The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence.

Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors, which is affected by a variety of autocrine and microenvironmental cues. Despite thorough investigations, the biology of dormant and/or cancer stem cells is still not fully elucidated, as for the mechanisms of their reawakening, while only the major molecular patterns driving the relapse process have been identified to date. These molecular patterns profoundly interfere with the elements of cellular proteostasis systems that support the efficiency of the recurrence process. As a major proteostasis machinery, we review the role of the ubiquitin-proteasome system (UPS) in tumor cell dormancy and reawakening, devoting particular attention to the functions of its components, E3 ligases, deubiquitinating enzymes and proteasomes in cancer recurrence. We demonstrate how UPS components functionally or mechanistically interact with the pivotal proteins implicated in the recurrence program and reveal that modulators of the UPS hold promise to become an efficient adjuvant therapy for eradicating refractory tumor cells to impede tumor relapse.

A Review of Artificial Intelligence in Breast Imaging.

With the increasing dominance of artificial intelligence (AI) techniques, the important prospects for their application have extended to various medical fields, including domains such as in vitro diagnosis, intelligent rehabilitation, medical imaging, and prognosis. Breast cancer is a common malignancy that critically affects women's physical and mental health. Early breast cancer screening-through mammography, ultrasound, or magnetic resonance imaging (MRI)-can substantially improve the prognosis for breast cancer patients. AI applications have shown excellent performance in various image recognition tasks, and their use in breast cancer screening has been explored in numerous studies. This paper introduces relevant AI techniques and their applications in the field of medical imaging of the breast (mammography and ultrasound), specifically in terms of identifying, segmenting, and classifying lesions; assessing breast cancer risk; and improving image quality. Focusing on medical imaging for breast cancer, this paper also reviews related challenges and prospects for AI.

Orthognathic Surgery Trending: Retrospective Ten Years Cases Analysis in Nineveh Province, Iraq.

AIMS: The study aimed at analyzing patient's case sheets in regard to the incidence of skeletal discrepancy present in cases and its relation with the demographic profile of the sample. All these are chronicled for more than 10 years periods. METHODOLOGY: This is a retrospective study analysis of the orthognathic case sheets for more than 10 years period. The total numbers of patients are 678. Patient's case sheet was already prepared by the Multi-Disciplinary Team Orthognathic Surgery Clinic in Al-Salam Teaching Hospital, which is the only authorized committee in Nineveh Health Directorate. RESULTS: The highest age percentage is between (18 and 27 y/76%). Angle class III cases are the uppermost cases (36%) from the total. A significant P value is clear at the level ≤0.05 and ≤0.01 between surgery type and discrepancy in anterior segmental osteotomies (upper and lower) which is performed in bi-maxillary protrusion cases and Angle class II cases (0.01**). Similarly, anterior segmental osteotomies (upper jaw only) which are indicated in both open bite and Angle Class II cases documented as a statistically significant P value (0.02*). The positive correlation is shown in all variables with the disharmony or facial discrepancies. Esthetic and beauty as causes for treatment recorded more than function in relation to time series. CONCLUSION: This study documents that patients with skeletal class III accounted for the largest percentage (64%) in the study group. A high increase in patients number seeking treatment for their discrepancy is obvious with time from 2009 till 2022.

Design and optimization of metamaterial-based highly-isolated MIMO antenna with high gain and beam tilting ability for 5G millimeter wave applications.

This paper presents a wideband multiple-input multiple-output (MIMO) antenna with high gain and isolation, as well as beam tilting capability, for 5G millimeter wave (MMW) applications. A single bow-tie antenna fed by a substrate-integrated waveguide (SIW) is proposed to cover the 28 GHz band (26.5-29.5 GHz) with a maximum gain of 6.35 dB. To enhance the gain, H-shaped metamaterial (MM)-based components are incorporated into the antenna substrate. The trust-region (TR) gradient-based search algorithm is employed to optimize the H-shape dimensions and to achieve a maximum gain of 11.2 dB at 29.2 GHz. The MM structure offers zero index refraction at the desired range. Subsequently, the MIMO system is constructed with two vertically arranged radiators. Another MM, a modified square resonator (MSR), is embedded between the two radiators to reduce the mutual coupling and to tilt the antenna main beam. Herein, the TR algorithm is again used to optimize the MSR dimensions, and to enhance the isolation to a maximum of 75 dB at 28.6 GHz. Further, the MSR can tilt the E-plane radiation by ± 20° with respect to the end-fire direction when alternating between the two ports' excitation. The developed system is validated experimentally with a good matching between the simulated and measured data.

wideband high-gain low-profile series-fed antenna integrated with optimized metamaterials for 5G millimeter wave applications.

This paper presents a series-fed four-dipole antenna with a broad bandwidth, high gain, and compact size for 5G millimeter wave (mm-wave) applications. The single dipole antenna provides a maximum gain of 6.2 dBi within its operational bandwidth, which ranges from 25.2 to 32.8 GHz. The proposed approach to enhance both gain and bandwidth involves a series-fed antenna design. It comprises four dipoles with varying lengths, and a truncated ground plane. These dipoles are connected in series on both sides, running in parallel through a microstrip line. The proposed design significantly enhances the bandwidth, which extends from 26.5 to 40 GHz. This frequency range effectively covers the 5G bands of 28 and 38 GHz. The expedited trust-region (TR) gradient-based search algorithm is utilized to optimize the dimensions of the antenna components, resulting in a maximum gain of 11.2 dBi at 38 GHz. To further enhance the gain, modified H-shaped metamaterial (MTM)-based unit cells are integrated into the antenna substrate. The TR algorithm is employed once more to optimize the MTM dimensions, yielding a maximum gain of 15.1 dBi at 38 GHz. The developed system is experimentally validated, showing excellent agreement between the simulated and measured data.

Risk Factors for Surgical-Site Infections After Liver Transplant: Does Perioperative Antibiotic Regimen Matter?

BACKGROUND: Surgical-site infections (SSIs) are common in liver transplant recipients. The optimal SSI antimicrobial prophylaxis agent and duration are not established. We aimed to explore risk factors for SSIs after transplant, with a particular interest in the impact of perioperative antibiotic regimen on the development of SSIs. METHODS: Retrospective study of adults undergoing liver transplant across 3 transplant programs between January 1, 2020, and June 01, 2021. RESULTS: Of 557 patients included in the study, 32 (5.7%) were infected or colonized with a multidrug-resistant organism (MDRO) within 1 y before liver transplant. Narrow-spectrum SSI prophylaxis with ceftriaxone or cefazolin alone was administered in 488 of 577 patients (87.6%); the remaining 69 patients (12.4%) received broad-spectrum prophylaxis with vancomycin and aztreonam (n = 40), piperacillin-tazobactam (n = 11), carbapenems (n = 8), ceftriaxone and another antibiotic (n = 7), and others. Patients with pretransplant MDRO were more likely to receive broad-spectrum coverage than those without pretransplant MDROs (28.1% versus 11.4%, P = 0.005). SSIs were identified in 40 patients (7.2%); 25 (62.5%) were organ-space infections, 3 (7.5%) were deep incisional infections, and 12 (30.0%) were superficial incisional infections. The median time from liver transplant to SSIs was 14 d (interquartile range, 10-20.2). MDROs were identified in 12 SSIs (30%). Multivariable analysis revealed no significant association between antimicrobial spectrum and risk of SSIs (P = 0.5), whereas surgical leak (P<0.001) and reoperation (P = 0.017) were independently associated with increased risk of SSIs. SSIs were not significantly associated with composite risk of death or liver allograft failure. CONCLUSIONS: The spectrum of antimicrobial prophylaxis did not impact the development of SSIs in liver transplant recipients.

Early Inflammatory Response of Dental Pulp in Response to Biodentin and Mineral Trioxide Aggregate as Pulp-capping Agents.

This study was carried out to observe immediate inflammatory response of Human Dental Pulp capped with Biodentin and Mineral Trioxide Aggregate (MTA). This prospective clinical study was carried out in the Department of Conservative Dentistry and Endodontics together with the Department of Orthodontia, Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from 2016 to 2018. A total number of eighty (80) permanent premolars teeth planned to be extracted for orthodontic alignment of occlusion were used as study sample. Those teeth were divided into two groups; Group A and Group B, having 40 teeth in each (n=40). An occlusal exposure of approximately 1.5mm in diameter was made. Then in -group A, exposed pulp were capped with 2-mm-thick layer of sterile Biodentin (Septodont) and in-group B with ProRoot White MTA (Dentsply). After pulp capping with the experimental material in respective group, cavities in all teeth were restored with glass ionomer cement. After 24 hours the teeth were extracted, fixed in 10% buffered formalin solution, then decalcified by 10.0% nitric acid and embedded in paraffin. Now 2 to 3-micron-thick serial sections were made in the linguo-buccal plane and finally stained with hematoxylin-eosin. Now pulpal inflammation in respect of type, intensity and extension, were determined by using a predetermined evaluation criterion under an optical microscope at 40× magnifications. Statistical differences among the experimental groups were analyzed by Descriptive analysis (Cross Tabulation) (p<0.05). Histologically both the tested materials produced immediate pulpal tissue reaction. 'Biodentin' found to be most immediate pulpal tissue reactive (reactive in 100% cases), Whereas, MTA produced immediate tissue reaction only in 50.0% cases. Immediate pulpal inflammatory reaction in response to tested material found to be statistically significant different between 'Biodentin' and 'MTA' (p=0.001). According to present study Biodentin is found to be more immediate pulpal tissue reactive than MTA when used as a pulp capping material.

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex.

BACKGROUND: Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). METHODS: Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. RESULTS: It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. CONCLUSIONS: These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

Engineering of nickel, cobalt oxides and nickel/cobalt binary oxides by electrodeposition and application as binder free electrodes in supercapacitors.

Cobalt oxide, nickel oxide and cobalt/nickel binary oxides were synthesised by electrodeposition. To fine tune composition of CoNi alloys, growth parameters including voltage, electrolyte pH/concentration and deposition time were varied. These produced nanomaterials were used as binder free electrodes in supercapacitor cells and tested using three electrode setup in 2 MKOH aqueous electrolyte. Cyclic voltammetry and galvanostatic charge/discharge were used at different scan rates (5-100 mV/s) and current densities (1-10 A/g) respectively to investigate the capacitive behaviour and measure the capacitance of active material. Electrochemical impedance spectroscopy was used to analyse the resistive/conductive behaviours of these electrodes in frequency range of 100 kHz to 0.01 Hz at applied voltage of 10 mV. Binary oxide electrode displayed superior electrochemical performance with the specific capacitance of 176 F/g at current density of 1 A/g. This hybrid electrode also displayed capacitance retention of over 83% after 5000 charge/discharge cycles. Cell displayed low solution resistance of 0.35 Ω along with good conductivity. The proposed facile approach to synthesise binder free blended metal electrodes can result in enhanced redox activity of pseudocapacitive materials. Consequently, fine tuning of these materials by controlling the cobalt and nickel contents can assist in broadening their applications in electrochemical energy storage in general and in supercapacitors in particular.

Virtual patient representation with silicone guide and a 3D scanner accessory for a user-friendly facial scanning workflow: A clinical report of smile design and ceramic veneers.

Digital smile design and ceramic veneers are described with virtual patient representation. The procedure included facial scanning with a 3D scanner accessory (Structure sensor pro; Occipital Inc) mounted on a tablet computer (iPad; Apple Inc) and an innovative chairside silicone guide to replace the intraoral scan body for a straightforward and user-friendly workflow.

From multi-segmented to core/shell nanorods: morphology evolution in Fe-Au nanorods by tuning fabrication conditions.

Aiming to obtain hybrid magneto-plasmonic nanostructures, we have developed multisegmented and core/shell structured Fe-Au nanorods using template assisted electrochemical deposition. A facile method of tuning the growth pattern of multisegmented nanorods into core/shell structured is demonstrated. With a precise control of current density and deposition time, a brick-stacked wire like growth led to the formation of hollow nanotubes that could be further tuned to multilayered hollow nanotubes and core/shell structured nanorods. TEM imaging and STEM-EELS technique were used to explore the morphology, microstructure and the distribution of Au and Fe in the nanorods. The easy magnetization direction was found to be perpendicular to the nanorods' growth direction in the segmented nanorods. On the other hand, core/shell nanorods exhibited isotropic behavior. Our findings provide deeper insights into the fabrication of hybrid nanorods and the opportunity to tune the fabrication method to vary their morphology accordingly. Such studies will benefit design of hybrid nanorods with specific morphologies and physical properties and hence their integration into sensing, spintronics and other potential biomedical and technological applications.

Outcomes of endoscopic retrograde cholangiography and percutaneous transhepatic biliary drainage in liver transplant recipients with a Roux-en-Y biliary-enteric anastomosis.

Backgrounds/Aims: Data regarding outcomes of endoscopic retrograde cholangiography (ERC) in liver transplant (LT) recipients with biliary-enteric (BE) anastomosis are limited. We report outcomes of ERC and percutaneous transhepatic biliary drainage (PTBD) as first-line therapies in LT recipients with BE anastomosis. Methods: All LT recipients with Roux-BE anastomosis from 2001 to 2020 were divided into ERC and PTBD subgroups. Technical success was defined as the ability to cannulate the bile duct. Clinical success was defined as the ability to perform cholangiography and therapeutic interventions. Results: A total of 36 LT recipients (25 males, age 53.5 ± 13 years) with Roux-BE anastomosis who underwent biliary intervention were identified. The most common indications for a BE anastomosis were primary sclerosing cholangitis (n = 14) and duct size mismatch (n = 10). Among the 29 patients who initially underwent ERC, technical success and clinical success were achieved in 24 (82.8%) and 22 (75.9%) patients, respectively. The initial endoscope used for the ERC was a single balloon enteroscope in 16 patients, a double balloon enteroscope in 7 patients, a pediatric colonoscope in 5 patients, and a conventional reusable duodenoscope in 1 patient. Among the 7 patients who underwent PTBD as the initial therapy, six (85.7%) achieved technical and clinical success (p = 0.57). Conclusions: In LT patients with Roux-BE anastomosis requiring biliary intervention, ERC with a balloon-assisted enteroscope is safe with a success rate comparable to PTBD. Both ERC and PTBD can be considered as first-line therapies for LT recipients with a BE anastomosis.

Identification of a novel founder variant in DNAI2 cause primary ciliary dyskinesia in five consanguineous families derived from a single tribe descendant of Arabian Peninsula.

Introduction: Primary ciliary dyskinesia (PCD) is caused by dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify disease causing genetic variants for PCD patients in the Kuwaiti population. Methods: A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was analysed for variant screening. Transmission electron microscopy (TEM) and immunofluorescent (IF) analyses were performed on nasal brushings to detect specific structural abnormalities within ciliated cells. Results: All the patients inherited the same founder variant in DNAI2 and exhibited PCD symptoms. TEM analysis demonstrated lack of outer dynein arms (ODA) in all analysed samples. IF analysis confirmed absence of DNAI1, DNAI2, and DNAH5 from the ciliary axoneme. Whole exome sequencing, autozygosity mapping and segregation analysis confirmed that seven patients carry the same homozygous missense variant (DNAI2:c.740G>A; p.Arg247Gln; rs755060592). Conclusion: DNAI2:c.740G>A is the founder variant causing PCD in patients belonging to a particular Arabian tribe which practices consanguineous marriages.

Additive Manufacturing of Dental Ceramics: A Systematic Review and Meta-Analysis.

PURPOSE: The purpose of this systematic review and meta-analysis was to evaluate the effect of using additive manufacturing (AM) for dental ceramic fabrication in comparison with subtractive manufacturing (SM), and to evaluate the effect of the type of AM technology on dental ceramic fabrication. MATERIALS AND METHODS: A search was conducted electronically in MEDLINE (via PubMed), EBSCOhost, Scopus, and Cochran Library databases, and also by other methods (table of contents screening, backward and forward citations, and grey literature search) up to February 12, 2022, to identify records evaluating additive manufacturing of ceramics for dental purposes in comparison with subtractive manufacturing. A minimum of 2 review authors conducted tstudy selection, quality assessment, and data extraction. Quality assessment was performed with Joanna Briggs Institute tool, and the quantitative synthesis was performed with the Comprehensive Meta-Analysis program (CMA, Biostat Inc). Hedges's g for effect size was calculated, with 0.2 as small, 0.5 as medium, and 0.8 as large. Heterogeneity was assessed with I2 and prediction interval (PI) statistics. Publication bias was investigated with funnel plots and grey literature search. Certainty of evidence was assessed with the Grading of Recommendations: Assessment, Development, and Evaluation (GRADE) tool. RESULTS: A total of 28 studies were included for the qualitative and quantitative synthesis; 11 in vitro studies on accuracy, 1 in vivo study on color, and 16 in vitro studies on physical and mechanical properties. Meta-analysis showed overall higher accuracy for SM compared with AM, with medium effect size (0.679, CI: 0.173 to 1.185, p = 0.009) and also for marginal (g = 1.05, CI: 0.344 to 1.760, p = 0.004), occlusal (g = 2.24, CI: 0.718 to 3.766, p = 0.004), and total (g = 4.544, CI: -0.234 to 9.323, p = 0.062) with large effect size; whereas AM had higher accuracy than SM with small effect size for the external (g = -0.238, CI: -1.215 to 0.739), p = 0.633), and internal (g = -0.403, CI: -1.273 to 0.467, p = 0.364) surfaces. For technology, self-glazed zirconia protocol had the smallest effect size (g = -0.049, CI: -0.878 to 0.78, p = 0.907), followed by stereolithography (g = 0.305, CI: -0.289 to 0.9, p = 0.314), and digital light processing (g = 1.819, CI: 0.662 to 2.976, p = 0.002) technologies. Flexural strength was higher for ceramics made by SM in comparison to AM with large effect size (g = -2.868, CI: -4.371 to -1.365, p < 0.001). Only 1 study reported on color, favoring ceramics made through combined AM and SM. CONCLUSIONS: Subtractive manufacturing had better overall accuracy, particularly for the marginal and occlusal areas, higher flexural strength, and more favorable hardness, fracture toughness, porosity, fatigue, and volumetric shrinkage; whereas AM had more favorable elastic modulus and wettability. Both methods had favorable biocompatibility. All studies on accuracy and mechanical properties were in vitro, with high heterogeneity and low to very low certainty of evidence. There is a lack of studies on color match and esthetics.

Immune Checkpoint Inhibitors as Therapy to Down-Stage Hepatocellular Carcinoma Prior to Liver Transplantation.

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied broadly, and are the mainstays of current treatment guidelines. As HCC incidence has continued to grow, and with more patients presenting with advanced disease, our current treatment modalities do not suffice, and better therapies are needed to improve disease-specific and overall survival. Until recently, sorafenib was the only systemic therapy utilized, and was associated with dismal results. The advent of immuno-oncology has been of significant interest, and has changed the paradigm of therapy for HCC. Lately, combination regimens including atezolizumab plus bevacizumab; durvalumab plus tremelimumab; and pembrolizumab plus Lenvatinib have shown impressive responses of between 25-35%; this is much higher than responses observed with single agents. Complete responses with checkpoint inhibitor therapy have been observed in advanced-stage HCC patients. These dramatic results have naturally led to several questions. Can or should checkpoint inhibitors, or other immunotherapy combinations, be used routinely before resection or transplant? Is there a synergistic effect of immunotherapy with locoregional therapy, and will pre-treatment increase disease-free survival after surgical intervention? Is it immunologically safe to use these therapies prior to transplantation? Much is still to be learned in terms of the dosing, timing, and overall utility of the use of immune checkpoint inhibitors for pre-transplant care and down-staging. More studies will be needed to understand the management of adverse events while maximizing the therapeutic window of these agents. In this review, we look at the current data on therapy with immune checkpoint inhibitors in advanced HCC, with a focus on pre-transplant treatment prior to liver transplant.

Infectious complications in acute graft-versus-host disease after liver transplantation.

Graft-versus-hostdisease (GVHD) following liver transplantation (LT) is rare but can lead tosignificant mortality. The leading cause of death following GVHD diagnosis isinfectious complications. However, there is a lack of clear descriptions concerning infection and antimicrobial management patterns. Our study aims toprovide the focused details of all infectious complications of acute GVHDfollowing LT. We retrospectively reviewed all adult LT recipients with acute GVHD at Mayo Clinic's Transplant Centers from January 1, 2010, to December 31, 2021. Detailed characteristics of infection in each case were described. Among 4,585 LTs performed during this period, 12 (0.3%) patients developed acuteGVHD. The median time from transplantation to GVHD diagnosis was 49.0 days [IQR 31.5-99.0]. Ten (83.3%) patients developed severe infections leading tomortality. The most common cause of infection was nosocomial bacteremia fromenteric bacteria such as vancomycin-resistant enterococci and gram-negative bacilli. Other infections included breakthrough invasive fungal infections,cytomegalovirus (CMV) reactivation, and Clostridioides difficile colitis. Antimicrobial prophylaxis strategies in most cases were based on the degree of neutropenia-these include levofloxacin for bacterial prophylaxis, nebulized pentamidine for Pneumocystis jiroveci pneumonia prophylaxis, posaconazole for invasive fungal prophylaxis, and valganciclovir based on CMVstatus. All GVHD patients with severe infections succumbed to thesecomplications. Ourstudy reiterates that despite prophylaxis, infectious complications in GVHDfollowing LT are common and lead to exceptionally high mortality. Individualizedantimicrobial treatment, prophylaxis and monitoring strategies remain a criticalcomponent of GVHD management. Further study to optimize these practices isrequired.

Clinical outcomes for hilar and extrahepatic cholangiocarcinoma with adjuvant, definitive, or liver transplant-based neoadjuvant chemoradiotherapy strategies: a single-center experience.

Background: We report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT). Methods: We included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival). Results: Sixty-five patients (nCRT, n=20; aCRT, n=16; dCRT, n=29) met inclusion criteria [median (range) age 65 years (27-84 years)]. Median posttreatment follow-up was 19.1 months (0.8-164.8 months) for all patients and 38.6, 24.3, and 9.0 months for the nCRT, aCRT, and dCRT groups, respectively. At 3 and 5 years, overall survival was 78% and 59% for the nCRT group; 47% and 35%, aCRT group; and 11% and 0%, dCRT group. Compared with the dCRT group, the nCRT group (hazard ratio =0.13, 95% CI: 0.05-0.33) and the aCRT group (hazard ratio =0.29, 95% CI: 0.14-0.64) had significantly improved overall survival (P<0.001). The 5-year local progression-free survival (50% nCRT vs. 30% aCRT vs. 0% dCRT, P<0.001) and 5-year disease-free survival (61% nCRT vs. 30% aCRT vs. 0% dCRT, P=0.01) were significantly better for strategies combined with surgery. Conclusions: Outcomes for patients with extrahepatic CCA were superior for those who underwent nCRT/orthotopic liver transplant or postsurgical aCRT than for patients treated with dCRT. The excellent outcomes after nCRT/orthotopic liver transplant provide additional independent data supporting the validity of this strategy. The poor survival of patients treated with dCRT highlights a need for better therapies when surgery is not possible.

Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score.

BACKGROUND AND AIMS: The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). APPROACH AND RESULTS: Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87. CONCLUSIONS: After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.