Mamoun Younes

Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival.

Increased expression of Glut1 and Glut3 has been reported in many human cancers, including nonsmall cell lung carcinoma (NSCLC). The aim of this study was to determine the biologic significance of Glut1 and Glut3 overexpression in Stage I NSCLC.

p53 protein accumulation in Barrett's metaplasia, dysplasia, and carcinoma: A follow-up study

BACKGROUND There is a significant interobserver and intraobserver variation in grading dysplasia in Barretts metaplasia. New markers are needed to optimize the assessment of potential risk of cancer development in these patients. The aim of this study is to explore the use of p53 as a marker of neoplastic progression in Barretts metaplasia. METHODS Immunohistochemistry was used to study p53 protein accumulation in 114 specimens from 54 patients with Barretts metaplasia. RESULTS Positive staining was found in 0% of the cases negative for dysplasia, 9% of those with low-grade dysplasia, 55% of those with high-grade dysplasia, and 87% of those with adenocarcinoma. Follow-up was available on 24 patients. Two patients who showed low-grade dysplasia and who were positive for p53 on biopsy showed high-grade dysplasia in follow-up biopsies. Of 21 patients who had biopsy specimens negative of p53, only one showed high-grade dysplasia on subsequent biopsy specimens. CONCLUSIONS Our data support the hypothesis that p53 plays an important role in the progression of Barretts metaplasia to adenocarcinoma. The follow-up study indicates that positive immunostaining for p53 may be an objective marker of neoplastic progression in Barretts metaplasia.

Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: Induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death

Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL‐R1, TRAIL‐R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti‐TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL‐R1 (HGS‐ETR1) and TRAIL‐R2 (HGS‐ETR2) this study demonstrated that both monoclonal antibodies activated caspase‐8 and induced cell death in five of nine human lymphoma cell lines, and induced >10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and >20% cell death in at least one‐thirds of the samples. HGS‐ETR1 and HGS‐ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase‐8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS‐ETR1 and HGS‐ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma.

Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

PURPOSE The clinicopathologic importance of a second estrogen receptor (ER), ER-beta, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-beta assay, probably because of the lack of standardized methodology, the presence of several ER-beta isotypes (ER-beta1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-beta status provides clinically useful information over what is already provided by the traditional ER-alpha/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues. PATIENTS AND METHODS Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti-ER-beta antibodies that detect ER-beta1-3 (ER-betaN), ER-beta1, and ER-betacx (ER-beta2). RESULTS Positive staining for ER-betaN or ER-beta1 was associated with significantly better survival. By contrast, ER-betacx status did not influence survival. In multivariate analysis, ER-beta1 status emerged as an independent predictor of recurrence and mortality. ER-beta1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-beta1 positivity was associated with significantly better survival in patients with ER-alpha-negative/PR-negative or ER-alpha-negative/PR-negative/human epidermal growth factor receptor 2-negative (triple-negative) tumors, which are widely believed to be hormone unresponsive, have poor prognosis, and require chemotherapy. CONCLUSION Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

Expression of estrogen receptors-α and -β in bladder cancer cell lines and human bladder tumor tissue

Estrogen receptors (ERs) are known to mediate important physiologic responses as well as the growth of some tumors in response to estradiol stimulation. In a previous study the selective ER modulator raloxifene was shown to induce apoptosis in an ERβ‐positive bladder cancer cell line. However, the expression of ERβ in human bladder cancer has not been thoroughly investigated.

p53 Protein Accumulation Is a Specific Marker of Malignant Potential in Barrett's Metaplasia

Our aim was to determine the sensitivity andspecificity of p53 accumulation as a marker of malignantpotential in Barretts metaplasia (BM). One hundredeighty biopsies from 61 patients with BM were evaluated for p53 accumulation by immunohistochemistry.Of 25 patients with LGD, 9 had p53-positive biopsies,and of these 5 (56%) developed HGD/CA, whereas 16 hadp53-negative biopsies and none (0%) developed HGD/CA after similar follow-up times (P = 0.0108). Asa marker of malignant potential in BM, p53 accumulationhas a sensitivity of 100%, specificity of 93%, and apredictive value of a positive test of 0.56, compared to sensitivity of 100%, specificity of 64%, andpredictive value of a positive test of 0.2 for ahistologic diagnosis of LGD. We conclude that: (1) p53accumulation is more specific and has better predictive value for subsequent development of HGD/CA thanhistologic diagnosis of LGD. (2) Patients with LGD andp53-positive biopsies are more likely to develop HGD/CA;therefore, they should be followed up more closely than those with LGD and p53-negativebiopsies.

Incidence and Survival Trends of Esophageal Carcinoma in the United States: Racial and Gender Differences by Histological Type

Background: The incidence of esophageal adenocarcinoma in White males has been reported to be increasing. The aims of this study were to determine: 1) the incidence trends of esophageal carcinoma in the United States with an emphasis on histologic type, sex, and ethnicity, 2) whether the reported increase in stage IV tumors can be confirmed, and 3) survival trends and factors affecting survival. Methods: Data from the SEER program of the National Cancer Institute with submission dates 1973-98 were used. Data on Hispanics were available for analysis only for the years 1992-98. Statistical analysis was performed utilizing SEER*Stat and SAS statistical software packages. Results: The incidence of adenocarcinoma in White males is still rising (7.8%/year; P < 0.0001); however, the same trend was observed for White females (6.48%/year; P < 0.0001), Hispanic males (3.91%/year; P < 0.02), and Hispanic females (9.4%/ year; P < 0.04). The incidence of squamous cell carcinoma has been steadily declining in White males and females and in Black females since 1973, with the incidence showing a dramatic and significant decline in Black males beginning in 1992 (8.53%/year; P = 0.0009). Stage 4 carcinoma is declining in incidence. Survival of patients with esophageal carcinomas has been improving. In a Cox multivariate model, independent prognostic factors in esophageal carcinoma included tumor stage, tumor type, gender, race, age at diagnosis, and year of diagnosis. Conclusions: 1) The incidence of adenocarcinoma continues to rise in White males and females, but also in Hispanics, while squamous cell carcinoma is declining; 2) the incidence of stage 4 carcinomas has been declining, and 3) survival has been steadily improving, independently of all other risk factors.

Adult mesoblastic nephroma: expansion of the morphologic spectrum and review of literature.

Mesoblastic nephroma (MN) is a distinctive tumor that is seen mostly in early infancy and that consists of classic and cellular (atypical) variants. Mesoblastic nephroma rarely occurs in adulthood, but MN in this age group still is poorly characterized because there are only 17 reported cases. We describe five additional cases of adult MN, including one case of the cellular variant, characterize the immunohistochemical profiles in detail, and critically review the previously reported cases. The collective data obtained from these 22 cases of adult MN showed that the patients predominantly were women (20 cases), ranging in age from 19 to 78 years, who were asymptomatic (5 cases) or had nonspecific signs and symptoms referable to a renal mass. Twenty tumors were classified as classic and 2 as cellular. The tumors were 2-24 cm, well circumscribed, and partially encapsulated and displayed a solid/ cystic cut surface, with a predominantly solid component in most tumors. One tumor, however, was almost purely cystic. Most tumors extended to the renal sinus. and some appeared entirely intrapelvic on imaging studies; however, gross and microscopic evaluation did not show destructive invasion of the pelvic wall. Extension of the tumor beyond the renal capsule has not been described. Each tumor was composed of epithelial and stromal components both. The epithelial component, which displayed no difference between the classic and cellular variants, was composed of isolated or clustered tubules and cysts lined by a benign epithelium with a wide range of cytologic differentiation. The stromal cells were composed of fibroblasts, myofibroblasts, and smooth muscle cells in various combinations. Stromal cellularity was low for the classic variant but high for the cellular variant. Hemorrhage, necrosis, and high mitotic index were noted in the stroma of the cellular, but not in the classic variant. Immunohistochemical study applied to the five current cases and seven normal control kidneys confirmed the presence of fibroblasts, myofibroblasts, smooth muscle cells, and prominent vessels in the stroma of each tumor. Most cysts and tubules within the tumors had a distinctive immunohistochemical profile, similar to that of collecting duct but different from those of other portions of the nephron in the normal control kidneys. After total or partial nephrectomy, without adjuvant chemotherapy or radiotherapy, 19 patients, including the 2 with cellular MN, were alive and well at 8-months to 48-years follow-up. Follow-up was not available in two patients. The remaining patient had recurrence at the surgical site 24 years after nephrectomy. Adult MN displays a distinctive morphologic spectrum that parallels that of its pediatric congener. It probably is a benign tumor that can be treated successfully by complete excision. The collecting duct differentiation expressed by most tubules and cysts of adult MN implies ureteric bud, which is the exclusive embryologic origin of collecting duct, as an important element in the histogenesis of this rare but fascinating type of tumor.

Expression of GCDFP-15 and AR decreases in larger or node-positive apocrine carcinomas of the breast

Aims : Apocrine carcinoma of the breast is typically, though not always, positive for gross cystic disease fluid protein‐15 (GCDFP‐15). In order to clarify the clinical significance of GCDFP‐15 in apocrine carcinomas, GCDFP‐15 expression was examined in apocrine carcinomas of different stages and compared with clinicopathological factors. Apocrine lesions reportedly exhibit an unusual immunohistochemical status, expressing androgen receptors (AR) instead of oestrogen receptors (ER), progesterone receptors (PR), or bcl‐2. Their expression was also examined.

Breast carcinoma in women over the age of 85: distinct histological pattern and androgen, oestrogen, and progesterone receptor status

Aims:  The pathogenesis of breast carcinoma in very elderly women is of interest, because oestrogen levels are likely to be extremely low during the development of the disease. In an effort to understand the pathogenesis of breast carcinoma in these women, this study was undertaken to compare the histological patterns and hormone receptor status of breast carcinomas arising in very elderly and younger women.