Microscopically positive margins for primary gastrointestinal stromal tumors: analysis of risk factors and tumor recurrence.

BACKGROUND: Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. STUDY DESIGN: We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. RESULTS: Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥ 10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio [HR] 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. CONCLUSIONS: Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥ 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years.

American College of Surgeons Oncology Group and the community surgeon.

The American College of Surgeons Oncology Group (ACOSOG) conducts cancer trials that are relevant to surgeons who treat patients with breast, thoracic, and gastrointestinal cancers. ACOSOG is funded by the National Cancer Institute and is charged with conducting prospective clinical trials that address important questions in academic and community practice settings. Examples include role of axillary dissection for microscopic nodal disease, neoadjuvant therapy for organ-conserving surgery, laparoscopic rectal cancer resection, mediastinal nodal staging, and sublobar resection for early-stage non-small cell lung cancer. Such trials are relevant to most practicing surgeons.

Features associated with successful recruitment of diverse patients onto cancer clinical trials: report from the American College of Surgeons Oncology Group.

BACKGROUND: The clinical trials mechanism of standardized treatment and follow-up for cancer patients with similar stages and patterns of disease is the most powerful approach available for evaluating the efficacy of novel therapies, and clinical trial participation should protect against delivery of care variations associated with racial/ethnic identity and/or socioeconomic status. Unfortunately, disparities in clinical trial accrual persist, with African Americans (AA) and Hispanic/Latino Americans (HA) underrepresented in most studies. STUDY DESIGN: We evaluated the accrual patterns for 10 clinical trials conducted by the American College of Surgeons Oncology Group (ACOSOG) 1999-2009, and analyzed results by race/ethnicity as well as by study design. RESULTS: Eight of 10 protocols were successful in recruiting AA and/or HA participants; three of four randomized trials were successful. Features that were present among all of the successfully recruiting protocols were: (1) studies designed to recruit patients with regional or advanced-stage disease (2 of 2 protocols); and (2) studies that involved some investigational systemic therapy (3 of 3 protocols). DISCUSSION: AA and HA cancer patients can be successfully accrued onto randomized clinical trials, but study design affects recruitment patterns. Increased socioeconomic disadvantages observed within minority-ethnicity communities results in barriers to screening and more advanced cancer stage distribution. Improving cancer early detection is critical in the effort to eliminate outcome disparities but existing differences in disease burden results in diminished eligibility for early-stage cancer clinical trials among minority-ethnicity patients.

Improved surgeon performance in clinical trials: an analysis of quality assurance audits from the American College of Surgeons Oncology Group.

BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) represents an organized effort by surgeons to participate in clinical trials research. To assess the quality of trial conduct by surgeons on a national level and the feasibility of improvement through education, this study examined the findings of the Quality Assurance Audit Program of the ACOSOG over time. STUDY DESIGN: Outcomes of 249 routine audits conducted from 2001 to 2004 were reviewed for major and minor deficiencies and overall performance (acceptable versus unacceptable) in compliance with regulatory requirements (REG) and patient case review (PCR). RESULTS: From 2001 to 2004, active trials have increased. Major deficiencies in REG fell from 31% to 20% for IRB documentation (p = 0.002) and from 31% to 9% for informed consent (p < 0.001). The major deficiency rates in PCR decreased from 21% to 6% (patient consent), 16% to 7% (eligibility), 13% to 7% (treatment), 34% to 6% (outcomes), 6% to 1% (toxicity), and 16% to 3% (data). During 2001 to 2004, the overall acceptable performance rates were 82%, 72%, 84%, and 92%, respectively, in REG (p = 0.093), and significantly improved in PCR (47%, 55%, 77%, 94%, respectively; p < 0.001). No difference was detected in acceptable rates between academic versus community sites, for either REG (86% versus 76%, respectively; odds ratio: 1.91; 95% CI: 0.87 to 4.19) or PCR (63% versus 68%, respectively; odds ratio: 0.81; 95% CI: 0.42 to 1.53). CONCLUSIONS: Despite initial deficiencies, surgical trials are now conducted with high standards nationwide. In response to educational programs, surgeon performance in clinical trials has measurably improved. Quality assurance audits have served both surveillance and educational roles.

Intradermal radioisotope is superior to peritumoral blue dye or radioisotope in identifying breast cancer sentinel nodes.

BACKGROUND: Sentinel lymph node (SLN) mapping and biopsy have emerged as the technique of choice for axillary staging of breast cancer. Several methods have been developed to identify SLNs, including peritumoral or intradermal injection of isosulfan blue dye or technetium sulfur colloid (TSC). We hypothesize that intradermal TSC is the optimal mapping technique and can be used alone to identify SLNs. STUDY DESIGN: From March 1997 through January 2001, 180 women with T1 and T2 invasive breast cancer and clinically negative axilla underwent SLN mapping and biopsy. Peritumoral TSC was injected in 74 patients, 62 of whom also received peritumoral blue dye. Intradermal TSC (above tumor) was performed in 94 patients, 76 of whom also received peritumoral blue dye. Technetium-rich nodes were identified intraoperatively using a hand-held gamma probe and blue nodes were identified visually. Hematoxylin- and eosin-stained SLN sections were examined by light microscopy for breast cancer metastases. RESULTS: Overall, the SLN mapping procedures were successful in 91% of patients. Peritumoral and intradermal TSC were successful in identifying SLNs in 78% and 97% of patients, respectively. Peritumorally injected isosulfan blue was successful in identifying 83% of SLNs. Intradermal TSC was found to be superior to peritumoral TSC and peritumoral blue dye in identifying SLNs (p = 0.00094, chi-squared, and p = 0.020, ANOVA). CONCLUSIONS: SLN mapping by intradermal TSC has a significantly higher success rate than peritumoral TSC or blue dye. There was minimal benefit in identifying additional SLNs with addition of peritumoral blue dye to intradermal TSC. So, SLN mapping and biopsy using intradermal-injected TSC can be used alone to effectively stage the axilla for breast cancer.

Hereditary nonpolyposis colorectal cancer: preventive management.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. Inherited mutations in the mismatch repair genes associated with this syndrome have an approximate 80% lifetime risk of colorectal cancer. Since there are no premonitory signs of susceptibility to HNPCC, family history is the initial method for identifying those at increased risk. At risk individuals should undergo genetic counseling and testing. Although an algorithmic indication for genetic testing in at risk HNPCC patients is yet to be determined, many advocate initial screening for microsatellite instability (MSI) of the cancer specimen in individuals suspected of carrying HNPCC mutations. Those who test positive for MSI can then undergo further testing for mutations in the associated germline mismatch repair genes. Techniques for detecting these mutations currently include in vitro synthesized-protein assay, single-strand conformational polymorphism, and DNA sequencing. Given the aggressive nature of HNPCC adenomas, individuals who test positive for HNPCC mutations are recommended to undergo yearly colonoscopic surveillance starting at the age of 25. A reasonable alternative to lifetime colonoscopic surveillance for the prevention of colorectal cancer in these individuals is prophylactic colectomy. The prevention of colorectal cancer through pharmacological means is under investigation as another option in the management of HNPCC patients. Specifically, chemoprevention trials are currently ongoing to evaluate the efficacy of COX-2 inhibitors in the prevention of colorectal cancer in HNPCC and familial adenomatous polyposis patients.

Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2.

Angiogenesis plays a critical role in metastasis and tumor growth. Human tumors, including colorectal adenocarcinoma, secrete angiogenic factors, inducing proliferation and chemotaxis of microvascular endothelial cells, eventually leading to tumor neovascularization. The chemokine interleukin 8 (IL-8; CXCL8) exerts potent angiogenic properties on endothelial cells through interaction with its cognate receptors CXCR1 and CXCR2. As CXCR1 and CXCR2 expression is differentially regulated in tissue-specific endothelial cells and effects of IL-8 on intestinal endothelial cells are not defined, we characterized the potential IL-8-induced angiogenic mechanisms in primary cultures of human intestinal microvascular endothelial cells (HIMEC) and IL-8 receptor expression in human intestinal microvessels. CXCR1 and CXCR2 expression on HIMEC were defined using reverse transcriptase-PCR, immunohistochemistry, flow cytometry, and Western blot analysis. IL-8-induced downstream signaling events were assessed using immunoblot analysis and immunofluorescence. The angiogenic effects of IL-8 on HIMEC were determined using proliferation and chemotaxis assays. HIMEC responded to IL-8 with rapid stress fiber assembly, chemotaxis, enhanced proliferation, and phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2). HIMEC express CXCR2, but not CXCR1. Neutralizing antibodies to CXCR2 diminished IL-8-induced chemotaxis and stress fiber assembly. Specific inhibitors of ERK 1/2 and phosphoinositide 3-kinase abrogated endothelial tube formation and IL-8-induced chemotaxis in HIMEC. IL-8 elicits angiogenic responses in microvascular endothelial cells isolated from human intestine by engaging CXCR2. We confirmed tissue expression of CXCR2 in human intestinal microvessels. Supported by the notion that malignant colonic epithelial cells overexpress IL-8, CXCR2 blockade may be a novel target for anti-angiogenic therapy in colorectal adenocarcinoma.

Radiofrequency ablation of liver tumors: influence of technique and tumor size.

BACKGROUND: Radiofrequency thermal ablation (RFA) of liver tumors is done by both radiologists and surgeons by using various techniques for a variety of indications. This report describes our initial experience with RFA in 45 patients with hepatic malignancies. METHODS: Patients with primary or secondary hepatic malignancies who were not candidates for resection underwent ultrasound-guided RFA under general anesthesia. End points were recurrence within or adjacent to the ablation zone or new hepatic or extrahepatic lesions. Product limit survival estimates for both ablation site recurrence-free survival and disease-free survival were calculated and compared for tumor size (less than 4 cm or 4 cm or greater), operative approach (percutaneous, laparoscopy, or open), and tumor type (hepatocellular cancer, colorectal cancer, or other metastatic disease). RESULTS: Patients with hepatocellular cancer (n = 11) and with secondary hepatic malignancies (n = 34) had 84 lesions ablated with a median follow-up of 12 months. Largest ablated tumor size of 4 cm or greater (P <.001) and the percutaneous approach (P <.02) were associated with worse ablation site recurrence-free survival but not overall disease-free survival (P =.06). The 15 patients with colorectal cancer had worse disease-free survival compared with other tumor types (P <.01). CONCLUSIONS: RFA of hepatic malignancies can be done by using a percutaneous, laparoscopic, or open approach. Local control appears superior for tumors less than 4 cm and when an open surgical approach is used. The difficulty in achieving prolonged disease-free survival, especially in colorectal cancer, underscores the need to investigate multimodality approaches that include local ablative techniques. Future RFA studies should consider tumor size, operative technique, and tumor type in trial design.

The sentinel node in colorectal carcinoma. Mapping technique, pathologic assessment, and clinical relevance.

One of the most important prognostic factors in colorectal cancer is the presence or absence of regional lymph node metastases. In many instances, micrometastatic disease may not be found on routine pathologic analysis using hematoxylin and eosin staining, but may be discovered only with immunohistochemical methods or polymerase chain reaction assay. Lymphoscintigraphy with biopsy of the sentinel nodes, defined as the first nodal basin in the drainage pathway of a tumor, was developed to provide accurate staging without the morbidity associated with the classic lymph node dissections performed for melanoma or breast cancer. This concept has recently been applied to colorectal cancers, but the method used is unique because oncologic principles of resection are still adhered to for the primary tumor along with en bloc resection of the locoregional mesenteric nodes, some of which are sentinel nodes. Sentinel nodes are ideal for sensitive pathologic techniques of detecting micrometastatic disease, as they often reflect the status of the entire locoregional nodal basin. Gross metastatic nodes reveal significant prognostic information and guide the use of adjuvant therapy in affected patients. However, the detection of micrometastatic disease in sentinel nodes by sensitive pathologic methods has not been proven to result in poor prognosis or benefit from adjuvant therapy for colorectal cancer.

Rectal cancer: the sphincter-sparing approach.

There is considerable skepticism regarding sphincter-preserving surgery for rectal cancer, and 40% to 60% APR rates are reported in many prospective studies. Despite radical surgery, 20% positive margin rates are frequently reported. Rectal carcinoma responds to preoperative chemoradiation therapy with a 10% to 15% pathologic complete response rate. Preoperative therapy offers an opportunity to reduce the positive margin rate and to reduce the APR rate. Because there is significant tumor regression with preoperative therapy, distal margins of less 1 cm are acceptable and do not result in suture line recurrence. APR rate of less than 10% is feasible and better chemotherapy with radiation therapy will reduce the APR to less than 5%.

Peritoneal and serum tumor markers predict recurrence and survival of patients with resectable gastric cancer.

BACKGROUND: Laparoscopy has become a useful adjunct for the staging of gastric cancer; yet, other than standard TNM staging, few additional variables can be used to predict survival. This study evaluated the utility of serum and peritoneal tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]-125) as predictors of locoregional recurrence and distant disease-free survival in patients with gastric cancer.METHODS: During the period June 1990 to February 1994, 86 patients with gastric cancer were evaluated and deemed resectable by preoperative imaging studies. Serum levels of CEA and CA-125 were determined, and all patients underwent laparoscopic staging. Peritoneal washings were obtained from all patients, and 56 of these samples were evaluated for levels of CEA and CA-125.RESULTS: Sixteen (19%) of the 86 patients were found to have metastatic disease at laparoscopy; 67 of the remaining 70 patients underwent potentially curative gastrectomy. Serum CEA and CA-125 levels were predictive of survival in the entire group of patients. In patients who underwent curative gastrectomy, serum CEA predicted survival, whereas peritoneal CA-125 predicted peritoneal recurrence.CONCLUSIONS: Elevated serum levels of CEA and CA-125 are predictive of decreased survival in patients with gastric cancer. Furthermore, determination of peritoneal CA-125 helps to identify those patients at an increased risk for recurrent peritoneal disease.