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Careful selection of patients with expiratory central airway collapse (ECAC) that may benefit from tracheobronchoplasty (TBP) can be aided by a short-term airway stent evaluation. This can be performed with either silicone Y-stents (SYSs) or uncovered self-expanding metallic airway-stents (USEMAS). No direct comparison has been made between these 2 stent types.This was a small retrospective review of consecutive patients that underwent a stent evaluation. A propensity score was used to match patients in the USEMAS and SYS groups. Outcomes included complications, changes in the health-related quality-of-life (HR-QoL), and changes in exercise capacity. Baseline measurements were compared with those obtained during stent evaluation and after TBP.Forty-two patients with severe ECAC underwent USEMAS placement, while 18 patients had an SYS placed. Propensity score matching resulted in 13 matched SYS and USEMAS pairs. The SYS group had an increased rate of mucus plugging (38.5% vs. 0%, P0.047). Although not statically significant, a clinical improvement was observed in HR-QoL and exercise capacity in the USEMAS group during stent placement. In patients who underwent TBP, both USEMAS and SYS groups had a statistically significant change in the Modified Medical Research Council Dyspnea Scale during stent evaluation and after TBP.In patients with severe ECAC, short-term evaluation with airway stents appears to be safe and improves respiratory symptoms, HR-QoL, and exercise capacity. The use of USEMAS led to a lower complication rate, a greater improvement in HR-QoL and exercise capacity, and appeared to better predict how the patients would respond to TBP.

Purpose: Indeterminate thyroid lesions on fine needle aspiration (FNA) harbor malignancy in about 25% of cases. Hemi- or total thyroidectomy has, therefore, been routinely advocated for definitive diagnosis. In this study, we analyzed miRNA expression in indeterminate FNA samples and determined its prognostic effects on final pathologic diagnosis.Experimental Design: A predictive model was derived using 29 ex vivo indeterminate thyroid lesions on FNA to differentiate malignant from benign tumors at a tertiary referral center and validated on an independent set of 72 prospectively collected in vivo FNA samples. Expression levels of miR-222, miR-328, miR-197, miR-21, miR-181a, and miR-146b were determined using reverse transcriptase PCR. A statistical model was developed using the support vector machine (SVM) approach.Results: A SVM model with four miRNAs (miR-222, miR-328, miR-197, and miR-21) was initially estimated to have 86% predictive accuracy using cross-validation. When applied to the 72 independent in vivo validation samples, performance was actually better than predicted with a sensitivity of 100% and specificity of 86%, for a predictive accuracy of 90% in differentiating malignant from benign indeterminate lesions. When Hurthle cell lesions were excluded, overall accuracy improved to 97% with 100% sensitivity and 95% specificity.Conclusions: This study shows that that the expression of miR-222, miR-328, miR-197, and miR-21 combined in a predictive model is accurate at differentiating malignant from benign indeterminate thyroid lesions on FNA. These findings suggest that FNA miRNA analysis could be a useful adjunct in the management algorithm of patients with thyroid nodules. Clin Cancer Res; 18(7); 2032–8. ©2012 AACR.

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El cambio climatico representa el desafio mas grande a escala global. Ante esta problematica, la arquitectura debe adaptarse para asegurar el confort higrotermico y la eficiencia energetica. La investigacion expone la adaptacion de dos edificaciones publicas en Costa Rica, para lograr el confort higrotermico ante la simulacion de escenarios de cambio climatico. Para delimitar la zona de estudio, se analizan los ambitos ecologico, demografico y economico regional. Se realiza un levantamiento de posibles casos de estudio, que se discriminan a partir de criterios de evaluacion del impacto de la intervencion. Para cada caso se desarrolla un analisis bioclimatico por escalas, a partir del cual se seleccionan dos casos a simular. Los archivos climaticos para simular los escenarios del 2080, se generan a partir de datos observados del Instituto Meteorologico Nacional (IMN) y datos proyectados del Centro de Investigaciones Geofisicas (CIGEFI). Finalmente, se desarrollan dos propuestas de adaptacion para cada caso seleccionado: una moderada y un rediseno total. Se evalua su comportamiento mediante el software de simulacion DesignBuilder® y se plantean recomendaciones de diseno. Palabras clave: Arquitectura bioclimatica, cambio climatico, confort higrotermico, adaptacion, simulacion.

Minimally invasive cardiac surgery (MICS) requires distinctive surgical skills compared to conventional cardiac surgery. Several single-infusion cardioplegic solutions have emerged to facilitate the procedure. Del Nido cardioplegia, developed for protection of immature hearts, is one such solution which is gaining popularity in adult cardiac surgery.

Objective There is a paucity of data on outcomes after isolated tricuspid valve surgery. This meta-analysis aims to compile available data on isolated tricuspid valve surgery and compare isolated tricuspid valve repair (iTVr) with isolated tricuspid valve replacement (iTVR) to elucidate outcomes after tricuspid valve surgery. Methods A literature search of 6 databases was performed. The primary outcomes was 30-day mortality. Secondary outcomes were early stroke, post-op pacemaker placement, and tricuspid reoperation within 5 years. Publication bias was explored using the funnel plot. Results Ten retrospective studies involving 1407 patients (iTVr group = 779 patients and iTVR group = 628 patients) were included. A cumulative analysis demonstrated a significant difference favoring iTVr for 30-day mortality (odds ratio [OR]: 10 studies [95% confidence interval [CI]]: 0.34 [0.18-0.66]); 4.7% versus 12.6%, for iTVr and iTVR, respectively. Post-op pacemaker placement favored iTVr (OR: 6 studies [95% CI]: 0.37 [0.18-0.77]). Although stroke rates and TV reoperation favored iTVr, they did not reach statistical significance. No publication bias was identified. Conclusions This meta-analysis demonstrates that iTVr has better 30-day mortality and fewer permanent pacemaker placements. Etiology and severity of TR, as well as careful patient selection remain the most important factors for optimal outcomes.

∙ Cerro Hoya National Park in Panama (CHNP) is one of the least explored protected areas in southern Mesoamerica. It houses the greatest ecosystem diversity in the degraded Azuero Peninsula, but its inaccessibility hinders expeditions and scientific research. Avian richness in CHNP was previously estimated by combining data from five ornithological expeditions at ca. 225 species. However, the highest altitude areas remained relatively unexplored and some historical records were not verified. We intensively surveyed highlands and foothills of CHNP and identified five new range extensions. One of these included a Selasphorus sp., of which we collected three male (two adults, one immature) and one female specimens. We compared morphology and plumage color patterns of these with closely related species in detail and confirm their likely classification with the endangered Glow-throated Hummingbird (Selasphorus ardens). This species is rare, with few documented sightings, confirmed specimens, and no unambiguous female museum specimen until now. We also confirmed historical records and provide 26 unlisted species (one by an external source) to CHNP. Our results confirm that Cerro Hoya is a highly biodiverse skyisland of Mesoamerica. We urge improved enforcement of its protection in combination with further studies of the ecology and evolutionary processes in this unique region. Resumen · Censos ornitológicos en ambientes de altura en el Parque Nacional Cerro Hoya (Azuero, Panamá) revelan nuevas extensiones de distribución, incluyendo un inusual colibrí (Selasphorus sp.) El Parque Nacional Cerro Hoya (PNCH) es una de las áreas protegidas menos exploradas de Panamá y el sur de Mesoamérica. Este alberga la mayor diversidad de ecosistemas en la degradada península de Azuero, pero su inaccesibilidad dificulta la investigación científica. Combinando datos de cinco expediciones ornitológicas, se estimó una riqueza aviar de alrededor de 225 especies. No obstante, las áreas de mayor altitud permanecieron relativamente inexploradas y algunos registros históricos no fueron verificados. Exploramos intensivamente las tierras altas y estribaciones del PNCH e identificamos cinco nuevas extensiones de distribución. Uno de estos incluye Selasphorus sp., del cual colectamos tres especímenes machos (dos adultos, un juvenil) y una hembra. Comparamos detalladamente la morfología y los patrones de coloración del plumaje con especímenes de especies relacionadas estrechamente. Confirmamos que estos individuos podrían pertenecer al amenazado Colibrí Ardiente (Selasphorus ardens). Esta especie es rara, con pocos avistamientos y especímenes de museo con información inconsistente, principalmente en hembras. También confirmamos los registros históricos y agregamos 26 especies no listadas para el PNCH (una obtenida por fuente externa). Nuestros resultados confirman que Cerro Hoya es una isla-cielo de gran biodiversidad en Mesoamérica. Es urgente mejorar la aplicación de su protección, así como estudiar la ecología y los procesos evolutivos en esta región única.

Objective: To describe experience with using intraoperative Transesophageal Echocardiography to reliably predict the size of the rapid deployment prosthetic valve by measuring the native aortic annulus Methods: Retrospective review of single institution series of patients undergoing Aortic Valve Replacement with Rapid Deployement Bioprosthetic Valves. Included were patients that had their native aortic valve replaced either isolated or as part of any additional procedure. Aortic annulus was measured prior to initiation of the operation using transesophageal echocardiography (TEE). Correlation analysis was conducted between Echocardiographic annular measurements and actual implanted valve sizes. Results: Twenty five patients underwent rapid deployment valve implantation in the aortic position. Of these, 36% of patients had the same size valve as the measured aortic annulus, 48% of patients had a valve implanted that was 1 mm different, and 16% of patients had 2 mm difference. The mean annular size based was 22.4 mm (range: 21-28 mm). The mean valve size implanted was 23.3 mm (range: 21-27 mm). There was no statistically significant difference between the mean annular measurement and the valve size selected (0.9 mm , p = 0.8). Conclusion: TEE can further enhance valve sizing and guidance through a proper and safe deployment. Although evident in our experience, larger scale studies are needed to further elucidate conclusions on the importance of avoiding under-sizing valves.

Vascular grafts (VGs) are medical devices intended to replace the function of a blood vessel. Available VGs in the market present low patency rates for small diameter applications setting the VG failure. This event arises from the inadequate response of the cells interacting with the biomaterial in the context of operative conditions generating chronic inflammation and a lack of regenerative signals where stenosis or aneurysms can occur. Tissue Engineered Vascular grafts (TEVGs) aim to induce the regeneration of the native vessel to overcome these limitations. Besides the biochemical stimuli, the biomaterial and the particular micro and macrostructure of the graft will determine the specific behavior under pulsatile pressure. The TEVG must support blood flow withstanding the exerted pressure, allowing the proper compliance required for the biomechanical stimulation needed for regeneration. Although the international standards outline the specific requirements to evaluate vascular grafts, the challenge remains in choosing the proper biomaterial and manufacturing TEVGs with good quality features to perform satisfactorily. In this review, we aim to recognize the best strategies to reach suitable mechanical properties in cell-free TEVGs according to the reported success of different approaches in clinical trials and pre-clinical trials.

Various types of prosthetic materials are available for usage in cardiac surgery to repair heart defects. PTFE, Dacron, and bovine pericardial are some examples of the most used materials for this purpose. In this article, the authors describe the potential failure of the CorMatrix®.

BackgroundHost-associated microbiomes, the microorganisms occurring inside and on host surfaces, influence evolutionary, immunological, and ecological processes. Interactions between host and microbiome affect metabolism and contribute to host adaptation to changing environments. Meta-analyses of host-associated bacterial communities have the potential to elucidate global-scale patterns of microbial community structure and function. It is possible that host surface-associated (external) microbiomes respond more strongly to variations in environmental factors, whereas internal microbiomes are more tightly linked to host factors.ResultsHere, we use the dataset from the Earth Microbiome Project and accumulate data from 50 additional studies totaling 654 host species and over 15,000 samples to examine global-scale patterns of bacterial diversity and function. We analyze microbiomes from non-captive hosts sampled from natural habitats and find patterns with bioclimate and geophysical factors, as well as land use, host phylogeny, and trophic level/diet. Specifically, external microbiomes are best explained by variations in mean daily temperature range and precipitation seasonality. In contrast, internal microbiomes are best explained by host factors such as phylogeny/immune complexity and trophic level/diet, plus climate.ConclusionsInternal microbiomes are predominantly associated with top-down effects, while climatic factors are stronger determinants of microbiomes on host external surfaces. Host immunity may act on microbiome diversity through top-down regulation analogous to predators in non-microbial ecosystems. Noting gaps in geographic and host sampling, this combined dataset represents a global baseline available for interrogation by future microbial ecology studies.

La paradoja de sorites es ampliamente conocida por mostrar las consecuencias contradictorias que pueden tener razonamientos que involucren términos vagos. Importantes filósofos de la escuela analítica como Bertrand Russell y Gottlob Frege apoyan fuertemente la idea de que las contradicciones surgidas en situaciones como la de la paradoja de sorites se deben en efecto a la vaguedad del lenguaje común. Este trabajo pretende proponer una metodología con base en la lógica difusa que muestra que los razonamientos de tipo sorites, a pesar de tener términos vagos, pueden ser consistentes y válidos. The sorites paradox is widely known for showing the contradictory consequences that reasoning with vague terms might have. Important analytic philosophers like Bertrand Russell and Gottlob Frege strongly supported the idea that contradictions like those in the sorites paradox are due to the vagueness of common language. This work attempts to propose a methodology based on fuzzy logic that shows that the sorites type reasoning are consistent and sound however the vague terms it might contain.

Purpose To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS). Patients and Methods We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated. Results Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS. Conclusion In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma.

Objective CD10 (neutral endopeptidase) is expressed in various normal and tumor cells, and its biological function can be controlled through enzymatic activity and signaling pathways. We investigated whether CD10 expression predicted disease recurrence and whether it correlated with histologic subtypes of stage I lung adenocarcinoma. Materials and methods We reviewed tumor slides of resected pathologic stage I lung adenocarcinomas (1995–2009). Tumors were classified according to the IASLC/ATS/ERS classification. CD10 immunohistochemistry was performed using tissue microarrays ( n =915). We combined the intensity (0–3) and distribution scores (0–2) for CD10 to create a total score (0–5). Risk of recurrence was estimated using competing risks methods. Results In the training cohort ( n =313), risk of recurrence of patients with high tumoral CD10 (score>1, n =57) was significantly higher (5-year cumulative incidence of recurrence [CIR], 37%) than in those with low CD10 (score≤1; n =256; 5-year CIR, 16%; P n =602, P =0.036). High tumoral CD10 was associated with higher risk of recurrence in acinar ( P =0.007) and papillary predominant tumors ( P =0.022). High tumoral CD10 was most frequently identified in micropapillary predominant (41%) and solid predominant tumors (34%). On multivariate analysis of intermediate-grade tumors, high tumoral CD10 remained a significant independent risk factor of recurrence (hazard ratio, 1.88; P =0.025). Conclusion In stage I lung adenocarcinoma, tumoral CD10 correlated with high-grade histology and was an independent predictor of recurrence in intermediate-grade tumors.

Introduction We previously reported the prognostic significance of the lung adenocarcinoma immune microenvironment. In this study, we preformed comprehensive analysis of immune markers and their associations with prognosis in patients with lung squamous cell carcinoma. Methods We reviewed surgically resected, solitary lung squamous cell carcinoma patients (n = 485; 1999–2009) who were randomly split into a training cohort (n = 331) and validation cohort (n = 154). We constructed tissue microarrays and performed immunostaining for CD3, CD45RO, CD8, CD4, FoxP3, CD20, CD68, CXCL12, CXCR4, CCR7, interleukin-7 receptor, and interleukin-12 receptor β2. Overall survival (OS) was analyzed using the log-rank test and the Cox proportional hazards model. Results Analysis of single immune cell infiltration revealed that high tumor-infiltrating CD10 + neutrophils were associated with worse prognoses in the training cohort (p = 0.021). Analysis of biologically relevant immune cell combinations identified that patients with high CD10 + neutrophil and low CD20 + lymphocyte had a significantly worse OS (5-year OS, 42%) than those with other combinations of CD10 and CD20 (5-year OS, 62%; p p = 0.032). For the multivariate analysis, high CD10/low CD20 immune cell infiltration was an independent predictor of OS in both the training cohort (hazard ratio=1.61, p = 0.006) and the validation cohort (hazard ratio=1.75; p = 0.043). Conclusion High CD10+/low CD20+ immune cell infiltration ratio is a significant prognostic factor of lung squamous cell carcinoma. Immunomodulatory therapy of tumor-specific neutrophil and B-lymphocyte responses may have applicability in the treatment of lung squamous cell carcinoma.

Purpose To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I non–small-cell lung cancer (NSCLC). Patients and Methods Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis. Results Of 2,186 patients, 1,532 (70.1%) were ≥ 65 years of age, including 638 (29.2%) ≥ 75 years of age. In patients < 65, 65 to 74, and ≥ 75 years of age, 5-year lung cancer–specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients ≥ 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer–specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients ≥ 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity ( P < .001), 1-year mortality ( P < .001), and noncancer-specific mortality ( P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer–specific mortality ( P = .002). Conclusion In patients who undergo curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases.

This study aims to determine the efficacy of calcimimetics in improving bone mineral density (BMD) in patients with primary hyperparathyroidism (pHPT) and compare those results to patients undergoing parathyroidectomy.Parathyroidectomy has been shown to improve BMD in pHPT, but calcimimetics have recently been advocated as a medical alternative to parathyroidectomy for pHPT.We identified 17 patients that were treated with calcimimetics for pHPT. Seventeen patients with pHPT who underwent parathyroidectomy served as surgical controls. Serum calcium level, parathyroid hormone (PTH) level, and femur and spine BMD T scores were compared before and 1 year after therapy.Both groups were demographically matched. Calcium levels normalized in 70.6% of medically versus 100% of surgically treated patients (P = 0.026). PTH levels normalized in 35% of patients treated with calcimimetics versus 76% of surgical patients (P = 0.036). Femur BMD improved in 18.8% of medically treated patients versus 58.8% of surgical patients (P = 0.032). Spine BMD improved in 70.6% of medically treated patients versus 82.4% of surgical patients (P = 0.69). Further analysis demonstrated that regardless of treatment, normalization of PTH was associated with significant improvement in femur (P = 0.03) and spine BMD (P0.001). Normalization of calcium without normalization of PTH did not impact BMD.Parathyroidectomy results in greater normalization of serum calcium and PTH levels and significantly improves cortical BMD compared to calcimimetics. Regardless of treatment, normalization of PTH is associated with significant improvement in spine and femur BMD, suggesting that the superior effects of surgery may be mediated by better control of PTH.

Background Over the past 3 decades, there has been a significant increase in the incidence of gastrointestinal carcinoid tumors in the United States. Incidentally discovered carcinoids in the lower gastrointestinal tract have probably contributed to this increase. In this study we aimed to compare the clinicopathologic characteristics of incidentally discovered carcinoids of the small and large bowel with those identified as a result of symptoms. Study Design We performed a retrospective review of 58 consecutive patients with nonappendiceal gastrointestinal carcinoids: 30 small bowel and 28 large bowel. We compared asymptomatic patients with lower gastrointestinal tract carcinoids identified by routine colonoscopy with those identified as a result of symptoms. Results Twenty-eight (48.3%) incidentally identified carcinoids (15 small bowel and 13 large bowel) were compared with 30 (51.7%) symptomatic carcinoids. Incidental ileal carcinoids were similar in size (mean ± SD, 1.3 ± 0.61 vs 1.7 ± 1.13, p=0.45) and incidence of lymph node metastases (12 in 15 vs 9 in 15, p=0.43) to symptomatic ileal carcinoids. However, incidental ileal carcinoids had a lower incidence of distant metastases (1 in 15 vs 7 in 15, p=0.035) compared with symptomatic ileal carcinoids. There was no difference in tumor size, extent of lymph node metastases, or distant metastases between incidental and symptomatic large bowel carcinoids. Conclusions Ileal carcinoids identified at screening colonoscopy are associated with a significantly decreased incidence of distant metastases compared with those identified after development of symptoms, despite similar size and extent of lymph node metastases. However, incidental large bowel carcinoids appear to have similar staging to those identified as a result of symptoms.

The effectiveness of prophylactic central neck dissection (pCND) in the treatment of patients with papillary thyroid carcinoma (PTC) to prevent local recurrence is controversial. We performed a meta-analysis to assess the effect of pCND on local recurrence in PTC. Exhaustive search of online search engines identified five retrospective studies that compared the local recurrence rates of PTC in patients without clinically detectable nodal disease in patients undergoing thyroidectomy + pCND (group A) to those undergoing thyroidectomy alone (group B). A meta-analysis was performed by the fixed effects method. Recurrence was documented by imaging, thyroglobulin detection, or reoperation. Location of recurrence was identified in either the central or lateral neck compartment. A total of 1264 patients were included, 396 in group A and 868 in group B. Follow-up ranged from 6 months to 27 years. The overall recurrence rate was 2.02% in group A versus 3.92% in group B (odds ratio [OR] = 1.05, 95% confidence interval [95% CI] 0.48–2.31). The recurrence rate in the central neck compartment in group A was 1.86% compared to 1.68% in group B (OR = 1.31, 95% CI 0.44–3.91). The recurrence rate in the lateral neck compartment in group A was 3.73% compared to 3.79% in group B (OR = 1.21, 95% CI 0.52–2.75). There was no statistically significant difference in the OR in the local recurrence between the two groups. This meta-analysis indicates that pCND does not greatly reduce local recurrence in thyroid cancer. However, the available studies have substantial limitations and a prospective multicenter study to determine the indications for pCND is warranted.

Protected only by the extreme ruggedness of its terrain, the montane regions of Cerro Hoya National Park are among the least biologically known regions of Central America. Here we provide a checklist of 225 bird species recorded from five expeditions to the region over the last 18 years, which represents lower species richness than many comparable areas in Panama and lower Central America. However, we recorded nine IUCN globally threatened species, three species with range extensions over 150 km to the southern Azuero Peninsula, and at least two previously unknown bird taxa. These facts suggest that our list of montane taxa from Cerro Hoya may be incomplete, and that this region represents one of the most important—and neglected—protected areas in Panama.

Background The preservation of microRNAs in formalin-fixed and paraffin-embedded (FFPE) tissue makes them particularly useful for biomarker studies. The utility of small RNA sequencing for microRNA expression profiling of FFPE samples has yet to be determined. Methods Total RNA was extracted from de-paraffinized and proteinase K-treated FFPE specimens (15–20 years old) of 8 human lung adenocarcinoma tumors by affinity chromatography on silica columns. MicroRNAs in the RNA preparations were quantified by the Illumina HiSeq 2000 sequencing platform with sequencing libraries prepared with the TruSeq Small RNA Sample Preparation Kit (version 2.0) to obtain unpaired reads of 50 b for small RNA fragments. MicroRNAs were also quantified using Agilent Human miRNA (release 16.0) microarrays that can detect 1,205 mature microRNAs and by quantitative reverse transcription (RT)-PCR assays. Results Between 9.1–16.9 million reads were obtained by small RNA sequencing of extracted RNA samples. Of these, only 0.6–2.3% (mean = 1.5%) represented microRNAs. The sequencing method detected 454–625 microRNAs/sample (mean = 550) compared with 200–349 (mean = 286) microRNAs detected by microarray. In Spearman correlation analyses, the average correlation coefficient for the 126 microRNAs detected in all samples by both methods was 0.37, and >0.5 for 63 microRNAs. In correlation analyses of the sequencing- and RT-PCR-based measurements, the coefficients were 0.19–0.95 (mean = 0.73) and >0.7, respectively, for 7 of 9 examined microRNAs. The average inter-replicate Spearman correlation coefficient for the sequencing method was 0.81. Conclusions Small RNA sequencing can be used to obtain microRNA profiles of FFPE tissue specimens with performance characteristics similar to those of microarrays, in spite of the fragmentation of ribosomal and messenger RNAs that reduces the method's informative capacity. The accuracy of the method can conceivably be improved by increasing sequencing depth and/or depleting FFPE tissue RNAs of ribosomal RNA fragments.

Background We sought to determine the prognostic variables associated with overall survival (OS) and recurrence-free probability (RFP) in patients with primary and secondary sternal tumors treated with surgical resection. Methods A retrospective analysis of patients who underwent resection of primary or secondary sternal tumors at 2 cancer institutes between 1995 and 2013 was performed. OS and RFP were estimated using the Kaplan-Meier method, and predictors of OS and RFP were analyzed using the Cox proportional hazards model. Results Sternal resection was performed in 78 patients with curative (67 [86%]) or palliative (6 [8%]) intent. Seventy-three patients (94%) had malignant tumors, of which 28 (36%) were primary and 45 (57%) were secondary malignancies. Sternal resections were complete in 13 patients (17%) and partial in 65 (83%). There were no perioperative deaths, and grade III/IV complications were noted in 17 patients (22%). The 5-year OS was 80% for patients with primary malignant tumors, 73% for patients with nonbreast secondary malignant tumors, and 58% for patients with breast tumors ( p = 0.85). In the overall cohort, R0 resection was associated with prolonged 5-year OS (84% vs 20%) on univariate ( p = 0.004) and multivariate (adjusted hazard ratio, 3.37; p = 0.029) analysis. On subgroup analysis, R0 resection was associated with improved OS and RFP only for patients with primary malignant tumors. Conclusions Sternal resection can achieve favorable OS for patients with primary and secondary sternal tumors. R0 resection is associated with improved 5-year OS and RFP in patients with primary malignant tumors. We did not detect a similar effect in patients with breast or nonbreast secondary tumors.

SUMMARY Micropapillary (MIP) histologic subtype included in the classification of lung adenocarcinomas (ADCs) is associated with both size- and stage-independent poor prognoses. MIP pattern in lung ADCs, even at small, early stages, correlates with high lymphovascular invasion, visceral pleural invasion and lymph node metastases. Recently, we reported that patients with a MIP component are at a higher risk of locoregional recurrence after limited resection. Identification of a MIP pattern is only possible with permanent pathologic sections; preoperative imaging, cytology or intraoperative frozen section specimens remain unreliable. The intermixed, heterogenous morphology of lung ADC presents a technical challenge in investigating the molecular biology of cells with MIP morphology. A comprehensive understanding of the biology of MIP morphology is vital for therapeutic interventions.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality and has increasingly become a disease of elderly patients. Elderly patients are underrepresented in clinical trials that evaluate treatments for NSCLC. It has been suggested that patients >65 years of age have less robust immune responses to infections, immunizations, and tumors compared with younger patients. With increasing focus and number of immunotherapy clinical trials for NSCLC, we investigated the relationship between patient age and the tumor immune microenvironment in NSCLC. Using tissue microarrays from 1,278 patients with surgically resected Stage I NSCLC (≤65 years [33%], 66–79 years [55%], and ≥80 years [12%]), we determined whether quantitative and qualitative immune cell infiltration in the tumor differed between younger and older patients. Furthermore, we investigated the prognostic value of immune cell infiltration with respect to recurrence in octogenarians. We found that there were no statistically significant differences between older and younger patients in tumoral immune infiltration or effector regulatory immune response ratios (FoxP3/CD3, FoxP3/CD4, and FoxP3/CD8 ratios). In octogenarians, presence of low tumoral CD68+ immune cells was an independent predictor of recurrence. In the uniform cohort of surgically selected and resected Stage I NSCLC patients, tumor immune cell infiltration among the older age group resembled other age groups. Our study provides information that supports inclusion of older age patients selected for surgical resection in neoadjuvant or adjuvant immunotherapy clinical trials for lung cancer.

The BRAF(V600E) mutation is present in 62% of radioactive iodine-resistant thyroid tumors and is associated with downregulation of the sodium-iodide symporter (NIS) and thyroid stimulating hormone receptor (TSHr). We sought to evaluate the combined effect of BRAF inhibition and TSH supplementation on (131)I uptake of BRAF(V600E)-mutant human thyroid cancer cells.WRO cells (a BRAF(V600E)-mutant follicular-derived papillary thyroid carcinoma cell line) were transfected with small interfering RNA targeting BRAF for 72 h in a physiological TSH environment. NIS and TSHr expression were then evaluated at three levels: gene expression, protein levels, and (131)I uptake. These three main outcomes were then reassessed in TSH-depleted media and media supplemented with supratherapeutic concentrations of TSH.NIS gene expression increased 5.5-fold 36 h after transfection (P = 0.01), and TSHr gene expression increased 2.8-fold at 24 h (P = 0.02). NIS and TSHr protein levels were similarly increased 48 and 24 h after transfection, respectively. Seventy-two hours after BRAF inhibition, (131)I uptake was unchanged in TSH-depleted media, increased by 7.5-fold (P 0.01) in physiological TSH media, and increased by 9.1-fold (P0.01) in supratherapeutic TSH media.The combined strategy of BRAF inhibition and TSH supplementation results in greater (131)I uptake than when either technique is used alone. This represents a simple and feasible approach that may improve outcomes in patients with radioactive iodine-resistant thyroid carcinomas for which current treatment algorithms are ineffective.

Purpose: Indeterminate thyroid lesions on fine needle aspiration (FNA) harbor malignancy in about 25% of cases. Hemi- or total thyroidectomy has, therefore, been routinely advocated for definitive diagnosis. In this study, we analyzed miRNA expression in indeterminate FNA samples and determined its prognostic effects on final pathologic diagnosis. Experimental Design: A predictive model was derived using 29 ex vivo indeterminate thyroid lesions on FNA to differentiate malignant from benign tumors at a tertiary referral center and validated on an independent set of 72 prospectively collected in vivo FNA samples. Expression levels of miR-222, miR-328, miR-197, miR-21, miR-181a, and miR-146b were determined using reverse transcriptase PCR. A statistical model was developed using the support vector machine (SVM) approach. Results: A SVM model with four miRNAs (miR-222, miR-328, miR-197, and miR-21) was initially estimated to have 86% predictive accuracy using cross-validation. When applied to the 72 independent in vivo validation samples, performance was actually better than predicted with a sensitivity of 100% and specificity of 86%, for a predictive accuracy of 90% in differentiating malignant from benign indeterminate lesions. When Hurthle cell lesions were excluded, overall accuracy improved to 97% with 100% sensitivity and 95% specificity. Conclusions: This study shows that that the expression of miR-222, miR-328, miR-197, and miR-21 combined in a predictive model is accurate at differentiating malignant from benign indeterminate thyroid lesions on FNA. These findings suggest that FNA miRNA analysis could be a useful adjunct in the management algorithm of patients with thyroid nodules. Clin Cancer Res; 18(7); 2032–8. ©2012 AACR.

Fine-needle aspiration (FNA) biopsies are the most accurate method for diagnosis of thyroid nodules. Unfortunately, biopsies are indeterminate 15-30% of the time and surgery is thus required for a definitive diagnosis. We aimed to determine whether specific descriptors of cytologic atypia mentioned in indeterminate FNA reports were associated with malignancy on final histopathology.Retrospective review of 1000 surgery patients identified 466 indeterminate FNA lesions that underwent either a hemi- or total thyroidectomy between 1998 and 2009. We screened FNA reports for specific descriptors of nuclear atypia. Univariate and multivariate analyses were performed to evaluate the independent effect of cytologic atypia descriptors on the risk of malignancy.Nuclear atypia on FNA conferred a risk of malignancy of 42% (P0.0001). Risk of malignancy increased from 17% for zero descriptors to 81.2% when four or more descriptors of atypia were described. Nuclear grooves and inclusions together conferred a risk of malignancy, specificity, and false positive rate of 79.3%, 98.2% and 1.8% respectively.The presence of four or more descriptors of cytologic atypia or the presence of both nuclear inclusions and grooves together confers a high risk of malignancy on final histopathology and a low false positive rate. These findings should be taken into consideration when interpreting FNA reports and total thyroidectomy should be considered for those patients at higher risk.

Background Mutation analysis is potentially a powerful tool to enhance the diagnostic accuracy of thyroid fine-needle aspiration (FNA) biopsy specimens. However, some clinicians may rely on a negative mutation panel to exclude malignancy. We aimed to determine the malignancy rate in indeterminate lesions with negative mutation analysis. Methods A literature review established a mutation analysis model using the prevalence of BRAF, RET, RAS, and PAX8/peroxisome proliferator-activated receptor-γ mutations in indeterminate lesions. This model was applied retrospectively to a study cohort of 466 consecutive indeterminate lesions that underwent hemi- or total thyroidectomy for definitive diagnosis, to evaluate its accuracy for identifying malignancy. Results Of 466 indeterminate lesions in the study, 30% (139) were malignant. These included 66 cases of papillary thyroid cancer, 45 cases of follicular variant of papillary thyroid cancer, 18 cases of follicular thyroid cancer, and 10 others. The risk of malignancy was 42% when cytologic atypia was present vs 17% without. The mutation analysis model would correctly identify only 48 of 139 (34%) of malignant indeterminate lesions. Therefore, when mutation analysis is negative, the overall risk of malignancy would be 23%. When atypia is present, the risk of malignancy would be 31% vs 13% in lesions without. Conclusion Indeterminate lesions with a negative mutation analysis still carry a significant risk of malignancy, especially in the presence of atypia, requiring surgery for definitive diagnosis.

argeting BRAFV600E using nanoliposomal-small nterfering RNA restores the expression of sodium iodide ymporter and increases the uptake of iodide in thyroid ancer cells aniel Buitrago MD, Hasan Aldailami BSC, Alexander Veach BSC, ilippo Filicori MD, Xavier M Keutgen MD, Mike Crowley BSC, oonsoo Jin SCD, Thomas J Fahey III MD, FACS, asa Zarnegar MD, FACS eill Cornell Medical College, New York, NY, Cornell University, thaca, NY and Memorial Sloan Kettering Cancer Center, New ork, NY