Jian Ying

Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic disorder affecting social behavior:

The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ∼28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior.

Metabolic complications with the use of mTOR inhibitors for cancer therapy.

BACKGROUND mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized. METHODS PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated. FINDINGS Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. INTERPRETATION The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.

Metabolic complications with the use of mTOR inhibitors for cancer therapy: A systematic review and meta-analysis.

398 Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). The risk of metabolic complications with these agents is not well characterized. METHODS PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. 16 eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia were extracted. Incidence rates and incident rate ratios were calculated. RESULTS In total, 24 trials (including 4,261 patients) were included. The average incidence rate of any grade metabolic adverse events and grade 3-4 metabolic adverse events was 0.70 per patient and 0.11 (95% CI, 0.08, 0.15) per patient respectively. Analysis of the 3,317 patients across 8 RCTs revealed that the log incidence rate ratio (IRR) of any grade metabolic adverse events with mTOR inhibitor therapy compared with control was 1.08 (95% CI, 0.84, 1.31) using a random-effects model. The risk of grade 3-4 adverse events was also increased with an IRR of 1.52 (95% CI, 1.05, 1.99). The IRR of all grade hyperglycemia was 1.08 (95% CI, 0.76, 1.40) and of grade 3-4 hyperglycemia was 1.66 (95% CI, 1.12, 2.20). The IRR of all grade hypertriglyceridemia was 0.91 (95% CI, 0.56, 1.26) and of grade 3-4 hypertriglyceridemia was 0.70 (95% CI,- 0.43, 1.83). The IRR of all grade hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65) and of grade 3-4 hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. CONCLUSIONS The risk of all grade and grade 3-4 metabolic adverse events are increased in patients treated with mTOR inhibitors compared with control. However, grade 3-4 metabolic adverse events remain relatively uncommon.

The BREASTrial Stage II: ADM Breast Reconstruction Outcomes from Definitive Reconstruction to 3 Months Postoperative.

Background: The Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial is a prospective randomized trial comparing outcomes of tissue expander breast reconstruction using either AlloDerm or DermaMatrix. The trial was divided into 3 outcome stages; this study reports stage II outcomes, which are those from the time of definitive reconstruction to 3 months postoperative. Methods: A randomized trial was conducted to compare complication rates between AlloDerm and DermaMatrix groups. The impact of matrix type, age, obesity, radiation therapy, chemotherapy, and reconstruction type on complications was analyzed with regression models. Results: Of the 128 patients (199 breasts) who were randomly assigned into the trial, 111 patients (173 breasts) were available for analysis in stage II. There was no difference in overall rates of complications (15.4% vs 18.3%, P = 0.8) or implant loss (2.2% vs 3.7%, P = 0.5) between the AlloDerm and DermaMatrix groups, respectively. Obesity was the only significant predictor of complications on regression analysis (odds ratio, 4.31, P = 0.007). Matrix type, age, radiation therapy, chemotherapy, or reconstruction type had no impact on the incidence/severity of complications. Conclusions: Acellular dermal matrix (ADM) will likely continue to have a role in breast reconstructive surgery; however, caution should be taken when using ADM because of relatively high complication rates, especially in obese patients. The particular ADM product should be selected based on individual surgeon preference, experience, and success rates. These data and forthcoming long-term outcomes from the Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial will enable surgeons to carefully weigh the risks and benefits of ADM use in breast reconstruction.

Nipple Sparing Mastectomy in Patients With Prior Breast Scars: Is It Safe?

Background Nipple-sparing mastectomy (NSM) preserves the native skin envelope, including the nipple-areolar skin, and has significant benefits including improved aesthetic outcome and psychosocial well-being. Patients with prior breast scars undergoing NSM are thought to be at increased risk for postoperative complications, such as skin and/or nipple necrosis. This study describes our experience performing NSM in patients who have had prior breast surgery and aims to identify potential risk factors in this subset of patients. Methods A retrospective review of all patients undergoing nipple sparing mastectomy at The University of Utah from 2005 to 2011 was performed. Fifty-two patients had prior breast scars, for a total of 65 breasts. Scars were categorized into 4 groups depending on scar location: inframammary fold, outer quadrant, periareolar, and circumareolar. Information regarding patient demographics, social and medical history, treatment intent, and postoperative complications were collected and analyzed. Results Eight of the 65 breasts (12%) developed a postoperative infection requiring antibiotic treatment. Tobacco use was associated with an increased risk of infection in patients with prior breast scars (odds ratio [OR], 7.95; 95% confidence interval [CI], 1.37–46.00; P = 0.0206). There was a 13.8% rate of combined nipple and skin flap necrosis and receipt of chemotherapy (OR, 5.00; CI, 1.11–22.46; P = 0.0357) and prior BCT (OR, 12.5; CI, 2.2–71.0; P = 0.004) were found to be associated with skin flap or NAC necrosis. Conclusions Nipple-sparing mastectomy is a safe and viable option for patients with a prior breast scar. Our results are comparable to the published data in patients without a prior scar. Caution should be exercised with patients who have a history of tobacco use or those requiring chemotherapy because these patients are at increased risk for infection and NAC/skin flap necrosis, respectively, when undergoing NSM in the setting of a prior breast scar.

The association between socioeconomic factors and breast cancer-specific survival varies by race

Although racial disparity is well described for oncologic outcomes, factors associated with survival within racial groups remains unexplored. The objective of this study is to determine whether breast cancer survival among White or Black patients is associated with differing patient factors. Women diagnosed with breast cancer from 1998 through 2012 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazard logistic regression was used to estimate cause-specific survival in the combined cohort, and separate cohorts of Black or White patients only. Main outcomes included cause-specific survival in cohorts of Black only, White only, or all patients adjusted for demographic and oncologic factors. A total of 406,907 Black (10.8%) or White (89.2%) patients diagnosed with breast cancer from 1998 through 2012 were isolated. Cancer-specific survival analysis of the combined cohort showed significantly decreased hazard ratio (H.R.) in patients from the higher economic quartiles (Q1: 1.0 (ref), Q2: 0.95 (p<0.01), Q3: 0.94 (p<0.01), Q4: 0.87 (p<0.001)). Analysis of the White only cohort showed a similar relationship with income (Q1: 1.0 (ref), Q2: 0.95 (p<0.01), Q3: 0.95 (p<0.01), Q4: 0.86 (p<0.001)). However, analysis of the Black only cohort did not show a relationship with income (Q1: 1.0 (ref), Q2: 1.04 (p = 0.34), Q3: 0.97 (p = 0.53), Q4: 1.04 (p = 0.47)). A test of interaction confirmed that the association between income and cancer-specific survival is dependent on patient race, both with and without adjustment for demographic and oncologic characteristics (p<0.01). While median county income is positively associated with cancer-specific survival among White patients, this is not the case with Black patients. Similar findings were noted for education level. These findings suggest that the association between socioeconomic status and breast cancer survival commonly reported in the literature is specific to White patients. These findings provide insight into differences between White and Black patients in cancer-specific survival.

The BREASTrial Stage II: ADM Breast Reconstruction Outcomes from the Time of Implant Exchange to 3 Months Post-Op.

www.PRSJournal.com 111 Suday, O cber 18 Figure 1. Complications rates for health states for each reconstructive modality. The overall complication rate for single-stage reconstruction is similar to staged-reconstruction (35% vs 34%). Rates of mastectomy skin necrosis and capsular contracture higher in single-stage reconstructions while seroma and hematoma are higher in expander-implant reconstructions. Infection rates are identical.

Abstract 6: The BREASTrial: Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial, Design and Stage I Outcomes of a Randomized Trial.

Methods: A prospective, randomized, placebo-controlled clinical trial was designed to describe the efficacy of injected Btx-A in alleviating pain due to Raynaud’s disease. Our secondary goal was to describe this minimally invasive therapy’s effects and impact on quality-of-life by measuring subjective pain scores, pain-free intervals, ulcer healing, changes in hand function, finger survival, and subsequent treatment choices. Study participants were randomized to receive injection with either placebo (normal saline) or 100 units of Btx-A into the palm around involved digital neurovascular bundles. Data collection included subjective evaluation of pain relief, serial photography of wound healing, and objective data on tissue perfusion using a Doppler perfusion imager and Periscan image analysis software.

The BREASTrial: Breast Reconstruction Evaluation of Acellular-Dermal Matrix as a Sling Trial, Design and Early Outcomes of a Randomized Trial

INTRODUCTION: Use of acellular dermal matrix (ADM) in tissue expander (TE) breast reconstruction has become a popular adjunct to the total submuscular technique. The risks and benefi ts of its use have recently been questioned. However, the majority of data available on the topic is from retrospective studies utilizing a single type of ADM, leaving many questions incompletely answered. The BREASTrial aims to prospectively compare the incidence/severity of complications in ADM breast reconstruction between two commonly used ADMs.

Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: A systematic review and meta-analysis.

362 Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). While pulmonary toxicities are a recognized adverse effect associated with this drug class, the frequency and risk of these side effects have not been well characterized. METHODS Clinical trials of mTOR inhibitors in solid tumors were identified through a search of PubMed and ASCO abstracts. Prospective studies of temsirolimus, everolimus, and ridaforolimus in solid tumors were evaluated for inclusion. 22 eligible phase II and phase III trials that included 4,242 patients were identified and included in a systematic review and meta-analysis. Adverse event data was extracted for pulmonary complications including pneumonitis, dyspnea, and cough. The incidence rate and the incidence rate ratios were determined for these pulmonary adverse events. RESULTS Based on our analysis of the 20 trials that reported pneumonitis, the incidence rate of any grade pneumonitis in patients with solid tumors treated with mTOR inhibitors is 0.11 (95% CI, 0.06-0.17). The incidence rate of grade 3 or 4 pneumonitis is 0.03 (95% CI, 0.01-0.04). The incidence rate ratio of any grade pneumonitis with mTOR inhibitors relative to controls is 18.9 (95% CI, 6.5-55.1), and the incidence rate ratio for the development of grade 3 or 4 pneumonitis is 7.9 (95% CI, 2.6-24.0). The incidence rates of any grade cough and dyspnea were found to be 0.23 (95% CI, 0.20-0.27) and 0.15 (95% CI, 0.10-0.21), respectively. The incidence rates of grade 3 or 4 cough and dyspnea are found to be 0.01 (95% CI, 0.00-0.01) and 0.03 (95% CI, 0.02-0.04), respectively. There was a statistically significant, but modest increase in risk of developing any grade cough (incidence rate ratio of 1.9 [95% CI, 1.6-2.4]) and grade 3 or 4 dyspnea (incidence rate ratio of 2.0 [95% CI, 1.2-3.3]) with mTOR inhibitors relative to controls. CONCLUSIONS This study confirms that mTOR inhibitors are associated with pulmonary adverse events and provides a quantitative estimation of the risk of these adverse events in solid tumor patients treated with these drugs. The majority of pulmonary adverse events are low grade.