Mahmoud Abdel-Rasoul

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab

BACKGROUND Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Zinc for Attention-Deficit/Hyperactivity Disorder: Placebo-Controlled Double-Blind Pilot Trial Alone and Combined with Amphetamine

OBJECTIVE To explore effects of zinc supplementation in American children with attention-deficit/hyperactivity disorder (ADHD). Mideastern trials reported significant benefit from 13-40 mg elemental zinc as the sulfate. METHOD We randomly assigned 52 children aged 6-14 with DSM-IV ADHD to zinc supplementation (15 mg every morning [qAM] or two times per day [b.i.d.] as glycinate, n = 28) or matched placebo (n = 24) for 13 weeks: 8 weeks monotherapy and then 5 weeks with added d-amphetamine (AMPH). AMPH dose was weight-standardized for 2 weeks and then clinically optimized by week 13. Zinc glycinate was chosen as having less gastrointestinal discomfort than sulfate. Hypotheses were that zinc would improve inattention more than placebo by effect size of d > 0.25 at 8 weeks; zinc+AMPH would improve ADHD symptoms more than placebo+AMPH by d > 0.25, and optimal dose of AMPH with zinc would be 20% lower than with placebo. An interim analysis requested by the National Institute of Mental Health resulted in an increased dosage, so that 20 received 15 mg/day qAM and 8 received 30 mg/day (15 mg b.i.d.) RESULTS Only the third hypothesis was upheld: Optimal mg/kg AMPH dose with b.i.d. zinc was 37% lower than with placebo. Other clinical outcomes were equivocal, sometimes favoring zinc, sometimes placebo, but objective neuropsychological measures mostly favored b.i.d. zinc (d = 0.36-0.7). Safety tests and adverse events were not different between groups. Copper and iron blood indices were not impaired by 8 weeks of 30 mg/day zinc. CONCLUSION Doses up to 30 mg/day of zinc were safe for at least 8 weeks, but clinical effect was equivocal except for 37% reduction in amphetamine optimal dose with 30 mg/day zinc (not with 15 mg). Possible reasons for difference from mideastern reports include endemic diets, population genetics, relative rate of zinc deficiency, difference in background nutrition, insufficient dosage or absorption, or wrong anion (sulfate may be necessary for reported benefit). Dose may be especially important: All visually impressive advantages over placebo appeared only with 15 mg b.i.d. rather than once a day. Future research should use larger doses than 15 mg/day, provide a basic recommended daily allowance/intake multivitamin/mineral supplement for all to standardize background nutrition, select participants for low zinc, and consider the issue of anion interaction.

Anatomic and pharmacokinetic properties of intravitreal bevacizumab and ranibizumab after vitrectomy and lensectomy.

Purpose: To determine the anatomic characteristics and pharmacokinetic properties of intravitreally placed bevacizumab and ranibizumab after pars plana lensectomy or pars plana vitrectomy and to compare these with nonoperated control eyes in a rabbit model. Methods: Three groups of six Dutch-belted rabbits each underwent pars plana vitrectomy, pars plana lensectomy, or served as nonsurgical controls. Twelve days after surgery, 3 rabbits from each group underwent intravitreal injection in one eye with 1.25 mg/0.05 mL I-124-bevacizumab or 0.5 mg/0.05 mL I-124-ranibizumab. Serial imaging with integrated positron emission and computed tomography (PET/CT) were obtained on Days 0, 2, 5, 7, 14, 21, 28, and 35. Measured radioactivity emission in becquerels/milliliter was used to calculate the half-lives for each agent. Results: The intravitreally placed radiolabeled agents were contained within the vitreous cavity for the duration of the study. The average clearance half-lives with standard error for bevacizumab and ranibizumab after correction for radioactive decay were, respectively, 4.22 ± 0.07 days and 2.81 ± 0.05 days in unoperated eyes, 2.30 ± 0.09 days (P < 0.0001) and 2.13 ± 0.05 days (P < 0.0001) after vitrectomy, and 2.08 ± 0.07 days (P = 0.0001) and 1.79 ± 0.05 days (P < 0.0001) after lensectomy. Conclusion: Intravitreal retention was longer for bevacizumab than ranibizumab within all study groups and was significantly reduced after vitrectomy and lensectomy for both agents. Consideration for more frequent intravitreal anti–vascular endothelial growth factor dosing regimens may be made for patients whose treated eyes have undergone previous vitrectomy or who are aphakic.

Indirubins Decrease Glioma Invasion by Blocking Migratory Phenotypes in Both the Tumor and Stromal Endothelial Cell Compartments

Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that β-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in glioma-bearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer.

Virtual temporal bone dissection system: OSU virtual temporal bone system: development and testing.

The objective of this project was to develop a virtual temporal bone dissection system that would provide an enhanced educational experience for the training of otologic surgeons.

Neoadjuvant Dual HER2-Targeted Therapy With Lapatinib and Trastuzumab Improves Pathologic Complete Response in Patients With Early Stage HER2-Positive Breast Cancer: A Meta-Analysis of Randomized Prospective Clinical Trials

BACKGROUND Randomized clinical trials (RCT) that evaluated the addition of lapatinib to trastuzumab plus neoadjuvant chemotherapy (NAC) in patients with HER2-positive, operable breast cancer revealed a questionable improvement in pathologic complete response (pCR) rate. We performed a meta-analysis of prospective RCTs that examined the effect of adding lapatinib to trastuzumab and NAC on pCR rate. METHODS PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs that compared lapatinib plus trastuzumab and NAC with trastuzumab in combination with NAC and that included pCR as the primary outcome. Our main objective was to estimate the effect of adding lapatinib to trastuzumab plus NAC on pCR rate, defined as no residual invasive cancer in breast and axillary lymph nodes. RESULTS In total, 1,017 patients with early stage breast cancer from 5 trials were included. Four trials examined the addition of lapatinib to trastuzumab plus NAC; this resulted in statistically significant improvement in pCR, defined as no residual carcinoma in breast and lymph nodes. The pCR rate was 55.76% and 38.36% in the lapatinib plus trastuzumab and the trastuzumab plus NAC arms, respectively (odds ratio [OR]: 1.94; 95% confidence interval [CI]: 1.44-2.60). In three trials, the rates of pCR, defined as no residual invasive carcinoma in breast only, for the lapatinib plus trastuzumab and trastuzumab-alone groups were 55.01% and 40.70%, respectively, also resulting in significant improvement (OR: 1.78; 95% CI: 1.27-2.50). CONCLUSION The addition of lapatinib to trastuzumab in combination with neoadjuvant chemotherapy significantly improves pCR rates in patients with HER2-positive breast cancer.

Clinical and economic outcomes of low-field intraoperative MRI-guided tumor resection neurosurgery

To compare low‐field (0.15 T) intraoperative magnetic resonance imaging (iMRI)‐guided tumor resection with both conventional magnetic resonance imaging (cMRI)‐guided tumor resection and high‐field (1.5 T) iMRI‐guided resection from the clinical and economic point of view.

Sexual Function After Intracavitary Vaginal Brachytherapy for Early-Stage Endometrial Carcinoma

Objective To describe the effects of intracavitary brachytherapy (IVB) on sexual function and quality of life of women with early-stage endometrial cancer. Methods Women with International Federation of Gynecology and Obstetrics stage I to stage II endometrial cancer treated surgically with or without IVB were identified and mailed questionnaires. Quality of life and sexual function were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the cervical cancer disease-specific module. Pertinent data from prior surgery and radiation treatments were abstracted retrospectively. Linear transformation of the survey subscale scores was conducted per European Organization for Research and Treatment of Cancer guidelines. Results Sixteen women in the IVB arm and 53 in the surgery-alone group completed the survey. Of the sexually active patients, 33% of the IVB patients and 42% of the surgery-alone patients felt their vagina was dry during sexual activity (P = 0.804) and 17% versus 20% felt their vagina was short (P = 0.884). Seventeen percent of patients in the IVB group felt their vagina was tight compared to 29% in the surgery-alone group (P = 0.891) and 0% versus 14% of patients reported pain during intercourse (P = 0.808). There was no statistically significant difference in sexual/vaginal functioning, sexual worry, or sexual enjoyment between the 2 groups. Conclusions Although both groups report vaginal changes that may affect sexual function, the patients treated with IVB reported similar outcomes on a sexual function questionnaire compared to patients treated with surgery alone.

Smokeless Tobacco Marketing and Sales Practices in Appalachian Ohio Following Federal Regulations

INTRODUCTION Smokeless tobacco (ST) use is increasingly prevalent among poor and vulnerable groups, especially rural males. Access to tobacco products, as well as marketing messages, is associated with tobacco usage. In June 2010, the Tobacco Control Act (TCA) marked the beginning of federal regulation of the sale and marketing of tobacco products--including ST. The goal of this study was to describe marketing practices over time and to provide early assessment of the federal regulation in rural tobacco-licensed retail outlets. METHODS Observational data were collected from a sample of retail outlets within three Ohio Appalachian counties. From an estimated 300 retail establishments, a stratified random sample was drawn (n = 86). Trained observers surveyed the sales and marketing of tobacco products. Baseline surveys were conducted between November 2009 and May 2010 before the TCA; follow-up surveys were repeated in August 2010. RESULTS Follow-up surveys were completed for 79 tobacco-licensed retail outlets. The majority of retail outlets were gas stations or convenience stores. Compared with baseline, there was a significant reduction in the frequency of exterior and interior advertisements observed after the TCA (p < .01). Despite the lack of change in the proportion of stores advertising ST, the number of ST brands being advertised doubled between baseline and follow-up. CONCLUSION Initial compliance with certain elements of the federal restrictions appears to be high in Appalachian Ohio. The significant increase in ST brands advertised suggests that advertising remains a clear presence in retail outlets in Appalachian Ohio.

Molecular Signaling and Dysfunction of the Human Reactive Enteric Glial Cell Phenotype: Implications for GI Infection, IBD, POI, Neurological, Motility, and GI Disorders.

Background:Clinical observations or animal studies implicate enteric glial cells in motility disorders, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal (GI) infections, postoperative ileus, and slow transit constipation. Mechanisms underlying glial responses to inflammation in human GI tract are not understood. Our goal was to identify the “reactive human enteric glial cell (rhEGC) phenotype” induced by inflammation, and probe its functional relevance. Methods:Human enteric glial cells in culture from 15 GI-surgical specimens were used to study gene expression, Ca2+, and purinergic signaling by Ca2+/fluo-4 imaging and mechanosensitivity. A nanostring panel of 107 genes was designed as a read out of inflammation, transcription, purinergic signaling, vesicular transport protein, channel, antioxidant, and other pathways. A 24-hour treatment with lipopolysaccharide (200 &mgr;g/mL) and interferon-&ggr; (10 &mgr;g/mL) was used to induce inflammation and study molecular signaling, flow-dependent Ca2+ responses from 3 mL/min to 10 mL/min, adenosine triphosphate (ATP) release, and ATP responses. Results:Treatment induced a “rhEGC phenotype” and caused up-regulation in messenger RNA transcripts of 58% of 107 genes analyzed. Regulated genes included inflammatory genes (54%/IP10; IFN-&ggr;; CxCl2; CCL3; CCL2; C3; s100B; IL-1&bgr;; IL-2R; TNF-&agr;; IL-4; IL-6; IL-8; IL-10; IL-12A; IL-17A; IL-22; and IL-33), purine-genes (52%/AdoR2A; AdoR2B; P2RY1; P2RY2; P2RY6; P2RX3; P2RX7; AMPD3; ENTPD2; ENTPD3; and NADSYN1), channels (40%/Panx1; CHRNA7; TRPV1; and TRPA1), vesicular transporters (SYT1, SYT2, SNAP25, and SYP), transcription factors (relA/relB, SOCS3, STAT3, GATA_3, and FOXP3), growth factors (IGFBP5 and GMCSF), antioxidant genes (SOD2 and HMOX1), and enzymes (NOS2; TPH2; and CASP3) (P < 0.0001). Treatment disrupted Ca2+ signaling, ATP, and mechanical/flow-dependent Ca2+ responses in human enteric glial cells. ATP release increased 5-fold and s100B decreased 33%. Conclusions:The “rhEGC phenotype” is identified by a complex cascade of pro-inflammatory pathways leading to alterations of important molecular and functional signaling pathways (Ca2+, purinergic, and mechanosensory) that could disrupt GI motility. Inflammation induced a “purinergic switch” from ATP to adenosine diphosphate/adenosine/uridine triphosphate signaling. Findings have implications for GI infection, inflammatory bowel disease, postoperative ileus, motility, and GI disorders.