Steven L. Chen

More extensive nodal dissection improves survival for stages I to III of colon cancer: a population-based study.

Objective:To determine whether analyzing more lymph nodes in colon cancer specimens improves survival. Summary Background Data:Increasing the number of lymph nodes analyzed has been reported to correlate with improved survival in patients with node-negative colon cancer. Methods:The Surveillance, Epidemiology, and End Results database was queried for all patients undergoing resection for histologically confirmed colon cancer between the years 1988 and 2000. Patients were excluded for distant metastases or if an unknown number of nodes was sampled. The number of nodes sampled was categorized into 0, 1 to 7, 8 to 14, and ≥15 nodes. Survival curves constructed using the Kaplan-Meier method were compared using log rank testing. A Cox proportional hazard model was created to adjust for year of diagnosis, age, race, gender, tumor grade, tumor size, TNM stage, and percent of nodes positive for tumor. Results:The median number of lymph nodes sampled for all 82,896 patients was 9. For all stages examined, increasing nodal sampling was associated with improved survival. Multivariate regression demonstrated that patients who had at least 15 nodes sampled as compared with 1 to 7 nodes experienced a 20.6% reduction in mortality independent of other patient and tumor characteristics. Conclusions:Adequate lymphadenectomy, as measured by analysis of at least 15 lymph nodes, correlates with improved survival, independent of stage, patient demographics, and tumor characteristics. Currently, most procedures do not meet this guideline. Future trials of adjuvant therapy should include extent of lymphadenectomy as a stratification factor.

The Prognostic Significance of Micrometastases in Breast Cancer: A SEER Population-Based Analysis

IntroductionThe prognostic significance of lymph node micrometastases in breast cancer is controversial. We hypothesized that the survival of patients with solely micrometastatic disease (N1mi) would be intermediate to patients with 1–3 tumor-positive lymph nodes (N1) and those with no positive lymph nodes (N0).MethodsWe queried the surveillance, epidemiology and end results (SEER) database for all patients between 1992 and 2003 with invasive ductal or lobular breast cancer without distant metastases and ≤3 axillary nodes with macroscopic disease. Patients were stratified by nodal involvement and compared using the Kaplan–Meier method. Cox proportional hazards regression was utilized to compare survival after adjusting for patient and tumor characteristics.ResultsBetween 1992 and 2003, N1mi diagnoses increased from 2.3% to 7% among the 209,720 study patients (p < 0.001). In a T-stage stratified univariate analysis, N1mi patients had a worse prognosis in T2 lesions. On multivariate analysis, N1mi remained a significant prognostic indicator across all patients (p < 0.0001) with a hazard ratio of 1.35 compared to N0 disease and 0.82 compared to N1 disease. Other negative prognostic factors included male gender, estrogen-receptor negativity, progesterone-receptor negativity, lobular histology, higher grade, older age, higher T-stage, and diagnosis in an earlier time period.ConclusionNodal micrometastasis of breast cancer carries a prognosis intermediate to N0 and N1 disease, even after adjusting for tumor- and patient-related factors. Prospective study is warranted and the results of pending trials are highly anticipated. Until then adjuvant therapy trials should consider using N1mi as a stratification factor when determining nodal status.

Chemokine Receptor CXCR4 Expression in Patients With Melanoma and Colorectal Cancer Liver Metastases and the Association With Disease Outcome

Objective:To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Summary Background Data:Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. Methods:Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative real-time RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. Results:Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P < 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P = 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P = not significant). Conclusions:CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (+) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome.

Prognostic impact of micrometastases in colon cancer: interim results of a prospective multicenter trial.

Objective:The 25% rate of recurrence after complete resection of stage II colon cancer (CC) suggests the presence of occult nodal metastases not identified by hematoxylin and eosin staining (H&E). Interim data from our ongoing prospective multicenter trial of sentinel node (SN) biopsy indicate a 29.6% rate of micrometastases (MM) identified by immunohistochemical staining (IHC) of H&E-negative SNs in CC. We hypothesized that these MM have prognostic importance. Methods:Between March 2001 and August 2006, 152 patients with resectable colorectal cancer were enrolled in the trial. IHC and quantitative RT-PCR (qRT) assay were performed on H&E-negative SNs. Results were correlated with disease-free survival. Results:The sensitivity of lymphatic mapping was significantly better in CC (75%) than rectal cancer (36%), P < 0.05. Of 92 node-negative CC patients 7 (8%) were upstaged to N1 and 18 (22%) had IHC MM. Four patients negative by H&E and IHC were positive by qRT. At a mean follow-up of 25 months, 15 patients had died from noncancer-related causes, 12 had developed recurrence, 5 had died of CC (2 with macrometastases, 3 with MM), and 7 were alive with disease. The 12 recurrences included 4 patients with SN macrometastases and 6 with SN MM (2 by IHC, 4 by qRT). One of the 2 SN-negative recurrences had other positive lymph nodes by H&E. All patients with CC recurrences had a positive SN by either H&E/IHC or qRT. No CC patient with a negative SN by H&E and qRT has recurred (P = 0.002). Conclusion:This is the first prospective evaluation of the prognostic impact of MM in colorectal cancer. These results indicate that the detection of MM may be clinically relevant in CC and may improve the selection of patients for adjuvant systemic chemotherapy. Patients with CC who are node negative by cumulative detection methods (H&E/IHC and qRT) are likely to be cured by surgery alone.

Lymphatic mapping and sentinel node analysis: current concepts and applications.

Since the introduction of sentinel node biopsy in 1990 as a minimally invasive surgical technique for the diagnosis of melanoma lymphatic metastases, the number of applications has expanded. We review applications and the current status of sentinel node biopsy in melanoma, breast, colon, gastric, esophageal, head and neck, thyroid, and lung cancer. Variations on techniques specific to each organ are explained, and the current role of sentinel node biopsy in diagnosis and treatment is discussed.

Surgical Resident Involvement Is Safe for Common Elective General Surgery Procedures

BACKGROUND Outcomes of surgical resident training are under scrutiny with the changing milieu of surgical education. Few have investigated the effect of surgical resident involvement (SRI) on operative parameters. Examining 7 common general surgery procedures, we evaluated the effect of SRI on perioperative morbidity and mortality and operative time (OpT). STUDY DESIGN The American College of Surgeons National Surgical Quality Improvement Program database (2005 to 2007) was used to identify 7 cases of nonemergent operations. Cases with simultaneous procedures were excluded. Logistic regression was performed across all procedures and within each procedure incorporating SRI, OpT, and risk-stratifying American College of Surgery National Surgical Quality Improvement Program morbidity and mortality probability scores, which incorporate multiple prognostic individual patient factors. Procedure-specific, SRI-stratified OpTs were compared using Wilcoxon rank-sum tests. RESULTS A total of 71.3% of the 37,907 cases had SRI. Absolute 30-day morbidity for all cases with SRI and without SRI were 3.0% and 1.0%, respectively (p < 0.001); absolute 30-day mortality for all cases with SRI and without SRI were 0.1% and 0.08%, respectively (p < 0.001). After multivariate analysis by specific procedure, SRI was not associated with increased morbidity but was associated with decreased mortality during open right colectomy (odds ratio 0.32; p = 0.01). Across all procedures, SRI was associated with increased morbidity (odds ratio 1.14; p = 0.048) but decreased mortality (odds ratio 0.42; p < 0.001). Mean OpT for all procedures was consistently lower for cases without SRI. CONCLUSIONS SRI has a measurable impact on both 30-day morbidity and mortality and OpT. These data have implications to the impact associated with surgical graduate medical education. Further studies to identify causes of patient morbidity and prevention strategies in surgical teaching environments are warranted.

Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins

Background: Despite intent to cure surgery with negative resection margins, locoregional recurrence is common in pancreatic cancer. Aims: To determine whether detection of K-ras gene mutation in the histologically negative surgical margins of pancreatic cancer reflects unrecognised disease. Patients: Seventy patients who underwent curative resection for pancreatic ductal adenocarcinoma were evaluated. Methods: All patients had surgical resection margins (pancreatic transection and retroperitoneal) that were histologically free of invasive cancer. DNA was extracted from these paraffin embedded surgical margins and assessed by quantitative real time polymerase chain reaction to detect the K-ras gene mutation at codon 12. Detection of K-ras mutation was correlated with standard clinicopathological factors. Results: K-ras mutation was detected in histologically negative surgical margins of 37 of 70 (53%) patients. A significant difference in overall survival was demonstrated between patients with margins that were K-ras mutation positive compared with negative (median 15 v 55 months, respectively; p = 0.0008). By univariate and multivariate analyses, detection of K-ras mutation in the margins was a significant prognostic factor for poor survival (hazard ratio (HR) 2.8 (95% confidence interval (CI) 1.5–5.3), p = 0.0009; and HR 2.8 (95% CI 1.4–5.5), p = 0.004, respectively). Conclusions: Detection of cells harbouring K-ras mutation in histologically negative surgical margins of pancreatic cancer may represent unrecognised disease and correlates with poor disease outcome. The study demonstrates that molecular-genetic evaluation of surgical resection margins can improve pathological staging and prognostic evaluation of patients with pancreatic ductal adenocarcinoma.

Lymph node ratio as a quality and prognostic indicator in stage III colon cancer.

Background:The presence and number of nodal metastasis significantly impact colon cancer prognosis. Similarly, the number of resected/evaluated nodes impacts staging accuracy. This ratio of metastatic to examined nodes or lymph node ratio (LNR) may have independent prognostic value in colon carcinoma. Purpose:To evaluate the impact of LNR on overall survival in colon cancer patients with fewer than 12 or 12 examined nodes or more. Methods:Patients (n = 36,712) with node-positive nonmetastatic colon cancer diagnosed between 1992 and 2004 were identified from the Surveillance, Epidemiology, and End Results database and stratified according to LNR and number of nodes examined. Survival was estimated by Kaplan-Meier method, and differences analyzed by log-rank test. A Cox proportional hazards model was used for multivariate analysis. Results:Patients with fewer than 12 nodes were older and male and had lower primary tumor stage, grade, and N stage (P < 0.01). Survival appeared greater with 12 total nodes examined or more (median 53 vs. 66 months, P < 0.001). Within each LNR stratum, survival with 12 nodes or more was improved for those with less than 10% of nodes positive for cancer, but was worse with higher LNRs (P < 0.01). Lymph node ratio was significantly associated with survival independent of total nodes (HR 1.24–5.12, P < 0.001). Other significant factors included age, race, tumor grade, stage, location, and N stage. Conclusion:Metastatic LNR independently estimates survival in Stage III colon cancer, irrespective of number of nodes examined. However, statistically significant differences in each LNR stratum between those with resection of fewer than 12 or 12 nodes or more would indicate that a 12-node minimum may still be necessary for accurate staging.

Negligible Effect of Selective Preoperative Biliary Drainage on Perioperative Resuscitation, Morbidity, and Mortality in Patients Undergoing Pancreaticoduodenectomy

OBJECTIVE To examine the effect of selective preoperative biliary drainage (BD) on perioperative resuscitation, morbidity, and mortality in patients undergoing pancreaticoduodenectomy. Biliary drainage prior to pancreaticoduodenectomy remains controversial. Proponents argue that it facilitates referral to high-volume tertiary centers, while detractors maintain that it increases surgical morbidity and mortality. DESIGN Retrospective analysis of single-institution tumor registry database. SETTING University medical center. PATIENTS From October 1, 2003, to May 31, 2008, 90 patients underwent pancreaticoduodenectomy for periampullary mass lesions. MAIN OUTCOME MEASURES Clinicopathologic data were reviewed and analyzed among patients who did and did not receive BD for their association with perioperative outcomes. chi(2) Analysis, independent-samples t tests, and Mann-Whitney U tests were used as appropriate. RESULTS Fifty-six patients (62%) underwent BD, and 34 (38%) did not. Intraoperative bile cultures were positive for 1 or more species of microorganisms in 88% of stented patients (35 of 40). There were no significant differences in fluid requirements, transfusion requirements, or surgery duration between patients who did and did not undergo BD. Estimated blood loss was increased in patients who received BD (625 mL vs 525 mL in patients who did not undergo BD; P = .03), while reoperation was significantly more common in nonstented patients (4% vs 15% in patients who did not undergo BD; P = .02). Intensive care unit stay, overall length of stay, pancreatic leak/abscess/fistula, infectious complications, postoperative percutaneous drainage, hospital readmission, and 30- and 90-day mortality were not significantly different between the 2 groups. CONCLUSIONS Although preoperative biliary stents may complicate the intraoperative management and lessen the postoperative complications of patients undergoing pancreaticoduodenectomy, only estimated blood loss and reoperation were significantly different in this cohort. Further study may reveal patient subgroups who may specifically benefit or suffer from preoperative biliary stenting. Currently, selective preoperative BD appears appropriate in the multidisciplinary management of patients with periampullary lesions.

Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer

PURPOSE To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). METHODS AND MATERIALS Seven breast cancer physicians from the University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. RESULTS Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having ≤ 10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk. CONCLUSIONS In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within the University of California Athena Breast Health Network.