Postoperative stereotactic radiosurgery for intracranial solitary fibrous tumors: systematic review and pooled quantitative analysis.

BACKGROUND: Intracranial solitary fibrous tumors (SFTs), formerly hemangiopericytomas (HPCs), are rare, aggressive dural-based mesenchymal tumors. While adjuvant radiation therapy has been suggested to improve local tumor control (LTC), especially after subtotal resection, the role of postoperative stereotactic radiosurgery (SRS) and the optimal SRS dosing strategy remain poorly defined. METHODS: PubMed, EMBASE, and Web of Science were systematically searched according to PRISMA guidelines for studies describing postoperative SRS for intracranial SFTs. The search strategy was defined in the authors' PROSPERO protocol (CRD42023454258). RESULTS: 15 studies were included describing 293 patients harboring 476 intracranial residual or recurrent SFTs treated with postoperative SRS. At a mean follow-up of 21-77 months, LTC rate after SRS was 46.4-93% with a mean margin SRS dose of 13.5-21.7 Gy, mean maximum dose of 27-39.6 Gy, and mean isodose at the 42.5-77% line. In pooled analysis of individual tumor outcomes, 18.7% of SFTs demonstrated a complete SRS response, 31.7% had a partial response, 18.9% remained stable (overall LTC rate of 69.3%), and 30.7% progressed. When studies were stratified by margin dose, a mean margin dose > 15 Gy showed an improvement in LTC rate (74.7% versus 65.7%). CONCLUSIONS: SRS is a safe and effective treatment for intracranial SFTs. In the setting of measurable disease, our pooled data suggests a potential dose response of improving LTC with increasing SRS margin dose. Our improved understanding of the aggressive biology of SFTs and the tolerated adjuvant SRS parameters supports potentially earlier use of SRS in the postoperative treatment paradigm for intracranial SFTs.

Prevalence of Long-Term Low Back Pain After Symptomatic Lumbar Disc Herniation.

OBJECTIVE: Lumbar disc herniation (LDH) is a global issue associated with potentially debilitating long-term consequences, including chronic low back pain (LBP). Short-term outcomes (<2 years) of patients with LDH have been extensively studied and demonstrate improvements in back and leg pain for both operative and conservative management. However, these improvements may not be sustained long-term (>2 years); patients with LDH may develop recurrent disc herniations, progressive degenerative disc disease, and LBP regardless of management strategy. Therefore, our objective is to determine the prevalence of chronic LBP after LDH, understand the relationship between LDH and chronic LBP, and investigate the relationship between radiological findings and postoperative pain outcomes. METHODS: We performed a literature review on the PubMed database via a combination medical subject heading and keyword-based approach for long-term LBP outcomes in patients with LDH. RESULTS: Fifteen studies (2019 patients) evaluated surgical and/or nonoperative outcomes of patients with LDH . Regardless of surgical or nonoperative management, 46.2% of patients with LDH experienced some degree of LBP long-term (range 2-27 years) as compared to a point prevalence of LBP in the general population of only 11.9%. CONCLUSIONS: Patients with LDH are more likely to experience long-term LBP compared to the general population (46.2% vs. 11.9%). Additionally, understanding the relationship between radiological findings and pain outcomes remains a major challenge as the presence of radiological changes and the degree of LBP do not always correlate. Therefore, higher quality studies are needed to better understand the relationship between radiological findings and pain outcomes.

Fundamentals of Intervertebral Disc Degeneration.

Lumbar disc degeneration is one of the leading causes of chronic low back pain. The degenerative cascade is often initiated by an imbalance between catabolic and anabolic processes in the intervertebral discs. As a consequence of extracellular matrix degradation, neoinnervation and neovascularization take place. Ultimately, this degenerative process results in disc bulging and loss of nucleus pulposus and water content and subsequent loss of disc height. Most patients respond to conservative management and surgical interventions well initially, yet a significant number of patients continue to suffer from chronic low back pain. Because of the high prevalence of long-term discogenic pain, regenerative biological therapies, including gene therapies, growth factors, cellular-based injections, and tissue-engineered constructs, have attracted significant attention in light of their potential to directly address the degenerative process. Understanding the pathophysiology of degenerative disc disease is important in both refining existing technologies and developing innovative techniques to reverse the degenerative processes in the discs. In this review, we aimed to cover the underlying pathophysiology of degenerative disc disease as well as its associated risk factors and give a comprehensive summary about the developmental, structural, radiological, and biomechanical properties of human intervertebral discs.

Surge and Mortality in ICUs in New York City's Public Healthcare System.

OBJECTIVES: To evaluate the impact of ICU surge on mortality and to explore clinical and sociodemographic predictors of mortality. DESIGN: Retrospective cohort analysis. SETTING: NYC Health + Hospitals ICUs. PATIENTS: Adult ICU patients with coronavirus disease 2019 admitted between March 24, and May 12, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hospitals reported surge levels daily. Uni- and multivariable analyses were conducted to assess factors impacting in-hospital mortality. Mortality in Hispanic patients was higher for high/very high surge compared with low/medium surge (69.6% vs 56.4%; p = 0.0011). Patients 65 years old and older had similar mortality across surge levels. Mortality decreased from high/very high surge to low/medium surge in, patients 18-44 years old and 45-64 (18-44 yr: 46.4% vs 27.3%; p = 0.0017 and 45-64 yr: 64.9% vs 53.2%; p = 0.002), and for medium, high, and very high poverty neighborhoods (medium: 69.5% vs 60.7%; p = 0.019 and high: 71.2% vs 59.7%; p = 0.0078 and very high: 66.6% vs 50.7%; p = 0.0003). In the multivariable model high surge (high/very high vs low/medium odds ratio, 1.4; 95% CI, 1.2-1.8), race/ethnicity (Black vs White odds ratio, 1.5; 95% CI, 1.1-2.0 and Asian vs White odds ratio 1.5; 95% CI, 1.0-2.3; other vs White odds ratio 1.5, 95% CI, 1.0-2.3), age (45-64 vs 18-44 odds ratio, 2.0; 95% CI, 1.6-2.5 and 65-74 vs 18-44 odds ratio, 5.1; 95% CI, 3.3-8.0 and 75+ vs 18-44 odds ratio, 6.8; 95% CI, 4.7-10.1), payer type (uninsured vs commercial/other odds ratio, 1.7; 95% CI, 1.2-2.3; medicaid vs commercial/other odds ratio, 1.3; 95% CI, 1.1-1.5), neighborhood poverty (medium vs low odds ratio 1.6, 95% CI, 1.0-2.4 and high vs low odds ratio, 1.8; 95% CI, 1.3-2.5), comorbidities (diabetes odds ratio, 1.6; 95% CI, 1.2-2.0 and asthma odds ratio, 1.4; 95% CI, 1.1-1.8 and heart disease odds ratio, 2.5; 95% CI, 2.0-3.3), and interventions (mechanical ventilation odds ratio, 8.8; 95% CI, 6.1-12.9 and dialysis odds ratio, 3.0; 95% CI, 1.9-4.7) were significant predictors for mortality. CONCLUSIONS: Patients admitted to ICUs with higher surge scores were at greater risk of death. Impact of surge levels on mortality varied across sociodemographic groups.

Intraoperative image guidance for cervical spine surgery.

Intraoperative image-guidance in spinal surgery has been influenced by various technological developments in imaging science since the early 1990s. The technology has evolved from simple fluoroscopic-based guidance to state-of-art intraoperative computed tomography (iCT)-based navigation systems. Although the intraoperative navigation is more commonly used in thoracolumbar spine surgery, this newer imaging platform has rapidly gained popularity in cervical approaches. The purpose of this manuscript is to address the applications of advanced image-guidance in cervical spine surgery and to describe the use of intraoperative neuro-navigation in surgical planning and execution. In this review, we aim to cover the following surgical techniques: anterior cervical approaches, atlanto-axial fixation, subaxial instrumentation, percutaneous interfacet cage implantation as well as minimally invasive posterior cervical foraminotomy (PCF) and unilateral laminotomy for bilateral decompression. The currently available data suggested that the use of 3D navigation significantly reduces the screw malposition, operative time, mean blood loss, radiation exposure, and complication rates in comparison to the conventional fluoroscopic-guidance. With the advancements in technology and surgical techniques, 3D navigation has potential to replace conventional fluoroscopy completely.

Minimally Invasive Posterior Cervical Foraminotomy Using 3-Dimensional Total Navigation: 2-Dimensional Operative Video.

Minimally invasive posterior cervical foraminotomy (MPCF) has shown comparable outcomes to those of an open approach, with shorter operation times and length of hospital stays, as well as decreased blood loss and inpatient analgesic use. This surgical technique is mainly used to treat unilateral radiculopathy due to foraminal soft disc fragments or bone spurs. Three-dimensional (3D) navigation-guidance facilitates the surgical workflow, and it is utilized in planning the incision, determining the extent of the medial facetectomy, and confirming sufficient decompression, especially in the lower cervical spine and cervicothoracic junction, where the shoulders make localization with fluoroscopy difficult. In this video, we present the case of a 49-yr-old male patient with mechanical neck pain and C8 radiculopathy due to multilevel cervical spinal stenosis with disc herniations and C7-T1 right-sided foraminal stenosis. There was loss of cervical lordosis at the upper levels. The patient underwent anterior cervical discectomy and fusion (ACDF) at the C4-5, C5-6, and C6-7 levels to treat mechanical neck pain and restore lordosis. In order to avoid an extra-level fusion and preserve motion, we performed a right-sided C7-T1 MPCF using a portable intraoperative computed tomography (iCT) scanner (Airo®; Brainlab AG, Feldkirchen, Germany), combined with 3D computer navigation to address the patient's radicular symptoms. Patient consent was obtained prior to performing the procedure.

Development of a Curriculum for Minimally Invasive Spine Surgery (MISS).

The purpose of this review is to describe how a curriculum for minimally invasive spine surgery (MISS) was developed and implemented. The authors discuss the curriculum roadmap, its target audience, and the educational process for teaching general skills and specific procedures in MISS. Initiated by AOSpine, a panel of experts within spinal surgery from multiple centers formed the minimally invasive spine surgery task force. Together, task force members redefined the standards and milestones of the MISS education and training. Therefore, we conclude that the MISS task force created a structured curriculum which will have a positive influence on daily practice for surgeons and patients worldwide.

Evolving Navigation, Robotics, and Augmented Reality in Minimally Invasive Spine Surgery.

Innovative technology and techniques have revolutionized minimally invasive spine surgery (MIS) within the past decade. The introduction of navigation and image-guided surgery has greatly affected spinal surgery and will continue to make surgery safer and more efficient. Eventually, it is conceivable that fluoroscopy will be completely replaced with image guidance. These advancements, among others such as robotics and virtual and augmented reality technology, will continue to drive the value of 3-dimensional navigation in MIS. In this review, we cover pertinent features of navigation in MIS and explore their evolution over time. Moreover, we aim to discuss the key features germane to surgical advancement, including technique and technology development, accuracy, overall health care costs, operating room time efficiency, and radiation exposure.

Indirect Decompression Failure After Lateral Lumbar Interbody Fusion-Reported Failures and Predictive Factors: Systematic Review.

BACKGROUND: In patients with symptomatic lumbar stenosis undergoing lateral transpsoas approach for lumbar interbody fusion (LLIF) surgery, it is not always clear when indirect decompression is sufficient in order to achieve symptom resolution. Indirect decompression failure (IDF), defined as "postoperative persistent symptoms of nerve compression with or without a second direct decompression surgery to reach adequate symptom resolution," is not widely reported. This information, however, is critical to better understand the indications, the potential, and the limitations of indirect decompression. OBJECTIVE: The purpose of this study was to systematically review the current literature on IDF after LLIF. METHODS: A literature search was performed on PubMed. We included randomized controlled trials and prospective, retrospective, case-control studies, and case reports. Information on sample size, demographics, procedure, number and location of involved levels, follow-up time, and complications were extracted. RESULTS: After applying the exclusion criteria, we included 9 of the 268 screened articles that reported failure. A total of 632 patients were screened in these articles and detailed information was provided. Average follow-up time was 21 months. Overall reported incidence of IDF was 9%. CONCLUSION: Failures of decompression via LLIF are inconsistently reported and the incidence is approximately 9%. IDF failure in LLIF may be underreported or misinterpreted as a complication. We propose to include the term "IDF" as described in this article to differentiate them from complications for future studies. A better understanding of why IDF occurs will allow surgeons to better plan surgical intervention and will avoid revision surgery.

Less Invasive Cervical Decompression via Unilateral Tubular Laminotomy Using 3-Dimensional Total Navigation: 2-Dimensional Operative Video.

This video demonstrates the step-by-step surgical technique for a less invasive cervical unilateral laminotomy for bilateral decompression (cervical ULBD). This technique allows surgeons to address bilateral cervical pathology while minimizing approach-related complications.1 In the video, we present the case of a 72-yr-old female patient with a past medical history of C3-C4 anterior cervical discectomy and fusion who presented in clinic with persistent posterior spinal cord compression and signal change. The patient had bilateral hand numbness, weakness, poor dexterity, and a positive Hoffman's sign. The patient was treated via a C3-C4 less invasive cervical ULBD using a mobile 3-dimensional (3D) C-arm (Ziehm Vision RFD 3D®, Nürnberg, Germany) combined with 3D computer navigation. Patient consent was obtained prior to performing the procedure. Contrary to anterior techniques, posterior cervical approaches avoid potential dysphasia, recurrent laryngeal nerve injury, and adjacent segment degeneration. Furthermore, the less invasive cervical ULBD results in decreased pain and postoperative narcotic usage, shorter hospital stays and fewer infections compared to open approaches, as well as a lower risk for postlaminectomy kyphosis and deformity, since it requires less muscle disruption and bony removal. Additionally, the use of total 3D navigation facilitates the workflow and minimizes radiation exposure.

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics.

The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.

A Longitudinally Extensive Spinal Cord Lesion Restricted to Gray Matter in an Adolescent Male.

Longitudinally extensive spinal cord lesions (LECL) restricted to gray matter are poorly understood as are their neurodevelopmental repercussions in children. We herein report the critical case of a 13-year-old male presenting with progressive quadriparesis found to have cervical LECL restricted to the anterior horns. Challenged with a rare diagnostic dilemma, the clinical team systematically worked through potential vascular, genetic, infectious, rheumatologic, and paraneoplastic diagnoses before assigning a working diagnosis of acute inflammatory myelopathy. Nuanced consideration of and workup for both potential ischemic causes (arterial dissection, fibrocartilaginous embolism, vascular malformation) and specific inflammatory conditions including Transverse Myelitis, Neuromyelitis Optica Spectrum Disorders (NMOSD), Multiple Sclerosis (MS), Acute Disseminated Encephalomyelitis (ADEM), and Acute Flaccid Myelitis (AFM) is explained in the context of a comprehensive systematic review of the literature on previous reports of gray matter-restricted longitudinally extensive cord lesions in children. Treatment strategy was ultimately based on additional literature review of treatment-refractory acute inflammatory neurological syndromes in children. A combination of high-dose steroids and plasmapheresis was employed with significant improvement in functional outcome, suggesting a potential benefit of combination immune-modulatory treatment in these patients. This case furthermore highlights quality clinical reasoning with respect to the elusive nature of diagnosis, nuances in neuroimaging, and multifocal treatment strategies in pediatric LECL.

Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight Associated with Atypical Antipsychotic Use.

OBJECTIVES: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use. METHODS: We studied the effects of metformin (Riomet®) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500-850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY-II) and a modified children's verbal learning task. RESULTS: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY-II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children. CONCLUSIONS: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications.

A Randomized, Placebo-Controlled Trial of Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorder: Open-Label Extension.

OBJECTIVE: A previous study reported on a 16-week placebo-controlled, randomized clinical trial (RCT) of metformin for weight stabilization in 61 children and adolescents 6 to 17 years old with autism spectrum disorder who were prescribed atypical antipsychotics. The present study describes the results of a 16-week open-label extension. METHOD: Fifty-two participants from the acute trial (85%) entered the extension; 22 had been on metformin during the initial RCT and 30 had been on placebo. Participants were re-titrated to 500 mg twice a day (6- to 9-year-olds) or 850 mg twice a day (10- to 17-year-olds) during the open-label extension. Primary outcome measure was change in body mass index (BMI) z-score after 16 weeks; secondary outcomes were change in additional body composition and metabolic parameters. RESULTS: After 16 weeks of open-label treatment, participants initially taking placebo during the RCT had lower BMI z-scores (mean 16-week change -0.10, p = .004). Statistically significant improvements also were noted in secondary body composition measures (weight z-score and BMI and weight percentile) but not in metabolic variables. Participants who initially had been taking metformin during the 16-week RCT maintained prior decreases in BMI z-scores but did not have additional weight loss. Three participants discontinued treatment because of an adverse event. No significant changes were noted on metabolic measures, although the decrease in hemoglobin A1c was large (∼1 mmol) and consistent across the acute and open-label phases. CONCLUSION: Metformin can be effective for decreasing weight gain associated with atypical antipsychotic use and maintaining prior improvement in children and adolescents with autism spectrum disorder. Clinical trial registration information-Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD); http://clinicaltrials.gov/; NCT01825798.

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.

IMPORTANCE: Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. OBJECTIVE: To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. DESIGN, SETTING, AND PARTICIPANTS: A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS: Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. RESULTS: Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). CONCLUSIONS AND RELEVANCE: Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01825798.

Kindergarten classroom functioning of extremely preterm/extremely low birth weight children.

BACKGROUND: Cognitive, behavioral, and learning problems are evident in extremely preterm/extremely low birth weight (EPT/ELBW, <28 weeks gestational age or <1000 g) children by early school age. However, we know little about how they function within the classroom once they start school. AIMS: To determine how EPT/ELBW children function in kindergarten classrooms compared to termborn normal birth weight (NBW) classmates and identify factors related to difficulties in classroom functioning. METHODS: A 2001-2003 birth cohort of 111 EPT/ELBW children and 110 NBW classmate controls were observed in regular kindergarten classrooms during a 1-hour instructional period using a time-sample method. The groups were compared on frequencies of individual teacher attention, competing or offtask behaviors, task management/preparation, and academic responding. Regression analysis was also conducted within the EPT/ELBW group to examine associations of these measures with neonatal and developmental risk factors, kindergarten neuropsychological and behavioral assessments, and classroom characteristics. RESULTS: The EPT/ELBW group received more individual teacher attention and was more often off-task than the NBW controls. Poorer classroom functioning in the EPT/ELBW group was associated with higher neonatal and developmental risk, poorer executive function skills, more negative teaching ratings of behavior and learning progress, and classroom characteristics. CONCLUSION: EPT/ELBW children require more teacher support and are less able to engage in instructional activities than their NBW classmates. Associations of classroom functioning with developmental history and cognitive and behavioral traits suggest that these factors may be useful in identifying the children most in need of special educational interventions.

TOX3 mutations in breast cancer.

TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs) in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe) was identified in one tumour (genomic DNA and cDNA). Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.