Search

Background: Currently, complete lymph node dissection (CLND) is recommended after identification of a metastatic lymph node by sentinel lymph node biopsy (SLNB). Guidelines suggest that CLND should be performed as a separate procedure, and a sufficient number of nodes should be examined. Our objective was to examine the utilization, timing, and adequacy of CLND for melanoma in the United States., Methods: From the National Cancer Data Base, patients diagnosed with stage I to III melanoma during 2004-2005 were identified. Multiple logistic regression was used to assess factors associated with CLND utilization, timing (separate operation from SLNB), and adequacy (examination of > or = 10 nodes)., Results: Of the 44,548 patients identified, 47.5% were pathologic stage IA, 23.8% stage IB, 14.1% stage II, and 14.6% stage III. Of the 17% (2942 of 17,524) with nodal metastases on SLNB, only 50% underwent a CLND. Patients were significantly less likely to undergo a CLND after SLNB if > 75 years old or had lower extremity melanomas. Of the patients who underwent a CLND, only 42% underwent the CLND at a separate procedure after the SLNB. Of those who underwent a CLND, 69.2% had > or = 10 nodes examined. Patients were significantly less likely to have > or = 10 nodes examined if they were > 75 years old or had lower extremity melanomas. Patients treated at NCCN/NCI-designated centers were significantly more likely to undergo nodal evaluation in concordance with established guidelines., Conclusions: Only half of patients with sentinel node-positive melanoma underwent CLND. Quality surveillance measures are needed to monitor, standardize, and improve the care of patients with malignant melanoma.

Background: Pancreatic neuroendocrine tumors (PNET) have a poorly defined natural history, and a staging system is not available. The objective of this study was to identify factors predicting survival after pancreatectomy for PNETs and to establish a postresection prognostic score., Patients and Methods: From the National Cancer Data Base (1985-2004), patients were identified who underwent PNET resection. Multivariable Cox proportional hazards modeling was used to assess the impact of patient, tumor, treatment, and hospital factors on survival. A prognostic score based on the predictive factors from the Cox model was developed., Results: Three thousand eight hundred fifty-one patients underwent resection for PNETs. Five-year overall survival was 59.3%, and the 10-year survival was 37.7%. On multivariable analysis, age, grade, distant metastases, tumor functionality, and type of resection were independent predictors of survival after resection of PNETs (P < 0.0001). Gender, race, socioeconomic status, tumor size, nodal status, margins, adjuvant chemotherapy, and hospital volume were not associated with survival. Age, grade, and distant metastases were the most significant predictors of survival and were incorporated into a PNET postresection prognostic score. The prognostic score correlated with outcomes and offered excellent survival discrimination by each of the 3 score subgroups: 76.7%, 50.9%, and 35.7% (P < 0.0001). The concordance index was 0.63 (95% CI 0.59-0.67), indicating reasonable agreement between actual outcomes and that predicted by the prognostic score., Conclusions: The prognostic score can be used to predict outcomes, guide adjuvant treatment, and stratify patients for clinical trials.

Background: Studies have demonstrated improved survival when 12 or more nodes are examined for colon cancer. The elderly comprise a major proportion of patients with colon cancer, but it is unknown if examination of 12 or more nodes is appropriate for older patients. Our objective was to assess differences in lymph node evaluation by age and to determine whether adequate nodal evaluation (12 or more nodes) is associated with improved survival in the elderly., Study Design: From the National Cancer Data Base (1998 to 2004), we identified 142,009 N0M0 patients who underwent colectomy for adenocarcinoma. Logistic regression was used to determine whether age is associated with adequate nodal examination. Multivariable modeling stratified by age was used to determine whether evaluation of 12 or more nodes is associated with improved survival., Results: The median number of nodes examined was similar with increasing age (less than 67 years: 11 nodes; 67 to 78 years: 10 nodes; greater than 78 years: 10 nodes). Patients older than 78 years underwent evaluation of 12 or more nodes less frequently than patients less than 67 years old: 47.7% versus 41.4% (p < 0.0001). When adjusted for patient, tumor, treatment, and hospital characteristics, patients greater than 78 years were less likely to have 12 or more nodes examined (odds ratio 0.68, 95% CI 0.65 to 0.70, p < 0.0001). Regardless of age, patients who had 12 or more nodes examined had better survival than those with less than 12 nodes examined (p < 0.0001)., Conclusions: The elderly account for nearly half of patients with colon cancer. Older patients undergo inadequate lymph node evaluation more frequently than younger patients do. Improving lymph node evaluation will result in more accurate pathologic staging for the elderly.

Purpose: Adequate lymph node evaluation is important to stage colon cancers and make adjuvant treatment decisions. Studies have demonstrated improved survival when >or= 12 nodes are examined. Our objective was to assess differences in the adequacy of nodal evaluation for right vs. left colon cancers., Methods: From the National Cancer Data Base (1998-2004), 142,009 N0M0 colon cancer patients were identified. Logistic regression was used to evaluate the number of nodes examined for right vs. left colectomies. Multivariable modeling was used to determine the impact of examining >or= 12 nodes on survival., Results: Of 142,009 patients, 79,444 (56 percent) had right colectomies, and 62,565 (44 percent) patients had left colectomies. More nodes were examined during right colectomies than left (median 12 vs. 8, P<0.0001). When adjusted for patient, tumor, and hospital factors, patients undergoing left colectomy were less likely to have >or= 12 nodes identified (P<0.0001). Patients were more likely to have >or= 12 nodes identified for right and left colon cancers at high-volume hospitals. Survival was better with examination of >or= 12 nodes for right and left colon cancers (P < 0.0001)., Conclusions: Evaluating >or= 12 nodes for right and left colon cancers is a feasible, clinically relevant, and modifiable factor that will likely improve patient outcomes.

Background: Despite guidelines that recommend total thyroidectomy for papillary thyroid cancer (PTC) greater than or equal to 1 cm, the extent of surgery remains controversial. We examined surgical practice patterns for PTC greater than or equal to 1 cm and identified factors that predict the use of total thyroidectomy., Methods: Of 90,382 patients in the National Cancer Center Data Base (NCDB) with PTC from 1985 to 2003, 57,243 patients had tumors greater than or equal to 1 cm and underwent total thyroidectomy or lobectomy. Trends in extent of surgery for PTC were examined over 2 decades. Logistic regression was used to identify factors that predict use of total thyroidectomy compared with lobectomy., Results: Use of total thyroidectomy increased from 70.8% in 1985 to 90.4% in 2003 (P < .0001). Patients were less likely to undergo total thyroidectomy if they were black, older than 45 years, had Medicare, had lower household incomes, or had less education (P < .0001). Moreover, patients treated at high-volume or academic centers were more likely to undergo total thyroidectomy than were patients examined at low-volume or community hospitals (P < .0001)., Conclusions: Use of total thyroidectomy for PTC greater than or equal to 1 cm increased over time. Differences in use of total thyroidectomy are related to patient, tumor, and hospital factors and likely reflect disparities in access to care.

Background: With increasing frequency, studies using cancer registries have evaluated the treatment effect of adjuvant radiation; however, these analyses generally do not include chemotherapy treatment data. Our objective is to evaluate the potential impact the absence of adjuvant chemotherapy data has on the estimated survival benefit attributed to adjuvant radiation therapy., Methods: Using the National Cancer Data Base, patients were identified who underwent surgery for cancers that often require radiation therapy: breast, esophageal, gastric, pancreatic, and rectal cancer. Cox proportional hazards modeling with and without chemotherapy as a predictor variable was used to assess the impact of radiation therapy on 5-year survival., Results: From 1998 to 1999, 295,206 patients underwent surgical resection for one of five cancers. Chemotherapy administration ranged from 27.5% for gastric to 56.1% for rectal cancer. For cancers where chemotherapy affected survival, the impact of radiation therapy was overestimated in the multivariate model when chemotherapy was not included. For example, radiation treatment for rectal cancer was associated with a 31% decrease in the risk of death in the model that did not control for chemotherapy; however, the addition of chemotherapy to the model resulted in only a 14% decrease in the risk of death associated with receiving radiation therapy., Conclusions: For selected tumor sites, the administration of chemotherapy is not evenly distributed among patients receiving and not receiving radiation. Survival analyses that do not include chemotherapy administration overestimate the beneficial impact of radiation on survival. Evaluating the effect of radiation on survival retrospectively without adjusting for chemotherapy administration should be done cautiously.

The natural history of pancreatic neuroendocrine tumors (PNET) remains poorly defined. Our objectives were to examine the clinicopathologic features of PNETs, to assess treatment trends over time, and to identify factors associated with undergoing resection. From the National Cancer Data Base (1985-2004), 9,821 patients were identified with PNETs. Clinicopathologic features and treatment trends were examined. Multivariable logistic regression was used to assess factors associated with undergoing resection. Of 9,821 patients with PNETs, 85% were nonfunctional, 7.1% were functional, and 7.9% were carcinoid tumors. Of the 3,851 (39.0%) patients who underwent pancreatectomy, 449 (11.7%) received adjuvant chemotherapy, and 254 (6.6%) received adjuvant radiation. From 1985 to 2004, utilization of pancreatectomy increased from 39.4 to 44.3% (P < 0.0001). Patients were less likely to undergo resection if they were > 55 years old, had tumors in the head of the pancreas, tumors > or = 4 cm, or had distant metastases (P < 0.0001). Patients treated at NCCN/NCI, academic, or high-volume hospitals were more likely to undergo resection. There are disparities in the utilization of pancreatectomy for PNETs. As PNETs have a better prognosis than adenocarcinoma, concerns regarding the morbidity and mortality of pancreatic surgery and neoplasms should not preclude resection.

Background: National efforts are underway to monitor the quality of patient care at Veterans Administration (VA) hospitals. The objective of this study was to examine treatment utilization and outcomes for localized pancreatic cancer at VA compared with non-VA hospitals., Methods: Using the National Cancer Data Base, patients with pretreatment clinical stage I/II pancreatic adenocarcinoma were identified. Treatment utilization and outcomes were assessed at VA compared with academic and community hospitals., Results: Of 35,009 patients, 2% were seen at VA, 38% at academic, and 54% at community hospitals. VA hospitals were more likely to use surgery (odds ratio 2.20, 95% confidence interval 1.73-2.79) and to administer adjuvant chemotherapy (odds ratio 1.77, confidence interval 1.28-2.46) compared with community hospitals. Adjusted perioperative mortality and 3-year survival rates after surgery were similar at VA and academic hospitals., Conclusions: For localized pancreatic cancer, patients treated at VA hospitals receive stage-specific treatments and have risk-adjusted perioperative and long-term survival rates that are comparable with those for patients treated at academic centers.

Purpose: To evaluate the experience with pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) at a single academic institution., Methods: A prospective pancreatic database was reviewed and identified 43 patients with IPMN who were managed operatively. Clinicopathologic features and predictors of outcome were examined. The World Health Organization pathologic classification of IPMN was utilized., Results: IPMN was diagnosed in 21% of patients who underwent pancreatic resection for solid or cystic mass lesions. Ninety-five percent of patients were symptomatic. Patients were managed with total pancreatectomy, pancreaticoduodenectomy, distal pancreatectomy, central pancreatectomy, or enucleation. Nine patients had adenomas, 14 had borderline neoplasms, 10 had carcinoma in situ, and 9 had invasive carcinoma. Overall, 23 patients (53%) had lesions with main duct involvement. Frozen section transection margins were positive for malignancy in 2 patients. With a mean follow-up of 17 months, the 5-year disease-specific survival for patients with main duct involvement was 67%. The 5-year disease-specific survival for patients with benign lesions was 100%, and 61% for patients with malignant lesions (P = .02). The presence of symptoms, increased CA 19-9, and tumor size were not predictive of malignancy. Increased serum bilirubin concentrations were predictive of malignancy (P = .03). Main duct involvement was also associated with malignancy (P < .02)., Conclusions: Cancer is found in 65% of patients with IMPN involving the main duct. Based on our data, patients with symptomatic, main duct involvement, especially those with an increased serum bilirubin, should be offered resection. Alternatively, patients with side branch IPMN may be managed conservatively.

Background: The American Joint Committee on Cancer (AJCC) 6(th) edition staging system for pancreatic adenocarcinoma specifically excludes pancreatic neuroendocrine tumors (PNETs), and a widely accepted staging classification does not exist. Our objective was to evaluate the feasibility of applying the AJCC pancreatic adenocarcinoma staging system to PNETs., Study Design: Patients with PNETs were identified from the National Cancer Data Base (1985 to 2004). Overall survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards modeling was used to evaluate the effect of tumor size, nodal status, and distant metastases on survival., Results: Of 4,793 patients with PNETs, 93.6% were of islet cell origin, and 6.4% were carcinoid tumors; 1,815 (37.9%) underwent resection. Overall 5-year survival rates were 29.2% for all patients, 55.4% for resected patients, and 15.6% for unresected patients. The AJCC staging system provided good prognostic survival discrimination between stage groups for resected patients (p < 0.0001). When comparing outcomes to those of patients with pancreatic adenocarcinoma, the estimated median survival was significantly better for resected patients with PNETs (60 versus 13 months, p < 0.0001). Distant metastasis was the only independent predictor of survival (p < 0.0001)., Conclusions: When applied to PNETs, the AJCC staging system for pancreatic adenocarcinoma provides survival discrimination by stage for surgical and nonsurgical patients. Survival rates are better for PNETs than for pancreatic adenocarcinoma, but the staging system can effectively stratify patients with PNETs.

Background: Despite decreased perioperative morbidity and mortality and clinical trials suggesting improved outcomes with adjuvant therapy, national practice patterns in the management of pancreatic cancer remain poorly defined. The purpose of the current study was to evaluate multimodality therapy utilization and outcomes relative to hospital type and volume., Methods: Using the National Cancer Data Base, stage-specific treatment patterns were analyzed for 301,033 patients with pancreatic adenocarcinoma. Logistic regression was used to evaluate treatment utilization. Cox proportional hazards modeling was utilized to evaluate the effect of multimodality therapy on survival., Results: Stage at presentation did not differ from 1985-1994 to 1995-2003; however, the percentage of patients receiving cancer-directed treatment increased from 45.1% to 51.8% (P < .001). Pancreatectomy for localized disease (AJCC 6th edition stages I and II) increased from 36.9% to 49.3% (P < .001). After resection, the use of adjuvant chemotherapy alone increased from 4.1% to 5.7% (P < .001), but the use of adjuvant radiation alone decreased from 7.0% to 4.6% (P < .001). Adjuvant chemoradiation use increased from 26.8% to 38.7% (P < .001). The use of surgery alone decreased from 62.1% (5213 of 8400 cases) to 49.9% (10,807 of 21,679 cases) (P < .001). Patients with localized pancreatic cancer were more likely to receive pancreatectomy and adjuvant chemoradiation at academic and high-volume centers (P < .001). Survival for localized disease was better after surgery with adjuvant therapy (hazards ratio [HR], 0.44; 95% confidence interval [95% CI], 0.42-0.47) and surgical resection alone (HR, 0.54; 95% CI, 0.52-0.57) compared with no treatment., Conclusions: To the authors' knowledge, the current study is the largest study regarding pancreatic cancer performed to date, and the first to investigate national practice patterns for multimodality therapy utilization. Multimodality therapy utilization has increased over time and appears to have a beneficial impact on survival., ((c) 2007 American Cancer Society.)

Background: The extent of surgery for papillary thyroid cancers (PTC) remains controversial. Consensus guidelines have recommended total thyroidectomy for PTC > or =1 cm; however, no study has supported this recommendation based on a survival advantage. The objective of this study was to examine whether the extent of surgery affects outcomes for PTC and to determine whether a size threshold could be identified above which total thyroidectomy is associated with improved outcomes., Methods: From the National Cancer Data Base (1985-1998), 52,173 patients underwent surgery for PTC. Survival was estimated by the Kaplan-Meier method and compared using log-rank tests. Cox Proportional Hazards modeling stratified by tumor size was used to assess the impact of surgical extent on outcomes and to identify a tumor size threshold above which total thyroidectomy is associated with an improvement in recurrence and long-term survival rates., Results: Of the 52,173 patients, 43,227 (82.9%) underwent total thyroidectomy, and 8946 (17.1%) underwent lobectomy. For PTC <1 cm extent of surgery did not impact recurrence or survival (P = 0.24, P = 0.83). For tumors > or =1 cm, lobectomy resulted in higher risk of recurrence and death (P = 0.04, P = 0.009). To minimize the influence of larger tumors, 1 to 2 cm lesions were examined separately: lobectomy again resulted in a higher risk of recurrence and death (P = 0.04, P = 0.04)., Conclusions: The results of this study demonstrate that total thyroidectomy results in lower recurrence rates and improved survival for PTC > or =1.0 cm compared with lobectomy. This is the first study to demonstrate that total thyroidectomy for PTC > or =1.0 cm improves outcomes.

Background: With the development of stage-specific treatments for pancreatic cancer, controversies exist concerning optimal clinical and pathologic staging. The most recent edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 6(th) Edition included some notable modifications. In anticipation of the 7(th) edition's publication, the authors evaluated the predictive ability of the current pancreatic adenocarcinoma staging system., Methods: By using the National Cancer Data Base (1992-1998), 121,713 patients were identified with pancreatic adenocarcinoma. All patients were restaged by AJCC 6(th) edition guidelines. Stage-specific overall survival was estimated by using the Kaplan-Meier method and compared with log-rank tests. Concordance indices were calculated to evaluate the discriminatory power of the staging system. Cox modeling was used to determine the relative impact of T, N, and M classification on survival., Results: For all patients, there was 5-year survival discrimination by stage (P < .0001). For patients who underwent pancreatectomy, stage predicted 5-year survival: stage IA, 31.4%; IB, 27.2%; IIA, 15.7%; IIB, 7.7%; III, 6.8%; IV, 2.8% (P < .0001). The concordance index for the staging system was 0.631 for all patients, 0.613 for those who underwent pancreatectomy, and 0.596 for patients who did not undergo resection. In patients who underwent pancreatectomy, tumor size, nodal status, and distant metastases were independent predictors of survival (P < .0001)., Conclusions: This is the first large-scale validation of the pancreatic cancer staging system. AJCC 6(th) edition staging guidelines are accurate with respect to survival. Further investigation is needed to integrate new molecular and biochemical markers into the staging scheme.

Background: Despite studies demonstrating improved outcomes, pessimism persists regarding the effectiveness of surgery for pancreatic cancer. Our objective was to evaluate utilization of surgery in early stage disease and identify factors predicting failure to undergo surgery., Methods: Using the National Cancer Data Base (1995-2004), 9559 patients were identified with potentially resectable tumors (pretreatment clinical Stage I: T1N0M0 and T2N0M0). Multivariate models were employed to identify factors predicting failure to undergo surgery and assess the impact of pancreatectomy on survival., Results: Of clinical Stage I patients 71.4% (6823/9559) did not undergo surgery; 6.4% (616/9559) were excluded due to comorbidities; 4.2% (403/9559) refused surgery; 9.1% (869/9559) were excluded due to age; and 38.2% (3,644/9559) with potentially resectable cancers were classified as "not offered surgery." Of the 28.6% (2736/9559) of patients who underwent surgery, 96.0% (2630/2736) underwent pancreatectomy, and 4.0% (458/2736) had unresectable tumors. Patients were less likely to undergo surgery if they were older than 65 years, were black, were on Medicare or Medicaid, had pancreatic head lesions, earned lower annual incomes, or had less education (P < 0.0001). Patients were less likely to receive surgery at low-volume and community centers. Patients underwent surgery more frequently at National Cancer Institute/National Comprehensive Cancer Network-designated cancer centers (P < 0.0001). Patients who were not offered surgery had significantly better survival than those with Stage III or IV disease but worse survival than patients who underwent pancreatectomy for Stage I disease (P < 0.0001)., Conclusions: This is the first study to characterize the striking underuse of pancreatectomy in the United States. Of early stage pancreatic cancer patients without any identifiable contraindications, 38.2% failed to undergo surgery.

Objective: To determine the optimal number of lymph nodes to examine for accurate staging of node-negative pancreatic adenocarcinoma after pancreaticoduodenectomy., Design, Setting, and Patients: Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program (1988-2002) were used to identify 3505 patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreas, including 1150 patients who were pathologically node negative (pN0) and 584 patients with a single positive node (pN1a). Perioperative deaths were excluded. Univariate and multivariate survival analyses were performed., Main Outcome Measure: Examination of 15 lymph nodes appears to be optimal for accurate staging of node-negative adenocarcinoma of the pancreas after pancreaticoduodenectomy., Results: The number of nodes examined ranged from 1 to 54 (median, 7 examined nodes). Univariate survival analysis demonstrated that dichotomizing the pN0 cohort on 15 or more examined lymph nodes resulted in the most statistically significant survival difference (log-rank chi(2) = 14.49). Kaplan-Meier survival curves demonstrated a median survival difference of 8 months (P < .001) in favor of the patients who had 15 or more examined nodes compared with patients with fewer than 15 examined nodes. Multivariate analysis validated that having 15 or more examined nodes was a statistically significant predictor of survival (hazard ratio, 0.63; 95% confidence interval, 0.49-0.80; P < .0001). Furthermore, a multivariate model based on the survival benefit of each additional node evaluated in the pN0 cohort demonstrated only a marginal survival benefit for analysis of more than 15 nodes. Approximately 90% of the pN1a cohort was identified with examination of 15 nodes., Conclusions: Examination of 15 lymph nodes appears to be optimal to accurately stage node-negative adenocarcinoma of the pancreas after pancreaticoduodenectomy. Furthermore, evaluation of at least 15 lymph nodes of a pancreaticoduodenectomy specimen may serve as a quality measure in the treatment of pancreatic adenocarcinoma.

Introduction: Resveratrol is a phenolic compound found in grape skins, mulberries, and certain nuts that has been shown to have antitumorigenic and anti-inflammatory properties. Macrophage inhibitory cytokine (MIC-1) is a member of the transforming growth factor beta (TGF-beta) superfamily that has been shown to have antitumorigenic activity and is up-regulated in resveratrol-treated cancer cells. Resveratrol inhibits proliferation of human pancreatic cancer cells; however, the exact mechanism of action is not known. In this study, we investigated the role of MIC-1 in resveratrol-induced growth inhibition of human pancreatic cancer cell lines., Methods and Results: Proliferation assays conducted with resveratrol-treated human pancreatic cancer cell lines (CD18 and S2-013) at 24, 48, and 72 h revealed inhibition of cell proliferation compared to controls. Using oligonucleotide microarray analysis, we identified marked up-regulation of MIC-1 gene expression in resveratrol-treated human pancreatic cancer S2-013 cells. Real-time RT-PCR performed in CD18 and S2-013 cells treated with resveratrol (0-100 mum) for 24 h confirmed concentration and time-dependent up-regulation of expression of one particular gene, MIC-1. Both cell lines pretreated with actinomycin D (a transcriptional inhibitor) and then resveratrol had reduced up-regulation of MIC-1 gene expression compared to those treated with resveratrol alone. Finally, resveratrol-induced growth inhibition was abolished in CD18 cells transfected with MIC-1 short interfering RNA., Conclusions: Resveratrol up-regulates MIC-1 gene expression in part at the transcriptional level in pancreatic cancer cells. Furthermore, MIC-1 appears to play a key role in resveratrol-induced growth inhibition in these cells.

Background: Sentinel lymph node (SLN) biopsy has become a standard of care for axillary lymph node staging in breast cancer and appears suitable for virtually all patients with clinically node-negative (cN0) invasive disease. However, its role in Paget's disease of the breast, a condition in which invasion may or may not be present, remains undefined., Methods: Among 7,083 consecutive SLN biopsy procedures, we retrospectively identified 39 patients with Paget's disease of the breast. Nineteen patients had no associated clinical/radiographic features ("Paget's only"), and 20 patients had associated clinical/radiographic findings ("Paget's with findings")., Results: The mean ages for the Paget's alone and with findings groups were 63.6 and 49.6 years, respectively. The use of breast conservation therapy was 32% in the Paget's alone group and 10% in the Paget's with findings group. Invasive carcinoma was found in 27% of patients in the Paget's alone group and 55% of patients in the Paget's with findings group. The success rate of SLN biopsy was 98%, and the mean number of SLNs removed was 3 in both groups. In the entire cohort of Paget's disease, 28% (11/39) of the patients had positive SLNs (11%, Paget's alone; 45%, Paget's with findings)., Conclusion: In our "Paget's only" cohort, invasive cancer was found in 27% of cases and positive SLNs in 11%. SLN biopsy should be considered in all patients with Paget's disease of the breast, whether associated clinical/radiographic findings are present.

Background: Metastatic gastric cancer has a dismal prognosis. We identified a subset of patients where surgical resection with therapeutic intent was undertaken in the setting of known metastatic disease., Methods: Review of a prospectively maintained database of gastric cancer patients at a single institution over a 19-year period was performed., Results: Thirty-seven patients with metastatic disease known prior to resection with therapeutic intent were identified out of 3384 patients with gastric cancer (1%). Twelve patients had positive peritoneal cytology as the only evidence of metastasis, 21 had gross metastasis limited to peritoneal surfaces, one had peritoneal and ovarian metastasis, one had liver metastasis, one had retropancreatic lymph node metastasis, and one had a malignant pleural effusion. Thirty-six patients (97%) received chemotherapy prior to resection, and 30 (81%) received postoperative chemotherapy. The median time from diagnosis to resection was 4.5 months (range 1-22) in patients receiving preoperative chemotherapy. Median survival was 12 months after resection with no three-year survivors. Predictors of worse prognosis were cytologic or pathologic evidence of persistent metastatic disease at the time of resection or at laparoscopy within six weeks of resection (P < .01), N3 disease (P = .03), and total gastrectomy or additional organ resection (P = .04). Metastatic disease as evidenced by cytology only was not associated with improved prognosis., Conclusions: Highly selected patients with metastatic gastric cancer undergoing surgical resection with therapeutic intent have a relatively poor prognosis. Persistent detectable metastatic disease after preoperative chemotherapy portends a particularly poor prognosis.

Background: Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro., Results: Apigenin caused both time- and concentration-dependent inhibition of DNA synthesis and cell proliferation in four pancreatic cancer cell lines. Apigenin induced G2/M phase cell cycle arrest. Apigenin reduced levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25, which are all proteins required for G2/M transition., Conclusion: Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer.

High-volume centers have low morbidity and mortality after pancreaticoduodenectomy (PD). Less is known about treatment pathways and their influence on intensive care unit (ICU) utilization. Patients who underwent PD at a tertiary cancer center during the five-year period between January 1998 and December 2003 were identified from a prospective database. Preoperative and intraoperative factors relating to ICU admission and outcome were analyzed. Five hundred ninety-one pancreaticoduodenectomies were performed during the study period. Of these, 536 patients had complete records for analysis. Of the 536 patients, 51 (10%) were admitted to the ICU after surgery. Admission to the ICU was associated with decreased overall survival (P < .0001). Of the preoperative predictors of ICU admission, serum creatinine, albumin, and increased body mass index (BMI) were associated with ICU admission (P = .02, .05, and .002, respectively). Age, blood glucose, diagnosis of diabetes mellitus, and chronic obstructive pulmonary disease were not predictive of ICU admission on univariate analysis. Of the intraoperative factors, longer operative time and estimated blood loss (EBL) correlated with ICU admission (P = .003 and .0001, respectively). On multivariate analysis, only preoperative BMI and intraoperative EBL were independent predictors of ICU admission (P = .03 and .003, respectively). Patients with a preoperative BMI greater than 30 had a substantially higher risk of ICU admission (relative risk 2.4). The majority of patients who undergo PD do not require admission to the ICU. Factors most associated with ICU admission after PD are increased preoperative BMI and intraoperative blood loss.

Background: Recent studies suggest local excision may be acceptable treatment of T1 adenocarcinoma of the rectum, but there is little comparative data with radical surgery to assess outcomes and quantify risk. We performed a retrospective evaluation of patients with T1 rectal cancers treated by either transanal excision or radical resection at our institution to assess patient selection, cancer recurrence, and survival., Methods: All patients who underwent surgery for T1 adenocarcinomas of the rectum (0-15 cm from anal verge) by either transanal excision (TAE) or radical resection (RAD) between January 1987 and January 2004 were identified from a prospective database. Data were analyzed using Fisher exact test, Kaplan-Meier method, and log-rank test., Results: Three hundred nineteen consecutive patients with T1 lesions were treated by transanal excision (n = 151) or radical surgery (n = 168) over the 17-year period. RAD surgery was associated with higher tumor location in the rectum, slightly larger tumor size, a similar rate of adverse histology, and a lymph node metastasis rate of 18%. Despite these features, patients who underwent RAD surgery had fewer local recurrences, fewer distant recurrences, and significantly better recurrence-free survival (P = 0.0001). Overall and disease-specific survival was similar for RAD and TAE groups., Conclusion: Despite a similar risk profile in the 2 surgical groups, patients with T1 rectal cancer treated by local excision were observed to have a 3- to 5-fold higher risk of tumor recurrence compared with patients treated by radical surgery. Local excision should be reserved for low-risk cancers in patients who will accept an increased risk of tumor recurrence, prolonged surveillance, and possible need for aggressive salvage surgery. Radical resection is the more definitive surgical treatment of T1 rectal cancers.

Commonly performed elective surgical procedures on the alimentary tract are carried out with low morbidity and low mortality in most hospitals in the United States. There are some procedures on the alimentary tract that are performed with a relatively low frequency and are associated with higher mortality. Volume is a surrogate marker associated with improved outcome, with relative differences being dependent on the complexity of the procedure and the frequency with which it is done. Both surgeon and institutional volume matters, but it seems that improved operative mortality can be reached with lower surgeon volume in high-volume institutions. It appears that volume can be substituted in part for by specialization and training, with improved outcomes based on specialist credentials and fellowship training.

Background: This study evaluated the influence of hand dominance on skill acquisition during a basic laparoscopic skills curriculum., Methods: A total of 27 surgical residents (5 postgraduate year 3 [PGY-3] and 22 PGY-2 residents) participated in a 4-week laparoscopic skills curriculum. The residents were pre- and posttested on six laparoscopic tasks during weeks 1 and 4. During weeks 2 and 3, the residents attended a proctored practice session. The results were compared using analysis of variance (ANOVA), (with significance determined by a p value less than 0.05., Results: The posttest scores were significantly higher than the pretest scores. On the pretest, lefthand-dominant (LHD) surgeons (n = 4) performed significantly better than righthand-dominant (RHD) surgeons (n = 23). In the analysis of individual task pretest scores, LHD surgeons performed significantly better on pattern cutting and vessel loop application. Posttest analysis of overall performance did not show significant differences between the RHD and LHD surgeons., Conclusions: Participation in a laparoscopic skills curriculum improved overall performance. The LHD surgeons demonstrated better initial performance, but posttest comparison showed no difference between the two groups.

The liver is a common site of hematogenous metastasis. In the past, patients with liver metastases were often deemed inoperable, and medical therapy conferred only minor survival benefit. However, advances in surgical techniques and chemotherapeutic agents during the past two decades have led to effective treatments for selected patients with metastases to the liver. Up to approximately 80% of the liver can be resected, and partial hepatectomy is now routinely performed with a perioperative mortality rate of <5%. Surgical resection of colorectal cancer metastatic to the liver results in a 5-year survival rate of 40%. These results are expected to improve even further with multimodality approaches that include newer chemotherapy regimens. Liver metastases from other primary tumors, such as neuroendocrine carcinoma and genitourinary tumors, are also treated effectively with liver resection. The indications for surgical treatment of liver metastases are broadening as a variety of novel therapies are being developed, including hepatic artery embolization, hepatic artery infusion of chemotherapy, and radiofrequency ablation.

Background: The Patient Self-Determination Act requires that patients entering hospitals be asked if they have an advance directive. This has led to increased awareness of advance directives, yet surgeons have paid little attention to their use among patients undergoing even major surgery. We sought to evaluate the use of advance directives in patients undergoing pancreaticoduodenectomy and esophagectomy., Methods: Patients undergoing these operations between 1996 and 2001 at a university teaching hospital were identified and reviewed for statement of advance directive, its presence in the chart, and impact on patient care., Results: A total of 252 patients met inclusion criteria. The number of patients with an advance directive increased, but had little impact on patient care., Conclusions: More patients having major surgery have advance directives, but the number present in the medical record remains low. Further attention to advance directives would foster increased communication between surgeons and patients and extend patient autonomy.

Background: Lymphatic mapping with sentinel lymphadenectomy (SL) has become more widely used as an alternative to axillary dissection for the staging of breast cancer. This study was conducted to evaluate the potential associations of patient and tumor characteristics with the lymphatic mapping failure rate., Study Design: Between September 1996 and April 2003, 1,094 breast cancer patients participated in a single-institution prospective SL protocol, which was conducted using technetium 99 m sulfur colloid alone to identify sentinel lymph nodes. During the validation phase, consisting of the first 80 patients, all patients had SL followed by axillary dissection. Beginning with the 81st patient, the standard technique consisted of radiolabeled colloid injection in a peritumoral distribution 16 to 24 hours before the operation, followed by SL alone for node-negative patients., Results: Of 1,094 consecutive patients, 62 (5.7%) did not map. Patients having more than 10 involved lymph nodes had a significantly higher incidence of mapping failure (40.9%) than those who were node-negative (5.3%) (odds ratio = 9.19, p = 0.002). Age was a factor predictive of mapping failure for node-negative patients 70+ years of age (odds ratio = 3.14, p = 0.018). Biopsy technique, tumor size, tumor location, cell type, and surgeon experience were not predictors of mapping failure, regardless of node status., Conclusions: The lymphatic mapping failure rate was associated with both anatomic and pathologic factors. Patients with extensive nodal involvement had a significantly greater chance of mapping failure. Among node-negative patients, those who were older were more likely to have mapping failure than those who were younger, suggesting that decreased breast density in postmenopausal women might provide an anatomic explanation for nonmapping.

We previously reported stable transfection of estrogen receptor alpha (ERalpha) into the ER-negative MDA-MB-231 cells (S30) as a tool to examine the mechanism of action of estrogen and antiestrogens [J. Natl. Cancer Inst. 84 (1992) 580]. To examine the mechanism of ERbeta action directly, we have similarly created ERbeta stable transfectants in MDA-MB-231 cells. MDA-MB-231 cells were stably transfected with ERbeta cDNA and clones were screened by estrogen response element (ERE)-luciferase assay and ERbeta mRNA expression was quantified by real-time RT-PCR. Three stable MDA-MB-231/ERbeta clones were compared with S30 cells with respect to their growth properties, ability to activate ERE- and activating protein-1 (AP-1) luciferase reporter constructs, and the ability to activate the endogenous ER-regulated transforming growth factor alpha (TGFalpha) gene. ERbeta6 and ERbeta27 clones express 300-400-fold and the ERbeta41 clone express 1600-fold higher ERbeta mRNA levels compared with untransfected MDA-MB-231 cells. Unlike S30 cells, 17beta-estradiol (E2) does not inhibit ERbeta41 cell growth. ERE-luciferase activity is induced six-fold by E2 whereas neither 4-hydroxytamoxifen (4-OHT) nor ICI 182, 780 activated an AP-1-luciferase reporter. TGFalpha mRNA is induced in response to E2, but not in response to 4-OHT. MDA-MB-231/ERbeta clones exhibit distinct characteristics from S30 cells including growth properties and the ability to induce TGFalpha gene expression. Furthermore, ERbeta, at least in the context of the MDA-MB-231 cellular milieu, does not enhance AP-1 activity in the presence of antiestrogens. In summary, the availability of both ERalpha and ERbeta stable breast cancer cell lines now allows us to compare and contrast the long-term consequences of individual signal transduction pathways.

Background: The finding of coexisting nodular thyroid disease during neck exploration for hyperparathyroidism (HPT) is reported to range from 20%-60%. Thus, the surgeon may encounter a second, unrelated lesion during open parathyroidectomy. Furthermore, with the recent introduction of minimally invasive surgery for HPT, the entire neck may not be explored, and it is important to know the potential risk of missing significant, concurrent thyroid disease. The diagnosis and timely treatment of associated thyroid abnormalities is desirable because a delay in operating would result in increased morbidity associated with a second neck exploration., Design: We examined our 25-year experience at a large tertiary academic medical center, to determine the incidence and type of concurrent thyroid disease seen in patients with HPT. The computerized records of the Department of Pathology, from 1974-1999, were reviewed for patients with primary HPT who underwent surgery., Results: A review of records from 580 patients who underwent surgery for primary HPT showed 103 (18%) patients with concomitant thyroid disease at surgery. All 103 underwent thyroid resection at the time of parathyroidectomy. Thyroid histology showed: 12 (12%): well-differentiated papillary carcinomas, 31 (30%): follicular adenomas, 49 (48%): nodular hyperplasias, 8 (8%): chronic lymphocytic thyroiditis, 1 benign cyst, 1 metastasis, and 1 normal., Conclusions: Synchronous thyroid disease was found in 18% of primary HPT patients undergoing surgery, and 12% of thyroid lesions were malignant. The overall malignancy rate was 2%. All primary malignancies found were papillary carcinomas, of which 7 of 12 (58%) were microcarcinomas. The significant association of simultaneous pathology in the two glands justifies preoperative thyroid imaging and fine-needle aspiration (FNA) biopsy to determine the best surgical approach for patients with HPT.

Background: The availability of laparoscopic adrenalectomy led us to review our experience and management of adrenal and extraadrenal pheochromocytoma., Methods: Seventeen patients undergoing pheochromocytoma resection from January 1997 to August 2001 were categorized as open, laparoscopic, or laparoscopic assisted depending on the surgical approach. Hospital records were reviewed., Results: There was no significant difference between the groups in patient age, weight or preoperative blockade. Operative times for open, laparoscopic, and laparoscopic assisted adrenalectomies were 202, 218, and 260 minutes, respectively. Estimated blood loss was 562 cc, 187 cc, and 925 cc. The average hospital length of stay was 6.2, 3.0, and 5.8 days., Conclusions: Laparoscopic removal resulted in longer operative times than open, but less operative blood loss and a shorter hospital stay. The laparoscopic assisted approach did not save time nor did it lead to earlier discharge. Laparoscopic adrenalectomy was comparable to the open approach, and is preferential in tumors less than 6 cm. An open approach remains our choice for larger or extraadrenal tumors.

Drug resistance to tamoxifen (Tam) is a significant clinical problem but the mechanism through which this occurs remains elusive. We have developed a number of xenograft models of Tam-stimulated growth that model breast cancer progression using estrogen receptor positive MCF-7 or T47D breast cancer cells. When estrogen-stimulated T47D:E2 tumors are treated long term with Tam, Tam-stimulated tumors develop (T47D:Tam) that are stimulated by both estrogen and Tam. When HER-2/neu status is determined, it is clear that the T47D:Tam tumors express significantly higher levels of HER-2/neu protein by immunohistochemistry and mRNA as measured by real-time RT-PCR. The T47D:Tam tumors also express higher levels of estrogen receptor and progesterone receptor protein than their estrogen-stimulated T47D:E2 counterparts. We compared out results to the MCF-7 model of Tam-stimulated growth. The MCF-7:Tam ST (estrogen- and Tam-stimulated) and MCF-7:Tam LT (estrogen-inhibited, Tam-stimulated) were bilaterally transplanted to account for any mouse to mouse variation and characteristic growth patterns were observed. TUNEL staining was performed on MCF-7:Tam LT treated with either estrogen or Tam and it was concluded that estrogen-inhibited tumor growth was a result of increased apoptosis. Three phases of tumor progression are described that involve increases in HER-2/neu expression, de-regulation of estrogen receptor expression and increases in apoptosis which in concert determine the phenotype of drug resistance to Tam.

The recognition of a new group of drugs, now named selective estrogen receptor modulators (SERMs) has revolutionized prospects for the prevention of breast cancer. New agents will continue to be tested against tamoxifen, the first SERM and an established treatment of ER positive breast cancer. Raloxifene a related SERM is used to treat and prevent osteoporosis with the potential beneficial side effect of preventing breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial will establish whether raloxifene is an improvement over tamoxifen. Most importantly, emerging information about the molecular pharmacology of SERMs will be used to decipher the mechanism of action at specific target sites around a woman's body. This knowledge can be used to design new SERMs and advance the prospects for multifunctional medicine to prevent breast cancer, osteoporosis and coronary heart disease.

Amino acid Asp-351 in the ligand binding domain of estrogen receptor alpha (ERalpha) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ERalpha complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor alpha target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ERalpha. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ERalpha allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ERalpha complex with the complete loss of estrogen-like activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ERalpha expression vectors. Profound differences in the agonist and antagonist actions of Ralcenter dotERalpha complexes were noted only in stable transfectants. The agonist activity of the Ralcenter dotERalpha complex was enhanced with D351E and D351Y ERalpha, but raloxifene lost its agonist activity with D351F ERalpha. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ERalpha. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ERalpha complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ERalpha complex.

This review explores the recent experience with, and the basis for, the use of selective estrogen receptor modulators to treat and prevent breast cancer. As new agents are unveiled, they will continue to be tested against tamoxifen. A number of new selective estrogen receptor modulators are in clinical development in an attempt to decrease the unwanted effects of tamoxifen. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. Additionally, two different classes of hormonal agents, the aromatase inhibitors and estrogen receptor down-regulators, which have no estrogen-like properties at any site, appear to be promising new treatments for advanced breast cancer.

Purpose: Resistance to tamoxifen (TAM) represents a significant challenge to the management of breast cancer. We previously reported that the estrogen receptor (ER)-negative hormone-independent T47D:C42 cell line has both elevated protein kinase Calpha (PKCalpha) protein expression and basal activator protein-1 activity compared with the parental ER+ (hormone-dependent) T47D:A18 cell line. Stable transfection of PKCalpha to the T47D:A18 breast cancer cell line results in increased basal activator protein-1 activity, reduced ER function, increased proliferation rate, and hormone-independent growth (Tonetti et al., Br. J. Cancer, 83: 782-791, 2000). In this report, we further characterize the role of PKCalpha overexpression in vivo to elucidate a possible molecular mechanism of tamoxifen resistance., Experimental Design: To determine whether the T47D:A18/PKCalpha cell line would produce hormone-independent tumors in athymic mice, we injected T47D:A18, T47D:A18/neo, or the T47D:A18/PKCalpha20 cell clones bilaterally into the mammary fat pads of athymic mice. Tumor growth was evaluated following treatment with estradiol (E2), TAM, and the pure antiestrogen, ICI 182,780., Results: Mice receiving either T47D:A18 or T47D:A18/neo cells produced tumors that grew in response to E2 treatment, whereas the untreated control and TAM-treated groups showed no tumor growth. Interestingly, mice receiving the T47D:A18/PKCalpha20 clone produced tumors in both the control and TAM groups, whereas tumor growth was inhibited in mice treated with E2. PKCalpha was also overexpressed in an MCF-7 tumor model that also exhibited TAM-stimulated and E2-induced regression., Conclusions: These results suggest that overexpression of PKCalpha in breast tumors results in hormone-independent tumor growth that cannot be inhibited by TAM treatment. Furthermore, the finding that E2 has an antitumor effect on breast tumors overexpressing PKCalpha is a novel observation that may have important therapeutic implications.

Hospital stays for thyroid and parathyroid surgery have decreased significantly with selected patients staying under 8 hours. Strategies to recognize hypocalcemia postoperatively vary. We examined timed postoperative calcium levels to determine how long one needs to monitor patients for hypoparathyroidism. We analyzed 120 consecutive patients having total/near-total thyroidectomy and/or parathyroidectomy between April 1998 and October 1999. Total and ionized serum calcium levels were obtained at 8, 16, and 22 hours postoperatively. Strict criteria for significant hypoparathyroidism were defined as a symptomatic patient, a total calcium value of less than 7.2 mg/dL, or an ionized calcium value of less than 1.0 mmol/L. Eighteen patients (15%) met criteria for hypocalcemia. The 8-hour ionized calcium level identified 40 per cent of those that needed supplementation. With the inclusion of the 16-hour ionized calcium value 94.5 per cent of patients who met criteria were identified. Of the 74 patients who had not previously received calcium at 22 hours after surgery only one patient with hypocalcemia was identified. Serial calcium values postoperatively add to the costs associated with an overnight hospital stay. In addition to clinical examination an ionized calcium level 16 hours postoperatively is sufficient to identify significant hypoparathyroidism in the majority of patients.

Tamoxifen is a valuable therapeutic agent with applications in the treatment and prevention of breast cancer. However, the development of drug resistance limits the usefulness of tamoxifen therapy. One form of drug resistance in breast cancer is tamoxifen-stimulated growth. We have addressed a mechanism how the tamoxifen-estrogen receptor (ER) complex can convert from being a blocking to stimulatory signal in breast cancer. We have described an effective assay system to study the action of antiestrogen-ER complex through the activation of transforming growth factor alpha gene in situ. The MDA-MB-231 breast cancer cells were stably transfected with cDNAs for wtER (D351), mutant Asp351Tyr ER (D351Y) and mutant Asp351Gly ER (D351G). The D351Y ER can enhance the estrogenic properties of 4OHT and change the pharmacology of raloxifene by converting it from antiestrogen to estrogen. We hypothesized that alterations in the charge of amino acid (aa) 351, and changes in the interaction with the side chain of an antiestrogen, are critical for the subsequent estrogenicity of the complex. Our goal was (1) to modulate the estrogenicity of the antiestrogen-ER complex by different aa substitutions at position 351 and (2) to examine the role of alterations in the side chain of antiestrogens on the estrogenicity of the complex. Substitution of tyrosine for aspartate at aa351 results in increased estrogenicity for a series of tamoxifen derivatives-ER complexes and the conversion of EM 652-ER and GW 7604-ER complexes from antiestrogenic to estrogen-like. Substitution of glycine for aspartate at aa 351 results in the conversion of 4OHT-ER complex from estrogen-like to antiestrogenic. We propose that the side chain of antiestrogens either neutralizes or displaces the charge at aspartate 351 thereby removing a charged site for the opportunistic binding of a novel coactivator. If no charge is present (D351G) then no coactivator can bind and the complex with any antiestrogen is not estrogen-like. However, if the charge is extended beyond the reach of an antiestrogen side chain (D351Y), then the coactivators bind and compounds are estrogen-like. The establishment of a relationship between the structure of the antiestrogen-ER complex and its function will enhance the development of novel compounds with unique biological activities and potentially avoid premature drug resistance.

The active metabolite of tamoxifen, 4-hydroxytamoxifen (4-OHT), is used in the laboratory for mechanistic studies of antiestrogen action. This compound binds to the estrogen receptor alpha (ER) and silences activating function 2 (AF2) in the ligand binding domain, but activating function 1 (AF1) at the other end of the ER remains constitutive and is considered to be ligand independent. Amino acid D351 in the ligand binding domain appears to be critical for interactions with the antiestrogenic side chain of antiestrogens. We have devised an assay to evaluate the biological activity of 351 mutant ERs and antiestrogens at the transforming growth factor alpha (TGFalpha) gene in situ (J. I. MacGregor Schafer et al., Cancer Res., 59: 4308-4313, 1999). The substitution of glycine for aspartate at position 351 results in the conversion of the 4-OHT:ER complex from estrogen-like to completely antiestrogenic. In cells stably expressing D351G ER, the ER retains responsiveness to estradiol (E2) and also retains antiestrogenic responsiveness to both raloxifene and ICI 182,780. The relative binding affinity of E2 for D351G ER (0.77 +/- 0.17 x 10(-9) M) is comparable with wild-type ER (0.42 +/- 0.08 x 10(-9) M). In addition, the D351G ER retains the ability to bind SRC-1 in the presence of E2, thus D351G ER AF2 activity has not been compromised. We also used a cell line stably expressing an ER with a triple mutation in helix 12 (D538A, E542A, and D545A) that ablated AF2 activity, which resulted in decreased effects of E2, suggesting that both AF1 and AF2 activity are required for maximal estrogen activity in MDA-MB-231 cells. Interestingly, the triple mutation also completely reduced the estrogen-like actions of 4-OHT. We propose that a specific mutation at amino acid 351 can allosterically silence AF1 in the 4-OHT:ER complex by either preventing the binding of coactivators or encouraging the binding of a corepressor molecule. We suggest that the 4-OHT-specific site responsible for estrogen-like actions can be referred to as AF2b. This binding site would consist of at least four carboxylic acids at amino acids 351 and 538, 542 and 545 in helix 12 to permit coactivator docking for gene activation. The AF2b site is distinct from AF2 for E2 action. Further studies will provide insight into the estrogen-like actions of tamoxifen in select tissues and breast tumors and identify a significant mechanism of drug resistance to tamoxifen.

The estrogen receptor (ER)-positive MCF-7 breast cancer cell line can be transplanted into athymic mice and grown into tumors with estradiol (E2) support. Tamoxifen (TAM) blocks E2-stimulated tumor growth; however, continuous TAM treatment results in transplantable tumors within a year that will grow with either E2 or TAM (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988). Although this model may represent the development of TAM resistance for the treatment of advanced breast cancer, no laboratory model exists to study the exposure of breast cancer to 5 years of adjuvant TAM therapy. We have addressed this issue and report the development and characterization of two tumor lines, MCF-7TAM and MT2, which have been serially transplanted into TAM-treated athymic mice for >5 years. The MCF-7TAM tumor rapidly regresses in response to E2 and then about 50% of tumors regrow in response to E2. Interestingly, tumor regression does not occur if TAM treatment is stopped, probably because E2 levels are too low in ovariectomized athymic mice. The development of the antitumor effect of E2 was documented for MT2 tumors over a 1-year period; TAM-stimulated tumor growth was retained, but E2 caused progressively less of a stimulatory effect. Most importantly, E2-stimulated tumors that regrew after initial tumor regression in both MCF-7TAM and MT2 lines were again responsive to TAM to block E2-stimulated growth. Unlike MCF-7 tumors, the MT2 tumor line contains a single point mutation, Asp351Tyr, in the ER, which was retained after the development of E2-stimulated regrowth. The mutation is associated with increased estrogen-like actions for the TAM-ER complex (A. S. Levenson et al., Br. J. Cancer, 77: 1812-1819, 1998), but we conclude that the mutant ER is not required for TAM resistance. On the basis of the new breast cancer models presented, we propose a cyclic sensitivity to TAM that may have important clinical implications: (a) it is possible that a woman's own estrogen may produce an antitumor effect on the presensitized micrometastatic disease after 5 years of TAM. Long-term antitumor action occurs because the drug is stopped, but resistance accumulates and tumors start to grow if adjuvant therapy is continued; and (b) although in the clinic TAM-resistant tumors respond to second-line therapies that cause estrogen withdrawal, e.g., pure antiestrogens or aromatase inhibitors, estrogen therapy may also be effective and return the tumor to TAM responsiveness. In this way, a hormone-responsive tumor may be controlled longer in the patient with advanced disease.

This commentary explores the recent experience with and the basis for the use of selective estrogen receptor modulators (SERMs) to prevent breast cancer. Chemoprevention has been a goal for many years. As newer agents are unveiled, they will continue to be tested against tamoxifen, the current standard for the treatment and prevention of breast cancer. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. The Study of Tamoxifen and Raloxifene (STAR) trial and prior prevention studies will be discussed in an attempt understand the bridge from the laboratory to the clinic.

Chondritis of the ear is a late sequela of deep partial thickness burns of the face. It is the purpose of this article to describe two patients who came to the emergency department 21 days and 35 days after sustaining deep partial thickness burns of the face from explosions. The patients were hospitalized for incision and drainage of the infected wound that included excision of the infected cartilage complemented by systemic antibiotic therapy.

Grease burns to the hand represent a serious and preventable hazard. These injuries account for over 10% of all major burns seen in the emergency department. These burns occur when the cook attempts to move a pan with burning cooking oil and inadvertently spills the oil on the hand holding the pan. These burns are usually full thickness because of either the high temperatures of the flaming oils or the subsequent ignition of clothing. This article describes a patient who received severe partial and full thickness burns to the dominant hand following a grease burn in the domestic setting. Prevention through improved consumer education and warning labels for cooking oils should reduce the incidence of these serious injuries.

Title III of the Americans with Disabilities Act (ADA) requires that hospitals and burn centers be designed and constructed so that all public and common-use areas are accessible. At least 10% of patient bedrooms and toilets must be accessible to persons with mobility disorders. The purpose of this study was to determine whether four hospitals with burn centers complied with Title III of the ADA. The burn centers agreed to participate in this study only if they were first assured anonymity, because of the Health Care Financing Administration of the U.S. Department of Health and Human Services requires that each hospital comply. With use of the ADA accessibility guidelines, we developed a survey instrument that was validated by a state government building inspector. This tool was used to inspect the burn center facility and common use areas in four hospitals with burn centers. In the four hospitals, numerous architectural barriers to persons with disabilities were noted. No burn center had a designated accessible room for persons with disabilities. The bedrooms, bathrooms, sinks, bathtubs, and toilets were not accessible to persons with disabilities. The common-use areas in the hospitals, in contrast, had few architectural barriers to persons with disabilities. Only one burn center had plans to eliminate architectural barriers in its hospital. Because the four hospitals with burn centers had numerous architectural barriers for persons with disabilities, it can be concluded they do not comply with Title III of the ADA and are subject to severe penalty from the Health Care Financing Administration and the U.S. Department of Justice.

This retrospective analysis of arthroplasty of the first metatarsophalangeal joint documents the incidence of surgery as well as the selection of the commercially available implants. During a 1-year period, 1994, arthroplasties were performed in 47 of the 1.7 million subscribers to Trigon Blue Cross Blue Shield of Virginia. Women received the majority of the arthroplasties (83%). Of the 47 cases, the silicone implant was predominantly used (83%). The most common indications for arthroplasty were hallux valgus (30%) and hallux rigidus (28%). Podiatrists performed 79% of the procedures, while orthopedic surgeons performed the remaining 21% of the cases. A prospective study is needed that will assess the long-term performance of the different implants.

The metatarsophalangeal joint of the great toe often requires an arthroplasty to correct joint disease and pain. Today, joint replacement systems are combinations of components manufactured to optimize biological ingrowth, mechanical interlock, press fit, and cementing. Three different types of arthroplasties are available to foot surgeons: the double stem hinged silicone implant, the two-component joint mimicking implant, and a hemi-implant available for the phalanx. No comprehensive studies on very large populations have been conducted to accurately evaluate the beneficial long-term effects of these implants. This review article describes the development of the toe arthroplasty, details the commercially available implants, and addresses the advantages and adverse effects of each implant.

This report describes the design, operation, and biomechanical performance of the Auto Suture Multifire Graftac-S disposable surgical staplers and absorbable tacks. The performance of this reloadable stapler has been compared to that of the Auto Suture Multifire Premium disposable skin stapler. The Premium stapler forms stainless steel staples to close the wound. The Graftac-S ejects absorbable tacks into the graft from a cartridge, which can be reloaded during a single operation. In two clinical trials of 10 patients each, the Graftac-S delivered absorbable tacks which were biocompatible and successfully secured the graft to the wound. The most obvious advantage of this device is that it obviates the need to remove the staples from the wound later. By the tenth postoperative day, about 90% of the tacks had extruded spontaneously, thereby reducing the amount of postoperative care required; discomfort to the patient during removal of the stainless steel staples is eliminated.