S U M M A R Y. Psychological distress was measured among women on the day of recall after mammogr... more S U M M A R Y. Psychological distress was measured among women on the day of recall after mammography in an official screening programme, and 4 weeks after the diagnosis was given. The Hospital Anxiety and Depression Scale (HADS) and a questionnaire to assess reactions to the examination were completed by 213 (97%) women aged 50-69 years.
The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiet... more The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiety and Depression Scale (HAD)) one year following surgery, with special focus on dispositional optimism/pessimism (measured by the Life Orientation Test (LOT-R), was examined in 165 women, newly diagnosed with breast cancer. Patients characteristics, appraisal of cancer diagnosis, beliefs about treatment efficacy, treatment decision-making participation, coping and emotional morbidity was assessed by self-rating questionnaires. Prevalence of anxiety and depression cases at time of diagnosis was 34 and 12%, respectively, and 26 and 9% after one year. Prevalence of emotional morbidity was significantly enlarged among pessimists at all assessments. Pessimism was the strongest predictor for anxiety (OR: 0.86 C.I. 95% 0.77 - 0.95) and depression (OR: 0.83, C.I. 95% 0.73 - 0.95) one year following breast cancer surgery. Optimists and pessimists differed not only in regard to coping styles, but also in regards to predictors of emotional morbidity. Optimists experiencing anxiety at time of breast cancer diagnosis had about six times higher risk of experiencing anxiety after one year, compared to optimists without preoperative anxiety. For pessimists, the more pessimistic one was about one's overall future the higher risk for developing anxiety following one year of breast cancer surgery. Pessimists, who endorse helpless/hopeless coping style when receiving a diagnosis of breast cancer, had three times greater risk for experiencing depression one year after breast cancer surgery, than pessimists who did not. Health care professionals should therefore provide intervention for pessimists, as well as for patients with high anxiety scores at time of diagnosis.
Women who participated in the hospital psychosocial support groups following breast cancer surger... more Women who participated in the hospital psychosocial support groups following breast cancer surgery were compared with non-participants. The Hospital Anxiety and Depression Scale and the EORTC quality of life questionnaire were used to measure emotional distress and quality of life at the time of diagnosis and after 12 months. The General Life Orientation Test-Revised was used to measure dispositional optimism. Of 165 women, 87% reported that they had been invited to participate, and 66% participated. The salient predictor for participating in support group was optimism (OR 0.89 CI: 95% 0.83-0.98, p ¼ 0:01). No significant difference was found between the prevalence of anxiety and depression caseness at the time of diagnosis, but after 12 months, the prevalence of anxiety caseness was significantly lower among the participants than that among the non-participants (19% vs 34%, p ¼ 0:04).
The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiet... more The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiety and Depression Scale (HAD)) one year following surgery, with special focus on dispositional optimism/pessimism (measured by the Life Orientation Test (LOT-R), was examined in 165 women, newly diagnosed with breast cancer. Patients characteristics, appraisal of cancer diagnosis, beliefs about treatment efficacy, treatment decision-making participation, coping and emotional morbidity was assessed by self-rating questionnaires. Prevalence of anxiety and depression cases at time of diagnosis was 34 and 12%, respectively, and 26 and 9% after one year. Prevalence of emotional morbidity was significantly enlarged among pessimists at all assessments. Pessimism was the strongest predictor for anxiety (OR: 0.86 C.I. 95% 0.77 - 0.95) and depression (OR: 0.83, C.I. 95% 0.73 - 0.95) one year following breast cancer surgery. Optimists and pessimists differed not only in regard to coping styles, but also in regards to predictors of emotional morbidity. Optimists experiencing anxiety at time of breast cancer diagnosis had about six times higher risk of experiencing anxiety after one year, compared to optimists without preoperative anxiety. For pessimists, the more pessimistic one was about one's overall future the higher risk for developing anxiety following one year of breast cancer surgery. Pessimists, who endorse helpless/hopeless coping style when receiving a diagnosis of breast cancer, had three times greater risk for experiencing depression one year after breast cancer surgery, than pessimists who did not. Health care professionals should therefore provide intervention for pessimists, as well as for patients with high anxiety scores at time of diagnosis.
Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, Jan 10, 1998
One of the disadvantages of breast conserving treatment compared with mastectomy is the higher ra... more One of the disadvantages of breast conserving treatment compared with mastectomy is the higher rate of local recurrence. Even though a local recurrence has no influence on survival, it is a psychological trauma for the woman it affects. Breast conserving treatment has been practised at Ullevaal Hospital since 1986. This study is based on data from 216 consecutive cases of breast conserving surgery, from January 1986 to March 1996. Mean observation time was 29 months. Nine (4.2%) patients experienced a local recurrence. Age, histological grade, and the size of the tumor were identified as risk factors, whereas there was no correlation between histology, axillary node involvement, and surgical margins.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2005
Interactions between luminal epithelial cells and their surrounding microenvironment govern the n... more Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER- and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expres...
483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutate... more 483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutated (ATM) mutations previously found to account for 83% of the disease alleles in Norwegian ataxia telangiectasia (AT) patients. Only one carrier was found. These results provide no evidence in favour of an excess risk of breast cancer associated with heterozygosity for classical AT mutations, but remain consistent with a maximum 2.4-fold increased risk.
The axillary lymph nodes of 100 lymph node-negative breast cancer patients with known bone marrow... more The axillary lymph nodes of 100 lymph node-negative breast cancer patients with known bone marrow status have been re-examined to explore the presence of micrometastasis in lymph nodes and the covariance of micrometastasis to bone marrow and lymph nodes. Nodes were serially sectioned at three intervals of 100 microm, followed by immunohistological (two sections) and haematoxylin-eosin staining (one section). Tumours were mainly T1 and T2, and the patients had on average 13 (4-22) lymph nodes removed. In two patients, micrometastasis was detected in one node. Another 25 patients possessed single positive immunostained cells mimicking tumour cells. These cells have been shown to be false positive cells by Perl and melanin staining. One patient had metastasis to several nodes missed by the original examination. Immunocytochemical detection of micrometastasis in bone marrow revealed 11 marrow-positive patients. This study has identified a low frequency of micrometastasis to lymph nodes, and no covariance with micrometastasis in the bone marrow was seen. Bone marrow micrometastasis may be an independent prognostic variable, separate from axillary node status.
S U M M A R Y . This study assesses the perception of the decision-making process of 25 surgeons ... more S U M M A R Y . This study assesses the perception of the decision-making process of 25 surgeons and 194 patients (aged 21-81 years) who had newly diagnosed breast cancer and had to undergo mastectomy or breast-conserving surgery (BCS). The majority of women wanted to participate in decision-making. When it was medically possible to give a choice between BCS and mastectomy, only 59% of women received a choice. The main reason that 11% of the women went against surgeon's recommendations was fear of cancer recurrence. The most influential factors for women were the surgeon's recommendation, and fear of cancer recurrence. Medical assessment and the cosmetic result were the most influential factors for the surgeons. Female surgeons were more influenced by their assessment of the women's need for security, than male.
The aim of the study was to explore the value of analyzing bone marrow (BM) for the presence of i... more The aim of the study was to explore the value of analyzing bone marrow (BM) for the presence of isolated tumor cell(s) (ITCs) in disease-free breast cancer patients 3 years after diagnosis. ITCs in BM at operation was found to be an independent prognostic factor in 817 breast cancer patients. Among these, 356 disease-free patients were analyzed with a second BM after 3 years follow-up (median 40 months, SD 3 months, range 29-52). ITC was detected by immunocytochemistry with anticytokeratine antibodies (AE1/AE3). The population consisted of 70% T1 and 72% node-negative patients. ITC in BM was detected in 15%. At a median of 25 months since the second BM aspiration (66 months since diagnosis), 32 patients had developed relapse, 12 local and 20 systemic. Of the patients with ITC in BM, 21% relapsed compared with 7% of the ITC-negative patients (P < 0.001). Ten patients died of breast cancer. Survival analyses showed that ITC in BM predicted reduced distant disease-free survival (DDFS) and breast cancer specific survival (BCSS; P < 0.001, log-rank test). Uni-and multivariate analyses of the prognostic value of N, T, estrogen receptor/progesterone receptor, and BM status, histological grade, vascular invasion, p53-, c-erb-B2-, and cathepsin D expression were performed. BM status was the only independent prognostic factor for both DDFS and BCSS, whereas c-erbB-2 and N status were independent for BCSS and vascular invasion and T status for DDFS. ITC in BM 3 years after diagnosis in disease-free breast cancer patients is an independent prognostic factor. Detection of residual disease by BM analysis at follow-up may unravel insufficient adjuvant treatment. The clinical implications should be further explored.
There is compelling evidence from transgenic mouse studies and analysis of mutations in human car... more There is compelling evidence from transgenic mouse studies and analysis of mutations in human carcinomas indicating that the TGF-β signal transduction pathway is tumor suppressive. We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of mammary carcinomas. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the type II TGF-β receptor (TβRII). There is also evidence that TGF-β can enhance the progression of tumors. This hypothesis is being tested in genetically modified mice. To attain complete loss of TβRII, we have generated mice with loxP sites flanking exon 2 of Tgfbr2 and crossed them with mice expressing Cre recombinase under control of the MMTV promoter/enhancer to obtain Tgfbr2 mgKO mice. These mice show lobuloalveolar hyperplasia. Mice are being followed for mammary tumor development. Tgfbr2 mgKO mice that also express polyoma virus middle T antigen under control of the MMTV promoter (MMTV-PyVmT) develop mammary tumors with a significantly shorter latency than MMTV-PyVmT mice and show a marked increase in pulmonary metastases. Our data do not support the hypothesis that TGF-β signaling in mammary carcinoma cells is important for invasion and metastasis, at least in this model system. The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2 flox/flox mice were crossed to attain Tgfbr2 fspKO mice. The Despite over a decade of scrutiny and over 20 published reports from various countries, the degree to which ATM mutations lead to breast References 1. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Biol Metab 1999, 68:419-423. 2. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, et al.: Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 2002, 32:185-190. 3. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA 2002, 99:925-930. 4. Concannon P: ATM heterozygosity and cancer risk. Nat Genet 2002, 32:89-90. 5. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, et al.: Dominant negative ATM mutations in breast cancer families.
The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marr... more The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marrow toxicity were studied in a phase I1 multicenter study. Sixty-three patients with nonresectable primary or secondary liver cancer were randomized to receive either i.a. mitomycin C 15 m&m2 first, followed 5 weeks later by mitomycin C 15 m&m2 plus DSM 360 mg administered into the hepatic artery (group I) or the same treatments in the opposite sequence (group 11). In 36 out of 47 patients who received at least 2 treatments, peripheral venous blood samples were analyzed for mitomycin C pharmacokinetics on a minimum of 2 paired courses. In all patients, the area under the concentration time curve (AUC) was significantly lower when the drug was co-administrated with DSM, but the terminal half-life (t,,J of mitomycin C was unchanged. In group I the addition of DSM resulted in a significantly lowered AUC, but not in group 11. The discrepancy between the 2 groups is probably due to differences in DSM-induced intra-hepatic shunting. The addition of DSM resulted in significantly higher platelet nadir values, but unchanged white blood cell count nadir value. In conclusion, DSM reduce the systemic exposure of mitomycin C and seem to lessen the haematologic toxicity judged from a less pronounced decrease in platelets.
Background. Several studies have reported an association between breast cancer unit volume and pr... more Background. Several studies have reported an association between breast cancer unit volume and prognosis. We hypothesize that this may be due to inappropriate coping with the recommended guidelines for adjuvant therapy rather than improper breast cancer surgery provided at smaller units. Methods. A cohort of 1131 patients with operable breast cancer (pT 1-2 and positive axillary lymph nodes, stage II) enrolled between 1984 and 1994 were analyzed. The women had participated in one of three prospective trials on adjuvant endocrine treatment and were enrolled from 50 centers in Norway. The hospitals were categorized into four groups according to the annual number of surgically treated breast cancer patients reported to the national discharge database in 1990. The hospitals were also stratifi ed according to whether they are university or non-university hospitals. To assess the effect of unit size on patient outcome, local recurrence rates and overall survival were compared in women treated at units with different patient volumes. Results. The median time from study enrolment to the end of the study was 10.5 years. Relapse-free survival and overall survival did not differ signifi cantly between the hospital groups based on the surgical workload or between university and non-university hospitals. Conclusions. Patient volume or teaching status of a hospital did not have any impact on the prognosis of pre-or postmenopausal stage II breast cancer patients included in the adjuvant endocrine trials. Our data support the hypothesis that differences in survival related to patient volume at the treatment units may be explained by inappropriate adjuvant systemic treatment.
S U M M A R Y. Psychological distress was measured among women on the day of recall after mammogr... more S U M M A R Y. Psychological distress was measured among women on the day of recall after mammography in an official screening programme, and 4 weeks after the diagnosis was given. The Hospital Anxiety and Depression Scale (HADS) and a questionnaire to assess reactions to the examination were completed by 213 (97%) women aged 50-69 years.
The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiet... more The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiety and Depression Scale (HAD)) one year following surgery, with special focus on dispositional optimism/pessimism (measured by the Life Orientation Test (LOT-R), was examined in 165 women, newly diagnosed with breast cancer. Patients characteristics, appraisal of cancer diagnosis, beliefs about treatment efficacy, treatment decision-making participation, coping and emotional morbidity was assessed by self-rating questionnaires. Prevalence of anxiety and depression cases at time of diagnosis was 34 and 12%, respectively, and 26 and 9% after one year. Prevalence of emotional morbidity was significantly enlarged among pessimists at all assessments. Pessimism was the strongest predictor for anxiety (OR: 0.86 C.I. 95% 0.77 - 0.95) and depression (OR: 0.83, C.I. 95% 0.73 - 0.95) one year following breast cancer surgery. Optimists and pessimists differed not only in regard to coping styles, but also in regards to predictors of emotional morbidity. Optimists experiencing anxiety at time of breast cancer diagnosis had about six times higher risk of experiencing anxiety after one year, compared to optimists without preoperative anxiety. For pessimists, the more pessimistic one was about one's overall future the higher risk for developing anxiety following one year of breast cancer surgery. Pessimists, who endorse helpless/hopeless coping style when receiving a diagnosis of breast cancer, had three times greater risk for experiencing depression one year after breast cancer surgery, than pessimists who did not. Health care professionals should therefore provide intervention for pessimists, as well as for patients with high anxiety scores at time of diagnosis.
Women who participated in the hospital psychosocial support groups following breast cancer surger... more Women who participated in the hospital psychosocial support groups following breast cancer surgery were compared with non-participants. The Hospital Anxiety and Depression Scale and the EORTC quality of life questionnaire were used to measure emotional distress and quality of life at the time of diagnosis and after 12 months. The General Life Orientation Test-Revised was used to measure dispositional optimism. Of 165 women, 87% reported that they had been invited to participate, and 66% participated. The salient predictor for participating in support group was optimism (OR 0.89 CI: 95% 0.83-0.98, p ¼ 0:01). No significant difference was found between the prevalence of anxiety and depression caseness at the time of diagnosis, but after 12 months, the prevalence of anxiety caseness was significantly lower among the participants than that among the non-participants (19% vs 34%, p ¼ 0:04).
The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiet... more The prevalence of and predictive factors for emotional morbidity (measured by the Hospital Anxiety and Depression Scale (HAD)) one year following surgery, with special focus on dispositional optimism/pessimism (measured by the Life Orientation Test (LOT-R), was examined in 165 women, newly diagnosed with breast cancer. Patients characteristics, appraisal of cancer diagnosis, beliefs about treatment efficacy, treatment decision-making participation, coping and emotional morbidity was assessed by self-rating questionnaires. Prevalence of anxiety and depression cases at time of diagnosis was 34 and 12%, respectively, and 26 and 9% after one year. Prevalence of emotional morbidity was significantly enlarged among pessimists at all assessments. Pessimism was the strongest predictor for anxiety (OR: 0.86 C.I. 95% 0.77 - 0.95) and depression (OR: 0.83, C.I. 95% 0.73 - 0.95) one year following breast cancer surgery. Optimists and pessimists differed not only in regard to coping styles, but also in regards to predictors of emotional morbidity. Optimists experiencing anxiety at time of breast cancer diagnosis had about six times higher risk of experiencing anxiety after one year, compared to optimists without preoperative anxiety. For pessimists, the more pessimistic one was about one's overall future the higher risk for developing anxiety following one year of breast cancer surgery. Pessimists, who endorse helpless/hopeless coping style when receiving a diagnosis of breast cancer, had three times greater risk for experiencing depression one year after breast cancer surgery, than pessimists who did not. Health care professionals should therefore provide intervention for pessimists, as well as for patients with high anxiety scores at time of diagnosis.
Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, Jan 10, 1998
One of the disadvantages of breast conserving treatment compared with mastectomy is the higher ra... more One of the disadvantages of breast conserving treatment compared with mastectomy is the higher rate of local recurrence. Even though a local recurrence has no influence on survival, it is a psychological trauma for the woman it affects. Breast conserving treatment has been practised at Ullevaal Hospital since 1986. This study is based on data from 216 consecutive cases of breast conserving surgery, from January 1986 to March 1996. Mean observation time was 29 months. Nine (4.2%) patients experienced a local recurrence. Age, histological grade, and the size of the tumor were identified as risk factors, whereas there was no correlation between histology, axillary node involvement, and surgical margins.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2005
Interactions between luminal epithelial cells and their surrounding microenvironment govern the n... more Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER- and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expres...
483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutate... more 483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutated (ATM) mutations previously found to account for 83% of the disease alleles in Norwegian ataxia telangiectasia (AT) patients. Only one carrier was found. These results provide no evidence in favour of an excess risk of breast cancer associated with heterozygosity for classical AT mutations, but remain consistent with a maximum 2.4-fold increased risk.
The axillary lymph nodes of 100 lymph node-negative breast cancer patients with known bone marrow... more The axillary lymph nodes of 100 lymph node-negative breast cancer patients with known bone marrow status have been re-examined to explore the presence of micrometastasis in lymph nodes and the covariance of micrometastasis to bone marrow and lymph nodes. Nodes were serially sectioned at three intervals of 100 microm, followed by immunohistological (two sections) and haematoxylin-eosin staining (one section). Tumours were mainly T1 and T2, and the patients had on average 13 (4-22) lymph nodes removed. In two patients, micrometastasis was detected in one node. Another 25 patients possessed single positive immunostained cells mimicking tumour cells. These cells have been shown to be false positive cells by Perl and melanin staining. One patient had metastasis to several nodes missed by the original examination. Immunocytochemical detection of micrometastasis in bone marrow revealed 11 marrow-positive patients. This study has identified a low frequency of micrometastasis to lymph nodes, and no covariance with micrometastasis in the bone marrow was seen. Bone marrow micrometastasis may be an independent prognostic variable, separate from axillary node status.
S U M M A R Y . This study assesses the perception of the decision-making process of 25 surgeons ... more S U M M A R Y . This study assesses the perception of the decision-making process of 25 surgeons and 194 patients (aged 21-81 years) who had newly diagnosed breast cancer and had to undergo mastectomy or breast-conserving surgery (BCS). The majority of women wanted to participate in decision-making. When it was medically possible to give a choice between BCS and mastectomy, only 59% of women received a choice. The main reason that 11% of the women went against surgeon's recommendations was fear of cancer recurrence. The most influential factors for women were the surgeon's recommendation, and fear of cancer recurrence. Medical assessment and the cosmetic result were the most influential factors for the surgeons. Female surgeons were more influenced by their assessment of the women's need for security, than male.
The aim of the study was to explore the value of analyzing bone marrow (BM) for the presence of i... more The aim of the study was to explore the value of analyzing bone marrow (BM) for the presence of isolated tumor cell(s) (ITCs) in disease-free breast cancer patients 3 years after diagnosis. ITCs in BM at operation was found to be an independent prognostic factor in 817 breast cancer patients. Among these, 356 disease-free patients were analyzed with a second BM after 3 years follow-up (median 40 months, SD 3 months, range 29-52). ITC was detected by immunocytochemistry with anticytokeratine antibodies (AE1/AE3). The population consisted of 70% T1 and 72% node-negative patients. ITC in BM was detected in 15%. At a median of 25 months since the second BM aspiration (66 months since diagnosis), 32 patients had developed relapse, 12 local and 20 systemic. Of the patients with ITC in BM, 21% relapsed compared with 7% of the ITC-negative patients (P < 0.001). Ten patients died of breast cancer. Survival analyses showed that ITC in BM predicted reduced distant disease-free survival (DDFS) and breast cancer specific survival (BCSS; P < 0.001, log-rank test). Uni-and multivariate analyses of the prognostic value of N, T, estrogen receptor/progesterone receptor, and BM status, histological grade, vascular invasion, p53-, c-erb-B2-, and cathepsin D expression were performed. BM status was the only independent prognostic factor for both DDFS and BCSS, whereas c-erbB-2 and N status were independent for BCSS and vascular invasion and T status for DDFS. ITC in BM 3 years after diagnosis in disease-free breast cancer patients is an independent prognostic factor. Detection of residual disease by BM analysis at follow-up may unravel insufficient adjuvant treatment. The clinical implications should be further explored.
There is compelling evidence from transgenic mouse studies and analysis of mutations in human car... more There is compelling evidence from transgenic mouse studies and analysis of mutations in human carcinomas indicating that the TGF-β signal transduction pathway is tumor suppressive. We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of mammary carcinomas. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the type II TGF-β receptor (TβRII). There is also evidence that TGF-β can enhance the progression of tumors. This hypothesis is being tested in genetically modified mice. To attain complete loss of TβRII, we have generated mice with loxP sites flanking exon 2 of Tgfbr2 and crossed them with mice expressing Cre recombinase under control of the MMTV promoter/enhancer to obtain Tgfbr2 mgKO mice. These mice show lobuloalveolar hyperplasia. Mice are being followed for mammary tumor development. Tgfbr2 mgKO mice that also express polyoma virus middle T antigen under control of the MMTV promoter (MMTV-PyVmT) develop mammary tumors with a significantly shorter latency than MMTV-PyVmT mice and show a marked increase in pulmonary metastases. Our data do not support the hypothesis that TGF-β signaling in mammary carcinoma cells is important for invasion and metastasis, at least in this model system. The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2 flox/flox mice were crossed to attain Tgfbr2 fspKO mice. The Despite over a decade of scrutiny and over 20 published reports from various countries, the degree to which ATM mutations lead to breast References 1. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Biol Metab 1999, 68:419-423. 2. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, et al.: Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 2002, 32:185-190. 3. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA 2002, 99:925-930. 4. Concannon P: ATM heterozygosity and cancer risk. Nat Genet 2002, 32:89-90. 5. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, et al.: Dominant negative ATM mutations in breast cancer families.
The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marr... more The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marrow toxicity were studied in a phase I1 multicenter study. Sixty-three patients with nonresectable primary or secondary liver cancer were randomized to receive either i.a. mitomycin C 15 m&m2 first, followed 5 weeks later by mitomycin C 15 m&m2 plus DSM 360 mg administered into the hepatic artery (group I) or the same treatments in the opposite sequence (group 11). In 36 out of 47 patients who received at least 2 treatments, peripheral venous blood samples were analyzed for mitomycin C pharmacokinetics on a minimum of 2 paired courses. In all patients, the area under the concentration time curve (AUC) was significantly lower when the drug was co-administrated with DSM, but the terminal half-life (t,,J of mitomycin C was unchanged. In group I the addition of DSM resulted in a significantly lowered AUC, but not in group 11. The discrepancy between the 2 groups is probably due to differences in DSM-induced intra-hepatic shunting. The addition of DSM resulted in significantly higher platelet nadir values, but unchanged white blood cell count nadir value. In conclusion, DSM reduce the systemic exposure of mitomycin C and seem to lessen the haematologic toxicity judged from a less pronounced decrease in platelets.
Background. Several studies have reported an association between breast cancer unit volume and pr... more Background. Several studies have reported an association between breast cancer unit volume and prognosis. We hypothesize that this may be due to inappropriate coping with the recommended guidelines for adjuvant therapy rather than improper breast cancer surgery provided at smaller units. Methods. A cohort of 1131 patients with operable breast cancer (pT 1-2 and positive axillary lymph nodes, stage II) enrolled between 1984 and 1994 were analyzed. The women had participated in one of three prospective trials on adjuvant endocrine treatment and were enrolled from 50 centers in Norway. The hospitals were categorized into four groups according to the annual number of surgically treated breast cancer patients reported to the national discharge database in 1990. The hospitals were also stratifi ed according to whether they are university or non-university hospitals. To assess the effect of unit size on patient outcome, local recurrence rates and overall survival were compared in women treated at units with different patient volumes. Results. The median time from study enrolment to the end of the study was 10.5 years. Relapse-free survival and overall survival did not differ signifi cantly between the hospital groups based on the surgical workload or between university and non-university hospitals. Conclusions. Patient volume or teaching status of a hospital did not have any impact on the prognosis of pre-or postmenopausal stage II breast cancer patients included in the adjuvant endocrine trials. Our data support the hypothesis that differences in survival related to patient volume at the treatment units may be explained by inappropriate adjuvant systemic treatment.
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Papers by R. Kåresen