Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age.

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.

Childhood medulloblastoma in Denmark 1960-1984. A population-based retrospective study.

Medulloblastoma is a common paediatric brain tumour, located in the cerebellum and in the IV ventricle, surpassed in frequency only by astrocytomas. 180 children below the age of 15 with a medulloblastoma of the posterior fossa were treated in Denmark in the 25-year period from 1960 to 1984 and followed up until the end of 1996, or until death. During the 25 years they accounted for 20% of all intracranial tumours in children in Denmark. All tumours were histologically verified. The mean annual incidence was 6.4x10(-6), decreasing slightly with a factor of 0.12x10(-6) per year. The male/female ratio was 2.1 - twice that of the background population of children (1.05). The 5-year survival rate following diagnosis, surgery and radiotherapy was 23%, and the 25-year survival rate was 16%. The 5-year survival rate was 8% in the first 5-year period of 1960-1964, increasing to 36% in the last period 1980-1984. Presumably the increase in survival depends on many factors, e.g. improved diagnostic methods and neuroanaesthesia, better operative technique (microscope), improvements in radiotherapy and the introduction of chemotherapy. The best predictive factors of a good prognosis were preoperative CSF shunting, radical tumour removal and complete radiotherapy, i.e. irradiation of the brain, tumour bed and spinal cord. The survival rate in the last five-year period was seven times higher than the survival rate found in a comparable Danish study from the years 1935-1959. Most of the children followed Collins law of risk index. The results of treatment in children with medulloblastoma remain unsatisfactory. Accordingly, participation in international prospective studies of multimodal treatment should be encouraged, possibly using chemotherapy prior to surgery.

Assessing mechanical allodynia in the rat paw with a new electronic algometer.

Von Frey filaments used for testing mechanical thresholds are mechanically unstable and their use is difficult to standardize. We have therefore constructed a hand-held electronic pressure algometer. The pressure algometer is connected to a computerized data collection system, allowing on-line display of the applied force as well as the application rate. Data stored on the computer can be replayed and further analyzed. Using this apparatus, we have measured the pressure-induced withdrawal thresholds in rats with surgically induced neuropathy. The probe, with a circular tip of 1.0 mm diameter, was applied manually with a pressure increasing by approximately 0.05 N/s. Presurgical thresholds were normally distributed with a mean of 0.415 N, showing no significant difference between paws. During 2 weeks after surgery, the thresholds of the operated side were significantly reduced (range, 0.209-0.318 N), while the thresholds of the non-operated side remained at higher values (range, 0.432-0.491 N). Thresholds of control rats without surgery were in the 0.380-0.520 N range, with no significant difference between paws. In an additional experiment it was shown that interobserver reliability was high, both between withdrawal threshold values obtained and between rates of application used. In conclusion, the electronic algometer allows standardization of testing, detailed documentation of each experiment and provides an objective and accurate method for measuring the reactions of test animals to mechanical stimuli.

Fetal alcohol syndrome at the turn of the 20th century. An unexpected explanation of the Kallikak family.

At the turn of the 20th century, studies of a family known in the literature as the Kallikaks were used to document the hereditary nature of mental retardation, poverty, and antisocial behavior. This family was said to authenticate eugenic theory, which states that heritable characteristics carried by individuals on "independent unit characters are unalterable determinants of behavior and performance. A review of the original Kallikak data, however, suggests that in utero exposure to alcohol rather than heredity contributed significantly to the transgenerational learning failure seen throughout the Kallikak pedigree. However, eugenic theory was so thoroughly accepted that the promotion and acceptance of "hereditary feeblemindedness" as the principal cause of the developmental problems in the affected offspring smothered the research efforts on in utero effects of alcohol until long after the eugenic concepts were abandoned later in the century.

Human papillomavirus, herpes simplex virus and other potential risk factors for cervical cancer in a high-risk area (Greenland) and a low-risk area (Denmark)--a second look.

The prevalence of human papillomavirus (HPV) infection and other risk factors were studied in a high risk area for cervical cancer (Greenland) and in a low risk area (Denmark). From Nuuk (Greenland) and Nykøbing Falster (Denmark), random samples of 150 women aged 20-39 years were drawn. A total of 129 and 126 women were included in Greenland and Denmark, respectively. The proportion of HPV infected women assessed by ViraPap was similar in Denmark and Greenland (4.8 vs 3.9%). When type specific polymerase chain reaction (PCR) was used, the total HPV detection rate was 38.9% in the Danish population and 43.4% in the Greenlandic. A similar interrelationship between Greenland and Denmark applied to the HPV types 11, 16, 18 and 33. No relationship was observed between HPV detection and number of partners for any of the diagnostic methods. Significantly more Greenlandic than Danish women had antibodies to HSV 2, 76.0% and 26.2%, respectively. The prevalence of self-reported histories of selected venereal diseases was also highest among Greenlanders, except for genital warts where the prevalence was similar in the two areas. Greenlandic women had significantly more sexual partners, earlier age at first intercourse, more current smokers and less use of barrier contraceptives compared to the Danish women. This study confirms the results of our previous population-based cross-sectional comparison study in these areas, corroborating the conclusion that the prevalence of detectable HPV infection does not seem to be a determinant of cervical cancer incidence. However, by using DNA hybridisation techniques, temporal virus shedding is only measured at one point in time. Detectable virus shedding may not correlate with the risk of cervical cancer. In fact, HPV DNA detection may have different implications in different populations. In Denmark, HPV DNA detection may reflect transient, recently acquired infection, whereas in Greenland, it is more indicative of chronic persistent infection.

The non-competitive NMDA receptor antagonist (+)MK-801 counteracts the long-lasting attenuation of the hypothermic response induced by acute doses of 8-OH-DPAT in the rat.

The effects of acute doses of 8-hydroxy 2-(di-n-dipropylamino)tetralin (8-OH-DPAT) on the hypothermic response, induced by a challenge dose of 8-OH-DPAT, were examined in rats. Acute doses of 8-OH-DPAT (1.0 or 0.5 mg/kg, s.c.) significantly attenuated the hypothermic response induced by 8-OH-DPAT (0.05 mg/kg, s.c.). The response to 8-OH-DPAT was almost abolished between 4 hr and 4 days and the attenuation of the response lasted for 21 days. On day 28 the response had returned to the control level. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine [(+)MK-801], blocked this long-lasting attenuation of the 8-OH-DPAT-induced hypothermic response. Given on its own, (+)MK-801 did not reduce body temperature, at the doses used in the experiments but the drug did block the acute effects of 8-OH-DPAT, at the same doses which blocked the attenuation of the hypothermic response. The present data suggest that stimulation of glutamate NMDA receptors may underlie the long-lasting effect of acute injections of 8-OH-DPAT.

Risk factors for cervical human papillomavirus and herpes simplex virus infections in Greenland and Denmark: a population-based study.

Risk factors for genital human papillomavirus (HPV) types 6/11 and 16/18 and any HPV type as well as for herpes simplex virus type 2 (HSV-2) infections were investigated in a population-based study of 1,600 randomly selected women (20-39 years) from Godthåb (native, Nuuk), Greenland, and Nykøbing Falster, Denmark. A total of 586 Greenlandic women and 661 Danish women were included, respectively. They all had a personal interview and a gynecologic examination with cervical smear and swab for HPV analysis (filter in situ hybridization). Moreover, a blood sample was obtained for analysis for HSV-2 antibodies by enzyme-linked immunosorbent assay. In view of the general concept of HPV as a sexually transmitted virus, it is unexpected that women with "multiple" partners revealed a significantly lower risk for all types of HPV than did women with "few" partners, the odds ratio (OR) being 40-60% decreased in women with greater than or equal to 30 partners compared with women who had 0-4 sexual partners. In contrast, the risk for HSV-2 infection was significantly increased among women with early age at first sexual intercourse (OR = 2.9 for age less than or equal to 13 vs. 14-16 years) and multiple partners (OR = 2.6 for greater than or equal to 20 vs. 0-4 partners) (hereafter referred to as "high sexual activity" as well as with an increasing number of sexually active years with an unprotected cervix (i.e., without the use of barrier contraceptives) (OR = 2.0 for greater than or equal to 15 vs. 0-9 years). The results of this study thus demonstrate a surprising risk pattern for HPV types 6/11 and 16/18, but a pattern for HSV-2 in line with that to be expected for a sexually transmitted virus. This could indicate the existence of factors, especially in women with high sexual activity, which interfere with the expression of HPV or with the ability to detect it and/or that HPV may be transmitted by means other than sexual contact.

Abnormal Papanicolaou smear. A population-based study of risk factors in Greenlandic and Danish women.

Possible risk factors for abnormal Papanicolaou smear were investigated in a population-based cross-sectional study. From Nuuk (Greenland) and Nykøbing Falster (Denmark), random samples of 800 women aged 20-39 years were drawn. Totals of 586 and 661 women were included in Greenland and Denmark, respectively. All women went through a personal interview, and had a gynecologic examination including a PAP smear and cervical swab for HPV analysis. A blood sample was taken for analysis of HSV type specific antibodies. Multiple sexual partners was the most important risk factor for abnormal cervical cytology (OR = 4.2). An infectious etiology was also indirectly supported by a relatively protective effect of barrier contraceptive methods (OR = 0.6). The simultaneous finding of HPV 16/18 as a significant risk factor (OR = 2.4) cannot be taken uncritically as support for a causal effect of this HPV type, since such a relationship between cytological changes of the cervix and HPV infection could also emerge if the positive PAP smear was not just a measure of intra-epithelial neoplasia but also an expression of the infection itself on the cervix.

Risk factors for cervical cancer in Greenland and Denmark: a population-based cross-sectional study.

The incidence of cervical cancer in Greenlandic women aged 20-39 years is nearly 6 times higher than in Danish women of the same age. Possible determinants of cervical cancer incidence were investigated in a population-based cross-sectional study. From Nuuk (Greenland) and Nykøbing Falster (Denmark) a sample of 800 women aged 20-39 years was drawn at random. A total of 586 and 661 women were studied in Greenland and Denmark, respectively. All underwent a personal interview. In Greenland, 13% of the women reported first intercourse before the age of 14 in contrast to 3.5% in Denmark, and nearly 85% of the Greenlanders had their sexual debut before the end of the 16th year of age whereas this applied to only 45% of the Danish women. The prevalence of women with 0-1 lifetime sexual partner was 20.4% in Denmark, and only 1.7% in Greenland. In contrast, 53.2% of the Greenlandic women reported more than 20 partners and 22.4% more than 40 partners. The corresponding figures for Denmark were 3.6% and 0.3%, respectively. In Greenland the most common contraceptive method was the use of intra-uterine devices (73.6%), whereas, in Denmark, oral contraceptive use was most frequent (87.9%). Few Greenlanders had ever used "barrier" contraceptives (diaphragm: 1.4%; condom: 18.1%) compared to Denmark (diaphragm: 10.1%; condom: 53.9%). As many as 87.4% were current smokers in Greenland (Denmark: 53.6%) and 5.6% claimed to have never smoked, whereas this applied to 35.3% in Denmark. The indications of a higher sexual activity (multiple partners, early age at first intercourse) in Greenland compared to Denmark are in line with the observed higher rates of sexually transmitted diseases and with the hypothesis that differences in cervical cancer incidence between Greenland and Denmark are determined by aspects of sexual background.

PIP: The incidence of cervical cancer in Greenlandic women ages 20-39 is nearly 6 times higher than in Danish women of the same age. Possible determinants of cervical cancer incidence were investigated in a population-based cross-sectional study. From Nuuk (Greenland) and Nykobing Falster (Denmark), a sample of 800 women ages 20-39 was drawn at random. A total of 586 and 661 women were studied in both countries. All underwent a personal interview.

Human papillomavirus, herpes simplex virus and cervical cancer incidence in Greenland and Denmark. A population-based cross-sectional study.

In Greenland, the incidence of cervical cancer is 5.7 times higher than in Denmark among women aged 20-39. From Nuuk (Greenland) and Nykøbing Falster (Denmark) a sample of 800 women aged 20-39 years was drawn at random. A total of 586 and 661 women were investigated in Greenland and Denmark respectively. All women had a gynecological examination including a PAP-smear and cervical scrape for HPV-analysis (filter in situ hybridization). A blood sample was taken for analysis of HSV type-specific antibodies (ELISA). The percentage of normal smears was identical in the 2 areas (95%). The total HPV 16/18 infection rate was 13% in Denmark and 8.8% in Greenland, and the age-adjusted prevalence rate in Greenland was only 67% of that in Denmark (95% CI: 0.05-0.89). The proportion of HPV 6/11 positivity was the same in Greenland and in Denmark (6.7% vs. 7.5%). A significantly higher proportion of the Greenlandic women had HSV-2 antibodies (68.2%) in comparison with Danish women (30.9%) (p less than 0.01). The prevalence of HSV-1 was also higher in Greenland, especially in women aged 20 to 24. Our finding of a higher HPV infection rate in Denmark than in Greenland, opposed to cervical cancer rates, does not support a role for these viruses as determinants of cervical cancer incidence. In contrast, the rate of HSV-2 infection co-varies with the observed incidence of cervical cancer. This is in line with the notion that differences in cervical cancer incidence between Denmark and Greenland are determined by aspects of sexual behavior.

Medroxyprogesterone acetate and prednisone in advanced breast cancer. A randomized trial.

In a randomised trial patients with progressive metastatic breast cancer were allocated to one of three different treatments. A: Prednisone 10 mg X 3 daily. B: Medroxyprogesterone acetate (MPA) orally 500 mg daily. C: MPA i.m. 1000 mg daily for 3 weeks followed by 500 mg i.m. weekly. The study included 150 patients and was well-balanced with respect to different prognostic parameters. Most patients (83%) were postmenopausal, and 95% had previously received chemo- or hormonal therapy. In the MPA treated patients, analysis of serum MPA levels was performed once a month. The response rates were 4.6, 7.9 and 12.5% in treatments A, B and C, respectively. This difference was not statistically significant (P greater than 0.05). Furthermore, the follow-up of serum MPA levels revealed no significant difference between responders and non-responders. Analysis of time to progression did not indicate any advantage of MPA over prednisone, irrespective of MPA schedule. In accordance with these data, there was no difference as regards survival in the three groups. In conclusion, the study indicated that MPA is not superior to prednisone in this group of heavily pretreated patients with advanced breast cancer.