Citations

Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Background:The cytologic diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) is controversial because of variation in how it is applied in practice, as well as uncertainty about patient management. We aimed to assess the percentage of thyroid fine-needle aspiration biopsies (FNABs) with AUS/FLUS diagnoses in different North American and European practice settings (e.g. community, academic, etc.), assess whether patients were managed according to current guidelines, and determine patient outcomes.Materials and Methods:A detailed questionnaire survey was posted in secure websites used separately by cytopathologists and cytotechnologists. The questionnaire was posted from August 1 through December 31, 2013.Results:Endocrinologists and cytopathologists performed 51.7% and 37.1% of thyroid FNABs, respectively. The Bethesda reporting system for thyroid FNAB was used in 90% of practices. The rate of AUS/FLUS varied widely among institutions, with 46.1% of represented institutions reporting AUS/FLUS rates of 3–10%. The median follow-up rate of patients with an initial AUS/FLUS diagnosis was 70% (range, 10–100%). For the majority of represented institutions (86.4%), patients with initial AUS/FLUS diagnosis had follow-up with endocrinologists. Of repeat AUS/FLUS thyroid FNABs, a median of 52% was considered benign, and 18% were suspicious of or positive for malignancy (median, 10% and 7.5%, respectively).Conclusions:Reporting of the AUS/FLUS category varied widely among different institutions. The median follow-up rate was lower than published guidelines. The most common follow-up diagnosis was benign thyroid nodule. Improved standardization of cytologic criteria should be adopted to reduce such variation.

Background and purpose A subset of patients with Alzheimer's disease ( AD ) present with early and prominent language impairment (aphasic AD ). Our previous study demonstrated an association between global β‐amyloid burden measured on [ 11 C] Pittsburgh compound B (PiB) positron emission tomography and general cognitive impairment, but not with aphasia, in such subjects. As a follow‐up, whether there is any association between regional β‐amyloid burden, atrophy on magnetic resonance imaging ( MRI ) and global cognitive impairment, aphasia or other cognitive and functional impairment in aphasic AD is assessed. Methods Forty‐four aphasic AD subjects who underwent PiB scanning and volumetric MRI and were determined to be positive for β‐amyloid deposition were analyzed. All had completed detailed neurological, neuropsychological and language batteries. Spearman's rank‐order correlation was utilized to assess for associations. Results Greater visuospatial impairment was associated with increased β‐amyloid burden in the primary visual cortex ( P = 0.001). Although there were many trends for associations between neurocognitive and language deficits and regional β‐amyloid burden, there were no strong associations that survived correction for multiple comparisons. However, neurocognitive and language impairment in these subjects strongly correlated with the degree of left lateral temporal and inferior parietal atrophy ( P < 0.004). Conclusions The findings from this study suggest a close relation between the severity of regional atrophy and cognitive and language impairment, but argue against a strong association between regional β‐amyloid burden and such deficits in aphasic AD subjects. Hence, other pathological factors may be driving the previously identified association between global β‐amyloid deposition and general cognitive impairment in aphasic AD .

Endogenous female sex hormones influence muscle sympathetic nerve activity (MSNA), a regulator of arterial blood pressure and important factor in hypertension development. Although ≈80% of American women report using hormonal contraceptives sometime during their life, the influence of combined oral contraceptives (OCs) on MSNA and systemic hemodynamics remains equivocal. The goal of this study was to determine whether women taking OCs have altered MSNA and hemodynamics (cardiac output and total peripheral resistance) at rest during the placebo phase of OC use compared with women with natural menstrual cycles during the early follicular phase. We retrospectively analyzed data from studies in which healthy, premenopausal women (aged 18–35 years) participated. We collected MSNA values at rest and hemodynamic measurements in women taking OCs (n=53; 25±4 years) and women with natural menstrual cycles (n=74; 25±4 years). Blood pressure was higher in women taking OCs versus those with natural menstrual cycles (mean arterial pressure, 89±1 versus 85±1 mm Hg, respectively; P =0.01), although MSNA was similar in both groups (MSNA burst incidence, 16±1 versus 18±1 bursts/100 heartbeats, respectively; P =0.19). In a subset of women in which detailed hemodynamic data were available, those taking OCs (n=33) had similar cardiac output (4.9±0.2 versus 4.7±0.2 L/min, respectively; P =0.47) and total peripheral resistance (19.2±0.8 versus 20.0±0.9 U, respectively; P =0.51) as women with natural menstrual cycles (n=22). In conclusion, women taking OCs have higher resting blood pressure and similar MSNA and hemodynamics during the placebo phase of OC use when compared with naturally menstruating women in the early follicular phase.

Purpose We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) –positive breast cancer treated in randomized trials. Methods A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) –positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. Results Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively. Conclusion Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.

Background and purpose Carotid blowout is a life threatening complication of invasive head and neck cancers and their treatments. This is commonly treated with endovascular embolization and carotid stenting. Using the Nationwide Inpatient Sample, we report the immediate clinical results of patients receiving embolization and/or stenting for treatment of carotid blowout associated with head and neck cancer. Materials and methods Using the Nationwide Inpatient Sample from the period 2003–2011, we defined carotid blowout patients as those with head and neck malignancies receiving carotid stenting and/or endovascular embolization without open surgery. Outcomes studied included mortality, acute ischemic stroke, hemiplegia/paresis, and other post-operative neurologic complications. Outcomes for the endovascular embolization and carotid stenting group were compared. Results A total of 1218 patients underwent endovascular treatment for carotid blowout. Of these, 1080 patients (88.6%) underwent embolization procedures and 138 patients (11.4%) underwent carotid stenting. The mortality rate of endovascular embolization patients was similar to that of carotid stenting patients (8.0%, 95% confidence interval (CI) = 6.5%–9.7% versus 10.2%, 95% CI=6.0%–16.4%, p = 0.36). Stroke rate was similar between embolization patients and stenting patients (2.3%, 95% CI=1.6%–3.4% vs. 3.4%, 95% CI=1.3%–8.4%, p = 0.43). Hemiplegia rates were significantly higher rate in stenting patients compared with endovascular occlusion patients (3.8%, 95% CI=1.3%–8.4% vs. 1.4%, 95% CI=1.4%–2.4%, p = 0.05). The rate of post-operative neurologic complications was higher in stenting patients compared with embolization patients (6.5%, 95% CI=3.3%–12.1% vs. 1.4%, 95% CI=0.9%–2.4%, p < 0.0001). Conclusions Given the natural history of carotid blowout, carotid stenting and endovascular embolization are acceptable means of treating this disease. Endovascular embolization remains the most common treatment among patients with head and neck cancers with lower overall rates of post-operative neurologic complications, including hemiplegia/paresis and stroke.

Purpose To (1) determine the incidence of symptomatic venous thromboembolic events (VTEs) after knee arthroscopy and arthroscopy‐assisted procedures at a single institution and (2) determine associated risk factors for VTEs in these patients. Methods The records of patients who underwent knee arthroscopy at a single institution between 1988 and 2008 were reviewed. Chemoprophylaxis was not routinely used. Confirmed VTEs occurring within 4 weeks after the index arthroscopy procedure were included. A 2:1 matched control group was generated to include patients in whom knee arthroscopy was performed by the same surgeon either on the same day or immediately before each case resulting in a VTE. Preoperative and perioperative data were collected with respect to demographic data, medical history, medications, and surgical and anesthesia data. Univariate and multivariate analyses were performed. Results During the study period, 12,595 patients underwent knee arthroscopy. Among these patients, 43 cases of VTEs (35 deep venous thromboses [DVTs], 5 pulmonary embolisms [PEs], and 3 DVTs that progressed to PEs) occurred, resulting in an incidence of 0.30% (95% confidence interval [CI], 0.22% to 0.41%) for DVT, 0.06% (95% CI, 0.03% to 0.12%) for PE, and 0.34% (95% CI, 0.25% to 0.46%) for VTEs overall. Factors associated with an elevated risk of symptomatic postoperative VTEs included a history of malignancy ( P = .01; odds ratio [OR], 6.3), a history of VTEs ( P = .02; OR, 5.2), or the presence of more than 2 classic risk factors for VTEs ( P = .01; OR, 13.6). Conclusions In this study, symptomatic VTEs were rare and occurred infrequently, with an incidence of 0.34% (95% CI, 0.25% to 0.46%), after knee arthroscopy and arthroscopy‐assisted cases in the absence of routine chemoprophylaxis. Patients with a history of VTEs, a history of malignancy, or 2 or more classic risk factors are at increased risk of VTEs after knee arthroscopy, and chemoprophylaxis should be considered in these select patients. Level of Evidence Level III, case‐control study.