promotes metastasis. Triple-negative breast cancer (TNBC) progression has been linked to ALDH1A3-induced gene expression changes. To investigate the mechanism of ALDH1A3-mediated breast cancer metastasis, we assessed the effect of ALDH1A3 on the expression of proteases and the regulators of proteases that degrade the extracellular matrix, a process that is essential for invasion and metastasis. This revealed that ALDH1A3 regulates the plasminogen activation pathway; it increased the levels and activity of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). This resulted in a corresponding increase in the activity of serine protease plasmin, the enzymatic product of tPA and uPA. The ALDH1A3 product all-trans-retinoic acid similarly increased tPA and plasmin activity. The increased invasion of TNBC cells by ALDH1A3 was plasminogen-dependent. In patient tumours, ALDH1A3 and tPA are co-expressed and their combined expression correlated with the TNBC subtype, high tumour grade and recurrent metastatic disease. Knockdown of tPA in TNBC cells inhibited plasmin generation and lymph node metastasis. These results identify the ALDH1A3-tPA-plasmin axis as a key contributor to breast cancer progression.

Abscopal responses in patients with metastatic melanoma involving skin and subcutaneous tissues treated with intralesional IL2 plus BCG.

Cutaneous melanoma is relatively common with increasing incidence and significant mortality. While the mainstay of therapy is surgical, patients with stage III and IV disease fare poorer than those with early-stage disease and often benefit from adjuvant therapies. While systemic immunotherapy has changed the landscape of melanoma treatment, for some patients systemic toxicities related to these treatments prohibit successful administration or completion of therapy. Moreover, it is becoming increasingly evident that nodal, regional, and in-transit disease appears to be resistant to systemic immunotherapy relative to responses observed in distant metastatic disease sites. In this scenario, intralesional immunotherapies may offer benefit. In this case series, we describe the use of intralesional IL-2 and BCG at our institution in ten patients with in-transit plus or minus distant cutaneous metastatic melanoma over the last twelve years. All patients received intralesional IL2 and BCG. Both treatments were very well tolerated with only grade 1/2 adverse events. In our cohort, complete clinical response was 60% (6/10), progressive disease in 20% (2/10), and no response in 20% (2/10) of patients. The overall response rate (ORR) was 70%. The median overall survival was 35.5 months and mean overall survival 43 months in this cohort. Herein we further highlight the clinical, histopathological, and radiological course of two complete responders, showing evidence of an abscopal effect with resolution of distant untreated metastasis. Together, this limited data supports the safe and effective use of intralesional IL2 and BCG for the treatment of metastatic or in-transit melanoma in this challenging patient cohort. To our knowledge, this is the first formal study to report on this combination therapy for the treatment of melanoma.

Cutaneous Breast Cancer Metastasis Is Effectively Treated With Intralesional Interleukin-2 and Imiquimod: A Case Report and Brief Literature Review.

Breast cancer is the most common non-cutaneous cancer affecting women worldwide and is a major cause of cancer-related morbidity and mortality in females. While many women are diagnosed with early-stage disease, a subset of women may present with isolated cutaneous metastases or recurrent locoregional cutaneous metastatic disease. There is a paucity of evidence for effective treatments for cutaneous breast cancer metastases. Herein, we present a case of hormone receptor negative, HER2 positive cutaneous breast cancer metastasis treated with intralesional IL-2 and topical imiquimod, which was well tolerated with only minor low grade side effects. We also present a brief literature review of immunotherapy for cutaneous breast cancer metastasis to frame the discussion around using minimally invasive local therapies for this disease. Together, this limited data suggests that intralesional IL-2 and imiquimod may be considered as a safe option when treating a patient with cutaneous breast cancer metastases.

The Relation of Grit and Surgical Specialty Interest Among Medical Students.

OBJECTIVE: The assessment of Grit among medical students applying to surgical residency programs may be useful, but the relationship between student Grit and surgical specialty interest is not clear. This study investigated whether medical student Grit differs based on interest in direct-entry surgical specialties. DESIGN: A literature search informed the development of a cross-sectional study assessing medical student ratings of the validated 6-item Short-Grit scale. Medical students also indicated their career preferences. SETTING: Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; a tertiary medical center. PARTICIPANTS: Surgical specialty interest and Grittiness were assessed among 297 (50.4%) pre-clerkship medical students in their first or second year of training. Data was collected from program applicants over 4 years. RESULTS: Medical students had high levels of Grit (M = 4.029, SD = 0.517). There was a significant difference in Grit level between medical students interested in cardiac surgery ([M = 4.197, SD = 0.471 vs M = 3.919, 0.518]; t(295) = 4.674, p < 0.001; Cohen's D = 0.556), general surgery ([M = 4.178, SD = 0.466 vs M = 3.916, 0.527]; t(295) = 4.434, p < 0.001; Cohen's D = 0.520), neurosurgery ([M = 4.238, SD = 0.457 vs M = 3.950, 0.518]; t(295) = 4.412, p < 0.001; Cohen's D = 0.575), plastic surgery ([M = 4.138, SD = 0.497 vs M = 3.967, 0.520]; t(295) = 2.747, p = 0.006; Cohen's D = 0.333), and vascular surgery (M = 4.248, SD = 0.368 vs M = 3.948, 0.541); t(295) = 4.570, p < 0.001; Cohen's D = 0.501). CONCLUSIONS: Medical students with a career interest in "poor lifestyle" surgical specialties have higher Grit than their peers. These findings may be noteworthy for surgical residency programs with high rates of attrition and burnout.

Case Report: Combined Intra-Lesional IL-2 and Topical Imiquimod Safely and Effectively Clears Multi-Focal, High Grade Cutaneous Squamous Cell Cancer in a Combined Liver and Kidney Transplant Patient.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide, with ever increasing incidence and mortality. While most patients can be treated successfully with surgical excision, cryotherapy, or radiation therapy, there exist a subset of patients with aggressive cSCC who lack adequate therapies. Among these patients are solid organ transplant recipients who due to their immunosuppression, develop cSCC at a dramatically increased rate compared to the normal population. The enhanced ability of the tumor to effectively undergo immune escape in these patients leads to more aggressive tumors with a propensity to recur and metastasize. Herein, we present a case of aggressive, multi-focal cSCC in a double organ transplant recipient to frame our discussion and current understanding of the immunobiology of cSCC. We consider factors that contribute to the significantly increased incidence of cSCC in the context of immunosuppression in this patient population. Finally, we briefly review current literature describing experience with localized therapies for cSCC and present a strong argument and rationale for consideration of an IL-2 based intra-lesional treatment strategy for cSCC, particularly in this immunosuppressed patient population.

Identifying opportunities to support patient-centred care for ductal carcinoma in situ: qualitative interviews with clinicians.

BACKGROUND: Women with ductal carcinoma in situ (DCIS) report poor patient-clinician communication, and long-lasting confusion and anxiety about their treatment and prognosis. Research shows that patient-centred care (PCC) improves patient experience and outcomes. Little is known about the clinician experience of delivering PCC for DCIS. This study characterized communication challenges faced by clinicians, and interventions they need to improve PCC for DCIS. METHODS: Purposive and snowball sampling were used to recruit Canadian clinicians by specialty, gender, years of experience, setting, and geographic location. Qualitative interviews were conducted by telephone. Data were analyzed using constant comparison. Findings were mapped to a cancer-specific, comprehensive PCC framework to identify opportunities for improvement. RESULTS: Clinicians described approaches they used to address the PCC domains of fostering a healing relationship, exchanging information, and addressing emotions, but do not appear to be addressing the domains of managing uncertainty, involving women in making decisions, or enabling self-management. However, many clinicians described challenges or variable practices for all PCC domains but fostering a healing relationship. Clinicians vary in describing DCIS as cancer based on personal beliefs. When exchanging information, most find it difficult to justify treatment while assuring women of a good prognosis, and feel frustrated when women remain confused despite their efforts to explain it. While they recognize confusion and anxiety among women, clinicians said that patient navigators, social workers, support groups and high-quality information specific to DCIS are lacking. Despite these challenges, clinicians said they did not need or want communication interventions. CONCLUSIONS: Findings represent currently unmet opportunities by which to help clinicians enhance PCC for DCIS, and underscore the need for supplemental information and supportive care specific to DCIS. Future research is needed to develop and test communication interventions that improve PCC for DCIS. If effective and widely implemented, this may contribute to improved care experiences and outcomes for women diagnosed with and treated for DCIS.

Guidance for management of cancer surgery during the COVID-19 pandemic.

Summary: During the coronavirus disease 2019 (COVID-19) pandemic, delaying lifesaving cancer surgeries must be done with extreme caution and thoughtfulness. Modelling indicates that delays in high-risk cancer surgeries beyond 6 weeks could affect long-term outcomes for thousands of Canadians. Consequently, it is possible that postponing cancer surgery without consideration of its implications could cost more lives than can be saved by diverting all surgical resources to COVID-19. This article provides general guidance on supporting curative surgical treatment where appropriate and with available resources.

Resolution of Metastatic Subungal Eccrine Porocarcinoma Treated with Intralesional Interleukin-2.

Eccrine porocarcinoma is a rare aggressive cutaneous malignancy. Complete surgical excision is the standard of care, although there are high rates of local and distant recurrence. We present a unique case of locally recurrent and metastatic subungal porocarcinoma successfully treated with intralesional interleukin-2.

Recommendations to improve patient-centred care for ductal carcinoma in situ: Qualitative focus groups with women.

BACKGROUND: Patient-centred care (PCC) improves health-care experiences and outcomes. Women with ductal carcinoma in situ (DCIS) and clinicians have reported communication difficulties. Little prior research has studied how to improve communication and PCC for DCIS. OBJECTIVE: This study explored how to achieve PCC for DCIS. DESIGN: Canadian women treated for DCIS from five provinces participated in semi-structured focus groups based on a 6-domain cancer-specific PCC framework to discuss communication about DCIS. Data were analysed using constant comparative technique. SETTING AND PARTICIPANTS: Thirty-five women aged 30 to 86 participated in five focus groups at five hospitals. RESULTS: Women said their clinicians used multiple approaches for fostering a healing relationship; however, most described an absence of desired information or behaviour to exchange information, respond to emotions, manage uncertainty, make decisions and enable self-management. Most women were confused by terminology, offered little information about the risks of progression/recurrence, uninformed about treatment benefits and risks, frustrated with lack of engagement in decision making, given little information about follow-up plans or self-care advice, and received no acknowledgement or offer of emotional support. DISCUSSION AND CONCLUSIONS: By comparing the accounts of women with DCIS to a PCC framework, we identified limitations and inconsistencies in women's lived experience of communication about DCIS, and approaches by which clinicians can more consistently achieve PCC for DCIS. Future research should develop and evaluate informational tools to support PCC for DCIS.

Squamous Cell Carcinoma with Regional Metastasis to Axilla or Groin Lymph Nodes: a Multicenter Outcome Analysis.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) of the trunk/extremities with nodal metastasis represents a rare but significant clinical challenge. Treatment patterns and outcomes are poorly described. PATIENTS AND METHODS: Patients with cSCC who developed axilla/groin lymph node metastasis and underwent curative-intent surgery between 2005 and 2015 were identified at four Canadian academic centers. Demographics, tumor characteristics, treatment patterns, recurrence rates, and mortality were described. Overall survival (OS) and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Predictors of survival and any recurrence were explored using Cox regression and logistic regression models, respectively. RESULTS: Of 43 patients, 70% were male (median age 74 years). Median follow-up was 38 months. Median time to nodal metastasis was 11.3 months. Thirty-one and 12 patients had nodal metastasis to the axilla and groin, respectively. A total of 72% and 7% received adjuvant and neoadjuvant radiation, respectively, while 5% received adjuvant chemotherapy. Following surgery, 26% patients developed nodal and/or distant disease recurrence. Crude mortality rate was 39.5%. Mean OS was 5.3 years [95% confidence interval (CI) 3.9-6.8 years], and 5-year OS was 55.1%. Mean DFS was 4.8 years (95% CI 3.3-6.2 years), and five-year DFS was 49.3%. Any recurrence was the only independent predictor of death [p = 0.036, odds ratio (OR) = 29.5], and extracapsular extension (p = 0.028, OR = 189) and age (p = 0.017, OR = 0.823) were independent predictors of recurrence. CONCLUSIONS: This represents the largest contemporary series to date of outcomes for patients with axilla/groin nodal metastases from cSCC. Despite aggressive treatment, outcomes remain modest, indicating the need for a continued multidisciplinary approach and integration of new systemic agents.

National consensus recommendations on patient-centered care for ductal carcinoma in situ.

PURPOSE: The purpose of this research was to generate recommendations on strategies to achieve patient-centered care (PCC) for ductal carcinoma in situ (DCIS). METHODS: Thirty clinicians (surgeons, medical/radiation oncologists, radiologists, nurses, navigators) who manage DCIS and 32 DCIS survivors aged 18 or older were nominated. Forty-six recommendations to support PCC for DCIS were derived from primary research, and rated in a two-round Delphi process from March to June 2018. RESULTS: A total of 29 clinicians and 27 women completed Round One, and 28 clinicians and 22 women completed Round Two. The 29 recommendations retained by both women and clinicians reflected the PCC domains of fostering patient-physician relationship (5), exchanging information (5), responding to emotions (1), managing uncertainty (4), making decisions (9), and enabling patient self-management (5). An additional 13 recommendations were retained by women only: fostering patient-physician relationship (1), exchanging information (3), responding to emotions (2), making decisions (3), and enabling patient self-management (4). Some recommendations refer to processes (i.e., ask questions about lifestyle or views about risks/outcomes to understand patient preferences); others to tools (i.e., communication aid). Panelists recommended a separate consensus process to refine the language that clinicians use when describing DCIS. CONCLUSIONS: This is the first study to generate guidance on how to achieve PCC for DCIS. Organizations that deliver or oversee health care can use these recommendations on PCC for DCIS to plan, evaluate, or improve services. Ongoing research is needed to develop communication tools, and establish labels and language for DCIS that optimize communication.

DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid.

All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

Evaluating TNM stage prognostic ability in a population-based cohort of gastric adenocarcinoma patients in a low-incidence country.

OBJECTIVES: TNM stage is the preeminent cancer staging system and a fundamental determinant of disease prognosis. Our goal was to evaluate the predictive power of TNM stage for gastric adenocarcinoma (GAC), in a low-incidence country. METHODS: A province-wide chart review of GAC patients diagnosed from April 1, 2005 to March 31, 2008 was conducted in Ontario and linked to routinely collected vital status data with a follow-up on March 31, 2012. TNM staging was classified using the sixth and seventh Union International for Cancer Control/American Joint Committee on Cancer editions. Kaplan-Meier and log-rank tests compared stage-stratified survival estimates. Discrimination was evaluated using Harrell's C statistic. RESULTS: The cohort included 2366 patients. One- and 5-year survival was 43% and 17%. Using the sixth edition, 9% of patients had stage I disease, 5.4% stage II, 7.3% stage III, and 64% stage IV; 15% were not staged. Using the seventh edition, 9% were stage I, 7.7% stage II, 16% stage III, and 54% stage IV; 14% were not staged. Stage-stratified 5-year survival ranged from 68% to 7% with the sixth edition and from 70% to 4% with the seventh edition. Harrell's C statistic was 0.64 (0.63-0.65) for the broad sixth edition staging categories and 0.68 (0.67-0.69) for the broad seventh edition. Discriminative power was similar for the refined stage categories and across multiple subgroup analyses; it was best in non-metastatic patients. CONCLUSION: Existing staging systems for GAC used in North America predict individualized prognosis poorly. The creation of a more complex prediction tool is necessary to provide accurate and precise prognostication information to oncologists, patients, and their families.

Patient and provider experiences with active surveillance: A scoping review.

OBJECTIVE: Active surveillance (AS) represents a fundamental shift in managing select cancer patients that initiates treatment only upon disease progression to avoid overtreatment. Given uncertain outcomes, patient engagement could support decision-making about AS. Little is known about how to optimize patient engagement for AS decision-making. This scoping review aimed to characterize research on patient and provider communication about AS, and associated determinants and outcomes. METHODS: MEDLINE, EMBASE, CINAHL, and The Cochrane Library were searched from 2006 to October 2016. English language studies that evaluated cancer patient or provider AS views, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings. RESULTS: A total of 2,078 studies were identified, 1,587 were unique, and 1,243 were excluded based on titles/abstracts. Among 344 full-text articles, 73 studies were eligible: 2 ductal carcinoma in situ (DCIS), 4 chronic lymphocytic leukemia (CLL), 6 renal cell carcinoma (RCC) and 61 prostate cancer. The most influential determinant of initiating AS was physician recommendation. Others included higher socioeconomic status, smaller tumor size, comorbid disease, older age, and preference to avoid adverse treatment effects. AS patients desired more information about AS and reassurance about future treatment options, involvement in decision-making and assessment of illness uncertainty and supportive care needs during follow-up. Only three studies of prostate cancer evaluated interventions to improve AS communication or experience. CONCLUSIONS: This study revealed a paucity of research on AS communication for DCIS, RCC and CLL, but generated insight on how to optimize AS discussions in the context of routine care or clinical trials from research on AS for prostate cancer. Further research is needed on AS for patients with DCIS, RCC and CLL, and to evaluate interventions aimed at patients and/or providers to improve AS communication, experience and associated outcomes.

Interventions are needed to support patient-provider decision-making for DCIS: a scoping review.

PURPOSE: Prognostic and treatment uncertainty make ductal carcinoma in situ (DCIS) complex to manage. The purpose of this study was to describe research that evaluated DCIS communication experiences, needs and interventions among DCIS patients or physicians. METHODS: MEDLINE, EMBASE, CINAHL and The Cochrane Library were searched from inception to February 2017. English language studies that evaluated patient or physician DCIS needs, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings. RESULTS: A total of 51 studies published from 1997 to 2016 were eligible for review, with a peak of 8 articles in year 2010. Women with DCIS lacked knowledge about the condition and its prognosis, although care partners were more informed, desired more information and experienced decisional conflict. Many chose mastectomy or prophylactic mastectomy, often based on physician's recommendation. Following treatment, women had anxiety and depression, often at levels similar to those with invasive breast cancer. Disparities were identified by education level, socioeconomic status, ethnicity and literacy. Physicians said that they had difficulty explaining DCIS and many referred to DCIS as cancer. Despite the challenges reported by patients and physicians, only two studies developed interventions designed to improve patient-physician discussion and decision-making. CONCLUSIONS: As most women with DCIS undergo extensive treatment, and many experience treatment-related complications, the paucity of research on PE to improve and support informed decision-making for DCIS is profound. Research is needed to improve patient and provider discussions and decision-making for DCIS management.

Improvement of consistency in delineating breast lumpectomy cavity using surgical clips.

BACKGROUND: Delineation of lumpectomy cavity for whole breast radiation therapy after breast conserving surgery can be challenging because of poor visualization of the cavity. The use of surgical clips on lumpectomy cavity walls has been suggested as an effective and low-cost method to improve the accuracy and consistency of lumpectomy cavity delineation. MATERIALS AND METHODS: Twenty-three eligible female breast cancer patients who were treated with lumpectomy and adjuvant radiation therapy were recruited for this study. During breast conserving surgery, four surgical clips were placed on the superior, inferior, lateral, and medial walls of the lumpectomy cavity. Patients were imaged prior and during radiation treatment. Software was developed to anonymize the image sets and digitally remove the clips from the computed tomography images. Three radiation oncologists contoured the lumpectomy cavity volume, with and without presence of clips. Contoured image sets were analyzed with regard to cavity volume, dimensions, and concordance index. Statistical analysis was performed using a paired t-test. RESULTS: The presence of clips significantly increased the average lumpectomy cavity volumes from 23.50 cc to 26.42 cc (P < 0.0001). The presence of clips also significantly increased the mean craniocaudal, anteroposterior, and mediolateral dimensions by 6.8, 2.3, and 2.9 mm, respectively (all P < 0.01). In addition, the presence of surgical clips improved the consistency in delineation in CC dimension by significantly decreasing the standard deviation (P < 0.006). CONCLUSIONS: The presence of surgical clips improves the accuracy of lumpectomy cavity delineation. However, consistency is only improved in CC dimension.

Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1.

Breast cancer subtyping, based on the expression of hormone receptors and other genes, can determine patient prognosis and potential options for targeted therapy. Among breast cancer subtypes, tumors of basal-like and claudin-low subtypes are typically associated with worse patient outcomes, are primarily classified as triple-negative breast cancers (TNBC), and cannot be treated with existing hormone-receptor-targeted therapies. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. In this study, we focus on retinoic acid receptor responder 1 (RARRES1) as a paradigm to determine if breast cancer subtype dictates protein function and gene expression regulation. Patient tumor dataset analysis and gene expression studies of a 26 cell-line panel, representing the five breast cancer subtypes, demonstrate that RARRES1 expression is greatest in basal-like TNBCs. Cell proliferation and tumor growth assays reveal that RARRES1 is a tumor suppressor in TNBC. Furthermore, gene expression studies, Illumina HumanMethylation450 arrays, and chromatin immunoprecipitation demonstrate that expression of RARRES1 is retained in basal-like breast cancers due to hypomethylation of the promoter. Additionally, expression of the cancer stem cell marker, aldehyde dehydrogenase 1A3, which provides the required ligand (retinoic acid) for RARRES1 transcription, is also specific to the basal-like subtype. We functionally demonstrate that the combination of promoter methylation and retinoic acid signaling dictates expression of tumor suppressor RARRES1 in a subtype-specific manner. These findings provide a precedent for a therapeutically-inducible tumor suppressor and suggest novel avenues of therapeutic intervention for patients with basal-like breast cancer.

Prognostic factors in metastatic gastric cancer: results of a population-based, retrospective cohort study in Ontario.

BACKGROUND: Stage IV gastric cancer is lethal, and little population-based research on prognostic factors has been performed in low-incidence countries. Therefore, we investigated the consistency of the associations of patient, disease and healthcare system factors identified in previous population-based research to understand their generalizability to other low-incidence populations. METHODS: A population-based, retrospective cohort study of patients diagnosed with Stage IV gastric cancer in Ontario between 1 April 2005 and 31 March 2008 was performed. Kaplan-Meier methodology and the log-rank test were used for bivariate analysis. Multivariate Cox proportional hazard regression was performed. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: On multivariate analysis, patient, disease and healthcare system factors were independent predictors of survival. Increasing age per 10 years (HR 1.07; 95% CI 1.02-1.10), a tumor located in the gastroesophageal junction (HR 1.09; 95% CI 0.94-1.27) or middle of the stomach (HR 1.14; 95% CI 0.97-1.35), presence of carcinomatosis (HR 1.61; 95% CI 1.42-1.83) and a larger burden of metastatic disease (2-3 sites of metastatic disease: HR 1.17; 95% CI 1.03-1.32; ≥ 4 sites: HR 1.69; 95% CI 1.30-2.20) were associated with worse prognosis. Female gender, receipt of surgery, chemotherapy and radiotherapy and treatment from a high-volume, gastric cancer specialist were all associated with significantly better prognosis. In addition, there was evidence of significant geographic variation in survival. CONCLUSION: This study provides supporting evidence for patient, disease and healthcare system prognostic factors in metastatic gastric cancer. Future work investigating the role of emerging molecular and biologic information will need to take these established prognostic factors into consideration.