Biomedical subjects

K J Cullen

Publications and source records attributed to K J Cullen.

At least 19 recordsLinked to original sources

PubMed2001

Planned neck dissection for advanced primary head and neck malignancy treated with organ preservation therapy: disease control and survival outcomes.

BACKGROUND: The role of planned neck dissection after organ preservation therapy with radiotherapy or chemotherapy/radiotherapy for advanced head and neck cancers presenting with clinically positive neck disease is still being elucidated. The aim of this study is to review the outcomes of such patients treated by organ preservation therapy at our institution. METHODS: A retrospective chart review of 33 patients who underwent planned neck dissections after organ preservation therapy for advanced primary head and neck malignancy. Endpoints measured were disease-free survival and local, regional, and distant control. SETTING: Tertiary metropolitan medical center. RESULTS: Two-year actuarial disease-free survival was 61%, and neck control was 92%, with only two failures in the neck. The use of neoadjuvant chemotherapy and total dose of radiotherapy did not correlate with neck control or disease-free survival. The presence of pathologically positive nodal disease at the time of neck dissection did not correlate with recurrent neck disease, but was a predictor of local recurrence (p = .0086). CONCLUSIONS: Our data suggest that for patients undergoing planned neck dissection after organ preservation therapy, neck control is obtained in almost all cases. The presence of pathologically positive nodal disease at the time of surgery may have implications for the incidence of local recurrence.

Combined Modality Therapy↗

PubMed2000

Prognostic value of c-erbB2 and other markers in patients treated with chemotherapy for recurrent head and neck cancer.

BACKGROUND: Chemotherapy is widely used in patients with recurrent head and neck cancer, but no clear markers are available that can predict response to treatment or survival in these patients. METHODS: Twenty-nine patients evaluated in this study had recurrent head and neck squamous carcinomas, previously treated with surgery and/or radiotherapy. Patients received either cisplatin and 5-fluorouracil (5-FU) (n = 15) or cisplatin and paclitaxel (Taxol) (n = 14). Expression of c-erbB2, p53, glutathione S-transferase pi, multidrug resistance-associated protein, thymidylate synthase, and glutathione synthetase were evaluated in biopsy tissues. RESULTS: Response to chemotherapy was significantly correlated with improved survival (progression-free survival, p =.0005; overall survival, p =. 007). Of the factors examined, expression of c-erbB2 was associated with significantly decreased progression-free survival (p =.023) and overall survival (p =.029). This was seen in patients treated with cisplatin/taxol but not in patients treated with cisplatin/5-FU. CONCLUSION: Expression of c-erbB2 may be a clinically useful predictor of survival in this group of patients.

Adult↗

PubMed2000

Decreased cisplatin/DNA adduct formation is associated with cisplatin resistance in human head and neck cancer cell lines.

PURPOSE: To evaluate the correlation between cisplatin sensitivity, intracellular glutathione, and platinum/DNA adduct formation (measured by atomic absorption spectroscopy) in a series of seven head and neck cancer cell lines, and to evaluate the effect of biochemical modulation of glutathione on platinum/DNA adduct formation and repair. METHODS: Cisplatin/DNA adducts were measured by atomic absorption spectroscopy. Glutathione content was measured by enzymatic assay and was modulated with buthionine sulfoximine. Apoptosis was measured by double-labeled flow cytometry. RESULTS: Intracellular glutathione concentration was strongly correlated with cisplatin resistance (P = 0.002, R2 = 0.7). There was also a statistically significant inverse correlation between cisplatin/DNA adduct formation and the IC50 for cisplatin in these cell lines. (P = 0.0004, R2 = 0.67). In addition, resistant cells were able to repair approximately 70% of cisplatin/DNA adducts at 24 h, while sensitive cells repaired less than 28% of adducts in the same period. However, despite the positive correlation between cellular glutathione and cisplatin resistance, there was no direct correlation between intracellular glutathione concentration and platinum/DNA adduct formation. Further, depletion of intracellular glutathione by buthionine sulfoximine did not dramatically alter formation of cisplatin/DNA adducts even though it resulted in marked increase in cisplatin cytotoxicity and was associated with increased apoptosis. CONCLUSIONS: These results suggest that glutathione has multiple effects not directly related to formation of cisplatin/DNA adducts, but may also be an important determinant of the cell's ability to repair cisplatin-induced DNA damage and resist apoptosis.

Antineoplastic Agents↗

PubMed2000

Local feedback mechanisms in human breast cancer.

Breast function and development are controlled by a variety of both local and systemic signals. Many of these signals are exerted by hormones and cytokines which are believed to be effectors in autoregulatory feedback loops. Recent studies have also suggested the involvement of such mechanisms in human breast cancer. For example, the disruption of a negative feedback system by malignant transformation can result in the loss of growth control or in increased malignant behavior of tumor cells. Conversely, pathological positive feedback loops can develop that enhance tumor growth and invasion by excessive release of stimulatory factors. These loops are often located at the site of tumor invasion and involve stromal-epithelial interactions. They can be composed of mutually stimulating or inhibiting cytokines and may include locally expressed sex steroids. Although most studies have concentrated on cell-cell interactions at the site of the primary tumor, a number of observations indicate their importance in metastases as well. A thorough analysis of the regulatory mechanisms within a malignant tumor is essential for the understanding of its unique behavior and for the investigation of more specific breast cancer therapies.

Breast Neoplasms↗

PubMed2000

Molecular markers predictive of response and prognosis in the patient with advanced squamous cell carcinoma of the head and neck: evolution of a model beyond TNM staging.

Advanced head and neck cancer is a disease with poor prognosis. TNM staging is an inadequate prognostic indicator of individual response to evolving multimodal therapies. New markers have been studied in progressively more refined analyses. Even though their role in predicting response and prognosis of head and neck cancer is still under evolution, it is becoming clear that individual markers are inadequate in constructing a prognostically meaningful tumor profile for each patient. Rather the combined study of a number of well-characterized markers acting in unrelated cellular pathways may be much more successful in defining prognostic patient categories of greater utility than traditional TNM staging. Special attention should also be paid to the expression pattern and location of tumor markers within the biopsy specimen as these parameters also appear to influence prognostic significance.

Biomarkers, Tumor↗

PubMed2000

Insulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women.

We explored the relationship between insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk. Also, we examined whether obesity, sex hormone-binding globulin (SHBG), and estradiol influenced IGF-1 concentrations. A pilot study of 60 postmenopausal African-American women (30 cases and 30 controls) was used. Plasma concentrations of IGF-1 were higher among the cases, as compared to the controls. A negative trend was seen for plasma concentrations of IGF-1 and TNM (tumor-node-metastasis) stage and IGF-1 and body mass index. IGF-1 was found to be associated negatively with SHBG. After adjustment, plasma concentrations of IGF-1 remained significantly and positively associated with breast cancer risk (odds ratio, 1.183; 95% confidence interval, 1.167-1.201). No significant associations for breast cancer risk were observed for estradiol, SHBG, and body mass index. Further research with a larger sample is needed to clarify the relationships between obesity and IGF-1 concentrations to breast cancer risk in this population.

Aged↗

PubMed1999

Complications from planned, posttreatment neck dissections.

OBJECTIVE: To report the complication rate from planned, posttreatment neck dissections in patients who show control of primary squamous cell carcinoma by chemotherapy and radiotherapy or radiotherapy alone. DESIGN: Retrospective review of case series. SETTING: Georgetown University Medical Center, Washington, DC. PATIENTS: Thirty-four patients with clinically positive neck disease treated with organ preservation therapy for squamous cell carcinoma of the head and neck. INTERVENTIONS: Planned neck dissection after treatment with chemotherapy and radiotherapy or radiotherapy alone. MAIN OUTCOME MEASURE: Perioperative complications. RESULTS: Forty-one neck dissections were performed on 34 patients. Complications were seen in 13 (38%) of 34 patients and 15 (37%) of 41 neck dissections. Wound complications occurred in 9 (22%) of 41 dissections. Neck dissection complication rate did not correlate with previous use of chemotherapy or with the use of brachytherapy at the primary site at the time of the neck dissection. Preoperative radiotherapy dose greater than 70 Gy was associated with complications in 58% vs 29% when preoperative dose was less than 70 Gy (P = .09). This trend was reflected primarily in wound complications (42% vs 14%; P = . 10) and reached significance for skin flap necrosis (33% vs 0%; P = .005). Other factors that were associated with increased complications were preoperative albumin level less than 38 g/L and early neck drain removal. CONCLUSIONS: The complication rate associated with planned posttreatment neck dissection is similar to that previously reported for neck dissection. Wound complications are more common when higher preoperative radiotherapy doses are used.

Carcinoma, Squamous Cell↗

PubMed1999

Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer.

Neoadjuvant cisplatin-based chemotherapy has been widely used in the last decade for organ preservation or unresectable disease in advanced stage head and neck cancer. We examined the expression of a series of tumor markers that have been associated with chemotherapy resistance in pretreatment biopsies from 68 patients who received cisplatin-based neoadjuvant chemotherapy at either of two institutions. Patients received either cisplatin/5-fluorouracil (n = 49) or cisplatin/paclitaxel (n = 19). Expression of p53, glutathione S-transferase pi (GSTpi), thymidylate synthase (TS), c-erbB2, and multidrug resistance-associated protein was examined by immunohistochemistry. Expression of glutathione synthetase mRNA was measured by in situ hybridization. The overall response rate for cisplatin-based neoadjuvant treatment was 79%. The expression of several of the tumor markers was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 81% in the p53-negative group, whereas it was 30% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of GST pi and TS was also significantly correlated with decreased OS after neoadjuvant treatment. At 3 years, the OS rate was 82% in the low GSTpi score group, compared to 46% in the high GSTpi score group (P = 0.0018). In the TS-negative group, the 3-year OS rate was 71% compared with 40% in the TS-positive group (P = 0.0071). We conclude that p53, GSTpi, and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer.

Adolescent↗

PubMed1998

Association between expression of glutathione-associated enzymes and response to platinum-based chemotherapy in head and neck cancer.

We examined the correlation between response to platinum-based chemotherapy and expression of glutathione S-transferase (GST), gamma-GGT (both by immunohistochemistry) and gamma-GCS (by in situ hybridization) in 51 patients with head and neck cancer, who received a total of 56 courses of chemotherapy. The overall response rate for the 56 chemotherapy treatment courses was 48%. The overall response rate (CR, PR) for patients with low GST scores was 88% (21 of 24), while among the patients with high GST scores, the overall response rate was 19% (6 of 32, P = 0.001). Patients with a low GST score were 4.7 times more likely to respond to chemotherapy than patients with high GST scores. GST scores corresponded to response in 84% of cases. Among 33 patients treated with chemotherapy for relapsed disease, the overall response rate for patients with low GST score was 70% (7 of 10), while among the patients with high GST scores, the overall response rate was 8.7% (2 of 23), P < 0.001). In contrast, both gamma-GCS and gamma-GGT showed a range of expression in these samples, but there was no significant correlation with treatment response. We conclude that GST expression correlates well with response to platinum based chemotherapy in head and neck cancer.

Aged↗

PubMed1998

Stromal IGF-II messenger RNA in breast cancer: relationship with progesterone receptor expressed by malignant epithelial cells.

In breast cancer, insulin-like growth factor II (IGF-II) is stromal in origin and is considered an important regulator of tumour epithelium growth. The presence of progesterone receptor (PR) is expression of an intact oestrogen regulatory pathway of breast malignant epithelial cells and represents a parameter of cell differentiation in breast cancer. In this study we have examined the relationship between IGF-II mRNA expression and ER, PR content in 75 breast cancer. Formalin-fixed paraffin-embedded tissue sections were used to preserve histological details. IGF-II mRNA was evaluated by in situ hybridisation method and ER, PR by immunohistochemistry. IGF-II mRNA was scored semi-quantitatively: 2.6% breast tumour specimen expressed no IGF-II mRNA, 46.7% had low levels of expression (IGF-II-) and 50.7% had moderate or high IGF-II mRNA content (IGF-II+). IGF-II mRNA was found in the stroma fibroblasts surrounding malignant lesions and no signal was detected in malignant epithelial cells. In contrast, ER and PR were expressed only by neoplastic epithelial cells and no immunoreactivity was found in the stroma: 50/75 (66.6%) breast cancer specimens were positive for ER (ER+) and 35 (46.6%) for PR (PR+). Both, IGF-II mRNA and PR were directly correlated with the stromal proliferation (p < 0.05 and p < 0.001, respectively). No relationship was found between IGF-II RNA and ER. In contrast 24/35 (73.5%) PR breast cancer tissues were IGF-II+ (p < 0.01) and a strong correlation was found between epithelial PR immunostaining and stromal IGF-II mRNA content (p < 0.003). Our data indicate that in breast cancer IGF-II mRNA is generally expressed by stromal cells and ER and PR by epithelial cancer cells, and that IGF-II mRNA expression is strongly related with both percentage and staining intensity of PR+ epithelial cancer cells. These data support the hypothesis that IGF-II produced by the fibroblasts may exert a paracrin effect on malignant epithelium regulating its differentiation.

Breast Neoplasms↗

PubMed1998

Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors.

Local environmental signals regulate the growth and development of both normal and malignant breast epithelium. Members of the insulin-like growth factor (IGF) family likely influence both of these processes. The localization of IGF2 to stroma specifically surrounding malignant breast epithelium indicates that this growth factor may play a critical role in the genesis or maintenance of this transformed phenotype. Recent studies have sought to understand the mechanism by which IGF2 expressing fibroblasts are localized to the periphery of malignant breast cancer cells. In addition, the consequences of the expression of IGF-signaling components likely expand beyond their direct effects on mitogenesis. Indirect effects predominantly associated with the IGF2 receptor could also influence the invasive potential of breast tumor cells.

Animals↗

PubMed1997

Glutathione content but not gamma glutamyl cysteine synthetase mRNA expression predicts cisplatin resistance in head and neck cancer cell lines.

PURPOSE: To correlate cellular glutathione content and gamma-glutamyl cysteine synthetase (gamma GCS) mRNA expression with cisplatin sensitivity in a panel of seven head and neck squamous cancer cell lines. METHODS: Cisplatin IC50 was determined for each cell line using a sodium tetreazolium (XTT) assay. Cellular glutathione content was measured by using a previously reported enzymic method. gamma GCS mRNA expression was measured using an RNase protection assay. RESULTS: Total cellular glutathione was an excellent predictor of cisplatin sensitivity in this series of cell lines. The IC50 for cisplatin in the cell line with the highest glutathione concentration was approximately 90 times higher than in the cell line with the lowest glutathione concentration. Regression analysis showed a highly statistically significant positive correlation between cisplatin IC50 and cellular glutathione (coefficient of determination R2 = 0.81, P = 0.0012). Some-what surprisingly, in contrast to previous studies in ovarian cancer, gamma GCS mRNA expression in these cell lines was not significantly predictive of either total cellular glutathione or cisplatin sensitivity (R2 = 0.005, P = 0.84). As expected, treatment of resistant cell lines with buthionine sulfoximine resulted in decreased cellular glutathione and enhanced cisplatin sensitivity. CONCLUSIONS: Our results suggest that glutathione may be an important determinant of cisplatin sensitivity in clinical head and neck cancer. Since cisplatin is the most active chemotherapy drug for the treatment of this disease, this correlation may have important clinical relevance. The lack of correlation between glutathione level and gamma GCS expression suggests that salvage or alternate synthetic pathways may be critical in these cells.

Buthionine Sulfoximine↗

PubMed1997

Coexpression of stromelysin-3 and insulin-like growth factor II in tumors of ectodermal, mesodermal, and endodermal origin: indicator of a fetal cell phenotype.

Stromelysin-3 (ST-3) is thought to play an important role in invasion and tumor progression. We have analyzed ST-3 expression in fibroblasts with defined topographical relations to breast cancers. We demonstrate that these fibroblasts exhibit the same distinctive pattern of messenger ribonucleic acid (mRNA) expression that we have previously shown for insulin-like growth factor II (IGF-II). Tumor-derived fibroblasts and skin fibroblasts produce abundant ST-3 mRNA. Fibroblasts from normal breast stroma distant from the malignant tumor in the same patient express considerably less ST-3 mRNA. When we analyzed ST-3 and IGF-II gene expression in sarcomas, we found a similar pattern of coexpression. Immunohistochemical analysis of IGF-II and ST-3 protein expression in sarcomas and breast tumors confirmed the mRNA data. ST-3 mRNA expression was also seen in most colon cancer cell lines, again matching reports of IGF-II gene expression. As the two proteins are known to play an important role during fetal growth and development, their coexpression in fibroblasts from malignant tumors of ectodermal (breast cancer) and mesodermal (sarcoma) origin and in epithelial cells of endodermal origin (colon cancer) implies a more primitive cellular phenotype. The regained ability to express such developmentally regulated proteins might, therefore, be a more general marker indicating a fetal-type phenotype of cells in a malignant tumor.

Breast Neoplasms↗

PubMed1996

IGF-II mRNA and protein are expressed in the stroma of invasive breast cancers: an in situ hybridization and immunohistochemistry study.

Insulin-like growth factor-II (IGF-II) is a potent mitogen for a variety of cell types and is considered an important regulator of breast cancer growth. In this study, we analyzed IGF-II mRNA and protein expression in a series of 80 cases of invasive breast cancer. Seventy-five cases produced informative results for IGF-II mRNA expression, and were scored on an arbitrary scale. Two cases (2.6%) had no significant IGF-II mRNA expression. 35 cases (46.7%) expressed low levels of IGF-II mRNA, 20 cases (26.7%) moderate IGF-II mRNA, while 18 (24%) expressed high levels of IGF-II message. Generally, IGF-II mRNA was expressed in the smooth muscle walls of blood vessels and ducts, as well as in the stroma tightly adjacent to and surrounding tumor epithelium. IGF-II mRNA content was also directly related to the amount of the stroma within the tumor (p < 0.05). In 10 cases (13.3%) IGF-II mRNA was detected in the stroma of normal lobules. Fifty-six out of 75 were positive for IGF-II immunostaining. Again, protein staining was generally observed in the smooth muscle of both blood vessels and ducts, as well as in the stroma surrounding tumor epithelium. In normal lobules and ducts the IGF-II protein was detected in the myoepithelium. Unequivocal IGF-II protein staining was seen in tumor epithelium in only three cases. The results of our study demonstrate that, in breast cancer, IGF-II mRNA is expressed in the smooth muscle and stromal components in the majority of invasive breast cancers. IGF-II expression correlates positively with the amount of stromal tissue present within a tumor. This suggests that IGF-II may have an important growth regulatory effect on breast tumor epithelium through paracrine pathways.

Adult↗

PubMed1996

Long-term follow-up of the Busselton six-year controlled trial of prevention of children's behavior disorders.

This study reports the follow-up in 1993 of 209 adults, aged 27 to 29 years, who as children had been enrolled in a controlled trial of the prevention of children's behavior disorders. One hundred four control subjects and 105 study subjects, representing 90% of the original cohort, responded to a questionnaire detailing their present social situation and habits, educational achievements, and emotional well-being. The study subjects overall reported significantly fewer neurotic symptoms (p <0.001) than the control subjects; the study women also reported significantly fewer depressive symptoms (p <0.001). A greater proportion of the study subjects, compared with control subjects, had undertaken a university degree or diploma (p <0.013), whereas fewer of the men had attended a school of technology (p <0.049). The study women were less likely to be obese, as defined by a body mass index of 25 or more (p <0.030). The study men and women tended to smoke less than their control subjects, though significant differences were not attained. These results in the experimental group reflected the behavior patterns recorded at 6 years of age, after initial preschool interventional therapy. It appears that the initial benefit obtained from active counseling of mothers about their preschool children's behavior may be long lasting, favorably affecting the individuals' psychologic well-being, educational achievements, and social habits as adults.

Adult↗

PubMed1996

Affinity for the insulin-like growth factor-II (IGF-II) receptor inhibits autocrine IGF-II activity in MCF-7 breast cancer cells.

We have investigated the autocrine regulation of insulin-like growth factor-II (IGF-II) signaling by the insulin-like growth factor-I receptor (IGF-IR) and the insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-IIR) in MCF-7 breast cancer cells, employing retroviruses encoding both IGF-I, IGF-II, and IGF-I and II mutants with reductions in affinity for either the IGF-IR or the IGF-IIR. These studies revealed reciprocal roles for IGF-IR and IGF-IIR affinity in the regulation of autocrine IGF-II activity. IGF-IR affinity was required for serum-free proliferation but also for efficient IGF-II secretion. In contrast, cellular proliferation, receptor tyrosine kinase-dependent signaling, and extracellular IGF-II protein accumulation were all reduced in the presence of IGF-IIR affinity. Inhibition of IGF-II signaling appeared to be the sole consequence of IGF-IIR affinity, as no cellular responses attributable to selective IGF-IIR binding by a reduced IGF-IR affinity IGF-II mutant could be detected. By operating as an IGF-II antagonist, the IGF-IIR has tumor suppressor-like properties, a suggestion consistent with reports of loss of heterozygosity at the IGF-IIR locus in a variety of human malignancies.

Amino Acid Sequence↗

PubMed1996

Immunohistochemical staining for glutathione S-transferase predicts response to platinum-based chemotherapy in head and neck cancer.

The glutathione S-transferases (GSTs) play an important role in the cell's defense against toxic substances. The GSTs are a family of enzymes produced by several genes that interact with distinct but overlapping substrates and that may play a role in resistance of tumor cells to several chemotherapeutic agents. We examined the correlation between expression of GSTs determined by immunohistochemistry and clinical response to platinum-based chemotherapy in 51 patients with head and neck cancer, who received a total of 56 courses of chemotherapy. The overall response rate for the 56 chemotherapy treatment courses was 48%. The overall response rate (complete response + partial response) for patients with low GST scores was 88% (21 of 24), whereas among the patients with high GST scores, the overall response rate was 19% (6 of 32; P = 0.001). Patients with a low GST score were 4.7 times more likely to respond to chemotherapy than patients with high GST scores. GST scores corresponded to response in 84% of cases. Among 23 patients treated with neoadjuvant chemotherapy, the overall response rate for patients with low GST scores was 100% (14 of 14), whereas among the patients with high GST scores, the overall response rate was 44% (4 of 9; P = 0.002). Among 33 patients treated with chemotherapy for relapsed disease, the overall response rate for patients with low GST scores was 70% (7 of 10), whereas among the patients with high GST scores, the overall response rate was 8.6% (2 of 23; P < 0.001). We conclude that GST expression correlates well with response to platinum-based chemotherapy in head and neck cancer.

Antineoplastic Agents↗

PubMed1995

Malignant breast epithelium selects for insulin-like growth factor II expression in breast stroma: evidence for paracrine function.

Paracrine interactions between stromal and epithelial cells are important influences on the growth and malignant behavior of breast cancers. Insulin-like growth factors I and II (IGF-I and II) are expressed by fibroblasts in benign and malignant breast lesions, and both are strong mitogens for a number of breast cancer epithelial cell lines in vitro. We have analyzed the stromal mRNA expression of IGF-I and IGF-II in matched sets of fibroblast cell lines derived from three locations in the affected breast of eight patients with breast cancer: (a) the breast tumor itself; (b) surrounding normal breast tissue; and (c) overlying breast skin. IGF-I expression was easily detected in all fibroblasts derived from normal breast tissue. In general, lesser amounts of IGF-I mRNA were detected in fibroblasts derived from breast tumors or skin. In contrast, IGF-II expression was detected at very low levels in only 3 of 8 normal breast fibroblasts, but was present in 6 of 8 tumor fibroblasts. IGF-II mRNA was expressed in all skin fibroblasts tested. IGF-II-negative stromal fibroblasts from normal breast, which were plated at low density and allowed to grow to confluence in the presence of MCF-7 breast tumor epithelial cells, demonstrated a marked increase in IGF-II mRNA expression. IGF-II in situ hybridization studies confirmed that IGF-II expression is seen at high levels in stroma of many invasive breast cancers but not normal breast. We conclude that paracrine influences, mediated by soluble factors released by breast tumor epithelium, are able to specifically increase expression of IGF-II in breast stroma, most likely by a process of clonal selection.

Breast↗