[The Willingness to Consent to the Linkage of Primary and Secondary Data: An Analysis Based on a Survey of Patients with Primary Breast Cancer in Northrhine Westfalia]. / Die Bereitschaft zum Datenlinkage von Routinedaten und Primärdaten ­ Eine Analyse auf Basis der Befragung von Patientinnen und Patienten mit primärem Mammakarzinom in NRW.

Introduction: By linking data it is possible to merge, for example, survey data with routine data from statutory health insurance (GKV), to gain benefit from the advantages of both. As personal data is involved, it is necessary to obtain consent. Previous studies show that willingness to release this kind of data for scientific research is limited. This fact restricts the number of participants and can cause selection bias. The aim of our study was to analyze willingness to consent to the linkage of survey data with statutory health insurance data in patients with primary breast cancer. Associations between approval and socio-demographic characteristics were explored. Method: In the annual survey of patients with primary breast cancer in certified breast centers in North Rhine-Westphalia, all included patients were questioned concerning their willingness to consent to data linkage. We distinguished between patients insured by AOK Rhineland/Hamburg and all other patients: based on cooperation with AOK Rhineland/Hamburg, we obtained consent to actually link the data for all patients insured there. All other patients were questioned in terms of their insurance and their willingness to consent in general. Results: A total of 2,387 questionnaires were returned, giving a return rate of 49.3%. For the AOK Rhineland/Hamburg-insured patients, the consent rate was at 89.6%. At 75.7%, positive attitudes towards data linkage turned out to be a bit lower for patients with other insurers. Under the assumption that all non-responders disapprove data linkage, still 38.1% of patients showed a positive attitude towards data linkage. As a result of the multivariable model, insurance status (private vs. statutory) and first language turned out to be the only significant factors influencing the response. The consent of patients insured by AOK Rhineland/Hamburg is not significantly influenced by any of the measured socio-demographic factors. Conclusion: Currently, there is not much knowledge on the acceptance of data linkage in patients suffering from an acute illness. Although our results are restricted to breast cancer patients, they are able to uncover problems and chances concerning data linkage.

Combined Preclinical Magnetic Particle Imaging and Magnetic Resonance Imaging: Initial Results in Mice.

PURPOSE: Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. MATERIALS AND METHODS: The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. RESULTS: A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. CONCLUSION: The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

Superparamagnetic iron oxide nanoparticles in biomedicine: applications and developments in diagnostics and therapy.

Superparamagnetic iron oxide nanoparticles (SPIO) can be used to image physiological processes and anatomical, cellular and molecular changes in diseases. The clinical applications range from the imaging of tumors and metastases in the liver, spleen and bone marrow, the imaging of lymph nodes and the CNS, MRA and perfusion imaging to atherosclerotic plaque and thrombosis imaging. New experimental approaches in molecular imaging describe undirected SPIO trapping (passive targeting) in inflammation, tumors and associated macrophages as well as the directed accumulation of SPIO ligands (active targeting) in tumor endothelia and tumor cells, areas of apoptosis, infarction, inflammation and degeneration in cardiovascular and neurological diseases, in atherosclerotic plaques or thrombi. The labeling of stem or immune cells allows the visualization of cell therapies or transplant rejections. The coupling of SPIO to ligands, radio- and/or chemotherapeutics, embedding in carrier systems or activatable smart sensor probes and their externally controlled focusing (physical targeting) enable molecular tumor therapies or the imaging of metabolic and enzymatic processes. Monodisperse SPIO with defined physicochemical and pharmacodynamic properties may improve SPIO-based MRI in the future and as targeted probes in diagnostic magnetic resonance (DMR) using chip-based µNMR may significantly expand the spectrum of in vitro analysis methods for biomarker, pathogens and tumor cells. Magnetic particle imaging (MPI) as a new imaging modality offers new applications for SPIO in cardiovascular, oncological, cellular and molecular diagnostics and therapy.

Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients.

Here, we present results from a clinical trial employing a new vaccination method using dendritic cells (DCs) transfected with mRNA from allogeneic prostate cancer cell lines (DU145, LNCaP and PC-3). In all, 20 patients were enrolled and 19 have completed vaccination. Each patient received at least four weekly injections with 2 x 10(7) transfected DCs either intranodally or intradermally. Safety and feasibility of vaccination were determined. Immune responses were measured as delayed-type hypersensitivity and by in vitro immunoassays including ELISPOT and T-cell proliferation in pre- and postvaccination peripheral blood samples. Serum prostate-specific antigen (PSA) levels and bone scans were monitored. No toxicity or serious adverse events related to vaccinations were observed. A total of 12 patients developed a specific immune response to tumour mRNA-transfected DCs. In total, 13 patients showed a decrease in log slope PSA. This effect was strengthened by booster vaccinations. Clinical outcome was significantly related to immune responses (n = 19, P = 0.002, r = 0.68). Vaccination with mRNA-transfected DCs is safe and results in cellular immune responses specific for antigens encoded by mRNA derived from the prostate cancer cell lines. The observation that in some patients vaccination affected the PSA level suggests that this approach may become useful as a treatment modality for prostate cancer patients.

Consequences of local recurrence of soft tissue sarcoma: 205 patients from the Scandinavian Sarcoma Group Register.

From the Scandinavian Sarcoma Group Register, information on 1,224 surgically-treated patients with soft tissue sarcoma (STS) of the extremity or trunk wall, diagnosed between 1987 and 1995, was collected. 205 patients, one third of whom were referred to a center with a local recurrence, had a total of 284 local recurrences. This analysis describes the treatment for these local recurrences, complications and risk of further recurrences. 169 patients were surgically treated for their first local recurrence. An intralesional or marginal margin was achieved in 110 of these patients, 59 of whom were also given radiotherapy. 54 of the 169 patients had a second local recurrence. The second local recurrence rate was 0.50 if the first local recurrence had been treated with only surgery with a marginal margin, compared to 0.28 if treated with surgery with a marginal margin and radiotherapy or with a wide margin (p = 0.0008). In extremity STS, the crude amputation rate for local recurrences was 0.22 (31 of 142)-i.e., higher than for primary tumors 0.09 (96 of 1065) (p < 0.0001). A high local recurrence rate after treatment outside of sarcoma centers has earlier been shown. We conclude that the consequences of local recurrence in terms of morbidity and costs justifies referral of STS patients for multidisciplinary evaluation and multimodality treatment.

Breast cancer in the contralateral breast: incidence and histopathology after unilateral radical treatment of the first breast cancer.

The objective of the study was to assess the 10-year cumulative risk and clinical risk factors for the development of a contralateral cancer and to compare the tumours histopathologically. Among 1980 consecutive radically treated breast carcinoma patients a separate malignant breast tumour was diagnosed in 90 and 74 could be histopathologically compared with the primary tumour. The 10-year cumulative risk was 6.5% (95% CI: 5-8%). There was no difference in 10-year cumulative risk in developing a second breast tumour comparing premenopausal (7.1%) with postmenopausal women (6.1%). The cumulative risk among premenopausal tamoxifen-treated women (19.3%) or among patients with relapse (13.8%) was significantly increased as compared to similar patients without tamoxifen or without relapse. Sixty-six percent of the tumours displayed different histopathology. Morphologically similar and different tumours developed almost equally among patients with synchronous tumours and in those with or without relapse. We conclude that a radically treated breast cancer patient has a 10-year cumulative risk of 6.5% to develop a new malignant breast tumour. In premenopausal women the tumour-protective effect of two years tamoxifen application seems questionable. Histopathological comparison of the bilateral breast tumours enables discrimination of bilateral breast tumours as two primaries in 2/3 of the patients with morphologically different tumours.

Influence of droloxifene on metastatic breast cancer as first-line endocrine treatment.

The effect of droloxifene (3-hydroxytamoxifen) given as first-line endocrine treatment was evaluated in 39 postmenopausal women with advanced receptor-positive or receptor-unknown breast cancer. The patients had not received any previous anticancer therapy apart from adjuvant treatment. The overall response rate (CR + PR) was 51% (8% CR, 43% PR), 95% confidence interval+/-15.7%. Median time to progression (all patients) was 8 months, the median time to response 2 months, while the median duration of response was 10 months. The drug was well tolerated with no major side effects recorded; 16% of the patients experienced hot flushes. The response to droloxifene recorded in the present study is in accordance with the response rates to tamoxifen as first-line treatment in identical groups of patients.

Hormone receptor measurements and survival in 1335 consecutive patients with primary invasive breast carcinoma.

The distribution of estrogen and progesterone receptors (ER, PR) was assessed in the primary tumour in 1335 of 2704 (49%) consecutive new breast carcinoma patients (HORMREC). In a subgroup of 757 radically treated patients without systemic adjuvant treatment (RADOP) the relation of the ER and PR content to relapse and survival was evaluated. Three levels were defined for ER: ER-: <10 fmol/mg protein, ER+: moderate ER content >/= 10-99 fmol/mg protein, and high ER content >/= 100 fmol/mg protein. In 1288 patients of the HORMREC group who were evaluable for ER, 1061 (82%) had ER+ tumours, 685 (65%) of moderate content and 376 (35%) of high content, respectively. Among 917 patients, evaluable for PR, 723 (79%) tumours were PR+ (>/= 20 fmol/mg protein), of them 352 (49%) with a moderate content (>/= 20-99 fmol/mg protein) and 371 (51%) with a high content ( >/= 100 fmol/mg protein). The median ER content was significantly increased among the post-menopausal women as compared to the premenopausal women, whereas the median PR content showed no such differences. For the RADOP patients, no correlation between ER status and the first site of relapse was seen, whereas PR+ tumours tended to relapse more often locally than PR- tumours. In the univariate analysis the five-and 10-year tumour-related survival rates for all patients were not correlated with ER or PR positivity. One subgroup of patients with favourable outcome was identified on the basis of hormone receptors: Premenopausal women with tumours of moderately elevated ER content. In the multivariate analysis tumour size and axillary node status were the only independent predictors of survival. Measurements of hormone receptor status give weak prognostic information in radically treated patients with breast cancer as long as no adjuvant systemic treatment is applied. As todays' adjuvant treatment is based on the knowledge of hormone receptor status of the primary tumour, this information should be obtained routinely.

Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group Phase II Study.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.

Risk-adapted treatment of clinical stage 1 non-seminoma testis cancer.

250 patients with clinical stage 1 non-seminomatous germ cell tumours of the testis (NSGCT 1) were included into a prospective multicentre protocol during 1990-1994 and treated according to three risk strata: patients without tumour cell invasion of vascular structures in the testis (VASC-) and elevated serum AFP levels (AFP+) at orchiectomy were considered low risk (LR) and only observed closely. VASC- and AFP- or VASC+ and AFP+ patients were presumed intermediate risk (IR) and pathologically staged (PS) by retroperitoneal lymph node dissection (RPLND). VASC+ and AFP-patients were regarded as high risk (HR) and received adjuvant chemotherapy (PEB x 3). At a median observation time of 40 (7-68) months, all patients were alive and without evidence of active germ cell cancer. The actuarial relapse rate in the 106 LR patients was 22%, and 70% (14/20) had elevated serum tumour markers at relapse. One of 32 (3%) HR patients relapsed with a resectable retroperitoneal mature teratoma despite adjuvant chemotherapy. Only 14% of the 99 IR patients who underwent RPLND had PS2 disease, and the actuarial relapse rate in 85 PS1 patients was 18%. This multicentre study demonstrated that excellent therapeutic outcome is possible when 18 comparatively small urological and oncological centres follow a strict and formal cancer care programme. The useful prognostic effect of VASC was once again verified. Pathological staging by RPLND in NSGCT1 is, in our opinion, not necessary, with presumed low-risk patients offered surveillance and high-risk patients offered adjuvant chemotherapy.

Prognosis of radically operated breast carcinoma patients. A retrospective study of 167 consecutive patients with emphasis on histopathological grading, reproducibility and mean nuclear area.

A retrospective study of 167 consecutive radically treated breast cancer patients with histopathologically confirmed ductal carcinoma is presented. The aim was to establish the prognostic significance and reproducibility of histopathological grading done independently by two pathologists. Further-more, the value of measurements of mean nuclear area (MNA) in the primary tumour was assessed. The two pathologists reviewed the same histological sections using a three-point scoring system based on tubular structures, number of mitoses and nuclear pleomorphism. Grading was identical for 70% of the tumours (Kappa value 0.51). With increasing MNA, the fraction of poorly differentiated tumours increased. In the univariate analysis, tumour-related survival was significantly related to histopathological grading when G3 tumours were compared to G1/G2 tumours (p < 0.05). In the multivariate analysis, tumour size (pT category), lymph-node status and grading were the only significant factors influencing patient outcome (p < 0.05). MNA had no significant prognostic value. A combination of tumour size and histopathological grading identifies a group of node-negative patients (pT2 G2/G3) who may have a less favourable prognosis and for whom adjuvant treatment may be beneficial.

Hospital-related differences in breast cancer management. Analysis of an unselected population-based series of 1353 radically operated patients.

A retrospective review is presented of 1353 consecutive patients with histopathologically confirmed invasive breast carcinoma treated radically with curative intent during the decade 1980-89. None had received adjuvant systemic therapy with hormones or prolonged chemotherapy. The distribution of lymph-node negative (N-) and lymph-node positive (N+) patients was 75% and 25%, respectively. The treatment and outcome were analysed as regards conventional prognostic parameters, in particular considering the axillary lymph-node status and the responsible hospital category (General Municipal Hospitals (MH)) versus Comprehensive Cancer Center (CC)). The most striking difference was detected as regards the number of examined lymph nodes. The median number of nodes described at the MH was 7, as compared to 14 at the CC (p < 0.001). In patients with pT1 tumours the highest rate of lymph-node positivity was observed when 10 or more axillary nodes were removed. Adjuvant radiotherapy reduced the loco-regional recurrence rate in the N-patients, whereas only the regional recurrences were reduced among the N+ patients. The five- and 10-year tumor-related survival rates were 86% and 76%, respectively, with no difference between the MH and the CC. As life-prolonging adjuvant hormone therapy and chemotherapy is now available for patients with axillary lymph node metastases, it is important that patients with breast cancer are operated adequately with the aim to remove at least 10 axillary lymph nodes. A thorough examination of the axillary content should be performed by the pathologist, and the number of resected lymph nodes and metastases should be reported. The establishment of nation-wide standard criteria for the management of breast cancer is recommended.

Analysis of adjuvant treatment in postmenopausal patients with stage II invasive breast carcinoma--a pattern of care study and quality assurance of 431 consecutive patients in Oslo 1980-1989.

A retrospective study of consecutive radically operated stage II postmenopausal breast carcinoma patients diagnosed in Oslo 1980-1989 is presented. The primary aim was to analyse to which extent the increasing knowledge of the new life-prolonging treatment with adjuvant tamoxifen influenced the clinical routine, and how the national recommendations were followed up. Secondary, the concomitant use of estrogen receptor (ER) analysis during the decade was to be assessed. Eligible were 150 patients without adjuvant treatment, 123 patients with radiotherapy alone, and 158 patients who had received systemic adjuvant hormone therapy. The percentage of patients without any adjuvant treatment decreased from 43% (1980 1983) to 29% (1987 1989) together with decreasing use of radiotherapy. Adjuvant tamoxifen treatment increased from 18% to 51%. In 1989, the year after publication of national recommendations of adjuvant tamoxifen treatment in stage II patients, 43% of the patients who were candidates for adjuvant tamoxifen failed to receive the therapy. Only 58% of all stage II patients had an ER analysis in the study period. The low compliance to a scientifically proven and publicly recommended adjuvant treatment of patients with stage II breast carcinoma is disappointing, as is the low performance of ER determination. To reduce the delay of implementation of new treatment modalities in the management of breast carcinoma a strict quality assurance program is needed.

[Primary invasive breast cancer in Oslo 1980-89. A population based study of 1942 unselected patients treated by radical surgery]. / Primaer invasiv cancer mammae i Oslo 1980-89. Populasjonsbasert studie av 1,942 uselekterte, radikalopererte brystkreftpasienter.

A retrospective review is presented of 1,942 consecutive patients with histopathologically confirmed invasive breast cancer, who where treated radically in Oslo from 1980 to 1989, either at General Municipal Hospitals (MH) or at a national Comprehensive Cancer Center (CC). The treatment and outcome were related to accepted medical parameters and the responsible hospital category. The median number of axillary lymph nodes described at the MH was 8, compared to 14 at the CC. During the period 1984 to 1986, 62% of the patients had an estrogen receptor analysis (MH 60%, CC 85%). Of the patients with N > or = 4, 36% received adjuvant hormone treatment (MH 32%, CC 67%), whereas the comparable percentage of patients with pT3/pT4 was 53%. The five- and ten-year cancer-related survival rates were 83% and 71% respectively, with no difference between the MH and the CC. As nation-wide criteria for the management of breast cancer have been accepted, compliance and monitoring by surgeons, pathologists and oncologists is imperative as part of quality assurance.

Primary invasive breast carcinoma in Oslo 1980-1989. Incidence and delay.

A retrospective review was performed on 2704 consecutive patients in Oslo in whom histologically or cytologically confirmed primary invasive breast carcinoma had been diagnosed between 1980 and 1989. The age-adjusted incidence rates were significantly higher in the city of Oslo compared with those of the whole country and remained unchanged during the study period. The percentage of patients who could be treated radically remained unchanged. Among the patients with radical treatment the distribution of pT category and stage was similar during the first and last years. The median delay (from onset of symptoms to start of treatment) of two months remained unchanged during the decade and was not related to patient's age, histological grade or tumour localization in the quadrants of the breast. With increasing duration of delay the number of patients not suitable for radical treatment increased. When considering all 2704 patients, the radicality of treatment, the patient's age and delay were correlated with tumour-specific survival and remained independent factors of tumour-specific survival in the multivariate analysis. The unchanged distribution of pT category and stage in the radically treated patients during the decade surveyed is most probably related to the lack of screening mammography in Norway.

Influence of treatment with the anti-oestrogen 3-hydroxytamoxifen (droloxifene) on plasma sex hormone levels in postmenopausal patients with breast cancer.

Plasma levels of oestradiol (Oe2), oestrone (Oe1) oestrone sulphate (Oe1S), androstenedione, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG) and the gonadotrophins (FSH and LH) were determined in 20 postmenopausal women with breast cancer treated with the anti-oestrogen droloxifene (3-hydroxytamoxifen). Plasma oestrogens were measured before and after 3, 6 and 12 months of therapy. The other hormones were measured before and after 6 months of therapy. Droloxifene treatment had no significant influence on plasma levels of Oe2. Plasma levels of Oe1 and Oe1S increased during treatment (mean increase of 11.9-15.9% and 24.5-69.4% respectively after different time-intervals on treatment). The Oe1S/Oe1 and Oe1S/Oe2 ratios increased by mean values of 13.8-45.2% and 25.9-52.4% respectively. Plasma SHBG increased significantly by a mean value of 73.9%, while FSH and LH fell non-significantly by 19.7% and 20.4% respectively. Plasma levels of testosterone, androstenedione, DHEA and DHEAS all increased during treatment, but none of these alterations were of statistical significance. While the influence of droloxifene on plasma SHBG resembled that which is seen during treatment with tamoxifen, its influence on plasma oestrogens and the gonadotrophins seems to be different. Possible explanations of such differences and the clinical implications of alterations in plasma hormones during treatment with droloxifene are discussed.

Transitional cell carcinoma of the renal pelvis and its expression of p53 protein, c-erbB-2 protein, neuron-specific enolase, Phe 5, chromogranin, laminin and collagen type IV.

Expression of p53 protein, c-erbB-2 protein, neuron-specific enolase (NSE), Phe 5, chromogranin, laminin and collagen type IV was studied by immunohistochemistry in formalin-fixed and paraffin-embedded specimens from 20 patients with renal pelvic carcinoma. Positive membrane-bound c-erbB-2 staining was not found in any case. Two tumors stained for p53 protein. Focal immunoreactivity for laminin was present in 55% and for collagen type IV in 80%. 25% of the cases were NSE positive. None of the tumors stained for Phe 5 or chromogranin. The results were compared with the clinical outcome and the immunohistological findings of p53 protein and c-erbB-2 protein in 13 cases of bladder carcinoma in the same patient group. Four of the thirteen bladder cancer specimens, but only 2 of the 20 renal pelvic cancer specimens, expressed p53 protein. As for renal pelvic carcinoma, c-erbB-2 protein was not expressed in bladder carcinoma. We conclude that p53 gene abnormalities may be of importance in the development of carcinoma in the renal pelvis and urinary bladder, but c-erbB-2 protein expression does not play a major role.

Carcinoma of the renal pelvis. Experience of 80 cases.

The clinical course and association with other urothelial carcinomas was studied in 80 patients with carcinoma of the renal pelvis. At the time of diagnosis macroscopic haematuria was the most common symptom. Urography and retrograde pyelography gave the most accurate diagnoses. Sixty-eight patients (85%) had transitional cell carcinomas, 39 had a history of another urothelial carcinoma either before or after the diagnosis of the renal tumour, usually in the urinary bladder. A previous urothelial carcinoma together with a small renal tumour were predictive of the subsequent development of another urothelial tumour. Regular cystoscopy is recommended during follow-up because of the short observed interval between the development of carcinoma of the renal pelvis and a subsequent urothelial malignancy. The overall five-year survival was 20%. Survival did not depend on the operation, but was significantly related to the extent of locoregional or distant metastases at the time of diagnosis. Patients with such renal tumours that were preceded by or associated with other urothelial carcinomas had a more favourable median survival (42 months) than patients whose renal tumour was their first urothelial carcinoma (19 months).

Droloxifene--a new anti-estrogen. A phase II study in advanced breast cancer.

Twenty-six patients with advanced breast cancer were treated with a new anti-estrogen, Droloxifene (3-hydroxy-tamoxifen). They had all used tamoxifen either in the adjuvant or the advanced situation. The dose schedule was 100 mg orally daily. Partial remissions were observed in 4 (15%) of the patients, and in another 5 patients stable disease (greater than 24 weeks of duration) was observed. Three of the responders were resistant to tamoxifen. Fourteen of the 26 patients had no side-effect. In 2 patients therapy had to be stopped due to fatigue. Droloxifene seems to be an interesting new anti-estrogen which should be further exploited.