Anil Potti

Predictive role of HER-2/neu overexpression and clinical features at initial presentation in patients with extensive stage small cell lung carcinoma

Although recent advances in therapy have improved the quality of life in patients with extensive stage small cell lung cancer (ESSCLC), prolonged survival is still uncommon. To determine the role of HER-2/neu overexpression and other clinical predictors (symptoms at presentation) of adverse outcome in ESSCLC, we performed a retrospective study on subjects with a biopsy-proven diagnosis of ESSCLC. HER-2/neu overexpression was evaluated using immunohistochemistry (IHC) performed on paraffin-embedded specimens. An IHC score of > or = 2+ was considered positive for overexpression. Between 1991 and 2000, 223 patients with ESSCLC were identified, of whom 193 patients (84 females, 109 males) with a mean age of 68.5 years (range: 42-90 years) had adequate tissue specimens for HER-2/neu testing. The symptoms at initial presentation and proportionate number of patients were: weight loss 61 (31.6%), cough 53 (27.5%), dyspnea 33 (17.1%), mass on chest radiograph 18 (9.3%), chest pain 15 (7.7%), asymptomatic 14 (7.2%) and others (weakness, lymphadenopathy, hoarseness and paraneoplastic syndromes) 29 (15.0%). Of the 193 specimens, 57 (29.5%) revealed HER-2/neu overexpression. The median survival for patients with ESSCLC who were HER-2/neu positive was 8 months (range: 1-25.5 months) while that in the HER-2/neu negative group was 16 months (range: 2-34 months). Interestingly, after adjusting for age, performance status and type of therapy, subset analysis revealed that the survival was significantly lower in HER-2/neu positive individuals (P<0.001; Mann-Whitney U-test). In our study, weight loss and cough were the two most common (59%) presenting complaints in patients with ESSCLC. Also, since HER-2/neu positivity was a marker for poor prognosis in ESSCLC, testing for overexpression may play a role in identifying patients at risk for shortened survival. Further studies would delineate whether HER-2/neu overexpression renders SCLC chemoresistant and thus, adversely affects outcome. There exists a need for randomized controlled trials to assess the role of Herceptin (alone or in combination with standard chemotherapy) in patients with ESSCLC.

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.

Role of Helicobacter pylori infection in the incidence and clinical course of monoclonal gammopathy of undetermined significance

Role of helicobacter pylori infection in the incidence and clinical course of monoclonal gammopathy of undetermined significance

Immunohistochemical determination of HER-2/neu, c-Kit (CD117), and vascular endothelial growth factor (VEGF) overexpression in malignant melanoma

Purpose To determine the prevalence and evaluate the possible prognostic value of the molecular targets in malignant melanoma, we studied the overexpression of HER-2/neu, c-Kit, and vascular endothelial growth factor (VEGF) in this patient population.Materials and methods Overexpression of HER-2/neu, c-Kit, and VEGF was evaluated using immunohistochemical assays in 202 archival tissue specimens.Results Only two patients (0.9%) revealed HER-2/neu overexpression, whereas 46 (22.8%) revealed c-Kit and 42 (20.8%) specimens showed VEGF overexpression. Multivariate analysis performed did not show a significant difference in survival between c-Kit-positive and c-Kit-negative groups (P=0.36) and VEGF-positive and VEGF-negative groups (P=0.25). Interestingly, c-Kit was more likely to be overexpressed in the superficial spreading type and VEGF was overexpressed preferentially in the amelanotic melanoma type.Conclusions HER-2/neu has no role in melanogenesis. Both c-Kit (expressed in superficial spreading disease) and VEGF (expressed in amelanotic melanoma) may have significant therapeutic implications as molecular targets, which warrants further investigation.

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.

Immunohistochemical determination of HER-2/neu overexpression in malignant melanoma reveals no prognostic value, while c-Kit (CD117) overexpression exhibits potential therapeutic implications

BACKGROUND: HER-2/neu and c-kit (CD117) onco-protein are increasingly being recognized as targets for therapy in solid tumors, but data on their role in malignant melanoma is currently limited. We studied the prevalence of overexpression of HER-2/neu and c-Kit in 202 patients with malignant melanoma to evaluate a possible prognostic value of these molecular targets in malignant melanoma. METHODS: Overexpression of HER-2/neu and c-Kit was evaluated using immunohistochemical assays in 202 archival tissue specimens. RESULTS: Between 1991 and 2001, 202 subjects (109 males; 54% and 93 females; 46%) with malignant melanoma were studied with a mean age of 57 years (age range: 15-101 years). The most common histologic type was amelanotic melanoma (n = 62; 30.7%) followed by superficial spreading melanoma (n = 54; 26.7%). The depth of penetration of melanoma (Breslow thickness, pT Stage) ranged from 0.4 mm (stage pT1) to 8.0 mm (stage pT4A). Mean thickness was 2.6 mm (stage pT3A). The ECOG performance scores ranged from 0 to 3. Only 2 patients (0.9%) revealed HER-2/neu overexpression, whereas 46 (22.8%) revealed c-Kit overexpression. Multivariate analysis performed did not show a significant difference in survival between c-Kit positive and negative groups (p = 0.36). Interestingly, not only was c-Kit more likely to be overexpressed in the superficial spreading type, a preliminary association between the presence or absence of c-Kit overexpression and the existence of another second primary tumor was also observed. CONCLUSIONS: The results of our large study indicate that the HER-2/neu onco-protein neither has a role in melanogenesis nor is a potential target for clinical trials with monoclonal antibody therapy. This indicates there is no role for its testing in patients with malignant melanoma. Although c-Kit, expressed preferentially in the superficial spreading type, may not have prognostic value, it does have significant therapeutic implications as a molecular target warranting further investigation.

Breast Metastasis from Non-Small-Cell Lung Carcinoma

Development of metastasis to the breast from lung cancer is very rare and the prognosis for such patients is poor. We present a patient who had metastasis to breast from non-small-cell lung cancer. It is important to distinguish a primary breast cancer from metastasis to the breast, as the therapy offered would be markedly different, with considerably different outcomes.

Angiosarcoma of the Small Intestine: A Possible Role for Thalidomide?

An 85-yr-old male presented with complaints of a 40-lb weight loss and a dull left upper quadrant abdominal pain. He also complained of decreased appetite, generalized weakness, generally not feeling well, and a dull left upper quadrant abdominal pain that was not relieved by food. He had a ventral and a left-sided inguinal hernia. Laboratory investigations revealed iron deficiency anemia, the cause of which was not apparent despite extensive investigation including computerized tomographic scans, esophagogastroduodenoscopy, and small-bowel follow-through examination. Surgical exploration for possible angiodysplasia, malignancy, and/or mesenteric ischemia revealed an incarcerated hernia, and the histopathological examination of the surgical specimen revealed high-grade angiosarcoma. The tumor showed strong positivity for vimentin and CD31 and a focal positivity for Factor VIII and CD34. At that time he was found to have hepatic metastases. He was started on thalidomide as an experimental measure with no change in the performance status and increasing evidence of necrosis in the metastatic lesion.

A model for clinical estimation of perioperative hemorrhage

The purpose of this study was to assess the accuracy of estimated blood loss (EBL) as a reliable predictor of actual blood loss during orthopedic procedures. Between 1999 and 2002, 198 orthopedic cases were reviewed. A retrospective review compiled preoperative and postoperative demographic and laboratory data from the surgical patients. Estimated blood loss data was-collected from the perioperative and anesthesia reports. Statistical nalysis of EBL vs. change in hemoglobin yielded a correlation e6efficient of 0.189 and a p value of 0.008. We used multiple linear regression to obtain a model to predict change in hemoglobin based on EBL and the intravenous fluids received. The model is as follows: predicted change in hemoglobin = 1.001 x estimated blood loss (in liters) + 0.441 x intravenous fluids received (in liters) + 2.334. The study population included 198 patients, 126 males and 72 females, who met our inclusion criteria. The mean age was 68.1 years (range: SD 12.5), induding 126 males (64%) and 72 females (37%). The mean amount of perioperative intravenous fluids given was 1,732 mL (SD: 773). The mean surgical time was 64.8 minutes (SD: 23.1). The mean preoperative hematocrit and hemoglobin levels were 40.9 g/dL (SD: 4.3) and 13.9 g/dL (SD: 1.6), respectively. The mean postoperative hematocrit and hemoglobin levels were 32.0 g/dL (SD: 6.0) and 10.7 g/dL (SD: 1.6), respectively. The mean difference of preoperative hemoglobin vs. postoperative hemoglobin was 3.3 g/dL (SD 2.1). In this retrospective study, clinical estimation of blood loss was closely correlated with actual change in perioperative hemoglobin. Accurately predicting the postoperative hemoglobin level may prevent many unnecessary blood transfusions and related complications.

Identification of HER-2/neu overexpression and the clinical course of lung carcinoma in non-smokers with chronic lymphocytic leukemia

Patients with CLL have an excess risk of developing second primary malignancies. The etiology of this excess risk is unclear, and has been thought to be related to smoking. HER-2/neu overexpression has evolved as a prognostic/predictive factor in some solid tumors. We reviewed our experience with non-smokers who had CLL and subsequently developed lung carcinoma, in an effort to better understand the clinical course of these patients, and to evaluate the role of HER-2/neu overexpression. We reviewed the records of all patients who had a diagnosis of both CLL and lung carcinoma between 1986 and 2000. HER-2/neu overexpression was estimated by immunohistochemistry (IHC) using the Hercep test (DAKO). An IHC score of 2+ or greater was considered positive. Overall survival was calculated from the date of diagnosis of lung carcinoma by the Kaplan-Meier product limit method. Fourteen non-smokers in whom a diagnosis of CLL was made at least 6 months prior to the diagnosis of lung carcinoma were identified. The median age for diagnosis of CLL in this group was 67 years while that for lung carcinoma was 70 years. The lung carcinomas included 10 non-small cell (NSCLC) and four small cell (SCLC) carcinomas. Nine specimens (six NSCLC and three SCLC) showed HER-2/neu overexpression. Interestingly, 90% of patients with advanced stage cancer (stage IIIB/IV NSCLC or extensive SCLC) overexpressed HER-2/neu. The presence of CLL did not alter outcome in patients with early stage lung cancer. However, after adjustment for age and performance status, patients with advanced stage NSCLC and CLL had a worse than expected outcome. HER-2/neu overexpression (independent of smoking) may be involved in the development/progression of lung cancer in patients with CLL, and has an associated worse outcome. It is appropriate to consider heightened surveillance of CLL patients for lung carcinoma.