Endocrine therapy plus zoledronic acid in premenopausal breast cancer.

BACKGROUND: Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. METHODS: We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. RESULTS: After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. CONCLUSIONS: The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial.

BACKGROUND: Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. METHODS: ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3.6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. FINDINGS: At a median follow-up of 62 months (range 0-114.4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51-0.91; p=0.009), although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44-1.03; p=0.067) and anastrozole arms (HR 0.68, 95% CI 0.45-1.02; p=0.061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0.67, 95% CI 0.41-1.07; p=0.09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1.08, 95% CI 0.81-1.44; p=0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1.75, 95% CI 1.08-2.83; p=0.02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). INTERPRETATION: Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. FUNDING: AstraZeneca; Novartis.

Sentinel lymph node biopsy is precise after primary systemic therapy in stage II-III breast cancer patients.

BACKGROUND: Sentinel lymph node biopsy (SLNB) without axillary lymph node dissection (ALND) in SLN negative patients is a standard of care for most breast cancer patients. SLNB for axillary staging after primary systemic therapy (PST) is still under discussion because of possibly reduced accuracy, while data are lacking. The purpose of this study was to evaluate the accuracy of SLNB after PST. MATERIALS AND METHODS: A total of 185 breast cancer patients were treated with PST; 160 patients received preoperative chemotherapy, and 25 patients received preoperative endocrine therapy. Thus, 143 of 160 patients with preoperative chemotherapy and 22 of 25 patients with preoperative endocrine therapy were eligible for evaluation. The combination of blue dye and radioactive tracer was used for identification of SLNs. All patients received SLNB and axillary lymph node dissection (ALND). Pathologic assessment of SLNs was performed and compared to non-SLN status. RESULTS: Pathologic complete response rates and breast conserving therapy rates were 15.4 and 78.3% in the preoperative chemotherapy group and 0 and 77.3% in the preoperative endocrine therapy group, respectively. Identification rate, sensitivity, overall accuracy, and false-negative rate were 81.1% (116 of 143), 91.7% (55 of 60), 95.7% (111 of 116), and 8.3% (5 of 60) in the preoperative chemotherapy group and 77.3% (17 of 22), 90.0% (9 of 10), 94.1% (16 of 17), and 10.0% (1 of 10) in the preoperative endocrine therapy group, respectively. DISCUSSION: SLNB after primary systemic therapy is accurate, and the results are comparable to those of primary SLNB. SLNB after PST could spare ALND in up to 40% of patients with primary positive axillary lymph nodes and should be considered as a standard for axillary staging in those patients.

Viral contamination in biologic manufacture and implications for emerging therapies.

Recombinant protein therapeutics, vaccines, and plasma products have a long record of safety. However, the use of cell culture to produce recombinant proteins is still susceptible to contamination with viruses. These contaminations cost millions of dollars to recover from, can lead to patients not receiving therapies, and are very rare, which makes learning from past events difficult. A consortium of biotech companies, together with the Massachusetts Institute of Technology, has convened to collect data on these events. This industry-wide study provides insights into the most common viral contaminants, the source of those contaminants, the cell lines affected, corrective actions, as well as the impact of such events. These results have implications for the safe and effective production of not just current products, but also emerging cell and gene therapies which have shown much therapeutic promise.

Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium.

BACKGROUND: Clinical trials indicate a beneficial effect of intracoronary infusion of progenitor cells on myocardial function in patients with ischemic heart disease. The extent and potential determinants of proangiogenic progenitor cell homing into the damaged myocardium after intracoronary infusion and the underlying mechanisms are still unknown. METHOD AND RESULTS: Circulating proangiogenic progenitor cells isolated from peripheral blood and cultivated for 3 days were labeled with radioactive indium oxine ((111)In-oxine). Radiolabeled proangiogenic progenitor cells (7.6+/-3.0 MBq, mean+/-SD) were administered to patients with previous myocardial infarction and a revascularized infarct vessel at various stages after infarction (5 days to 17 years). Viability of the infarcted myocardium was determined by (18)F-fluorodeoxyglucose-positron emission tomography and microcirculatory function by intracoronary Doppler measurements. One hour after application of progenitor cells, a mean of 6.9+/-4.7% (range, 1% to 19%; n=17) of total radioactivity was detected in the heart, which declined to 2+/-1% after 3 to 4 days. Average activity within the first 24 hours was highest among patients with acute myocardial infarction (14 days to 1 year; 4.5+/-3.2%; n=4) or a chronic stage (infarct age >1 year; 2.5+/-1.6%; n=5). Low viability of the infarcted myocardium and reduced coronary flow reserve were significant (P<0.05) predictors of proangiogenic progenitor cell homing. CONCLUSIONS: In patients after myocardial infarction undergoing intracoronary infusion of (111)In-oxine-labeled proangiogenic progenitor cells, a substantial amount of radioactivity is detected for several days in the heart, indicating homing of progenitor cells to the myocardium. The amount of proangiogenic progenitor cells retained in the heart decreased progressively with time after the acute myocardial infarction. Proangiogenic progenitor cells preferentially home to extensive acute myocardial infarcts characterized by low viability and reduced coronary flow reserve.

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy.

BACKGROUND: The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. METHODS: ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. FINDINGS: 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15.5-96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p=0.058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference 0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058], p=0.07) compared with baseline. INTERPRETATION: Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.

Predictors of mastectomy in a certified breast center - the surgeon is an independent risk factor.

The current study examined predictors of mastectomy in a certified breast center with the main impact on the factor surgeon. A total of 663 patients were analyzed for their mastectomy rates. Included were patients with T1 and T2 tumors, who had their surgery performed by one of three specialized breast surgeons with a workload of at least 50 new breast cancer cases per year. On multivariate analysis central tumor localization, positive lymph node status, nonunifocality, large tumor size, and the surgeon were independent predictors of mastectomy. Surgeon A had a mastectomy rate of 30.5% (50/164), surgeon B 26.9% (43/160) respectively, and surgeon C had a mastectomy rate of 15.8% (27/171), p = 0.005. Patients, who had surgery performed by surgeon A or surgeon B were 2.34 [95% confidence interval (CI): 1.38-3.97, p < 0.005] respectively 1.96 (95% CI: 1.14-3.36, p = 0.01) times as likely to have a mastectomy than patients who had surgery performed by surgeon C. Even in a certified breast center with specialized breast surgeons the surgeon is an independent risk factor of mastectomy, as the tumor criteria are given at the time of diagnosis.

Single chain Fab (scFab) fragment.

BACKGROUND: The connection of the variable part of the heavy chain (VH) and and the variable part of the light chain (VL) by a peptide linker to form a consecutive polypeptide chain (single chain antibody, scFv) was a breakthrough for the functional production of antibody fragments in Escherichia coli. Being double the size of fragment variable (Fv) fragments and requiring assembly of two independent polypeptide chains, functional Fab fragments are usually produced with significantly lower yields in E. coli. An antibody design combining stability and assay compatibility of the fragment antigen binding (Fab) with high level bacterial expression of single chain Fv fragments would be desirable. The desired antibody fragment should be both suitable for expression as soluble antibody in E. coli and antibody phage display. RESULTS: Here, we demonstrate that the introduction of a polypeptide linker between the fragment difficult (Fd) and the light chain (LC), resulting in the formation of a single chain Fab fragment (scFab), can lead to improved production of functional molecules. We tested the impact of various linker designs and modifications of the constant regions on both phage display efficiency and the yield of soluble antibody fragments. A scFab variant without cysteins (scFabDeltaC) connecting the constant part 1 of the heavy chain (CH1) and the constant part of the light chain (CL) were best suited for phage display and production of soluble antibody fragments. Beside the expression system E. coli, the new antibody format was also expressed in Pichia pastoris. Monovalent and divalent fragments (DiFabodies) as well as multimers were characterised. CONCLUSION: A new antibody design offers the generation of bivalent Fab derivates for antibody phage display and production of soluble antibody fragments. This antibody format is of particular value for high throughput proteome binder generation projects, due to the avidity effect and the possible use of common standard sera for detection.

A comparative study of different vector designs for the mammalian expression of recombinant IgG antibodies.

Monoclonal antibodies (Mab) are the fastest growing group of biopharmaceuticals in development. For production in mammalian cells, the four polypeptide chains of the immunoglobulin diheterotetramer must be assembled prior to exit from the endoplasmic reticulum. Various recombinant Mab expression vectors have been developed utilizing mono-and bicistronic expression cassettes encoded on one or two plasmids. However, there are only few studies providing information on the type of vector design optimal for stable or transient production of recombinant IgG. Consequently, in this study, we have constructed a series of mammalian expression vectors for the production of recombinant human or chimeric IgG antibodies with different expression cassette designs. Versions for monocistronic and bicistronic expression with different promoters and cistron arrangements were generated. Antibody production levels were evaluated in transiently transfected 293T and CHO-K1 cells. Furthermore, stable CHO cell lines were generated and analyzed for antibody production levels and stability. Our results indicate that compared to monocistronic expression, EMCV IRES-mediated bicistronic expression constructs yield similar antibody expression levels and show long-term stability in CHO cell lines. Addition of a third cistron encoding YFP was shown to facilitate screening and isolation of clones using a FACS sorter.

Migrants and Refugees in Europe: Challenges, Experiences and Contributions.

Due to the current geopolitical situation more refugees from crisis countries were and will be treated in Europe. In 2015 the number of displaced people reached an unprecedented level, with more than one million crossing into Europe. The migration itself can impair both mental and physical health. Therefore, the provision of medical care for refugees and migrants is a novel and major challenge for the health care systems in Europe. In this article we describe our experiences and contribution in providing medical care for refugees who have newly arrived in Stuttgart, Baden-Wuerttemberg, Germany. Furthermore, we report our experiences from a tertiary referral University center in Regensburg, Bavaria, Germany. We focus on challenges in both the outpatient and the inpatient setting, with a special focus on intensive care patients. In addition, we provide an overview about the spectrum of diseases in this specific patient cohort.

Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial.

BACKGROUND: Tamoxifen has been the standard adjuvant treatment for postmenopausal women with hormone-responsive early breast cancer for more than 20 years. However, the third-generation aromatase inhibitor anastrozole has proven efficacy and tolerability benefits compared with tamoxifen when used as initial adjuvant therapy. We investigate whether women who have received a period of adjuvant tamoxifen would benefit from being switched to anastrozole. METHODS: We present a combined analysis of data from two prospective, multicentre, randomised, open-label trials with nearly identical inclusion criteria. Postmenopausal women with hormone-sensitive early breast cancer who had completed 2 years' adjuvant oral tamoxifen (20 or 30 mg daily) were randomised to receive 1 mg oral anastrozole (n=1618) or 20 or 30 mg tamoxifen (n=1606) daily for the remainder of their adjuvant therapy. The primary endpoint was event-free survival, with an event defined as local or distant metastasis, or contralateral breast cancer. Analysis was by intention to treat. FINDINGS: 3224 patients were included in analyses. At a median follow-up of 28 months, we noted a 40% decrease in the risk for an event in the anastrozole group as compared with the tamoxifen group (67 events with anastrozole vs 110 with tamoxifen, hazard ratio 0.60, 95% CI 0.44-0.81, p=0.0009). Both study treatments were well tolerated. There were significantly more fractures (p=0.015) and significantly fewer thromboses (p=0.034) in patients treated with anastrozole than in those on tamoxifen. INTERPRETATION: These data lend support to a switch from tamoxifen to anastrozole in patients who have completed 2 years' adjuvant tamoxifen.

A dosimetric comparison of IORT techniques in limited-stage breast cancer.

BACKGROUND AND PURPOSE: For intraoperative radiotherapy (IORT) during breast-conserving treatment four different techniques have been addressed: interstitial brachytherapy, an inflatable balloon with a central high-dose-rate source (MammoSite), a miniature orthovolt system (Intrabeam), and linac-based electron radiotherapy (IOERT). The dosimetric properties of these methods are compared. MATERIAL AND METHODS: Planning target volumes (PTVs) of the same size but of different shapes are assumed, corresponding to the technique's specific situs. Dose distributions for the PTVs and for surrounding tissues are demonstrated by dose-volume histograms and a list of physical parameters. A dose inhomogeneity index (DII) is introduced to describe the deviation of a delivered from the prescribed dose, reaching its minimal value 0 in case of perfect homogeneity. RESULTS: In terms of DII, IOERT reaches the lowest value followed by the MammoSite, the Intrabeam and interstitial implants. The surrounding tissues receive the smallest average dose with IOERT, closely followed by the orthovolt system. CONCLUSION: When comparing simplified geometric figures, IOERT delivers the most homogeneous dose distributions. However, in clinical reality PTVs often present asymmetric shapes instead of ideal geometries. Due to a strictly centric dose fall-off, any system with a round central applicator will have technical limits. During IOERT margin-directed applicator guidance is possible and interstitial brachytherapy allows for polygonal dose shaping. These techniques seem to be superior for asymmetric PTV irradiation.

Positron emission tomography in combination with sentinel node biopsy reduces the rate of elective neck dissections in the treatment of oral and oropharyngeal cancer.

PURPOSE: To assess the impact of a diagnostic ladder including [(18)F]fluorodeoxyglucose positron emission tomography (PET) and lymphoscintigraphy guided sentinel node biopsy (LS/SNB) on neck treatment in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). PATIENTS AND METHODS: Prospectively, 62 patients with resectable T1-3 OOSCC underwent computed tomography (CT) and PET. Patients without neck uptake in PET were defined as cN0 and were accrued for LS/SNB. Results were correlated with histopathology. The traditional guidelines according to CT findings were compared to the actual regimen and the outcome. RESULTS: Sensitivity, specificity, validity, and positive and negative predictive value of PET versus CT were 72% v 89%, 82% v 77%, 79% v 80.5%, 62% v 61.5%, and 88% v 94.5% (not significant). Thirty-eight PET negative patients underwent LS/SNB. Sentinel lymph nodes were found in all 38 patients. Five patients had positive nodes (PET false-negatives) and underwent neck dissection (ND). Fifty-one neck sides in 36 patients who were CT-negative would have been treated with selective ND according to the guidelines, and at least 45 neck sides would have had to undergo extensive ND because of positive CT findings (96 of 124 neck sides). In contrast, PET in combination with LS/SNB spared 59 neck sides, and 41 of 124 neck sides actually underwent ND as a result of PET staging, LS/SNB, and intraoperative decision. After a median follow-up of 35 months, two patients (both cN+ve and pN+ve) suffered from neck relapses. CONCLUSION: Diagnostics using PET in combination with LS/SNB considerably reduced the number of extensive ND in OOSCC as compared to CT without locoregional hazard.

Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5.

PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death. RESULTS: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195). CONCLUSION: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.

Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6.

PURPOSE: To determine whether the addition of aminoglutethimide to tamoxifen is able to improve the outcome in postmenopausal patients with hormone receptor-positive, early-stage breast cancer. PATIENTS AND METHODS: A total of 2,021 postmenopausal women were randomly assigned to receive either tamoxifen for 5 years alone or tamoxifen in combination with aminoglutethimide (500 mg/d) for the first 2 years of treatment. Tamoxifen was administered at 40 mg/d for the first 2 years and at 20 mg/d for 3 years. RESULTS: All randomized and eligible patients were included in the analysis according to the intention-to-treat principle. After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P =.89). The corresponding data for overall survival at 5 years were 91.4% and 91.2%, respectively (P =.74). More patients failed to complete combination treatment (13.7%) because of side effects as compared to tamoxifen alone (5.2%; P =.0001). CONCLUSION: Aminoglutethimide given for 2 years in addition to tamoxifen for 5 years does not improve the prognosis of postmenopausal patients with receptor-positive, lymph node-negative or lymph node-positive breast cancer.

Evaluation of tartrate-resistant acid phosphatase (TRACP) 5b as bone resorption marker in irradiated bone metastases.

BACKGROUND: The aim of our study was to evaluate if the determination of the active isoform 5b of tartrate-resistant acid phosphatase (TRACP 5b) provides the possibility to monitor the effect of local radiotherapy in bone metastases and if TRACP 5b will predict further osseous progression. MATERIALS AND METHODS: In 48 breast cancer patients with bone metastases, patients' characteristics, diagnostic imaging and laboratory investigation, tumor- and therapy-related parameters were registered at the beginning and the end of radiotherapy, as well as 6 and 12 weeks afterwards. TRACP 5b activity was measured using a solid phase immunofixed enzyme activity assay with the monoclonal antibody O1A. RESULTS: During follow-up, progression in another part of the skeleton was diagnosed in 31 patients (65%). There was a significant decrease of TRACP 5b in patients without progression in non-irradiated regions, whereas in progressive disease, TRACP 5b levels remained stable with a slightly increasing tendency (p < 0.007). In patients with < or =3 metastases, all TRACP 5b values were significantly lower than the values of those with >3 metastases (p = 0.01). CONCLUSION: In patients without further osseous progression, TRACP 5b is able to monitor the effectiveness of local radiotherapy. The estimation of sensitivity and specificity based on each TRACP 5b value demonstrates that the ability to discriminate between those patients with or without osseous progression increases with time.

Sentinel node biopsy as staging tool in a multimodality treatment approach to cancer of the oral cavity and the oropharynx.

OBJECTIVES: Feasibility of sentinel lymph node (SLN) biopsy in head and neck cancer as a staging tool embedded in a multimodality regimen including neoadjuvant intraarterial chemotherapy. STUDY DESIGN AND SETTING: 39 patients with oral and anterior oropharyngeal cancer classified N0 by [18 F]FDG-PET underwent SLN scintigraphy. Selective SLN biopsy without elective neck dissection (ND) was performed, immediately followed by radical resection of the primary tumor. Histopathology included step-serial sections and immunocytochemistry. RESULTS: Lymphoscintigraphy detected 104 spots. In 15 patients there was bilateral drainage. 114 SLN were excised due to additional intraoperative discrimination. 95% of visualised SLN could be removed. Histology was positive in 3 patients (8%), all underwent ND which yielded another positive node in 2 cases. Median observation time was 30 months. Two patients (5%) had a neck relapse in combination with a second primary. CONCLUSIONS: SLN biopsy as only surgical staging tool seems to be feasible. SIGNIFICANCE: Method promises reduction of elective ND and morbidity in N0 patients.

A global analysis of protein expression profiles in Sinorhizobium meliloti: discovery of new genes for nodule occupancy and stress adaptation.

A proteomic examination of Sinorhizobium meliloti strain 1021 was undertaken using a combination of 2-D gel electrophoresis, peptide mass fingerprinting, and bioinformatics. Our goal was to identify (i) putative symbiosis- or nutrient-stress-specific proteins, (ii) the biochemical pathways active under different conditions, (iii) potential new genes, and (iv) the extent of posttranslational modifications of S. meliloti proteins. In total, we identified the protein products of 810 genes (13.1% of the genome's coding capacity). The 810 genes generated 1,180 gene products, with chromosomal genes accounting for 78% of the gene products identified (18.8% of the chromosome's coding capacity). The activity of 53 metabolic pathways was inferred from bioinformatic analysis of proteins with assigned Enzyme Commission numbers. Of the remaining proteins that did not encode enzymes, ABC-type transporters composed 12.7% and regulatory proteins 3.4% of the total. Proteins with up to seven transmembrane domains were identified in membrane preparations. A total of 27 putative nodule-specific proteins and 35 nutrient-stress-specific proteins were identified and used as a basis to define genes and describe processes occurring in S. meliloti cells in nodules and under stress. Several nodule proteins from the plant host were present in the nodule bacteria preparations. We also identified seven potentially novel proteins not predicted from the DNA sequence. Post-translational modifications such as N-terminal processing could be inferred from the data. The posttranslational addition of UMP to the key regulator of nitrogen metabolism, PII, was demonstrated. This work demonstrates the utility of combining mass spectrometry with protein arraying or separation techniques to identify candidate genes involved in important biological processes and niche occupations that may be intransigent to other methods of gene expression profiling.

rhTSH stimulation before radioiodine therapy in thyroid cancer reduces the effective half-life of (131)I.

UNLABELLED: Recombinant human thyroid-stimulating hormone (rhTSH) is effectively used for exogenous thyroid-stimulating hormone (TSH) stimulation before diagnostic (131)I scintigraphy. It is not yet widely used for preparation of patients receiving a therapeutic amount of radioiodine. METHODS: The results of 64 consecutive therapeutic applications of rhTSH with regard to clinical tolerance and side effects were evaluated in comparison with 163 radioiodine therapies (RITs) done on patients with hypothyroidism after thyroxine withdrawal during the same period. All therapies-applying 1.1-10 GBq of (131)I-used a standardized protocol of patient preparation and activity application. RITs were followed by daily whole-body uptake measurements for 2-6 d, and a biexponential curve fit was used to obtain a short initial and afterward a long effective half-life of (131)I. Patients after rhTSH were evaluated as a whole group (group A, n = 64) and as a subset of that group with normal thyroglobulin (hTG) levels (group D, n = 18). Patients after endogenous TSH stimulation were evaluated as a whole group (group B, n = 163), as a subset of that group excluding all ablative RITs (group C, n = 113), and as a subset of that subset with normal hTG levels (group E, n = 87). RESULTS: rhTSH-stimulated patients showed significantly higher TSH values than did endogenously stimulated patients (P < 0.001). Furthermore, the effective half-life of (131)I was significantly prolonged after endogenous stimulation (e.g., 0.43 d for group A vs. 0. 54 d for group B, P < 0.001). All rhTSH applications were tolerated well and without serious side effects. The only side effects were 2 cases of nausea and headache. CONCLUSION: The use of rhTSH for stimulation of TSH before RIT is safe but also significantly reduces the effective half-life of (131)I. This is mainly due to a reduced renal iodine clearance in the hypothyroid state, but the bioavailability of radioiodine may be slightly overestimated because of larger amounts of intestinal (131)I after endogenous TSH stimulation.