Angiogenesis does not predict clinical response to doxorubicin monotherapy in patients with locally advanced breast cancer.
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Antibiotics, Antineoplastic↗
Biomedical subjects
J E Varhaug
Publications and source records attributed to J E Varhaug.
Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas.
c-erbB-3 and c-erbB-4 protein expression was analyzed using immunohistochemistry in 138 fresh-frozen thyroid tissue samples from 106 patients, including 56 cases of papillary thyroid carcinoma. Increased expression of c-erbB-3 and c-erbB-4 proteins was observed in papillary carcinomas compared to nonneoplastic thyroid tissue. No amplifications of the c-erbB-3 and c-erbB-4 genes were detected. Coexisting overexpression of epidermal growth factor receptor, c-erbB-2, c-erbB-3, and c-erbB-4 was demonstrated in 36 (64%) of 56 papillary thyroid carcinomas. These findings suggest a common regulatory mechanism for the type I (epidermal growth factor receptor-related) receptors in papillary thyroid carcinomas and provide numerous possibilities for functional receptor interactions.
Biomarkers, Tumor↗
Cytoplasmic localization of EGF receptor in papillary thyroid carcinomas: association with the 150-kDa receptor form.
We have previously reported that papillary thyroid carcinomas show an increased expression of EGFR mRNA and protein, compared to non-tumorous thyroid tissue. EGFR immunoreactivity was localized to the cytoplasm as well as to the membrane in papillary carcinomas. To further study EGFR protein expression in human thyroid tissue, we performed immunohistochemistry and Western blots of 64 different thyroid tissue samples from 36 patients, including 23 patients with papillary carcinomas. Two receptor forms were identified in human thyroid tissue, a 170-kDa and a 150-kDa form. The 150-kDa receptor form was more pronounced in papillary carcinomas, while the 170-kDa receptor was the dominant form in non-malignant thyroid tissues. Predominance of the 150-kDa EGFR in the tumour samples was associated with strong cytoplasmic EGFR staining. EGFR gene structure, protein synthesis and maturation were found to be normal. Immunoprecipitation and Western-blot analysis of EGFR from the human thyroid SGHTL-34 cells after increased ligand concentration showed a decreased amount of the mature 170-kDa receptor and a relative increase in the 150-kDa receptor. We have previously demonstrated the presence of a TGF-alpha-EGFR autocrine loop in papillary thyroid carcinomas, and this may explain increased receptor turnover and accumulation of a cytoplasmic degradation product.
Blotting, Western↗
Aggressive thyroid carcinoma with predominant cribriform growth pattern. Case report.
Thyroid carcinomas demonstrate a morphological and biological spectrum from highly differentiated to undifferentiated (anaplastic) tumours, and the poorly differentiated carcinomas probably occupy an intermediate position, being characterized by a more solid structure. The present thyroid carcinoma, which occurred in a 77 year old male, showed a distinct cribriform growth pattern with marked apoptosis and high-grade features such as nuclear plemorphism, frequent mitotic figures, tumour necrosis and vascular invasion, suggesting the presence of a poorly differentiated carcinoma. Metastatic spread to the regional lymph nodes and lungs were present at the time of diagnosis, and the patient died after 15 months with progressive disease. It should be further studied whether cribriform structure may represent an independent feature of aggressive clinical behaviour.
Aged↗
Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients.
The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5-fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.
Adult↗
Primary systemic treatment with weekly doxorubicin monotherapy in women with locally advanced breast cancer; clinical experience and parameters predicting outcome.
Sixty-three patients (median age 64 years) with locally advanced breast cancer (T3, T4 and/or N2) were treated with primary 'neoadjuvant' chemotherapy given as weekly doxorubicin monotherapy (14 mg/m2 per dose). Seven patients had solitary distant metastasis at the time of diagnosis. Twenty-eight patients (45%) achieved 'partial response' to primary chemotherapy. Twenty-nine patients (46%) had 'stable disease', and 6 patients (9%) had 'progressive disease' during treatment. Following chemotherapy, 52 patients were subjected to surgery and another 4 patients had surgery performed after radiotherapy. Surgery was considered impossible in only three patients. After a median observation time of 23 months, local recurrences were observed in 2 patients, one with progressive disease and one with stable disease during chemotherapy. Univariate analyses revealed that large tumour size, high histological grade and high mitotic frequency were associated with poor primary response to chemotherapy. Recent studies have demonstrated a correlation between p53-mutations and chemotherapy response.
Adult↗
Inherited breast carcinoma--prospective findings in 1,194 women at risk.
According to preset criteria, 1,194 women at risk for inherited breast carcinoma were selected and subjected to examination. Six hundred and three women were examined once, 591 were followed for a mean of 1.8 years. Twenty infiltrating cancers (median age 49 years) and 16 precancers (median age 44 years) were found, demonstrating that breast carcinoma continued to occur in the selected families as expected under the hypothesis of dominant inheritance. At first round, 14 (1.2%) infiltrating carcinomas and a total of 22 (1.8%) cancers or precancers were found. Incidence rates of 0.58% pr. year for infiltrating cancers, and 1.04% pr. year for cancer or precancer were calculated. This confirms the tentative conclusions that were drawn in our previous report. These are the first prospective reports documenting how to delineate a high risk group for premenopausal breast cancer, and how to diagnose cancer at an early stage. All but two affected women had cancer without lymph node metastasis. Although a longer observation time is needed, we cautiously conclude that the results are in keeping with our aim of providing safety for those at risk. Clinical use of predictive genetic testing may be implemented within these families.
Adult↗
Oncoproteins and tumor progression in papillary thyroid carcinoma: presence of epidermal growth factor receptor, c-erbB-2 protein, estrogen receptor related protein, p21-ras protein, and proliferation indicators in relation to tumor recurrences and patient survival.
BACKGROUND: The prognostic relevance of activated oncogenes and oncoproteins has not been well studied in papillary thyroid cancer, which is slow-growing, with only regional spread in most cases. Therefore, the influence of some protein markers and tumor cell proliferation on disease progress in a series of patients with surgically treated papillary thyroid carcinoma was studied. METHODS: One hundred twenty-seven patients with papillary thyroid carcinoma larger than 10 mm in greatest dimension were studied retrospectively, and the majority were treated with total or near-total thyroidectomy. Immunohistochemical and flow cytometric analyses of paraffin embedded tumor material were performed and the results were related to time to recurrence and thyroid cancer deaths using the univariate product-limit survival analysis and the multivariate Cox' regression method. RESULTS: Immunohistochemical expression of c-erbB-2 protein, estrogen receptor-related protein (p29), which may be regarded as an indicator of hormone-dependent growth, S-phase, G2M-phase, sex, age, histologic grade, and primary tumor extent were all of significant prognostic importance in univariate analyses of patient survival. In the final Cox' model, however, only male sex (P = 0.017), older age, (P < 0.00005) and high grade histologic features (P = 0.006) were associated independently with decreased survival. Among females, decreased expression of c-erbB-2 protein was independently related to decreased patient survival (P = 0.019). In multivariate analysis of time to recurrence, lymph node status (P = 0.0001), epidermal growth factor (EGF) receptor expression (P = 0.013) and estrogen receptor-related protein (P = 0.007) were independent risk indicators, and S-phase fraction (P = 0.074) showed a borderline significance. CONCLUSION: In this study, sex, age, and histologic grade were independent indicators of deaths from thyroid cancer. Lymph node metastases, EGF-receptor expression, and decreased estrogen receptor-related protein staining persisted as prognostic variables in the final multivariate analysis of recurrence free survival. Alterations in these oncogenes thus seem to play some role in disease progression in papillary thyroid carcinoma, although conventional variables are still important as prognostic indicators.
Adolescent↗
Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive, node positive breast cancer: a randomized study.
370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.
Antineoplastic Agents, Hormonal↗
Morbidity, ability to swallow, and survival, after oesophagectomy for cancer of the oesophagus and cardia.
OBJECTIVE: To study survival, morbidity, and ability to swallow, after oesophagectomy for cancer of the oesophagus and cardia. DESIGN: Prospective open study. SETTING: University hospital, Norway. SUBJECTS: 83 patients, 38 with squamous cell carcinoma and 45 with adenocarcinoma of the oesophagus and cardia. INTERVENTIONS: Transhiatal (n = 51) and transthoracic (n = 32) oesophagectomy. Oesophageal replacement was by either stomach (n = 80) or colon (n = 3). Cervical anastomosis was used in all but 2. MAIN OUTCOME MEASURES: Early and late morbidity and mortality, length of stay in intensive care unit and in hospital, and survival analysis. RESULTS: 30 Day and in hospital mortality were 0 and 4% for transhiatal, and 6% and 9% for transthoracic, oesophagectomy. Complications included recurrent nerve palsy (n = 7), anastomotic leaks (n = 5), and chylothorax (n = 4). 17 Patients (22%) needed dilatations for stenosis of the anastomosis, and 71 (85%) of the patients left hospital within four weeks of operation. Survival analysis showed a 5 year survival rate of 33% for patients with adenocarcinoma operated on for cure and a 2 year survival of 28% for patients with squamous cell carcinoma. CONCLUSIONS: Oesophagectomy for cure is worthwhile as some patients are cured and most of the remainder have prolonged relief of their dysphagia. Palliative resections should not be done in patients with distant metastases or invasion of adjacent organs by the tumour because of long stay in hospital, appreciable morbidity, and short life expectancy.
Adenocarcinoma↗
[Primary treatment of locally advanced breast cancer with neoadjuvant chemotherapy].
Since February 1991, in Health Region 3, patients with recently diagnosed Stage III breast cancer have been treated with neoadjuvant chemotherapy. This treatment includes 16 weeks of chemotherapy prior to local treatment, usually consisting of mastectomy and postoperative radiotherapy. 48 patients have so far undergone this treatment. The majority (43 patients) received chemotherapy consisting of weekly doses of Adriamycin. Even with a high average age the therapy has been well tolerated. 60% of the patients partially responded to the therapy, an additional 15% experienced minimal response. At this point it would be premature to evaluate the long term effect of the therapy. It is very interesting, however, that at this stage we have not observed any local recidive in patients who showed primary response to chemotherapy. Following primary treatment of this group of patients, local recidive is usually a frequent and early observation.
Aged↗
Evidence against involvement of APC mutation in papillary thyroid carcinoma.
Papillary thyroid carcinoma (PTC) is one of several tumours associated with familial adenomatous polyposis (FAP), an inherited tumour syndrome which appears to result from germ-line mutation of the APC tumour suppressor gene. Here we investigate the possibility that somatic mutation of APC might play a role in sporadic PTC. 16 cases of PTC together with matched normal tissue were examined by single-strand conformation polymorphism (SSCP) analysis, concentrating on the mutation cluster region (MCR) of the APC gene (codons 1286-1513). No evidence of mutation was observed in any sample. We conclude that APC mutation, at least in the MCR, is not a significant causal mechanism in sporadic PTC.
Adolescent↗
Demonstration of a TGF-alpha-EGF-receptor autocrine loop and c-myc protein over-expression in papillary thyroid carcinomas.
Autocrine growth stimulation has been identified in several types of human cancer. In the present study we wanted to establish whether autocrine stimulation of the epidermal-growth-factor receptor (EGF-r) by its ligand, transforming growth factor alpha (TGF-alpha) occurs in thyroid neoplasia. We examined 190 fresh, frozen thyroid tissue samples from 70 patients by immunohistochemistry with antibodies to EGF-r, TGF-alpha, c-erbB-2 and c-myc. EGF-r expression was detected in 17 out of 19 papillary carcinomas, TGF-alpha expression in 10, and c-erbB-2 expression in 15. No papillary carcinoma expressed TGF-alpha without also expressing EGF-r. Concomitant expression of EGF-r, TGF-alpha and c-erbB-2 was seen in 7 papillary carcinomas. No EGF-r, TGF-alpha or c-erbB-2 immunopositivity was found in normal-appearing thyroid tissue (25 cases), whereas a few of the non-neoplastic lesions (colloid goitres and diffuse hyperplasias) expressed either EGF-r or TGF-alpha. c-myc expression was detectable in all tissue samples, and expression was invariably nuclear. Increased expression was observed in 10 out of 19 papillary carcinomas, and 8 of these also co-expressed EGF-r and TGF-alpha. In situ hybridization confirmed the presence of TGF-alpha mRNA in tumour epithelium of TGF-alpha-immunopositive samples. The concomitant expression of EGF-r, TGF-alpha and TGF-alpha mRNA gives evidence for a TGF-alpha-EGF-r autocrine loop in thyroid papillary carcinomas. The increased c-myc expression may reflect the proliferative advantage of these tumours.
Carcinoma, Papillary↗
Prognostic impact of EGF-receptor in papillary thyroid carcinoma.
In this study of papillary thyroid carcinomas, immunopositivity for EGF-receptor was present in a majority of the cases (96%), although different staining patterns were observed. A distinct membraneous reaction was found in 46%, whereas cytoplasmatic positivity of various degrees was present in 90% of the cases. Strong cytoplasmic EGF-receptor staining was significantly associated with extra-thyroidal growth of the primary tumour (P = 0.009), and it was furthermore related to decreased recurrence free survival (P = 0.006). Membraneous EGF-receptor staining was not associated with recurrence free survival or patient survival. Multivariate Cox analysis showed that lymph node metastases (P = 0.0009) and cytoplasmic EGF-receptor staining (P = 0.0048) was independent indicators of tumour recurrences in this group of surgically treated papillary thyroid carcinomas.
Adolescent↗
Preoperative endocrine tumor localization utilizing a cost-effective approach.
Endocrine tumors commonly produce characteristic clinical signs, and laboratory tests lead to accurate diagnosis in a high percentage of cases. The successful management of these tumors usually requires complete surgical resection. A large number of preoperative localization procedures to facilitate the operative management of these tumors have been developed. This report reviews the recent contributions to this literature, with a particular emphasis on cost-effective use of these procedures.
Adenoma↗
Prognostic importance of various clinicopathological features in papillary thyroid carcinoma.
The influence of various pathological features on tumour recurrences and cancer deaths has been studied in 173 consecutive cases of surgically treated papillary thyroid carcinoma recorded in 1971-1985. During the follow-up (median 7.3 years), 18.6% of the 161 radically treated patients had recurrent disease, and 8.7% died of thyroid cancer. In the univariate life-table analysis, recurrence-free survival was significantly related to age, pTNM category, tumour size, presence of certain growth patterns, tumour necrosis, tumour infiltration in surrounding thyroid tissue and thyroid gland capsule, lymph node metastases, presence of extra-nodal tumour growth and number of positive lymph nodes, whereas only tumour diameter, thyroid gland capsular infiltration and presence of extra-nodal tumour growth remained as significant prognostic factors in the multivariate analysis. Regarding thyroid cancer deaths, sex, age, pTNM category, radicality of surgical treatment, tumour diameter, macroscopic appearance, cellular atypia, tumour necrosis, thyroid gland capsular infiltration, vascular invasion, extra-thyroidal extension and lymph node metastases were all significant variables in the univariate analysis. However, only sex, age, radicality of surgical treatment and vascular invasion were found to be significant predictors of thyroid cancer deaths in the final multivariate Cox model, whereas cellular atypia and necrosis showed a borderline significance. Our study thus documents the independent importance of certain histological features for morbidity and mortality in surgically treated cases of papillary thyroid cancer.
Adolescent↗
Expression of c-erbB-2 protein in papillary thyroid carcinomas.
c-erbB-2 protein expression was investigated immunohistochemically in frozen thyroid tissue specimens from 42 patients using a polyclonal sheep antibody. c-erbB-2 immunoreactivity was detected in 12 out of 17 papillary carcinomas, while no c-erbB-2 protein immunostaining was seen in cases of follicular adenoma (five cases), follicular carcinoma (five cases) or medullary carcinoma (one case), nor in cases of non-neoplastic tissue, including normal thyroid tissue from tumour-bearing glands. RNA was extracted from 51 thyroid tissue samples from 34 of the above patients, and c-erbB-2 mRNA was analysed by slot-blot hybridisation. c-erbB-2 mRNA was detectable in all samples, but papillary carcinomas and lymph node metastases showed significantly higher levels of c-erbB-2 mRNA compared to non-neoplastic tissue. The present demonstration of positive c-erbB-2 immunostaining in papillary thyroid carcinomas is contradictory to previous findings on formalin-fixed, paraffin-embedded material, and emphasises the importance of tissue quality for c-erbB-2 protein detection.
Carcinoma, Papillary↗