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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.

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®.

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.

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