Syed A. Mehdi

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.

Late adrenal metastasis in operable non-small-cell lung carcinoma.

Treatment of early-stage (I, II, and some IIIA) non–small-cell lung cancer (NSCLC) is curative resection. Simultaneous isolated adrenal metastasis represents a dilemma. Although many studies addressing the management of adrenal metastasis diagnosed simultaneously with NSCLC have been published, only very few reports of late adrenal metastasis can be found in the literature. Our purpose is to discuss the management of solitary late (metachronous) adrenal metastasis from operable NSCLC based on published experience. We describe a patient with a solitary metachronous adrenal metastasis diagnosed 3 years after resection of NSCLC. Adrenalectomy was done, followed by combination chemotherapy with paclitaxel and carboplatin. MEDLINE literature on similar cases was reviewed and updated. Only 18 cases have been reported from 1965 to 2000. The median interval between the diagnosis of NSCLC and development of adrenal metastasis was 11.5 months. All patients were male. Unilateral adrenal metastases were reported in 15 patients, whereas 3 had bilateral metastases. Five patients were treated with adrenalectomy, and eight patients were treated with adrenalectomy and postoperative adjunctive chemotherapy. Chemotherapy alone was used in two patients and two patients underwent palliative radiation therapy. One patient was treated with intraarterial chemotherapy followed by radiation therapy. Solitary metachronous adrenal metastases are rare. There are no standard treatment guidelines for this group of patients. Review of the literature showed that median survival after treatment was 19 months for the group treated with adrenalectomy followed by chemotherapy; 15 months for the chemotherapy group; 14 months for the adrenalectomy group; and 8 months for the group treated with palliative radiation.

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.

Immunohistochemical identification of HER-2/neu overexpression and CD117 (c-kit) expression in multiple myeloma

Multiple myeloma (MM) is the most common plasma cell dyscrasia. Conventional therapy results in a median survival of 3-5 years. Patients with B-cell disorders and coexistent HER-2/ neu overexpression in solid tumors have a poorer prognosis than those without an underlying B-cell disorder. This, and the recent success of the tyrosine kinase inhibitor, imatinib mesylate in chronic myelogenous leukemia, led us to evaluate the incidence and role of c-kit (CD117) and HER-2/ neu overexpression in MM. We conducted a retrospective study to determine the incidence of HER-2/ neu and c-kit overexpression in MM. HER-2/ neu overexpression was evaluated using the DAKO Hercep test and c-kit overexpression was assessed using conventional immunohistochemistry (IHC); 69 patients with a diagnosis of MM were identified, of whom, 31 patients (19 males and 12 females) had an adequate pathological specimen available for IHC testing; 4 out of 31 patients (12.9%) showed HER-2/ neu overexpression, while 5/31 (16.13%) showed CD117 expression. Two patients (6.45%) showed both HER-2/ neu and c-kit overexpression. Although both HER-2/ neu and c-kit are not expressed very frequently in patients with MM, there appears to be a subgroup of patients in whom, either one or both these oncogenes is overexpressed. Given our small sample size, it is difficult to comment on the effect of CD117 and/or HER-2/ neu overexpression on survival. Future larger studies are needed to define the association in MM and to determine if the presence of one (CD117 or HER-2/ neu ) has an effect on overexpression of the other oncoprotein. Furthermore, it would be beneficial to identify the molecular nature of the interplay between HER-2/ neu and c-kit, if any. Target-directed signal transduction inhibition therapy using tyrosine kinase inhibitors, may be a distinct possibility in a select group of patients with MM.

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.

Chromosomal anomalies in two coexistent myeloproliferative disorders

A 58-year-old male presented with fatigue, tiredness, and pruritus after hot showers and an elevated white blood cell count (20000/mm(3)). A diagnosis of polycythemia vera (PV) was made after investigation revealed a low erythropoietin and elevated leukocyte alkaline phosphatase (LAP) score; he was treated with repeated phlebotomies. Two years later he developed elevated white counts again and investigation revealed Philadelphia chromosome positive (19/20 cells) chronic myelocytic leukemia (CML). The karyotype also revealed trisomy 9 in 1 of 20 cells. He was treated with imatinib mesylate and went into clinical, hematologic, cytogenetic, and molecular remission. Repeat chromosomal analysis revealed absence of Philadelphia chromosome and BCR/ABL translocation but presence of trisomy 9. To our knowledge, this is the first reported case of coexisting PV and CML both associated with separate chromosomal abnormalities. This also raises an interesting therapeutic consideration of using concomitant imatinib mesylate and hydroxyurea.

An indolent B-cell lymphoma with t(2;8)(p12;q24) abnormality and absence of C-MYC amplification and TP53 deletion. A new variant?

The translocation between chromosomes 2 and 8, t(2;8), is well known for its strong association with high-grade Burkitt lymphoma. However, the significance of this translocation in indolent lymphoproliferative disorders is not clear. We present the case of a 75-year-old white male with left upper quadrant abdominal pain, splenomegaly, and an elevated white cell count of 30.3x10(9) cells/L (84% large lymphoid cells with scanty cytoplasm and prominent central nucleoli). Immunophenotyping revealed a clonal B-cell population coexpressing CD5, CD19, and CD20 with weak CD23 and CD25 and very weak, restricted, surface lambda. The cytogenetic analysis showed all 20 cells with t(2;8)(p12;q24.3). In addition, four of the 20 cells also showed a second translocation: t(12;17)(p13;q21). Molecular analysis using c-myc and p53 probes showed normal results with no indication of amplification of C-MYC or deletion of TP53. The patient was managed as an indo-lent/low-grade lymphoproliferative disorder with excellent response to eight cycles of fludarabine.

Concomitant bilateral herpes zoster opthalmicus

Hassan Pervez and colleagues present a Clinical Picture purporting to show concomitant bilateral herpes zoster opthalmicus without providing conclusive evidence of the diagnosis. In the Tzanck test, the presence of giant epithelial cells and multinucleated giant cells in stained material from the base of vesicular lesions is taken to indicate the presence of alpha herpes viruses, but does not identify the causative agent. Antigen detection, nucleic acid testing, or viral culture of the material is needed to establish whether herpes simplex virus 1, 2, or varicella zoster virus is responsible. Laboratory diagnosis is of particular relevance in this case given the bilateral distribution of the rash (and the possible absence of associated pain and eye involvement). Identification of the specific virus responsible is not an academic exercise. Herpes simplex virus and varicella zoster virus warrant very different dosages of antiviral medications and vary in their prognostic significance, especially in the elderly patient. Eithne M E MacMahon

Isolated Hepatic Metastasis from Prostate Carcinoma

Worldwide, prostate cancer is considered the second most common cancer in men. Most common sites for metastatic disease are lymph nodes and bones. However, isolated liver metastasis from prostate cancer is rare. We present a 75 year-old male with prostate adenocarcinoma diagnosed 7 years ago. With rising PSA, he underwent imaging and found to have isolated hepatic metastasis. After left hepatic lobectomy, his PSA dramatically decreased to < 0.01. Physicians should be aware of isolated hepatic metastasis in patients with prostate cancer. Metastasectomy should be considered in such case, and combined medical and surgical approach may prolong the overall survival.