Nutritional Assessment and Malnutrition in Patients With Cirrhosis.

We sought to determine the incidence and outcomes of malnutrition in patients with cirrhosis. We performed a retrospective chart review of 134 patients listed for liver transplant (LT) to assess the presence and degree of malnutrition identified by the Subjective Global Assessment score at the time of initial transplant evaluation, follow-up nutrition visits, and at the time of transplant. Number of admissions/readmissions to the hospital, reason for hospitalization(s), and length of stay were determined. Malnutrition was prevalent at initial nutrition visit (51.9%) and underdiagnosed. By the time of transplant, 61% of the patients were identified as malnourished. Most patients (52%) were awaiting LT for more than 180 days. The change in Subjective Global Assessment score after the initial nutrition assessment was statistically significant (p ≤ .007), with worsening malnutrition severity. Seventy-one patients (53%) required hospitalization while awaiting transplant, with a median hospital stay of 9 days. Nutrition expertise is required for prompt and accurate diagnosis of malnutrition in patients with cirrhosis. Nurses caring for patients with advanced liver disease are in a prime position to provide guidance to optimize patient outcomes.

Evolving Role of Liver Transplantation in Elderly Recipients.

The need for liver transplantation (LT) among older patients is increasing, but the role of LT in the elderly (≥70 years) is not well defined. We retrospectively reviewed all primary LTs from 1998 through 2016 at our center. Survival and associated risk factors were analyzed with Cox regression and Kaplan-Meier methods for LT recipients in 3 age groups: <60, 60-69, and ≥70 years. Among 2281 LT recipients, the median age was 56 years (range, 15-80 years), and 162 were aged ≥70 years. The estimated 5- and 10-year patient survival probabilities for elderly LT recipients were lower (70.8% and 43.6%) than for recipients aged 60-69 years (77.2% and 64.6%) and <60 years (80.7% and 67.6%). Patient and graft survival rates associated with LT improved over time from the pre-Model for End-Stage Liver Disease era to Share 15, pre-Share 35, and Share 35 for the cohort overall (P < 0.001), but rates remained relatively stable in septuagenarians throughout the study periods (all P > 0.45). There was no incremental negative effect of age at LT among elderly patients aged 70-75 years (log-rank P = 0.32). Among elderly LT recipients, greater requirement for packed red blood cells and longer warm ischemia times were significantly associated with decreased survival (P < 0.05). Survival of LT recipients, regardless of age, markedly surpassed that of patients who were denied LT, but it was persistently 20%-30% lower than the expected survival of the general US population (P < 0.001). With the aging of the population, select older patients with end-stage liver diseases can benefit from LT, which largely restores their expected life spans.

The Impact of Reexcision and Residual Disease on Local Recurrence Following Breast-Conserving Therapy.

PURPOSE: Risk factors for local recurrence (LR) following breast-conserving therapy (BCT) inform the need for local therapy. A Danish population-based cohort study identified residual disease on reexcision as an independent risk factor for LR but was limited by incomplete data on biologic subtype (Bodilsen et al. 2015 in Ann Surg Oncol 22: S476-S485). We sought to elaborate this risk in an independent cohort with clearly defined biologic subtypes. METHODS: The study population included patients with localized invasive breast cancer with complete biologic subtype data treated with BCT with one or zero reexcisions at one institution from 1998 to 2008. Cumulative incidence of LR was calculated using competing risk analysis, and associated risk factors were evaluated using Cox proportional hazards regression. RESULTS: A total 1073 consecutive patients were included with a median follow-up of 10 years. The 10-year LR rates were 2.4% [95% confidence interval (CI) 1.4-3.9%] without reexcision, 6.0% (95% CI 3.8-8.9%) with reexcision, and 8.2% (95% CI 4.1-14.0%) with any reexcised residual disease. On univariate regression, residual disease [hazard ratio (HR) = 1.50, p = 0.31] was not significantly associated with LR. Subtype other than luminal A/luminal-HER2 (luminal B HR = 2.29, p = 0.033; HER2/triple-negative HR = 2.85, p = 0.004), age (HR = 0.95 per year, p < 0.001), and nodal involvement (HR = 1.12 per involved node, p = 0.001) remained significant on multivariate regression. The impact of residual disease was confounded by its association (p < 0.001) with nodal involvement. CONCLUSIONS: Our findings suggest that LR is associated with younger age, nodal involvement, and biologic subtype but not with residual disease at reexcision. The study's power is limited by the low incidence of LR despite detailed clinical data and long-term follow-up. Further study is required.

The need for preoperative baseline arm measurement to accurately quantify breast cancer-related lymphedema.

Breast cancer-related lymphedema (BCRL) is a feared outcome of breast cancer treatment, yet the push for early screening is hampered by a lack of standardized quantification. We sought to determine the necessity of preoperative baseline in accounting for temporal changes of upper extremity volume. 1028 women with unilateral breast cancer were prospectively screened for lymphedema by perometry. Thresholds were defined: relative volume change (RVC) ≥10 % for clinically significant lymphedema and ≥5 % including subclinical lymphedema. The first postoperative measurement (pseudo-baseline) simulated the case of no baseline. McNemar's test and binomial logistic regression models were used to analyze BCRL misdiagnoses. Preoperatively, 28.3 and 2.9 % of patients had arm asymmetry of ≥5 and 10 %, respectively. Without baseline, 41.6 % of patients were underdiagnosed and 40.1 % overdiagnosed at RVC ≥ 5 %, increasing to 50.0 and 54.8 % at RVC ≥ 10 %. Increased pseudo-baseline asymmetry, increased weight change between baselines, hormonal therapy, dominant use of contralateral arm, and not receiving axillary lymph node dissection (ALND) were associated with increased risk of underdiagnosis at RVC ≥ 5 %; not receiving regional lymph node radiation was significant at RVC ≥ 10 %. Increased pseudo-baseline asymmetry, not receiving ALND, and dominant use of ipsilateral arm were associated with overdiagnosis at RVC ≥ 5 %; increased pseudo-baseline asymmetry and not receiving ALND were significant at RVC ≥ 10 %. The use of a postoperative proxy even early after treatment results in poor sensitivity for identifying BCRL. Providers with access to patients before surgery should consider the consequent need for proper baseline, with specific strategy tailored by institution.

Novel Evidence-Based Classification of Cavernous Venous Occlusive Disease.

PURPOSE: The primary aim of our study was to determine whether an evidence-based rationale could categorize cavernous venous occlusive disease into mild, moderate and severe erectile dysfunction. MATERIALS AND METHODS: A total of 863 patients underwent color duplex Doppler ultrasound from January 2010 to June 2013 performed by a single urologist. We identified a cohort of 75 patients (8.7%) with a diagnosis of cavernous venous occlusive disease based on a unilateral resistive index less than 0.9, and right and left peak systolic velocity 35 cm per second or less after visual sexual stimulation. At a median followup of 13 months patients were evaluated for treatment efficacy. RESULTS: A total of 75 patients with a median age of 60 years (range 19 to 83) and a mean body mass index of 26.3 kg/m(2) (range 19.0 to 39.3) satisfied the criteria of cavernous venous occlusive disease. When substratified into tertiles, resistive index cutoffs were obtained, including mild cavernous venous occlusive disease-81.6 to 94.0, moderate disease-72.6 to 81.5 and severe disease-59.5 to 72.5. Using these 3 groups the phosphodiesterase type 5-inhibitor failure rate (p = 0.017) and SHIM (Sexual Health Inventory for Men) score categories (1 to 10 vs 11 to 20, p = 0.030) were statistically significantly different for mild, moderate and severe cavernous venous occlusive disease. Treatment satisfaction was also statistically significantly different. Penile prosthetic placement was a more common outcome among patients with erectile dysfunction and more severe cavernous venous occlusive disease. CONCLUSIONS: Our retrospective analysis supports a correlation between the phosphodiesterase type 5 inhibitor failure rate, SHIM score and the rate of surgical intervention using resistive index values. Our data further suggest that an evidence-based classification of cavernous venous occlusive disease by color Doppler ultrasound is possible and can triage patients to penile prosthetic placement.

Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy.

OBJECTIVE: To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/mL and rising as the definition of BCR. PATIENTS AND METHODS: We included 577 patients who received SRT for a rising PSA after radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models. RESULTS: With a median follow-up of 5.5 years after SRT, 354 patients (61%) experienced BCR. At 5 years after SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for the PSA level before SRT (RR [doubling]: 1.25, P < 0.001), pathological tumour stage (RR [T3a vs T2] 1.21, P = 0.19; RR [T3b/T4 vs T2] 2.09, P < 0.001; overall P < 0.001), Gleason score (RR [7 vs <7] 1.63, P < 0.001; RR [8-10 vs <7] 2.28, P < 0.001; overall P < 0.001), and surgical margin status (RR [positive vs negative] 0.71, P = 0.003). We combined these four variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score = 0-1: 66%, Score = 2: 46%, Score = 3: 28%, Score = 4: 19%, and Score = 5-7: 15%. CONCLUSION: We developed a scoring system that provides an estimation of the risk of BCR after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting.

Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum.

Thal amyloid phase, which describes the pattern of progressive amyloid-ß plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

Salvage autologous fascial sling after failed synthetic midurethral sling: Greater than 3-year outcomes.

OBJECTIVE: To determine long-term surgical outcomes of salvage autologous fascial sling placement after a failed synthetic midurethral sling. METHODS: Women who had undergone autologous fascial sling placement without concomitant pelvic surgery for a failed synthetic midurethral sling utilizing mesh with a minimum follow up of 36 months were identified. Charts were reviewed, and patients were contacted by telephone. Success was determined by the Patient Global Impression of Improvement. Secondary measures included the Incontinence Severity Index questionnaire, patient recommendation of the autologous fascial sling and need for further incontinence surgery. RESULTS: A total of 35 patients met the criteria, and 21 were successfully contacted. Of those contacted, the median age at surgery was 67 years (range 53-81 years) and at the time of the survey was 75 years (range 63-84 years) with median follow up of 74 months (range 36-127 years). Preoperatively, 12 patients (57.1%) had urethral hypermobility and 13 patients (61.9%) had mixed urinary incontinence. Eight patients (38.1%) had concomitant sling excision with five of those combined with urethrolysis at the time of the salvage operation. Patient Global Impression of Improvement success was noted in 16 patients (76.2%). A total of 11 patients (52.4%) were dry or had slight incontinence by the Incontinence Severity Index. One patient required additional anti-incontinence surgery (4.8%). A total of 18 patients (85.7%) recommended the autologous fascial sling. No statistical impact was noted with sling excision (P = 0.62), mixed urinary incontinence (P = 0.61), age at surgery (P = 0.23), age at follow up (P = 0.15), length of follow up (P = 0.71) or first surgery type (transobturator tape vs retropubic; P = 1.00). CONCLUSIONS: Autologous fascial sling provides reasonable long-term success as a salvage operation for failed midurethral slings.

Accuracy and Validity of Goniometer and Visual Assessments of Angular Joint Positions of the Hand and Wrist.

PURPOSE: To compare goniometric and visual assessments of angular hand joint and wrist joint positions measured by board-certified hand surgeons and certified hand therapists. We hypothesized that visual estimation would be similar to the goniometric measurement accuracy of digital and wrist joint positions. METHODS: The wrist, index finger metacarpophalangeal (MCP) joint, and index finger proximal interphalangeal (PIP) joint were evaluated in different positions by 40 observers: 20 board-certified hand surgeons and 20 certified hand therapists. Each observer estimated the position of the wrist, index MCP joint, and index PIP joint of the same volunteer, who was positioned in low-profile orthoses to reproduce predetermined positions. Following visual estimation, the participants measured the same joint positions using a goniometer. The control measurement was digitally determined by a radiologist who obtained radiographs of the hand and wrist positions in each orthosis. Observers were blinded to the results of control measurements. RESULTS: When considering all joints at all positions, neither visual assessments nor goniometer assessments were consistently within ± 5° of the measurements obtained on control radiographs. When considering individual joints, goniometer measurements were significantly closer to control radiograph measurements than the visual assessments for all 3 PIP joint positions. There was no difference for the measurements at the wrist or for 2 of the 3 MCP joint positions. Significant differences between surgeon and therapist joint angle measurements were not observed when comparing visual and goniometer assessments to radiograph controls. CONCLUSIONS: Compared with radiograph measurements, neither visual nor goniometer assessment displayed high levels of accuracy. On average, visual assessment of the angular positions of the index MCP and wrist joint were as accurate as the goniometer assessment, whereas goniometer assessment of the angular position of the PIP joint was more accurate than visual assessment. There was a relatively high degree of between-observer variability in measurements, and therefore, no one person's measurements could be consistently relied upon to be accurate. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Is mastectomy undertreatment for low-risk breast cancers eligible for breast-conserving therapy?

BACKGROUND: Biomarkers are routinely used to predict responses to systemic therapies, but their utility for predicting responses to local therapy for breast cancer is not known. This study determined whether biomarkers could predict responses to breast-conserving therapy (BCT) and mastectomy. METHODS: A review of the Surveillance, Epidemiology, and End Results database identified women diagnosed with early-stage invasive ductal breast cancer and treated with BCT or mastectomy from 1998 to 2008. The estrogen receptor (ER) status and the histologic grade were used to construct 3 biomarker profiles: low risk (ER-positive, low/intermediate grade), intermediate risk (ER-positive, high grade), and high risk (ER-negative, any grade). The primary measured outcome was disease-specific survival (DSS). RESULTS: BCT and mastectomy were performed in 114,486 patients (59.2%) and 79,035 patients (40.8%), respectively. There were 122,420 low-risk patients (63.3%), 34,341 intermediate-risk patients (17.7%), and 36,760 high-risk patients (19.0%). Multivariate analyses were performed separately for patients with low-, intermediate-, and high-risk tumors. The adjusted hazard ratios for DSS for patients who underwent mastectomy versus BCT for low-, intermediate-, and high-risk tumors were 1.66 (95% confidence interval [CI], 1.54-1.79; P < .001), 1.40 (95% CI, 1.29-1.53; P < .001), and 1.27 (95% CI, 1.19-1.35; P < .001), respectively. CONCLUSIONS: Patients with ER-positive, low-grade breast cancers who underwent mastectomy had a 66% increase in disease-specific mortality versus those who underwent BCT. Biomarker profiles defined by the ER status and grade may improve the selection of local therapy for breast cancer.

Effects of immediate reconstruction on adjuvant chemotherapy in breast cancer patients.

BACKGROUND: Recent studies have shown that patients undergoing immediate breast reconstruction after mastectomy have a higher rate of complications relative to patients undergoing mastectomy alone. Conflicting data exist on how these complications impact adjuvant treatment. We sought to quantify the additional risk associated with immediate breast reconstruction after mastectomy and determine how these risks influence adjuvant chemotherapy. METHODS: A retrospective review of women undergoing mastectomy for breast cancer and immediate breast reconstruction between January 2007 and December 2012 was conducted. We abstracted clinicopathological variables and stratified women according to the type of reconstruction and presence of surgical complications. Additionally, time to adjuvant chemotherapy was assessed. RESULTS: Overall, 56 of 199 (28%) women suffered 70 complications, of which hematoma, skin necrosis, cellulitis, or seroma accounted for 53 (76%) of the complications. The start date of adjuvant therapy was known in 116 (58%) of the women with invasive cancer. Overall, patients that underwent immediate breast reconstruction did not have delay in adjuvant treatment when compared to patients with no reconstruction (41 days vs 42 days, P = 0.61). Women with a complication did have a significantly longer interval to adjuvant chemotherapy when compared to those with no complications (47 days vs 41 days, P = 0.027). When further stratified by type of reconstruction, although there were differences in time to adjuvant chemotherapy, none of these reached significance (tissue expanders: 45 days vs 41 days, P = 0.063; flap reconstruction: 72 days vs 49 days, P = 0.25). CONCLUSIONS: Immediate reconstruction after mastectomy does not delay additional cancer treatment. Overall, when complications do occur, adjuvant therapy is significantly delayed, though the median delay was only 6 days.

Very early mobilization in stroke patients treated with intravenous recombinant tissue plasminogen activator.

BACKGROUND: There are limited prospective data on the relative safety of very early mobilization of stroke patients after intravenous recombinant tissue plasminogen activator (IV rtPA) in stroke patients. We hypothesized that very early patient mobilization within 24 hours after IV rtPA administration for acute ischemic stroke would be safe and feasible. METHODS: The study was a prospective observational safety and feasibility study involving very early mobilization of stroke patients by physical therapy/occupational therapy within 24 hours after IV rtPA administration for treatment of ischemic stroke. A premobilization safety checklist was completed before mobilization to ensure hemodynamic stability. We assessed adverse safety events, including changes in patient symptoms, changes in vital signs, and bleeding complications. RESULTS: Eighteen patients were enrolled in the study, and informed consent was obtained. One hundred percent of patients were evaluated with a premobilization safety checklist; 72.2% (13 of 18) were mobilized without any adverse event. Eighty-nine percent (42 of 47) of mobilization activities were tolerated without an adverse response. One patient was orthostatic, and 1 patient had transient worsening of hemiparesis. No patient had intracranial bleeding or permanent worsening of neurologic deficits. CONCLUSIONS: Very early mobilization within 24 hours of ischemic stroke for patients who receive IV rtPA appears to be relatively safe and feasible in most patients. Patients who are mobilized within 24 hours of IV rtPA require detailed neurologic and vital sign monitoring.

Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.

We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein-protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems-level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14-protein core network critical to the viability of multiple EGFR-mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR-mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance.

Incremental risk associated with contralateral prophylactic mastectomy and the effect on adjuvant therapy.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) is expected to add surgical morbidity but this incremental risk has not yet been defined. We sought to quantify the additional risks associated with CPM and determine how these risks influence the time to adjuvant therapy. METHODS: We identified women undergoing mastectomy for unilateral breast cancer and stratified them according to the use of CPM and the presence and laterality of surgical complications. We measured time to adjuvant therapy. RESULTS: Of 352 patients, 205 (58 %) underwent unilateral mastectomy (UM) and 147 (42 %) underwent bilateral mastectomy (BM) [BM = UM + CPM]. Overall, 94/352 (27 %) women suffered 112 complications (BM: 46/147 [31 %] vs. UM: 48/205 [23 %]; p = 0.11), of which hematoma, skin necrosis, cellulitis, or seroma accounted for 94/112 (84 %) complications. Reoperation was required in 37/352 (10 %) women. Among those undergoing BM, morbidity occurred only in the prophylactic breast in 19/147 (13 %) women and risk did not differ with immediate reconstruction (13/108 [12 %]) or without (6/39 [15 %]). Of these 19 patients, 10 (53 %) required reoperation. Women with any complication had a longer interval to adjuvant therapy when compared with those without (49 days vs. 40 days; p < 0.001). When stratified according to side, complications in the prophylactic breast were not associated with a delay in treatment (UM: 58 days vs. BM: prophylactic side; 41 days vs. BM: cancer side: 50 days; p = 0.73). CONCLUSIONS: CPM confers additional morbidity in one in eight women, of whom half require reoperation. Despite this, in our series CPM did not delay adjuvant therapy. Given the rising incidence of patients seeking CPM, they should be informed of this risk.

Long-term results of aortouniiliac stent grafts for the endovascular repair of abdominal aortic aneurysms.

BACKGROUND: Long-term follow-up of patients with aortouniiliac (AUI) grafts is lacking in the current literature. The purpose of this study was to review the outcomes of endovascular aneurysm repair (EVAR) using commercially available AUI devices with femorofemoral bypass in patients whose aortoiliac anatomy was unfavorable for bifurcated repair. METHODS: A retrospective review of 35 patients from September 2000 to February 2012, who underwent EVAR with commercially manufactured AUI devices, was performed. These comprised 35 of 372 (9.4%) patients who underwent EVAR during that period. Patient records were reviewed to determine morbidity, mortality, and survival after AUI repair. Patients were followed at 1-, 3-, 6-, and 12-month intervals with computed tomography (CT) scans during each visit. Median follow-up was 40 months (range: 2-135 months). RESULTS: Median age at surgery was 76 years (range: 60-93). The median preoperative aneurysm diameter was 57 mm (range: 45-71) and the median postoperative diameter was 53 mm (range: 29-80). Two type II endoleaks occurred on 1-month CT, whereas 10 endoleaks (type I [3], II [6], and III [1]) occurred during follow-up after 1 month. Migration of the stent graft occurred in 9% (n=3). Secondary procedures were required in 26% (n=9), whereas tertiary procedures were required in 3% (n=1). One patient required treatment for thrombosis of the iliac extension and 2 required treatment for thrombosis of the femorofemoral component. Mortality over the follow-up period was 34% (n=12) with no deaths occurring within 30 days. CONCLUSIONS: High-risk patients who present with aortoiliac anatomy unsuitable for bifurcated stent graft placement should be offered AUI graft placement as a potential alternative to open repair.

The impact of site of graduate medical education training and other factors on physician employee retention.

This study sought to determine if the site of graduate medical training or other factors impact the length of institutional employment. Physician hires for the home institution were catalogued from January 1, 1996, through December 31, 2006. In analyzing the 253 physician hires, we found no statistically significant advantage in employee retention associated with hiring "one's own" or with U.S. medical school graduates.

Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer.

Androgen deprivation therapy has been the standard of care in prostate cancer due to its effectiveness in initial stages. However, the disease recurs, and this recurrent cancer is referred to as castration-resistant prostate cancer (CRPC). Radiotherapy is the treatment of choice; however, in addition to androgen independence, CRPC is often resistant to radiotherapy, making radioresistant CRPC an incurable disease. The molecular mechanisms by which CRPC cells acquire radioresistance are unclear. Androgen receptor (AR)-tyrosine 267 phosphorylation by Ack1 tyrosine kinase (also known as TNK2) has emerged as an important mechanism of CRPC growth. Here, we demonstrate that pTyr(267)-AR is recruited to the ATM (ataxia telangiectasia mutated) enhancer in an Ack1-dependent manner to up-regulate ATM expression. Mice engineered to express activated Ack1 exhibited a significant increase in pTyr(267)-AR and ATM levels. Furthermore, primary human CRPCs with up-regulated activated Ack1 and pTyr(267)-AR also exhibited significant increase in ATM expression. The Ack1 inhibitor AIM-100 not only inhibited Ack1 activity but also was able to suppress AR Tyr(267) phosphorylation and its recruitment to the ATM enhancer. Notably, AIM-100 suppressed Ack1 mediated ATM expression and mitigated the growth of radioresistant CRPC tumors. Thus, our study uncovers a previously unknown mechanism of radioresistance in CRPC, which can be therapeutically reversed by a new synergistic approach that includes radiotherapy along with the suppression of Ack1/AR/ATM signaling by the Ack1 inhibitor, AIM-100.

Tripartite motif containing 28 (Trim28) can regulate cell proliferation by bridging HDAC1/E2F interactions.

BACKGROUND: Trim28 appears up-regulated in many cancers. RESULTS: In early stage lung tumors high Trim28 correlates with increased overall survival and Trim28 reduces cell proliferation in model lung cancer cell lines through E2F interactions. CONCLUSION: Trim28 may have a tumor suppressing role in the early stages of lung cancer. SIGNIFICANCE: These results suggest a complex role for Trim28 in lung cancer. Trim28 is a poorly understood transcriptional co-factor with pleiotropic biological activities. Although Trim28 mRNA is found in many studies to be up-regulated in both lung and breast cancer tissues relative to normal adjacent tissue, we found that within a panel of early-stage lung adenocarcinomas high levels of Trim28 protein correlate with better overall survival. This surprising observation suggests that Trim 28 may have anti-proliferative activity within tumors. To test this hypothesis, we used shRNAi to generate Trim28-knockdown breast and lung cancer cell lines and found that Trim28 depletion led to increased cell proliferation. Likewise, overexpression of Trim28 led to decreased cell proliferation. Confocal microscopy indicated co-localization of E2F3 and E2F4 with Trim28 within the cell nucleus, and co-immunoprecipitation assays demonstrated that Trim28 can bind both E2F3 and E2F4. Trim28 overexpression inhibited the transcriptional activity of E2F3 and E2F4, whereas Trim28 deficiency enhanced their activity. Co-immunoprecipitations further indicated that Trim28 bridges an interaction between E2Fs 3 and 4 and HDAC1. Promoter-reporter assays demonstrated that the ability of HDAC1 to repress E2F3 and E2F4-driven transcription is dependent on Trim28. Trim28 depletion increased E2F3 and E2F4 DNA binding activity, as measured by chromatin-immunoprecipitation (ChIP) assays while simultaneously reducing HDAC1 binding. Finally, ChIP-ReChIP experiments demonstrated that Trim/E2F complexes exist on several E2F-regulated promoters. Taken together, these results suggest that Trim28 has anti-proliferative activity in lung cancers via repression of members of the E2F family that are critical for cell proliferation.

Ultrathin primary is a marker for worse prognosis in lymph node-positive cutaneous melanoma.

BACKGROUND: Lymph lymph node metastasis from melanoma ≤0.50 mm (ultrathin) is an infrequent event. However, because many newly diagnosed melanomas are ultrathin, a significant proportion of patients who present with lymph node disease have an ultrathin melanoma. The authors hypothesized that ultrathin melanomas that present with lymph node metastasis represent biologically aggressive lesions with a worse prognosis. METHODS: The Surveillance, Epidemiology, and End Results registry data were queried to identify patients with cutaneous melanoma who presented with lymph node metastasis diagnosed between 1998 and 2008. Hazard ratios (HRs) from Cox proportional hazards regression models were used to compare disease-specific survival (DSS) between various tumor depths. RESULTS: In total, 6134 patients with lymph node-positive melanoma were identified and stratified according to tumor depth, including 588 (10%) with a tumor depth ≤0.50 mm, 519 (8%) with a tumor depth from 0.51 to 1.00 mm, 1669 (27%) with a tumor depth from 1.01 to 2.00 mm, 1871 (31%) with a tumor depth from 2.01 to 4.00 mm, and 1487 (24%) with a tumor depth >4.00 mm; and the respective 5-year DSS rates were 63%, 76%, 75%, 60%, and 43%. Multivariable analysis confirmed a similar trend in HRs for DSS: The HR was 1.00 for a tumor depth ≤0.50 mm (reference category) and 0.64 (P < .001), 0.65 (P < .001), 0.95 (P = .57), and 1.42 (P < .001) for tumor depths of 0.51 to 1.00 mm, 1.01 to 2.00 mm, 2.01 to 4.00 mm, and >4.00 mm, respectively. This association of tumor depth with DSS persisted for N1 and N2 disease but not for N3 disease. CONCLUSIONS: Ultrathin melanoma (≤0.50 mm) was identified as a marker of poor prognosis in the setting of lymph node metastasis. These results may improve recommendations for adjuvant therapy, surveillance protocols, and risk stratification for clinical trials.

Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry.

INTRODUCTION: The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated. METHODS: Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests. RESULTS: IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors. CONCLUSIONS: IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design.