[Erythropoietin - state of science]. / Erythropoietin - aktueller Stand der Wissenschaft.

After a century of research and medical use, erythropoietin (EPO) has more therapeutic approaches than ever in history. After cloning its gene in 1984, EPO obtained FDA license for clinical use in 1989. EPO and its analogues are mainly used for treatment of the anaemias of chronic renal failure and malignancies. Regarding research of the past 15 years, tremendous efforts were made for improvement of bioactivity, half-life and alternative application. Today, there are human cell-lined derived EPO, SEP, CEPO, CERA and drugs which are linked to different pathways of signaling. Due to the fact that these substances are not detectable with standardized methods of detection, it must be assumed that the abuse in sport is still possible. Moreover it was found out that the EPO receptor and EPO synthesis are also expressed by non-hematopoietic tissues, e. g. heart myocytes, ovarian and glial cells. On these tissues EPO is linked to promote cell proliferation and differentiation, angiogenesis or inhibition of apoptosis. This detection offered approaches in treatment for apoplexia and cardiac infarction and even in preventive treatment of cardiovascular diseases which led to an interest of manifold subject categories.

Implementation of a forearm support to reduce the amount of irradiated lung and heart in radiation therapy of the breast.

We compared simulator images of medial tangential fields taken in two positions: (1) with the ipsilateral arm abducted, holding a 'L-bar' armrest and (2) with both arms extended above the head in a forearm support. The average maximum heart distance as well as the central lung distance decreased significantly by 3.4 (SE 0.9) and 4.7 (SE 1.1) mm, respectively, when the new forearm support was used. The estimated normal tissue complication probability for excess cardiac mortality decreased by on average 3.1% (SE 1.3%). For some patients, a greater amount of the axilla was included in the field. We recommend the use of the forearm support during breast cancer treatment with tangential fields to decrease the amount of heart and lung inside the fields.

[Bilateral breast carcinoma and local recurrence: prevalence of BRCA-1 and BRCA-2 gene mutations in an unselected patient sample]. / Bilaterales Mammakarzinom und Lokalrezidiv: Prävalenz von BRCA-1- und BRCA-2-Genmutationen an einem unselektionierten Kollektiv.

BACKGROUND: Mutations of the BRCA 1/BRCA 2 genes strongly predispose towards the development of contralateral breast cancer. We therefore investigated a hospital-based series of patients with bilateral breast cancer and a comparison group of patients with unilateral breast cancer, pairwise matched by age and family history, for mutations of the BRCA 1/BRCA 2 genes. PATIENTS AND METHODS: Between 1995 and 2000 genomic DNA from blood samples of 75 patients with bilateral breast cancer, who received postoperative radiotherapy, was analyzed for mutations of all coding regions and flanking intron sequences of the BRCA 1/BRCA 2 genes by single strand conformation polymorphism analysis (SSCP) and sequencing of aberrant findings. The results were compared to 75 unilateral breast cancer patients who were screened for common mutations in the BRCA 1 and BRCA 2 genes. Treatment results of patients with bilateral disease were analyzed with regard to a possible carriership of a BRCA 1/BRCA 2 gene mutation. RESULTS: Five distinct frameshift deletions (one in BRCA 1, four in BRCA 2) were identified in six patients with bilateral breast cancer. Three of six carriers developed local relapse, whereas this was the case in only nine of 69 non-carriers. After radiotherapy local relapse occurred in five patients (five of 126 irradiated breasts or chest walls). Three of these patients (60%) were carriers of a pathogenic BRCA 1/BRCA 2 mutation. In the comparison group of patients with unilateral breast cancer three pathogenic BRCA 1 mutations were identified. CONCLUSIONS: We failed to confirm an increased prevalence of BRCA 1/BRCA 2 mutations in our hospital-based series of patients with bilateral breast cancer. However, local relapse, especially when occurring after radiotherapy, may be predictive for an underlying pathogenic BRCA 1 and BRCA 2 gene mutation in patients with bilateral breast cancer.

Variability in target volume delineation on CT scans of the breast.

PURPOSE: To determine the intra- and interobserver variation in delineation of the target volume of breast tumors on computed tomography (CT) scans in order to perform conformal radiotherapy. MATERIALS AND METHODS: The clinical target volume (CTV) of the breast was delineated in CT slices by four radiation oncologists on our clinically used delineation system. The palpable glandular breast tissue was marked with a lead wire on 6 patients before CT scanning, whereas 4 patients were scanned without a lead wire. The CTV was drawn by each observer on three separate occasions. Planning target volumes (PTVs) were constructed by expanding the CTV by 7 mm in each direction, except toward the skin. The deviation in the PTV extent from the average extent was quantified in each orthogonal direction for each patient to find a possible directional dependence in the observer variations. In addition, the standard deviation of the intra- and interobserver variation in the PTV volume was quantified. For each patient, the common volumes delineated by all observers and the smallest volume encompassing all PTVs were also calculated. RESULTS: The patient-averaged deviations in PTV extent were larger in the posterior (42 mm), cranial (28 mm), and medial (24 mm) directions than in the anterior (6 mm), caudal (15 mm), and lateral (8 mm) directions. The mean intraobserver variation in volume percentage (5.5%, 1 SD) was much smaller than the interobserver variation (17.5%, 1 SD). The average ratio between the common and encompassing volume for the four observers separately was 0.82, 0.74, 0.82, and 0.80. A much lower combined average ratio of 0.43 was found because of the large interobserver variations. For the observer who placed the lead wire, the intraobserver variation in volume was decreased by a factor of 4 on scans made with a lead wire in comparison to scans made without a lead wire. For the other observers, no improvement was seen. Based on these results, an improved delineation protocol was designed. CONCLUSIONS: Intra- and especially interobserver variation in the delineation of breast target volume on CT scans can be rather large. A detailed delineation protocol making use of CT scans with lead wires placed on the skin around the palpable breast by the delineating observer reduces the intraobserver variation. To reduce the interobserver variation, better imaging techniques and pathology studies relating glandular breast tissue to imaging may be needed to provide more information on the extent of the clinical target volume.

Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status.

PURPOSE: This study was performed to determine the long-term outcome for women with mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. METHODS AND MATERIALS: An analysis was performed of 422 mammographically detected intraductal breast carcinomas in 418 women from 11 institutions in North America and Europe. All patients were treated with breast-conserving surgery followed by definitive breast irradiation. The median follow-up time was 9.4 years (mean, 9.4 years; range, 0.1-19.8 years). RESULTS: The 15-year overall survival rate was 92%, and the 15-year cause-specific survival rate was 98%. The 15-year rate of freedom from distant metastases was 94%. There were 48 local failures in the treated breast, and the 15-year rate of any local failure was 16%. The median time to local failure was 5.0 years (mean, 5.7 years; range, 1.0-15.2 years). Patient age at the time of treatment and final pathology margin status from the primary tumor excision were both significantly associated with local failure. The 10-year rate of local failure was 31% for patient age < or = 39 years, 13% for age 40-49 years, 8% for age 50-59 years, and 6% for age > or = 60 years (p = 0.0001). The 10-year rate of local failure was 24% when the margins of resection were positive, 9% when the margins of resection were negative, 7% when the margins of resection were close, and 12% when the margins of resection were unknown (p = 0.030). Patient age < or = 39 years and positive margins of resection were both independently associated with an increased risk of local failure (p = 0.0006 and p = 0.023, respectively) in the multivariable Cox regression model. CONCLUSIONS: The 15-year results from the present study demonstrated high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of mammographically detected ductal carcinoma in situ of the breast using breast-conserving surgery and definitive breast irradiation. Younger age and positive margins of resection were both independently associated with an increased risk of local failure. The 15-year results in the present study serve as an important benchmark for comparison with other treatment modalities. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of appropriately selected patients with mammographically detected ductal carcinoma in situ of the breast.

Salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ of the breast.

BACKGROUND: The purpose of the current study is to evaluate the outcome of salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast. METHODS: An analysis was performed of 42 patients with local only first failure (n = 41) or local-regional only first failure (n = 1) after breast-conserving surgery and radiation treatment had been given for DCIS of the breast. Surgical treatment at the time of local recurrence included mastectomy (n = 37; 88%) or excision (n = 5; 12%). Adjuvant systemic therapy at the time of local recurrence was chemotherapy (n = 3; 7%), tamoxifen (n = 8; 19%), both (n = 1; 2%), none (n = 29; 69%), or unknown (n = 1; 2%). The median interval from the time of initial treatment to local recurrence was 4.8 years (range = 1.0-15.2 yrs). The median follow-up after salvage treatment was 4.5 years (range = 0.2-12.8 yrs). RESULTS: At the time of the local recurrence, 22 patients (52%) had invasive ductal carcinoma, 18 patients (43%) had DCIS, 1 patient (2%) had invasive lobular carcinoma, and 1 patient (2%) had angiosarcoma. After salvage treatment, the rate of overall survival and the rate of cause specific survival for all 42 patients were 92% at both 5- and 8-years after treatment. The rate of freedom from distant metastases was 89% at 5 and 8 years. Favorable prognostic factors after salvage treatment were DCIS as the histology of the local recurrence and mammography only as the method of detection of the local recurrence. CONCLUSIONS: The results of salvage treatment in the current study demonstrated that local recurrences were salvaged with high rates of survival and freedom from distant metastases. These results support the use of breast-conserving surgery and radiation for initial management of DCIS of the breast.

A method to improve the dose distribution of interstitial breast implants using geometrically optimized stepping source techniques and dose normalization.

BACKGROUND AND PURPOSE: The standard linear source breast implant of our institution was compared with alternative linear source implant geometries and a stepping source implant, to evaluate the possibility of minimizing the treated volume. Normalization to a higher isodose than the conventional 85% of the mean central dose (MCD) was investigated for the stepping source implant to reduce the thickness of the treated volume and to increase dose uniformity. The purpose of this study was to develop an implant geometry yielding a high conformity and a more uniform dose distribution over the target volume. MATERIALS AND METHODS: The dose distributions of four implant geometries were compared for a planning target volume (PTV) of 48 cm(3). Implants #1 (standard) and #2 had linear sources arranged in a triangular pattern of equal lengths and lengths adapted to the shape of the PTV. Implants #3 and #4 were squared pattern arranged implants with linear sources and a stepping source with geometric optimized dwell times. The active lengths were adapted to the shape of the PTV. Using implant #4 for PTVs of different volumes, the reference dose (RD) was normalized to 85 and 91% of the MCD. RESULTS: Comparing implants #2, #3, and #4 with #1, the treated volume (V(100)) encompassed by the reference isodose was reduced by 22, 35, and 37%, respectively. The volumes receiving a dose of at least 125% (V(125)) of the reference dose was reduced by 16, 30, and 30%, respectively. The conformation number increased being 0.30, 0.39, 0.47, and 0.48 for implants #1, #2, #3, and #4, respectively. The average reduction of V(125) when the dose was normalized to 91% compared with 85% of the MCD was 18%. CONCLUSIONS: A conformal treatment to a PTV could be best achieved with a geometrically optimized stepping source plan with needles arranged in a squared pattern. Reduction of high dose volumes within the implant was obtained by normalizing the RD to 91% instead of 85% of the MCD.

Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation.

BACKGROUND: Radiotherapy prevents local recurrence of breast cancer after breast-conserving surgery. We evaluated the effect of a supplementary dose of radiation to the tumor bed on the rates of local recurrence among patients who received radiotherapy after breast-conserving surgery for early breast cancer. METHODS: After lumpectomy and axillary dissection, patients with stage I or II breast cancer received 50 Gy of radiation to the whole breast in 2-Gy fractions over a five-week period. Patients with a microscopically complete excision were randomly assigned to receive either no further local treatment (2657 patients) or an additional localized dose of 16 Gy, usually given in eight fractions by means of an external electron beam (2661 patients). RESULTS: During a median follow-up period of 5.1 years, local recurrences were observed in 182 of the 2657 patients in the standard-treatment group and 109 of the 2661 patients in the additional-radiation group. The five-year actuarial rates of local recurrence were 7.3 percent (95 percent confidence interval, 6.8 to 7.6 percent) and 4.3 percent (95 percent confidence interval, 3.8 to 4.7 percent), respectively (P<0.001), yielding a hazard ratio for local recurrence of 0.59 (99 percent confidence interval, 0.43 to 0.81) associated with an additional dose. Patients 40 years old or younger benefited most; at five years, their rate of local recurrence was 19.5 percent with standard treatment and 10.2 percent with additional radiation (hazard ratio, 0.46 [99 percent confidence interval, 0.23 to 0.89]; P=0.002). At five years in the age group 41 to 50 years old, no differences were found in rates of metastasis or overall survival (which were 87 and 91 percent, respectively). CONCLUSIONS: In patients with early breast cancer who undergo breast-conserving surgery and receive 50 Gy of radiation to the whole breast, an additional dose of 16 Gy of radiation to the tumor bed reduces the risk of local recurrence, especially in patients younger than 50 years of age.

Energetic requirement of carbachol-induced Ca2+ signaling in single mouse beta-cells.

Insulin secretion is under multifactorial control by glucose and neurohumoral factors like acetylcholine (ACH), which activate the Ca2+/phospholipase C signaling pathway. All insulin secretagogues elevate cytosolic free Ca2+ ([Ca2+]i) that is central to the stimulation of insulin secretion. The actions of ACH on [Ca2+]i are glucose dependent but the metabolic steps involved are only partly understood. Here we have characterized the metabolic steps by which glucose exerts its synergistic effects on ACH-linked Ca2+-signals. [Ca2+]i was measured in single fura-2 loaded beta-cells. The ACH analog carbachol (3 microM) caused rise in [Ca2+]i that was strongly dependent on the extracellular glucose concentration ranging from 0-10 mM. Iodoacetate, which blocks glycolysis, thereby preventing the generation of NADH and ATP from glucose metabolism, and rotenone or antimycin, which inhibit complex 1 and 2 of the mitochondrial respiratory chain, respectively, inhibited in glucose (6 mM) the carbachol-induced Ca2+ signal to a similar extent as glucose deprivation. This demonstrates that glucose metabolism and generation of ATP through oxidative phosphorylation of energy rich substrates like NADH and FADH2 are required for carbachol-induced Ca2+ signals. While sodium arsenate, which prevents net glycolytic production of ATP without inhibiting glycolysis, had no significant effect on the carbachol-induced Ca2+-signal, the mitochondrial pyruvate transport inhibitor alpha-cyano-4-hydroxycinnamate and the Krebs cycle inhibitor monofluoroacetate strongly suppressed the rise in [Ca2+]i elicited by carbachol. While pyruvate was ineffective, methyl pyruvate, a membrane-permeant pyruvate analog, and alpha-ketoisocaproate in combination with glutamine, which are both substrates for mitochondrial ATP production, could restore the carbachol-induced Ca2+ signal in glucose-free medium. These data demonstrate for the first time that Krebs cycle metabolism of glucose and ATP formation through oxidative phosphorylation is critical for the glucose dependency of ACH-linked Ca2+-signals in mouse beta-cells, and they suggest that mitochondrial metabolism plays a key role in the interactive regulation of beta-cells by neurohumoral factors activating the Ca2+/phospholipase C signaling pathway.

An improved technique for breast cancer irradiation including the locoregional lymph nodes.

PURPOSE: To find an irradiation technique for locoregional irradiation of breast cancer patients which, compared with a standard technique, improves the dose distribution to the internal mammary-medial supraclavicular (IM-MS) lymph nodes. The improved technique is intended to minimize the lung dose and reduce the dose to the heart. METHODS AND MATERIALS: The standard technique consists of an anterior mixed electron/photon IM-MS field. In the improved technique, an oblique electron and an oblique asymmetric photon field are combined to irradiate the IM lymph nodes. To irradiate the MS lymph nodes, a combination of an anterior electron and an anterior asymmetric photon field is used. For both the standard and the improved technique, tangential photon fields are used to irradiate the breast. Three-dimensional (3D) treatment planning was performed for 8 patients with various breast sizes for these two techniques. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) were compared for both techniques. The field dimensions and energy of the standard technique were determined at simulation, whereas for the improved technique the fields were designed by CT-based treatment planning. RESULTS: The dose in the breast planning target volume was essentially the same for both techniques. For the improved technique, combined with 3D localization information, an improvement in the IM-MS planning target coverage is seen. The volume within the 95% isodose surface was on average 25% (range, 0-64%) and 74% (range, 43-90%) for the standard and improved technique, respectively. The heart generally receives less dose with the improved technique. However, sometimes a small but acceptable increase in lung dose is found. CONCLUSION: The improved technique, combined with localization information of the IM-MS lymph nodes, greatly improves the dose distribution in the planning target volume for a large group of patients without significantly increasing the dose to organs at risk.

Cardiac and lung complication probabilities after breast cancer irradiation.

PURPOSE: To assess for locoregional irradiation of breast cancer patients, the dependence of cardiac (cardiac mortality) and lung (radiation pneumonitis) complications on treatment technique and individual patient anatomy. MATERIALS AND METHODS: Three-dimensional treatment planning was performed for 30 patients with left-sided breast cancer and various breast sizes. Two locoregional techniques (Techniques A and B) and a tangential field technique, including only the breast in the target volume, were planned and evaluated for each patient. In both locoregional techniques tangential photon fields were used to irradiate the breast. The internal mammary (IM)-medial supraclavicular (MS) lymph nodes were treated with an anterior mixed electron/photon field (Technique A) or with an obliquely incident mixed electron/photon IM field and an anterior electron/photon MS field (Technique B). The optimal IM and MS electron field dimensions and energies were chosen on the basis of the IM-MS lymph node target volume as delineated on CT-slices. The position of the tangential fields was adapted to match the IM-MS fields. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) for the heart and lung were compared for the three techniques. In the beam's eye view of the medial tangential fields the maximum distance of the heart contour to the posterior field border was measured; this value was scored as the Maximum Heart Distance. RESULTS: The lymph node target volume receiving more than 85% of the prescribed dose was on average 99% for both locoregional irradiation techniques. The breast PTV receiving more than 95% of the prescribed dose was generally smaller using Technique A (mean: 90%, range: 69-99%) than using Technique B (mean: 98%, range: 82-100%) or for the tangential field technique (mean: 98%, range: 91-100%). NTCP values for excess cardiac mortality due to acute myocardial ischemia varied considerably between patients, with minimum and maximum values of 0.1 and 7.5% (Technique A), 0.1 and 5.8% (Technique B) and 0.0 and 6.1% (tangential tech.). The NTCP values were on average significantly higher (P<0.001) by 1.7% (Technique A) and 1.0% (Technique B) when locoregional breast irradiation was given, compared with irradiation of the left breast only. The NTCP values for the tangential field technique could be estimated using the Maximum Heart Distance. NTCP values for radiation pneumonitis were very low for all techniques; between 0.0 and 1.0%. CONCLUSIONS: Technique B results in a good coverage of the breast and locoregional lymph nodes, while Technique A sometimes results in an underdosage of part of the target volume. Both techniques result in a higher probability of heart complications compared with tangential irradiation of the breast only. Irradiation toxicity for the lung is low in all techniques. The Maximum Heart Distance is a simple and useful parameter to estimate the NTCP values for cardiac mortality for tangential breast irradiation.

Tolbutamide and diazoxide modulate phospholipase C-linked Ca(2+) signaling and insulin secretion in beta-cells.

Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca(2+) and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K(+) channels (K(ATP) channels), respectively, interact with PLC-linked Ca(2+) signals in HIT-T15 and mouse beta-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca(2+) signals were enhanced by tolbutamide (3-300 microM) and inhibited by diazoxide (10-100 microM). The effects of tolbutamide and diazoxide on PLC-linked Ca(2+) signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca(2+) channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca(2+) or store-operated Ca(2+) influx through non-L-type Ca(2+) channels. In the absence of glucose, PLC-linked Ca(2+) signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 microM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca(2+) signaling and insulin secretion from pancreatic beta-cells by modulating K(ATP) channels, thereby determining voltage-sensitive Ca(2+) influx.

Primary axillary radiotherapy as axillary treatment in breast-conserving therapy for patients with breast carcinoma and clinically negative axillary lymph nodes.

BACKGROUND: The objective of the current study was to evaluate the effectiveness and morbidity of primary axillary radiotherapy in breast-conserving therapy for postmenopausal, clinically axillary lymph node negative patients with early stage breast carcinoma. METHODS: Between 1983-1997, 105 patients with clinically negative axillary lymph nodes and breast carcinoma were treated with wide local excision followed by radiotherapy to the breast, and axillary and supraclavicular lymph node areas. Adjuvant treatment with tamoxifen was given to 75 patients. The median follow-up of patients still alive was 41 months (range, 8-137 months). Fifty-five patients with no evidence of disease at last follow-up were examined prospectively with respect to late functional damage. RESULTS: The mean age of the patients was 64 years. Three patients developed a local recurrence. No isolated axillary lymph node recurrence was observed. In two patients, axillary recurrence was accompanied by distant metastases. The 5-year disease free interval and the overall survival were 82% (standard error [SE], 6%) and 83% (SE, 6%), respectively. In five patients, arm edema was reported and impaired shoulder function was reported in seven patients. Prospectively scored, arm edema was reported subjectively by the patient in 4% and objectively measured in 11% of cases. Impaired shoulder function was reported subjectively in 35% and objectively measured in 17% of cases. No brachial plexus neuropathy was noted. CONCLUSIONS: Primary axillary radiotherapy for postmenopausal women with clinically lymph node negative, early stage breast carcinoma was found to result in low axillary lymph node recurrence rates with only limited late complications. Therefore, primary axillary radiotherapy should be considered as axillary treatment in selected patients as an alternative to axillary lymph node dissection.

Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer.

PURPOSE: To evaluate both qualitative and quantitative scoring methods for the cosmetic result after breast-conserving therapy (BCT), and to compare the usefulness and reliability of these methods. METHODS AND MATERIALS: In EORTC trial 22881/10882, stage I and II breast cancer patients were treated with tumorectomy and axillary dissection. A total of 5318 patients were randomized between no boost and a boost of 16 Gy following whole-breast irradiation of 50 Gy. The cosmetic result was assessed for 731 patients in two ways. A panel scored the qualitative appearance of the breast using photographs taken after surgery and 3 years later. Digitizer measurements of the displacement of the nipple were also made using these photographs in order to calculate the breast retraction assessment (BRA). The cosmetic results after 3-year follow-up were used to analyze the correlation between the panel evaluation and digitizer measurements. RESULTS: For the panel evaluation the intraobserver agreement for the global cosmetic score as measured by the simple Kappa statistic was 0.42, considered moderate agreement. The multiple Kappa statistic for interobserver agreement for the global cosmetic score was 0.28, considered fair agreement. The specific cosmetic items scored by the panel were all significantly related to the global cosmetic score; breast size and shape influenced the global score most. For the digitizer measurements, the standard deviation from the average value of 30.0 mm was 2.3 mm (7.7%) for the intraobserver variability and 2.6 mm (8.7%) for the interobserver variability. The two methods were significantly, though moderately, correlated; some items scored by the panel were only correlated to the digitizer measurements if the tumor was not located in the inferior quadrant of the breast. CONCLUSIONS: The intra- and interobserver variability of the digitizer evaluation of cosmesis was smaller than that of the panel evaluation. However, there are some treatment sequelae, such as disturbing scars and skin changes, that can not be evaluated by BRA measurements. Therefore, the methods of cosmetic evaluation used in a study must be chosen in a way that balances reliability and comprehensiveness.

Low risk of locoregional recurrence of primary breast carcinoma after treatment with a modification of the Halsted radical mastectomy and selective use of radiotherapy.

BACKGROUND: The purpose of the current study was to evaluate the locoregional recurrence rate after treatment of patients with operable breast carcinoma with a modification of the Halsted radical mastectomy and the selective use of radiotherapy and to identify risk factors for locoregional recurrence. METHODS: Between 1979-1987, 691 consecutive patients underwent mastectomy after a negative biopsy of the axillary apical lymph nodes. The median age of the patients was 59 years (range, 26-89 years). The clinical tumor size was < 2 cm in 72 patients, 2-5 cm in 387 patients, and >5 cm in 169 patients; 16 patients had a T4 tumor. Surgery was comprised of a modification of the Halsted radical mastectomy, including at least part of the pectoralis major muscle and the entire pectoralis minor muscle, in 573 patients; 303 patients had positive axillary lymph nodes. Adjuvant radiotherapy to the chest wall and regional lymph nodes was given to 74 patients, whereas an additional 414 patients underwent irradiation to the internal mammary and medial supraclavicular lymph nodes. The median follow-up was 91 months. RESULTS: The actuarial overall survival rate was 82% at 5 years and 63% at 10 years. The 10-year chest wall and regional lymph node control rates, including patients with prior distant failures, were 95% and 94%, respectively. The only two significant prognostic factors for locoregional recurrence on multivariate analysis were lymph node status and pathologic tumor size. CONCLUSIONS: Excellent locoregional control can be achieved with a modified technique of radical mastectomy in patients with negative apical biopsy and the selective use of comprehensive radiotherapy. These results may serve as a reference outcome for comparison with other locoregional treatment strategies.

Lymphoscintigraphy in oncology: a rediscovered challenge.

The validation of the sentinel node concept in oncology has led to the rediscovery of lymphoscintigraphy. By combining preoperative lymphatic mapping with intraoperative probe detection this nuclear medicine procedure is being increasingly used to identify and detect the sentinel node in melanoma, breast cancer, and in other malignancies such as penile cancer and vulvar cancer. In the past lymphoscintigraphy has been widely applied for various indications in oncology, and in the case of the internal mammary lymph-node chain its current use in breast cancer remains essential to adjust irradiation treatment to the individual findings of each patient. In another diagnostic area, lymphoscintigraphy is also useful to document altered drainage patterns after surgery and/or radiotherapy; its use in breast cancer patients with upper limb oedema after axillary lymph-node dissection or in melanoma patients with lower-extremity oedema after groin dissection can provide information for physiotherapy or reconstructive surgery. Finally, the renewed interest in lymphoscintigraphy in oncology has led not only to the rediscovery of findings from old literature reports, but also to a discussion about methodological aspects such as tracer characteristics, image acquisition or administration routes, as well as to discussion on the study of migration patterns of radiolabelled colloid particles in the context of cancer dissemination. All this makes the need for standardized guidelines for lymphoscintigraphy mandatory.

[Locoregional radiotherapy after mastectomy and chemotherapy for breast cancer: prolonged survival and better local tumor control]. / Locoregionale radiotherapie na mastectomie en chemotherapie wegens mammacarcinoom: verlengde overleving en betere lokale tumorcontrole.

In two recent randomized clinical trials from Denmark and Canada the usefulness of radiotherapy was evaluated in premenopausal patients with breast cancer who had been operated and in whom the findings indicated a poor prognosis. Over 2000 patients participated. After follow-up periods of 10 and 15 years, respectively, addition of locoregional therapy to mastectomy and chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) was found to result in better locoregional control and a better disease-free survival. These studies also demonstrated, for the first time, that the overall survival was increased after postoperative radiotherapy. In view of these findings, the indication for postoperative locoregional radiotherapy in breast cancer in the Netherlands should be reconsidered.

Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer.

PURPOSE: To test whether the intrinsic radiosensitivity of skin fibroblasts from breast cancer patients correlates with the degree of breast fibrosis after breast conserving therapy. METHODS: In a systematic study design, 79 patients were selected from an earlier study group of 385 patients based on observed fibrosis and seven identified clinical risk factors for fibrosis development. In vitro radiosensitivity of patients' dermal fibroblasts was determined by clonogenic assay of early passage cultures. Survival was determined after irradiation at 0, 2 and 4 Gy, given in two fractions of 2 Gy with a 6 h interval. RESULTS: There was a significant inter-patient variation for SF2 values (coefficient of variation = 40%). The ratio of SF2 values for fibroblasts from patients with breast fibrosis versus those without was 0.80 (95% CI: 0.60-1.07). This was a statistically non-significant trend (p = 0.13). The same ratio for a derived value for SF2 ((SF2 + square root of SF4)/2) was 0.88 (p = 0.19). CONCLUSIONS: A significant variation in intrinsic radiosensitivity of breast cancer patients' dermal fibroblasts was observed. However, the degree of radiosensitivity did not show a significant correlation with fibrosis development. This indicates that the use of fibroblast radiosensitivity will have a limited usefulness for predicting fibrosis following breast irradiation.

Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement.

BACKGROUND: Uncontrolled studies suggest that high-dose chemotherapy is beneficial in patients with breast cancer and multiple metastases to the axillary lymph nodes. Many physicians accept this treatment as standard care. We aimed to assess adjuvant high-dose chemotherapy in breast cancer in a phase II randomised trial. METHODS: 97 women aged younger than 60 years, who had breast cancer with extensive axillary-node metastases (confirmed by a tumour-positive infraclavicular lymph-node biopsy), received three courses of up-front chemotherapy (FE120C). This regimen consisted of cyclophosphamide 500 mg/m2, epirubicin 120 mg/m2, and 5-fluorouracil 500 mg/m2 once weekly for 3 weeks. After surgery, stable patients or those who responded to chemotherapy were randomly assigned conventional therapy (fourth course of FE120C, followed by radiation therapy and 2 years of tamoxifen [40 patients]) or high-dose therapy (identical treatment but an additional high-dose regimen and peripheral-blood progenitor-cell [PBPC] support after the fourth FE120C course [41 patients]). This high-dose regimen comprised cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2. The primary endpoint was overall and disease-free survival. All analyses were by intention to treat. FINDINGS: No patients died from toxic effects of chemotherapy. With a median follow-up of 49 (range 21-76) months, the 4-year overall and relapse-free survivals for all 97 patients were 75% and 54%, respectively. There was no significant difference in survival between the patients on conventional therapy and those on high-dose therapy. INTERPRETATION: High-dose therapy is associated with substantial cost and acute toxic effects, but also has potentially irreversible long-term effects. Until the benefit of this therapy is substantiated by large-scale phase III trials, high-dose chemotherapy should not be used in the adjuvant treatment of breast cancer, apart from in randomised studies.

Impairment of ATP-induced Ca2+ -signalling in human thyroid cancer cells.

Extracellular nucleotides like ATP that activate the Ca2+ -phosphatidylinositol (PI) signalling pathway have been suggested to participate in the regulation of normal human thyroid function. We examined, whether P2y-purinergic receptors are expressed on human thyroid cancer cells and whether post-receptor Ca2+ signalling is altered by malignant transformation. Extracellular ATP caused a biphasic increase in cytosolic free Ca2+ ([Ca2+]i) in normal human thyrocytes and in human follicular (FTC) and papillary (PTC) thyroid carcinoma cells. In FTC and PTC cell lines the dose-response curves for ATP-induced changes in [Ca2+]i were shifted to the right when compared with normal thyrocytes, whereas in undifferentiated thyroid carcinoma (UTC) cells even high concentrations of ATP (500 microM) failed to stimulate a rise in [Ca2+]i. By contrast, ATP stimulated inositol 1,4,5-trisphosphate (IP3) formation and capacitative Ca2+ entry was operational as judged by thapsigargin in normal thyrocytes and all thyroid cancer cells. Thus, P2y-purinergic receptors are expressed on thyroid tumor cells independent of degree of differentiation. In UTC cells, however, impairment in the Ca2+ -phosphatidylinositol (PI) signalling cascade occurs distal to the formation of IP3 and proximal to the activation of capacitative Ca2+ entry. Disturbed ATP-induced Ca2+ -signalling and alterations in the Ca2+ -PI signalling cascade may contribute to decreased expression or loss of specific thyroid functions in thyroid cancer cells.