Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

[Strategies to Overcome Acquired Resistance to EGFR-TKI Therapy Based on T790M Specific Substances using Osimertinib as an Example]. / Strategien zur Überwindung der erworbenen EGFR-TKI-Resistenz durch T790M spezifische Substanzen am Beispiel von Osimertinib.

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed.

Ozone production chemistry in the presence of urban plumes.

Ozone pollution affects human health, especially in urban areas on hot sunny days. Its basic photochemistry has been known for decades and yet it is still not possible to correctly predict the high ozone levels that are the greatest threat. The CalNex_SJV study in Bakersfield CA in May/June 2010 provided an opportunity to examine ozone photochemistry in an urban area surrounded by agriculture. The measurement suite included hydroxyl (OH), hydroperoxyl (HO2), and OH reactivity, which are compared with the output of a photochemical box model. While the agreement is generally within combined uncertainties, measured HO2 far exceeds modeled HO2 in NOx-rich plumes. OH production and loss do not balance as they should in the morning, and the ozone production calculated with measured HO2 is a decade greater than that calculated with modeled HO2 when NO levels are high. Calculated ozone production using measured HO2 is twice that using modeled HO2, but this difference in calculated ozone production has minimal impact on the assessment of NOx-sensitivity or VOC-sensitivity for midday ozone production. Evidence from this study indicates that this important discrepancy is not due to the HO2 measurement or to the sampling of transported plumes but instead to either emissions of unknown organic species that accompany the NO emissions or unknown photochemistry involving nitrogen oxides and hydrogen oxides, possibly the hypothesized reaction OH + NO + O2 → HO2 + NO2.

Vestibular compensation in cerebellar stroke patients.

BACKGROUND AND PURPOSE: There is little evidence about the site where compensatory vestibular mechanisms in patients with cerebellar strokes take place. METHODS: To determine whether the location of a cerebellar lesion might be a crucial variable in vestibular compensation a sample of 22 patients with cerebellar stroke were tested for graviceptive function in the acute and chronic stage. RESULTS: Our statistical anatomical lesion analysis indicated that mainly lesions of the cerebellar hemispheres (lobule V, VI, VIIa) hinder vestibular compensation and might lead to an overcompensation. CONCLUSIONS: Overcompensation-induced dysfunction can be explained by the absence of cerebellar inhibitory signals.

Repetition suppression versus enhancement--it's quantity that matters.

Upon repetition, certain stimuli induce reduced neural responses (i.e., repetition suppression), whereas others evoke stronger signals (i.e., repetition enhancement). It has been hypothesized that stimulus properties (e.g., visibility) determine the direction of the repetition effect. Here, we show that the very same stimuli can induce both repetition suppression and enhancement, whereby the only determining factor is the number of repetitions. Repeating the same, initially novel low-visible pictures of scenes for up to 5 times enhanced the blood oxygen level-dependent (BOLD) response in scene-selective areas, that is, the parahippocampal place area (PPA) and the transverse occipital sulcus (TOS), presumably reflecting the strengthening of the internal representation. Additional repetitions (6-9) resulted in progressively attenuated neural responses indicating a more efficient representation of the now familiar stimulus. Behaviorally, repetition led to increasingly faster responses and higher visibility ratings. Novel scenes induced the largest BOLD response in the PPA and also higher activity in yet another scene-selective region, the retrospenial cortex (RSC). We propose that 2 separable processes modulate activity in the PPA: one process optimizes the internal stimulus representation and involves TOS and the other differentiates between familiar and novel scenes and involves RSC.

Lesions to the posterior insular cortex cause dysarthria.

BACKGROUND: Up to now, there are few systematic studies in a sufficient number of patients with lesions involving the insular cortex (IC) examining whether damage of the IC is directly related to dysarthria. Thus, this is the first study applying modern voxel-lesion behaviour mapping (VLBM) aimed to examine whether the IC is involved in dysarthria - and if so - which part of the IC is involved. METHODS: Twenty-five patients with acute stroke lesions affecting the IC and peri-insular region were investigated employing VLBM analysis. RESULTS: Present data indicated that dysarthria is associated with stroke lesions affecting the right- and left-sided posterior IC. CONCLUSIONS: Owing to the known extensive spectrum of cortical and subcortical somatosensory and motor connections, it seems that the IC might be one region involved in the generation of speech motor execution.

Ebstein's anomaly of the tricuspid valve in association with tetralogy of fallot and absent pulmonary valve syndrome.

Ebstein's anomaly and absent pulmonary valve syndrome belong to the rarest congenital heart defects. Their association has never been reported so far. We present the unusual case of a fetus at 23 weeks of gestation with Ebstein's anomaly, tetralogy of Fallot, absent pulmonary valve and agenesis of the arterial duct. The main diagnostic features were apical displacement of the septal leaflet of the tricuspid valve with an offset from the mitral valve of 8 mm, a pronounced atrialization of the right ventricle, a large malalignment ventricular septal defect with overriding aorta in combination with absence of the pulmonary valve leaflets, to and fro flow pattern over the stenotic pulmonary valve annulus, turbulent flow in the pulmonary trunk, massive dilatation of the pulmonary trunk plus the pulmonary arteries and a right aortic arch with retroesophageal course of an aberrant left subclavian artery. The arterial duct and the thymus were absent. The remaining fetal anatomy was unremarkable. Amniocentesis revealed a normal male karyotype; 22q11 microdeletion was ruled out. After being counseled on the unfavorable prognosis, the parents opted for termination of pregnancy. The prenatal cardiac findings were confirmed at autopsy; however, a severely hypoplastic thymus was found instead of the suspected aplasia.

Atmospheric Carbon and Transport - America (ACT-America) Data Sets: Description, Management, and Delivery.

The ACT-America project is a NASA Earth Venture Suborbital-2 mission designed to study the transport and fluxes of greenhouse gases. The open and freely available ACT-America data sets provide airborne in situ measurements of atmospheric carbon dioxide, methane, trace gases, aerosols, clouds, and meteorological properties, airborne remote sensing measurements of aerosol backscatter, atmospheric boundary layer height and columnar content of atmospheric carbon dioxide, tower-based measurements, and modeled atmospheric mole fractions and regional carbon fluxes of greenhouse gases over the Central and Eastern United States. We conducted 121 research flights during five campaigns in four seasons during 2016-2019 over three regions of the US (Mid-Atlantic, Midwest and South) using two NASA research aircraft (B-200 and C-130). We performed three flight patterns (fair weather, frontal crossings, and OCO-2 underflights) and collected more than 1,140 h of airborne measurements via level-leg flights in the atmospheric boundary layer, lower, and upper free troposphere and vertical profiles spanning these altitudes. We also merged various airborne in situ measurements onto a common standard sampling interval, which brings coherence to the data, creates geolocated data products, and makes it much easier for the users to perform holistic analysis of the ACT-America data products. Here, we report on detailed information of data sets collected, the workflow for data sets including storage and processing of the quality controlled and quality assured harmonized observations, and their archival and formatting for users. Finally, we provide some important information on the dissemination of data products including metadata and highlights of applications of ACT-America data sets.

Anatomical correlates of ocular motor deficits in cerebellar lesions.

Humans are able to stabilize the images of moving targets on the retina by means of smooth pursuit eye movements. After the pontine level, all smooth pursuit pathways pass through the cerebellum. Previous animal studies gave evidence that two specific lesion sites within the cerebellum cause smooth pursuit disorders: those of the flocculus/paraflocculus and the vermis including lobule VI, VII, the uvula and the deep cerebellar nuclei. To date, there have been only a few lesion studies in patients with smooth pursuit disorders that do not allow direct comparison with a control group. In the present study, new lesion mapping techniques determined which cerebellar structures were involved in patients with deficits of smooth pursuit eye movements, slow phase of optokinetic nystagmus (OKN) and fixation suppression of vestibulo-ocular reflex, i.e. in eye movements that are considered to belong to the smooth pursuit system. The aim was to elucidate whether there is an anatomical and clinical link between these different eye movement disorders. Seventeen patients with acute, mainly unilateral cerebellar infarctions and an intact gain of the smooth pursuit system were compared with 11 patients with cerebellar lesions and deficient gain of sinusoidal smooth pursuit eye movements by means of lesion-mapping imaging. In addition, lesion analyses were conducted in subgroups with impaired fixation suppression of vestibulo-ocular reflex and deficient gain of the slow phase of the OKN. The uvula and partly the vermal pyramid were found to be the structures commonly damaged in patients with deficient gain of the horizontal sinusoidal smooth pursuit eye movement, of the slow phase of the OKN and impaired fixation suppression of vestibulo-ocular reflex; and were less involved in patients with intact smooth pursuit system. The present data give evidence for an anatomical link between sinusoidal smooth pursuit eye movements, fixation suppression of vestibulo-ocular reflex and the slow phases of OKN implying that the uvula and the vermal pyramid are important structures for generating slow phases within the smooth pursuit network in humans.

Are signs of ocular tilt reaction in patients with cerebellar lesions mediated by the dentate nucleus?

A sensitive clinical sign of a vestibular tone imbalance in the roll plane is the ocular tilt reaction (OTR), a combination of skew deviation, ocular torsion and head and perceptual tilts such as tilts of the subjective visual vertical (SVV). Of these OTR components tilts of SVV are the most frequent. While these signs are regularly seen in patients with unilateral brainstem lesions, only a few case studies are available on their occurrence in patients with cerebellar lesions. Thus, the question arises whether cerebellar structures may be involved in contra- and/or ipsiversive tilts of the perceived vertical and other signs of OTR. We used lesion-mapping techniques in a total of 31 patients with acute cerebellar strokes, all showing at least a significant tilt of SVV. Twenty-three patients had a contraversive tilt of the SVV; they were compared with eight patients with ipsiversive tilts. MRI/CT lesion mapping revealed that in patients showing contraversive signs of OTR in general and contraversive SVV tilts in particular the dentate nucleus was the commonly damaged structure. In contrast, in ipsiversive signs of OTR, the dentate nucleus was spared and lesions were located in the biventer lobule, the middle cerebellar peduncle, the tonsil and the inferior semilunar lobule. These data suggest that the dentate nucleus is a critical anatomical structure within the cerebellum, belonging to a network involved in vestibular processing such as the perception of verticality. Therefore, a lesion of the dentate nucleus can lead to tilts of the SVV in the contraversive direction, i.e. a vestibular tone imbalance to the contralateral side, whereas cerebellar lesions excluding the dentate nucleus can induce a tone imbalance to the ipsilesional side.

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study.

BACKGROUND: Endocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor-positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. PATIENTS AND METHODS: Post-menopausal hormone receptor-positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. RESULTS: Among 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90-3.42), sleep disorders (HR 1.95; 95% CI, 1.41-2.70) and other AEs (HR 2.03; 95% CI, 1.51-2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74-1.84). CONCLUSIONS: These results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. CLINICAL TRIALS NUMBER: CFEM345DDE19.

Biomechanical comparison of two side plate fixation techniques in an unstable intertrochanteric osteotomy model: Sliding Hip Screw and Percutaneous Compression Plate.

BACKGROUND: Our objective was to determine the biomechanical primary stability of two different side plate fixation devices in an unstable intertrochanteric cadaver model: the Sliding Hip Screw with an additional derotation screw was compared with the Percutaneous Compression Plate. METHODS: Eight pairs of human cadaver femurs were tested for comparison of the primary stability of the two implants in two modes: (a) cyclic loading up to 200 N, 400 N, 600 N, 800 N, and 1000 N, respectively. In vitro combined axial and bending loads were applied. Angular displacements of the proximal head fragment during loading were recorded in rotational, varus-valgus, and anterior-posterior directions. (b) The load to failure was determined. FINDINGS: Specimens fixed with the Percutaneous Compression Plate showed higher displacements in the varus during loading up to 200 N (P=0.033), and 400 N (P=0.001), compared to the Sliding Hip Screw. A similar tendency was observed for higher loads. The Percutaneous Compression Plate allowed more external rotation of the proximal fragment only at loads up to 800 N (P=0.019). No statistical difference could be found for the slight migrations in the posterior direction. Load to failure also revealed no statistical difference between the two implants. INTERPRETATION: The Percutaneous Compression Plate as a double-axis fixation device with a sliding capability allows higher displacements in the varus direction and also in external rotation at 800 N loading compared to the Sliding Hip Screw as a single-axis fixation device combined with an additional derotation screw. While both implants are successful used in clinical practice, this should be considered in treatment of unstable intertrochanteric fractures with inferior comminution in osteoporotic patients.

Resection of multiple lung metastases--where are the limits?

Multiple lung metastases present a serious and challenging problem with increasing incidence for thoracic surgeons. In the lung metastasis management a significant role belongs to laser lung-parenchyma-saving resection. This parenchyma saving technique allows a removal of significant higher number of lung nodules in comparison to conventional techniques (stapler, clamp resection). Performing the lung metastasectomy by this manner, the only remaining question is the limitation of this technique. In this retrospective study, the results after Nd:YAG Laser (1318 nm, 40 Watt) interventions are being presented, the limitations of this technique are being discussed (Tab. 3, Fig. 4, Ref. 9).

Insula and sensory insular cortex and somatosensory control in patients with insular stroke.

BACKGROUND: In functional imaging studies, the insular cortex (IC) has been identified as an essential part of the processing of a whole spectrum of multimodal sensory input. However, there are no lesion studies including a sufficient number of patients, which would reinforce the functional imaging data obtained from healthy subjects. Such lesion studies should examine how damage to the IC affects sensory perception. We chose acute stroke patients with lesions affecting the IC in order to fill this gap. METHODS: A comprehensive sensory profiling by applying a quantitative sensory testing protocol was performed and a voxel-lesion behaviour mapping analysis in 24 patients with acute unilateral cortical damage was applied. RESULTS: Our data demonstrate that patients with lesions of the posterior IC have deficits in temperature perception, but did not show other sensory deficits such as hot or cold pain perception associated with specific lesion locations. CONCLUSION: Our data allow the conclusion that the posterior IC may represent the major region responsible for encoding warm and cold perception in the brain. To what extent focal IC lesions may also impair pain processing or induce post-stroke pain has to be addressed in future studies including more patients.

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study.

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1-5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5-10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information.

Naloxone inhibits not only stress-induced analgesia but also sympathetic activation and baroreceptor-reflex sensitivity.

Interactions between the sympathetic nervous system and pain are manifold and still have not been sufficiently characterized. Accordingly, several possible neuronal pathways have been described as being involved in mental stress-induced analgesia. We studied the role of the endogenous opioidergic system in stress-induced analgesia in 14 healthy participants in a double-blind cross-over trial. Naloxone or placebo was applied while electrical pain stimulation was started and electrical current increased. After reaching a constant stimulation at 30 mA, a color word interference test (Stroop task) was performed in a stressful and a non-stressful version. Blood pressure, heart rate and baroreflex sensitivity were continuously recorded to assess autonomic activation. Each participant was tested with naloxone and placebo with a randomized and balanced order of trials. The major results are that the opioid-receptor antagonist naloxone prevented (1) stress-induced reduction of tonic current-induced pain, (2) attenuated the simultaneous activation of the sympathetic nervous system, and (3) reduced the counteraction of sympathetic activation by vagal baroreceptor mechanisms. Thus, the opioidergic system not only modulates nociceptive input but also the interplay with vegetative responses. We conclude that acute stress, sympathetic activation and analgesia might be linked via vagal reflexes, which are disturbed when opioid receptors are blocked. This mechanism might underlie increased perception of noxious stimuli in patients with chronic pain or mood disorders.

Anatomical correlate of positive spontaneous visual phenomena: a voxelwise lesion study.

OBJECTIVES: Visual phenomena such as phosphenes, photopsias, or complex visual hallucinations occur in patients with lesions affecting the occipital, parietal, or temporal lobe. Whether these phenomena are provoked by lesions in specific anatomical regions is still uncertain. To determine which brain regions might be involved in such visual phenomena, we used new brain imaging and lesion analysis tools that allow a direct comparison with control patients. METHODS: Visual phenomena were investigated in a total of 23 patients with acute infarctions along the visual pathways (6 patients with left-sided and 17 patients with right-sided lesions). RESULTS: Ten of these 23 patients (43%) reported positive spontaneous visual phenomena (PSVP). Nine of the 10 patients (90%) with PSVP reported phosphenes; only 3 of the 10 (30%) reported photopsias. Statistical voxelwise lesion-behavior mapping revealed that the areas specifically related to PSVP are V1, V2, and the optic radiation. CONCLUSIONS: Disinhibition of earlier visual areas after lesions of the visual cortex and its afferent fibers seems to be the crucial mechanism in the genesis of visual phenomena in acute stroke patients.

Incidence and diagnosis of anosognosia for hemiparesis revisited.

BACKGROUND: In previous studies, the incidence of anosognosia for hemiparesis has varied between 17% and 58% in samples of brain damaged patients with hemiparesis. OBJECTIVE: To determine whether this wide variation might be explained by the different criteria used for diagnosing anosognosia. METHODS: 128 acute stroke patients with hemiparesis or hemiplegia were tested for anosognosia for hemiparesis using the anosognosia scale of Bisiach et al. RESULTS: 94% of the patients who were rated as having "mild anosognosia"-that is, they did not acknowledge their hemiparesis spontaneously following a general question about their complaints-suffered from, and mentioned, other neurological deficits such as dysarthria, ptosis, or headache. However, they immediately acknowledged their paresis when they were asked about the strength of their limbs. Their other deficits clearly had a greater impact. These patients had significantly milder paresis than those who denied their disorder even when asked directly about their limbs. CONCLUSIONS: Patients who do not mention their paresis spontaneously but do so when questioned about it directly should not be diagnosed having "anosognosia." If this more conservative cut off criterion is applied to the data of the present as well as previous studies, a frequency of between 10% and 18% for anosognosia for hemiparesis is obtained in unselected samples of acute hemiparetic stroke patients. The incidence thus seems smaller than previously assumed.

Chronic ethanol consumption selectively stimulates rectal cell proliferation in the rat.

Cell proliferation was examined in the gastrointestinal tract of 30 pair fed rats having received an isocaloric liquid diet containing 36% of total calories either as ethanol or carbohydrates for four weeks. Utilising the metaphase arrest technique with vincristine, cell proliferation was measured as crypt cell production rate. This was selectively increased in the rectal mucosa of ethanol fed rats (19.1 +/- 2.0 vs 9.1 +/- 1.8 cells/crypt/h; p less than 0.005). There was a concomitant increase in proliferative compartment size (48.1 +/- 5.6% vs 30.1 +/- 8.5% of crypt population size; p less than 0.001). Serum gastrin concentrations were also found to be significantly increased after ethanol feeding (172 +/- 51 vs 106 +/- 27 pmol/l; p less than 0.01). The ethanol dependent proliferative changes in the rectal mucosa are predictive of higher susceptibility of this site to carcinogenesis, supporting experimental and epidemiological data. Increased gastrin concentrations may partly explain the observed rectal hyperproliferation. Other possible causes cannot, however, be excluded.

c-myc activation renders proliferation of Epstein-Barr virus (EBV)-transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1.

Two genetic events contribute to the development of endemic Burkitt lymphoma (BL) infection of B lymphocytes with Epstein-Barr virus (EBV) and the activation of the protooncogene c-myc through chromosomal translocation. The viral genes EBV nuclear antigen 2 (EBNA2) and latent membrane protein 1 (LMP1) are essential for transformation of primary human B cells by EBV in vitro; however, these genes are not expressed in BL cells in vivo. To address the question whether c-myc activation might abrogate the requirement of the EBNA2 and LMP1 function, we have introduced an activated c-myc gene into an EBV-transformed cell line in which EBNA2 was rendered estrogen-dependent through fusion with the hormone binding domain of the estrogen receptor. The c-myc gene was placed under the control of regulatory elements of the immunoglobulin kappa locus composed a matrix attachment region, the intron enhancer, and the 3' enhancer. We show here that transfection of a c-myc expression plasmid followed by selection for high MYC expression is capable of inducing continuous proliferation of these cells in the absence of functional EBNA2 and LMP1. c-myc-induced hormone-independent proliferation was associated with a dramatic change in the growth behavior as well as cell surface marker expression of these cells. The typical lymphoblastoid morphology and phenotype of EBV-transformed cells completely changed into that of BL cells in vivo. We conclude that the phenotype of BL cells reflects the expression pattern of viral and cellular genes rather than its germinal center origin.