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Repeat renal surgery is technically demanding with a high morbidity rate. We describe a novel surgical approach, a salvage robotic transmesenteric off-clamp partial nephrectomy for the management of a renal cell carcinoma in a patient with a history of VHL and multiple prior renal surgeries on the affected kidney. Upon pathological review, the specimen was diagnosed as clear cell RCC, Fuhrman Grade 3, with negative surgical margins. The patient suffered no post-operative complications and had a rapid convalescence. This approach is a feasible and safe alternative in select patients with a significant history of renal surgeries and favorable anatomy. Keywords: Partial nephrectomy, Renal cell carcinoma, Robotics, Surgical approach, von Hippel-Lindau

293 Background: Active surveillance (AS) is now considered a well-accepted alternative for low-favorable intermediate risk prostate cancer over definitive therapy. Few studies have incorporated the use of multi-parametric MRI (mpMRI) into the treatment paradigm. In this study we investigate imaging findings that are predictive of a patient dropping off AS. Methods: Our institutional database was queried for all patients who met criteria for active surveillance from 11/2003 to 5/2017. Criteria for inclusion included ≥ 2 mpMRIs, ≥ 2 prostate biopsies, and a diagnosis of Gleason Grade group (GG) 1 or higher. Patients were excluded if they received any other therapy for the treatment of their prostate cancer such as radiation, chemotherapy, focal therapy, or immunologic therapy. Patient demographics, mpMRI, biopsy and most recent follow-up data were recorded. Factors, including PSA density (PSAD), PSA, lesion size, and PI-RADS category, associated with AS progression were evaluated in Cox Proportional Hazards Model. Results: An analysis of a total of 212 patients were performed during the study time interval. 88 patients were dropped from AS during this time and of those patients the median amount of time before removal was 4.70 years (range, 0.7-10.5). On univariable analysis, PI-RADS category (HR, 1.302 for every increase in 1 unit of the PI-RADS category; 95% CI, 1.046-1.62, p = 0.01) and PSAD (HR, 4.98 for every increase in 0.001 ng/mL/cc; 95% CI, 2.127-11.66; p < 0.001) were found to be associated with being removed from AS. On multivariable analysis, both PI-RADS score (HR, 1.281 for every increase in 1 unit of the PI-RADS category; 95% CI, 1.025-1.6; p = 0.003) and PSAD (HR, 4.188 for every increase in 0.001 ng/mL/cc; 95% CI, 1.640-10.7; p < 0.001) remained associated with being removed from AS. Conclusions: PI-RADS categories and PSAD predict the risk of a patient to drop off active surveillance. AS. Patients with these criteria should be considered high risk in any current AS protocol.[Table: see text]

283 Background: MRI/US fusion guided prostate biopsy (FBx) has been shown to detect clinically significant prostate cancer (csCaP) at higher rates and with fewer cores than standard prostate biopsy. Size plays an important role in assigning a suspicion level (PI-RADS) to lesions identified on MRI. However, tumor characteristics may pose challenges to accurately characterizing the lesion despite the size. This study sought to determine if there are size cutoffs at which a lesion may be accurately characterized as clinically significant cancer with a single biopsy core. Methods: A retrospective analysis of a prospectively maintained database of all patients undergoing FBx at an academic referral center between May 2014 and January 2018 was conducted. At least two FBx cores were taken from each lesion identified on mpMRI. GEE-based univariate logistic regression model with exchangeable correlation was used determine if size was a significant predictor of positive and negative agreement. Predictability of size as a significant continuous predictor was quantified by AUC. Size thresholds at which multiple cores per lesion are needed to avoid missing > 2% of csCaP were calculated, allowing for a 25% discordance rate. Results: An analysis of a total of 1141 FBx of 2200 lesions was performed during the study time interval. Size was a significant predictor of both positive (OR = 2.43, 1.83-3.23, p < 0.01) and negative (OR = 0.58, 0.44-0.76, p < 0.01) agreement of csCaP. AUC% for positive and negative agreement was 65.8 and 57.6, respectively. Size thresholds of 0.65 and 1.70 cm limited CS cancers missed by skipping a second targeted biopsy core to 2% while allowing for a 25% discordance. Conclusions: These data indicate that clinically significant prostate cancer in lesions less than 0.65 cm and greater than 1.70 cm may be characterized with a single targeted biopsy core, sparing 33.5% of lesions (21% patients) a double core targeted biopsy.

The frequency of co-occurrence between germ cell tumor (GCT) components in non-seminomatous germ cell tumor (NSGCT) orchiectomy specimens and their correlation with histologic findings in subsequent retroperitoneal lymph node dissection (RPLND) specimens have not been well characterized. The objective of the study was to report the first detailed clinicopathologic analysis of NSGCT orchiectomy and RPLND samples to determine the likelihood and agreement of the co-occurrence of GCT components. A total of 118 consecutive patients with NSGCT treated between 1988 and 2012 who underwent both orchiectomy and RPLND at a single academic tertiary care center were analyzed. Statistical analysis of co-occurrence likelihood and agreement of GCT components was performed, both within and between orchiectomy and RPLND specimens. Embryonal carcinoma was the most frequent component present in orchiectomy specimens, and there were multiple significant associations between orchiectomy GCT components; seminoma occurred less frequently with embryonal carcinoma (OR 0.29 [95% confidence interval (CI) 0.11–0.75]; p

To evaluate whether incidental pathologic T3a (pT3a) upstaging after partial nephrectomy (PN) for clinical T1 disease results in inferior oncologic outcomes compared to pT1a-b disease.Retrospective chart review was completed at the University of Michigan and Moffitt Cancer Center to identify patients undergoing PN for clinical T1 masses between 1995 and 2015. A total of 1955 patients were identified, of which 95 had pT3a upstaging. Median follow-up was 38.2 months. Patients with pT3a disease were individually matched by clinicopathologic features with patients undergoing PN with pT1a-b disease in a 1:2 ratio. Kaplan-Meier analysis and univariate and multivariable Cox proportional hazards regression analysis were performed. Primary endpoint was recurrence-free survival (RFS). Secondary endpoints were all-cause mortality, cancer-specific survival (CSS), and rates of local and distant recurrence.Recurrence rates were significantly higher in pT3a disease compared to pT1a-b controls (P .01). In those patients with pT3a upstaging, 3- and 5-year RFS were 81% and 58%, compared to 86% and 75% in pT1a-b controls (P = .01). CSS at 3 and 5 years were 91% and 90% in pT3a disease and 100% and 97% in pT1a-b controls (P .01). All-cause mortality at 3 and 5 years were 82% and 71% in pT3a disease and 93% and 80% in pT1a-b controls (P = .04). Univariate and multivariable analysis of pT3a disease demonstrated no association between demographic or pathologic characteristics and RCC recurrence.Patients with pT3a upstaging following PN experience a significantly reduced RFS and CSS when compared to pT1 disease.

Results of recent trials have shown the superiority of mpMRI to TRUS-guided systematic biopsy for detecting clinically significant prostate cancer. However, only performing an mpMRI risks missing MRI-invisible lesions and, therefore, there might be added value in performing both targeted and systematic biopsies in biopsy-naive patients.

Background Parathyroid carcinoma (PTCA) is an exceptionally rare malignancy, often with a clinical presentation similar to that of benign atypical parathyroid adenoma. Its low incidence portends unclear guidelines for management. Accordingly, thorough examination of clinical and pathologic variables was undertaken to distinguish between PTCA and atypical adenomas. Study Design This was a retrospective analysis of a prospective database at a tertiary academic referral center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of PHPT. Of these, 52 harbored aggressive parathyroid tumors: parathyroid carcinomas (n = 18) and atypical adenomas (n = 34). We analyzed the surgical and clinicopathologic tumor characteristics, and did a statistical analysis. We measured preoperative and intraoperative variables, and postoperative and pathologic outcomes. Results Parathyroid carcinoma patients present with significantly increased tumor size (3.5 cm vs 2.4 cm, respectively; p = 0.002), mean serum calcium (13.0 vs 11.8 mg/dL, respectively; p = 0.003) and intact parathyroid hormone (iPTH) levels (489 vs 266 pg/mL, respectively; p = 0.04), and a higher incidence of hypercalcemic crisis, compared with patients with atypical adenomas (50% vs 19%, respectively; p = 0.072). Parathyroid carcinoma more frequently lacks a distinct capsule (47.1% vs 12.9%, respectively; p = 0.03) and adheres to adjacent structures (77.8% vs 20.6%, respectively; p = 0.017). Of note, there was no significant difference in loss of parafibromin expression between groups. Conclusions Clinical distinction between PTCA and atypical adenomas is of critical importance in determining the appropriate extent of resection and follow-up. Loss of parafibromin has not been shown to distinguish between PTCA and atypical adenoma; clearer definition of clinicopathologic criteria for PTCA is warranted and may lead to improved postoperative management.

Background Remedial cervical exploration for persistent or recurrent primary hyperparathyroidism can be technically difficult, but is expedited by accurate preoperative localization. We investigated the use of real-time super selective venous sampling (sSVS) in the setting of negative noninvasive imaging modalities. Study Design We performed a retrospective analysis of a prospective database incorporating real-time sSVS in a tertiary academic medical center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of primary hyperparathyroidism. Of these, 31 represented remedial patients who had undergone one (n = 28) or more (n = 3) earlier cervical explorations and had noninformative, noninvasive preoperative localization studies. Results We extended the use of the rapid parathyroid hormone assay in the interventional radiology suite, generating near real-time data facilitating onsite venous localization by a dedicated interventional radiologist. The predictive value of real-time sSVS localization was investigated. Overall, sSVS correctly predicted the localization of the affected gland in 89% of cases. Of 31 patients who underwent sSVS, a significant rapid parathyroid hormone gradient was identified in 28 (90%), localizing specific venous drainage of a culprit gland. All patients underwent subsequent surgery and were biochemically cured, with the exception of one who had metastatic parathyroid carcinoma. Three patients with negative sSVS were also explored and cured. Conclusions Preoperative parathyroid localization is of paramount importance in remedial cervical explorations. Real-time sSVS is a sensitive localization technique for patients with persistent or recurrent primary hyperparathyroidism, when traditional noninvasive imaging studies fail. These results validate the utility and benefit of real-time sSVS in guiding remedial parathyroid surgery.

Background: Patients with inherited immune deficiency diseases often require surgical procedures, and their immune defects may predispose them to surgical complications. Methods: A thorough review of pertinent literature and current practice guidelines on surgery in patients with immune deficiency. Results: Peri-operative infections are a key, but not a singular, consideration in managing patients with a primary immune deficiency. Bleeding diathesis, gastrointestinal complications, pulmonary complications, and poor incision healing may also be idiosyncratic features unique to particular immune deficiency diseases. Patients with complex genetic syndromes that include immune deficiency also may display non-immunologic abnormalities that are equally important to surgical care. Conclusion: Greater awareness of primary immune deficiencies and a comprehensive evaluation of such patients in close consultation with an immunologist can minimize surgical complications and optimize patient outcomes.

OBJECTIVE To evaluate whether incidental pathologic T3a (pT3a) upstaging after partial nephrectomy (PN) for clinical T1 disease results in inferior oncologic outcomes compared to pT1a-b disease. MATERIALS AND METHODS Retrospective chart review was completed at the University of Michigan and Moffitt Cancer Center to identify patients undergoing PN for clinical T1 masses between 1995 and 2015. A total of 1955 patients were identified, of which 95 had pT3a upstaging. Median follow-up was 38.2 months. Patients with pT3a disease were individually matched by clinicopathologic features with patients undergoing PN with pT1a-b disease in a 1:2 ratio. Kaplan-Meier analysis and univariate and multivariable Cox proportional hazards regression analysis were performed. Primary endpoint was recurrence-free survival (RFS). Secondary endpoints were all-cause mortality, cancer-specific survival (CSS), and rates of local and distant recurrence. RESULTS Recurrence rates were significantly higher in pT3a disease compared to pT1a-b controls (P

Objective Integrated 6-year cardiothoracic surgical residency programs have recently been implemented in the United States. We report the results of the first published nationwide survey assessing the motivations, satisfaction, and ambitions of integrated 6-year residents. Methods A 63-question web-based survey was distributed to 83 residents enrolled in 21 Accreditation Council for Graduate Medical Education–accredited integrated 6-year programs in November 2013. There was an outstanding 69% response rate. Results The median age of integrated 6-year residents was 29 years with women comprising 24%. A clear majority had faculty mentorship (95%) and significant clinical exposure in medical school. Focused (100%) and abbreviated (74%) training curricula were identified as the top advantages of integrated 6-year programs; the format itself was a significant factor (46%) in career choice. Most integrated 6-year residents (95%) were satisfied with their program; 80.7% were satisfied with their operative experience thus far. Career plans skewed toward adult cardiac surgery (67%), followed by pediatric cardiac (24%) and general thoracic (9%) surgery; 49% were not particularly concerned about future employment, with 65% foreseeing an increase in opportunities. Specialized training (eg, aortic, heart failure, minimally invasive, congenital) was anticipated by 77%. Most integrated 6-year residents envision an academic career (94.7%). Conclusions This survey takes an important snapshot of the nascent integrated 6-year format. Mentorship and intense clinical exposure are critical in attracting applicants. Purported advantages of the format are holding true among integrated 6-year residents, with the majority satisfied with their programs. These early data indicate that this format holds significant promise in attracting and retaining highly qualified trainees to academic cardiothoracic surgery.

While radical cystectomy (RC) with pelvic lymph node dissection (PLND) represents the accepted gold standard for the treatment of muscle-invasive bladder cancer, this treatment approach is associated with significant morbidity. As such, bladder preservation strategies are often utilized in patients who are either deemed medically unfit due to significant comorbidities or whom decline management with RC and PLND secondary to its associated morbidity. In a select group of patients, meeting strict criteria, bladder preservation approaches may be employed with curative intent. Trimodal therapy, consisting of complete transurethral resection of bladder tumor (TURBT), chemotherapy, and radiation therapy has demonstrated durable oncologic control and long-term survival in a number of studies. The review presented here provides a description of trimodal therapy and the role of TURBT in bladder preservation for patients with muscle-invasive bladder cancer.

101 Background: Prostate multi-parametric magnetic resonance imaging (mpMRI) can precisely depict prostate cancer (PCa) location and adverse pathologic features. Surgeons can utilize this information to maximize sparing of the neurovascular bundles (NVBs) during radical prostatectomy (RP) while avoiding a positive surgical margin (PSM). We detail the technique of using preoperative mpMRI to quantify its effect regarding nerve-sparing and rates of PSMs. Methods: A prospectively maintained database was queried for robotic-assisted RPs (RARPs) with preoperative mpMRI between 2007-2017. Imaging margin risk factors (iMRF) were defined on mpMRI as frank extraprostatic extension (EPE), possible EPE, and capsular irregularity (capsular bulge, lesion-capsule contact, or lesion adjacency to the neurovascular bundles). Surgical adjustments to nerve-sparing technique (full sparing, partial sparing, and wide excision) were made based on these findings. Results: Five hundred thirty-two patients comprising 1041 prostate sides were included for analysis. Overall, PSM rate was found in 80/1041 (7.7%) sides of the prostate. iMRF were seen in 313/1041 (30.1%) prostate sides, for which adjustments were made in 244/313 (78.0%) of these. In the 69/244 (22.0%) cases where full nerve-sparing was performed despite iMRF, PSM rate was 20/69 (29%) compared to 33/244 (13.5%), p = 0.002. MRI-guided surgical adjustments decreased PSM risk by 68% and 15% in pT3 and pT2 cases, respectively. On multivariable analysis, logPSA (odds ratio [OR] 4.06, [95% CI 2.40-12.3], p < 0.001) and iMRF (OR 1.78, [95% CI 1.01-3.16], p = 0.047) were significantly associated with PSM while nerve-sparing adjustment was significantly associated with decreased risk of PSM (OR 0.38 [95% CI 0.22-0.66], p = 0.001). Conclusions: MRI effectively detects risks for PSM and guides surgical adjustments to decrease PSM rates. As prostate MRI is more frequently acquired for PCa screening and biopsy, we show its additional value for RP planning and potentially improved outcomes.

108 Background: MRI fusion prostate biopsy has been shown to improve detection of clinically significant prostate cancer, however the degree of this benefit is poorly characterized in large clinical trials. Methods: 1750 MRI targeted plus sextant biopsies were performed in 1742 male patients from 2007 to 2017. Patient demographics, PSA, prostate volume, primary and secondary Gleason scores, Johns Hopkins Grade Groups, number of MRI targeted lesions, number of cores obtained, and biopsy yield were recorded. Results: The patient population consisted of men averaging 62.9-year-old (36-86) with a mean PSA 9.6ng/mL, and prostate volume of 59.2 ml. A total of 804 cancers were detected on sextant biopsy and 839 were detected on MRI targeted biopsy. Relative to targeted biopsy, sextant biopsy detected only significantly more Gleason 6 disease (14% vs 21.5%, p < 0.0001) than targeted biopsy. Targeted biopsy detected more Gleason 7 (21% vs 16.6%, p = 0.0009) and Gleason 8-10 (13.4% vs 9.4%). Additionally, Gleason 7 sub-stratification demonstrated substantially more Gleason 4+3 detection in targeted group vs sextant biopsy (4% vs 0.5%, p < 0.0001). When stratified by Grade Group targeted biopsy detected 76% more Grade Group 3-5 cancers (p < 0.0001) and 17.7% less Gleason Group 1-2 cancers (p < 0.0001). Only 1.7% of Grade Group 3-5 cancers were detected on sextant biopsy alone, where as 15.7% of Grade Group 3-5 cancers were detected on targeted biopsy alone. Conclusions: MRI targeted biopsy significantly increases the likelihood of detecting clinically significant cancer and decreases the risk of indolent cancer detection. These finding strongly support the use of MRI targeted biopsy when possible.

110 Background: Epidemiologic data suggests a link between obesity and increased risk of aggressive prostate cancer (PCa). Therefore, the accurate detection of prostate cancer is paramount in obese men. We sought to characterize the PCa lesions seen on multiparametric magnetic resonance imaging (mpMRI) in both obese (OB) and non-obese (nOB) patients. In addition, we examined whether obesity affects the accuracy of fusion biopsy (FBx) versus systematic biopsy (SBx). Methods: Data from patients who underwent FBx, SBx, or both, and subsequent prostatectomy at a single institution between 2007-2017 were reviewed. Men were stratified into three groups based on body mass index (BMI): normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). mpMRIs were analyzed to determine prostate size, lesion size, lesion location, and evidence of ≥T3 disease. FBx and SBx were compared to prostatectomy specimens. These variables were then analyzed between the OB and nOB groups. Results: 487 patients were included: 109 (19%) normal weight, 266 (48%) overweight, and 185 (33%) obese. No statistical differences were noted in age, PSA, or clinical stage. mpMRI showed similar prostate size, index and total lesion diameter, lesion location, and Prostate Imaging Reporting and Data System (PIRADS) score between BMI categories. In OB patients, FBx was better able to predict final Gleason score (GS) than SBx, 60% vs 47%, p = 0.0474, OR 1.67 (1.00-2.80). The rate of upgrading after SBx was higher for OB men versus nOB men, 44% vs 34%, p = 0.034, OR 1.52 (1.01-2.29). However, risk of upgrading returned to that of nOB men with FBx, 20% vs 17%, p = 0.538, OR 1.21 (0.658-2.23). Conclusions: FBx is a more accurate measure of the true GS in OB patients than SBx, and there is a significantly greater risk of underrepresenting PCa on SBx in OB patients. These findings were not associated with differences in prostate sizes and lesion characteristics on mpMRI. This suggests that obesity may cause technical challenges with prostate biopsies that may be overcome by improved visualization and targeting of FBx.

104 Background: MRI/US fusion guided prostate biopsy (FBx) has been shown to detect clinically significant prostate cancer (csCaP) at higher rates and with fewer cores than standard prostate biopsy. However, the number of targeted cores needed to accurately characterize lesions identified on multiparametric MRI (mpMRI) is unknown. This study sought to determine factors that predict the number of cores needed to accurately characterize lesions during FBx of patients on active surveillance. Methods: A retrospective analysis of a prospectively maintained database of all patients undergoing FBx at an academic referral center between May 2014 and January 2018 was conducted. At least two FBx cores were taken from each lesion identified on mpMRI. Patient and lesion specific factors were analyzed to determine factors that predict the necessity to obtain additional cores to detect csCaP. GEE-based univariate logistic regression model with exchangeable correlation was used to estimate the effects of clinical characteristics including race, BMI, PSA, PSA density (PSAD), lesion location, and PI-RADS score on the proportion of positive and negative agreement. Predictability of a significant continuous predictor was quantified by AUC. The most significant patient-level predictor (PSAD) was further analyzed to determine thresholds at which multiple cores per lesion are needed to avoid missing csCaP. Results: An analysis of a total of 1141 FBx were performed during the study time interval. PSA (OR=1.57, 1.20-2.05, p2 or greater than 0.26 ng/ml2, lesions may be acceptably characterized with a single targeted biopsy core.

TNF, signaling through TNFR2, has been implicated in tissue repair, a process that in the heart may be mediated by activated resident cardiac stem cells (CSCs). The objective of our study is to determine whether ligation of TNFR2 can induce activation of resident CSCs in the setting of ischemic cardiac injury. We show that in human cardiac tissue affected by ischemia heart disease (IHD), TNFR2 is expressed on intrinsic CSCs, identified as c-kit+/CD45−/VEGFR2− interstitial round cells, which are activated as determined by entry to cell cycle and expression of Lin-28. Wild-type mouse heart organ cultures subjected to hypoxic conditions both increase cardiac TNF expression and show induced TNFR2 and Lin-28 expression in c-kit+ CSCs that have entered cell cycle. These CSC responses are enhanced by exogenous TNF. TNFR2−/− mouse heart organ cultures subjected to hypoxia increase cardiac TNF but fail to induce CSC activation. Similarly, c-kit+ CSCs isolated from mouse hearts exposed to hypoxia or TNF show induction of Lin-28, TNFR2, cell cycle entry, and cardiogenic marker, α-sarcomeric actin (α-SA), responses more pronounced by hypoxia in combination with TNF. Knockdown of Lin-28 by siRNA results in reduced levels of TNFR2 expression, cell cycle entry, and diminished expression of α-SA. We conclude that hypoxia-induced c-kit+ CSC activation is mediated by TNF/TNFR2/Lin-28 signaling. These observations suggest that TNFR2 signaling in resident c-kit+ CSCs induces cardiac repair, findings which provide further understanding of the unanticipated harmful effects of TNF blockade in human IHD.

Context Over the previous2 decades, there have been numerous advancements in the diagnostic evaluation, therapeutic management, and postoperative assessment of genitourinary malignancies. Objective To present a review of current and novel imaging modalities and their utility in the assessment of therapeutic response in the systemic management of renal, testicular, and prostate cancers. Evidence acquisition A PubMed/Medline search of the current published literature inclusive of prospective and retrospective original research, systematic reviews, and meta-analyses was conducted evaluating imaging modalities for renal cell carcinoma, prostate cancer, and testicular cancer. All relevant literature was individually reviewed and summarized to provide a concise description of the currently available imaging modalities and their efficacy in assessing treatment response of the genitourinary malignancies targeted in this review. Evidence synthesis Conventional imaging techniques play a pivotal role in predicting the treatment response of genitourinary malignancies and have, therefore, been incorporated into clinical guidelines. Advancements in imaging technology have led to increased utilization for prognostication of a genitourinary cancer’s response to therapy. Conclusions A good understanding of current recommended imaging techniques to evaluate treatment response in genitourinary malignancies is of paramount importance for today’s clinician, who faces increasing treatment modalities. Patient summary In this review, we summarize available imaging modalities in the evaluation of treatment response in kidney, prostate, or testicular tumors. We believe that a good understanding of current imaging modalities is of paramount importance for healthcare providers treating these cancers.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy that generally conveys a poor prognosis. Currently, surgical resection is considered the lone curative treatment modality. In addition, the low prevalence of ACC has limited effective clinical trial design to develop evidence-based approaches to ACC therapy. The proper role of radio- and chemotherapy treatment for ACC is still being defined. Similarly, the molecular pathogenesis of ACC remains to be fully characterized. Despite these challenges, progress has been made in several areas. After years of refinement, an internationally accepted staging system has been defined. International collaborations have facilitated increasingly robust clinical trials, especially regarding agent choice and patient selection for chemotherapeutics. Genetic array data and molecular profiling have identified new potential targets for rational drug design as well as potential tumor markers and predictors of therapeutic response. However, these advances have not yet been translated into a large outcomes benefit for ACC patients. In this paper, we summarize established therapy for ACC and highlight recent findings in the field that are impacting clinical practice.

Perioperative injuries to an allograft exacerbate graft rejection, which in humans is primarily mediated by effector memory T cells. IL-6 transcripts in human coronary artery segments rapidly increase posttransplantation into immunodeficient mouse hosts compared with those of pretransplant specimens and fall dramatically by 30 d. Adoptive transfer of human PBMCs allogeneic to the artery 2 d postoperatively results in T cell infiltrates and intimal expansion 4 wk later. Ab neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration but increases the relative expression of CD161 while decreasing other Th17 markers. Coculture of MHC class II-expressing human endothelial cells (ECs) with allogeneic CD4+ memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell–EC cocultures results in enhanced T cell proliferation of CD161+ CD4+ T cells, reduces total T cell proliferation upon restimulation in secondary cultures (an effect dependent on CD161+ T cells), increases expression of FOXP3 in CD161+ T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161+ regulatory T cells.

Despite pro-fibrotic effects, transforming growth factor (TGF)-β prevents arteriosclerosis by suppressing effector leukocytes and promoting smooth muscle differentiation. However, previous observations of increased TGF-β expression in arteriosclerotic plaques are not consistent with that of an effective protective factor. We investigated the expression, regulation, and responses of TGF-β in human arterial tissues and cells.The expression of TGF-β by intrinsic vascular cells was lower in arteriosclerotic than non-diseased coronary arteries. Activation of resident and infiltrating leukocytes did not elicit TGF-β production from coronary artery segments in organ culture. Instead, the basal expression of TGF-β by coronary arteries decreased after vessel procurement and ex vivo culture. Activation of cultured smooth muscle cells and endothelial cells with phorbol ester and ionophore also decreased TGF-β expression. Isolated cell types representing those found in the artery wall were all capable of signaling in response to TGF-β, however production of the cytoprotective molecule, interleukin-11 was cell type-dependent and restricted to smooth muscle cells and fibroblasts. Interleukin-11 reduced smooth muscle cell apoptosis to T cell effectors.Inflammation and cellular activation diminish the basal expression of TGF-β by quiescent human vascular cells. Induction of interleukin-11 may contribute to the anti-arteriosclerotic actions of TGF-β.

Small bowel volvulus in the absence of a congenital anomaly is rare but has been described in post-operative patients after abdominal surgery and is usually related to inflammatory conditions. The authors describe an adolescent girl with small bowel volvulus secondary to an oral fiber bolus after laparoscopic appendectomy that required emergency laparotomy and reduction. She subsequently developed early post-operative complete bowel obstruction requiring re-laparotomy and resection.

Attitudes, career goals, and educational experiences of general surgery residents are profiled during the acquisition of a community residency program by an academic residency program.The study population included all general surgery residents postgraduate years 2-5 in a tertiary academic medical center divided into community program matriculants (CPM) or academic program matriculants (APM). A survey compared perceptions before and after residency amalgamation in seven training categories as follows: relationships among residents, relationships with faculty, systems interactions, clinical training, surgical training, scholarship, and career plans. Responses were recorded on a Likert scale. Fisher exact test and one-sided t-test were applied.Thirty-five trainees (83%) participated, 23 APM (66%) and 12 CPM (34%). Neither cohort reported significant negative perceptions regarding surgical training, career planning, or scholarship (P 0.05). There was a greater likelihood of significant negative perceptions regarding inter-resident relationships among CPM (P 0.05). CPM perceived significantly improved opportunities for scholarship (P 0.01) and nationwide networking through faculty (P 0.05) after acquisition. There was a nearly significant trend toward CPM perceiving greater access to competitive specialties after acquisition. Overall, CPM perceptions were affected more often after acquisition; however, when affected, APM were less likely to be positively affected (odds ratio, 2.9).Acquisition of a community surgery residency by an academic program does not seem to negatively affect trainees' perceptions regarding training. The effect of such acquisition on CPMs' decision to pursue competitive fellowships remains ill defined, but CPM perceived improved research opportunities, faculty networking, and programmatic support to pursue a career in academic surgery.

Importance Locoregional anesthesia, conscious sedation, and exploration via a limited incision have become a well-accepted approach for the treatment of patients with primary hyperparathyroidism with image-localized, presumed single-gland disease. However, to our knowledge, this minimally invasive technique has never been investigated in patients with multigland disease. Objective To extrapolate the technique of locoregional anesthesia, conscious sedation, and exploration via a limited incision to perform minimally invasive bilateral exploration in patients who have multigland hyperplasia. Design, Setting, and Participants Retrospective analysis at a tertiary academic referral center of 100 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidism due to parathyroid hyperplasia between January 19, 2010, and July 30, 2013, who were included in a prospective database. Interventions All patients underwent subtotal parathyroidectomy using either conventional treatment (bilateral neck exploration under general anesthesia) or extended minimally invasive parathyroidectomy (ex-MIP; locoregional anesthesia, conscious sedation, and exploration via a limited incision). Patients in the ex-MIP group who required conversion to general anesthesia were analyzed in the ex-MIP group on an intent-to-treat basis. Main Outcomes and Measures Patient cure and complication rates, length of stay, and total hospital charges. Results Of the 100 consecutive patients with parathyroid hyperplasia, 29 received conventional treatment and 71 underwent ex-MIP. In the ex-MIP group, 11 of 71 patients (15.5%) required conversion to general anesthesia. There were no differences between the ex-MIP and conventional treatment groups in age (mean [SD], 62.2 [12.2] vs 57.7 [15.2] years; P = .12), sex (59 [83.1%] vs 23 [79.3%] female; P = .78), preoperative serum calcium level (mean [SD], 11.1 [0.9] vs 10.8 [0.8] mg/dL; to convert to millimoles per liter, multiply by 0.25; P = .15), preoperative serum parathyroid hormone level (mean [SD], 114.5 [56.8] vs 137.8 [83.4] pg/mL; to convert to nanograms per liter, multiply by 1; P = .10), complications (4 vs 0 complications; P = .32), or cure rates (98.6% vs 96.6%; P = .50). Importantly, the ex-MIP group had a significant reduction in length of stay compared with the conventional treatment group (mean [SD], 1.01 [0.02] vs 1.35 [0.24] days; P = .04). They also had lower total hospital charges, but the difference was not statistically significant (mean, $23 199 vs $27 312; P = .17). Conclusions and Relevance Parathyroidectomy with bilateral neck exploration under general anesthesia has been the standard of care for the treatment of parathyroid hyperplasia. We demonstrate that ex-MIP can provide equivalent cure and complication rates with a shorter hospital stay and a mean hospital charge reduction of more than $4000 per case.

Objective The recently implemented integrated 6-year (I-6) format represents a significant change in cardiothoracic surgical residency training. We report the results of the first nationwide survey assessing I-6 program directors' impressions of this new format. Methods A 28-question web-based survey was distributed to program directors of all 24 Accreditation Council for Graduate Medical Education-accredited I-6 training programs in November 2013. The response rate was a robust 67%. Results Compared with graduates of traditional residencies, most I-6 program directors with enrolled residents believed that their graduates will be better trained (67%), be better prepared for new technological advances (67%), and have superior comprehension of cardiothoracic disease processes (83%). Just as with traditional program graduates, most respondents believed their I-6 graduates would be able to independently perform routine adult cardiac and general thoracic operations (75%) and were equivocal on whether additional specialty training (eg, minimally invasive, heart failure, aortic) was necessary. Most respondents did not believe that less general surgical training disadvantaged I-6 residents in terms of their career (83%); 67% of respondents would have chosen the I-6 format for themselves if given the choice. The greater challenges in training less mature and experienced trainees and vulnerability to attrition were noted as disadvantages of the I-6 format. Most respondents believed that I-6 programs represent a natural evolution toward improved residency training rather than a response to declining interest among medical school graduates. Conclusions High satisfaction rates with the I-6 format were prevalent among I-6 program directors. However, concerns with respect to training relatively less experienced, mature trainees were evident.

Endometriosis is a common disease in women of childbearing age and is defined as the presence of endometrial glands and stroma in organs outside of the uterine cavity. Appendiceal endometriosis is very uncommon and accounts for a small fraction of all cases of extrapelvic endometriosis. Cases of that which occur during pregnancy are extremely rare with an incidence that ranges between 3 and 8 deliveries per 10 000. This makes the diagnosis extremely difficult and represents a challenge in the management of the patient. In this report we describe the case of a pregnant woman who underwent ileocecectomy for perforated appendicitis stemming from endometriosis and subsequent pre-term delivery of a 31-week-old fetus.

Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells. The killing of β-cells is not currently measurable; β-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify β-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure β-cell death in a clinical trial of teplizumab. We studied 43 patients with recent-onset T1D, 13 nondiabetic subjects, and 37 patients with T1D treated with FcR nonbinding anti-CD3 monoclonal antibody (teplizumab) or placebo. Patients with recent-onset T1D had higher rates of β-cell death versus nondiabetic control subjects, but patients with long-standing T1D had lower levels. When patients with recent-onset T1D were treated with teplizumab, β-cell function was preserved (P < 0.05) and the rates of β-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of β-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased β-cell death. © 2013 by the American Diabetes Association.

Adequate vitamin D levels may promote cardiovascular health by improving endothelial function and down-regulating inflammation. The objective of this pilot trial was to investigate the effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease (CAD). Using a double-blind placebo wait-list control design, 90 subjects with CAD and vitamin D deficiency (< 20 ng/ml) were randomized 1:1 to 50,000 IU of oral ergocalciferol or placebo weekly for 12 weeks. Endothelial function (reactive hyperemia peripheral arterial tonometry, RH-PAT), circulating adhesion molecules, and pro-inflammatory cytokines were measured at baseline and 12 weeks. The median increase in serum 25-vitamin D from baseline was 26 ± 17 ng/ml in the active group and 4 ± 8 ng/ml in the placebo group (between-group difference = 22 ng/ml, p < 0.001). The median within-subject change in RH-PAT score was 0.13 ± 0.73 with active treatment and −0.04 ± 0.63 with placebo (between-group difference = 0.17, p = 0.44). Within-group and between-group differences in intercellular adhesion molecule levels were greater with placebo (between-group difference = 6 ng/ml, p = 0.048). Vascular cell adhesion molecule levels decreased in both groups by a similar magnitude (median difference between groups = 8.5 ng/ml, p = 0.79). There was no difference between groups in magnitude of reduction in interleukin (IL)-12 (−8.6 ng/ml, p = 0.72) and interferon-gamma (0.52 ng/ml, p = 0.88). No significant differences in blood pressure, e-selectin, high-sensitivity c-reactive protein, IL-6 or the chemokine CXCL-10 were found with treatment. In conclusion, repleting vitamin D levels in subjects with CAD failed to demonstrate any benefits on surrogate markers of cardiovascular health. These results question the role of vitamin D supplementation in modifying cardiovascular disease.

Arteriosclerosis is characterized by the local activation of effector T cells leading to production of proinflammatory cytokines, such as IFN (interferon)-γ and IL-17, within the vessel wall. Conversely, the production of antiinflammatory cytokines, for example, TGF-β, by regulatory lymphocytes is known to inhibit both the differentiation of naïve T cells into effector T cells and the development of arteriosclerosis in murine models. We investigated the role of TGF-β on the alloreactivity of human effector memory T cells (Tem). Quiescent vascular cells, but not Tem, expressed TGF-β. Blockade of TGF-β activity in cocultures of CD4(+) Tem with allogeneic endothelial cells significantly increased IFN-γ, but not IL-17, secretion. Additionally, serologic neutralization of TGF-β in immunodeficient mouse hosts of human coronary artery grafts into which allogeneic human T cells were adoptively transferred resulted in heavier medial infiltration by Tem, greater loss of medial smooth muscle cells and increased IFN-γ production within the grafts without significantly reducing either intimal injury or IL-17 production. Protective effects of TGF-β may be limited by fewer TGF-β-expressing vascular cells within the intimal compartment, by a reduction in the expression of TGF-β by vascular cells in rejecting grafts, or possibly to less effective suppression of Tem than naïve T cells.

Atherosclerosis of native coronary arteries and graft arteriosclerosis in transplanted hearts are characterized by activation of innate and adaptive immune responses. Nucleic acids generated by infections or cell death have been detected within arteriosclerotic lesions, and it is known that microbial and synthetic nucleic acids evoke inflammatory responses in cultured vascular cells. In this study, we report that model RNA, but not DNA, instigated robust cytokine and chemokine production from intact human coronary arteries containing both intrinsic vascular cells and resident/infiltrating leukocytes. An ssRNA analog induced TNF-α and IFN-γ–induced protein of 10 kDa secretion by isolated human PBMCs, but not vascular cells. Conversely, synthetic dsRNA induced these inflammatory mediators by vascular cells, but not PBMCs. IFN-γ, a cytokine linked to atherosclerosis and graft arteriosclerosis, potentiated the inflammatory responses of intact arteries and cultured vascular smooth muscle cells (VSMCs) to polyinosinic:polycytidylic acid [poly(I:C)] and was necessary for inflammatory responses of VSMC to self-RNA derived from autologous cells. IFN-γ also induced the expression of TLR3, melanoma differentiation-associated gene 5, and retinoic acid-inducible gene I dsRNA receptors. Small interfering RNA knockdown revealed that TLR3 mediated VSMC activation by poly(I:C), whereas melanoma differentiation-associated gene 5 was more important for VSMC stimulation by self-RNA. IFN-γ–mediated induction of dsRNA receptors and priming for inflammatory responses to poly(I:C) was confirmed in vivo using immunodeficient mice bearing human coronary artery grafts. These findings suggest that IFN-γ, and by inference adaptive immunity, sensitizes the vasculature to innate immune activators, such as RNA, and activation of IFN-γ–primed vascular cells by exogenous or endogenous sources of RNA may contribute to the inflammatory milieu of arteriosclerosis.