Adjuvant cyclic Tamoxifen and Megestrol acetate treatment in postmenopausal breast cancer patients--longterm follow-up.

AIMS: To evaluate possible differences in effect on recurrence-free survival (RFS) and overall survival (OS) in node positive postmenopausal breast cancer patients receiving Tamoxifen or cyclic Tam and Megestrol acetate as adjuvant treatment. METHODS: Between 1989 and 1994, 489 patients with pT(1-2)pN+ hormone receptor positive or unknown tumours were included in a randomized national multicenter study to receive either Tam alone or cyclic Tam (8 weeks) and MA (8 weeks) for 2 years. Final follow-up was completed as of June 2002. Time from start of treatment to first recurrence and novel primary breast tumour, overall survival and cancer specific survival were estimated. RESULTS: No differences in RFS, OS or cancer specific survival were observed between the two treatment groups. CONCLUSIONS: Adjuvant treatment used as standard Tam alone, compared to Tam and MA, as employed in this group of patients gave similar outcomes. Side effects that led to cessation of study medication were observed in both arms.

Laparoscopic navigation pointer for three-dimensional image-guided surgery.

BACKGROUND: The main drawback with the laparoscopic approach is that the surgeon is unable to palpate vessels, tumors, and organs during surgery. Furthermore, the laparoscope provides only surface view of organs. There is a need for more advanced visualizations that can enhance the view to include information below the surface of the organs for planning of the procedure and for control and guidance during treatment. METHODS: We propose three-dimensional (3D) navigation technology based on preoperatively acquired magnetic resonance or computed tomography data used in combination with a laparoscopic navigation pointer (LNP). The LNP has an attached position tracker that allows the surgeon to control the display of images interactively before and during surgery. This study evaluated the patient registration accuracy, the feasibility of image-based navigation and, qualitatively, the navigation precision in the retroperitoneum during laparoscopic surgery. RESULTS: This technology was used during the treatment of six patients (involving adrenalectomies and a neuroma protruding into the pelvis). An average patient registration accuracy of 6.90 mm was achieved. The precision during navigation in the retroperitoneum was, in some cases, better than the patient registration accuracy suggested. The technology helped the surgeons to understand better the anatomy and to locate blood vessels. CONCLUSIONS: In the reported cases, the LNP was a useful tool for image guidance in laparoscopic surgery, both for planning the surgical approach in detail and for guidance. The authors believe that adominal 3D image guidance using an LNP has a large potential for improving laparoscopic surgery, especially when vessels and anatomic relations may be difficult to identify using only a laparoscope. Accordingly, they believe this new technology could increase safety and make it easier for the surgeon to perform successful laparoscopic surgery.

Abnormal chromosome 8 copy number in cytological smears from breast carcinomas detected by means of fluorescence in situ hybridization (FISH).

Numerical change in chromosome 8 is an acquired abnormality associated with high clinical stage and may be involved in the conversion of carcinoma in situ in the breast to invasive carcinoma. Fine needle aspiration smears from 53 cases of breast carcinoma were hybridized with centromeric probes for chromosome 8 and the X chromosome. Thirty-eight cases revealed chromosome 8 copy gain. Of the 45 grade II and III tumours, 28 showed polysomy (>3 signals) and six showed trisomy. Of the eight grade I tumours, four were trisomic, none were polysomic. There were only two cases of chromosome 8 copy loss (one each of grade I and III). X chromosome polysomy was also a frequent finding although the signal counts were similar to those for chromosome 8 in only a few cases. Chromosome 8 polysomy occurs frequently in breast carcinoma and high copy number (>3) is associated with high malignancy grade.

Adjuvant endocrine treatment (goserelin vs tamoxifen) in pre-menopausal patients with operable node positive stage II breast cancer. A prospective randomized national multicenter study.

AIMS: To evaluate possible differences in effect on time to recurrence and overall survival in node positive pre-menopausal breast cancer patients (age < or = 50 years) receiving LHRH analogue or tamoxifen as adjuvant endocrine treatment. METHODS: Between January 1989 and July 1994, 320 patients with node positive (pN(+)) and hormone receptor positive or receptor status unknown tumors were included and randomized in a national multicenter study to receive either tamoxifen or goserelin as adjuvant treatment for two years. Primary surgical treatment was employed according to current standards. Final follow-up was completed as of December 2000. Time to events were estimated by the Kaplan-Meier method, and compared by the log rank test. Relative risks were estimated by the Cox's proportional hazards model. RESULTS: No differences in time to first recurrence or overall survival were observed between treatment groups. Proportions of patients in each group having a second breast cancer were also similar. CONCLUSIONS: Standard adjuvant treatment with tamoxifen as compared to adjuvant LHRH analogue therapy employed in this group of breast cancer patients gave similar outcomes, but the number of patients was too small to formally exclude a potentially clinically relevant difference in survival.

Axillary lymph node metastases in breast cancer: preoperative detection with dynamic contrast-enhanced MRI.

Metastatic involvement of axillary lymph nodes is one of the most important prognostic variables in breast cancer. The aim of our work was to study the value of dynamic contrast-enhanced MR imaging in revealing axillary lymph node metastases from breast cancer. A total of 65 patients with invasive breast cancer treated with axillary lymph node dissection were preoperatively evaluated by MRI. T1-weighted dynamic contrast-enhanced 3D images were acquired using a coil covering the breast and the axilla. The dynamic contrast enhancement, size, and morphology of the axillary lymph nodes were registered. Histopathological examination revealed axillary lymph node metastases in 24 patients. When using a signal intensity increase in the lymph nodes of >100% during the first postcontrast image as a threshold for malignancy, 57 of 65 patients were correctly classified (sensitivity 83%, specificity 90%, accuracy 88%). These results were not improved when lymph node size and morphology were used as additional criteria. Axillary lymph nodes can be evaluated as a part of an MR-mammography study without substantial increase in examination time, and provide the surgeon with knowledge about the localization of possible metastatic lymph nodes.

Breast lesions: evaluation with dynamic contrast-enhanced T1-weighted MR imaging and with T2*-weighted first-pass perfusion MR imaging.

PURPOSE: To evaluate the diagnostic value of an imaging protocol that combines dynamic contrast-enhanced T1-weighted magnetic resonance (MR) imaging and T2*-weighted first-pass perfusion imaging in patients with breast tumors and to determine if T2*-weighted imaging can provide additional diagnostic information to that obtained with T1-weighted imaging. MATERIALS AND METHODS: One hundred thirty patients with breast tumors underwent MR imaging with dynamic contrast-enhanced T1-weighted imaging of the entire breast, which was followed immediately with single-section, T2*-weighted imaging of the tumor. RESULTS: With T2*-weighted perfusion imaging, 57 of 72 carcinomas but only four of 58 benign lesions had a signal intensity loss of 20% or more during the first pass, for a sensitivity of 79% and a specificity of 93%. With dynamic contrast-enhanced T1-weighted imaging, 64 carcinomas and 19 benign lesions showed a signal intensity increase of 90% or more in the first image obtained after the administration of contrast material, for a sensitivity of 89% and a specificity of 67%. CONCLUSION: T2*-weighted first-pass perfusion imaging can help differentiate between benign and malignant breast lesions with a high level of specificity. The combination of T1-weighted and T2*-weighted imaging is feasible in a single patient examination and may improve breast MR imaging.

Characterization of neoplastic and normal human breast tissues with in vivo (1)H MR spectroscopy.

The purpose of this study was to evaluate whether the detection of choline-containing compounds in in vivo (1)H magnetic resonance spectroscopy (MRS) of breast lesions is specific for carcinomas, whether a choline peak in in vivo (1)H MRS can be detected under physiological conditions of increased metabolism in breast parenchyma, and whether analysis of lipid signals can differentiate between various breast lesions and tissues. Forty patients and volunteers were examined with in vivo (1)H MR spectroscopy. Three spectra with identical localization but increasing echo times were obtained. Choline-containing compounds were detected in 9 of 11 carcinomas and in 2 of 11 benign lesions. A choline signal was also detected in five of seven volunteers who were breast-feeding at the time of examination, demonstrating that choline compounds can be detected by in vivo (1)H MRS in breast tissue under physiological conditions. Analysis of lipid signals did not contribute to differentiation between various breast lesions and tissues. J. Magn. Reson. Imaging 1999;10:159-164.

Differentiating benign and malignant breast lesions with T2*-weighted first pass perfusion imaging.

PURPOSE: Invasive breast carcinomas and fibroadenomas are often difficult to differentiate in dynamic contrast-enhanced T1-weighted MR imaging of the breast, because both tumors can enhance strongly after contrast injection. The purpose of this study was to evaluate whether the addition of T2*-weighted first pass perfusion imaging can increase the differentiation of malignant from benign lesions. MATERIAL AND METHODS: Nine patients with invasive carcinomas and 10 patients with contrast enhancing fibroadenomas were examined by a dynamic contrast-enhanced T1-weighted 3D sequence immediately followed by a single slice T2*-weighted first pass perfusion sequence positioned in the contrast-enhancing lesion. RESULTS: The carcinomas and the fibroadenomas were impossible to differentiate based on the contrast enhancement characteristics in the T1-weighted sequence. The signal loss in the T2*-weighted perfusion sequence was significantly stronger in the carcinomas than in the fibroadenomas (p = 0.0004). CONCLUSION: Addition of a T2*-weighted first pass perfusion sequence with a high temporal resolution can probably increase the differentiation of fibroadenomas from invasive carcinomas in contrast-enhanced MR imaging of the breast.

In vivo 1H MRS of normal breast and breast tumors using a dedicated double breast coil.

Image-guided localized proton MR spectroscopy (MRS) of normal breasts and breast tumors (ductal and undifferentiated carcinomas) was performed using a dedicated double breast coil. In vivo 1H MR spectra from 10 normal volunteers showed signals from water and lipids only, even in breasts with small contribution of fatty breast tissue. In the spectra from 6 of the 12 examined patients, an intense signal assigned to choline compounds was detected. The signal was also detected at lower levels in the remaining patients. This study shows that in vivo 1H MRI/MRS examinations of breast tumors can be performed within an examination time of 45 to 60 minutes. Signals from breast tumor metabolites may be detected using in vivo 1H MRS.

Inherited breast carcinoma--prospective findings in 1,194 women at risk.

According to preset criteria, 1,194 women at risk for inherited breast carcinoma were selected and subjected to examination. Six hundred and three women were examined once, 591 were followed for a mean of 1.8 years. Twenty infiltrating cancers (median age 49 years) and 16 precancers (median age 44 years) were found, demonstrating that breast carcinoma continued to occur in the selected families as expected under the hypothesis of dominant inheritance. At first round, 14 (1.2%) infiltrating carcinomas and a total of 22 (1.8%) cancers or precancers were found. Incidence rates of 0.58% pr. year for infiltrating cancers, and 1.04% pr. year for cancer or precancer were calculated. This confirms the tentative conclusions that were drawn in our previous report. These are the first prospective reports documenting how to delineate a high risk group for premenopausal breast cancer, and how to diagnose cancer at an early stage. All but two affected women had cancer without lymph node metastasis. Although a longer observation time is needed, we cautiously conclude that the results are in keeping with our aim of providing safety for those at risk. Clinical use of predictive genetic testing may be implemented within these families.

1H NMR spectroscopic characterization of perchloric acid extracts from breast carcinomas and non-involved breast tissue.

High-resolution 1H NMR spectra were obtained from perchloric acid extracts of breast tumor specimens and adjacent non-involved tissue. Two-dimensional shift-correlated and homonuclear J-resolved spectroscopy were used to identify coupled resonances in the spectra. Chemical shifts, multiplicities and spin-spin coupling constants of several non-resolved resonances in the one-dimensional spectra could be determined by the two-dimensional methods. Several differences in the metabolite content of the two types of extracts were established. The spectra of extracts from non-involved tissue were dominated by signals from glucose and other carbohydrates, while most of the tumors had very low or no detectable levels of glucose. High concentrations of lactate, taurine and succinate, an increase of the phosphocholine level, and a very low phosphocreatine level were characteristic findings in the 1H spectra of tumor extracts. The variation in the level of myo-inositol follows the variation in glucose for the two types of tissue. Scyllo-inositol was for the first time observed in the NMR spectra from breast tissue. Uridine 5'-diphospho-N-acetylglucosamine and uridine 5'-diphospho-N-acetylgalactosamine have been identified and there is an increased level of these two hexoses in the tumor tissue. These results provide insight into breast tumor metabolism, by simultaneously detecting a large number of metabolites and demonstrate the potential for using 1H NMR spectroscopy for studying different metabolic pathways in breast tumors. At the same time they provide useful information for interpretation of in vivo 1H NMR spectra of breast tumors.

Comparative signal intensity measurements in dynamic gadolinium-enhanced MR mammography.

Increases in signal intensity enhancement were measured in defined regions of interest (ROIs) to allow distinction between malignant and benign tumors with dynamic gadolinium-enhanced magnetic resonance (MR) mammography. Twenty patients with palpable breast lesions (15 malignant, five benign) underwent MR mammography. The dynamic gradient-echo sequence was performed with intravenous bolus injection of gadopentetate dimeglumine and consisted of 25 images with a time resolution of 30 seconds. Contrast enhancement was calculated by comparing user-defined ROIs on pre- and postcontrast images. An increase in signal intensity of 70% or more on the 1-minute postcontrast image was used as the criterion of malignancy. MR mammographic results correlated with histopathologic findings in all patients when the defined ROI was in the most enhancing part of the tumor. For the ROI in areas of submaximal enhancement or when the ROI surrounded the whole lesion, only five and nine tumors, respectively, fulfilled the malignancy criterion. All malignant tumors showed large variations in signal intensity enhancement that depended on the position of the ROI in the tumor. Dynamic, gadolinium-enhanced MR mammography allows distinction of benign from malignant breast tumors when the selected ROI is in the most enhancing part of the lesion.

Androgen metabolism in the different lobes of the prostate gland of intact, gonadectomized or hypophysectomized rats with or without androgen substitution.

The effect of gonadectomy or hypophysectomy and the effect of substitution with testosterone, upon the reductive and oxidative metabolic transformations of testosterone, 4-androstene-3,17-dione, 17 beta-hydroxy-5 alpha-androstane-3-one, 5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol using NAD(H) and NADP(H) as added cofactors were examined in homogenates from the ventral (VP), lateral (LP) and dorsal prostate (DP), and coagulating gland (CG) of adult Wistar rats. The fall in serum testosterone induced by gonadectomy or hypophysectomy led to reduced activity of 5 alpha-reductase, NADP(H)-dependent 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR), NAD-dependent 3 alpha-HSOR, 3 beta-HSOR and 17 beta-HSOR, indicating that these enzymes are androgen dependent. The NADP dependent oxidation of 5 alpha-androstane-3 alpha, 17 beta-diol in LP increased upon hypophysectomy and gonadectomy. Testosterone substitution of gonadectomized or hypophysectomized rats generally maintained enzymatic activity at the level of the control group, except for the 5 alpha-reductase activity which fell in spite of this treatment. Hypophysectomy or gonadectomy had different effects on the activity of several androgen metabolizing enzymes; 5 alpha-reductase activity in DP and CG, NAD(H) dependent 3 alpha-HSOR in VP and NADPH dependent 3 beta-HSOR activity in LP, DP and CG. There were marked differences between the rat prostatic lobes, both concerning the activity of the androgen metabolizing enzymes and the responses to the different treatment modalities.

In vitro proton NMR spectroscopy of extracts from human breast tumours and non-involved breast tissue.

Proton (1H) nuclear magnetic resonance (NMR) spectra were obtained from perchloric acid (PCA) extracts of 11 breast tumours and non-involved breast tissue from 7 of the same patients. The spectra were correlated with histopathologic diagnosis. The tumour group consisted of 8 ductal carcinomas, 1 ductal carcinoma with an extensive intraductal component, 1 intraductal carcinoma and 1 fibroadenoma. Higher content of lactate, succinate and phosphocholine and low levels of glucose and inositol were characteristic findings in the tumour group as compared to non-involved breast tissue. 1H NMR spectra of PCA extracted breast specimens provide a comprehensive window into the metabolic activities of the tissue.

Dose-dependent induction of ornithine decarboxylase and S-adenosyl-methionine decarboxylase activity by testosterone in the accessory sex organs of male rats.

The dose-dependent induction of ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase (AMDC) activity in the different lobes of the prostate and the seminal vesicles (SV), 24 hours after administration of testosterone to castrated Wistar rats, has been studied. ODC and AMDC activities were low in all lobes 10 days after castration. A dose of approximately 300 micrograms testosterone/100 g body weight (B.W.) gave an ODC activity of 50 percent of maximum response, and at 600 micrograms/100 g B.W. maximum activity was reached in all the prostatic lobes and the SV. In the lateral and dorsal prostate, and the coagulating gland, the dose of testosterone giving 50% of maximum AMDC activity was reached after administration of between 450 and 600 micrograms/100 g B.W. In the ventral prostate and SV, the dose giving a 50% response was approximately 700 micrograms/100 g B.W. In conclusion, all prostatic lobes showed a clear dose-response relationship concerning the activity of ODC and AMDC following administration of different doses of testosterone. We have found minor differences in androgen responsiveness between the lobes when looking at the dose requirements for induction of AMDC activity. The dose-response curves could possibly be useful as a rapid in vivo bioassay for compounds with anti-androgenic properties in the prostate.

Androgen regulation of polyamine synthesis in seminal vesicle and in different lobes of the rat prostate.

Endogenous levels of the polyamines putrescine, spermidine, and spermine have been examined in the 10(6) m/s2 supernatant of different lobes of the rat prostate and in the seminal vesicles of castrates, androgen-stimulated castrates, and intact controls. Content of the polyamines varied between the lobes, with spermidine highest in intact animals. After castration, the content of polyamines fell significantly in all lobes but the coagulating gland (CG). Spermidine levels were highest, except in the lateral prostate (LP) and CG, where the content of putrescine was highest. In castrated animals treated with testosterone propionate for 72 h, the amount of the three polyamines examined increased dramatically in the ventral prostate (VP) and moderately in the CG and seminal vesicle (SV). Concerning individual polyamines, spermidine increased significantly in all lobes, while putrescine increased significantly only in the two saccular parts of rat prostate, i.e., CG and SV. Spermidine content decreased significantly in the DP. Major differences in the content of the three polyamines--putrescine, spermidine, and spermine--in the various tissues studied have been found. Moreover, distinct differences among intact, castrated, and testosterone-treated castrated animals have been revealed.

Light microscopic morphometric analysis of castration effects in the different lobes of the rat prostate.

The morphologic effects of androgen deprivation in the different lobes of the rat prostate were examined by light microscopic morphometry. The prostates of Wistar male rats (260-340 g) were fixed in situ by glutaraldehyde perfusion in castrated animals 1 week after gonadectomy and in intact animals. The ventral (VP), dorsal (DP), and lateral (LP) lobes as well as the coagulating gland (CG) were dissected out, weighed, and processed for light microscopy. Using stereologic methods the following parameters were estimated for each lobe: volume fraction of connective tissue, epithelium and glandular lumina, average epithelial height, average epithelial cell volume, and total number of epithelial cells. Castration leads to a 58-76% reduction of the wet weight of all prostatic lobes. The decrease of glandular tissue is greater in VP than in LP, DP, and CG. In VP and LP, there is a 39-45% reduction of the epithelial height, and this effect is less pronounced in DP and CG. For all lobes, the shrinkage of average epithelial cell volume is in the same range (25-30%). Moreover, in VP and LP, there is a 70% reduction of the total number of cells, whereas the reduction is less in DP and CG. It thus seems that the reduction of prostatic epithelial tissue mass upon castration is due to a reduction of the number of cells as well as a reduction of the volume of individual cells. VP and LP appear to be more androgen-dependent than DP and CG.

Ornithine decarboxylase and S-adenosylmethionine decarboxylase activity in the accessory sex organs of intact, castrated, and androgen-stimulated castrated rats.

We have studied the activities of ornithine decarboxylase and adenosylmethionine decarboxylase in the 10(6)-m/s2 supernatants of the different lobes of the prostate and the seminal vesicles of castrates, androgen-stimulated castrates, and intact controls. After castration L-ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (AMDC) activities fell in all tissues examined. The induction of kinetics was followed for 72 h after administration of testosterone propionate to castrated rats. AMDC activities increased more rapidly than ODC activities in every tissue studied. Peak activities were reached more rapidly in the dorsal lobe than in the other tissues. ODC activity of the ventral lobe increased linearly for 48 h after stimulation. In the other tissues studied, ODC activity reached a maximum after 24 h and thereafter leveled off or decreased. In conclusion we have found distinct differences in ODC and AMDC activity in various tissues and major differences between treatment groups, with near extinction of activity at castration. In castrates stimulated with testosterone, the between-group differences prevailed but with different patterns of ODC versus AMDC activity. AMDC is seemingly rate-limiting in polyamine synthesis in stimulated tissues, while ODC controls synthesis in tissues from castrated rats.

Bioassay of gastrin, using the totally isolated, vascularly perfused rat stomach. A biomodel sensitive to gastrin in physiological concentrations.

A bioassay sensitive to gastrin (G 1-17) in physiological concentrations and suitable for testing of biological activity of minor amounts of radioiodinated gastrin is reported. G 1-17 was iodinated by a gentle Iodo-gen method and purified to high specific activity (1900 Ci/mmol). Totally isolated vascularly perfused rat stomachs were prepared and stimulated by graded amounts of G 1-17. Gastrin 'dose'-dependently increased the acid output from 5.7 +/- 1.0 mueq/40 min (basal) to a maximum of 58.8 +/- 10.0 mueq/40 min at a concentration of 520 pmol/l in the vascular perfusate. The lowest G 1-17 concentration that significantly increased the acid output from the basal value was 65 pmol/l, corresponding to a dose of 17.5 ng/stomach-hour. 125I-G 1-17 also increased the acid output significantly at this threshold dose. The amount of lactic acid enzymatically determined in the luminal perfusate was negligible, indicating a true parietal cell stimulation. Accordingly, a very sensitive bioassay for gastrin, suitable for testing of biological activity of G 1-17 and 125I-G, is described. Significant acid responses were obtained with physiological concentrations of gastrin, requiring less than 100 ng of hormone and labelled hormone, respectively, to show biological activity.