Search

Purpose To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer. Patients and Methods Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor– and/or progesterone receptor–positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP). Results In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively. Conclusion Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.

The cell-cycle regulating protein p27(Kip1) (p27) has dual roles by acting as both a cdk inhibitor and as an assembly factor for different cdk complexes. Loss of p27 has been linked to malignant features in tumours; however, the exact role of p27 deregulation in breast cancer regarding prognostic and treatment predictive information has not been fully clarified. We have evaluated p27 expression in 328 primary, Stage II breast cancers from premenopausal patients who had been randomised to either tamoxifen treatment or no adjuvant treatment after surgery. p27 was associated with the oestrogen receptor and cyclin D1, and p27 downregulation was associated with high proliferation. There was no association between recurrence-free survival (RFS) and p27 (HR = 0.800, 95% CI 0.523-1.222, p = 0.300), indicating that p27 is not a prognostic marker. The predictive value of p27 was analysed by comparing RFS in tamoxifen-treated and untreated patients in subgroups of low and high p27 expression (HR = 0.747, 95% CI 0.335-1.664, p = 0.474 and HR = 0.401, 95% CI 0.240-0.670, p < 0.001, respectively). Only patients with p27-high tumours benefited from tamoxifen (multivariate interaction analysis p = 0.034). Our study suggests that p27 downregulation is associated with tamoxifen resistance in premenopausal breast cancer but is not linked to impaired prognosis.

BACKGROUND: CYP2C8/9 polymorphisms may influence breast cancer-free survival after diagnosis due to their role in the metabolism of tamoxifen, paclitaxel, and other chemotherapy. cytochrome P450 (CYP)2C8/9 metabolise arachidonic acid to epoxyeicosatrienoic acids, which enhance migration and invasion in vitro and promote angiogenesis in vivo. We aimed to investigate the frequency of CYP2C8/9 polymorphisms in relation to breast tumour characteristics and disease-free survival. METHODS: A prospective series of 652 breast cancer patients from southern Sweden was genotyped for CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3. Blood samples and questionnaires were obtained pre- and postoperatively. Clinical information and tumour characteristics were obtained from patients' charts and pathology reports. RESULTS: Frequencies of CYP2C8/9 polymorphisms were similar to healthy European populations. Significantly less node involvement (P=0.002) and fewer PR+ tumours (P=0.012) were associated with CYP2C8*4. Median follow-up was 25 months and 52 breast cancer-related events were reported. In a multivariate model, CYP2C8/9*3/*1*/*2/*1 was the only factor associated with increased risk for early events in 297 tamoxifen-treated, ER-positive patients, adjusted HR 2.54 (95%CI 1.11-5.79). The effect appeared to be driven by CYP2C8*3, adjusted HR 8.56 (95%CI 1.53-51.1). CONCLUSION: Polymorphic variants of CYP2C8/9 may influence breast tumour characteristics and disease-free survival in tamoxifen-treated patients. (Less)

A 16-year-old girl presented with a left-sided abdominal mass. X-ray examination and computed tomography disclosed a well-defined tumor close to the tail of the pancreas, stretching the pancreatic branches from the splenic artery as demonstrated by arteriography. Ultrasonography suggested a partly cystic character. Cytologic fine-needle biopsy, histopathological and electron microscopical examination disclosed a cysto-papillary tumor, probably benign, and of an exocrine, ductular origin, and with pseudo-cystic areas similar to those found in adenoid cystic carcinoma of salivary glands. Immunohistochemistry did not demonstrate the presence of polypeptide hormones. The patient is without signs of tumor recurrence 18 months after operation.

Background: In a pilot prospective consecutive series on 50 patients with recurrent breast cancer, results of sentinel lymph node biopsy (SLNB) are reported. The interval between primary operation and recurrence was 8 years (range 1-18 years). Only three patients had not undergone dissection of the axilla (ALND). Results: In 51% of patients scintigraphy disclosed sentinel nodes (SN). At operation SN was identified in 45% of patients corresponding to 83% of the SN's visualized by the scintigraphy. SN contained metastases in seven cases (16%), and the treatment plan was changed as a consequence of the SN examination. Conclusion: SLNB can identify SN at a high rate, and the findings may influence further planning of treatment. SLNB should be a future standard procedure in operations for recurrent breast cancer. Next step should be a randomized study.

Background: Sentinel lymph node biopsy is an established staging method in early breast cancer. After a negative biopsy, most institutions will not perform a completion axillary dissection. The present study reports the current axillary recurrence (AR) rate, overall and disease-free survival in the Swedish Multicenter Cohort Study. Methods: From 3534 patients with primary breast cancer

Purpose: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor–positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as “positive” or “negative” using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. Experimental Design: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. Results: Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70); P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84); P = 0.010] survival. Conclusions: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER.

Angiogenesis is a prognostic indicator in primary breast cancer regulated by specific angiogenic factors and their receptors. Vascular endothelial growth factor-A (VEGF-A), so far considered the most important, acts through dimerization of the receptor VEGFR2/KDR within the receptor tyrosine kinase family of VEGF receptors. In order to study the interplay between VEGF-A and VEGFR2/KDR in breast cancer we evaluated their expression by immunohistochemistry in 102 breast cancers organized in a tumor tissue array system allowing semi-quantitative evaluation of cytoplasmatic staining intensity. In addition, VEGF-A165 was analyzed by an enzyme immuno assay (ELISA) in protein extracts prepared from frozen tissue from 98 of 102 tumors included in the array. Cytoplasmatic staining of VEGF of varying intensity was observed in all samples and correlated with the ELISA results of VEGF content (p = 0.007). Interestingly, VEGFR2/KDR expression correlated with VEGF expression using immunohistochemistry, indicating that VEGF and VEGFR2/KDR may be co-expressed in breast cancer. Furthermore, high levels of VEGF-A165 in the protein extracts was associated with impaired short time survival but not long term survival whereas immunohistochemically assessed VEGF and VEGFR2/KDR were not significantly associated with survival. In summary, immunohistochemically based analysis of VEGF using a tumor tissue array system seems to be a useful method for VEGF quantification in breast cancer here validated using an ELISA based method. The tumor tissue array system enables opportunities of simultaneous analysis of markers engaged in angiogenesis justifying further studies using larger series of tumors.

Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma.The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness0.8 mm and/= 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease.The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively.In this long term follow-up study, local recurrences were found to be rare among patients with tumors0.8 mm thick and/= 2.0 mm thick. No difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm.

BACKGROUND The traditional surgical treatment for primary malignant melanoma has often been a wide excision with a margin of about 5 cm. Since the risk of local recurrences is dependent on tumor thickness, thin tumors ( 0.8 and; cc 2.0 mm. The trial includes 769 patients. Patients with melanomas of the skin of the head, neck, hands, feet, or vulva were not included in the trial. In the event of an excision biopsy for diagnosis, radical surgery was completed within 6 weeks. The median follow-up time was 5.8 years for estimation of survival and 4.0 years for diagnosis of recurrent disease. RESULTS No significant differences have been observed between the treatment groups regarding local or regional recurrences or survival. CONCLUSIONS We recommend an excision with a margin of 2 cm for cutaneous malignant melanoma with a tumor thickness > 0.8 and; cc 2.0 mm. Cancer 1996;77:1809-14.

Background Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. Methods Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. Results DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63–2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09–8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. Conclusions The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.

In a population-based, matched case-control study from the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, the relation between the use of sunbeds or sunlamps and malignant melanoma was investigated. Between July 1, 1988, and June 30, 1990, a total of 400 melanoma patients and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire containing different epidemiologic variables. Questions regarding the use of sunbeds or sunlamps were included. The odds ratio for developing malignant melanoma after ever having used sunbeds or sunlamps was 1.3. Considering all age groups, the odds ratio was significantly elevated after exposure more than 10 times a year to sunbeds or sunlamps (odds ratio (OR) = 1.8). When the study was restricted to patients and controls younger than age 30 years because the use of tanning devices is much more common among young persons, the odds ratio was higher (OR = 7.7 for more than 10 times a year vs. none). These findings were independent of constitutional factors and factors regarding sun exposure. A dose-response relation was evident. Furthermore, among melanoma patients in this young age group, the ratio of females to males was significantly higher than in older patients. When different melanoma presentation sites were considered, only lesions of the trunk were significantly associated with sunbed or sunlamp use (OR = 4.2 for more than 10 times a year vs. none).

Background. Complementary and alternative medicine (CAM) use is common among breast cancer patients. Several CAM therapies may have negative side effects or interact with conventional therapies. We studied biologically based CAM use with and without vitamins/minerals in relation to patient and tumor characteristics as well as treatment in an ongoing prospective cohort of 855 primary breast cancer patients. Methods. Patients from two hospitals in southern Sweden were included. Pre-operative and follow-up questionnaires containing questions on food intake, lifestyle, and concomitant medications, including natural remedies, were completed up to five years postoperatively. Clinical information was obtained from clinical records and tumor characteristics from pathology reports. Results. CAM and/or vitamins/minerals were used by 34.2% pre-operatively and by 57.9% during at least one visit. Over 100 different preparations were reported. At least eight of the commonly used preparations may interact with conventional breast cancer therapies. CAM users more often had a BMI

Tissue factor (TF)-mediated protease-activated receptor (PAR)-2 signaling is associated with a promigratory, invasive and proangiogenic phenotype in experimental models of breast cancer and has been mechanistically coupled to phosphorylation of the TF cytoplasmic domain (pTF). However, the clinical relevance of these findings is unknown. Here, we provide the first in vivo evidence of TF phosphorylation in experimental as well as clinical breast cancer tumors. pTF was demonstrated in MDA-MB-231 xenografts and in tumors from the MMTV-PyMT transgene model of spontaneous murine breast adenocarcinoma. Tumors from PAR-2-deficient transgenic mice were negative for pTF, thus linking pTF to PAR-2 signaling. The clinical correlation between TF, pTF, PAR-1, PAR-2 and vascular endothelial growth factor (VEGF)-A was determined by immunohistochemistry on tumors from a cohort of 172 consecutive primary breast cancer patients, with a median follow-up time of 50 months. In 160 evaluable patient tumors, pTF was associated with TF (p = 0.01) and cancer cell expression of PAR-1 (p = 0.001), PAR-2 (p = 0.014) and VEGF-A (p = 0.003) using chi(2) test. PAR-2 and VEGF-A were coexpressed (p = 0.013) and associated with a more aggressive phenotype. Interestingly, all patients experiencing recurrences had tumors expressing pTF and PAR-2, and pTF alone as well as coexpression of pTF and PAR-2 were significantly correlated with shorter recurrence-free survival (log rank test, p = 0.04 and p = 0.02, respectively). This study provides the first evidence to link PAR-2 expression and TF phosphorylation to clinical data in human breast cancer. In conjunction with experimental tumor models, these data support an important role of TF-PAR-2 signaling in breast cancer recurrence.

A therapeutic dose of labelled 5-fluorouracil (5-FU) was infused via the hepatic artery during 30 min with or without ligation of the left portal venous branch in Wistar rats with a secondary liver cancer in the left lateral lobe. After another 60 min, the incorporation of 5-FU into the acid soluble fraction (ASF), ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), was determined in tumor, ligated and unligated liver lobes, small intestine, kidney, and bone marrow. The liver nucleotide profile was examined with isotachophoresis. Portal venous branch ligation (PVBL) caused the following changes, compared with the unligated control group: in the tumor, the incorporation of 5-FU into RNA and DNA decreased and the ratio RNA/acid-soluble fraction labelling decreased. The incorporation increased in intestinal and bone marrow RNA. It was unchanged in liver and kidney. The ratio of tumor to peripheral normal-tissue (small intestine, bone marrow, and kidney) labelling of RNA and DNA decreased. Liver nucleotides (F) UTP, (F)UDP-glucuronic acid, (F)UDP-N-acetylhexosamine, and NAD were lower in the ligated than in the unligated liver lobe. ATP and energy charge did not decrease significantly. In conclusion, PVBL in conjunction with hepatic arterial administration of 5-FU increased systemic drug exposure and possibly decreased hepatic tumor anabolism. It has not been examined how this interferes with the therapeutic effect.

Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949-1988 developed angiosarcomas in edematous arms (Stewart-Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980-2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16%. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer.

17 beta-Hydroxysteroid dehydrogenases (17HSDs) are involved in the local regulation of sex steroids. 17HSD1 converts oestrone (El) to the more potent oestradiol (E2) and 17HSD2 catalyses the reverse reaction. The aim of this study was to investigate the expression of these enzymes in premenopausal breast cancers and to analyse if they have any prognostic or tamoxifen predictive value. Premenopausal patients with invasive breast cancer, stage II (UICC), were randomised to either 2 years of adjuvant tamoxifen (n = 276) or no tamoxifen (n = 288). The median follow-up was 13.9 years (range 10.5-17.5). The expression of 17HSD1 and 17HSD2 was analysed with immunohistochemistry using tissue microarrays. The enzyme expression level (-/+/++/+++) was successfully determined in 396 and 373 tumours, respectively. Women with hormone-receptor positive tumours, with low levels (-/+/++) of 17HSD1, had a 43% reduced risk of recurrence, when treated with tamoxifen (Hazard Ratio (HR) = 0.57; 95% confidence interval (CI), 0.37-0.86; p = 0.0086). On the other hand high expression (+++) of 17HSD1 was associated with no significant difference between the two treatment arms (HR = 0.91; 95% CI, 0.43-1.95; p = 0.82). The interaction between 17HSD1 and tamoxifen was significant during the first 5 years of follow-up (p = 0.023). In the cohort of systemically untreated patients no prognostic importance was observed for 17HSD1. We found no predictive or prognostic value for 17HSD2. This is the first report of 17HSD1 in a cohort of premenopausal women with breast cancer randomised to tamoxifen. Our data suggest that 17HSD1 might be a predictive factor in this group of patients. (C) 2009 Elsevier Ltd. All rights reserved.

A prospective randomized trial testing regional hyperthermic perfusion with melphalan has been conducted. Sixty-nine patients with recurrent malignant melanoma of the extremities were randomly allocated to surgery (36 patients) or surgery plus regional perfusion (33 patients). Prognostic variables concerning primary tumor as well as the recurrent disease were evenly distributed in the groups, excluding any bias in the randomization. Median tumor-free survival after randomization was 17 months in the perfusion group and 10 months in the control group. There were 15 locoregional recurrences in the perfusion group and 24 in the control group. The tumor-free survival curve was significantly (P = .044) better for the perfusion group than for the control group. Median survival time after randomization was 57 months in the perfusion group and 35 months in the control group. This difference was not significant. One patient died within 1 month after perfusion of pulmonary embolism. Regional hyperthermic perfusion after surgery of recurrent malignant melanoma should only be recommended in prospective and controlled trials, until its value has been proven in several randomized studies.

Nude rats heterotransplanted with human melanoma metastasis were injected subcutaneously on the hind paw with 125I-labelled monoclonal antibody 96.5 and with control antibody 131I-OKT3. The elimination from the injection site followed a biexponential function. The uptake in the inguinal lymph nodes on the side of the injection was initially high, but after 90 h it equalled the control side. The uptake in the tumour was slower than after i.v. injection but higher than in other tissues except blood. More than 80% of the activity in the dissected liver represented circulating blood. The uptake ratio of 96.5/OKT3 was c.3 in the tumours but c. 1 in all other tissues including blood. The capillary filtration coefficient was proportional to the uptake in organs like liver, lungs and muscle. It is concluded that subcutaneously injected radiolabelled monoclonal antibodies are initially transported via the lymph but then mainly distributed via the blood reaching the different tissues including tumours.

Aim: The objective of the present study was to evaluate the prospective use of immunohistochemistry (IHC) for histopathological diagnosis of sentinel lymph node(s) (SLN) in primary breast cancer using stage migration and non-SLN metastases as endpoints in relation to metastatic involvement. Method: Serial sectioning and prospective use of IHC were applied to SLN examination in addition to routine haematoxylin-eosin staining in 174 consecutive patients with unifocal T1-T2 breast cancer included in a National Sentinel Node Study. Axillary lymph node dissection (ALND) was performed in all cases with macrometastases, micrometastases and isolated tumour cells (ITC). Results: The SLN was found in 173/174 patients and a metastatic foci was found in 50 patients including 28/50 with macrometastases, 16/ 50 with micrometastases and 6/50 with ITC. IHC detected 3/16 of the micrometastases and 4/6 of ITC. Stage migration from NO to N1mi was encountered in 3/132 patients by use of IHC. Non-SLN metastases were noted in 15/28 of patients with macrometastases and in 3/16 of patients with micrometastases, whereas no patient with ITC had additional metastases (p = 0.007). Conclusion: The prospective use of lHC and serial sectioning for histopathological diagnosis of SLNs increased the detection rate of N1mi and ITC, but only 3/132 patients were stage-migrated by use of IHC. Patients with ITC did not have any risk of non-SLN metastases, supporting that ALND can safely be omitted in this group of patients. (C) 2006 Elsevier Ltd. All fights reserved. (Less)

Purpose Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance. Patients and Methods Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors. Results VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status. Conclusion Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

In Sweden from 1980 to 1995 there was an overall decrease of 56% in mean length of stay (MLOS) for surgical curative breast cancer treatment. The objective of this study was to separate the possible impact of tumour size and lymph node dissemination and changes in surgical procedures. All women diagnosed (n=13 290) with breast cancer between 1982 and 1995 were selected from the Southern Swedish Tumour Register. Data on LOS, diagnoses, and surgical procedures were obtained from the Swedish Hospital Discharge Register. A multi-factorial model was fitted to the data. Discharges where patients were treated with breast conserving surgery had more than two days shorter MLOS (-2.49, 95% CI -1.66) compared with mastectomy. Although TNM data imply a shift from T2 to smaller T1 among operated women the effect on MLOS is negligible when controlled for age, type of operation etc. Changes in clinical practice such as changes in operation technique can explain approximately 13% of the total decrease in MLOS.

Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in early breast cancer, although in premenopausal patients the number of studies comparing tamoxifen vs no treatment are limited. We report herein the effect on RFS of adjuvant tamoxifen treatment in a multicentre trial of premenopausal patients with stage II breast cancer patients randomised between 1986 and 1991 to 2 years of tamoxifen treatment (n = 276) or no treatment (n = 288). The receptor status of the tumour was known for 541 (96%) of the patients included. Tamoxifen treatment significantly increased RFS in patients with hormone receptor-positive (oestrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)) tumours (Relative Risk (RR) 0.65; 95% Confidence Interval (CI): 0.48–0.89, P = 0.006), and the beneficial effect of tamoxifen was extended to patients with indicators of poor prognosis, such as young age and nodal-positivity. PR status was a significant predictor of response to tamoxifen in multivariate models with testing of interactions of hormone receptor status and adjuvant therapy.

Estimation of microvessel density (MVD) in primary breast cancer in core needle biopsies (CNB) may predict response to systemic therapy. The aim of the present study was to explore the accuracy of assessment of MVD in CNB related to MVD in excised tumours.MVD was estimated in core biopsies and subsequently excised tumours in 54 consecutive patients with breast cancer without pre-operative treatment.The correlation between MVD in CNB and excised tumours was non-significant. However, in tumours larger than 20 mm (r=0.56, p=0.005) and in lobular carcinomas (r=0.55, p=0.014) a significant correlation was observed.The overall accuracy between estimation of MVD on CNB and excised breast tumours was non-significant. The usefulness of MVD in CNB as a marker of response to systemic therapy should be further validated before it can be used in clinical practice.

Angiogenic activity defined by microvessel density or measurement of vascular endothelial growth factor is a key process under physiological and malignant conditions in steroid hormone responding organs. The aim of this study was to relate microvessel density (MVD) in primary breast cancer to reproductive data and use of exogenous hormones.MVD was calculated retrospectively in forty-two consecutive tumours and related to clinical, histopathological and gynecological data.Tumours in ever-users of oral contraceptive therapy (OC) had lower MVD (p = 0.002), a finding not explained by smaller tumour size or lower histological grade. There was no influence on MVD by other reproductive data.These preliminary data on a supposed interaction between the use of OC and angiogenesis in breast cancer indicate that biological properties in breast tumours may be altered by ever-use of OC, but have to be further explored in an extended number of patients.

This report by The Swedish Council on Technology Assessment in Health Care (SBU) reviews, classifies, and grades the scientific literature on cancer chemotherapy in some major tumour types, describes the practice of chemotherapy in Sweden, compares practice with scientific knowledge, and analyses the costs and cost-effectiveness of chemotherapy. The report is intended primarily for decision-makers at various levels, both practitioners and administrators. It is also of interest for the medical profession. The extensive body of scientific literature was reviewed according to strict criteria that reflected the scientific weight of the literature. Sixteen experts representing different disciplines (oncology, surgery, internal medicine, health economy and quality of life research) participated in the literature review. Each section was discussed within the project group and was reviewed by at least one, but usually two international researchers. Additional input was provided by national experts representing different scientific disciplines. For the final evaluation to be as close to the objective truth as possible, a concerted effort was made to guarantee objectivity and thorough assessment of current knowledge about the effects of chemotherapy on the selected cancers. The tumour types selected for this assessment include firstly those types where three investigations had shown an increased use of chemotherapy in Sweden during the latest decade. These were non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, colorectal cancer and urinary bladder cancer. Secondly, the two tumour types comprising the greatest number of patients treated with chemotherapy in Sweden, breast cancer and haematological malignancies, were included. Among the haematological malignancies, the most prevalent ones, acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), aggressive non-Hodgkin's lymphoma (NHL) of the large B-cell type and indolent NHL of follicular type were evaluated. These constitute about 75%, of all haematological malignancies. Thirdly, ovarian cancer was included since chemotherapy has been extensively used and since, at the time of the planning of this overview, a group of very expensive drugs, the taxanes, had preliminarily shown promising results. A wealth of scientific literature has been published on cancer therapy. The review presented in this report is limited to scientific studies judged to be important for evaluating chemotherapy efficacy. Assessments of the content and quality of these studies, and a critical summary of the results in all stages of the selected tumours, have never before been attempted in this way. However, similar comprehensive overviews of certain stages of the tumours have previously been made. These overviews were also critically evaluated. Totally 1,496 studies involving 558,743 patients were reviewed. The survey of practice of chemotherapy use involved all departments of surgery, urology, gynaecology, internal medicine including haematologic units, pulmonary medicine and general and gynaecologic oncology at 16 hospitals in two health care regions in Sweden, covering 39% of the Swedish population. During the 4 weeks of the survey, all patients with the diagnoses concerned who received chemotherapy were registered. The study included 1,590 patients. The working group's general conclusions are summarised in the following points: The literature on the effects of chemotherapy is extensive. Chemotherapy has a well-documented role in the curative and palliative treatment of patients with several types of cancer. The use of chemotherapy is of utmost importance for the possibility of cure in certain tumour types. In other tumours, chemotherapy increases the possibility of cure when added to local and regional treatments, particularly surgery. In the instances of no possibility of cure, chemotherapy may to a variable extent improve both patient survival and well-being. In Sweden chemotherapy is largely used in accordance with that documented in the scientific literature. The extent of both over- and under-treatment seems to be limited but cannot be excluded at the individual patient level. The literature-based knowledge is scientifically of lower quality in the most chemotherapy sensitive tumours than in tumours showing more limited sensitivity. In the more sensitive tumours, positive effects on a symptomatic stage and survival were seen several decades ago. In those days, clinical treatment studies did not fulfil the current high quality requirements. Small life-prolonging effects of chemotherapy are sometimes very well documented in large, high quality scientific studies. Some of these s

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for breast cancer is based on 233 randomised studies, 9 meta-analysis of randomised studies, a population-based cohort study and 18 overviews/retrospective analyses including a total of 155,243 patients. The conclusions reached can be summarised into the following points: Adjuvant treatment-- There is solid scientific support from randomised studies that adjuvant polychemotherapy at 10 years will result in an absolute mortality reduction for patients younger than 50 years by 12% for node positive (34% relative mortality reduction corresponding to an estimated median survival prolongation of several years) and 6% for node negative patients. For women aged 50 to 69 years, the corresponding figures for node positive and node negative patients are 6% and 2%, respectively (approximately 11% relative mortality reduction). Anthracycline-containing combinations result in an absolute survival benefit at five years of 3%, compared with non-anthracycline based polychemotherapy. There are indications that the taxane paclitaxel may further improve the survival compared with anthracyclines. However, the limited data preclude conclusions for the routine care. The addition of tamoxifen to chemotherapy further enhances the survival benefit for receptor positive subgroups. The roles of more dose-intensive regimens, including high-dose therapy with stem cell support, are presently studied in randomised investigations. The data presented so far are conflicting but they do not in general support high-dose therapy. Quality of life, based on analyses of randomised studies, demonstrate that adjuvant polychemotherapy has an initial detrimental effect, but long-term follow-up of treated patients demonstrates no impairment of quality of life compared with untreated patients. Polychemotherapy in standard doses should be offered to premenopausal node positive patients, and the corresponding postmenopausal group with a receptor-negative breast cancer and to node negative patients with high risk factors. Polychemotherapy should be combined with tamoxifen to all patients with receptor-positive tumours. Due to a need of more knowledge in this field, patients should be included in investigational protocols. Locally advanced breast cancer-- Based on current knowledge, treatment of patients with locally advanced breast cancer should include neoadjuvant/preoperative polychemotherapy since there is evidence from controlled studies that such therapy will statistically significantly increase the number of patients who can be offered breast-conserving surgery. Indirect comparisons also demonstrate survival improvements, but the scientific support is equivocal. Metastatic breast cancer-- The median survival for patients with metastatic disease treated with conventional chemotherapy doses and regimens is 12 to 24 months. Retrospective cohort studies indicate that the use of non-anthracycline containing chemotherapy compared with no chemotherapy might add a survival gain of six to nine months. However, this estimation is based on equivocal data. Based on overview data, polychemotherapy results in a statistically significant survival gain compared with single-agent therapy. Based on repeated randomised studies, the addition of anthracyclines increases the response rate and statistically significantly improves the survival compared with non-anthracycline containing chemotherapy, except for CMF combined with prednisone/prednisolone, which will statistically significantly improve the survival compared with some anthracycline combinations. Second line therapy using vinorelbine or docetaxel is statistically significantly better than other regimens with a time to progression and survival benefit in the order of one to three months based on few randomised studies. The role, if any, of third line therapy is yet to be demonstrated. In the metastatic setting, conventional chemotherapy improves the quality of life. In standard care, first line therapy should contain an anthracycline and second line therapy using vinorelbine or docetaxel could be offered to selected patients failing first line therapy. Based on numerous randomised studies, breast cancer demonstrates a positive dose-response relationship both in the adjuvant situation and for metastatic disease. However, in the conventional dose-range there seems to be a plateau in the dose-response curve, with no further survival gains for high

The present study was designed to study 5-FU pharmacokinetics after interferon. Weekly bolus 5-FU (500 mg/m2), immediately followed by leucovorin (60 mg/m2) was given in 14 weekly cycles to 55 gastrointestinal and breast cancer patients. Interferon-alpha was given on days 2, 4 and 6, starting from cycle 2 at a dose of 0.5 million units (MU) and stepwise increased to 12 MU in cycles 12 and 13. Five patients could not tolerate the treatment even at the lowest dose of interferon and 22 patients were unavailable for the pharmacokinetic analysis because of dose reductions of 5-FU. Five patients were able to follow the protocol to 12 MU, whereas most patients were unable to continue owing to toxicity. 5-FU pharmacokinetics was analysed every second cycle. Peak concentration and AUC were increased after 12 MU of interferon, but no other significant influence of interferon on pharmacokinetic parameters of 5-FU was observed.

Background. Regional therapy for colorectal liver metastases aimed at prolonging survival has not been tested fully in a randomized trial with untreated control subjects. This study explored the efficacy of temporary hepatic artery occlusion followed by intraportal infusion of 5-fluorouracil(5-FU) and oral allopurinol as biochemical modulators in prolonging the survival of patients with nonresectable liver metastases and no extrahepatic cancer. Methods. Eighty-four patients were considered for randomization, of whom 24 were excluded at laparotomy because of extrahepatic cancer (n = 17) or resectable lesions (n = 5). In two patients, no cancer was identified in the liver. Thirty-two patients were allocated to receive treatment, and 28 were allocated to receive no regional or systemic treatment. Six patients were excluded after randomization because of major protocol violations. Results. The median survival time for patients was 17 months (range, 0–66), and for control subjects, the me dian was 8 months (range, 0–31). Log rank analysis demonstrated a significant survival benefit for treatment versus no treatment (P = 0.0039). (In two patients, early death was due to toxicity from the wrong dose of 5-FU and the wrong route of administration, respectively; the mean and median survival were reduced by 1 month). Conclusion. This study identified a treatment modality that prolongs survival in patients with nonresectable liver metastases and no extrahepatic metastases from colorectal cancer, suggesting that control subjects receiving no therapy may not be necessary in future randomized trials.

Nude rats were heterotransplanted with human melanoma metastases on both thighs. Ten days later a bolus of 125I-labelled monoclonal antibody (MAb) 96.5 was injected through a catheter in the common femoral artery. The femoral vein was clamped for 15 min to obstruct the venous outflow from the injected leg. The specific tissue uptake (%/g) in the tumour on the injected side compared to the non-injected side showed initially higher uptake (ratio 7.2 at 3 h). After 24 h there were no side differences. The tumour to muscle ratio was 2.8 at 3 h when injected and control sides were compared. Intravenous or subcutaneous injection gave similar specific tissue uptake as regional arterial injection after 24 h. Tissue to plasma ratios were similar after intravenous and subcutaneous injection of monoclonal antibodies. Intraarterial injection of a bolus of labelled monoclonal antibodies and obstructing the venous outflow thus increased the tumour uptake during a short period of time during which the contrast enhancement was three-fold.

A therapeutic dose of labelled 5-fluorouracil (5-FU) was infused via the hepatic artery during 30 min with or without a simultaneous temporary clamping of the portal vein in a model of secondary liver cancer in Wistar rats. After another 60 min, the incorporation of 5-FU into the acid soluble fraction, RNA and DNA was determined in tumor, liver, small intestine, kidney, and bone marrow. The liver and intestinal nucleotide profiles were examined with isotachophoresis. Temporary portal vein clamping caused the following changes, as compared with the control group with intraarterial infusion only: in the liver, the incorporation of 5-FU into the acid soluble fraction increased without a concomitant increase into the RNA or of the level of (F)UTP. Liver ATP decreased. In the tumor, the ratio of RNA to acid soluble fraction labelling decreased. There was a generally decreased ratio of tumor to peripheral normal tissue (small intestine and kidney) labelling. In conclusion, portal vein clamping in conjunction with hepatic arterial administration of 5-FU led to a decreased anabolism of 5-FU in the liver and tumor, and increased systemic drug exposure. It is not known how this interferes with the therapeutic effect.

This study supports the opinion that liver resection or metastasis enucleation with a margin of normal tissue around the tumor for liver metastases from colorectal cancer can be recommended. The 3-year survival rate of 20–25% is far better than the 3-year survival rates reported after resection of the primary organ for cancers such as, for example, the pancreas and esophagus and is almost as good as that of surgery of primary rectal cancer Dukes' C. Liver resection has an acceptably low postoperative mortality (less than 10%), morbidity, and complication rate.

In a model of secondary liver cancer in Wistar rats, the effect of different administration routes on the uptake of 3H-uridine into tumor and several normal tissues was studied. The rats were inoculated with a tumor cell suspension in the central liver lobe. Ten days later, they were distributed into four groups with a catheter placed in the gastroduodenal artery, the portal vein, one of the femoral veins, or in the peritoneal cavity. 3H-uridine was injected 46 h later and after an additional 90 minutes the animals were anesthetised and pieces of liver tumor and normal tissues were removed and frozen. The incorporation into the acid-soluble fraction and RNA was analyzed. In a separate experiment, 3H-fluorouridine was administered by the gastroduodenal artery and a comparison was made with the uptake of 3H-uridine. A significantly higher amount of uridine was incorporated into the tumor by the arterial route. The intraportal and intraperitoneal routes were comparable, while a somewhat higher incorporation was found by the systemic route. The consequences of using the different routes upon the incorporation into RNA of tumor and dose-limiting organs are demonstrated. With the aid of this experimental model, it is possible to evaluate further the effect by different manipulations on different drugs regarding the administration route.

Sixty-four patients with melanoma (28 with clinical stage I disease and 36 with clinical stages II through IV disease) were fine-needle biopsied on suspicion of recurrent melanoma. Eighty-four biopsies were aspirated percutaneously and three at exploratory laparotomy. A tumor mass was present at 81 biopsies. The remaining biopsies were taken with the guidance of liver scan or fluoroscopy. In the patients with the diagnosis of recurrent malignant melanoma the cytodiagnosis was correct in 45 patients out of 47. One patient was diagnosed as breast cancer and one as malignant mesenchymal tumor. Of 40 biopsies considered normal, three were revised to be melanoma. No false-positive diagnosis was found. The frequency of false-negative diagnosis was 6%. Fine-needle-aspiration cytology is a suitable method to establish a correct diagnosis when there is a suspicion of recurrent disease during the follow-up of melanoma patients. The high diagnostic accuracy in patients with enlarged lymph nodes is excellent and makes the method preferable to diagnostic surgical excision biopsies.

With the aim of potentiating the anti-tumour effect of interferon in metastatic malignant melanoma by concomitant inhibition of suppressor T cells, oral cimetidine (histamine-2 receptor antagonist) medication was added to interferon (HuIFN-alpha(Le] therapy in a series of 20 patients. While no objective tumour responses were recorded with interferon treatment alone administered intramuscularly or intratumorally, six patients had objective tumour regressions on subsequent combined therapy. Five out of eight patients with metastases confined to skin and subcutaneous tissue had complete tumour regressions while one patient with skin and lung metastases achieved an extensive partial regression of the skin tumour and a complete roentgenological regression of the lung metastasis. Three additional patients attained a stable disease status for prolonged periods of time. Histopathological examinations confirmed disappearance and/or degeneration of melanoma cells and demonstrated a marked lymphocyte infiltration in tumour sites of the patients with objective tumour regression.

Seventeen patients were given DTIC, 200 mg/m2/day in five-day courses every four to six weeks. In four patients (stage II) treated on an adjuvant basis, tumor recurrence has been verified in three. Four of the palliatively treated patients were also given DTIC by regional intra-arterial infusion with minimal positive tumor effect and minimal toxicity. 5-S-cysteinyldopa excretion in urine was checked continuously in all patients. Tumor recurrence was revealed in two patients given DTIC on an adjuvant basis three and four months before clinical signs of tumor. In the palliatively treated patients, 5-S-cysteinyldopa excretion increased in 5/6 patients judged to have stable disease, before tumor progression was clinically detectable. The use of 5-S-cysteinyldopa examination is a valuable adjunct to the follow-up of the effect of DTIC therapy in melanoma patients.

Liver scintigraphy (99Tcm sulphur colloid) was performed in 118 patients with malignant melanoma. In 73 patients diagnosed as stage I, the pretreatment evaluation showed one false-negative and one false-positive examination. During follow-up there were ten abnormal liver scintigraphies; one was later correlated to liver metastases. In 46 patients diagnosed as stage II-IV, the pretreatment liver scintigraphy yielded false-negative results in 36% and false-positive results in 15%. The predictive values of positive and negative tests were 44% and 81%, respectively. The yields of liver tests (S-alkaline phosphatase, S-gamma-glutamyl-transferase) in patients with liver metastases were low. This study demonstrated the limitations of liver scintigraphy for diagnosis of liver metastases in patients with malignant melanoma.

One hundred fifty-five patients, laparotomized because of colorectal cancer, were retrospectively evaluated with special attention given to the natural course of untreated synchronous liver metastases. The median survival time for patients with synchronous liver metastases was 4.5 months. The survival time was mainly influenced by the extent of tumor involvement in the liver. Patients with elevated levels of serum-alkaline phosphatase at the time of operation had a significantly shorter survival time than those with normal values. Serum alkaline phosphatase levels are a good indication of prognosis. The incidence of synchronous liver metastases was 16 percent. This low rate is partly explained by the development of metachronous liver metastases in five patients within 1 year. Comparison with previous reports, often more than 10 years old, revels that the poor prognosis of patients with untreated liver metastases from colorectal cancer has remained unchanged.

A low-cost microprocessor-based temperature controller for hyperthermia experiments on rats is described. The system directs a microwave generator, used for heating, by feedback power regulating signals in accordance with the temperature in the animal. The microwave power is pulsed for short on-and-off periods and the temperature recordings are carried out during the off periods. More than 300 hyperthermia runs have been carried out on rats using this fully automated unit. The controller can direct the hyperthermia to the predetermined level with a deviation of +or-0.1 degrees C for systemic hyperthermia. For local hyperthermia in the liver, individual recorded mean temperatures were up to -0.5 degrees C from the preset temperature.

Lymphoscintigraphy using 99mTcSb2S3 colloid was performed in 32 patients with malignant melanoma. Subcutaneous injections were made peritumorally in 20 patients and dorsopedally in 12 patients. Regional lymph node dissections were carried out on the following day in 16 patients and the resected lymph nodes were weighted, measured for radioactivity, and examined by light microscopy. Lymph flow to regional lymph nodes was shown in all but 2 patients. Twenty-nine of 239 lymph nodes contained metastases. Radioactivity was demonstrated in 17 of these nodes. In 5 of 11 patients with metastatic disease, the highest uptake was found in cancerous lymph nodes. The specific activity-uptake distribution in isolated ilio-inguinal lymph nodes after a dorsopedal injection was log-normal with a mean of 0.05%/g indicating a good saturation of colloid particles. This investigation concludes that the observed lymph flow directions in patients injected peritumorally are of value for the follow-up. Quantitative lymphoscintigraphy in patients with melanoma of the lower extremities is, however, of no value for excluding ilio-inguinal lymph node metastases.

Between 1976 and 1982, 110 isolated regional lymph node dissections (RLND) for melanoma were performed as a prophylactic procedure (PLND) in 44 and therapeutic procedure (TLND) in 64 patients. The prevalence of metastases was 20 % in the PLND group. The number of patients with complications in the PLND were 17/44 (39 %) and in the TLND 39/64 (61 %). Local wound complications dominated. Serum collections occurred in 25 % of PLND patients and 45 % of TLND patients (p < 0.05), and infections, skin necrosis, and cellulitis in respectively 11 % and 22 %. The incidence of lymphedema was 10 % in PLND and 23 % in TLND patients. Regarding the anatomic sites, there were significantly more seromas after axillary dissection in TLND patients compared with PLND patients (p < 0.05). However, no difference was observed between groin dissections in the 2 groups. The socioeconomic effects in terms of hospital stay and further therapeutic measures were pronounced when complications occurred.

Metastases in 25 patients with intracranial metastases from malignant melanoma were extirpated. Two patients had a second operation after six and ten months because of tumor recurrence. Single brain metastases were found in 20 and multiple in five patients. The interval between the primary tumor and the intracranial metastases varied from 17 years to six months. Three patients died due to complications from surgery. The median survival time was five months (mean survival ten months). Complete relief of symptoms was observed in 17 and partial relief in two patients. The quality of life was improved in 17 patients and 14 of these 17 went back to their ordinary occupation. The indications for neurosurgery are restricted in patients with extracranial or with multiple intracranial metastases.

Two cases with postoperative acute acalculous cholecystitis diagnosed by computed tomography (CT) and ultrasonography are described. This rare postoperative complication is briefly reviewed. The mortality from this complication is high because the diagnosis is often missed. Use of diagnostic tools such as ultrasonography and CT increases the possibilities of reaching a correct diagnosis and therefore improves the prognosis.

A case of veno-occlusive disease of the liver with fatal outcome after dacarbazine (DTIC) therapy for melanoma is reported. There was a fulminant clinical course from start of symptoms until death. At autopsy the liver was enlarged and firm with signs of venous congestion. Small- and medium-sized hepatic veins were blocked by thrombosis. Eosinophilic infiltrations were found around the vessels. Published cases from the literature are reviewed and pertinent features discussed.

In a model of secondary liver cancer in Wistar rats, the incorporation of tracer doses of pyrimidines and 5-fluoropyrimidines into the acid-soluble fraction, RNA and DNA of several normal tissues and of an experimental adenocarcinoma of the colon transplanted to the liver of rat was determined 90 min after infusion of the substances via the gastroduodenal artery. There was a higher incorporation after injection of FUra than after uracil into tumor RNA. There was very little labeling of DNA by FdUrd but a greater labeling of RNA following injection of this substance than following deoxyuridine in all tissues including tumor except in liver, where it was of the same magnitude. All fluoro compounds gave high labeling of the acid-soluble fraction of the kidney and liver. The experiments will be continued with therapeutic doses of the fluoro compounds.