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Extramammary Paget disease is a rare cutaneous malignancy that most commonly affects the genitals, perianal area, and axilla of elderly patients. Delays in care often lead to high levels of disease burden for patients. Thus, evidence-based recommendations are paramount in mitigating morbidity and mortality for this unique patient population. This 2-part continuing medical education series provides a complete picture of extramammary Paget disease. Part 2 of this continuing medical education series focuses on the complex management of extramammary Paget disease including surgical and noninvasive therapies, as well as novel approaches for advanced disease. [ABSTRACT FROM AUTHOR]

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer. [ABSTRACT FROM AUTHOR]

While racial and ethnic disparities are well documented in access to total joint arthroplasty (TJA), little is known about the association between having limited English proficiency (LEP) and postoperative care access. This study seeks to correlate LEP status with rates of revision surgery after hip and knee arthroplasty. This was a retrospective cohort study of patients aged ≥ 18 years who underwent either total hip or total knee arthroplasty between January 2013 and December 2021 at a single academic medical center. The predictor variable was English proficiency status, where LEP was defined as having a primary language that was not English. Multivariable regressions controlling for potential demographic and clinical confounders were used to calculate adjusted odds ratios of undergoing revision surgery within 1 and 2 years after primary arthroplasty for patients who have LEP, compared to English proficient patients. A total of 7,985 hip and knee arthroplasty surgeries were included in the analysis. There were 577 (7.2%) patients who were classified as having LEP. Patients who have LEP were less likely to undergo revision surgeries within 1 year (1.4% versus 3.2%, P =.01) and 2 years (1.7% versus 3.9%, P =.006) of primary TJA. Patients who have LEP had adjusted odds ratios of 0.45 (confidence interval: 0.22-0.92, P =.03) and 0.44 (confidence interval: 0.23-0.85, P =.01) of receiving revision surgery within 1 and 2 years, respectively. Patients who have LEP, compared to English proficient patients, were less likely to undergo revision surgeries at the same institution up to 2 years after hip and knee arthroplasty. These findings suggest that patients who have LEP may face barriers in accessing postoperative care. • Limited English proficiency patients have decreased use of arthroplasty revision surgery. • This may represent another instance of language-associated disparities in access to care. • More research is needed to understand the drivers of reduced use of revision surgery. [ABSTRACT FROM AUTHOR]

Lisfranc injuries present a challenge due to their ubiquity though frequent missed diagnoses. A paucity of data exists associating the contribution of bone density to injury type. This investigation compares the regional bone density between Lisfranc injury types using computed-tomography (CT)-derived Hounsfield units. A retrospective chart review identified patients with gross ligamentous and avulsion-type Lisfranc injuries determined by CT examination of the second metatarsal base and medial cuneiform. Regional bone density was assessed by averaging the Hounsfield units of the first metatarsal base, navicular, cuboid, calcaneus, and talus between 2 reviewers. Density was compared between injury type, isolated concomitant forefoot, and mid/hindfoot fractures. One hundred thirty-four patients were separated into avulsion (n = 85) and ligamentous (n = 49) groups. No statistically significant difference in patient body mass index, age, smoking status, or Quenu and Kuss injury pattern was observed between groups. The regional bone density of the cuboid (p =.03) and talus (p =.04) was greater in the ligamentous group. Lower extremity concomitant mid/hindfoot fracture patients exhibited greater regional bone density in the ligamentous group in all assessed bones (p ≤.04) except the calcaneus. Ligamentous injuries of the Lisfranc complex are associated with increased regional bone density among patients sustaining concomitant mid/hindfoot fractures. This study expands the utility of regional bone density analysis in foot and ankle trauma. [ABSTRACT FROM AUTHOR]

Background: Despite numerous advances in the implant design and surgical technique, improvement in patient satisfaction following total knee arthroplasty (TKA) has plateaued. Various TKA alignment strategies have been introduced that impact the coronal positioning of the tibial component relative to the native joint line. This study aims to analyze if postoperative variance of the joint line from preoperative native alignment is correlated with changes in patient-reported outcomes following primary TKA.Methods: A retrospective review of an academic center's patient population identified all primary TKAs between 2013 and 2021 with full-length, standing radiographs and patient-reported outcome measures (PROMs) data. These measures included the Knee injury and Osteoarthritis Outcome Score for Joint Replacement, Patient-Reported Outcome Measurement Information System, and Veterans RAND 12 scores. Preoperative and postoperative radiographic measurements for hip-knee angle, tibia-metaphyseal angle, tibial-axis orientation angle, and joint-line obliquity angle were recorded. Three-month, 1-year, and 2-year PROM scores were correlated with the change in degrees for each of the angles using a Spearman's correlation. A Mann-Whitney U-test was used to compare angular changes with a change in PROM scores.Results: One hundred and ninety nine patients (204 knees) with a mean age of 67 years were included. Average follow-up was 23 months. Three-month, 1-year, and 2-year follow-up rates were 93%, 64%, and 34%, respectively. Improvements were seen across all PROMs regardless of an angular change.Conclusion: There were no clear correlations between PROMs and variation in joint line obliquity in the coronal plane. These data suggest that the magnitude of the variation in coronal tibial alignment from native alignment does not impact PROMs. Further study is indicated to correlate an angular change with functional measures. [ABSTRACT FROM AUTHOR]

Introduction: Federally Qualified Health Centers serve 29.8 million low-income patients across the U.S., many of whom have unaddressed social risks. In 2019, for the first time, data on social risk screening capabilities were collected from every U.S. Federally Qualified Health Center. The objectives of this study were to describe the national rates of social risk screening capabilities across Federally Qualified Health Centers, identify organizational predictors of screening, and assess between-state heterogeneity.Methods: Using a 100% sample of U.S. Federally Qualified Health Centers (N=1,384, representing 29.8 million patients) from the 2019 Uniform Data System, the primary outcome was whether a Federally Qualified Health Center collected data on patients' social risk factors (yes/no). Summary statistics on the rates of social risk screening capabilities were generated in aggregate and by state. Linear probability models were then used to estimate the relationship between the probability of social risk screening and 7 key Federally Qualified Health Center characteristics (e.g., Federally Qualified Health Center size, Medicaid MCO contract, Medicaid accountable care organization presence). Data were analyzed in 2020‒2021.Results: Most (71%) Federally Qualified Health Centers collected social risk data, with a between-state variation. The most common screener was the Protocol for Responding to and Assessing Patients' Assets Risks and Experiences (43% of Federally Qualified Health Centers that screened), whereas 22% collected social risk data using a nonstandardized screener. After adjusting for other characteristics, Federally Qualified Health Centers with social risk screening capabilities served more total patients, were more likely to be located in a state with a Medicaid accountable care organization, and were less likely to have an MCO contract.Conclusions: There has been widespread adoption of social risk screening tools across U.S. Federally Qualified Health Centers, but between-state disparities exist. Targeting social risk screening resources to smaller Federally Qualified Health Centers may increase the adoption of screening tools. [ABSTRACT FROM AUTHOR]

The lack of biomarkers to inform antidepressant selection is a key challenge in personalized depression treatment. This work identifies candidate biomarkers by building deep learning predictors of individual treatment outcomes using reward processing measures from functional magnetic resonance imaging, clinical assessments, and demographics. Participants in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study (n = 222) underwent reward processing task-based functional magnetic resonance imaging at baseline and were randomized to 8 weeks of sertraline (n = 106) or placebo (n = 116). Subsequently, sertraline nonresponders (n = 37) switched to 8 weeks of bupropion. The change in Hamilton Depression Rating Scale was measured after treatment. Reward processing, clinical measurements, and demographics were used to train treatment-specific deep learning models. The predictive model for sertraline achieved R 2 of 48% (95% CI, 33%–61%; p < 10−3) in predicting the change in Hamilton Depression Rating Scale and number-needed-to-treat (NNT) of 4.86 participants in predicting response. The placebo model achieved R 2 of 28% (95% CI, 15%–42%; p < 10−3) and NNT of 2.95 in predicting response. The bupropion model achieved R 2 of 34% (95% CI, 10%–59%, p < 10−3) and NNT of 1.68 in predicting response. Brain regions where reward processing activity was predictive included the prefrontal cortex and cerebellar crus 1 for sertraline and the cingulate cortex, caudate, orbitofrontal cortex, and crus 1 for bupropion. These findings demonstrate the utility of reward processing measurements and deep learning to predict antidepressant outcomes and to form multimodal treatment biomarkers. [ABSTRACT FROM AUTHOR]

Purpose: To assess the correlation between changes in hip capsule morphology with improvements in patient-reported outcome (PRO) scores after arthroscopic surgery for femoroacetabular impingement syndrome (FAIS) using the periportal capsulotomy technique.Methods: Twenty-eight patients with cam morphology FAIS (without arthritis, dysplasia, or hypermobility) were prospectively enrolled before arthroscopic labral repair and femoroplasty through periportal capsulotomy (anterolateral/midanterior portals) without closure. Patients completed the Hip Disability and Osteoarthritis Outcomes Score (HOOS) and had nonarthrographic 3T magnetic resonance imaging (MRI) scans of the affected hip before and 1 year after surgery. Anterior capsule thickness, posterior capsule thickness, anterior-posterior capsule thickness ratio, and proximal-distal anterior capsule thickness ratio were measured on axial-oblique MRI sequences. Pearson correlation coefficients were calculated to determine the association between hip capsule morphology and PRO scores.Results: Postoperative imaging showed that for all 28 patients (12 female), labral repairs and capsulotomies had healed within 1 year of surgery. Analysis revealed postoperative decreases in anterior hip capsule thickness (1395.4 ± 508.4 mm3 vs 1758.4 ± 487.9 mm3; P = .003) and anterior-posterior capsule thickness ratio (0.92 ± 0.33 vs 1.12 ± 0.38; P = .02). Higher preoperative anterior-posterior capsule thickness ratio correlated with lower preoperative scores for HOOS pain (R = -0.43; P = .02), activities of daily living (ADL) (R = -0.43; P = .02), and sport (R = -0.38; P = .04). Greater decrease from preoperative to postoperative anterior-posterior capsule thickness ratio correlated with greater improvement for HOOS pain (R = -0.40; P = .04), ADL (R = -0.45; P = .02), and sport (R = -0.46; P = .02).Conclusions: Periportal capsulotomy without closure demonstrates capsule healing by 1 year after arthroscopic FAIS treatment. Changes in hip capsule morphology including decreased anterior-posterior capsule thickness ratio after surgery may be correlated with improvements in patient pain, function, and ability to return to sports.Level Of Evidence: Level II, prospective cohort study. [ABSTRACT FROM AUTHOR]

Various techniques of surgical detachment for treatment of insertional Achilles tendinopathy have been described, including lateral release, medial release, central tendon splitting (CTS), and complete detachment. A systematic review of electronic databases was performed, encompassing 17 studies involving 703 patients and 746 feet, to compare outcomes associated with surgical takedown techniques. Observed results include wound complication rates (CTS 2.8%; Lateral 0%; Medial 0.4%; Complete 1.3%), postoperative rupture rates (CTS 0.7%; Lateral 0.8%; Medial 0.7%; Complete 2.6%), rate of revision (CTS 0.4%; Lateral 0.9%; Medial 4.2%; Complete 2.6%), rate of infection (CTS 1.1%; Lateral 1.7%; Medial 3.7%; Complete 6.5%). Lateral takedown group was found to have a statistically significant lower rate of complications compared to the complete takedown group (p =.0029). In light of these results, it is recommended that patient characteristics such as case specific tendon pathology and calcaneal morphology take precedent in determining the surgical approach to Achilles takedown. [ABSTRACT FROM AUTHOR]

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Introduction: Predictive biomarkers of Parkinson's Disease progression are needed to expedite neuroprotective treatment development and facilitate prognoses for patients. This work uses measures derived from resting-state functional magnetic resonance imaging, including regional homogeneity (ReHo) and fractional amplitude of low frequency fluctuations (fALFF), to predict an individual's current and future severity over up to 4 years and to elucidate the most prognostic brain regions.Methods: ReHo and fALFF are measured for 82 Parkinson's Disease subjects and used to train machine learning predictors of baseline clinical and future severity at 1 year, 2 years, and 4 years follow-up as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Predictive performance is measured with nested cross-validation, validated on an external dataset, and again validated through leave-one-site-out cross-validation. Important predictive features are identified.Results: The models explain up to 30.4% of the variance in current MDS-UPDRS scores, 55.8% of the variance in year 1 scores, and 47.1% of the variance in year 2 scores (p < 0.0001). For distinguishing high and low-severity individuals at each timepoint (MDS-UPDRS score above or below the median, respectively), the models achieve positive predictive values up to 79% and negative predictive values up to 80%. Higher ReHo and fALFF in several regions, including components of the default motor network, predicted lower severity across current and future timepoints.Conclusion: These results identify an accurate prognostic neuroimaging biomarker which may be used to better inform enrollment in trials of neuroprotective treatments and enable physicians to counsel their patients. [ABSTRACT FROM AUTHOR]

Introduction: Community health centers often screen for and address patients' unmet social needs. This study examines the degree to which community health center patients report receiving social needs assistance and compares measures of access and quality between patients who received assistance versus similar patients who did not.Methods: A nationally representative sample of 4,699 nonelderly adults receiving care at community health centers from the 2014-2015 Health Resources and Services Administration Health Center Patient Survey was used, representing 12.6 million patients. The exposure-having "received social needs assistance"-was based on whether a patient received any community health center assistance accessing social programs (e.g., applying for government benefits) or basic needs (e.g., obtaining transportation, housing, food). Using logistic regression models with inverse probability of treatment weights, outcomes for patients who received social needs assistance with similar patients who did not were compared. Study outcomes, reported as absolute adjusted differences, included reporting a community health center as a usual source of care, reporting the emergency department as a usual source of care, perceived quality of care, and willingness to recommend the community health center to others. Data were analyzed in 2020.Results: Of the sample, 36% reported receiving social needs assistance, where the most common form of assistance was applying for government benefits. Relative to similar patients who did not receive social needs assistance, patients receiving assistance were significantly more likely to report a community health center as their usual source of care (adjusted difference=7.2 percentage points, 95% CI=2.2, 12.1) and to report perceived quality of care as "the best" (adjusted difference=11.1, 95% CI=5.4, 16.9). They were significantly less likely to report the emergency department as their usual source of care (adjusted difference= -4.2, 95% CI= -7.0, -1.3).Conclusions: As community health centers and other providers consider providing social needs assistance to patients, these results suggest that doing so may be associated with improved access to and quality of care. [ABSTRACT FROM AUTHOR]

Management of patients with heart failure with reduced ejection fraction requires timely initiation and titration of guideline-directed medical therapy (GDMT). However, optimizing GDMT in clinical practice can be challenging given the need for frequent clinic visits and limited provider time. Pharmacists have been shown to improve outcomes through both in-person and telehealth visits in various chronic disease states. Here, we report results of a mixed collaborative in-person and pharmacist-led telehealth program on optimization of GDMT. This was a retrospective study of symptomatic patients with an ejection fraction <50% seen in a heart failure clinic before and after integration of a pharmacist in April 2022. Patients were seen by a pharmacist in collaboration with a physician or physician assistant during regularly scheduled in-person appointments. Between appointments, patients were seen independently by a pharmacist through telehealth visits with the objective of initiating and titrating GDMT. Medications and target doses were defined according to the 2022 AHA/ACC/HFSA Heart Failure Guideline. GDMT regimens were assessed at the initial, 1-month, and 3-month visits for patients seen in clinic between April 2021-October 2021 (historical control) and April 2022-October 2022 (intervention group). The primary outcome was the change in average number of GDMT medications over 3 time intervals (baseline, initial, 1 month, and 3 month) within a 3-month period. A linear mixed-effects regression model adjusting for baseline characteristics was constructed to evaluate the association of pharmacist integration into the clinic with the number of GDMT. A total of 108 patients were included (n=50 control, n=58 intervention). Baseline characteristics were similar with an average GDMT per patient of 2.52 in the control and 2.5 in the intervention group. Patients in the intervention group had a greater increase in the average number of GDMT at each time interval compared to patients in the historical group when controlling for confounders (difference in change = +0.16 GDMT; 95% CI: 0.06, 0.25). The average GDMT per patient at 3 months was 2.68 in the control group (+0.06 medications increased per time interval, 95% CI: -0.01, 0.13) and 3.17 in the intervention group (+0.22 medications increased per time interval, 95% CI: 0.15, 0.28). The proportion of patients with any medication initiation or dose titration was higher in the intervention group. The integration of pharmacists within a heart failure clinic led to a significant increase in the optimization of GDMT for heart failure patients. Future studies are needed to evaluate the impact of this intervention on heart failure hospitalizations, mortality, and cost savings. [ABSTRACT FROM AUTHOR]

Objective: To evaluate trends in the utilization of active surveillance (AS) in a nationally representative cancer database. AS has been increasingly recognized as an effective strategy for patients with small renal masses but little is known about national usage patterns.Methods: We identified patients with clinical T1a renal masses within the National Cancer Database in 2010 through 2014. Patients were classified according to initial management strategy received including AS, surgery, ablation, or other treatment. We characterized time trends in the use of AS vs definitive therapy and examined clinical and socio-demographic determinants of AS among patients with small renal masses using multivariable logistic regression models.Results: We identified 59,189 patients who satisfied the inclusion criteria. Of the total cohort, 1733 (2.9%) individuals received initial management with AS, while 57,456 (97.1%) received definitive treatment. Surveillance rates remained below 5% in all years. On multivariate analysis, patient age (OR: 1.08, 95% CI 1.08-1.09), smaller tumor size of <2 cm vs ≥2 cm (OR: 2.43, 95% CI: 2.20-2.7, P < .0001), management at an academic center vs community center (OR: 2.05, 95% CI: 1.83-2.29), and African American vs Caucasian race (OR: 1.56, 95% CI:1.35-1.80) were independently associated with use of AS as initial management.Conclusion: In a representative national cohort of patients with small renal masses, we observed clinical and facility-level differences in the utilization of active surveillance in patients with T1a renal masses. Further investigation is warranted to better understand the forces underlying initial management decisions for patients with small renal masses. [ABSTRACT FROM AUTHOR]

Abstract Introduction A study was conducted to assess if there is an association between pharmacy students' perceptions of their preparedness to contribute to emergency responses and their current work status. Methods A cross-sectional analysis was conducted using data from a student perception survey completed by third-year pharmacy students. The survey collected demographic information on age, gender, level of education, ethnicity, and pharmacy-related work experience. A series of Likert scale items were used to assess students' perceptions regarding their competency in specific skills areas essential for participation in emergency responses. An independent samples t -test was used to compare mean scores for Likert scale items between working and nonworking students. Multivariate linear regression models were developed to determine if work status was an independent predictor of students' self-reported competencies after adjusting for covariates. Results Sixty-six of 69 (95.7%) students completed the student perception survey. Students currently working in a pharmacy reported higher mean scores on several of the measured competencies. After covariates adjustment, current work status was associated with higher scores on self-reported competencies related to proficiency in evaluating information from patient assessment and collaborating with other individuals to develop processes related to the optimizing flow of care. Conclusions These results suggest that students who are working tend to have more confidence in their ability to contribute to emergency responses as well as work better in a team setting. Incorporating cases related to emergency response readiness in pharmacy curriculum may be needed to enhance skills and confidence of non-working pharmacy students. [ABSTRACT FROM AUTHOR]

Summary DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation. [ABSTRACT FROM AUTHOR]

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function. [Display omitted] • Neurons take up glucose and metabolize it by glycolysis to supply TCA metabolites • HP 13C MRS shows disrupted brain energy when neuronal glucose metabolism is disrupted • Mice require neuronal glucose uptake and glycolysis for learning and memory • Galactose metabolism is upregulated to compensate for disrupted glucose metabolism Whether neurons can and must take up glucose and metabolize it by glycolysis was unclear, especially in vivo. Li et al. combine metabolomics and live imaging of human neurons with mouse models disrupting key steps in glucose metabolism to demonstrate that neurons require glucose uptake and glycolysis for normal function. [ABSTRACT FROM AUTHOR]

Minimally invasive pancreaticoduodenctomy (MIPD) is a technically challenging procedure. Current laparoscopic equipment with its limited range of motion, poor surgeon ergonomics, and lack of 3D view has limited the addition of MIPD. The robotic platform is able to overcome these limitations, allowing the recreation of time-honored open surgical principles of this procedure through a minimally invasive approach. We present here the technical aspects of the University of Pittsburgh robotic-assisted pancreaticoduodenctomy. [ABSTRACT FROM AUTHOR]

Clinically, HPV-positive oropharyngeal cancers (OPCs) have been shown to have a distinct prognosis, compared to HPV-negative tumours, particularly in survival rates and responses to treatment. These patients have better survival chances and improved prognosis, indicating that a more exhaustive knowledge of these distinctions would aid in the discovery of clinical approaches for both HPV-positive and negative tumours. Furthermore, there is increasing evidence that HPV-related oropharyngeal cancers constitute an epidemiological, molecular, and clinical distinct form as compared to non-HPV related ones therefore, the treatment of these specific subtype of oropharyngeal cancers should adopt a distinct clinical treatment pipeline. Our review will examine the current approaches for the diagnosis and treatment of OPC and discuss the relevance of de-escalation clinical trials in progress. [ABSTRACT FROM AUTHOR]

The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) undergoing surgical resection is controversial. We sought to define the incidence of major and microscopic vascular invasion relative to ICC tumor size, and identify predictors of microscopic vascular invasion in patients with ICC ≥5 cm. A total of 443 patients undergoing surgical resection for ICC between 1973 and 2011 at one of 11 participating institutions were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. As tumor sized increased, the incidence of microscopic vascular invasion increased: <3 cm, 3.6 %; 3-5 cm, 24.7 %; 5-7 cm, 38.3 %; 7-15 cm, 32.9 %, ≥15 cm, 55.6 %; ( p < 0.001). Increasing tumor size was also found to be associated with worsening tumor grade. The incidence of poorly differentiated tumors increased with increasing ICC tumor size: <3 cm, 9.7 %; 3-5 cm, 19.8 %; 5-7 cm, 24.2 %; 7-15 cm, 21.1 %; >15 cm, 31.6 % ( p = 0.04). The presence of perineural invasion (odds ratio [OR] = 2.98) and regional lymph node metastasis (OR = 4.43) were independently associated with an increased risk of microscopic vascular invasion in tumors ≥5 cm (both p < 0.05). Risk of microscopic vascular invasion and worse tumor grade increased with tumor size. Large tumors likely harbor worse pathologic features; this information should be considered when determining therapy and prognosis of patients with large ICC. [ABSTRACT FROM AUTHOR]

Introduction: Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. Methods: We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. Results: During the median follow up duration of 31 months (range 1–208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34–3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01–2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10–2.25; P = .04), and tumor size ≥5 cm (HR, 1.84; 95% CI, 1.28–2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. Conclusion: Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence. [Copyright &y& Elsevier]

Abstract: In the quest for novel tools for early detection and treatment of cancer, we propose the use of multimers targeting overexpressed receptors at the cancer cell surface. Indeed, multimers are prone to create multivalent interactions, more potent and specific than their corresponding monovalent versions, thus enabling the potential for early detection. There is a lack of tools for early detection of pancreatic cancer, one of the deadliest forms of cancer, but CCK2-R overexpression on pancreatic cancer cells makes CCK based multimers potential markers for these cells. In this Letter, we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R. [Copyright &y& Elsevier]

Background: Gallstones appear more frequently in patients with cirrhosis and open cholecystectomy in this patient population is associated with higher morbidity and mortality. The aim of the present study was to evaluate experience with laparoscopic cholecystectomy in patients with cirrhosis and to provide recommendations for management. Methods: Retrospective review of laparoscopic cholecystectomy in patients with cirrhosis from March 1999 to May 2008 was performed. Peri-operative characteristics and subgroup analysis were performed in patients with Child-Pugh's classes A, B and C cirrhosis. Results: A total of 68 patients were reviewed in this study. In all, 69% of the patients were Child's class A. The most common indication for cholecystectomy was chronic/symptomatic cholelithiasis (68%). Compared with patients with Child's class B and C, laparoscopic cholecystectomy in patients with Child's class A was associated with significantly decreased operative time ( P= 0.01), blood loss ( P= 0.001), conversion to open cholecystectomy ( P= 0.001) and length of hospital stay ( P= 0.001). Conclusions: Laparoscopic cholecystectomy in patients with cirrhosis is feasible with no mortality and low morbidity, especially in patients with Child's class A cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain. [Copyright &y& Elsevier]

Objectives: Kidney masses suspicious for malignancy are frequently detected by cross-sectional imaging; however, little is known about the burden of surgical treatment for tumors found to be benign following excision.Material and Methods: We queried the National Inpatient Sample to identify records of individuals who received surgical treatment for renal neoplasms between 2004 and 2014. We characterized temporal treatment trends, patient demographics, treatment related complications, and charges.Results: We identified 7,099 (8.5%) and 76,892 (91.5%) patients who were treated for benign and malignant tumors, respectively. Benign masses accounted for 14.8% of partial and 5.5% of radical nephrectomies. The rates of surgery for benign tumors have remained steady (P = 0.058). The frequency of inpatient death was higher in those with malignant disease (0.63% vs. 0.18%, P < 0.0001). Median length of stay was longer for individuals with malignant renal tumors (4.86 vs. 4.12 days, P < 0.0001). The total discharge bill adjusting for inflation for benign or malignant renal surgery increased each year (R2 = 0.428, R2 = 0.719, P = 0.001, P = 0.0311, respectively). As of 2014, the estimated national inpatient cost of management for benign renal tumors was $153 million dollars ($55,573/individual).Conclusions: 8.5% of inpatient renal surgical admissions are performed for benign masses. There has been a trend toward decreased operative management for benign renal tumors over time. Surgical management remains a significant economic burden. Efforts to prospectively evaluate modalities for pretreatment identification should be further pursued. [ABSTRACT FROM AUTHOR]

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer's disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the positive predictive value (PPV) of the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) assessment method in patients with a single suspicious finding on prostate multiparametric magnetic resonance imaging (mpMRI).Patients and Methods: A total of 176 patients underwent MRI/ultrasound fusion-targeted prostate biopsy after the detection of a single suspicious finding on mpMRI. The PPV for cancer detection was determined based on PI-RADS v2 assessment score and location.Results: Fusion biopsy detected prostate cancer in 60.2% of patients. Of these patients, 69.8% had Gleason score (GS) ≥7 prostate cancer. Targeted biopsy detected 90.5% of all GS≥7 prostate cancer. The PPV for GS≥7 detection of PI-RADS v2 category 5 (P5) and category 4 (P4) lesions was 70.2% and 37.7%, respectively. This increased to 88% and 38.5% for P5 and P4 lesions in the peripheral zone (PZ), respectively. Targeted biopsy did not miss GS≥7 disease compared with systematic biopsy in P5 lesions in the PZ and transition zone.Conclusion: The PPV of PI-RADS v2 for prostate cancer in patients with a single lesion on mpMRI is dependent on PI-RADS assessment category and location. The highest PPV was for a P5 lesion in the PZ. [ABSTRACT FROM AUTHOR]

Background: Studies have shown contradictory results regarding the survival outcomes among white, African American, and Asian patients with mycosis fungoides (MF).Objective: To evaluate the survival outcomes among white, African American, and Asian patients with MF and to determine other prognostic factors of the disease.Methods: The US National Cancer Database was used to identify patients with histologically confirmed MF from 2004 to 2014. Clinicopathologic, socioeconomic, and treatment data were compared among the races by using the chi-square test. Overall survival was evaluated by using the log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis.Results: Of 4459 patients with MF, 77.7% were white, 19.2% were African American, and 3.2% were Asian. Older age, treatment received in a community facility, government insurance, higher Charlson-Deyo score, male sex, higher clinical stage, receipt of radiotherapy or chemotherapy, and African American race were predictors of poor overall survival on multivariate analysis (P < .001), whereas Asian race trended toward improved outcomes (P = .07).Limitations: Retrospective analysis.Conclusion: African American patients with MF demonstrated poorer survival than white patients after accounting for disease characteristics, socioeconomic factors, and types of treatment, warranting further investigation into the underlying biology of MF and prescribed treatment modalities. [ABSTRACT FROM AUTHOR]

Objectives: Loss of renal parenchyma after surgery may contribute to chronic kidney disease; however, the long-term consequences of chronic kidney disease may differ by cause. We analyzed the outcomes of patients with end-stage renal disease (ESRD) based on various medical and surgical causes.Materials and Methods: In the United States Renal Data System from the period 1983 to 2007, patients with renal tumors, traumatic surgical loss, diabetes, or other known causes were identified. The annual incidence, prevalence, and influence of age, race, sex, and primary cause on survival were evaluated.Results: Of 1.3 million patients, 6,812 (0.49%) had renal malignancy-related ESRD (RM-ESRD). An increased over time was noted in the standardized incidence rates of patients with RM-ESRD (R2 = 0.973, P<0.0001). Patients with RM-ESRD had a worse median survival (1.9 vs. 3.4 y, P<0.0001), whereas those with ESRD related to nonmalignant surgical loss had improved survival (3.8 y) compared to diabetic ESRD (P<0.0001). The 5-year cancer-specific mortality was higher for RM-ESRD (30.9% vs. 5.5%, P<0.0001) compared to ESRD from other known causes; however, the non-cancer-specific mortality was improved compared to patients with ESRD with diabetic causes (P<0.0001). Limitations include retrospective analysis and lack of specific clinical data, such as cancer grade.Conclusions: The incidence of RM-ESRD is increasing, possibly owing to the increased rate of renal cell carcinoma treatment. Although overall survival for RM-ESRD was worse than either that of nonmalignant surgical loss or other known causes, non-cancer-specific mortality was decreased compared to diabetic causes, likely due to systemic effects by cause of ESRD. [ABSTRACT FROM AUTHOR]

Objective: To determine the negative predictive value of multiparametric magnetic resonance imaging (mpMRI), we evaluated the frequency of prostate cancer detection by 12-core template mapping biopsy in men whose mpMRI showed no suspicious regions.Methods: Six hundred seventy patients underwent mpMRI followed by transrectal ultrasound (TRUS)-guided systematic prostate biopsy from December 2012 to June 2016. Of this cohort, 100 patients had a negative mpMRI. mpMRI imaging sequences included T2-weighted and diffusion-weighted imaging, and dynamic contrast enhancement sequences.Results: The mean age, prostate-specific antigen, and prostate volume of the 100 men included were 64.3 years, 7.2 ng/mL, and 71 mL, respectively. Overall cancer detection was 27% (27 of 100). Prostate cancer was detected in 26.3% (10 of 38) of patients who were biopsy-naïve, 12.1% (4 of 33) of patients who had a prior negative biopsy, and in 44.8% (13 of 29) of patients previously on active surveillance; Gleason grade ≥7 was detected in 3% of patients overall (3 of 100). The negative predictive value of a negative mpMRI was 73% for all prostate cancer and 97% for Gleason ≥7 prostate cancer.Conclusion: There is an approximately 3% chance of detecting clinically significant prostate cancer with systematic TRUS-guided biopsy in patients with no suspicious findings on mpMRI. This information should help guide recommendations to patients about undergoing systematic TRUS-guided biopsy when mpMRI is negative. [ABSTRACT FROM AUTHOR]