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.

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.

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.

Multi-level factors influence the implementation and use of complex innovations in cancer care: a multiple case study of synoptic reporting.

BACKGROUND: The implementation of innovations (i.e., new tools and practices) in healthcare organizations remains a significant challenge. The objective of this study was to examine the key interpersonal, organizational, and system level factors that influenced the implementation and use of synoptic reporting tools in three specific areas of cancer care. METHODS: Using case study methodology, we studied three cases in Nova Scotia, Canada, wherein synoptic reporting tools were implemented within clinical departments/programs. Synoptic reporting tools capture and present information about a medical or surgical procedure in a structured, checklist-like format and typically report only items critical for understanding the disease and subsequent impacts on patient care. Data were collected through semi-structured interviews with key informants, document analysis, nonparticipant observation, and tool use/examination. Analysis involved production of case histories, in-depth analysis of each case, and a cross-case analysis. Numerous techniques were used during the research design, data collection, and data analysis stages to increase the rigour of this study. RESULTS: The analysis revealed five common factors that were particularly influential to implementation and use of synoptic reporting tools across the three cases: stakeholder involvement, managing the change process (e.g., building demand, communication, training and support), champions and respected colleagues, administrative and managerial support, and innovation attributes (e.g., complexity, compatibility with interests and values). The direction of influence (facilitating or impeding) of each of these factors differed across and within cases. CONCLUSIONS: The findings demonstrate the importance of a multi-level contextual analysis to gaining both breadth and depth to our understanding of innovation implementation and use in health care. They also provide new insights into several important issues under-reported in the literature on moving innovations into healthcare practice, including the role of middle managers in implementation efforts and the importance of attending to the interpersonal aspects of implementation.

How do surgeons decide to refer patients for adjuvant cancer treatment? Protocol for a qualitative study.

BACKGROUND: Non-small cell lung cancer, breast cancer, and colorectal cancer are commonly diagnosed cancers in Canada. Patients diagnosed with early-stage non-small cell lung, breast, or colorectal cancer represent potentially curable populations. For these patients, surgery is the primary mode of treatment, with (neo)adjuvant therapies (e.g., chemotherapy, radiotherapy) recommended according to disease stage. Data from our research in Nova Scotia, as well as others', demonstrate that a substantial proportion of non-small cell lung cancer and colorectal cancer patients, for whom practice guidelines recommend (neo)adjuvant therapy, are not referred for an oncologist consultation. Conversely, surveillance data and clinical experience suggest that breast cancer patients have much higher referral rates. Since surgery is the primary treatment, the surgeon plays a major role in referring patients to oncologists. Thus, an improved understanding of how surgeons make decisions related to oncology services is important to developing strategies to optimize referral rates. Few studies have examined decision making for (neo)adjuvant therapy from the perspective of the cancer surgeon. This study will use qualitative methods to examine decision-making processes related to referral to oncology services for individuals diagnosed with potentially curable non-small cell lung, breast, or colorectal cancer. METHODS: A qualitative study will be conducted, guided by the principles of grounded theory. The study design is informed by our ongoing research, as well as a model of access to health services. The method of data collection will be in-depth, semi structured interviews. We will attempt to recruit all lung, breast, and/or colorectal cancer surgeons in Nova Scotia (n ≈ 42), with the aim of interviewing a minimum of 34 surgeons. Interviews will be audiotaped and transcribed verbatim. Data will be collected and analyzed concurrently, with two investigators independently coding and analyzing the data. Analysis will involve an inductive, grounded approach using constant comparative analysis. DISCUSSION: The primary outcomes will be (1) identification of the patient, surgeon, institutional, and health-system factors that influence surgeons' decisions to refer non-small cell lung, breast, and colorectal cancer patients to oncology services when consideration for (neo)adjuvant therapy is recommended and (2) identification of potential strategies that could optimize referral to oncology for appropriate individuals.

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.

Exploring the interpersonal-, organization-, and system-level factors that influence the implementation and use of an innovation-synoptic reporting-in cancer care.

BACKGROUND: The dominant method of reporting findings from diagnostic and surgical procedures is the narrative report. In cancer care, this report inconsistently provides the information required to understand the cancer and make informed patient care decisions. Another method of reporting, the synoptic report, captures specific data items in a structured manner and contains only items critical for patient care. Research demonstrates that synoptic reports vastly improve the quality of reporting. However, synoptic reporting represents a complex innovation in cancer care, with implementation and use requiring fundamental shifts in physician behaviour and practice, and support from the organization and larger system. The objective of this study is to examine the key interpersonal, organizational, and system-level factors that influence the implementation and use of synoptic reporting in cancer care. METHODS: This study involves three initiatives in Nova Scotia, Canada, that have implemented synoptic reporting within their departments/programs. Case study methodology will be used to study these initiatives (the cases) in-depth, explore which factors were barriers or facilitators of implementation and use, examine relationships amongst factors, and uncover which factors appear to be similar and distinct across cases. The cases were selected as they converge and differ with respect to factors that are likely to influence the implementation and use of an innovation in practice. Data will be collected through in-depth interviews, document analysis, observation of training sessions, and examination/use of the synoptic reporting tools. An audit will be performed to determine/quantify use. Analysis will involve production of a case record/history for each case, in-depth analysis of each case, and cross-case analysis, where findings will be compared and contrasted across cases to develop theoretically informed, generalisable knowledge that can be applied to other settings/contexts. Ethical approval was granted for this study. DISCUSSION: This study will contribute to our knowledge base on the multi-level factors, and the relationships amongst factors in specific contexts, that influence implementation and use of innovations such as synoptic reporting in healthcare. Such knowledge is critical to improving our understanding of implementation processes in clinical settings, and to helping researchers, clinicians, and managers/administrators develop and implement ways to more effectively integrate innovations into routine clinical care.

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.

Reflections on knowledge brokering within a multidisciplinary research team.

Knowledge brokering (KB) may be one approach of helping researchers and decision makers effectively communicate their needs and abilities, and move toward increased use of evidence in health care. A multidisciplinary research team in Nova Scotia, Canada, has created a dedicated KB position with the goal of improving access to quality colorectal cancer care. The purpose of this paper is to provide an in-progress perspective on KB within this large research team. A KB position ("knowledge broker") was created to perform two primary tasks: (1) facilitate ongoing communication among team members; and (2) develop and maintain collaborations between researchers and decision makers to establish partnerships for the transfer and use of research findings. In this article, we discuss our KB model and its implementation, describe the broker's functions and activities, and present preliminary outcomes. The primary functions of the KB position have included: sustaining team members' engagement; harnessing members' expertise and sharing it with others; developing and maintaining communication tools/strategies; and establishing collaborations between team members and other stakeholders working in cancer care. The broker has facilitated an integrated knowledge translation approach to research conduct and led to the development of new collaborations with external stakeholders and other cancer/health services researchers. KB roles will undoubtedly differ across contexts. However, descriptive assessments can help others determine whether such an approach could be valuable for their research programs and, if so, what to expect during the process.

Evaluating survivorship care plans: results of a randomized, clinical trial of patients with breast cancer.

PURPOSE: An Institute of Medicine report recommends that patients with cancer receive a survivorship care plan (SCP). The trial objective was to determine if an SCP for breast cancer survivors improves patient-reported outcomes. PATIENTS AND METHODS: Women with early-stage breast cancer who completed primary treatment at least 3 months previously were eligible. Consenting patients were allocated within two strata: less than 24 months and ≥ 24 months since diagnosis. All patients were transferred to their own primary care physician (PCP) for follow-up. In addition to a discharge visit, the intervention group received an SCP, which was reviewed during a 30-minute educational session with a nurse, and their PCP received the SCP and guideline on follow-up. The primary outcome was cancer-related distress at 12 months, assessed by the Impact of Event Scale (IES). Secondary outcomes included quality of life, patient satisfaction, continuity/coordination of care, and health service measures. RESULTS: Overall, 408 survivors were enrolled through nine tertiary cancer centers. There were no differences between groups on cancer-related distress or on any of the patient-reported secondary outcomes, and there were no differences when the two strata were analyzed separately. More patients in the intervention than control group correctly identify their PCP as primarily responsible for follow-up (98.7% v 89.1%; difference, 9.6%; 95% CI, 3.9 to 15.9; P = .005). CONCLUSION: The results do not support the hypothesis that SCPs are beneficial for improving patient-reported outcomes. Transferring follow-up to PCPs is considered an important strategy to meet the demand for scarce oncology resources. SCPs were no better than a standard discharge visit with the oncologist to facilitate transfer.

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.

Quantifying limitations in chemotherapy data in administrative health databases: implications for measuring the quality of colorectal cancer care.

Reliable chemotherapy data are critical to evaluate the quality of care for patients with colorectal cancer who are treated with curative intent. In Canada, limitations in the availability and completeness of chemotherapy data exist in many administrative health databases. In this paper, we discuss these limitations and present findings from a chart review in Nova Scotia that quantifies the completeness of chemotherapy capture in existing databases. The results demonstrate that even basic information on cancer treatment in administrative databases can be insufficient to perform the types of analyses that most decision-makers require for quality-of-care measurement.

A polymorphic variant of the insulin-like growth factor type I receptor gene modifies risk of obesity for esophageal adenocarcinoma.

BACKGROUND: To investigate potential biologic mechanisms underlying the association between obesity and risk for esophageal adenocarcinoma (EADC), we studied the frequency of a common polymorphism of the insulin-like growth factor I receptor (IGF-IR) gene in patients with either gastroesophageal reflux disease (GERD), premalignant Barrett esophagus (BE) and or invasive EADC. METHODS: Using a well characterized series of 431 individuals enrolled in a case-control study, we studied the frequency of the IGF-IR gene polymorphism, G1013A. RESULTS: On multivariate analysis controlling for age and gender, in comparison to asymptomatic controls, obese individuals with the polymorphic A-variant (G/A, A/A) were found to have significantly increased risk for EADC (OR 4.81; 95%CI 1.09-21.15), whereas obese individuals with the G/G variant were not at statistically significant increased risk (OR 2.69; 95%CI 0.41-17.62). Similarly, compared to asymptomatic controls, only obese individuals with the A-variant (G/A, A/A) were at increased risk for BE (OR 3.11; 95%CI 1.12-8.63), while obese individuals with the G/G variant were not at increased risk for BE (OR 2.91; 95%CI 0.69-12.15). CONCLUSION: We conclude that the common IGF-IR gene polymorphism G1013A modulates the risk of obesity for EADC, an effect most likely mediated by altered the receptor function by influencing gene transcription or mRNA stability. These findings further implicate the insulin-like growth factor axis in the molecular pathogenesis of EADC, and represent a plausible mechanistic link underlying the association between obesity and malignancy.

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.

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.

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.

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.

Factors influencing waiting times for elective laparoscopic cholecystectomy.

INTRODUCTION: Health Canada states that waiting list information and management systems in Canada are woefully inadequate, especially for elective surgical procedures. Understanding the reasons for waiting is paramount to achieving fairness and equity. The objective of this study was to examine the impact of demographic and clinical factors and surgeon volume on waiting times for laparoscopic cholecystectomy (LC). METHODS: We comprehensively applied a wait-list database for all surgical procedures across a division of general surgery and performed a chart review of all patients undergoing LC in 2002 to collect additional demographic and clinical data. We excluded patients undergoing LC on an emergent basis or as a secondary procedure. For each patient, we calculated 2 time intervals: time from the receipt of consult to the surgical consult (interval A) and time from the surgical consult to the LC (interval B). Surgeons were categorized a priori into low- and high-volume groups, based on the median number of procedures they had performed. All analyses examining waiting times were performed with nonparametric methods. RESULTS: The study cohort included 294 patients; most (94.6%) underwent LC for biliary colic. The median waiting times for interval A and interval B were 22 days and 50 days, respectively. No associations were identified between any of the examined waiting times, sex, diagnosis or Charlston Comorbidity Index. High surgeon volume was associated with longer waiting times for interval A (median 26 v. 19 d; p=0.04) and interval B (median 58 v. 35 d; p=0.003) and was also associated with a greater number of episodes of biliary colic (2.7 v. 2.0; p=0.03). CONCLUSION: There is significant variability in specific waiting times for LC, which appears to be associated with surgeon volume. Better prioritization of patients undergoing nonemergent LC is required to improve patient care.