Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial.

BACKGROUND: Tamoxifen has been associated with an increased risk of stroke. There is, however, little information on the effect in the post-treatment period. Using data from the Swedish Breast Cancer Group adjuvant trial of 5 vs 2 years of tamoxifen treatment, we now report both short-term and long-term effects on morbidity as well as mortality because of cerebrovascular disease. METHODS: Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry was used to define events of disease. Hazard ratios (HRs) were estimated using Cox regression. RESULTS: Comparing patients randomised to 5 years of tamoxifen with patients randomised to 2 years of tamoxifen, the incidence of cerebrovascular diseases was increased (HR 1.70, 95% CI 1.05-2.75) during the active treatment phase and reduced after the active treatment period (HR 0.78, 95% CI 0.63-0.96), and the difference in HR between the two time-periods was significant (P=0.0033). The mortality from cerebrovascular diseases was increased during the treatment period (HR 3.18, 95% CI 1.03-9.87) and decreased during the post-treatment period (HR 0.60, 95% CI 0.40-0.90) with a significant difference in HR between the two periods of follow-up (P=0.0066). Similar results were seen for subgroups of cerebrovascular diseases, such as stroke and ischaemic stroke. CONCLUSION: In an adjuvant setting, tamoxifen was associated with an increased risk of cerebrovascular disease during treatment, but a decreased risk in the post-treatment period.

Histopathological risk factors for ipsilateral breast events after breast conserving treatment for ductal carcinoma in situ of the breast--results from the Swedish randomised trial.

AIM: The primary aims were to study risk factors for an ipsilateral breast event (IBE) after sector resection for ductal carcinoma in situ of the breast (DCIS) in a trial comparing adjuvant radiotherapy to no therapy and to assess predictive factors for response to radiotherapy. Secondary aims were to analyse reproducibility of the histopathological evaluation and to estimate correctness of diagnosis in the trial. SETTING: A randomised trial in Sweden (the SweDCIS trial), including 1046 women with a median of 5.2 years of follow-up in a population, offered routine mammographic screening. METHODS: A case-cohort design with a total of 161 cases of IBE (42 of those being members of the subcohort) and 284 sampled for the sub-cohort. Ninety five percent of the participants' slides could be retrieved and were re-evaluated by three experienced pathologists. RESULTS: Low nuclear grade (NG 1-2) and absence of necrosis halves the risk of IBE in both irradiated and non-irradiated patients. Lesion size, margins of excision and age at diagnosis did not modify these associations. The presence of necrosis modified the effect of radiotherapy: relative risk was 0.40 with necrosis present and 0.07 with necrosis absent (p-value for interaction 0.068). In all subsets of prognostic factors, radiotherapy conferred a substantial benefit. The risk factors for in situ and invasive IBE were similar. The agreement between pathologists was moderate (kappa=0.486). Correctness of diagnosis in the subcohort of SweDCIS was 84.8%. CONCLUSION: Although nuclear grade and necrosis carry prognostic information, we could not define a group with very low risk after sector resection alone. Radiotherapy has a protective effect in all substrata of risk factors studied. The interaction between the presence of necrosis and radiotherapy is a clinically and biologically relevant research area.

Prognostic significance of nuclear DNA content in mammary adenocarcinomas in humans.

The value of the determination of the DNA content of tumor cells for the assessment of the prognosis of mammary adenocarcinoma was studied in 36 patients, who survived for at least 15 years after the cancer had been found and in another 42 patients who died within a 2-year period of diagnosis. The results show a distinct correlation between the type of the DNA histograms of the carcinoma and the grade of cancer. This correlation was particularly apparent among patients surviving for at least 15 years despite the occurrence of metastases or relapses after primary treatment, i.e., in patients not cured by their first treatment.

A large deletion disrupts the exon 3 transcription activation domain of the BRCA2 gene in a breast/ovarian cancer family.

We describe the identification of a large deletion in the BRCA2 gene as the disease-causing mutation in a Swedish breast/ovarian cancer family. The 5068-bp deletion encompassed the 3' region of exon 3, including the 3' splice site and most of intron 3, and it resulted on the mRNA level in an inframe exon 3 skipping. The junction site also included an insertion of 4 bp (CCAT). The mutation (nt504del5068insCCAT) resulted in a genotype absent of the two transcription activation regions localized to exon 3. The breast cancer phenotype associated with the described mutation resembled the phenotype of breast cancer found in both BRCA1 and BRCA2 mutation carriers. This is the first report of a large deletion as the disease-causing mutation in the BRCA2 gene.

Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII.

PURPOSE: To explore prognostic factors for locoregional failures (LRF) among women treated for invasive breast cancer within clinical trials of adjuvant therapies. PATIENTS AND METHODS: The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group randomized trials. A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy, and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months' duration and/or tamoxifen. Median follow-up is 12 to 15.5 years. RESULTS: In women with node-negative disease, factors associated with increased risk of LRF were vascular invasion (VI) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients. Of the 1,275 patients, 345 (27%) met criteria for the highest risk groups, and the 10-year cumulative incidences of LRF with or without distant metastases were 16% for premenopausal and 19% for postmenopausal women. For the node-positive cohort, number of nodes and tumor grade were factors for both menopausal groups, with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients. Of the 4,077 patients, 815 (20%) met criteria for the highest risk groups, and 10-year cumulative incidences were 35% for premenopausal and 34% for postmenopausal women. CONCLUSION: LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer, as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease. In addition to number of positive lymph nodes, predictors of LRF include tumor-related factors, such as vascular invasion, higher grade, and larger size.

The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation.

The most recurrent BRCA1/BRCA2 mutation in Sweden is the BRCA1 mutation 3171ins5. In the western part of Sweden this mutation accounts for as much as 77% of identified mutations in these two genes. Our aim was to analyse in detail the haplotype and founder effects of the 3171ins5 and furthermore attempt to estimate the time of origin of the mutation. In the study we included eighteen apparently unrelated families with hereditary breast and/or ovarian cancer. At least one individual in each family had previously tested positive for the 3171ins5 mutation. Polymorphic microsatellite markers were used for the haplotype analyses. The markers were located within or flanking the BRCA1 gene spanning a region of 17.3 cM. We found several different haplotypes both for disease alleles and for the normal alleles. However, a conserved haplotype of 3.7 cM was observed in the 3171ins5 carriers spanning over four markers located within or very close to the BRCA1 gene. As this haplotype was not present in any of the normal controls it is highly likely that this is a mutation identical by descent, i.e. a true founder. The results from the haplotype analyses were used to estimate the age of the mutation. Estimations based on the P(excess) and linkage disequilibrium gives a first appearance of the mutation sometime around the 6th century, approximately 50 generations ago.

Soft tissue sarcoma after treatment for breast cancer--a Swedish population-based study.

The aim was to quantify the risk of post-treatment sarcoma in breast cancer patients. All 122,991 women with a breast cancer from 1958 to 1992 in the Swedish Cancer Register were followed up for soft tissue sarcomas and 116 were found, giving a standardised incidence ratio of 1.9 (95% CI 1.5-2.2). The absolute risk was 1.3 per 10(4) person-years. The sarcomas were located in the breast region or on the ipsilateral arm in 63% (67/106). There were 40 angiosarcomas and 76 sarcomas of other types. In a case-control study, angiosarcoma correlated significantly with lymphoedema of the arm, odds ratio (OR) 9.5 (95% CI 3.2-28.0), but no correlation with radiotherapy was observed. For other types of sarcoma there was a correlation with the integral dose. The dose-response relationship indicated that the risk increased linearly with the integral dose to 150-200 J and stabilised at higher energies. The OR was 2.4 (95% CI 1.4-4.2) for an energy of 50 J, approximately corresponding to the radiation of the breast after breast-conserving surgery. Thus, only oedema of the arm correlated with angiosarcoma, but for other types of sarcoma the integral dose of radiotherapy was a predictor of the risk.

A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer.

The aim of this study was to describe and characterise a founder mutation of the BRCA1 gene in western Sweden. Of 62 families screened for BRCA mutations, 24 had BRCA1 mutations and two had BRCA2 mutations. Tumours that occurred in family members were histologically reviewed and mutational status was analysed using archival paraffin-embedded tissues. The same BRCA1 mutation, 3171ins5, was found in 16 families who were clustered along the western coast of Sweden. Mutation analysis revealed a maternal linkage in 13 families and a paternal linkage in 3. There was complete agreement between mutation analysis results obtained from blood and archival tissues. The penetrance of breast or ovarian cancer by age 70 years was estimated to be between 59 and 93%. There were no differences in survivals between breast or ovarian cancer patients with the mutation and age-matched controls. Thus, a predominant BRCA1 gene founder mutation associated with a high risk of breast and ovarian cancer has been identified and found to occur in a restricted geographical area, thereby allowing timely and cost-effective mutation screening using blood samples or archival histological material.

Breast conservation surgery, with and without radiotherapy, in women with lymph node-negative breast cancer: a randomised clinical trial in a population with access to public mammography screening.

The effect of postoperative radiotherapy after sector resection for stage I-II lymph node-negative breast cancer was evaluated in a patient population with access to public mammographical screening. 1187 women were randomised to no further treatment or postoperative radiotherapy following a standardised sector resection and axillary dissection. Radiation was administered to a dose of 48-54 Gy. Median age was 60 years, and median size of the detected tumours was 12 mm. Of the women 65% had their tumours detected by mammographical screening. The relative risk (RR) of ipsilateral breast recurrence was significantly higher in the non-irradiated patients compared with the irradiated patients, RR=3.33 (95% Confidence Interval (CI) 2.13-5.19, P<0.001). The corresponding cumulative incidence at 5 years was 14% versus 4%, respectively. Overall survival (OS) was similar, RR=1.16 (95% CI 0.81-1.65, P=0.41), with 5 year probabilities of 93 and 94%, respectively. Recurrence-free survival (RFS) at 5 years was significantly lower in the non-irradiated women, 77% versus 88% (P<0.001). Although women above 49 years of age, whose tumours were detected with mammographical screening, had the lowest rate of ipsilateral breast recurrence in this study, the cumulative incidence of such event amounted to 10% at 5 years if radiotherapy was not given. Such a recurrence rate has been considered as unacceptably high, but is, however, in the same range as that reported after lumpectomy and postoperative radiotherapy in published series.

Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen.

Serum proteins and lipoproteins were determined in 23 menopausal females after surgery for early forms of breast cancer and the results compared with data from a matched group of randomly selected healthy females. The patients were randomly divided into 2 groups, one serving as a control group, the other receiving 40 mg tamoxifen daily for 2 months. Breast cancer patients were found to have significantly higher concentrations of serum cholesterol than controls (7.90 +/- 1.15 vs. 6.87 +/- 1.18 mmol/l, P less than 0.001), which was the result of a 16% higher concentration in LDL cholesterol (P less than 0.05) and a 13% higher concentration in HDL cholesterol (P less than 0.05). During tamoxifen therapy total TG tended to increase, whereas total cholesterol fell. Significant lipoprotein changes were found in the LDL fraction where LDL-TG increased from 0.46 to 0.56 (P less than 0.01) and LDL cholesterol fell from 5.11 to 4.10 mmol/l (P less than 0.001). During tamoxifen therapy haptoglobin and orosomucoid concentrations fell significantly (P less than 0.01), whereas those of alpha-antitrypsin and ceruloplasmin increased (P less than 0.001). Factors such as diet and weight may explain the differences between breast cancer patients and controls. The tamoxifen-induced changes indicate that this anti-oestrogen exerted a mild oestrogen-like effect with regard to protein and lipoprotein metabolism.

Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group.

PURPOSE: A controversy exists regarding whether it is safe to delay radiation therapy until the completion of chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Within the context of two concurrent randomized clinical trials we had the opportunity to evaluate outcomes for patients who received breast irradiation after completing different durations of chemotherapy. METHODS AND MATERIALS: From July 1986 to April 1993 the International Breast Cancer Study Group (IBCSG) Trial VI randomly assigned 1554 pre/perimenopausal node-positive breast cancer patients to receive cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for either three consecutive courses on months 1-3, or six consecutive courses on months 1-6, both with or without reintroduction CMF. IBCSG Trial VII randomly assigned 1266 postmenopausal node-positive breast cancer patients to receive tamoxifen for 5 years, or tamoxifen for 5 years with three early cycles of CMF, both with or without three courses of delayed CMF. Both trials allowed a choice of mastectomy, or breast-conserving surgery plus radiation therapy, and both were stratified by type of surgery. Radiotherapy was delayed until the initial block of CMF was completed; 4 or 7 months after surgery for pre/perimenopausal patients, and 2 or 4 months after surgery for postmenopausal patients. Over both trials, 718 eligible patients elected to receive breast-conserving surgery plus radiation therapy: 433 on Trial VI, and 285 on Trial VII. Four-year actuarial total failure rates (failure at any site), risks of developing distant metastases (DM at any time during observation), and overall survival (OS) were estimated using the Kaplan-Meier method. To avoid potential bias due to competing causes of failure, only patients who could be followed for at least 4 years (enrolled prior to July 1, 1990) were used to evaluate the patterns of first relapse site. Crude percents of local failure with or without other sites (LF), distant metastases including regional nodal failure (DM/RNF), or other first events (second primaries/death without recurrence) were estimated for each treatment group. For this report, an intent to treat analysis was performed at a median follow-up of 48 months. RESULTS: No differences were found in the 4-year actuarial total failure rates, risk of developing distant metastases, and overall survival among the two radiotherapy groups of each study. The cumulative incidence of types of first failure and the 4-year crude rates showed no treatment differences in the patterns of site of first event. Estimates for the 4-year crude percent of local failures were 8 and 9% for pre/perimenopausal patients who had radiation therapy at 4 or 7 months after surgery, and 3 and 6% for postmenopausal patients who had radiation therapy at 2 months or 4 months after surgery. CONCLUSIONS: For node positive patients receiving breast-conserving surgery followed by radiation therapy, the incidence of breast recurrence in the conserved ipsilateral breast within 4 years was between 8 and 9% for pre/perimenopausal patients and between 3 and 6% for postmenopausal patients. After 48 months of median follow-up, administering radiation therapy after three or six cycles of CMF for pre/perimenopausal women, or after no cycles or three cycles of CMF for postmenopausal women does not influence overall efficacy or local control in this series.

Radiation therapy in operable breast cancer: results from the Stockholm trial on adjuvant radiotherapy.

In a randomized trial, 960 women with Stage 1-3 operable breast cancer were treated by a modified radical mastectomy alone, or by the same procedure, preceded or followed by radiotherapy (4500 rad to the breast/chest wall, and internal mammary, axillary and supraclavicular lymph nodes). Up to ten years after treatment, there is an increasing gap between the recurrence-free survival of the irradiated patients and the surgical controls. Between the two types of radiotherapy, there was no difference. There were significantly fewer distant metastases and a tendency for improved survival in node positive patients treated with postoperative radiotherapy, compared to the surgical controls, this difference was, however, statistically not significant.

The main infiltrating cell in xenograft rejection is a CD4+ macrophage and not a T lymphocyte.

Porcine fetal islet-like cell clusters (ICC) or isolated rat islets were implanted under the kidney capsule of normoglycemic rats. The animals were sacrificed 1, 3, 6, 12, or 24 days after transplantation, and a detailed morphological and phenotypic characterization of the different cellular subtypes infiltrating the xenograft was performed and compared with the rejection of allogeneic islets. In xenograft rejection a progressive infiltration of large, polygonal, macrophage-like cells, which with time became the dominating cellular subtype, occurred. These cells expressed the CD4 antigen and the macrophage-specific ED1 antigen. From day 6 and onward, a majority of the macrophage-like cells also expressed the CD8 antigen and the macrophage-specific differentiation antigen ED2. T lymphocytes, defined by their TCR alpha/beta or CD2 expression, were found in low numbers and mainly in the periphery of the graft. At the later stages of xenorejection a substantial number of eosinophilic granulocytes were also found. The allograft rejection, on the contrary, was characterized by a progressive infiltration of T lymphocytes, which with time became the dominating cellular subtype. No clear immunoglobulin or complement deposition was seen in the transplants before day 12, when IgG deposition was found in central necrotic areas of the xenograft. Previous experiments in rodents have underlined the crucial importance of CD4 positive cells in the xenograft rejection process. However, in none of these studies it was conclusively demonstrated that the CD4-expressing cells were T lymphocytes. The presence of CD4-expressing macrophages heavily infiltrating the porcine xenograft seen in our study may thus be in agreement with previous studies in which the anti-CD4 reactive cells were erroneously designated T lymphocytes. Interestingly, the findings in xenograft rejection in the present study have striking similarities with the defense mechanisms active against infections by large parasites such as helminths.

Xenograft rejection of porcine islet-like cell clusters in normal and natural killer cell-depleted mice.

Fetal porcine islet-like cell clusters (ICC) were transplanted under the renal capsule of normoglycemic normal or athymic (nu/nu) C57BL/6 mice. Control animals were implanted with allogeneic minced kidney tissue from C57BL/Ks mice. The animals were killed 6 or 14 days after transplantation and the grafts were processed for flow cytometric analyses or immunohistochemistry. Xenograft destruction was evident in normal mice on day 6 after transplantation. The majority of infiltrating cells were macrophage-like cells expressing the F4/80 antigen. Lymphocytes expressing the CD3 antigen were in minority and mainly located in the peripheral parts of the ICC xenograft. The frequency and distribution of CD4+ cells were found to resemble those of the CD3+ cells. A large number of infiltrating cells, including several macrophage-like cells, expressed the Thy 1.2 antigen. Flow cytometry of infiltrating cells in the ICC xenograft revealed that approximately half of the cells expressing the F4/80 antigen also expressed Thy 1.2 and/or CD4. No cells were found expressing both the F4/80 and CD8 antigens. Both the F4/80 single-positive and the F4/80, CD4 double-positive cells were found to be larger and more granular than the CD4 single-positive cells. No co-expression of CD4 or Thy 1.2 with the F4/80 antigen was detected on cells infiltrating allogeneic tissue grafts. Moreover, a relative large number of cells (approximately 15%) in the xenograft expressed the NK 1.1 antigen as determined by flow cytometry. The role of natural killer (NK) cells in islet xenograft rejection was further evaluated in mice depleted of NK cells, using intraperitoneal injections of the monoclonal antibody NK 1.1. The simultaneous inoculation and subsequent growth of the NK cell-sensitive beta 2-microglobulin-deficient mutant, C4.4-25-, lymphoma cell line EL-4 served as an in vivo control of NK cell depletion. However, all NK cell-depleted mice rejected the ICC xenograft. In contrast, athymic mice permanently accepted the porcine ICC xenograft but, readily rejected the NK cell-sensitive lymphoma cell line. Taken together, ICC xenograft rejection in mice seems to be T cell dependent, as evidenced in the nude mice model, while the main effector cell appears to be a macrophage with a unique phenotype.

Role of antibody synthesis and complement activation in concordant xenograft retransplantation.

A mouse-to-rat heart retransplantation model was used to study the effects of complement depletion and antibody production with regard to graft survival and anti-donor antibody specificity. Retransplantation was performed 3 weeks after the first transplantation in the presence of absence of 15-deoxyspergualin (DSG) immunosuppression. Untreated animals rejected their first graft after 3 days and retransplantation resulted in a hyperacute rejection within 2 min. A low titer of preformed anti-mouse lymphocytotoxic antibodies of the IgM subclass was found in serum collected from the unoperated rat. The rejection gave rise to a synthesis of IgG antidonor antibodies reacting with both graft endothelium and sarcolemma. Immunofluorescent staining of the rejected first heart graft showed moderate IgM and IgG antibody deposits on the graft vascular endothelium, while only IgG was found in the second graft. There was no C3 deposition found in the first mouse graft, as was the case in the second mouse graft. Anti-mouse antibodies cross-reacted with hamster antigens and a hyperacute rejection of a hamster heart graft occurred in a mouse-sensitized rat. Immunofluorescent staining revealed that the antibodies did not bind to hamster heart endothelium, as was expected, but, instead, to graft sarcolemma. DSG treatment prolonged the survival of the first graft by a median of 8 days. Continuous treatment until retransplantation resulted in a prolongation to 30 (20-127) min of the survival of the second graft and no increase in antibody titers against mouse antigens was observed. However, immunofluorescent staining revealed a weak binding of anti-mouse antibodies of the IgM subclass in the rejected mouse heart graft. Additional complement depletion with cobra venom factor in DSG-treated animals resulted in a prolongation of the median graft survival to 48 hr (6-96). No sign or minimal signs of antibody deposition were found in these grafts, but histology revealed massive mononuclear infiltration. In conclusion, xenograft transplantation in a concordant situation results in a shift of antidonor antibody Ig synthesis from IgM to IgG. If daily DSG treatment is administered from the day of transplantation, this reduces the synthesis of antidonor antibodies, and if complement is also depleted, the survival of the second graft is prolonged. The significance of the mononuclear infiltration remains to be established.

Soft tissue sarcoma after treatment for breast cancer.

In a register study all women in the West of Sweden Health Care Region with a breast cancer diagnosed between 1960 and 1980 (n = 13,490) were followed up in the Swedish Cancer Register to the end of 1988 for later occurrence of a soft tissue sarcoma (STS). Nineteen sarcomas were reported, whereas 8.7 were expected and the relative risk (RR) was 2.2 (CI 95% 1.3-3.4). The absolute risk was 1.7/10(4) person years (PY) in comparison with 0.8 expected. To obtain a more detailed analysis of the associations between arm lymphoedema, radiotherapy and STS development, and to control the quality of the register data, a case control study was also performed. Clinical records from the different hospitals in the region were collected for all the 19 cases as well as for three selected controls per case. The histopathology of the cases were reviewed, and one of the cases was reclassified as a malignant melanoma and excluded from further analysis. Thirteen of the cases were clustered around the treated breast area. To quantify the exposure to radiotherapy, the integral dose was estimated. The presence of lymphedema was included as a binary variable in the analysis. The exact conditional randomisation test indicated a significant correlation between the integral dose and the development of an STS (p = 0.008) and this association was still significant after stratification for arm oedema. A conditional logistic regression analysis with STS as the dependent variable and the integral dose as the explanatory variable gave an odds ratio (OR) of 5.2/100 J (CI 95% 1.3-21.2), and if this regression was restricted only to the STS developing in the radiation fields the OR was 3.2/100 J (CI 95% 0.8-12.9). Thus, the excess of STS in this breast cancer cohort was very low (0.9/10(4) PY). However the integral dose correlates well to the development of STS and can be useful in quantifying even small risks of secondary malignancies in the breast cancer population.

Combined treatment with temporary short-term high dose rate iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma.

PURPOSE: To evaluate the treatment outcome after radical radiotherapy of localized prostate cancer in 50 patients (38 patients with stage T1-2 and 12 patients with stage T3) after a median follow-up time of 45 months (range 18-92 months). METHODS: The treatment was given by combination of external beam radiotherapy (50 Gy) and brachytherapy (2 x 10 Gy). The brachytherapy was given using TRUS-guided percutaneously inserted temporary needles with a high dose rate remote afterloading technique with Ir-192 as the radionuclide source. Three target definitions and dose levels inside the prostate gland were used. Local control was evaluated by digital rectal examination, TRUS-guided biopsies and serum PSA evaluations. RESULTS: Clinical and biopsy verified local control was achieved in 48 of the 50 (96%) patients; for stage T1-2 in 37 of 38 (97%) patients and for stage T3 in 11 of 12 (92%) patients. A posttreatment serum PSA level < or =1.0 ng/ml was seen in 42 (84%) patients, values from >1.0 to < or =2.0 ng/ml were seen in four (8%) patients and values exceeding 2.0 were seen in four (8%) patients. The late toxicity was minimal. CONCLUSION: The local control results and the minimal toxicity after the combined radiotherapy treatment are promising. However, long term results are necessary before general use.

Undernotification of diagnosed cancer cases to the Stockholm Cancer Registry.

A study of undernotification to the Stockholm Regional Cancer Registry comprised cancer diagnosed in 1978. Non-notified cases were identified by linking the cancer register with two independent sources of information viz. the Swedish cause-of-death register (fatal cases) and the regional in-patient care register (non-fatal cases). The estimated deficit in the cancer register for 1978 was 4% of the total cancer incidence for that year. The unreported non-fatal cases were followed up for five years, during which time more than half of the cancer diagnoses were entered on death certificates. If the cancer register had been supplemented with information from death certificates, therefore, only about 1% of all non-notified cases would have remained unregistered five years after diagnosis.

Intracranial tumors after radium treatment for skin hemangioma during infancy--a cohort and case-control study.

The risk of developing intracranial tumors was studied in a Swedish cohort of 11,805 infants treated with 226Ra for hemangioma of the skin between 1930 and 1965. The cohort was followed up in the Swedish Cancer Register during the years 1958 through 1992, giving 402,958 person-years at risk. Forty-seven intracranial tumors developed in 46 individuals. The standardized incidence ratio (SIR) was 1.80 (95% CI 1.32-2.39). An excess number of cases was found for many histopathological subgroups, although the excess was statistically significant only for gliomas (n = 23, SIR 1.89, 95% CI 1.20-2.83) and meningiomas (n = 8, SIR 2.42, 95% CI 1.06-4.77). Absorbed doses to the brain have been calculated. The mean dose to the brain was only 7.2 cGy. The dose response was evaluated by Poisson regression methods. There was an excess of intracranial tumors in all dose categories, but no clear dose-response relationship could be seen for the data. This indicates that explanations other than irradiation may also be involved. The selection of the reference population has been studied and confirmed to be representative. For individuals treated before 7 months of age, however, the data could be fitted to both the linear and the linear-quadratic model. These results may indicate that the youngest infants may be more sensitive to ionizing radiation and that even very low doses to the brain may increase the risk for intracranial tumors.

Outcome of reproduction in women irradiated for skin hemangioma in infancy.

The possible impact of early gonadal irradiation on the results of future pregnancies is unclear. This study is based on the progeny of 17,393 women who were treated with irradiation for skin hemangiomas at the age of 18 months or less. The mean ovarian dose was 6 cGy, and the maximum was 8.55 Gy. Using Swedish central health registers, the outcome of delivery was studied in these women; 19,494 infants born were identified. The treated women deviated from the general population by having a longer education and by smoking less. This may explain a reduced risk for low birth weight and preterm birth (not related to radiation dose). Women with ovarian doses greater than 1 cGy had fewer infants than women with a lower ovarian dose. An excess of perinatal deaths was evident as well as a slight excess in the rate of malformation, but neither was related to dose. There was a statistically significant trend of an increasing rate of neural tube defects with ovarian dose, possibly a chance result of multiple statistical testing. Cleft lip/palate occurred at levels significantly below expectation. No increase in the rate of infants with Down syndrome or in childhood malignancies was detected. No major adverse results in outcome of delivery were seen after ovarian irradiation in childhood with the possible exception of neural tube defects.