Tissue-engineered cellulose tubes for microvascular and lymphatic reconstruction: A translational and feasibility study.

BACKGROUND: Lymphedema microsurgery is an emerging treatment modality, with dissimilar long-term outcomes. One of the main technical challenges in lymphatic microsurgery is the identification and availability of suitable donor vessels for anastomosis. Tissue engineering using biomaterials has demonstrated promise in addressing vessel quality issues in other fields, but its application in microsurgery is still limited. METHODS: Decellularized cellulose tubes were developed and bioengineered by decellularizing stems of Taraxacum-Ruderalia. The microscopic structure, mechanical properties, and residual DNA content of the cellulose tubes were evaluated. Human and murine skin fibroblasts and dermal lymphatic endothelial cells were isolated and cultured for recellularization studies. Biocompatibility, proliferative capacity, and ex-vivo endothelialization of the cellulose tubes were assessed as potential interposition grafts. Finally, the engineered cellulose tubes were assessed as interposing xenografts for lymphovenous anastomoses (LVA) in an ex-vivo swine limb model. RESULTS: The decellularized cellulose tubes exhibited a suitable microscopic structure, mechanical properties, and low residual DNA content. The tubes showed adequate biocompatibility, supported cell proliferation, and facilitated spontaneous ex-vivo endothelialization of lymphatic endothelial cells. In the swine limb model, LVA using the engineered cellulose tubes was successfully performed. CONCLUSION: This translational study presents the use of decellularized cellulose tubes as an adjunct for micro and supermicrosurgical reconstruction. The developed tubes demonstrated favorable structural, mechanical, and biocompatible properties, making them a potential candidate for improving long-term outcomes in lymphedema surgical treatment. The next translational step would be trialing the obtained tubes in a microsurgical in-vivo model.

The Influence of Serpentine Soil on the Early Development of a Non-Serpentine African Thistle, Berkheya radula (Harv.) De Wild.

Serpentine soils are rich in heavy metals and poor in nutrients, limiting plant species' performance and survival. Nevertheless, specificities of such limitations as well as adaptability features required for thriving in serpentine environments are barely known. The Barberton Greenstone Belt in South Africa is an example of an area containing serpentine soil with adapted vegetation. In this study, a pot experiment was performed to compare development features (i.e., germination rates, leaf count, leaf length, biomass and photosynthetic capacity) during the early development of the non-serpentine species Berkheya radula, a genus consisting of known metal hyperaccumulators from serpentine areas in South Africa. B. radula was grown in serpentine soils taken from the Barberton region. B. radula leaves had heavy metals in concentrations that confirmed the species as a phytoextractor. There were trends for enhanced productivity and photosynthesis in the serpentine treatments compared to the control. Leaf count, leaf length, electron transport efficiency (ψEo/(1 - ψEo), density of reaction centers and PIABS,total were significantly and positively correlated with at least one of the heavy metals in the leaves. Germination rates were positively influenced by K, whereas biomass and the density of reaction centers were negatively affected by Ca and P, and only Ca, respectively. The heavy metals Zn, Ni and Co were positively correlated with each other, whereas they were negatively correlated with the macronutrients K, Ca and P. The latter correlated positively with each other, confirming higher fertility of the control soil. Our study suggests that B. radula exhibits metallophyte characteristics (i.e., preadapted), despite not naturally occurring on metal-enriched soil, and this provides evidence that the potential for bioaccumulation and phytoremediation is shared between serpentine and non-serpentine species in this genus.

'Double Whamm' and 'Triple Whamm' combinations in hospitalized surgical patients - real life data from a tertiary teaching hospital.

The 'Triple-Whamm'-combination (TW) of renin-angiotensin-aldosteron-system-inhibitors (RAASI), diuretics and non-steroidal anti-inflammatory drugs (NSAID) can cause acute kidney injury (AKI), especially with additional risk factors like chronic kidney disease (CKD) or surgery. Thus, patients on 'Double-Whammy'-combination (DW) of RAASI and diuretics should receive postoperative NSAID only following risk-benefit-evaluation. Currently, there are no data how often surgical patients take DW/TW at admission and postoperatively. The objective of this study was to firstly assess the prevalence of DW/TW-patients, secondly, to evaluate postoperative NSAID use in DW-patients and possible effects on renal function (RF). In a seven-month retrospective study, the pre-hospital medication of patients admitted to surgical wards of a tertiary teaching hospital was screened for intake of TW-drugs and renal impairment (RI; eGFR <60 ml/min/1.73 m 2 ), respectively. For patients admitted with a DW-combination of RAASI and diuretic and undergoing surgery, postoperative NSAID use was recorded and checked against internal guidelines for postoperative pain management recommending as first line NSAID therapy ibuprofen in bone surgery and novaminsulfone in visceral surgery. If NSAID were taken, RF was followed for five days. Of 2007 patients, 343 (17.1%) presented with DW in pre-hospital medication and 28 (1.4%) with TW, which 19/28 (67.9%) took only on demand. Upon admission, RI was present in 113 (32.9%) DW-patients and 9 (33.3%) TW-patients. 227/343 (66.2%) DW-patients underwent surgery and 34/227 (15.0%) were prescribed postoperative NSAID. 24/227 (10.6%) actually received NSAID and 4/24 (16.7%) had a decrease of RF with one showing AKI. In our hospitalized surgical patients, TW-combination in pre-hospital medication was rare. The intake of DW-combination was common but only a small number actually received NSAID after surgery. When a TW-combination was given postoperatively, renal function decreased in every sixth patient. Thus, the absolute number of AKI following a TW-combination was small, however, the individual risk for TW-caused AKI should be considered when choosing postoperative pain management. Guidelines for postoperative NSAID use should consider the patient individual risk factors for AKI, thereby increasing drug safety.

Importance of preserving redundant pulp skin in thumb terminalization to allow subsequent reconstruction with on-top toe transfer: A clinical case (with video).

Traumatic thumb amputations can seriously jeopardise hand function. Several alternatives for reconstructing an opposable thumb have been described, including distraction osteogenesis, index finger pollicisation and free toe transfer. We present in this article the case of a young male patient that sustained a circular saw injury to his non-dominant thumb which resulted in loss of his distal phalanx. Preserving the sensate pulp allowed later reconstruction with an on-top free second toe transfer achieving a satisfactory outcome.

[Current indications for plasma therapy in dermatology]. / Aktuelle Indikationen der Plasmatherapie in der Dermatologie.

BACKGROUND: Plasma medicine is gaining increasing interest and provides a multitude of dermatological applications. Cold atmospheric pressure plasma (CAP) can be used in clinical applications without harming the treated tissue or in a tissue destructive manner. It consists of a complex mixture of biologically active agents, which can act synergistically on the treated material or tissue. OBJECTIVES: A summary of the current research findings regarding dermatological applications of CAP is provided. METHODS: Literature on CAP applications in dermatology has been screened and summarized. RESULTS: CAP exerts antimicrobial, tissue-stimulating, blood-flow-stimulating but also pro-apoptotic effects. By exploiting these properties, CAP is successfully applied for disinfection and treatment of chronic ulcerations. Furthermore, positive effects of CAP have been shown for the treatment of tumors, actinic keratosis, scars, ichthyosis, atopic eczema as well as for alleviation of pain and itch. CONCLUSIONS: While the use of CAP for disinfection and wound treatment has already moved into clinical practice, further applications such as cancer treatment are still exploratory.

Managing Uncertainty in Runoff Estimation with the U.S. Environmental Protection Agency National Stormwater Calculator.

The U.S. Environmental Protection Agency National Stormwater Calculator (NSWC) simplifies the task of estimating runoff through a straightforward simulation process based on the EPA Stormwater Management Model. The NSWC accesses localized climate and soil hydrology data, and options to experiment with low-impact development (LID) features for parcels up to 5 ha in size. We discuss how the NSWC treats the urban hydrologic cycle and focus on the estimation uncertainty in soil hydrology and its impact on runoff simulation by comparing field-measured soil hydrologic data from 12 cities to corresponding NSWC estimates in three case studies. The default NSWC hydraulic conductivity is 10.1 mm/h, which underestimates conductivity measurements for New Orleans, Louisiana (95 ± 27 mm/h) and overestimates that for Omaha, Nebraska (3.0 ± 1.0 mm/h). Across all cities, the NSWC prediction, on average, underestimated hydraulic conductivity by 10.5 mm/h compared to corresponding measured values. In evaluating how LID interact with soil hydrology and runoff response, we found direct hydrologic interaction with pre-existing soil shows high sensitivity in runoff prediction, whereas LID isolated from soils show less impact. Simulations with LID on higher permeability soils indicate that nearly all of pre-LID runoff is treated; while features interacting with less-permeable soils treat only 50%. We highlight the NSWC as a screening-level tool for site runoff dynamics and its suitability in stormwater management.

Association of Maternal Vitamin D Deficiency with Early Childhood Caries.

Alaska Native (AN) children experience one of the highest reported rates of severe early childhood caries (S-ECC). Serum vitamin D concentrations in AN childbearing women in the Yukon Kuskokwim Delta (YKD) region have decreased since the 1960s to currently low levels, related to a decrease in traditional marine diet. Recent studies suggest an association between prenatal vitamin D (25(OH)D) concentrations in mothers and S-ECC in their infants. We used independent t tests to analyze the influence of prenatal 25(OH)D levels in YKD AN mothers on S-ECC in their children using data collected in the Maternal Organics Monitoring Study (MOMS). Maternal 25(OH)D levels were assessed at prenatal visits and in cord blood. We queried electronic dental records to assess early childhood caries (ECC) status using highest decayed, missing, filled, primary teeth (dmft) scores at 12 to 59 mo of age. We examined prenatal and cord blood for 76 and 57 mother/infant pairs, respectively. Children 12 to 35 mo of age with "deficient" cord blood (25(OH)D <30 nmol/L) had a mean dmft score twice as high as children who were "nondeficient" at birth (9.3 vs. 4.7; P = 0.002). There was no significant difference in mean dmft scores for children aged 36 to 59 mo with deficient versus nondeficient cord blood 25(OH)D (10.9 vs. 8.7 P = 0.14). There was no significant difference in mean dmft scores for children aged 12 to 35 mo whose mothers had "sufficient" versus "insufficient" 25(OH)D during prenatal visits (9.0 vs. 7.4; P = 0.48). In this small sample, children with deficient vitamin D levels in cord blood had a dmft score at 12 to 35 mo 2-fold higher than children with nondeficient cord blood. Maternal 25(OH)D may influence the primary dentition, and improving vitamin D status in pregnant women might affect ECC rates in their infants.

Future directions for monitoring and human health research for the Arctic Monitoring and Assessment Programme.

For the last two and a half decades, a network of human health experts under the Arctic Monitoring and Assessment Program (AMAP) has produced several human health assessment reports. These reports have provided a base of scientific knowledge regarding environmental contaminants and their impact on human health in the Arctic. These reports provide scientific information and policy-relevant recommendations to Arctic governments. They also support international agreements such as the Stockholm Convention on Persistent Organic Pollutants (POPs) and the Minamata Convention on Mercury. Key topics discussed in this paper regarding future human health research in the circumpolar Arctic are continued contaminant biomonitoring, health effects research and risk communication. The objective of this paper is to describe knowledge gaps and future priorities for these fields.

Genotype and risk of tumour rupture in gastrointestinal stromal tumour.

BACKGROUND: Tumour rupture is a strong predictor of poor outcome in gastrointestinal stromal tumours (GISTs) of the stomach and small intestine. The objective was to determine whether tumour genotype was associated with risk of rupture. METHODS: Rupture was classified according to the definition proposed by the Oslo Sarcoma Group. Since January 2000, data were registered retrospectively for all patients at Oslo University Hospital undergoing surgery for localized GIST of the stomach or small intestine. Tumour genotype was analysed by Sanger sequencing. RESULTS: Two hundred and nine patients with mutation data available were identified. Tumour rupture occurred in 37 patients. Among the 155 patients with KIT exon 11 mutations, an increased risk of rupture was observed with a deletion or insertion-deletion (25 of 86, 29 per cent) compared with substitutions (5 of 50, 10 per cent) or duplications/insertions (2 of 19, 11 per cent) (P = 0·014). Notably, rupture occurred in 17 of 46 tumours (37 per cent) with deletions involving codons 557 and 558 (del557/558) versus 15 of 109 (13·8 per cent) with other exon 11 mutations (P = 0·002). This association was confined to gastric tumours: 12 of 34 (35 per cent) with del557/558 ruptured versus six of 77 (8 per cent) with other exon 11 mutations (P = 0·001). In multivariable logistic regression analysis, del557/558 and tumour size were associated with an increased likelihood of tumour rupture, but mitotic count was not. CONCLUSION: Gastric GISTs with KIT exon 11 deletions involving codons 557 and 558 are at increased risk of tumour rupture. This high-risk feature can be identified in the diagnostic evaluation and should be included in the assessment when neoadjuvant imatinib treatment is considered.

[Achilles tendinopathy]. / Tendinopathie d'Achille.

Achilles tendinopathy (AT) is the most common cause of posterior heel pain. It is most often due to mechanical stress related to overload or overuse of muscle-tendon unit. It also may be associated in a minority of cases with inflammatory arthritis. Pain secondary to AT is generally located in the corporeal part of the tendon or its attachment to the bone and is worsened by exercise. Examination can reveal a painful swelling or thickening on palpation. Additional tests are not routinely recommended but may be useful. Treatment should be tailored to the stage of tendinopathy and to functional disability, and should include an assessment of predisposing factors, analgesia and physiotherapy. Other treatments (shock waves, ultrasound) are less well documented. The indications and effectiveness of infiltrations are controversial and are reserved for chronic AT. The risk benefit ratio should be well discussed with the patient.

[Best practice use of corticosteroids in rheumatoid arthritis]. / Le bon usage de la prednisone dans la polyarthrite rhumatoïde.

Since the 50s oral glucocorticoids including prednisone are used in the management of rheumatoid arthritis due to their efficacy and the limited availability of the other treatments in the past. Thereafter numerous studies confirmed the usefulness of prednisone in controlling clinical inflammatory manifestations and the progression of radiographic damage. Sixty years later the position of prednisone in the treatment strategy of rheumatoid arthritis is still controversial, considering the presence of numerous side effects and the availability of other effective treatments. If prednisone can be reasonably used in some situations either as bridging therapy in combination with other treatments or in case of flare, its long-term use should be avoided.

Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids.

Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1-/-) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1-/- mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1-/- during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1-/- mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1-/-. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1-/- mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.

Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene.

BACKGROUND AND PURPOSE: Although morphine is a very effective analgesic, its narrow therapeutic index and severe side effects limit its therapeutic use. Previous studies indicated that the pharmacological responses of opioids are modulated by genetic and pharmacological invalidation of tachykinin receptors. Here we address the role of substance P and neurokinin A, which are both encoded by the tachykinin 1 (tac1) gene, as modulators of opioid effects. EXPERIMENTAL APPROACH: The analgesic and side effect potential of morphine was compared between wild-type and tac1 null mutant mice. KEY RESULTS: Morphine was a more potent analgesic in tac1 null mutant mice, that is, in the absence of substance P/neurokinin A signalling. Interestingly, the most serious side effect of acute morphine, that is respiratory depression, was reduced in tac1(-/-) animals. Comparing the addictive potential of morphine in wild-type and knockout animals we found that morphine preference was similar between the genotypes. However, the aversive effect of withdrawal precipitated by naloxone in morphine-dependent animals was significantly reduced in tac1 knockout mice. Behavioural sensitization, the underlying mechanism of addiction, was also significantly lower in tac1(-/-) mice. CONCLUSION AND IMPLICATIONS: The analgesic potential of morphine was increased in tac1 knockout mice. In contrast, both the ventilatory suppressing effect and the addictive potential of morphine were reduced. These results suggest that reducing activity of the tachykinin system may be a possible strategy to improve the pharmacological potential of morphine.

Impact of a quasi-stochastic cellular automaton backscatter scheme on the systematic error and seasonal prediction skill of a global climate model.

The impact of a nonlinear dynamic cellular automaton (CA) model, as a representation of the partially stochastic aspects of unresolved scales in global climate models, is studied in the European Centre for Medium Range Weather Forecasts coupled ocean-atmosphere model. Two separate aspects are discussed: impact on the systematic error of the model, and impact on the skill of seasonal forecasts. Significant reductions of systematic error are found both in the tropics and in the extratropics. Such reductions can be understood in terms of the inherently nonlinear nature of climate, in particular how energy injected by the CA at the near-grid scale can backscatter nonlinearly to larger scales. In addition, significant improvements in the probabilistic skill of seasonal forecasts are found in terms of a number of different variables such as temperature, precipitation and sea-level pressure. Such increases in skill can be understood both in terms of the reduction of systematic error as mentioned above, and in terms of the impact on ensemble spread of the CA's representation of inherent model uncertainty.

Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene.

Substance P is known to be involved in respiratory rhythm and central pattern-generating mechanisms, especially during early development. We therefore studied respiratory responses in transgenic newborn mice (Tac1(-/-)) lacking substance P and neurokinin A (NKA). In vivo, the effects of intermittent isocapnic hypoxia (IH) and hypercapnia were studied using whole body flow plethysmography at P2-3 and P8-10. In vitro, anoxic responses and the effects of hypocapnic and hypercapnic conditions were studied in brain stem-spinal cord preparations (C4 activity) at P2. Hypoxic challenge considerably modified the respiratory activity in transgenic mice displayed in vivo as an attenuated increase in tidal volume during IH. Transgenic mice also showed a more prominent posthypoxic frequency decline in vivo, and posthypoxic neuronal arrests appeared more often in vitro. We recognized two types of sigh activity: with or without a following pause. During IH, the amount of sighs with a pause decreased and those without increased, a redistribution that became stronger with age only in controls. Intermittent anoxia induced long-term facilitation effects in controls, but not in Tac1(-/-) animals, manifested as an increase in burst frequency in vitro and by an augmentation of ventilation during posthypoxic periods in vivo. Thus our data demonstrate that a functional substance P/NKA system is of great importance for the generation of an adequate respiratory response to hypoxic provocation in newborn mice and during early maturation. It also indicates that substance P (and/or NKA) is involved in the development of the plasticity of the respiratory system.

Circumpolar maternal blood contaminant survey, 1994-1997 organochlorine compounds.

During the past 20 years a number of studies have found neurological and immunological effects in the developing fetus and infants exposed to background or only slightly elevated levels of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs). To address concerns arising from possible increased human exposure in the Arctic and possible effects of POPs, all circumpolar countries agreed in 1994 to monitoring of specific human tissues for contaminants in the Arctic under the Arctic Monitoring and Assessment Program (AMAP). Mothers in eight circumpolar countries contributed blood samples that were analysed at a single laboratory for 14 PCB congeners (IUPAC No. 28, 52, 99, 105, 118, 128, 138, 153, 156, 170, 180, 183, 187) and 13 organochlorine pesticides (aldrin, beta-hexachlorocyclohexane (beta-HCH), dichlordiphenyltrichloroethane (p,p'-DDT), diphenyldichloroethylene (p,p'-DDE), dieldrin, heptachlorepoxide, hexachlorobenzene (HCB), mirex, and the chlordane derivatives alpha-chlordane, gamma-chlordane, cis-nonachlor, oxychlordane and trans-nonachlor). Inuit mothers from Greenland and Canada have significantly higher levels of oxychlordane, transnonachlor and mirex than mothers from Norway, Sweden, Iceland and Russia. Inuit mothers from Greenland also have significantly higher levels of these contaminants than Inuit mothers from Canada and Alaska. These differences among Inuit groups may represent regional dietary preferences or different contaminant deposition patterns across the Arctic. Levels of PCBs are also elevated among some arctic populations due to their consumption of marine mammals and are in the range where subtle effects on learning and the immune system have been reported. The Russian mothers who consume mainly food imported from southern Russia have elevated levels of DDT, DDE, beta-HCH and a higher proportion of lower chlorinated PCB congeners. This study has allowed an assessment of the variation of contaminants such as PCBs and various organochlorine pesticides (DDT, chlordane, etc.) in human populations around the circumpolar north.

Lessons from genetic profiling in soft tissue sarcomas.

Soft tissue sarcomas represent a heterogeneous group of tumors and include over 50 histotypes. Some of these tumor types are characterized by specific chromosomal translocations, whereas other types show complex genetic aberrations. The recent developments within gene expression technologies have now been applied to studies of soft tissue sarcomas (STS) and the first results indicate that genetic signatures are useful for classification and diagnosis. Distinctive expression profiles have been found in e.g. gastrointestinal stromal tumors (GISTs), synovial sarcomas, malignant peripheral nerve sheath tumors (MPNSTs), and in subsets of liposarcomas. The more pleomorphic tumor types, such as high-grade variants of leiomyosarcomas, malignant fibrous histiocytomas (MFHs), fibrosarcomas, and subtypes of liposarcomas, show a greater variability among the expression profiles, but interestingly subsets with distinctive expression profiles can be identified also among these tumors. The data available place many of the genes hypothesized to be involved in the development of a certain type of STS, such as the KIT gene in GIST development, among the top discriminating genes. Thereby expression profiling provides novel insights into the pathogenesis of STS. Although much work remains to be done to validate the data and to define optimal discriminating gene lists, the current lessons from gene expression studies in STS are encouraging and imply that genetic signatures may serve as diagnostic and prognostic markers and may help identify novel therapeutic strategies.

Patients with Paget disease of nipple and with palpable mass in breast have unfavorable prognosis.

Recent data indicate that in breast cancer patients the presence of Paget disease of the nipple may be related to poor prognosis. Therefore, we decided to assess long-term results of the treatment of such patients, and to assess the relationship between the physical and pathological findings and prognosis. The files of 60 patients with Paget disease of the nipple who were treated between 1977 and 2000 were analyzed retrospectively with respect to the results of physical and pathologic examinations, disease recurrence and survival. In 38/60 patients, the cancer was invasive. In 26/60 patients, palpable masses in the breast were diagnosed. The 5-year overall survival probability was 0.68; the probability was 0.82 for patients without palpable masses, 0.51 for those with palpable masses, 0.91 for patients without invasive cancer and 0.58 for patients with associated invasive cancer. In conclusions, patients with Paget disease of the nipple and with palpable mass in the breast had unfavorable diagnosis. The nature of all nipple changes should be explained as early as possible in order to diagnose the disease when no mass is palpable in the breast.

Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy.

For treatment of early breast cancer in older women, little evidence is available from randomised trials. We conducted a randomised trial comparing modified radical mastectomy (MRM) with tamoxifen (TAM) as the sole initial therapy in 164 patients aged >/=70 years with operable breast cancer. 82 were treated by MRM and 82 with TAM. Survival curves were estimated using the Kaplan-Meier method: multivariate analyses were performed using the Cox's proportional hazards model. Endpoints included survival, time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. After a median follow-up of approximately 10 years, there was a significantly decreased time to progression in the TAM only group (logrank P<0.0001) and significantly shorter time to local progression within the TAM group (logrank P<0.0001). Overall survival of the two groups was similar. The results indicate that tamoxifen alone leads to an unacceptably high rate of local progression or relapse.