Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway.

The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to up-regulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage.

Advanced glycation end products activate a chymase-dependent angiotensin II-generating pathway in diabetic complications.

BACKGROUND: Angiotensin II is a key mediator of diabetes-related vascular disease. It is now recognized that in addition to angiotensin-converting enzyme, chymase is an important alternative angiotensin II-generating enzyme in hypertension and diabetes. However, the mechanism of induction of chymase in diabetes remains unknown. METHODS AND RESULTS: Here, we report that chymase is upregulated in coronary and renal arteries in patients with diabetes by immunohistochemistry. Upregulation of vascular chymase is associated with deposition of advanced glycation end products (AGEs), an increase in expression of the receptor for AGEs (RAGE), and activation of ERK1/2 MAP kinase. In vitro, AGEs can induce chymase expression and chymase-dependent angiotensin II generation in human vascular smooth muscle cells via the RAGE-ERK1/2 MAP kinase-dependent mechanism. This is confirmed by blockade of AGE-induced vascular chymase expression with a neutralizing RAGE antibody and an inhibitor to ERK1/2 and by overexpression of the dominant negative ERK1/2. Compared with angiotensin-converting enzyme, chymase contributes to the majority of angiotensin II production (>70%, P<0.01) in response to AGEs. Furthermore, AGE-induced angiotensin II production is blocked by the anti-RAGE antibody and by inhibition of ERK1/2 MAP kinase activities. CONCLUSIONS: AGEs, a hallmark of diabetes, induce chymase via the RAGE-ERK1/2 MAP kinase pathway. Chymase initiates an important alternative angiotensin II-generating pathway in diabetes and may play a critical role in diabetic vascular disease.

HER-2/neu and CD117 (c-kit) overexpression in patients with pesticide exposure and extensive stage small cell lung carcinoma (ESSCLC).

BACKGROUND: The rate of detection of HER-2/neu and CD117 (c-kit) overexpression in small cell lung cancer (SCLC) has varied widely; between 5-35% and 21-70% respectively. METHODS: To evaluate the relationship between pesticide exposure and HER-2/neu and CD117 overexpression in extensive stage SCLC (ESSCLC), we identified patients with ESSCLC and assessed pesticide exposure using a predetermined questionnaire. An exposure index (hours/day x days/year x years) > or = 2400 hours was considered as 'exposed.' HER-2/neu overexpression was evaluated on archival tissue using the DAKO Hercep test, and CD117 testing was performed using immunohistochemistry (A4052 polyclonal antibody). RESULTS: 193 ESSCLC patients were identified. Pesticide exposure data could be obtained on 174 patients (84 females and 109 males) with a mean age of 68.5 years. 53/174 (30.4%) revealed HER-2/neu overexpression. 54/174 (31.03%) specimens showed CD117 overexpression by IHC. On multivariate analysis, HER-2/neu overexpression was associated with diminished survival (p < 0.001). In comparison, CD117 expression did not have an adverse prognostic value (p = 0.025). 41/53 (77.4%) patients with HER-2/neu overexpression and 47/121 (38.8%) patients without overexpression had exposure to pesticides (odds ratio: 5.38; p < 0.01). Among the cohort tested for CD117, 29/54 (53.7%) patients with CD117 overexpression and 59/120 (49.2%) patients without CD117 overexpression had pesticide exposure (odds ratio: 1.18; p = 0.12). CONCLUSION: Pesticide exposure affects HER-2/neu but not CD117 overexpression. Future studies are needed to determine specific pesticide(s)/pesticide components that are responsible for HER-2/neu overexpression in ESSCLC, and to validate our findings in other solid tumors that overexpress HER-2/neu.

Effect of pesticide exposure on HER-2/neu overexpression seen in patients with extensive stage small cell lung carcinoma.

PURPOSE: The aim of this study was to evaluate the relationship, if any, between pesticide exposure and overexpression of the HER-2/neu oncoprotein in extensive stage small cell lung cancer (ESSCLC). EXPERIMENTAL DESIGN: The records of all patients with a diagnosis of ESSCLC from January 1991 through April 2001 were reviewed in our retrospective study. Pesticide risk (herbicide and insecticide) was assessed by telephone interviews using a predetermined questionnaire with emphasis on type of exposure, use of protective measures, and duration of exposure. An exposure index was calculated (h/day x days/year x years), and patients with an index > 2400 h were considered as exposed. HER-2/neu overexpression was assessed by immunohistochemistry using the Hercep test developed by Dako. Statistical analysis was performed using SPSS-10. RESULTS: A total of 193 patients (84 females and 109 males), with a mean age of 68.5 years (range, 42-90 years) were included in the study. Of these, 57 (29.5%) revealed HER-2/neu overexpression by immunohistochemistry. After adjusting for age, smoking, Eastern Cooperative Oncology Group score, and treatment, HER-2/neu overexpression was associated with a statistically significant diminished survival (P < 0.001; Mann-Whitney U test). We contacted 53 of 57 patients with overexpression and 121 of 136 patients without HER-2/neu overexpression to ascertain a history of pesticide exposure. Forty-one of 53 (77.4%) patients with HER-2/neu overexpression and 47 of the 121 patients without overexpression (38.8%) were exposed to pesticides. We found that patients with history of pesticide exposure had a higher risk of having HER-2/neu overexpression (odds ratio, 5.38; P < 0.01, 95% confidence interval, 2.5-11.2) CONCLUSIONS: HER-2/neu is overexpressed in approximately 30% patients with ESSCLC and is associated with decreased survival. Also, pesticide exposure seems to be related to HER-2/neu overexpression seen in our patient population. Future studies are needed to validate our findings and also to determine which pesticide(s)/pesticide components are actually responsible for HER-2/neu overexpression seen in ESSCLC.

Hyperhomocysteinemia and the risk of thromboembolic phenomenon in patients with chronic renal failure.

Thromboembolic phenomena are a major cause of morbidity and mortality in patients with end-stage renal disease. Studies in patients with chronic renal failure (CRF) have demonstrated an increased relative risk of coronary artery disease (CAD) in association with hyperhomocysteinemia (HHe). However, very little data exist about the causal relationship between HHe and cerebrovascular diseases (CVA) in patients with CRF. We report the results of our observational retrospective study to determine the effect of HHe on CVA and CAD in patients with CRF (defined as creatinine clearance <50 ml/min). One hundred ten male patients were eligible for our study performed at a Veterans Affairs Medical Center. Age range was 36-86 years (median age 67 years). A fasting plasma HC level >15 micromol/l was considered as HHe. Thirty-four patients were on dialysis. Eight patients were postrenal transplantation. Our study results showed that a homocysteine (HC) level greater than 15 micromol/l was an independent predictor of CVA, after adjusting for potential confounders. Adjusted odds ratio (OR) for CVA was 10.9 (CI: 1.8-67.2, p=.01). Although our study results suggest a strong relationship between HHe and CVA, they failed to demonstrate an association between HHe and CAD. There exists a need for larger prospective randomized clinical trials to evaluate the effect of HHe on the incidence of CVA and CAD in patients with CRF.

Myeloproliferative syndromes and the associated risk of coronary artery disease.

INTRODUCTION: Of the major myeloproliferative syndromes (MPS) [polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukemia (CML) and myelofibrosis (MF)], PV and ET are reported to be associated with increased thrombotic complications. However, the relationship between these myeloproliferative syndromes and coronary artery disease (CAD) is unclear. METHODS: We performed a retrospective chart review to evaluate the prevalence of CAD in patients with diagnosed with MPS between 1991 and 2001. RESULTS: One hundred and eighty-one patients (100 males, 81 females) with a mean age of 72.5 years were included. Twenty-nine patients, 19 males and 10 females (16%, 95% CI: 12.0-24.0) had CAD. These included 6/53 (11.3%, 95% CI: 1.5-20.2) patients with CML, 1/26 (3.8%, 95% CI: -4.4 to 12.8) patients with PV, 5/30 (16.7%, 95% CI: 2.5-30.8) patients with ET, 3/7 (42.9%, 95% CI: 12.3-87.7) patients with MF and 14/65 (21.5%, 95% CI: 13.1-37.8) patients with co-existent MPS. Comparing the risk of CAD with CML as a baseline, MF had an OR of 8.2 (p < 0.01, 95% CI: 1.7-39), PV-0.4 (p = 0.4, 95% CI: 0.04-3.2), ET-1.6 (p = 0.7, 95% CI: 0.43-6.2) and patients with co-existent MPS-2.8 (p=0.07, 95% CI: 0.91-8.6). However, after adjusting for age, sex, dyslipidemia, diabetes, hypertension and tobacco use, the difference in the prevalence of CAD between the various categories of MPS was not significant. CONCLUSION: Contrary to conventional belief, we did not find an increased prevalence of CAD in patients with either PV or ET. In fact, patients with MF had a significantly higher prevalence of CAD. However, this difference appears to be due to the increased age at diagnosis of MF. The conventional risk factors for CAD appear to be the major determinants of CAD among patients with MPS.

An epidemiological study evaluating the relationship of distance from a tertiary care cancer center to early detection of colorectal carcinoma.

OBJECTIVE: AJCC stage at diagnosis determines the treatment approach and indirectly predicts outcome in patients with colorectal carcinoma. The purpose of our study was to investigate whether there was a delay in diagnosis leading to a more advanced stage at diagnosis (which affects outcome) of patients with colorectal cancers because of distance from a referral center, after positive fecal occult blood testing (FOBT). DESIGN: Our retrospective observational study involved all cases of colonic and rectosigmoid cancers that were referred for an endoscopic procedure after an initial positive FOBT done as a part of routine screening in asymptomatic patients. PARTICIPANTS: Roger Maris Cancer Center and University of North Dakota School of Medicine and Health Sciences. RESULTS: Between the years 1996-2001, 178 subjects with biopsy-proven colon cancer and 80 patients with rectosigmoid cancer were included in our study. Pearson's correlation coefficients were constructed to look at the relationship between distance from a referral center (place where the diagnosis was made) and stage at diagnosis in patients with colonic and rectosigmoid malignancies. For the colon cancer group, the regression coefficient between AJCC stage at diagnosis and distance from the referral center was 0.013 and for rectosigmoid cancers it was 0.12. Even after stratifying distances into tertiles, the correlation coefficients did not show a significant relationship (0.04 for colon and 0.16 for rectosigmoid cancers). CONCLUSION: Distance (of residence) from a tertiary care center does not seem to be a barrier to early diagnosis of colorectal carcinoma and primary care providers in rural settings are referring patients appropriately leading to optimal outcomes.

Identification and relationship of HER-2/neu overexpression to short-term mortality in primary malignant brain tumors.

INTRODUCTION: HER-2/neu overexpression has been associated with poor prognosis in solid tumors. The extent to which HER-2/neu is overexpressed in human central nervous system malignancies is unclear. We retrospectively analyzed a large cohort of patients with primary brain tumors to evaluate the prognostic role of HER-2/neu overexpression and clinical characteristics at presentation in patients with shortened survival (< 6 months). MATERIALS AND METHODS: Between 1986 and 2001, 136 patients (81 males, 55 females) with a mean age of 69 years (age range: 49-78 years), with a biopsy-proven diagnosis of a primary malignant brain tumor and survival of < six months from the time of diagnosis, were identified. Archival tissue samples were analyzed for HER-2/neu overexpression using the Hercep immunohistochemical assay. A score of 2+ or greater on the assay was considered positive for HER-2/neu overexpression. Short-term mortality (less than 6 months) and its predictors were evaluated using multiple logistic regression. RESULTS: Mean overall survival was 2.8 months. HER-2/neu overexpression was detected in 23 out of 136 specimens (17%). However, HER-2/neu overexpression did not predict increased 6-month mortality (p = 0.43). Interestingly, the presence of HER-2/neu overexpression was associated with a significantly increased risk of an associated second primary malignancy in addition to the primary brain tumor. Other factors examined did not predict increased 6-month mortality either, including site of tumor (p = 0.54), tumor histology (p = 0.77) and presenting symptoms (p = 0.32). CONCLUSION: Her-2/neu overexpression was detected in 17% of patients with primary brain tumors, but, did not predict increased short-term mortality in patients with brain tumors surviving less than six months. We were not able to identify any clinical variables that could predict survival in our patient population. At present, there are few reliable prognostic indicators for brain tumors. Further studies are needed to specify whether certain tumor subtypes are more likely to overexpress HER-2/neu and to evaluate the role of HER-2/neu as a target for therapy in malignant brain tumors.

Role of immunohistochemical identification of Her-2/neu and detection of variability in overexpression in pancreatic carcinoma.

INTRODUCTION: Her-2/neu overexpression has been recently shown to be a poor prognostic factor in breast carcinoma. Overexpression has also been demonstrated in adenocarcinoma of the pancreas but the significance is unclear. We attempted to study the role of Her-2/neu overexpression, detected by immunohistochemistry, in pancreatic carcinoma and also examined for variability of overexpression across different tissue sections on individual tumor specimen. MATERIALS AND METHODS: Records of all patients with adenocarcinoma of the pancreas, diagnosed and followed between 1986 and 2001 at a tertiary care oncology center were reviewed. Archival pathological samples were analyzed for Her-2/neu expression using the Hercep immunohistochemical assay (DAKO). A score of 2+ or greater on the assay was considered positive for Her-2/neu expression. When tumors were found to be Her-2/neu-positive, they were assessed for variability of expression of Her-2/neu by staining different sections of individual tumor blocks. Log-rank tests and Cox proportional hazards methods were used to analyze survival data. RESULTS: Three hundred and eight patients were included in our study. The mean age was 70 years. Forty-eight out of 308 specimens (16%) were positive for Her-2/neu expression. The mean survival in the Her-2/neu-positive group was 11 months and in the Her-2/neu-negative group was 7 months (p=.03). Of the 48 patients with Her-2/neu-positive tumors, 16 showed variable overexpression (33%). Multivariate analysis did not reveal statistical difference in survival between the uniformly expressing and variably expressing tumors. CONCLUSION: Her-2/neu overexpression detected by immunohistochemistry does not appear to be a poor prognostic factor in patients with adenocarcinoma of the pancreas. Also, there is significant variability in the level of Her-2/neu expression across tumor sections in individual patients, which can potentially lead to considerable misclassification. Hence, we believe that, pending further studies, Her-2/neu may not be an appropriate target for therapy in pancreatic adenocarcinoma.

Predictive value of clinical features at initial presentation in pancreatic adenocarcinoma: a series of 308 cases.

Pancreatic cancer is the fourth leading cause of cancer death in both men and women with a mortality incidence ratio of 0.99. In an effort to describe the role of clinical features at initial presentation, we conducted a retrospective observational study in patients with a biopsy-proven diagnosis of adenocarcinoma of the pancreas. Between 1986 and 2001, 308 patients (160 males, 148 females) were diagnosed with pancreatic adenocarcinoma. The mean age at diagnosis was 70.1 yr (range: 34-96 yr). The mean survival was 7.6 mo (range: 0-97 mo). Statistical analysis was performed using log-rank tests and analysis of variance. As expected, age at diagnosis was a significant factor affecting survival, with older patients doing relatively poorly (p < 0.05). Patients with a good performance status performed significantly better than those with a poor performance status (p < 0.01). In addition, the presence of the tumor in the head of the pancreas was a predictor for improved survival (p < 0.01). Although smoking increased the chances of detection at an earlier age, neither diabetes mellitus nor a positive smoking history had a statistically significant effect on the survival. Pancreatic adenocarcinoma is a disease of the elderly associated with a poorer outcome. Knowledge of possible clinical predictors of survival may lead to better patient counseling regarding prognosis.

Transforming growth factor-beta and Smad signalling in kidney diseases.

Extensive studies have demonstrated that transforming growth factor-beta (TGF-beta) plays an important role in the progression of renal diseases. TGF-beta exerts its biological functions mainly through its downstream signalling molecules, Smad2 and Smad3. It is now clear that Smad3 is critical for TGF-beta's pro-fibrotic effect, whereas the functions of Smad2 in fibrosis in response to TGF-beta still need to be determined. Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE). These pro-fibrotic factors can activate Smads directly and independently of TGF-beta. They can also cause renal fibrosis via the ERK/p38 MAP kinase-Smad signalling cross-talk pathway. In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGF-beta, angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases. Results from these studies indicate that Smad signalling is a key and final common pathway of renal fibrosis. In addition, TGF-beta has anti-inflammatory and immune-regulatory properties. Our most recent studies demonstrated that TGF-beta transgenic mice are protected against renal inflammation in mouse obstructive and diabetic models. Upregulation of renal Smad7, thereby blocking NF.kappaB activation via induction of IkappaBalpha, is a central mechanism by which TGF-beta inhibits renal inflammation. In conclusion, TGF-beta signals through Smad2/3 to mediate renal fibrosis, whereas induction of Smad7 inhibits renal fibrosis and inflammation. Thus, targeting Smad signalling by overexpression of Smad7 may have great therapeutic potential for kidney diseases.

Spinal epidural abscess after corticosteroid injections.

Although spinal epidural abscess is uncommon, its incidence is likely to rise with increasing use of epidural injections for the control of lower back pain. We report a case of spinal epidural abscess after epidural steroid injection. The abscess resolved with conservative medical management.

Effect of low-molecular-weight heparin on potassium homeostasis.

BACKGROUND: Low-molecular-weight heparins (LMWHs) are being preferred to unfractionated heparin (UFH) because of their superior convenience and a comparable or slightly better toxicity profile. Whether LMWH has an inhibitory effect on aldosterone that causes hyperkalemia is yet uncertain. METHODS: Twenty-eight patients (all male; mean age: 70 years, range 52-87 years) placed on LMWH therapy (40 mg subcutaneously every 12 h) for deep venous thrombosis prophylaxis after an operation were included in the study. Transtubular potassium concentration gradient (TTKG) was calculated 1 day prior to LMWH therapy and again after 4 days of treatment. Of the 28 patients enrolled in the study, we were able to calculate the TTKG in only 19 patients: 9 had a urinary osmolarity (either before or after LMWH therapy) less than the serum osmolarity, making the TTKG calculation unreliable. The Wilcoxon signed-rank test was used to analyze differences in the median serum potassium levels and TTKG before and after LMWH therapy. RESULTS: All patients had adequate renal function (creatinine clearance >90 ml/min). Mean (+/- SD) serum potassium concentration before LMWH was 4.25 (+/- 0.40) mmol/dl. It increased to 4.35 (+/- 0.41) mmol/dl after initiating LMWH therapy (p = 0.09). Similarly, the mean (+/- SD) TKKG calculated was 5.52 (+/- 2.33) before and 5.97 (+/- 3.06) after 4 days of LMWH (p = 0.54). CONCLUSIONS: Unlike UFH, LMWH (Lovenox in doses used for postoperative prophylaxis against deep venous thrombosis does not seem to have a significant effect on potassium homeostasis.

Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme.

Her-2/neu or c-erbB-2, a 185-kD protein is an important prognostic indicator/target for therapy in metastatic breast carcinoma. Recent reports have also identified a role for Her-2/neu overexpression in other solid tumors. We performed a retrospective analysis to evaluate the prevalence and prognostic role of Her-2/neu overexpression in patients with glioblastoma multiforme (GBM). Data collection (chart review) included demographic information, symptoms at presentation, histologic grade, survival time, and treatment offered. Testing for Her-2/neu overexpression was performed on paraffin-embedded archival tumor tissue using immunohistochemistry (IHC) (Hercep test). An IHC score of 2+ or greater was considered overexpression. An experienced pathologist who was blinded from the clinical history performed all the IHC testing. Between 1990 and 2001, 149 subjects (68 females, 81 males) with a biopsy-proven diagnosis of GBM were identified. Age range was 26 to 79 years (mean: 64 years) and overall mean survival was 12 months. Her-2/neu overexpression was detected in 23 patients (15.4%). Interestingly, the median survival for patients whose pathologic specimens revealed Her-2/neu overexpression was 4 months compared to those who lacked overexpression, in whom survival was 8 months. After adjusting for age, performance status, smoking history, and treatment, logistic regression analysis (with a survival of <3 months as the dependent variable) revealed that Her-2/neu overexpression significantly (p < 0.01) increased the odds of early mortality (<3 months). The results of our large study indicate that Her-2/neu overexpression may be a poor prognostic marker in patients with GBM. In addition, in a proportion of subjects (15.4%), Her-2/neu may be a potential target for tumor-specific monoclonal antibody therapy. The role of trastuzumab (alone or in combination with conventional therapy) needs to be evaluated.

Determination of HER-2/neu overexpression and clinical predictors of survival in a cohort of 347 patients with primary malignant brain tumors.

INTRODUCTION: HER-2/neu overexpression has been associated with poor prognosis in a variety of malignancies. The extent and relevance of HER-2/neu overexpression in human central nervous system (CNS) malignancies is unclear. We retrospectively analyzed a large cohort of patients with primary malignant brain tumors to evaluate the role of HER-2/neu overexpression, clinical characteristics at presentation, and other predisposing factors as predictors of survival. MATERIALS AND METHODS: Records of 347 adult patients (193 males, 154 females) diagnosed and followed between 1986 and 2001 with a biopsy-proven diagnosis of a primary malignant brain tumor at a tertiary care oncology center were reviewed. Archival pathologic samples were analyzed for HER-2/neu overexpression using the Hercep immunohistochemical (IHC) assay (DAKO). A score of 2+ or greater on the assay was considered positive for HER-2/neu overexpression. Mortality and its predictors were evaluated using multiple logistic regression. (This study was approved and reviewed by the Institutional Review Board Committee [IRB] of University of North Dakota School of Medicine and Health Sciences.) RESULTS: Among the 347 adult patients with a mean age of 53 years (range; 41-73 years), overall mean survival was 23 months (range; 0-151 months). It was found that 10.4% of the archival pathologic samples showed presence of HER-2/neu overexpression by IHC. The HER-2/neu overexpression predicted significantly increased mortality [p = 0.01, analysis of variance (ANOVA)]. Other clinical predictors associated with increased mortality included site of tumor (occipital and parietal lobes) (p = 0.02, ANOVA), tumor histology (glioblastoma) (p < 0.01, ANOVA), and presenting symptom (nausea/vomiting) (p < 0.01, ANOVA). Also, there was a higher incidence of associated primary malignancies (outside the CNS) in the HER-2/neu overexpression group (30% vs. 7%). CONCLUSIONS: HER-2/neu overexpression seen in 10.4% appears to predict a slight increased mortality in patients with primary malignant brain tumors, especially glioblastoma multiforme, and is associated with a high incidence of a second primary malignancy outside the CNS. Additionally, our data suggests that other clinical variables were predictive of increased mortality, including tumor location (occipital), histology (glioblastoma), and presenting symptoms (nausea/vomiting). The large, heterogeneous sample employed in our study allows more definitive conclusions to be made with regard to the usefulness of HER-2/neu and other clinical predictors of survival in patients with primary brain tumors.