Darryl Carter

Prognostic Significance of Vascular Endothelial Growth Factor Protein Levels in Oral and Oropharyngeal Squamous Cell Carcinoma

PURPOSE Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis in many different tumor types. VEGF levels may affect tumor growth, metastatic potential, and response to radiotherapy. This study assesses the prognostic value of VEGF protein levels in a cohort of patients with oral and oropharyngeal squamous cell carcinomas. The relationships between clinical outcome and the covariables of tumor-node-metastasis stage, disease stage (I to IV), grade, margin status, race, sex, and age were also determined. PATIENTS AND METHODS Chart review identified 77 patients with oral or oropharyngeal squamous cell carcinoma treated with gross total surgical resection and postoperative radiation between 1981 and 1992. Sufficient follow-up data and tumor tissue were available in 56 patients (73%). VEGF protein levels were determined using immunohistochemistry. The association between VEGF status, covariables, and outcome was assessed in a bivariate and multivariate model using two-sided statistical tests. RESULTS Twenty-three tumors (41%) were positive for VEGF expression. VEGF-positive tumors were more likely to recur locally (relative risk [RR] = 3.08; 95% confidence interval [CI], 1.03 to 9.24) and distantly (RR = 4.62; 95% CI, 1.41 to 15.10). In bivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.66; 95% CI, 1.27 to 5.56) and overall survival (RR = 3.21; 95% CI, 1.63 to 6.32). In multivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.75; 95% CI, 1.30 to 5.79) and overall survival (RR = 3.53; 95% CI, 1.75 to 7.13). CONCLUSION In this cohort, VEGF positivity was the most significant predictor of poor prognosis. VEGF status may prove to be an important prognostic factor in head and neck cancer.

Carcinoma in situ of the breast

A series of 87 cases of carcinoma in situ of the breast was reviewed. In 49 cases in which lobular carcinoma in situ was shown on biopsy, three patients were found to have inyasive carcinoma in the subsequently done mastectomy. All three of these cases were in a group of 14 patients shown to have bilateral lobular carcinoma in situ on biopsy. In a group of 38 patients with intraductal carcinoma on biopsy, seven were found to have invasive carcinoma in the mastectomy that was subsequently done. Lymph node metastases were found in one patient in the lobular group and four patients in the intraductal group. Three patients in the intraductal group died of cancer. None in the lobular group has died of cancer.

A clinical and histopathologic analysis of the results of conservation surgery and radiation therapy in stage I and II breast carcinoma

One hundred eighty women with clinical Stage I or II operable breast carcinoma were treated by radiotherapy following local tumor excision at Yale‐New Haven Hospital through 1980. With a median follow‐up time of 6.9 years, the actuarial 5‐year overall and disease‐free survival rates were 82% and 78%, respectively. The 5‐year actuarial breast‐recurrence‐free survival rate was 92%. Several clinical‐histopathologic features and treatment parameters were assessed for their significance as predictors of local breast failure or distant relapse. Cox lifetable regression analysis showed that patients with clinical Stage II carcinomas had significantly worse overall and relapse‐free survival rates, but clinical stage alone had no effect on the rate of breast recurrence. Furthermore, a decrease in overall and disease‐free survival was evident when necrosis was present in the tumor or when patients had an infiltrating lobular carcinoma. Breast recurrence‐free survival was also influenced adversely by the presence of these two tumor features, especially when either tumor necrosis or infiltrating lobular carcinoma was found in conjunction with clinical Stage II lesions. Other histologic features such as grade, vascular invasion, perineural invasion, or the presence of an intraductal component of carcinoma did not affect outcome, nor did the treatment techniques employed appear to have a differential effect.

Intracystic papillary carcinoma of the breast after mastectomy, radiotherapy or excisional biopsy alone

Intracystic papillary carcinoma of the breast (IPC) was distinguished from the more common papillary intraductal carcinoma (DCIS) and infiltrating duct carcinoma with a papillary pattern. IPC was defined as a solitary tumor with a pattern recognizable as carcinoma which is confined to a dilated duct. A series of 41 such cases was collected from three institutions. Twenty‐nine patients underwent mastectomy; 11 of them had axillary dissections. None of these patients had metastatic disease in the axillary lymph nodes or recurrence in the follow‐up period which averaged five years. Eleven patients did not have mastectomy or radiotherapy. Eight of these patients (followed for an average of ten years) had no recurrence. The only patients who developed invasive carcinoma were those with DCIS as well as IPC in the excisional biopsy. The data suggest that IPC is much more likely to be cured by local treatment than is IPC accompanied by DCIS. Cancer 52:14‐19, 1983.

Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: Histopathologic features and their prognostic implications

PURPOSE To study the histopathologic features of CT screen-detected Stage IA adenocarcinomas to determine whether survival differed by the proportion of bronchioloalveolar component (BAC) or by the presence of multiple lesions in node-negative patients. METHODS Five pathologists with expertise in pulmonary pathology examined 279 resected cases of adenocarcinomas, 30 mm or less in length diagnosed by CT screening for lung cancer. The panel determined the consensus diagnosis for each case, identified additional cancers, and classified each case as solitary or non-solitary. The presence and proportion of BAC was also documented. RESULTS Of the cases of adenocarcinoma, 20 (7%) were BAC subtype, 246 (88%) mixed subtype and 13 (5%) adenocarcinoma-OTHER. BAC cases manifested as non-solid and part solid nodules, mixed as solid and part-solid, and other as solid only. Kaplan-Meier 10-year survival rates were 100% for BAC and adeno-MIXED with 90-99% BAC cases, 95% for mixed with 1-90% BAC, 90% for those without a BAC component, and 75% for other cases. Fifty (18%) cases were non-solitary carcinomas and 44 of these were node negative; the non-solitary node-negative cases had the same excellent prognosis as solitary node-negative cases. CONCLUSIONS The proportion of BAC component was a positive prognostic factor and correlated with CT consistency. Contrary to staging predictions, cases of non-solitary node-negative adenocarcinoma had the same excellent prognosis as solitary node-negative cases, suggesting that most of the small, node-negative multiple carcinomas probably represent multiple primaries rather than intrapulmonary metastasis.

Characterization of a murine model of endotoxin-induced acute lung injury.

Endotoxin-induced microvascular lung injury in mice is a commonly used experimental model of the acute respiratory distress syndrome (ARDS). The present paper aimed to characterize this popular model in a comprehensive and systematic fashion. Male C57bl/6 mice (n = 5) were administered an LD55 dose of E. coli endotoxin (15 mg/kg, i.p.), and lungs were harvested at several time points and evaluated for injury as well as for expression of a variety of inflammatory mediators. Endotoxin induced many features characteristic of acute microvascular lung injury. These included early (1-2 h) expression of inflammatory mediators (IL-1&agr;, IL-1&bgr;, IL-4, IL-6, IL-10, TNF-&agr;, interferon-&agr;, interferon-&ggr;, and MCP-1) and leukocyte accumulation in lung tissue (lung myeloperoxidase activity 18.5 ± 7.8 U/g tissue, P < 0.05), followed by pulmonary edema (lung water content index 17.4% ± 2.5%, P < 0.05) and mortality. Histopathological evaluation of lung tissue was compatible with these findings. The characterization of this murine model of endotoxin-induced microvascular injury will facilitate its utilization in ARDS research.

Microsatellite instability in ovarian neoplasms.

Microsatellite instability has been observed in a variety of sporadic malignancies, but its existence in sporadic ovarian cancer has been the subject of conflicting reports. We have performed a polymerase chain reaction-based microsatellite analysis of DNAs extracted from the neoplastic and non-neoplastic tissues of 41 ovarian cancer patients. Tumour-associated alterations were observed in seven (17%) of these cases. Clinicopathological correlations revealed that: (1) alterations among tumours classified as serous adenocarcinomas occurred with relatively low frequency (2/24 or 8%); (2) most of the tumours with microsatellite alterations (5/7 or 71%) were of less common histopathological types (epithelial subtypes such as endometrioid and mixed serous and mucinous, or non-epithelial types such as malignant mixed Müllerian or germ cell tumours); (3) tumour-associated alterations were observed in 3/4 (75%) of the patients with stage I tumours vs 4/37 (11%) of the patients with stage II, III and IV tumours (P = 0.01); (4) tumour-associated microsatellite instability was found to occur with similar frequencies among patients with and without clinical features suggestive of familial disease, including positive family history, early onset, or multiple primary tumours. In summary, we have observed microsatellite alterations in the neoplastic tissues of ovarian cancer patients with diverse genetic backgrounds and clinicopathological features. The pattern of alterations is consistent with the possibility that multiple mechanisms may be responsible for microsatellite instability in ovarian neoplasms.

Incidence of BRCA1 and BRCA2 Mutations in Young Korean Breast Cancer Patients

PURPOSE The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively. METHODS Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining. RESULTS In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors. CONCLUSION The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.

Breast Carcinoma Tumor Characteristics in Black and White Women

A significant disparity in mortality rates exists between black and white patients with breast carcinoma. This study was designed to compare breast carcinoma tumor characteristics by race and to examine the possible reasons for these differences.

EVALUATION OF HER-2 NEU ONCOPROTEIN EXPRESSION AS A PROGNOSTIC INDICATOR OF LOCAL RECURRENCE IN CONSERVATIVELY TREATED BREAST CANCER: A CASE-CONTROL STUDY

PURPOSE The purpose of this study is to determine the prognostic significance of overexpression of the HER-2 neu oncoprotein with respect to local relapse following conservative surgery and radiation therapy (CS + RT). METHODS AND MATERIALS Twenty consecutive patients who sustained a local recurrence as the first and only site of failure following CS + RT comprised the case population base for this study. Only patients who received no adjuvant systemic chemotherapy or tamoxifen were selected for analysis. Following the identification of 20 consecutive local-relapse patients, the patient database was searched for 20 matching control patients who did not sustain a local relapse. Each control patient was matched to the index case with respect to age, menopausal status, follow-up, primary histology, axillary nodal status, and primary tumor size. Both index cases and the matched control group received full course radiation therapy, to a total dose of 64 Gy to the tumor bed. The paraffin-embedded blocks of the original primary tumor of the local-relapse cases and the primary tumor of 20 matched controls were processed for immunohistochemical staining of the HER-2 neu oncoprotein. Each slide was rated on the 3-point scale, 0 representing no stain, 1+ indicating light staining, and 2+ denoted heavy staining (overexpression). RESULTS Of the 20 index cases, with each of the matched controls, 16 were evaluable for analysis. The 4 cases that were eliminated had inadequate paraffin-embedded material in either the case or the match control for adequate staining. By design of the study, the index case group and control group had similar ages (52 years index vs. 51.4 control), follow-up (10.8 years index vs. 10.5 years control), and histologies. For the immunostaining, a value of 2+ was considered to denote high activity and overexpression, and 0 and 1+ were considered negative values. Using these criteria, a total of 9 of the 16 index cases (56%) exhibited overexpression of HER-2 neu oncoprotein, and only 3 of the 16 control cases (18%) demonstrated high immunoreactivity. The difference in immunostaining between the index and control cases was statistically significant by a Pierson chi-square analysis at the p = 0.03 level. CONCLUSIONS In this matched case-control study, overexpression of the HER-2 neu oncoprotein appears to have prognostic significance with respect to local relapse in the conservatively treated breast. The correlation of overexpression of HER-2 neu by multivariable analysis with other prognostic factors for local recurrence warrants further investigation. The clinical implications of the study are discussed.