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BACKGROUND & AIMS: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. METHODS: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. RESULTS: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). CONCLUSIONS: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. IMPACT AND IMPLICATIONS: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

The sodium-potassium ATPase (Na/K-ATPase, NKA) establishes ion gradients that facilitate many physiological functions including action potentials and secondary transport processes. NKA comprises a catalytic subunit (alpha) that interacts closely with an essential subunit (beta) and regulatory transmembrane micropeptides called FXYD proteins. In the heart, a key modulatory partner is the FXYD protein phospholemman (PLM, FXYD1), but the stoichiometry of the alpha-beta-PLM regulatory complex is unknown. Here, we used fluorescence lifetime imaging and spectroscopy to investigate the structure, stoichiometry, and affinity of the NKA-regulatory complex. We observed a concentration-dependent binding of the subunits of NKA-PLM regulatory complex, with avid association of the alpha subunit with the essential beta subunit as well as lower affinity alpha-alpha and alpha-PLM interactions. These data provide the first evidence that, in intact live cells, the regulatory complex is composed of two alpha subunits associated with two beta subunits, decorated with two PLM regulatory subunits. Docking and molecular dynamics (MD) simulations generated a structural model of the complex that is consistent with our experimental observations. We propose that alpha-alpha subunit interactions support conformational coupling of the catalytic subunits, which may enhance NKA turnover rate. These observations provide insight into the pathophysiology of heart failure, wherein low NKA expression may be insufficient to support formation of the complete regulatory complex with the stoichiometry (alpha-beta-PLM)2.

Simple Summary: The DIRECT Registry study is a prospective trial of irreversible electroporation (IRE) using the NanoKnife System for the treatment of patients with Stage 3 pancreatic adenocarcinoma (PDAC). The data from this United States Food and Drug Administration Investigational Device Exemption study aims to assess the safety and effectiveness of IRE in a real-world setting in the treatment of Stage 3 PDAC after induction chemotherapy when combined with standard of care (SOC) compared to SOC alone. Background/Objectives: Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy with no progression before enrollment. Endpoints were 30- and 90-day mortality and adverse events (AEs). Results: Eighty-seven IRE and 27 SOC subjects were enrolled in the registry. Mean ages were 64.0 ± 8.4 and 66.4 ± 9.9 years, and mean anterior/posterior tumor diameters were 2.2 ± 0.7 cm and 3.2 ± 1.3 for the IRE and SOC groups respectively (p = 0.0066). All IRE procedures were performed using an open approach. The 90-day all-cause mortality was 5/83 (6.0%) and 2/27 (7.4%) for the IRE and SOC groups, respectively. Two subjects in the IRE group died from treatment-related complications, and one patient in the SOC group died due to chemotherapy-related complications. Conclusions: Initial results from the DIRECT registry study indicate the use of IRE for curative intent tumor ablation in combination with induction chemotherapy has equivalent morbidity and mortality rates when compared to standard-of-care chemotherapy alone. [ABSTRACT FROM AUTHOR]

Native mass spectra of large, polydisperse biomolecules with repeated subunits, such as lipoprotein Nanodiscs, can often be challenging to analyze by conventional methods. The presence of tens of closely spaced, overlapping peaks in these mass spectra can make charge state, total mass, or subunit mass determinations difficult to measure by traditional methods. Recently, we introduced a Fourier Transform-based algorithm that can be used to deconvolve highly congested mass spectra for polydisperse ion populations with repeated subunits and facilitate identification of the charge states, subunit mass, charge-state-specific, and total mass distributions present in the ion population. Here, we extend this method by investigating the advantages of using overtone peaks in the Fourier spectrum, particularly for mass spectra with low signal-to-noise and poor resolution. This method is illustrated for lipoprotein Nanodisc mass spectra acquired on three common platforms, including the first reported native mass spectrum of empty "large" Nanodiscs assembled with MSP1E3D1 and over 300 noncovalently associated lipids. It is shown that overtone peaks contain nearly identical stoichiometry and charge state information to fundamental peaks but can be significantly better resolved, resulting in more reliable reconstruction of charge-state-specific mass spectra and peak width characterization. We further demonstrate how these parameters can be used to improve results from Bayesian spectral fitting algorithms, such as UniDec. Graphical Abstract ᅟ.

Gallbladder cancer is a rare but highly lethal malignant disorder. Historically, it had been deemed a terminal illness with 5-year survival rates varying from 0% to 12% and a median [...], Background: The extent of resection required in advanced gallbladder cancer is controversial. We aimed to describe the management and outcomes in patients with resected stage T2 and T3 gallbladder cancer. Methods: In this population-based study, all T2 and T3 gallbladder cancer cases from Jan. 1, 2002, to Mar. 31, 2012, were identified from the Ontario Cancer Registry; pathology reports were linked and abstracted. The type of resection was classified as extended (cholecystectomy + liver resection, with or without bile duct resection) or simple (cholecystectomy only). We used Kaplan-Meier survival analysis to model time to death and evaluated factors associated with overall survival using the Cox proportional hazards regression model. Results: A total of 370 patients were included, 232 with T2 disease and 138 with T3 disease. The proportions who underwent extended resection were 24.1% (56/232) and 37.0% (51/138), respectively. The unadjusted 5-year overall survival rates for simple and extended resection were 39.7% and 49.5%, respectively, for T2 disease (p = 0.03), and 13.5% and 22.8%, respectively, for T3 disease (p = 0.05). In adjusted analysis, extended resection significantly improved overall survival among patients with T2 disease (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.97), whereas higher grade of differentiation, presence of lymphovascular invasion and positive lymph nodes led to worse survival. Extended resection was not associated with improved survival in the T3 group; however, in subgroup analysis stratified by lymph node status, a trend toward improved overall survival with extended resection was seen in node-negative patients (HR 0.20, 95% CI 0.03-1.06). Conclusion: Extended resection improved overall survival in T2 disease regardless of nodal status but appeared most beneficial in node-negative T3 disease. The finding that extended resection was offered only to a small proportion of eligible patients highlights the need for improved knowledge translation at national surgical meetings. Contexte : On ne s'entend pas sur l'ampleur de la résection requise dans les cas de cancer avancé de la vésicule biliaire. Nous avons voulu décrire la prise en charge et les résultats chez les patients opérés pour résection d'un cancer de la vésicule biliaire de stades T2 et T3. Méthodes : Dans cette étude basée dans la population, tous les cas de cancer de la vésicule biliaire de stades T2 et T3 entre le 1er janvier 2002 et le 31 mars 2012 ont été identifiés à partir du Registre des cas de cancer de l'Ontario; les rapports d'anatomopathologie ont été reliés et résumés. La résection était classée soit élargie (cholécystectomie + résection hépatique, avec ou sans résection du canal cholédoque) ou simple (cholécystectomie seulement). Nous avons utilisé l'analyse de survie de Kaplan-Meier pour modéliser la durée de la survie et évalué les facteurs associés à la survie globale à l'aide du modèle de régression aléatoire proportionnelle de Cox. Résultats : En tout, 370 patients ont été inclus, dont 232 présentaient un stade T2 et 138 un stade T3. Les proportions soumises à une résection élargie ont été de 24,1% (56/232) et 37,0% (51/138), respectivement. Les taux de survie globaux non ajustés à 5 ans pour les résections simples et élargies ont été de 39,7% et de 49,5%, respectivement, pour les T2 (p = 0,03), et de 13,5% et de 22,8%, respectivement pour les T3 (p = 0,05). Dans l'analyse ajustée, la résection élargie a signifieativement amélioré la survie globale chez les patients au stade T2 (rapport de risques [RR] 0,51, intervalle de confiance [IC] de 95% 0,30-0,97), tandis qu'un degré plus élevé de différenciation, la présence d'envahissement lymphovasculaire et de ganglions lymphatiques positifs ont donné lieu à une survie moindre. La résection élargie n'a pas été associée à une amélioration de la survie dans le groupe T3; par contre, dans une analyse de sous-groupes stratifiés en fonction de l'atteinte des ganglions lymphatiques, nous avons observé une tendance à l'amélioration globale de la survie après la résection élargie chez les patients dont les ganglions étaient négatifs (RR 0,20, IC de 95% 0,03-1,06). Conclusion : La résection élargie a amélioré la survie globale des patients au stade T2, indépendamment de l'atteinte ganglionnaire, mais a semblé plus bénéfique chez les patients au stade T3 dont les ganglions étaient négatifs. Le fait que la résection élargie n'ait été offerte qu'à une faible proportion de patients admissibles rappelle qu'il faut insister davantage sur l'application des connaissances lors des congrès nationaux de chirurgie.

The authors designed and evaluated an innovative, branded campaign called 'Adelante' to promote positive youth development (PYD) and reduce risk behaviors among Latino youth near Washington, DC. Repeated cross-sectional surveys were conducted in the intervention and a comparison community to evaluate campaign exposure and changes in PYD outcomes. The sample consisted of 1549 Latino and immigrant adolescents surveyed at three time points in intervention and comparison communities. A social marketing campaign was implemented using outdoor advertising, Web, video and social media channels to promote PYD and health outcomes over a 1-year period from 2015 to 2016. Measures included media use; self-reported exposure to campaign promotions; Adelante message receptivity; validated PYD scales; substance use, sexual risk taking, violence-related knowledge, attitudes, beliefs, intentions and risk behavior. Outcomes were regressed first on campaign exposure to examine dose--response effects of the Adelante campaign over time. Second, we compared outcomes between the Adelante and comparison communities. We observed a positive effect of self-reported exposure on multiple outcomes, including improvements in pro-violence and sexual risk outcomes and lower pro-violence attitudes and lower risky attitudes toward sex. Adelante was effective in improving youth risk outcomes and offers a promising model for future health promotion with Latino and immigrant populations.

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.

ImportanceRacial disparities in use of analgesia in emergency departments have been previously documented. Further work to understand the causes of these disparities must be undertaken, which can then help inform the development of interventions to reduce and eradicate racial disparities in health care provision.ObjectiveTo evaluate racial differences in analgesia administration, and particularly opioid administration, among children diagnosed as having appendicitis.Design, setting, and participantsRepeated cross-sectional study of patients aged 21 years or younger evaluated in the emergency department who had an International Classification of Diseases, Ninth Revision diagnosis of appendicitis, using the National Hospital Ambulatory Medical Care Survey from 2003 to 2010. We calculated the frequency of both opioid and nonopioid analgesia administration using complex survey weighting. We then performed multivariable logistic regression to examine racial differences in overall administration of analgesia, and specifically opioid analgesia, after adjusting for important demographic and visit covariates, including ethnicity and pain score.Main outcomes and measuresReceipt of analgesia administration (any and opioid) by race.ResultsAn estimated 0.94 (95% CI, 0.78-1.10) million children were diagnosed as having appendicitis. Of those, 56.8% (95% CI, 49.8%-63.9%) received analgesia of any type; 41.3% (95% CI, 33.7%-48.9%) received opioid analgesia (20.7% [95% CI, 5.3%-36.0%] of black patients vs 43.1% [95% CI, 34.6%-51.4%] of white patients). When stratified by pain score and adjusted for ethnicity, black patients with moderate pain were less likely to receive any analgesia than white patients (adjusted odds ratio = 0.1 [95% CI, 0.02-0.8]). Among those with severe pain, black patients were less likely to receive opioids than white patients (adjusted odds ratio = 0.2 [95% CI, 0.06-0.9]). In a multivariable model, there were no significant differences in the overall rate of analgesia administration by race. However, black patients received opioid analgesia significantly less frequently than white patients (12.2% [95% CI, 0.1%-35.2%] vs 33.9% [95% CI, 0.6%-74.9%], respectively; adjusted odds ratio = 0.2 [95% CI, 0.06-0.8]).Conclusions and relevanceAppendicitis pain is undertreated in pediatrics, and racial disparities with respect to analgesia administration exist. Black children are less likely to receive any pain medication for moderate pain and less likely to receive opioids for severe pain, suggesting a different threshold for treatment.