Survey of American and Canadian general surgeons' perceptions of margin status and practice patterns for breast conserving surgery.

Although breast conservation surgery (BCS) is commonly performed, several aspects of the procedure remain controversial. We undertook a cross-sectional survey to compare Canadian (CDN) and American (AM) general surgeons' reported BCS practice patterns to better understand the cross-border differences in early-stage breast cancer surgery care. A modified Dillman Method survey was mailed to 1,447 AM and 1,443 CDN surgeons. Factors evaluated included preoperative assessment, margin definition, surgical techniques, and re-excision practices. The response rate was 26% and 51% for AM and CDN surgeons, respectively. There was variation in use of preoperative core biopsies. American surgeons required wider margins for invasive cancer and ductal carcinoma in situ, and more often recommend re-excision for invasive cancer with 1 and 2 mm margins (p < 0.05). There was also variability in surgical techniques used for intraoperative margin assessment. Wide variation in BCS practice was observed, with some of this variability related to surgeon country.

Examining stage IIB survival in a population-based cohort of patients with colorectal cancer.

BACKGROUND: In Nova Scotia, Canada, a previous study of colorectal cancer (CRC) cases diagnosed between January 1, 2001, and December 31, 2005, found that patients with stage IIB CRC had similar 5-year overall survival (OS) to those with stage IIIC cancer. This study sought to examine factors contributing to the observed stage IIB outcome, specifically nodal harvest, receipt of chemotherapy, and use of a new coding system to derive stage. METHODS: The provincial cancer registry identified all CRC cases diagnosed during the study period and staged this cohort using the Collaborative Stage (CS) Data Collection System. All patients with stage II and III cancer in the cohort were examined. Kaplan-Meier (KM) survival curves compared 5-year OS for patients with stage IIB cancer based on the factors of interest, and compared patients with stage IIB cancer to those with stage IIA and III cancer. RESULTS: OS for patients with stage IIB cancer (n = 187) was 44.7%, and differed depending on adequacy of nodal harvest (P = .005) and whether pathological or clinical/mixed evidence was used to derive stage (P = .013). Pathologically-staged patients with stage IIB cancer who had adequate nodal harvest had marginally improved OS compared to pathologically-staged patients who had inadequate nodal harvest (P = .07), and improved survival compared to patients with clinical/mixed stage (P = .004). Pathologically-staged patients with stage IIB cancer with adequate nodal harvest demonstrated similar 5-year OS to those with stage IIA and III cancer (P = .52 and P = .25, respectively). Cox proportional hazards models supported these findings. CONCLUSIONS: The inclusion of clinical/mixed evidence into staging classification and, perhaps to a lesser extent, the adequacy of nodal harvest appear to contribute to the observed worse survival for patients with stage IIB versus stage III cancer.

Impact of comorbidity and healthcare utilization on colorectal cancer stage at diagnosis: literature review.

PURPOSE: Individuals diagnosed with cancer close to death have low access to enrollment in palliative care programs. The purpose of this literature review was to assess the usefulness of pre-diagnostic comorbidity and healthcare utilization as indicators of late-stage colorectal cancer (CRC) diagnosis, to help with early identification of individuals who may benefit from palliative care. METHODS: A literature search was conducted in relevant databases using title/abstract terms which included "cancer," "stage," "diagnosis," "determinants," "predictors," and "associated." Included studies examined whether comorbidity and/or healthcare utilization had an impact on the stage at which CRC was diagnosed. A standardized data abstraction form was used to assess the eligibility of each study. Thirteen articles were included in the literature review. These studies were assessed and synthesized using qualitative methodology. RESULTS: We found much heterogeneity among study variables. The findings of this literature review point to the presence of comorbidity and non-emergent healthcare utilization as having no association with late-stage diagnosis. Conversely, emergency room presentation (ERP) was associated with late-stage diagnosis. CONCLUSIONS: The results of this literature review did not find strong evidence to suggest that comorbidity and healthcare utilization are potential indicators of late-stage diagnosis. However, ERP may be useful as a flag for consideration of prompt referral to palliative care. Additional research is required to identify potential indicators of late-stage diagnosis that may be available in administrative databases, particularly in the area of healthcare utilization.

A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine (Tylenol 3) after outpatient breast surgery.

BACKGROUND: The combination of acetaminophen, codeine, and caffeine (Tylenol 3, T3) is a standard postoperative analgesia after breast surgery despite the adverse effects and variable efficacy of narcotics. This study compared the efficacy of a nonnarcotic approach (acetaminophen and ibuprofen; AcIBU) to T3 after outpatient breast surgery. METHODS: This double-blind randomized equivalence trial involved patients undergoing outpatient breast surgery. Patients were randomized (stratified by procedure type) to receive AcIBU or T3 four times daily for 7 days, or until free of pain. Pain intensity, measured four times daily by the visual analog scale, was the primary outcome; secondary outcomes were pain relief with analgesic, days until freedom from pain, adverse effects, discontinuation of drug as a result of adverse effects, and patient satisfaction. RESULTS: There were 71 patients randomized to AcIBU and 70 patients to T3. Repeated measures analysis showed no significant difference in average pain intensity over 7 days (AcIBU 19.9 mm vs. T3 20.6 mm; P = 0.78). Similarly, there was no significant difference in pain relief with analgesic (P = 0.46). Although no difference in the incidence of adverse effects was observed (P = 0.94), discontinuation of the study drug as a result of adverse effects was more common with T3 (19 % vs. 6 %; P = 0.018). No significant differences were identified in days until freedom from pain or patient satisfaction; 92 % of AcIBU and 89 % of T3 patients were satisfied with their pain control (P = 0.55). CONCLUSIONS: AcIBU is a safe, effective method of pain control after outpatient breast surgery. Compared to T3, it provides at least equivalent analgesia and has a more tolerable adverse effect profile.

Improving nodal harvest in colorectal cancer: so what?

BACKGROUND: Adequate nodal harvest (≥12 lymph nodes) in colorectal cancer has been shown to optimize staging and has been proposed as a quality indicator of colorectal cancer care. We previously demonstrated a population-based improvement in adequate nodal harvest over time, particularly with the use of an audit and feedback strategy. The goal of this current study is to evaluate the impact of improved adequate nodal harvest on 3 relevant clinical outcomes: node positivity rate, use of adjuvant chemotherapy, and survival. METHODS: This current population-based study included all patients undergoing resection for primary stage I-III colorectal cancer in Nova Scotia, Canada, from January 1, 2001 to December 31, 2005. Linkage of the provincial cancer registry with other administrative databases (hospital discharge data, physician claims data, and national census data) provided clinical, demographic, diagnostic, treatment event, and survival data. The association between increase in adequate node harvest and relevant clinical outcomes was examined for all patients and in a subgroup analysis of patients who received care in a health district that used audit and feedback to improve nodal harvest. RESULTS: Among the 2,250 patients, the median nodal harvest was 8, and the overall node positive rate was 35.9%. Despite significant improvement in the proportion of patients undergoing adequate nodal harvest over time (P<.0001), no significant change was observed in the node positivity rate (P=.51), proportion of patients undergoing adjuvant chemotherapy (P=.83), or survival (P=.25). In the subgroup analysis confined to patients where audit and feedback was used to improve nodal harvest rates, clinical outcomes were not improved. CONCLUSIONS: Although improvements in the rate of adequate nodal harvest did occur over time, no corresponding meaningful improvement in clinical outcomes was noted. Given the need that quality indicators not only be associated with outcome, but also that outcome improves as such indicators are optimized, this study questions the inclusion of a nodal harvest≥12 lymph nodes as a quality indicator of colorectal cancer care.

A team approach to improving colorectal cancer services using administrative health data.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Canada and accounts for 11.9% of all cancer-related mortality. Fortunately, previous studies have provided evidence of improved outcomes from access to timely and appropriate health services along the disease trajectory in CRC. As a result, the CIHR/CCNS Team in Access to Colorectal Cancer Services in Nova Scotia (Team ACCESS) was created to build colorectal cancer (CRC) research capacity in Nova Scotia (NS) and to study access to and quality of CRC services along the entire continuum of cancer care. OBJECTIVES: The objectives of this paper are to: 1) provide a detailed description of the methodologies employed across the various studies being conducted by Team ACCESS; 2) demonstrate how administrative health data can be used to evaluate access and quality in CRC services; and 3) provide an example of an interdisciplinary team approach to addressing health service delivery issues. METHODS: All patients diagnosed with CRC in NS between 2001 and 2005 were identified through the Nova Scotia Cancer Registry (NSCR) and staged using the Collaborative Stage Data Collection System. Using administrative databases that were linked at the patient level, Team ACCESS created a retrospective longitudinal cohort with comprehensive demographic, clinical, and healthcare utilization data. These data were used to examine access to and quality of CRC services in NS, as well as factors affecting access to and quality of care, at various transition points along the continuum of care. Team ACCESS has also implemented integrated knowledge translation strategies targeting policy- and decision- makers. DISCUSSION: The development of Team ACCESS represents a unique approach to CRC research. We anticipate that the skills, tools, and knowledge generated from our work will also advance the study of other cancer disease sites in NS. Given the increasing prevalence of cancer, and with national and provincial funding agencies promoting collaborative research through increased funding for research team development, the work carried out by Team ACCESS is important in the Canadian context and exemplifies how a team approach is essential to comprehensively addressing issues surrounding not only cancer, but other chronic diseases in Canada.

The impact of audit and feedback on nodal harvest in colorectal cancer.

BACKGROUND: Adequate nodal harvest (≥ 12 lymph nodes) in colorectal cancer has been shown to optimize staging and proposed as a quality indicator of colorectal cancer care. An audit within a single health district in Nova Scotia, Canada presented and published in 2002, revealed that adequate nodal harvest occurred in only 22% of patients. The goal of this current study was to identify factors associated with adequate nodal harvest, and specifically to examine the impact of the audit and feedback strategy on nodal harvest. METHODS: This population-based study included all patients undergoing resection for primary colorectal cancer in Nova Scotia, Canada, from 01 January 2001 to 31 December 2005. Linkage of the provincial cancer registry with other databases (hospital discharge, physician claims data, and national census data) provided clinicodemographic, diagnostic, and treatment-event data. Factors associated with adequate nodal harvest were examined using multivariate logistic regression. The specific interaction between year and health district was examined to identify any potential effect of dissemination of the previously-performed audit. RESULTS: Among the 2,322 patients, the median nodal harvest was 8; overall, 719 (31%) had an adequate nodal harvest. On multivariate analysis, audited health district (p < 0.0001), year (p < 0.0001), younger age (p < 0.0001), non-emergent surgery (p < 0.0001), more advanced stage (p = 0.008), and previous cancer history (p = 0.03) were associated with an increased likelihood of an adequate nodal harvest. Interaction between year and audited health district was identified (p = 0.006) such that the increase in adequate nodal harvest over time was significantly greater in the audited health district. CONCLUSIONS: Improvements in colorectal cancer nodal harvest did occur over time. A published audit demonstrating suboptimal nodal harvest appeared to be an effective knowledge translation tool, though more so for the audited health district, suggesting a potentially beneficial effect of audit and feedback strategies.

What Matters in Cancer Survivorship Research? A Suite of Stakeholder-Relevant Outcomes.

The outcomes assessed in cancer survivorship research do not always match the outcomes that survivors and health system stakeholders identify as most important in the post-treatment follow-up period. This study sought to identify stakeholder-relevant outcomes pertinent to post-treatment follow-up care interventions. We conducted a descriptive qualitative study using semi-structured telephone interviews with stakeholders (survivors, family/friend caregivers, oncology providers, primary care providers, and cancer system decision-/policy-makers) across Canada. Data analysis involved coding, grouping, detailing, and comparing the data by using the techniques commonly employed in descriptive qualitative research. Forty-four participants took part in this study: 11 survivors, seven family/friend caregivers, 18 health care providers, and eight decision-makers. Thirteen stakeholder-relevant outcomes were identified across participants and categorized into five outcome domains: psychosocial, physical, economic, informational, and patterns and quality of care. In the psychosocial domain, one's reintegration after cancer treatment was described by all stakeholder groups as one of the most important challenges faced by survivors and identified as a priority outcome to address in future research. The outcomes identified in this study provide a succinct suite of stakeholder-relevant outcomes, common across cancer types and populations, that should be used in future research on cancer survivorship care.

Stakeholder-Identified Interventions to Address Cancer Survivors' Psychosocial Needs after Completing Treatment.

The interventions used in cancer-survivorship care do not always address outcomes important to survivors. This study sought to understand stakeholders' views on the key concerns of cancer survivors after treatment and the interventions needed to meet survivors' and families' psychosocial needs after completing cancer treatment. We conducted a descriptive qualitative study using semi-structured interviews with stakeholders (survivors, family/friend caregivers, oncology providers, primary care providers, and cancer system decision-/policy-makers) from across Canada. For the data analysis, we used techniques commonly employed in descriptive qualitative research, such as coding, grouping, detailing, and comparing the data. There were 44 study participants: 11 survivors, seven family/friend caregivers, 18 health care providers, and eight decision-/policy-makers. Stakeholder-relevant interventions to address survivors' psychosocial needs were categorized into five groups, as follows: information provision, peer support, navigation, knowledge translation interventions, and caregiver-specific supports. These findings, particularly interventions that deliver timely and relevant information about the post-treatment period and knowledge translation interventions that strive to integrate effective tools and programs into survivorship care, have implications for future research and practice.

Psychosocial Distress in Adult Patients Awaiting Cancer Surgery during the COVID-19 Pandemic.

Cancer causes substantial emotional and psychosocial distress, which may be exacerbated by delays in treatment. The COVID-19 pandemic has resulted in increased wait times for many patients with cancer. In this study, the psychosocial distress associated with waiting for cancer surgery during the pandemic was investigated. This cross-sectional, convergent mixed-methods study included patients with lower priority disease during the first wave of COVID-19 at an academic, tertiary care hospital in eastern Canada. Participants underwent semi-structured interviews and completed two questionnaires: Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS). Qualitative analysis was completed through a thematic analysis approach, with integration achieved through triangulation. Fourteen participants were recruited, with cancer sites including thyroid, kidney, breast, prostate, and a gynecological disorder. Increased anxiety symptoms were found in 36% of patients and depressive symptoms in 14%. Similarly, 64% of patients experienced moderate or high stress. Six key themes were identified, including uncertainty, life changes, coping strategies, communication, experience, and health services. Participants discussed substantial distress associated with lifestyle changes and uncertain treatment timelines. Participants identified quality communication with their healthcare team and individualized coping strategies as being partially protective against such symptoms. Delays in surgery for patients with cancer during the COVID-19 pandemic resulted in extensive psychosocial distress. Patients may be able to mitigate these symptoms partially through various coping mechanisms and improved communication with their healthcare teams.

Optimizing resource allocation and patient flow: process analysis and reorganization in three chemotherapy outpatient clinics.

Optimizing human and physical resources is a major concern for cancer care decision-makers and practitioners. This issue is particularly acute in the context of ambulatory out patient chemotherapy clinics, especially when - as is the case almost everywhere in the industrialized world - the number of people requiring systemic therapy is increasing while budgets, staffing and physical space remain static. Recent initiatives at three hospital-based chemotherapy units - in Halifax, Toronto and Kingston - shed light on the value of process analysis and reorganization for using existing human and physical resources to their full potential, improving patient flow and enhancing patient satisfaction. The steps taken in these settings are broadly applicable to other healthcare settings and would likely result in similar benefits in those environments.

Regulation of CDX2 expression in esophageal adenocarcinoma.

Reflux of acidic gastric contents and bile acids into the lower esophagus has been identified to have a central role in esophageal malignancy and is reported to upregulate caudal-related homologue 2 (CDX2), a regulatory gene involved in embryonic development and axial patterning of the alimentary tract. The aim of this study was to characterize the expression of CDX2 in a well-defined series of human esophageal tissues, comprising reflux-induced esophagitis, premalignant Barrett esophagus (BE), and primary esophageal adenocarcinoma (EADC). To explore potential molecular regulatory mechanisms, we also studied the expression of beta-catenin, SOX9, and CDX2 promoter methylation in esophageal tissues, in addition to the effect of bile acids and nitric oxide (NO) on CDX2 expression in the normal human esophageal cell line Het1A. Relative to matched normal esophageal epithelia, CDX2 was overexpressed in esophagitis (37% for RNA; cytoplasmic immunoreactivity in 48% of tissues), a high proportion (91%) of BE tissues, and in EADC (57% for RNA; cell nuclear immunopositivity in 80%). An association with beta-catenin expression was seen, but not with SOX9 or CDX2 promoter methylation. In Het1A cells, CDX2 was upregulated following exposure to bile acids and NO, alone and in combination. These results further implicate CDX2 and beta-catenin in the molecular pathogenesis of human EADC. The observed synergistic effect of NO on the efficacy of bile acid-induction of CDX2 suggests a novel role for NO in modulating the development of the Barrett phenotype and esophageal adenocarcinogenesis.

A phase II experience with neoadjuvant irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) for colorectal liver metastases.

BACKGROUND: Chemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM). Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy), and it provides in vivo chemosensitivity data. METHODS: A phase II trial was initiated in which patients with resectable CLM received CPT-11, 5-FU and LV for 12 weeks. Metastasectomy was performed unless extrahepatic disease appeared. Postoperatively, patients with stable or responsive disease received the same regimen for 12 weeks. Patients with progressive disease received either second-line chemotherapy or best supportive care. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and safety. RESULTS: 35 patients were accrued. During preoperative chemotherapy, 16 patients (46%) had grade 3/4 toxicities. Resection was not possible in 5 patients. One patient died of arrhythmia following surgery, and 1 patient had transient liver failure. During the postoperative treatment phase, 12 patients (55%) had grade 3/4 toxicities. Deep venous thrombosis (DVT) occurred in 11 patients (34%) at various times during treatment. Of those who underwent resection, median DFS was 23.0 mo. and median OS has not been reached. The overall survival from time of diagnosis of liver metastases was 51.6 mo for the entire cohort. CONCLUSION: A short course of chemotherapy prior to hepatic metastasectomy may serve to select candidates best suited for resection and it may also direct postoperative systemic treatment. Given the significant incidence of DVT, alternative systemic neoadjuvant regimens should be investigated, particularly those that avoid the use of a central venous line. TRIAL REGISTRATION: ClinicalTrials.gov NCT00168155.

Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett's esophagus and esophageal adenocarcinoma.

Nitric oxide (NO) has been implicated as a potential causative factor for endogenous p53 mutations in gastrointestinal malignancy. To investigate the role of NO in esophageal adenocarcinoma (EADC), we studied patterns of p53 mutations, expression of inducible nitric oxide synthase (iNOS) and the tissue accumulation of nitrotyrosine (NTS), a stable reaction product of NO and a marker for cellular protein damage, in human premalignant and malignant esophageal epithelia. Tissues were obtained from patients with gastroesophageal reflux disease (GERD)-induced esophagitis (n = 76), Barrett's esophagus (BE; n = 119) and primary EADC (n = 54). DNA sequencing was used to characterize p53 mutations, RT-PCR to study iNOS mRNA expression, and immunohistochemistry to study NTS. Relative to self-matched normal epithelia, a progressive increase in iNOS mRNA expression was seen in GERD (30%; 23/76), BE (48%; 57/119), and EADC (63%; 34/54) tissues (P < 0.001). Among patients with EADC, elevated levels of NTS immunoreactivity were more frequent in tumors with p53 mutations (11/21; 52%) compared with tumors with wild-type p53 (9/33; 27%; P = 0.063), and specifically in tumors with p53 mutations at CpG dinucleotides (10/12; 83%) compared with non-CpG p53 mutations (1/9; 11%; P = 0.008). The increasing frequency of iNOS (mRNA) overexpression in GERD, BE and EADC supports the hypothesis that an active inflammatory process, most likely a consequence of GERD, underlies molecular progression to EADC. The highly significant association between NTS, reflecting chronic NO-induced cellular protein damage, and endogenous p53 mutations at CpG dinucleotides, provides further evidence for a molecular link between chronic inflammation and esophageal malignancy.

Alternative splicing of the FGF antisense gene: differential subcellular localization in human tissues and esophageal adenocarcinoma.

Overexpression of FGF-2 is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer, and these risks are reduced in tumors co-expressing the FGF antisense (FGF-AS) RNA. The aim of this study was to characterize the expression of alternatively spliced FGF-AS transcripts and encoded nudix-motif proteins in normal human tissues and in esophageal adenocarcinoma, and to correlate their expression with clinicopathologic findings and outcome. Three alternatively spliced FGF-AS transcripts encoding GFG/NUDT6 isoforms with distinct N termini were detected in various human tissues including esophageal adenocarcinoma. Expression of each isoform as a fusion protein with enhanced green fluorescent protein revealed differential subcellular trafficking: hGFGa is localized to mitochondria by an N-terminal targeting sequence (MTS), whereas hGFGb and hGFGc were localized in the cytoplasm and nucleus. Mutation/deletion analysis confirmed that the predicted MTS was necessary and sufficient for mitochondrial compartmentalization. The predominant FGF-AS mRNA expressed in esophageal tumors was splice variant b. GFG immunoreactivity was detected in the cytoplasm of all esophageal adenocarcinomas and in 88% of tumor cell nuclei. Although we found a trend towards reduced disease-free survival in patients with FGF-2 overexpressing esophageal adenocarcinomas, significantly worse disease-free survival was noted among patients whose tumors did not also overexpress the FGF-AS b isoform (p = 0.03). Tetracycline-inducible FGF-AS b expression in stably transfected human Seg-1 esophageal adenocarcinoma cells resulted in a significant suppression of steady state FGF-2 mRNA content and cell proliferation. Our data implicate the FGF-AS b isoform in modulation of FGF-2 expression and clinical outcome in esophageal adenocarcinoma.

Uptake of elective laparoscopic colectomy for colon cancer in Canada from 2004/05 to 2014/15: a descriptive analysis.

BACKGROUND: Evidence from randomized controlled trials published since 2004 shows that elective laparoscopic colectomy for colon cancer improves short-term postoperative outcomes with equivalent oncologic outcomes compared to open colectomy. The objective of this study was to examine the uptake of elective laparoscopic colectomy in Canada and compare its use among Canadian provinces. METHODS: In this descriptive analysis, we identified from hospital discharge abstracts all patients in the Canadian provinces (except Quebec) who underwent elective colectomy for colon cancer between 2004/05 and 2014/15. We compared temporal changes in the proportion of patients who underwent laparoscopic colectomy or open colectomy among provinces using logistic regression. RESULTS: Of 63 504 patients who underwent elective colectomy between 2004/05 and 2014/15, 19 691 (31.0%) underwent laparoscopic colectomy. The annual proportion of patients who underwent laparoscopic colectomy increased from 9.2% in 2004/05 to 51.5% in 2014/15 (mean annual percent increase 4.2%). There were significant differences between provinces in the overall proportion of patients who underwent laparoscopic colectomy (p < 0.001), ranging from 7.6% in Newfoundland and Labrador to 36.9% in Ontario. By 2014/15, most colectomy procedures were performed laparoscopically in 3 provinces; British Columbia (60.2%), Ontario (59.4%) and Alberta (53.1%). In addition to year and province, urban residence, younger age, female sex, fewer medical comorbidities, high surgeon volume, high hospital volume and right-sided tumours were significantly associated with increased likelihood of laparoscopic colectomy. INTERPRETATION: Although the use of laparoscopic colectomy increased rapidly between 2004/05 and 2014/15 in Canada, substantial interprovincial variation exists. Further knowledge-translation strategies are needed to ensure equal access to laparoscopic colectomy for all Canadians.

Selective cyclooxygenase-2 inhibition suppresses basic fibroblast growth factor expression in human esophageal adenocarcinoma.

Inhibition of cyclooxygenase (COX)-2 is reported to suppress growth and induce apoptosis in human esophageal adenocarcinoma (EADC) cells, although the precise biologic mechanism is unclear. In this study we tested the hypothesis that the antitumor activity of COX-2 inhibitors may involve modulation of basic fibroblast growth factor (FGF-2), which is overexpressed in EADC. We evaluated the effects of NS-398, a selective COX-2 inhibitor, on FGF-2 expression and proliferation of EADC cell lines that express COX-2 and those that do not. We also correlated COX-2 and FGF-2 expression with clinico-pathologic findings and outcome in a well-characterized series of surgically resected EADC tissues. Seg-1 cells robustly expressed COX-2 and FGF-2, whereas Bic-1 cells expressed neither transcript. FGF-2 was reduced to undetectable levels in Seg-1 cells following NS-398 treatment, but increased within 4 h of drug removal. NS-398 significantly inhibited the growth of Seg-1 cells, and this effect was ameliorated by addition of exogenous FGF-2. In contrast, NS-398 had no effect on Bic-1 cell proliferation and FGF-2 alone had no effect on proliferation of either cell line. NS-398, or a neutralizing anti-FGF-2 antibody, induced apoptosis in Seg-1 cells, and these effects were inhibited by addition of exogenous FGF-2. COX-2 protein was strongly expressed in 46% (10/22) of EADCs, and was associated with a trend towards reduced disease-free survival. These findings indicate that the antitumor effects of COX-2 inhibition in EADC cells may be mediated via suppression of FGF-2, and that COX-2 may be a clinically relevant molecular marker in the management of human EADC.

Basic fibroblast growth factor (FGF-2) overexpression is a risk factor for esophageal cancer recurrence and reduced survival, which is ameliorated by coexpression of the FGF-2 antisense gene.

PURPOSE: The basic fibroblast growth factor (FGF-2) gene is bidirectionally transcribed to generate overlapping sense and antisense (FGF-AS) mRNAs. FGF-AS has been implicated in the post-transcriptional regulation of FGF-2 expression. The aim of this study was to characterize FGF-2 and FGF-AS in esophageal cancer and to correlate their expression with clinicopathologic findings and outcome. EXPERIMENTAL DESIGN: Reverse transcription-PCR was used to study FGF-2 and FGF-AS mRNA expression (normalized to glyceraldehyde-3-phosphate dehydrogenase) in 48 esophageal cancers relative to matched histologically normal esophageal epithelia (internal control). We used Cox proportional hazards analysis to calculate hazard ratios for recurrence and survival of patients with underexpression relative to the overexpression of FGF-2 and/or FGF-AS. RESULTS: Overexpression of FGF-2 mRNA, by comparison with tumors underexpressing FGF-2, was associated with significantly increased risk for tumor recurrence (hazard ratio, 3.80; 95% confidence interval, 1.64-8.76) and reduced overall survival (hazard ratio, 2.11; 95% confidence interval, 1.0-4.58). When the effects of FGF-2 and FGF-AS were considered simultaneously, the association of FGF-2 mRNA overexpression with recurrence and mortality was even more pronounced, whereas FGF-AS mRNA overexpression was associated with reduced risk for recurrence and improved survival. CONCLUSIONS: Overexpression of FGF-2 mRNA is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing the FGF-AS mRNA. These data support the hypothesis that FGF-AS is a novel tumor suppressor that modulates the effect of FGF-2 expression and may have potential clinical application to the development of novel therapeutic strategies.

Decision-making by surgeons about referral for adjuvant therapy for patients with non-small-cell lung, breast or colorectal cancer: a qualitative study.

BACKGROUND: Because surgeons are the main gatekeepers to oncology services, understanding how they make decisions related to referral for adjuvant therapies is important to optimize referral rates and use of oncology services for patients with potentially curable disease. We examined decision-making by surgeons related to referral to oncology services for patients having undergone curative-intent surgery for non-small-cell lung, breast or colorectal cancer. METHODS: We conducted a qualitative study, whose design was guided by the principles of grounded theory. Semi-structured interviews were held with 29 surgeons who performed non-small-cell lung, breast or colorectal cancer surgery in the province of Nova Scotia. Data were collected and analyzed concurrently. Analysis involved an inductive, grounded approach using constant comparative analysis. Data collection and analysis continued until theoretical saturation was reached. RESULTS: Seven factors influenced the surgeons' decision-making related to referral to oncology services: indications and contraindications for therapy; patients' beliefs and preferences; a belief that oncologists are the experts; knowledge of local standards of care; consultation with oncology colleagues; navigating patient logistics (e.g., lodging, caregiving responsibilities, insurance coverage); and system resources and capacity. INTERPRETATION: Our study's findings provide a novel understanding of how surgeons make decisions about oncology referral and point to potential areas for intervention to promote referral to oncology services for patients for whom adjuvant therapy is recommended.

Health System-Level Factors Influence the Implementation of Complex Innovations in Cancer Care.

BACKGROUND: The movement of new knowledge and tools into healthcare settings continues to be a slow, complex and poorly understood process. In this paper, we present the system-level factors important to the implementation of synoptic reporting tools in two initiatives (or cases) in Nova Scotia, Canada. METHODS: This study used case study methodology. Data were collected through interviews with key informants, document analysis, non-participant observation and tool use/examination. Analysis involved production of case histories, analysis of each case and a cross-case analysis. RESULTS: The healthcare system's delivery and support structure, information technology infrastructure, policy environment and history of collaboration and inter-organizational relationships influenced tool implementation in the two cases. CONCLUSIONS: The findings provide an in-depth, nuanced understanding of how healthcare system components can influence the implementation of a new tool in clinical practice.