Breast cancer in a female to male transgender patient 20 years post-mastectomy: Issues to consider.

The incidence of breast cancer reduces by almost 90% after bilateral mastectomy. This applies also to female-to-male (FtM) trans-gender who undergo bilateral mastectomy as part of gender reassignment surgery (GRS). To date, there are only four reported cases in the literature on FtM transgender breast cancer. We present a case of a female-to-male transgender patient who was diagnosed with breast cancer 20 years after having bilateral mastectomy performed as part of GRS. We will describe all similar cases from literature and discuss some important issues related to transgender breast cancer.

Essential role of Cdc42 in cardiomyocyte proliferation and cell-cell adhesion during heart development.

Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cell migration, proliferation, differentiation and survival. However, the role of Cdc42 in heart development remains largely unknown. To determine the function of Cdc42 in heart formation, we have generated a Cdc42 cardiomyocyte knockout (CCKO) mouse line by crossing Cdc42 flox mice with myosin light chain (MLC) 2a-Cre mice. The inactivation of Cdc42 in embryonic cardiomyocytes induced lethality after embryonic day 12.5. Histological analysis of CCKO embryos showed cardiac developmental defects that included thin ventricular walls and ventricular septum defects. Microarray and real-time PCR data also revealed that the expression level of p21 was significantly increased and cyclin B1 was dramatically decreased, suggesting that Cdc42 is required for cardiomyocyte proliferation. Phosphorylated Histone H3 staining confirmed that the inactivation of Cdc42 inhibited cardiomyocytes proliferation. In addition, transmission electron microscope studies showed disorganized sarcomere structure and disruption of cell-cell contact among cardiomyocytes in CCKO hearts. Accordingly, we found that the distribution of N-cadherin/ß-Catenin in CCKO cardiomyocytes was impaired. Taken together, our data indicate that Cdc42 is essential for cardiomyocyte proliferation, sarcomere organization and cell-cell adhesion during heart development.

Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy.

OBJECTIVES: An intravenous (IV) formulation of brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, has been developed. We investigated the safety, tolerability, and pharmacokinetics of adjunctive IV BRV administered as a bolus or infusion to adults with epilepsy. METHODS: A phase III, multicenter, randomized, four-arm, parallel-group study (NCT01405508) of patients aged 16-70 years with focal or generalized epilepsy uncontrolled by 1-2 antiepileptic drugs was undertaken. The study comprised a 7-day baseline period, a 7-day double-blind run-in period (oral BRV 200 mg/day or placebo [PBO] twice daily [BID]), and 4.5-day open-label evaluation period (IV BRV 200 mg/day BID; 2-min bolus or 15-min infusion, total nine doses). Patients were randomized 1:1:1:1 PBO/BRV bolus; PBO/BRV infusion; BRV/BRV bolus; BRV/BRV infusion. Safety and tolerability were assessed using adverse events, electrocardiography, vital signs, and laboratory assessments. BRV plasma concentrations were measured before and 15 min after the first and last IV doses. RESULTS: Of the 105 patients randomized (53.3% women; 77.1% white; mean [standard deviation; SD] age 41.6 [12.2] years), 103 (98.1%) completed the study. Treatment-emergent adverse event (TEAE) incidence during IV BRV was similar whether IV BRV was initiated first (70.6%) or followed oral BRV (66.0%), and whether it was administered as a bolus (71.2%) or infusion (65.4%). Injection-related TEAEs were reported by 9.6% of patients following bolus and 11.5% following infusion. No serious TEAEs were reported. IV BRV plasma concentrations were higher after the first dose in the conversion groups than initiation groups, and slightly higher in the bolus arm than the infusion arm; concentrations were similar in all patients after the last IV dose. SIGNIFICANCE: IV BRV was generally well tolerated, with similar tolerability as a bolus or infusion and independent of de novo administration or as conversion from oral BRV tablets. IV BRV may be an option for patients who are unable to receive oral BRV.

Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial.

PURPOSE: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16-70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. METHODS: This was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up-titration for 12 weeks, followed by down-titration or entry into a long-term follow-up study. The primary efficacy end point was percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment-emergent adverse events (TEAEs). KEY FINDINGS: Of 399 randomized patients, 398 were included in the intent-to-treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long-term follow-up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue. SIGNIFICANCE: In this study of adjunctive BRV (20-100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20-100 mg/day was well tolerated without up-titration, with a high completion rate.

Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial.

PURPOSE: To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. METHODS: This was a phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT00504881) in adults (16-70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16 weeks). KEY FINDINGS: A total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV- and 91.7% PBO-treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV- and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. SIGNIFICANCE: Adjunctive BRV given at individualized tailored doses (20-150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.

Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial.

PURPOSE: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial-onset (focal) seizures. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial (N01253; NCT00464269). Adults aged 16-70 years with well-characterized partial epilepsy not fully controlled despite treatment with one or two antiepileptic drugs (AEDs) were enrolled. Patients who experienced eight or more partial-onset seizures, whether or not secondarily generalized, during the 8-week prospective baseline period were randomized (1:1:1:1) to receive twice-daily placebo (PBO) or BRV (5, 20, or 50 mg/day) without titration. The primary efficacy endpoint was percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/week during the 12-week treatment period. Comparison of BRV with PBO was sequential (50, 20 mg/day, then 5 mg/day). Secondary endpoints included ≥50% responder rate and median percent reduction from baseline in partial-onset seizure frequency/week. Post hoc analyses included the primary efficacy endpoint evaluated over 28 days and exploratory subanalyses of efficacy by seizure subtype. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory tests, electrocardiography, vital signs, and physical and neurologic examinations. KEY FINDINGS: Of 400 patients randomized, 396 were included in the intent-to-treat (ITT) population (PBO n = 98, BRV 5 mg/day n = 97, BRV 20 mg/day n = 100, BRV 50 mg/day n = 101) and 392 comprised the modified ITT (mITT) population. A total of 361 (91.2%) of 396 patients completed the study. Most patients (78.3%) were receiving two concomitant AEDs. Percent reduction in partial-onset seizure frequency/week over PBO was -0.9% (p = 0.885) for BRV 5 mg/day, 4.1% (p = 0.492) for BRV 20 mg/day, and 12.8% (p = 0.025) for BRV 50 mg/day (mITT population). Statistical significance was also achieved for the percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/28 days for BRV 50 mg/day (22.0%; p = 0.004) but not for the other BRV dose groups. In the BRV 50 mg/day group, statistical significance was also seen for the ≥50% responder rate (BRV 32.7% vs. PBO 16.7%; p = 0.008) and median percent reduction from baseline in partial-onset seizure frequency/week (BRV 30.5% vs. PBO 17.8%; p = 0.003). In the exploratory subanalysis by seizure subtype, median percent reduction from baseline in seizure frequency/week and ≥50% responder rate were numerically greater than PBO in the BRV 20 and 50 mg/day groups for simple partial, complex partial, and secondarily generalized seizures. BRV was generally well tolerated, with the majority of TEAEs being mild-to-moderate in intensity. Of the TEAEs reported by ≥5% patients, those with a frequency >3% higher than PBO for any dose of BRV compared with PBO were somnolence, dizziness, fatigue, influenza, insomnia, nasopharyngitis, vomiting, diarrhea, urinary tract infection, and nausea. SIGNIFICANCE: Adjunctive BRV at a daily dose of 50 mg was associated with statistically significant reductions in seizure frequency compared with PBO. All doses of BRV showed good tolerability throughout the study.

Machine learning used to determine features of importance linked to overnight stay after patellar tendon repair.

Purpose: The purpose of this study is to determine if machine learning is an effective method to identify features of patients who may need a longer postoperative stay following a patellar tendon repair. Methods: The American College of Surgeons National Quality Improvement Program (ACS-NSQIP) was used to collect 1173 patients who underwent patellar tendon repair. Machine learning (ML) was then applied to determine features of importance in this patient population. Several algorithms were used: Random Forest, Artificial Neural Network, Gradient Boosting, and Support Vector Machine. These were then compared to the American Society of Anesthesiologists (ASA) classification system based logistic regression as a control. Results: Random Forest (RF) was determined to be the best performing algorithm, with an AUC of 0.72, accuracy of 77.66 %, and precision of 0.79, and recall of 0.96. All other algorithms performed similarly to the control. RF gave the highest permutation feature importance to age (PFI 0.25), BMI (PFI 0.19), ASA classification (PFI 0.14), hematocrit (PFI 0.12), and height (PFI 0.11). Conclusions: This study shows that machine learning can be used as a tool to identify features of importance for length of postoperative stay in patients undergoing patellar tendon repair. RF was found to be a better performing model than logistic regression at determining patients predisposed to longer length of stay as determined by AUC. This supported the study's hypothesis that ML can provide an effective method for identifying features of importance in patients requiring a longer postoperative stay after patellar tendon repair.

A Systematic Review of the Usage of Lidocaine in Hip Replacement Surgery.

Hip replacement procedures, professionally known as hip arthroplasty, are one of the most common orthopedic procedures. Due to the variation in this procedure, the use and types of anesthetics differ. One such commonly used anesthetic is lidocaine. Since there are currently no standardized or general procedures for the application of lidocaine for perioperative hip arthroplasty procedures, this review aims to delve into this topic. A literature review surrounding the key terms "hip replacement" and "lidocaine" was performed on PubMed. After reviewing 24 randomized control trials, statistical analyses between groups that had no lidocaine versus groups that did were performed. The results showed that there was no statistical significance between various age groups and the use of lidocaine. One percent (1%) and 2% injected into the lumbar region were the most commonly reported doses of lidocaine, with 2% often being the first test dose. Other conclusions were that lidocaine was used for general anesthesia for individuals that underwent hip arthroplasty due to an underlying condition (cauda equina syndrome, ankylosing spondylitis, etc.). Lidocaine was also used for postoperative pain relief, which is a potential concern from its addictive qualities. This investigation outlines the current stance and usage of lidocaine in perioperative hip arthroplasty while noting its limitations.

An overview of benvitimod for the treatment of psoriasis: a narrative review.

INTRODUCTION: The most frequently prescribed first-line treatment for limited (mild-to-moderate) psoriasis is topical corticosteroids, which are associated with several adverse effects with long term use. Benvitimod is an aryl hydrocarbon receptor immunomodulator that is both efficacious and tolerable for use in patients with mild to severe psoriasis with a body surface area (BSA) range of 1-20%. AREAS COVERED: In this review, the authors conducted a PubMed and Google Scholar search of key words and a review of clinical trials. They discuss the targeted mechanism of action for psoriasis, efficacy and safety profile of topical benvitimod, and its indications. Benvitimod affects key regulators of psoriasis, including proinflammatory markers and skin barrier proteins. Benvitimod is well-tolerated in patients with mild to severe plaque psoriasis. Treatment-emergent adverse events (TEAEs) include pruritus, contact dermatitis, and folliculitis; however, the majority of TEAEs were mild to moderate in severity, and most resolved without further treatment. A limitation of this study includes a small number of trials due to the dr' novelty. EXPERT OPINION: Benvitimod may serve as a good alternative for psoriatic patients who desire a nonsteroidal topical option. The usefulness of benvitimod may be limited by prior authorizations that discourage healthcare providers from prescribing the medication and poor outcomes.

Sex determination of mummies through multi-elemental analysis of head hair using electrothermal vaporization coupled to inductively coupled plasma optical emission spectrometry.

Sex determination of human remains is of great archaeological significance, as it provides a more complete picture of social and familial structures within ancient societies. Typically performed through examination of bones in the pelvic region, accurate sex determination can be exceedingly challenging in the absence of a sufficiently preserved skeleton. Here, a method for sex determination in living humans, involving measurement of magnesium, strontium, sulfur, and zinc in head hair along with multivariate statistics, was applied for the first time to hair collected from 500 year-old mummies originating from Peru. Hair samples were washed in doubly deionized water, dried, and ground prior to analysis via electrothermal vaporization coupled to inductively coupled plasma optical emission spectrometry; only 2 mg of hair is required for analysis. Point-by-point internal standardization was performed with Ar i 430.010 nm to compensate for sample loading effects on the plasma. Peak areas were integrated and mass corrected before being used in combination with multivariate analysis. Although principal component analysis provided insufficient separation between the sexes, linear discriminant analysis (LDA) was highly effective for sex determination. Using mummy hair as the LDA model enabled accurate sex prediction of the mummies, showing that, despite the age of the hair, the samples still contain the necessary elemental information for sex determination. For accurate sex determination of mummies using hair collected from living humans, magnesium had to be replaced by sodium due to significant differences in dietary habits. With this simple modification, hair from living humans in North America could be used to successfully predict the sex of individuals who lived more than 500 years ago in Peru. This work paves the way for broader use of non-skeletal sex determination methods within the field of archaeology, filling a significant gap.

Viral Burden and Clearance in Asymptomatic COVID-19 Patients.

Background: Containing coronavirus disease 2019 (COVID-19) has been difficult, due to both the large number of asymptomatic infected individuals and the long duration of infection. Managing these challenges requires understanding of the differences between asymptomatic vs symptomatic patients and those with a longer duration of infectivity. Methods: Individuals from Los Angeles were tested for COVID-19, and a group positive for COVID-19 chose to have follow-up testing. Associations between symptoms and demographic factors, viral burden measured by cycle threshold (CT) value, and duration of polymerase chain reaction (PCR) positivity were analyzed. Results: Eighteen point eight percent of patients were positive for COVID-19. Asymptomatic COVID-19-positive patients were significantly younger than symptomatic patients (2.6 years; P < .001). There were no differences in average CT between asymptomatic and symptomatic patients. The estimated median duration of COVID-19 PCR positivity was 23 days. Being asymptomatic throughout the course of infection was the only factor associated with a shorter course of COVID-19 PCR positivity (21 vs 28 days; P = .002). Conclusions: We found important differences and similarities between asymptomatic and symptomatic COVID-19-positive patients, the most meaningful being a similar level of virus as measured by PCR, but a shorter duration of PCR positivity for asymptomatic patients. These findings suggest that asymptomatic patients may have more efficient clearance of virus, which may be relevant for management and screening.

Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers.

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.

Understanding the Psychosocial Needs of Women who Present with Advanced Breast Cancer.

INTRODUCTION: Advanced breast cancer (ABC) remains common in Singapore. In 2019, 22.1% of breast cancer patients presented with ABC in our institution. Despite increasing affluence and the advent of national mammographic screening, the incidence of ABC has not changed significantly. This suggests inherent differences in women who present late. We aim to explore the socio-economic background, knowledge and attitudes of women who present with ABC. METHODS: Between December 2013 and July 2015, 100 patients who presented consecutively with ABC in a tertiary institution in Singapore were recruited to participate in an interviewer-led questionnaire exploring psychosocial and economic issues. RESULTS: Among the 100 patients, 63 and 37 presented with stages 3 and 4 breast cancer respectively. Median age was 57 (27-86), 52% had at least secondary education, 53% had no formal employment and 71% were married; 88% were aware of breast cancer symptoms, 82% were aware that mammography can help detect cancer, 82% believed that current treatment modality for breast cancer is effective, 96% had never undergone a mammography and 52.9% felt mammograms were unnecessary. A total of 64% presented symptomatic from the breast tumour, with a median duration of 3 months. Many of the patients were aware of breast cancer symptoms and the utility of mammography. However, a group of patients did not comply with screening. This may be due to poor understanding about breast screening and detection in its asymptomatic phase. CONCLUSION: Further public education to improve understanding of breast cancer and screening mammography may help to improve rates for earlier detection of breast cancer.

Prkaa1 Metabolically Regulates Monocyte/Macrophage Recruitment and Viability in Diet-Induced Murine Metabolic Disorders.

Myeloid cells, including monocytes/macrophages, primarily rely on glucose and lipid metabolism to provide the energy and metabolites needed for their functions and survival. AMP-activated protein kinase (AMPK, its gene is PRKA for human, Prka for rodent) is a key metabolic sensor that regulates many metabolic pathways. We studied recruitment and viability of Prkaa1-deficient myeloid cells in mice and the phenotype of these mice in the context of cardio-metabolic diseases. We found that the deficiency of Prkaa1 in myeloid cells downregulated genes for glucose and lipid metabolism, compromised glucose and lipid metabolism of macrophages, and suppressed their recruitment to adipose, liver and arterial vessel walls. The viability of macrophages in the above tissues/organs was also decreased. These cellular alterations resulted in decreases in body weight, insulin resistance, and lipid accumulation in liver of mice fed with a high fat diet, and reduced the size of atherosclerotic lesions of mice fed with a Western diet. Our results indicate that AMPKα1/PRKAA1-regulated metabolism supports monocyte recruitment and macrophage viability, contributing to the development of diet-induced metabolic disorders including diabetes and atherosclerosis.

Majority of flat epithelial atypia diagnosed on biopsy do not require surgical excision.

BACKGROUND: Borderline risk lesions such as flat epithelial atypia (FEA) are increasingly being diagnosed on biopsy. The need for surgery is being debated. In this study, we determined the frequency of histological upgrade following a diagnosis of FEA on biopsy and evaluated potential predictive factors. METHODS: Retrospective review was done of 194 women who underwent biopsy of indeterminate lesions (total 195 lesions) that were diagnosed as FEA. The review covered a 10-year period. Cases where malignancy was also present together with FEA within the same biopsy cores were excluded. RESULTS: Lesions diagnosed as FEA on biopsy were mostly asymptomatic and presented as microcalcifications on mammogram. Flat epithelial atypia was the only abnormality detected in one-third of cases, was associated with a benign or another borderline lesion in another third and was associated with atypical ductal hyperplasia (ADH) in another third. Six patients (3.1%) were later found to have ductal carcinoma-in-situ (DCIS) at surgery. The presence of ADH in the biopsy was the only predictor of histological upgrade to malignancy (P = 0.04, OR 11.24, 95% CI 1.10 - 115.10), and was present in 5 of the 6 patients. Surgery was advised in the last patient because of radiology-pathology discordance. Thirty-six lesions (18.5%) were not excised and no interval progression or malignancy was found on follow up. CONCLUSION: Histological upgrade to malignancy was uncommon in lesions found on biopsy to be FEA. Non-operative management of biopsy-proven FEA can be considered in the absence of ADH and radiology-pathology discordance.

Efficacy and safety of levetiracetam as adjunctive treatment of refractory partial seizures in a multicentre open-label single-arm trial in Korean patients.

This prospective, open-label study evaluated the efficacy and safety of adjunctive levetiracetam (LEV) in Korean adults with uncontrolled partial epilepsy. Study patients had to have an average of at least 1 and not more than 14 partial seizures per month (averaged over a 3-month historical baseline) despite the use of one or two AEDs. Patients initially received LEV 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of LEV could be increased or decreased once if seizure control was insufficient or tolerability warranted, respectively. Seizure count and adverse events (AEs) were recorded by patients. Global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated. A total of 100 patients were enrolled and 92 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 43.2%. The >or=50% and >or=75% responder rates were 45.4% and 36.1%, respectively. Seizure freedom throughout the 16-week treatment period was observed in 17 patients. On investigator's GES, 81 patients were considered improved, with 41 patients showing marked improvement. Most QOLIE-31 scales improved significantly. Treatment-emergent AEs were reported in 59 patients. Three most common AEs were somnolence (36%), dizziness (12%), and headache (8%). Adjunctive LEV therapy was effective and well-tolerated in Korean adults with refractory partial epilepsy.

Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis.

Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specific Adora2a deletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice. In human primary retinal microvascular endothelial cells, hypoxia induces the expression of ADORA2A by activating HIF-2α. ADORA2A knockdown decreases hypoxia-induced glycolytic enzyme expression, glycolytic flux, and endothelial cell proliferation, sprouting and tubule formation. Mechanistically, ADORA2A activation promotes the transcriptional induction of glycolytic enzymes via ERK- and Akt-dependent translational activation of HIF-1α protein. Taken together, these findings advance translation of ADORA2A as a therapeutic target in the treatment of proliferative retinopathies and other diseases dependent on pathological angiogenesis.Pathological angiogenesis in the retina is a major cause of blindness. Here the authors show that adenosine receptor A2A drives pathological angiogenesis in the oxygen-induced retinopathy mouse model by promoting glycolysis in endothelial cells via the ERK/Akt/HIF-1α pathway, thereby suggesting new therapeutic targets for disease treatment.

Levetiracetam extended release for the treatment of patients with partial-onset seizures: A long-term, open-label follow-up study.

This was an open-label study (N01281 [NCT00419393]) assessing the long-term safety of extended-release levetiracetam (LEV XR) in patients with partial-onset seizures (POS); the study was a follow-up to a double-blind, randomized, historical controlled, multicenter, conversion to monotherapy study (N01280 [NCT00419094]). Eligible patients initially received LEV XR 2000 mg/day; dose adjustments and the addition of other antiepileptic drugs (AEDs) were permitted. Overall, 190 patients were enrolled, 189 (99.5%) received LEV XR (safety and efficacy populations) and 166 patients (87.4%) completed the study. The study duration in completed patients was 5.5-24.6 months. Mean daily dose of LEV XR was 2131 mg/day. Treatment-emergent adverse events (TEAEs) occurred in 126 patients (66.7%); most were of mild or moderate severity. Five patients (2.6%) had a TEAE that led to treatment discontinuation. Treatment-emergent serious adverse events occurred in 22 patients (11.6%). Twenty-six patients (13.8%) experienced a psychiatric TEAE. The median 7-day normalized POS frequency was: 1.38 at N01280 study baseline; 0.50 at the first visit of N01281 (last visit of N01280); and 0.00-0.36 between all subsequent visits. Overall, 171 patients (90.5%) entered the N01281 study on LEV XR monotherapy; 65.3% (32/49) of patients remained on monotherapy for 12 months and 47.1% (8/17) for 18 months. While remaining on LEV XR monotherapy, 27/139 patients (19.4%) were seizure-free at 6 months and 8/49 (16.3%) at 12 months. In conclusion, LEV XR was well tolerated when administered as long-term monotherapy or in combination with other AEDs in patients with inadequately controlled POS.

Mastectomy rates remain high in Singapore and are not associated with poorer survival after adjusting for age.

Recent reports have suggested that women undergoing mastectomy, instead of wide local excision (WLE) for Stage I and II breast cancers have poorer overall survival. This is particularly important in our setting where mastectomy rates are high. In this study, we evaluated the trends in mastectomy and WLE over a 10-year period at a single institute, identified factors more common among women who underwent mastectomy and specifically examined the effect of surgery on outcome. Retrospective review was performed of 2244 women who underwent curative surgery for non-metastatic breast cancer at our institute from 1st January 2001 to 31st December 2010. Mastectomy rates remained high over the 10 years, ranging from 43 to 59 %. Older women, those with symptoms, larger tumours and clinical nodal involvement were more likely to receive mastectomy (P < 0.05). The type of surgery (mastectomy or WLE) did not affect survival in women with ductal carcinoma-in situ, while women with invasive cancer appeared to survive longer when treated with WLE (P < 0.01). Surgery type was not an independent predictor of overall survival and the survival advantage with WLE did not remain after adjusting for age, implying that the effect on survival had been confounded by the fact that older women tended to undergo mastectomy. Mastectomy remains common among our local women, with further studies being needed to evaluate factors involved in decision-making. Older women and those with significant co-morbidities were more likely to undergo mastectomy and this contributed to an apparent survival advantage following WLE.

Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India.

This article describes regulatory approaches for approval of "generic" orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the "original" product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as "generic" and "reference" drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.