Correction: Gill et al. Report from the 24th Annual Western Canadian Gastrointestinal Cancer Consensus Conference on Colorectal Cancer, Richmond, British Columbia, 28-29, October 2022. Curr. Oncol. 2023, 30, 7964-7983.

Karen Mulder was not included as an author in the original publication [...].

Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs.

One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and excipients from 16 putative BCS Class III drug substances in a total of 19 drug products via 133 approved abbreviated new drug applications (ANDAs) containing in vivo bioequivalence (BE) studies in human subjects during the time period from 2006 to 2022. We included the BCS Class III drugs in this study by referring to published literature, the World Health Organization (WHO) BCS Class I-IV list, FDA internal assessments, and physicochemical properties (high solubility and low permeability) of specific drug substances. Based upon all 133 approved generic formulations in this study, the highest amount of each different compendial excipient with a total of 40 is defined as its corresponding typical amount that has not shown any potential impact on in vivo drug absorption. In the present study, although only 30.08% of the investigated generic formulations met Q1 the same/Q2 similar formulation criteria for the BCS Class III biowaiver, and while approximately 69.92% failed to meet those criteria with non-Q1/Q2 similar formulations, all test/reference ratios (T/R) and 90% confidence intervals for all instrumental PK parameters (AUC0-t, AUC0-inf, and Cmax) met the bioequivalence (BE) criteria (80-125%). The results of formulation assessment suggest that the commonly used excipients without atypical amounts did not impact absorption of 16 putative BCS Class III drug substances. The rate and extent of absorption of drugs appears to be more dependent upon the biopharmaceutic and physiochemical properties of BCS Class III drug substance and less, or not dependent upon their formulations, excipients, and the excipients class. Our findings may lead to a more flexible formulation design space regarding the stringent BCS Class III formulation criteria.

Report from the 24th Annual Western Canadian Gastrointestinal Cancer Consensus Conference on Colorectal Cancer, Richmond, British Columbia, 28-29, October 2022.

The 24th annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Richmond, British Columbia, on 28-29 October 2022. The WCGCCC is an interactive multidisciplinary conference attended by healthcare professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals such as dieticians, nurses and a genetic counsellor participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

CHRFAM7A reduces monocyte/macrophage migration and colony formation in vitro.

OBJECTIVE AND DESIGN: CHRFAM7A is a unique human gene that encodes a dominant negative inhibitor of the α7 nicotinic acetylcholine receptor. We have recently shown that CHRFAM7A is expressed in human leukocytes, increases cel-cell adhesion, and regulates the expression of genes associated with leukocyte migration. MATERIAL: Human THP-1, RAW264.7 and HEK293 cells. METHODS: Cell migration, cell proliferation and colony formation in soft agar to compare the biological activity of vector vs. CHRFAM7A-transduced cells. RESULTS: We show that gene delivery of CHRFAM7A into the THP-1 human monocytic cell line reduces cell migration, reduces chemotaxis to monocyte chemoattractant protein, and reduces colony formation in soft agar. CONCLUSION: Taken together, the findings demonstrate that CHRFAM7A regulates the biological activity of monocytes/macrophages to migrate and undergo anchorage-independent growth in vitro.

Treatment for occult breast cancer: A propensity score analysis of the National Cancer Database.

BACKGROUND: Controversy exists regarding optimal treatment of occult breast cancer (OBC). Treatment options include mastectomy alone (MAST), radiation alone (XRT), or mastectomy with radiation (MXRT). METHODS: We queried the National Cancer Database from 2004 to 2014 for patients with OBC who underwent MAST, XRT, or MXRT. We utilized propensity score matching to perform three head-to-head comparisons. Kaplan-Meier analysis was performed to compare overall survival (OS). RESULTS: A total of 190 patients received XRT, 237 received MAST, and 244 received MXRT. In the MXRT vs. XRT comparison, 5-year OS was 78.2% and 82.8%, respectively. In the MXRT vs. MAST comparison, 5-year OS was 81.5% and 86.7%, respectively. In the MAST vs. XRT comparison, 5-year OS was 83.2% and 82.5%, respectively. There was no difference in OS for all paired comparisons. CONCLUSIONS: There were no OS differences in patients undergoing MAST, XRT, or MXRT, suggesting that breast conservation can be considered in patients with OBC.

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response.

A subset of genes in the human genome are uniquely human and not found in other species. One example is CHRFAM7A, a dominant-negative inhibitor of the antiinflammatory α7 nicotinic acetylcholine receptor (α7nAChR/CHRNA7) that is also a neurotransmitter receptor linked to cognitive function, mental health, and neurodegenerative disease. Here we show that CHRFAM7A blocks ligand binding to both mouse and human α7nAChR, and hypothesized that CHRFAM7A-transgenic mice would allow us to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the systemic inflammatory response syndrome that accompanies severe injury and sepsis. We found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. We also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. Together, the findings point to a pathophysiological inflammatory consequence to the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, not to mention the onset of neurodegenerative disease.

CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor.

INTRODUCTION: CHRFAM7A is a uniquely-human gene that encodes a human-specific variant of the alpha-7 nicotinic acetylcholine receptor (α7nAchR). While the homopentameric α7nAChR consists of 5 equal subunits, previous studies demonstrated that CHRFAM7A expression disrupts the formation of α7nAChR homopentamers. Here we use a rat neuronal cell line expressing CHRFAM7A and a transgenic mouse expressing CHRFAM7A to define the alpha-bungarotoxin (α-BTX) binding in vitro and in vivo. METHODS: Rat PC12 cells were stably transfected with human CHRFAM7A. α-BTX, a protein that irreversibly binds the α7nAchR, was utilized to assess the capacity for CHRFAM7A to interfere with α 7AchR subunits using immunohistochemistry and flow cytometry. To evaluate the effects of CHRFAM7A on α7nAchR at the neuromuscular junction in vivo, transgenic mice were engineered to express the uniquely human gene CHRFAM7A under the control of the EF1-α promoter. Using this model, muscle was harvested and CHRFAM7A and CHRNA7 gene expression evaluated by PCR. Binding of α-BTX to the α7nAchR in muscle was compared in sibling-matched wild-type C57 mice by immunostaining the neuromuscular junction using α-BTX and neurofilament antibodies. RESULTS: Expression of CHRFAM7A in transfected, but not vector cells, was confirmed by PCR and by immunoblotting using an antibody we raised to a peptide sequence unique to CHRFAM7A. CHRFAM7A decreased α-BTX binding as detected by immunohistochemistry and flow cytometry. In vivo, α-BTX co-stained with neurofilament at the neuromuscular junction in wild-type mice, however, α-BTX staining was decreased at the neuromuscular junction of CHRFAM7A transgenic mice. CONCLUSION: CHRFAM7A expression interferes with the binding of α7nAchR to α-BTX. Understanding the contribution of this uniquely human gene to human disease will be important in the identification of potential therapeutic targets.

Precious cargo: Modulation of the mesenteric lymph exosome payload after hemorrhagic shock.

BACKGROUND: Trauma/hemorrhagic shock (T/HS) causes a release of proinflammatory mediators into the mesenteric lymph (ML) that may trigger a systemic inflammatory response and subsequent organ failure. Recently, we showed that exosomes in postshock ML are biologically active mediators of this inflammation. Because the specific inflammatory mediators in postshock ML exosomes have yet to be characterized, we hypothesized that T/HS would lead to a distinct ML proinflammatory exosome phenotype that could be identified by proteomic analysis. We further hypothesized that their regulation by the neuroenteric axis via the vagus nerve would modify this proinflammatory profile. METHODS: Male rats underwent an established T/HS model including 60 minutes of HS followed by resuscitation. Mesenteric lymph was collected before HS (preshock) and after resuscitation (postshock). A subset of animals underwent cervical vagus nerve electrical stimulation (VNS) after the HS phase. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) followed by protein identification, label free quantification, and bioinformatic analysis was performed on exosomes from the pre-shock and post-shock phases in the T/HS and T/HS + vagus nerve electrical stimulation groups. Biological activity of exosomes was evaluated using a monocyte nuclear factor kappa B (NF-κB) activity assay. RESULTS: ML exosomes express a distinct protein profile after T/HS with enrichment in pathways associated with cell signaling, cell death and survival, and the inflammatory response. Stimulation of the vagus nerve following injury attenuated the transition of ML exosomes to this T/HS-induced inflammatory phenotype with protein expression remaining similar to pre-shock. Monocyte NF-κB activity was increased after exposure to ML exosomes harvested after T/HS, while ML exosomes from preshock had no effect on monocyte NF-κB expression. CONCLUSION: Postshock ML exosomes carry a distinct, proinflammatory protein cargo. Stimulating the vagus nerve prevents the T/HS-induced changes in ML exosome protein payload and suggests a novel mechanism by which the neuroenteric axis may limit the systemic inflammatory response after injury.

Use of nitroglycerin ointment to treat primary and secondary Raynaud's phenomenon: a systematic literature review.

Raynaud's phenomenon (RP) is a microvascular condition in which reversible ischemic attacks occur in the extremities. Due to the unpredictable nature of these attacks, pharmacologic agents that can be administered on as-needed basis are currently being sought after. Topical nitrates are well suited for as-needed use, and several different formulations have been studied for the treatment of RP, including ointments, gels, patches, and tapes. However, these different dosage forms are not all equal in terms of safety and efficacy, and not every one is commercially available for use in clinical practice. Nitroglycerin ointment is commercially available, and it has less systemic side effects than other topical formulations. Since its role in the treatment of RP has not yet been completely established, we performed a systematic search of Medline, Embase, and the Cochrane Central Register of Controlled Trials to evaluate its safety and efficacy. A total of 1125 studies were identified, and 7 were included in our review. Although the included studies used different measures of efficacy, the majority reported positive responses to nitroglycerin ointment. The benefit of nitroglycerin ointment in the treatment of RP may be further realized through more robust investigation.

Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4.

Acute lung injury (ALI) is a common cause of morbidity in patients after severe injury due to dysregulated inflammation, which is believed to be driven by gut-derived inflammatory mediators carried via mesenteric lymph (ML). We have previously demonstrated that nano-sized extracellular vesicles, called exosomes, secreted into ML after trauma/hemorrhagic shock (T/HS) have the potential to activate immune cells in vitro Here, we assess the function of ML exosomes in the development of T/HS-induced ALI and the role of TLR4 in the ML exosome-mediated inflammatory response. ML exosomes isolated from rats subjected to T/HS stimulated NF-κB activation and caused proinflammatory cytokine production in alveolar macrophages. In vivo experiments revealed that intravenous injection of exosomes harvested after T/HS, but not before shock, caused recruitment of inflammatory cells in the lung, increased vascular permeability, and induced histologic ALI in naive mice. The exosome-depleted supernatant of ML had no effect on in vitro and in vivo inflammatory responses. We also demonstrated that both pharmacologic inhibition and genetic knockout of TLR4 completely abolished ML exosome-induced cytokine production in macrophages. Thus, our findings define the critical role of exosomes secreted into ML as a critical mediator of T/HS-induced ALI through macrophage TLR4 activation.-Kojima, M., Gimenes-Junior, J. A., Chan, T. W., Eliceiri, B. P., Baird, A., Costantini, T. W., Coimbra, R. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4.

Gut epithelial cell-derived exosomes trigger posttrauma immune dysfunction.

BACKGROUND: Exosomes are extracellular vesicles that act as endogenous mediators of the immune response. We have previously shown that exosomes released into mesenteric lymph (ML) following trauma (T)/hemorrhagic shock (HS) induce proinflammatory cytokine production in macrophages and are involved in the pathogenesis of postshock acute lung injury. However, the cellular origin of ML exosomes and their role in the posttrauma immune response remains unclear. We hypothesized that exosomes released from damaged-intestinal epithelial cells contribute to posttrauma immune dysfunction by altering the function of dendritic cells (DCs), key regulators of the adaptive immunity. METHODS: Male rats underwent cannulation of the femoral artery, jugular vein and ML duct. T/HS was induced by laparotomy and 60 minutes of hemorrhagic shock followed by resuscitation. The ML was collected before (preshock) and after T/HS (post-T/HS) for isolation of exosomes. Surface epitopes of exosomes isolated from ML were assessed by flow cytometry to determine their cellular origin and phenotypic changes. The immunomodulatory effects of ML exosomes on DCs were assessed by Annexin V apoptosis assay, expression of costimulatory molecules, and antigen-presenting capacity to lymphocytes. RESULTS: Exosomes isolated from ML highly expressed CD63 (exosome marker) and epithelial cell-specific marker, suggesting their derivation from intestinal epithelial cells. The expression of immunomodulatory molecules, such as major histocompatibility complex class II and Fas ligand on ML exosomes, was significantly increased after T/HS. Coincubation of DCs with exosomes isolated from ML after T/HS increased DC apoptosis twofold compared with preshock ML exosomes. Furthermore, post-T/HS ML exosomes significantly suppressed lipopolysaccharide-mediated expression of CD80 and CD86 on DCs as well as decreased their antigen-presenting capacity to induce lymphocytes proliferation. CONCLUSION: Gut epithelial cells release immunomodulatory exosomes into the ML after T/HS and resuscitation. Mesenteric lymph exosomes may be critical mediators of posttraumatic immunosuppression causing depletion and dysfunction of DCs.

Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF.

Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1) and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C) mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors.

A meta-analysis of acculturation/enculturation and mental health.

This meta-analytic study examined the relationship among the constructs of acculturation, enculturation, and acculturation strategies (i.e., integration, assimilation, separation, marginalization), and mental health. Data from 325 studies (163 journal articles and 162 dissertation studies) were analyzed using a random-effects model, across a broad spectrum of negative mental health (NM: depression, anxiety, psychological distress, and negative affect) and positive mental health (PM: self-esteem, satisfaction with life, and positive affect). Overall, acculturation was favorably associated with both NM (negatively) and PM (positively), whereas enculturation was favorably related only to PM (positively). In fact, enculturation was positively related to anxiety. The specifics of these relations were further examined using the following moderators: (a) researchers' operationalization of acculturation/enculturation (i.e., linearity, dimensionality); (b) contextual influences (i.e., when and where the study was conducted); and (c) sample characteristics (i.e., voluntariness of residency, race, gender, age). Overall, bilinear measures of acculturation indicated a positive association with PM, while unilinear measures did not. External acculturation (e.g., language, behaviors) and internal enculturation (e.g., identity) were most favorably related to mental health. The place of study had differential effects on the relation of enculturation and NM. Acculturation appeared to be especially important to Asian Americans, whereas enculturation was to African Americans. Differential effects of age suggested the need to consider life-span development of needs and social roles in relation to acculturation and enculturation. Both correlational analyses and mean comparisons affirmed that integration was the most favorable acculturation strategy to mental health. Implications for research, practice, and theory are discussed.

Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability.

BACKGROUND: Altered permeability of the blood-brain barrier (BBB) is a feature of numerous neurological conditions including multiple sclerosis, cerebral malaria, viral hemorrhagic fevers and acute hemorrhagic leukoencephalitis. Our laboratory has developed a murine model of CD8 T cell-initiated central nervous system (CNS) vascular permeability in which vascular endothelial growth factor (VEGF) signaling plays a prominent role in BBB disruption. FINDINGS: In this study, we addressed the hypothesis that in vivo blockade of VEGF signal transduction through administration of peptide (ATWLPPR) to inhibit neuropilin-1 (NRP-1) would have a therapeutic effect following induction of CD8 T cell-initiated BBB disruption. We report that inhibition of NRP-1, a co-receptor that enhances VEGFR2 (flk-1) receptor activation, decreases vascular permeability, brain hemorrhage, and mortality in this model of CD8 T cell-initiated BBB disruption. We also examine the expression pattern of VEGFR2 (flk-1) and VEGFR1 (flt-1) mRNA expression during a time course of this condition. We find that viral infection of the brain leads to increased expression of flk-1 mRNA. In addition, flk-1 and flt-1 expression levels decrease in the striatum and hippocampus in later time points following induction of CD8 T cell-mediated BBB disruption. CONCLUSION: This study demonstrates that NRP-1 is a potential therapeutic target in neuro-inflammatory diseases involving BBB disruption and brain hemorrhage. Additionally, the reduction in VEGF receptors subsequent to BBB disruption could be involved in compensatory negative feedback as an attempt to reduce vascular permeability.

Polymerase II promoter strength determines efficacy of microRNA adapted shRNAs.

Since the discovery of RNAi and microRNAs more than 10 years ago, much research has focused on the development of systems that usurp microRNA pathways to downregulate gene expression in mammalian cells. One of these systems makes use of endogenous microRNA pri-cursors that are expressed from polymerase II promoters where the mature microRNA sequence is replaced by gene specific duplexes that guide RNAi (shRNA-miRs). Although shRNA-miRs are effective in directing target mRNA knockdown and hence reducing protein expression in many cell types, variability of RNAi efficacy in cell lines has been an issue. Here we show that the choice of the polymerase II promoter used to drive shRNA expression is of critical importance to allow effective mRNA target knockdown. We tested the abundance of shRNA-miRs expressed from five different polymerase II promoters in 6 human cell lines and measured their ability to drive target knockdown. We observed a clear positive correlation between promoter strength, siRNA expression levels, and protein target knockdown. Differences in RNAi from the shRNA-miRs expressed from the various promoters were particularly pronounced in immune cells. Our findings have direct implications for the design of shRNA-directed RNAi experiments and the preferred RNAi system to use for each cell type.

Primary tumor resection in patients presenting with metastatic colorectal cancer: analysis of a provincial population-based cohort.

PURPOSE: We conducted a Canadian population-based study to assess surgical practice patterns and outcomes among patients with metastatic colorectal cancer (mCRC) at diagnosis. METHODS: We reviewed a provincial cancer registry for 2 years. Four hundred eleven patients presenting with mCRC were stratified by primary tumor resection status. Baseline characteristics, treatment modalities, and outcomes were assessed. RESULTS: Seventy percent of patients underwent resection. Resected patients were less likely to have rectal primaries (16% vs. 42%, P < or = 0.001) and had more obstructive symptoms (47% vs. 31%, P < or = 0.001) or bleeding (26% vs. 6%, P < or = 0.001). They experienced fewer tumor-related complications (4% vs. 22%, P < or = 0.001). Use of first-line chemotherapy was similar (61% vs. 58%, P = 0.54), but the resection cohort was more likely to receive doublet chemotherapy (57% vs. 36%, P < or = 0.01) and metastatectomy (10% vs. 0%, P < or = 0.0001). Among patients with rectal tumors, radiation use was comparable (63% vs. 58%, P = 0.68). Median survival was longer in the resection group (14 vs. 6 months, P < or = 0.001). CONCLUSIONS: Most patients presenting with mCRC underwent primary resection. Colonic tumors, obstruction, and bleeding were associated with resection. In situ primaries conferred more complications, despite similar use of radiation in cases of rectal cancer. Unresected patients were less likely to receive doublet chemotherapy or metastatectomy, and had inferior survival.