Lester W. Johnson

Prospective Study of Eukaryotic Initiation Factor 4E Protein Elevation and Breast Cancer Outcome

ObjectiveTo validate the authors’ initial hypothesis-generating observation that eukaryotic initiation factor 4E (eIF4E) protein elevation predicts a higher cancer recurrence rate in patients with stage 1 to 3 breast cancer. Summary Background DataTumor size and nodal status continue to be the two most important independent prognostic markers in breast cancer, despite well-documented limitations. In a previous smaller retrospective study, eIF4E, important in the regulation of protein synthesis of mRNAs with long or complex 5′ untranslated regions, appeared promising as an independent predictor of breast cancer recurrence. MethodsSpecimens and clinical data from 191 patients with stage 1 to 3 breast cancer were accrued prospectively. Data collected include stage of disease, tumor grade, age at diagnosis, and menopausal status. Endpoints measured were disease recurrence and cancer-related death. eIF4E protein level was quantified using Western blot analysis. Immunohistochemical staining was used to determine estrogen receptor, progesterone receptor, and HER-2/ neu receptor status. Statistical analysis include Cox proportional hazards model, log-rank test, Kaplan-Meier survival curve, Fisher exact test, and t test. ResultsPatients were divided into three groups based on tertile distribution of eIF4E: low, defined as less than 7.5-fold elevation (n = 64); intermediate, defined as 7.5- to 14-fold elevation (n = 61); and high, defined as more than 14-fold elevation (n = 66). The relative risk for cancer recurrence with intermediate elevation was 4.1 times that of patients with low elevation. For patients with high elevation, the relative risk for recurrence was higher, at 7.2 times that of the low group. The relative risk for cancer-related death for high elevation was 7.3 times that of patients with low eIF4E. Using multivariate analysis, high eIF4E remained an independent predictor of cancer recurrence after adjusting for tumor size, tumor grade, nodal disease, estrogen receptor status, progesterone receptor status, and menopausal status. ConclusionsHigh eIF4E is an independent predictor of cancer recurrence in patients with stage 1 to 3 breast cancer. The relative risk for cancer recurrence increases with eIF4E protein elevation. High eIF4E elevation is also associated with an increased relative risk for cancer-related death.

High Chemokine Receptor CXCR4 Level in Triple Negative Breast Cancer Specimens Predicts Poor Clinical Outcome

INTRODUCTION Basal-like tumors or triple negative breast cancers are those that lack hormone-receptor and HER-2 expressions. They are considered to be aggressive tumors, and molecular mechanism to account for this is poorly understood. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that high CXCR4 overexpression level in cancer specimens predicts a poor outcome in patients with triple negative breast cancers. METHODS One hundred fifty-one patients with triple negative breast cancers were prospectively accrued and analyzed. All had undergone standardized treatment and surveillance protocols. From each specimen, CXCR4 levels were detected using Western blots. Results were quantified against 1 microg of HeLa cells (positive controls). CXCR4 expression was defined as high (>or=6-fold) or low (<6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. RESULTS At a median follow-up of 37 mo, patients whose tumors had high CXCR4 overexpression (>or=6-fold) had a significantly higher incidence of cancer recurrence (P=0.014) and cancer-related death (P=0.026) than those in the low CXCR4 group (<6-fold). After adjusting for tumor size and nodal status, the relative risk for cancer recurrence and death in the high CXCR4 group was 2.1-fold (P=0.007; 95% CI: 1.22 to 3.8) and 2-fold (P=0.047; 95% CI: 1.01 to 4.06) higher than those in the low CXCR4 group, respectively. CONCLUSION High CXCR4 overexpression in cancer specimens predicts a worse outcome in patients who have triple negative breast cancer.

High eIF4E, VEGF, and microvessel density in stage I to III breast cancer.

Objective:In a prospective trial, to determine if eIF4E overexpression in breast cancer specimens is correlated with VEGF elevation, increased tumor microvessel density (MVD) counts, and a worse clinical outcome irrespective of nodal status. Summary and Background Data:In vitro, the overexpression of eukaryotic initiation factor 4E (eIF4E) up-regulates the translation of mRNAs with long 5′-untranslated regions (5′-UTRs). One such gene product is the vascular endothelial growth factor (VEGF). Methods:A total of 114 stage I to III breast cancer patients were prospectively accrued and followed with a standardized clinical surveillance protocol. Cancer specimens were quantified for eIF4E, VEGF, and MVD. Outcome endpoints were cancer recurrence and cancer-related death. Results:eIF4E overexpression was found in all cancer specimens (mean ± SD, 12.5 ± 7.6-fold). Increasing eIF4E overexpression correlated with increasing VEGF elevation (r = 0.24, P = 0.01, Spearmans coefficient), and increasing MVD counts (r = 0.35, P < 0.0002). Patients whose tumor had high eIF4E overexpression had shorter disease-free survival (P = 0.004, log-rank test) and higher cancer-related deaths (P = 0.002) than patients whose tumors had low eIF4E overexpression. Patients with high eIF4E had a hazard ratio for cancer recurrence and cancer-related death of 1.8 and 2.1 times that of patients with low eIF4E (respectively, P = 0.009 and P = 0.002, Cox proportional hazard model). Conclusions:In breast cancer patients, increasing eIF4E overexpression in the cancer specimens correlates with higher VEGF levels and MVD counts. Patients whose tumors had high eIF4E overexpression had a worse clinical outcome, independent of nodal status. Thus, eIF4E overexpression in breast cancer appears to predict increased tumor vascularity and perhaps cancer dissemination by hematogenous means.

A Prospective Trial on Initiation Factor 4E (eIF4E) Overexpression and Cancer Recurrence in Node-Positive Breast Cancer

Objective:A previous study of patients with stage I to III breast cancer showed that those patients whose tumors were in the highest tertile of eIF4E overexpression experienced a higher risk for recurrence. This study was designed to determine whether high eIF4E overexpression predicts cancer recurrence independent of nodal status by specifically targeting patients with node-positive disease. Methods:The prospective trial was designed to accrue 168 patients with node-positive breast cancer to detect a 2.5-fold increase in risk for recurrence. eIF4E level was quantified by Western blots as x-fold elevated compared with breast tissues from noncancer patients. End points measured were disease recurrence and cancer-related death. Statistical analyses performed include survival analysis by the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Results:One hundred seventy-four patients with node-positive breast cancer were accrued. All patients fulfilled study inclusion and exclusion criteria, treatment protocol, and surveillance requirements, with a compliance rate >95%. The mean eIF4E elevation was 11.0 ± 7.0-fold (range, 1.4–34.3-fold). Based on previously published data, tertile distribution was as follow: 1) lowest tertile (<7.5-fold) = 67 patients, 2) intermediate tertile (7.5–14-fold) = 54 patients, and 3) highest tertile (>14-fold) = 53 patients. At a median follow up of 32 months, patients with the highest tertile had a statistically significant higher cancer recurrence rate (log-rank test, P = 0.002) and cancer-related death rate (P = 0.036) than the lowest group. Relative risk calculations demonstrated that high eIF4E patients had a 2.4-fold increase in relative risk increase for cancer recurrence (95% confidence interval, 1.2–4.1; P = 0.01). Conclusions:In this prospective study designed to specifically address risk for recurrence in patients with node-positive breast cancer, the patients whose tumors were in the highest tertile of eIF4E overexpression had a 2.4-fold increase in relative risk for cancer recurrence. Therefore, eIF4E overexpression appears to be an independent predictor of a worse outcome in patients with breast cancer independent of nodal status.

Race/Ethnicity Has No Effect on Outcome for Breast Cancer Patients Treated at an Academic Center with a Public Hospital

Background: African American women have a higher breast cancer mortality rate than Caucasian women. To understand this difference, socioeconomic status (SES) needs to be controlled, which can be achieved by evaluating outcome within a population that is underinsured or low SES. We elected to examine the effect of race/ethnicity on outcome of patients with operable breast cancer by evaluating outcome in a population with low SES and similar access to care. Methods: From a prospective breast cancer database created in 1998, we examined outcome for 786 patients with stage 0 to III breast cancer treated up to September 2008. Patients were treated at Louisiana State University Health Sciences Center in Shreveport and E.A. Conway Hospital and the majority received standard definitive surgery as well as appropriate adjuvant treatment. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, Cox proportional hazards model, independent-samples t test, and χ2 test. P ≤ 0.05 was considered statistically significant. Results: Sixty percent of patients were African American and over two thirds of patients were classified as either free care or Medicaid. The 5-year overall survival (OS) for African American and Caucasian patients was similar (81% and 84%, respectively; P = 0.23). On multivariate analysis, race/ethnicity was not an independent predictor of OS (P = 0.5); OS for the entire cohort was comparable with what was reported in the National Cancer Data Base. Conclusion: In a predominantly indigent population, race/ethnicity had no effect on breast cancer outcome. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2157–61)

Potential utility of sentinel node biopsy in the original surgical assessment of Hürthle cell tumors of the thyroid: 23-year institutional review of Hürthle cell neoplasms

Great difficulty still exists in determining the potential malignancy of Hürthle cell tumors of the thyroid gland. Indications for the extent of resection vary greatly in the reported literature. Sentinel node biopsy has shown its usefulness as a prognostic indicator in both melanoma and breast cancer. The feasibility of using it as an integral part of Hürthle cell tumor surgery was investigated and is discussed.

Chemokine receptor CXCR4 overexpression predicts recurrence for hormone receptor-positive, node-negative breast cancer patients.

BACKGROUND The expected outcome for hormone receptor-positive, node-negative patients should be favorable. However, some patients do develop metastatic disease and the mechanism for this observation is poorly understood. CXCR4 is a chemokine receptor that has been implicated to play a pivotal role in breast cancer growth and metastasis. Its predictive role has not been fully evaluated. We determined to see whether CXCR4 can predict outcome in this subset of patients. METHODS We accrued and analyzed data from 101 patients with hormone receptor-positive, node-negative breast cancers. The CXCR4 level was detected using Western blots and its level was defined as either low (<6.6-fold) or high (≥6.6-fold). Primary end points were systemic cancer recurrence and death. Statistical analysis performed included Spearmans correlation, Kaplan-Meier survival analysis, and Cox proportional hazard model. RESULTS Although benign breast tissues had an undetectable level of CXCR4, all 101 cancer specimens had overexpressed CXCR4 (mean 6.4 ± 3.4-fold). There were 79 patients in the low CXCR4 group and 22 patients in the high CXCR4 group. High CXCR4 overexpression was predictive of both cancer recurrence (P = .002) and overall survival (P = .0012). CONCLUSION High CXCR4 overexpression in primary tumors was predictive of worse outcomes in hormone receptor-positive, node-negative breast cancer patients.

The Role of Whole-Body Fluorine-18-FDG Positron Emission Tomography in the Detection of Recurrence in Symptomatic Patients with Stages II and III Breast Cancer

BackgroundThe role of whole-body fluorine-18-FDG positron emission tomography (FDG-PET) as an adjunct localize recurrence in stages II and III breast cancer patients who present with clinical suspicion for recurrence is not well established. We report our experience in such a patient population.MethodsA retrospective review of all patients with stages II and III breast cancer who had a whole-body FDG-PET scan was performed.ResultsOf the 23 patients who fit the criteria, 9 had stage II and 14 had stage III breast cancer. Overall sensitivity, specificity, and accuracy were 81%, 100%, and 87%, respectively. Positive and negative predictive values for stages II and III were 100% and 83%, respectively, and 100% and 50%, respectively. FDG-PET detected two recurrences that were missed by conventional imagings, but such recurrences were local and amenable for biopsy.ConclusionsIn patients with stages II and III breast cancer who present with a suspicion for recurrent disease, a whole-body FDG-PET scan may be a useful adjunct in the evaluation of recurrence. However, its added benefit over conventional imaging should be questioned.

A contemporary experience of open aortic reconstruction in patients with chronic atherosclerotic occlusion of the abdominal aorta

OBJECTIVE To examine and report surgical results from a contemporary experience of open abdominal aortic reconstruction in patients with chronic atherosclerotic abdominal aortic occlusion (CAAAO). METHODS Between January 1999 through May 2010, 54 patients with CAAAO were identified and retrospectively reviewed. CAAAOs were categorized into infrarenal aortic occlusions (IRAOs) and juxtarenal aortic occlusions (JRAOs) based on superior extension of thrombus and requirement for supra-renal aortic clamping to repair. Morbidity, mortality, hospital stay, and operative variables were assessed. The χ2 or Fisher test and the Wilcoxon rank sum test were used to compare demographic and operative variables between two aortic occlusion groups (IRAO and JRAO). Univariate and multivariate analyses were performed to assess factors associated with surgical outcomes and hospital stay. The Kaplan-Meier method was used to calculate survival and patency rates. RESULTS Fifty patients underwent aortic reconstructions with aorto-bifemoral or iliac bypass, and three underwent a remote axillo-femoral bypass procedure. There were 35 (64.8%) males, and 19 (35.2%) females. Median age was 51.9 years (range, 32-72 years). Of the two CAAAO groups, there were 20 IRAOs and 33 JRAOs. Aorto-renal thromboendartectomy was performed in 26 (49.1%) patients; 26 (75.8%) among JRAOs versus 1 (5%) of IRAOs (P<.01). Proximal aortic clamps were required in 28 (85%) of JRAOs and 3 (15%) of IRAOs (P<.01). Thirty-day and in-hospital mortality was zero. Median length of hospital stay was 7 days (range, 4 to 66 days), and median intensive care unit length of stay was 3 days (range, 1-22 days). Complications included cardiopulmonary dysfunction in four (8%), postoperative renal insufficiency in 10 (18.9%), and other postoperative complications in 15 (28.3%). All 10 with renal insufficiency recovered renal function to baseline creatinine or a creatinine value<1.1 mg/dL. Mean increases in right and left ankle-brachial indicess were 0.54±0.25 and 0.59±0.22, respectively. On univariate analysis, coronary artery disease and African American race were predictors of postoperative complications (P=.048). Age was significantly associated with total complications. Patients with postoperative complications and/or renal insufficiency were older than those without such complications (P=.02) Independent predictors of prolonged hospital stay were intraoperative blood replacement (P=.003), postoperative complications (P<.01), and postoperative renal insufficiency (P<.01). Prolonged intensive care unit stay was predicted by JRAO (P=.04), postoperative complications (P=.02), and postoperative renal insufficiency (P=.013). Survival at 3, 5, and 7 years were 86.6%, 76.5% and 50.9%, respectively. The reduced survival rates were predicted by previous myocardial infarction and existing coronary artery disease (P<.01). CONCLUSION Abdominal aortic reconstruction is a safe method for treating CAAAO with low associated morbidity and mortality. Aorto-renal thromboendartectomy with supra-renal aortic clamping and aortic replacement remains an effective treatment for those with significant pararenal aortic disease, and can be performed without significant renal impairment.

Delayed small bowel perforation following blunt abdominal trauma: A case report and review of the literature

We report a case of delayed presentation of a small bowel perforation following blunt abdominal trauma (BAT). An initial computed tomography (CT) scan revealed that the patient (a 32-year-old man) had a mesenteric hematoma, which was managed conservatively. Four weeks later, he returned to the hospital complaining of abdominal pain. A CT scan of the abdomen showed a thickened loop of the small bowel adjacent to the mesenteric hematoma at the level of the ileum. He was discharged home, but re-presented with acute abdomen 6 weeks post-trauma. An exploratory laparotomy was performed, which showed a perforated thickened loop of the ileum forming a phlegmon in the lower abdomen. In the English medical literature, only eight other reports of delayed post-traumatic presentation of ileal/jejunal perforation following BAT have been reported. We propose that post-traumatic intestinal perforation be considered in the differential diagnosis even in patients who experience a delayed small bowel perforation following BAT.