Estrogen and progesterone receptors in breast cancer: relationships to tumour histopathology and survival of patients.

Estrogen receptor (ER) and progesterone receptor (PR) concentrations were measured in the tumours of 399 cases of primary breast carcinoma. Histological type and histological grading was also analysed. The correlation between survival and histological grading was observed and found to be of high significance statistically. Longer survival of patients with ER- and/or PR-positive tumours was also observed, but the ER and PR prognostic value did not reach the same magnitude as histological alone. The prognostic accuracy in breast cancer, when histological grading, ER and PR were used together, failed to reach statistically significant values. A lower proportion of ER- and PR-positive tumours were found in histological grade III. The majority of the tumours belonging to specific histological variants of carcinoma were ER- and/or PR-positive. Relationships between ER, PR, menopausal status, and age were also noted. It was apparent that the prognostic value of PR concentrations in the tumour was more relevant than that of ER alone.

Action of recombinant interferons and interleukin 2 in modulating radiation effects on viability and cytotoxicity of large granular lymphocytes.

We have evaluated in vitro the modulating effect of interferon (IFN) alpha, beta and gamma as well as interleukin 2 (IL-2) on the radiosensitivity of large granular lymphocytes (LGL) having natural killer cell activity. LGL were treated with IFNs or IL-2 in concentrations from 1 to 1000 U/ml before or after a single or a split dose of irradiation. The viability of LGL was measured by intracellular ATP, and cytotoxicity by a 51Cr release assay. Both viability and cytotoxicity were clearly higher when IFNs and IL-2 were used before irradiation. Some IFNs were slightly radiosensitizing in ATP studies. Only IFN gamma in a concentration of 1000 U/ml was significantly radioprotective in cytotoxicity tests when used before irradiation. IL-2 had a significant concentration-dependent radioprotective effect in cytotoxicity when used before or after irradiation, and in the viability of preincubated LGL. No combination of IFNs and IL-2 was more radioprotective than IL-2 used alone. IL-2 retarded the time dependent decrease of ATP and 51Cr release levels after irradiation. According to our results, IL-2 is a radioprotective substance for LGL.

Open phase II study of high-dose toremifene as first-line therapy for advanced breast cancer.

In an open phase II study conducted in Finland and Latvia, 73 postmenopausal women were treated with 240 mg of toremifene (Fareston) as first-line therapy for advanced breast cancer. Among the 56 patients evaluable for responses, 59% achieved objective responses [complete response (CR) plus partial response (PR)], 29% showed no change (NC), and 12% had progressive disease (PD). When all treated patients were included, the objective response rate was 47%. Several very long durations of responses up to 86 months and survival durations up to 95 months were observed. In assessable patients, the best objective response rates were seen in those with soft-tissue (74%) and visceral (60%) disease. In 54% of patients with very large inoperable primary cancers, a PR was achieved. Half of patients reported side effects, about 60% of which were mild; 30%, moderate; and 5%, severe. Based on response rate and safety, high-dose toremifene is useful as first-line therapy for advanced breast cancer.

Surgical treatment of local recurrences of breast carcinoma in the skin and subcutaneous tissues.

Twenty-six cases of local recurrence of breast carcinoma in the skin and subcutaneous tissues after treatment with radical excision and large skin grafts or reconstruction are presented. Seventy-seven per cent of the patients were alive 2 years after the treatment. As a chest wall recurrence of breast cancer in the absence of distant metastases does not always indicate a generalization of the disease, radical reconstructive surgery is recommended as the therapy of choice.

Late radiation damage to the rat femur and the NSD formula.

The extraction of 86Rb chloride, the red blood cell volume and the mineral content in the rat femur have been studied 7 months after local X-irradiation. Doses were given as 3, 6 and 9 fractions over three weeks. The total doses used were based on NSD value of 1450 and 1900 on the basis of the results from our previous single dose irradiation studies. The reduction in the extraction of 86Rb chloride was statistically significant for all fractionation schemes and at both NSD levels. In the whole femur, with bone marrow, the extraction was reduced by 33% to 46%. In the hard bone the reduction was less only 18% to 38%. There was no significant difference between the fractionation schemes used at each NSD level. The red blood cell volume was significantly reduced in the whole femur, with bone marrow, with no difference between the fractionation schemes. However, there was no change in the hard bone. The dry bone weight was reduced by 3 to 6% with no significant difference between the different fractionation schemes. The dose levels predicted by the NSD formula produced approximately the same damage to the rat femur 7 months after the irradiation when the dry weight and the extraction of 86Rb chloride were used as end points for the evaluation of the severity of late radiation damage.

Elective treatment of regional lymph nodes in malignant melanoma.

Malignant melanoma of Clark level II to V was studied in 96 patients. An elective dissection or elective irradiation of the regional lymph nodes was performed in 45 patients, whereas 51 patients were not treated electively. No statistically significant differences were observed as to the survival or recurrence-free time in the regional lymph nodes in either of these two patient groups. Between the patient groups with or without selective treatment, there was not any significant difference either, even when the prognosis and recurrence of the patients were correlated to the invasion level of the primary melanoma according to Clark or Breslow.

The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial.

Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).

Aneuploid DNA content and high S-phase fraction of tumour cells are related to poor prognosis in patients with primary breast cancer.

The prognostic impact of DNA content and S-phase fraction (SPF) of tumour cells was studied in 93 patients with primary breast cancer. Aneuploid DNA content and high SPF were clearly associated with poor differentiation state of tumours and absence of steroid, especially progesterone receptors. Aneuploidy and high SPF tended to become more common with increasing primary tumour size, with more extensive nodal involvement and with more advanced stage of the cancer. Patients with diploid tumours had a slightly longer disease-free interval and survival than those with aneuploid tumours, whereas below median SPF as compared to above median SPF was associated with significantly longer (P less than 0.01) relapse-free interval and survival in patients with stage II-III cancer. We conclude that the DNA analysis of tumour cells is a promising method for the estimation of prognosis in breast cancer patients.

Serum CA 15-3 assay in the diagnosis and follow-up of breast cancer.

Serum CA 15-3 values were determined in 177 patients with primary breast cancer and in 41 with non-malignant breast disease. Increased preoperative serum CA 15-3 values (greater than 38 U ml-1) were observed in 7%, 17%, 64% and 67% of patients with stage I, II, III and IV disease, respectively and in none of the patients with benign breast disease. Patients with elevated serum CA 15-3 values had poor 3-year cumulative survival (27%). In the postoperative follow-up 9% of patients with no clinical evidence of disease, 33% with a single metastasis and 67% with two or more metastases had elevated values. Increasing or decreasing serum CA 15-3 values correlated with the clinical outcome in 26 out of 27 cases (96%), whereas serum values remaining in the reference range had no predictive value. At the time of recurrence elevated serum CA 15-3 values were also observed in patients with normal preoperative values. Increased serum CA 15-3 values preceded the clinical detection of tumour recurrence by up to 13 months. In conclusion, serum CA 15-3 levels had prognostic value in breast cancer, reflected the extent of clinically detectable disease and the presence of occult metastatic disease. Further research is warranted on the benefits of CA 15-3 assays in relation to adjuvant chemotherapy as well as the earlier detection and treatment of metastatic disease.

Elevated serum HMFG antigen levels in breast and ovarian cancer patients measured with a sandwich ELISA.

HMFG antigen is a tumour associated glycoprotein that has been immunohistochemically shown to be expressed by malignant cells in breast and ovarian and to a lesser degree in gastro-intestinal carcinomas. We have developed a non-isotopic sandwich ELISA for secretory HMFG antigen utilizing a polyclonal catcher and a tracer monoclonal antibody (MAb). 52/52 of healthy medical students (controls) had a serum value under 400 U/ml whereas 15/30 patients (50%) with evident ovarian cancer and 13/37 (35%) with advanced breast cancer had a value exceeding 400 U/ml. From other patients with malignant tumours 2/14 (14%) with endometrial carcinoma, 0/5 with cervical carcinoma, 0/5 with vulvar carcinoma, 1/33 with gastro-intestinal carcinoma, 0/4 with oesophageal carcinoma and 2/45 of patients with leukemia or lymphoma had an elevated serum HMFG value. Four cases of Crohn disease, 3 cases of ulcerative colitis and 2 cases of pelvic inflammatory disease all showed a serum value below 400 U/ml. Progression of ovarian cancer was accompanied by increasing serum HMFG antigen levels. The antigen detected by our assay is different from CA 125 but may be related with the tumour associated antigen CA 15-3.

High dose toremifene (240 mg daily) is effective as first line hormonal treatment in advanced breast cancer. An ongoing phase II multicenter Finnish-Latvian cooperative study.

The efficacy of high dose toremifene (240 mg daily) in postmenopausal women with advanced breast cancer is investigated in this ongoing study. At present, 38 patients are fully evaluable. Ten patients have CR (26%), 16 PR (42%) (objective response rate 68%), 8 NC (21%), and 4 PD (11%). Most objective responses are in soft tissue tumors (14/17, 82%). The response rate is equally high in patients with positive or unknown estrogen receptor (ER) status. Median duration of responses and survival are not yet evaluable. Of 48 patients evaluable for side-effects, 22 (46%) experienced some kind of toxicity, which was mild in 64% of cases, moderate in 29%, and mostly of estrogenic type. The study will continue to confirm the results thus far obtained.

Seasonal variation of endogenous uveitis in south-western Finland.

PURPOSE: To evaluate if there is a seasonal pattern to the incidence of endogenous uveitis in south-western Finland with special reference to acute anterior uveitis. METHODS: The incidence rates per month of the 414 new uveitis cases from years 1980-82 and 1988 in the district of Turku University Hospital were calculated. The months of the year were grouped into warm (June to September), transitional (April, May, October, November), and cold (December to March) seasons based on the mean air temperature of the months in Turku. RESULTS: We observed a statistically significant increase in the incidence of all uveitis cases in the warm and transitional seasons compared with the cold season (p=0.030 and p=0.008 respectively). A similar seasonal trend was found among anterior uveitis cases, but not among the intermediate, posterior or panuveitis cases. The incidence of acute anterior uveitis cases was higher in the transitional than in the cold season (p=0.025). No seasonal variation of the incidence was found in the subgroup of acute anterior uveitis where ankylosing spondylitis had been confirmed (p=0.70). CONCLUSION: The present data suggests that there is seasonal variation of the incidence of uveitis in south-western Finland.

Uveitis in children: population-based study in Finland.

PURPOSE: To investigate the incidence and prevalence rates of different types of uveitis in children, and to compare them with the rates in adults. SUBJECTS AND METHODS: For this population-based retrospective study the medical records of all residents of the district of Turku University Hospital with a diagnosis of uveitis seen at the Eye Clinic of Turku University Hospital during the years 1980-1982 and 1988 were reviewed. RESULTS: A total of 1122 uveitis cases were identified, and 55 (4.9%) of them were children under 16 years. The incidence per 100 000 population per year for all uveitis cases in children was 4.3 (95% confidence interval [CI], 2.2 to 6.4), and the prevalence was 27.9 (95% CI, 17.1 to 38.6), which was significantly lower compared with the rates in adults (p=0.001 for incidence and prevalence). The vast majority of children, 50 (90.9%), had anterior uveitis (AU), and the incidence and prevalence rates of AU were significantly lower than in adults (p=0.001 for incidence and prevalence). Three (5.5%) children had posterior uveitis (PU), but there was no significant difference in the incidence and only marginally significant difference in the prevalence rate of PU in children compared with the rates in adults (p=0.33 for incidence, and p=0.07 for prevalence). Only one case (1.8%) was found with intermediate and one with panuveitis, but no new cases. The commonest diagnostic groups in children were AU associated with juvenile rheumatoid arthritis, idiopathic acute anterior uveitis, and idiopathic chronic anterior uveitis. Toxoplasmic retinochoroiditis was found in all of the PU cases with the incidence 0.3, and the prevalence 1.1, which did not differ significantly from the rates in adults (p=1.0 for incidence, and p= 0.48 for prevalence). CONCLUSION: Uveitis is rarer in children than in adults. However, in contrast to studies from tertiary referral centers, the distribution of different forms of uveitis in children in this population-based study seems to resemble the distribution in adults.

Treatment results of nasopharyngeal cancer--a nationwide survey from Finland.

The nationwide experience of treating nasopharyngeal cancer in Finland during the period 1980-1989 was reviewed. Of the 107 patients included in the present analysis, 13 were treated palliatively only, and three had metastatic disease at their first clinical presentation, whereas the rest (n = 91) were treated with radical radiotherapy, of whom, 8 patients received adjuvant chemotherapy after radiotherapy. The 5-year actuarial survival rates of these 91 patients was 52%, and by the UICC stage they were classified as follows: stage I 75% (n = 12), stage II 60% (n = 5), stage III 59% (n = 34), and stage IV 38% (n = 40). According to the Cox's stepwise proportional hazard model the most important factors influencing favourable survival were the total dose of radiotherapy expressed in terms of Biologically Effective Dose (BED) with a time factor, a small size of the primary tumour and a high performance status according to the WHO scale, whereas the most important factors influencing the local control analysis were the total dose of radiotherapy (expressed in BED) and the cervical lymph node status.

Tumour DNA ploidy as an independent prognostic factor in breast cancer.

We determined nuclear DNA content from 308 archival paraffin-embedded malignant breast tumours and evaluated the survival of the patients by univariate and multivariate statistical analyses. The overall 8-year survival rate of stage I-III breast cancer patients was 74.3% in DNA-diploid and 51.2% in DNA-aneuploid tumours (P less than 0.0001). DNA ploidy had prognostic significance in both node-negative and node-positive breast cancer, primarily in cases with steroid receptor-positive tumours. In a Cox multivariate analysis DNA ploidy (P = 0.001), primary tumour size (P = 0.0007), nodal status (P = 0.04) and the content of progesterone receptors (P = 0.0008) emerged as significant independent prognostic factors, whereas oestrogen receptor status, age and menopausal status of the patients had no significant independent prognostic value. If the histological grade of ductal carcinomas was also included in the Cox model, both grade and DNA ploidy had independent prognostic effect. In conclusion, our results indicate that the analysis of DNA ploidy is a useful adjunct in the assessment of prognosis for breast cancer patients.

Improving the prognostic value of DNA flow cytometry in breast cancer by combining DNA index and S-phase fraction. A proposed classification of DNA histograms in breast cancer.

To optimize the prognostic value of DNA flow cytometry in breast cancer the authors calculated several parameters from the DNA histogram, including the DNA index, the size and number of aneuploid peaks as well as S-phase and G2/M-phase cell cycle fractions. Of these, DNA index and S-phase fraction (SPF) proved to be the most valuable prognostic indices. DNA aneuploidy was associated with a three-fold risk of death as compared to DNA diploidy (P less than 0.0001). The highest risk of death was associated with hypertetraploid (greater than 2.20) DNA index, whereas a tetraploid DNA index (1.80-2.20) was associated with a relatively low risk. The SPF had significant additional prognostic value in both DNA diploid (P = 0.0002) and DNA aneuploid (P = 0.02) tumors. By combining DNA index and SPF the authors defined three types of DNA histograms, which were associated with favorable, intermediate, and poor prognosis of the patients. DNA diploidy together with low (less than 7%) SPF (type I DNA histogram) was associated with very favorable prognosis, whereas DNA aneuploidy with high DNA index (greater than 2.20) or high (greater than 12%) SPF (type III DNA histogram) was related to the worst prognosis with approximately eight-fold relative risk of death. In a Cox multivariate regression analysis the type of DNA histogram was an independent and most powerful prognostic indicator in breast cancer. The other independent factors in the Cox analysis were primary tumor size, nodal status, and progesterone receptor status.