Biomedical subjects

William Gerald

Publications and source records attributed to William Gerald.

26 records · Page 2Linked to original sources

PubMed2003

HER 2/neu expression and gene amplification in colon cancer.

HER 2/neu is an important oncogene in breast cancer, but the prevalence and significance of HER 2/neu gene amplification in colon cancer have been poorly documented. We have evaluated HER 2/neu gene amplification and protein overexpression in a series of colon cancers to assess the frequency, concordance and clinical significance of these events. HER 2/neu gene copy number was measured in 154 primary colon tumors, 15 liver metastases and matched normal tissues using a quantitative PCR/ligase detection reaction (LDR) technique developed and validated in our laboratory. HER 2/neu copy number was confirmed by fluorescent in situ hybridization (FISH) in all tumors found to have gene amplification. In an independent and blinded fashion, HER 2/neu expression was assessed in paraffin sections from 139 of the tumor specimens using the HercepTest kit. HER 2/neu gene amplification was observed in 4 (2.4%) of the 169 tumor specimens and in none of the normal tissues. There was no apparent association with stage of disease, tumor grade or patient survival. Among 139 cases evaluated by immunohistochemistry (IHC), HER 2/neu overexpression was seen in 5 cases (3.6%). There was extremely high concordance (kappa = 0.852) between gene amplification and protein overexpression. The low prevalence of HER 2/neu gene amplification and protein overexpression suggests that this oncogene plays an infrequent role in the development and progression of colon cancer. These data indicate that the primary mechanism of dysregulated HER 2/neu expression in colon cancer, as in breast cancer, is gene amplification.

Adult↗

PubMed2003

Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence.

BACKGROUND: Recent data indicate that the risk of developing a thyroid neoplasm clearly is increased after high-dose, therapeutic radiation therapy during childhood. To better understand the time course, natural history, and histopathology of thyroid lesions that develop after high-dose irradiation, the authors undertook a retrospective study of all survivors of childhood and adolescent malignancies who were treated at Memorial Sloan-Kettering Cancer Center and who developed a clinically apparent thyroid neoplasm. METHODS: The authors searched the data base of the Department of Pediatrics, the hospital-based tumor registry, and the hospital medical records database for patients with thyroid neoplasms. RESULTS: Thirty-three patients were identified who developed a thyroid neoplasm after therapeutic radiation. Primary diagnoses were Hodgkin disease (n = 18 patients), non-Hodgkin lymphoma (n = 10 patients), acute lymphoblastic leukemia (n = 2 patients), acute myeloid leukemia (n = 1 patient), Wilms tumor (n = 1 patient), and neuroblastoma (n = 1 patient). The median age at the time of diagnosis of the primary malignancy was 12.0 years (range, 3.7-18.3 years), the median radiation dose to the thyroid gland was 2400 centigrays (cGy; range, 1000-4200 cGy), and the median interval from the time of radiation therapy until the recognition of thyroid disease was 13.0 years (range, 6.2-30.1 years). Thirteen of 33 thyroid lesions (39%) were malignant (11 papillary carcinomas and 2 follicular carcinomas). Age at diagnosis, gender ratio, and time elapsed since initial treatment did not differ between patients with malignant and benign lesions, but the median radiation dose to the thyroid was lower in patients who had malignant disease compared with patients who had benign disease (2000 cGy vs. 2950 cGy; P = 0.03). Disease was confined to the neck in all patients who had malignant thyroid lesions; after a median follow-up of 6.5 years (range, 0.9-12 years), none of the patients developed progressive or recurrent disease. CONCLUSIONS: Data from this study suggest that a high proportion of clinically apparent thyroid neoplasms that develop after therapeutic radiation for a childhood malignancy are malignant. However, most of these thyroid malignancies do not appear to behave in an aggressive fashion. Because thyroid neoplasms may not become evident for decades after radiation therapy, all individuals who are at risk require life-long follow-up.

Adenoma↗

PubMed2003

Detection of HER-2/neu gene amplification in breast cancer using a novel polymerase chain reaction/ligase detection reaction technique.

BACKGROUND: Gene amplification is the primary mechanism of HER-2/neu overexpression in breast cancer and is a strong predictor of prognosis. Currently screening for HER-2/neu gene amplification in breast cancer is done by fluorescent in-situ hybridization (FISH), which is accurate but costly and labor intensive. We have evaluated a new PCR (polymerase chain reaction)-based assay for the detection of HER-2/neu gene amplification in human breast cancer. STUDY DESIGN: A total of 15 breast cancer cell lines and 14 breast cancer specimens were evaluated. HER-2/neu status of the tumors was evaluated by FISH and then assessed using a quantitative polymerase chain reaction/ligase detection reaction (PCR/LRD) technique. RESULTS: Amplification of the HER-2/neu gene was detected in seven cell lines previously reported to have amplification and no amplification was found in any of the six that had been reported not to have amplification. In the assessment of breast specimens the PCR/LDR and FISH assays were in complete agreement. All 10 tumors with amplification by FISH were also amplified by PCR/LDR. CONCLUSIONS: The PCR/LDR technique successfully detects HER-2/neu gene amplification in clinical breast cancer specimens and shows 100% concordance with FISH. This technique is an accurate and rapid alternative to FISH with the potential for automation and high throughput analysis of HER-2/neu status in breast cancer.

Breast Neoplasms↗

PubMed2003

Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors.

Angiogenic defects in Id mutant mice inhibit the growth of tumor xenografts, providing a genetic model for antiangiogenic stress. Our work tests the consequences of such stress on progression of more physiological Pten+/- tumors. While tumor growth occurs despite impaired angiogenesis, disruption of vasculature by Id loss causes tumor cells to experience hypoxia and necrosis, the extent of which is tumor dependent. We show that bone-marrow-derived endothelial precursors contribute functionally to neovasculature of some but not all Pten+/- tumors, partially rescuing Id mutant phenotype. We demonstrate that loss of Id1 in tumor endothelial cells results in downregulation of several proangiogenic genes, including alpha6 and beta4 integrins, matrix metalloprotease-2, and fibroblast growth factor receptor-1. Inhibition of these factors phenocopies loss of Id in in vivo angiogenesis assays.

Animals↗

PubMed2002

Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3.

Markedly increased levels of cyclooxygenase-2 (COX-2) mRNA, protein, and prostaglandin E(2) synthesis were detected in HER-2/neu-transformed human mammary epithelial cells (184B5/HER) compared with its nontransformed partner cell line (184B5). HER-2/neu stimulated COX-2 transcription via the Ras --> Raf --> MAPK pathway. The inductive effects of HER-2/neu were mediated, in part, by enhanced binding of AP-1 (c-Jun, c-Fos, and ATF-2) to the cyclic AMP-response element (-59/-53) of the COX-2 promoter. The potential contribution of the transcription factor PEA3 was also investigated. Elevated levels of PEA3 were detected in 184B5/HER cells. A PEA3 site (-75/-72) was identified juxtaposed to the cyclic AMP-response element. HER-2/neu-mediated activation of the COX-2 promoter was blocked by mutagenizing the PEA3 site or overexpressing antisense to PEA3. To determine whether HER-2/neu status was also a determinant of COX-2 expression in vivo, we compared levels of COX-2 protein in HER-2/neu-positive and -negative human breast cancers. Increased amounts of COX-2 were detected in HER-2/neu-positive tumors. Taken together, these results suggest that closely spaced PEA3 and cyclic AMP-response elements are required for HER-2/neu-mediated induction of COX-2 transcription. The clear relationship between HER-2/neu status and COX-2 expression in human breast tumors suggests that this mechanism is likely to be operative in vivo.

Base Sequence↗

PubMed2002

Disialoganglioside GD2 and a novel tumor antigen: potential targets for immunotherapy of desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive and often misdiagnosed neoplasm of children and young adults. It is chemotherapy-sensitive, yet patients often relapse off therapy because of residual microscopic disease at distant sites: peritoneum, liver, lymph node, and lung. Strategies directed at minimal residual disease (MRD) may be necessary for cure. Monoclonal antibodies selective for cell surface tumor-associated antigens may have utility for diagnosis and therapy of MRD, as recently demonstrated in advanced-stage neuroblastoma (JCO 16: 3053, 1998). We examined DSRCT samples for the expression of two tumor antigens that could serve as possible targets for antibody-based immunotherapeutic approaches. PROCEDURES: Using immunohistochemistry, we studied the expression of two antigens: (1) G(D2) using antibody 3F8 and (2) a novel antigen using antibody 8H9 in a panel of 46 freshly frozen DSRCT. G(D2) is a disialoganglioside, which is widely expressed among neuroectodermal tumors as well as adult sarcomas. 8H9 recognizes a 58 kDa surface antigen expressed among neuroectodermal, mesenchymal, and epithelial tumors with restricted expression on normal tissues. RESULTS: Thirty-two of 46 (70%) tumors were reactive with 3F8, and 44 of 46 (96%) with 8H9. Both G(D2) and the 58 kDa antigen were localized to tumor cell membrane and stroma. In general, immunoreactivity was stronger and more homogeneous with 8H9 than with 3F8. There was no correlation between expression of either antigen or clinical outcome. CONCLUSIONS: G(D2) and the novel tumor antigen recognized by 8H9 are potential targets for immunodiagnosis and antibody-based therapy of DSRCT. Med Pediatr Oncol 2002;39:547-551.

Adolescent↗

PubMed2002

A phase II trial of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.

Bryostatin-1 is a macrocyclic lactone that has been shown to modulate Protein Kinase C activity and has demonstrated antitumor activity in vitro and in vivo. Fifteen patients with metastatic or recurrent squamous cell carcinoma of the head and neck were treated with bryostatin-1 at a dose of 25 mcg/m2 by continuous intravenous infusion over 24 hours once weekly for three weeks followed by a break week to complete a four-week cycle. There were no major objective responses in the 14 evaluable patients. One patient with nasopharynx cancer had disease stabilization for 4 months prior to being removed from the study due to medical issues. This clinical benefit corresponded to a radiographic decrease in metabolic activity on positron emission tomograpy (PET) scan as well as molecular evidence of tumor apoptosis in a poly[ADP-ribose] polymerase (PARP) cleavage assay. Bryostatin-1 is not recommended for use as a single agent for the treatment of squamous cell head and neck cancer. Further investigation is warranted to determine the strength of the correlation between bryostatin-1 activity and PARP cleavage as a surrogate molecular marker of apoptosis.

Adult↗

PubMed2002

Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience.

PURPOSE: Irinotecan is a novel antineoplastic agent that works by inhibiting the enzyme, topoisomerase 1. Although not extensively studied in children, preclinical studies and several phase I trials indicate activity against a variety of relapsed solid tumors when administered on a protracted schedule. This report describes an institutional experience with irinotecan for the treatment of pediatric solid tumors. PATIENTS AND METHODS: Twenty-two heavily pretreated children with multiply relapsed tumors were treated with courses of irinotecan at 20 mg/m2 per day for 10 days [(every day x 5) x 2]. RESULTS: Of the 19 patients evaluable for response, four achieved an objective response, including two complete responses and one partial response among four patients with rhabdomyosarcoma and one additional patient with an undifferentiated sarcoma with rhabdomyoblastic features, and one patient with a fibrosarcoma had stable disease. Among three patients with non-Hodgkin lymphoma, one achieved a partial response and one had stable disease. Diarrhea was the most commonly observed toxicity. CONCLUSION: Irinotecan appears to have promising single-agent activity, particularly against rhabdomyosarcoma. with minimal hematopoietic toxicity, making it ideal for further evaluation in patients at high risk with newly diagnosed disease, particularly in combination with other active agents with nonoverlapping toxicities.

Adolescent↗