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Dana A Dominguez,1 Xin Wei Wang1,2 1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; 2Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USACorrespondence: Xin Wei Wang Tel +1 240 760 6858Fax +1 240 541 4444Email xw3u@nih.govAbstract: Advances in Next-Generation Sequencing (NGS) technology have led to a rapid expansion in the application of “precision medicine,” attempting to personalize therapies and improve outcomes for cancer patients. While these technologies carry great promise, evidence for translation to patient outcomes is lacking. This is especially true in hepatocellular carcinoma (HCC), where multiple factors have hampered efforts to develop effective targeted therapies. We sought to review how application of NGS in HCC has translated to patient outcomes and what barriers stand in the way of further progress.Keywords: next generation sequencing, hepatocellular carcinoma, precision medicine, sequencing

Background: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer., Methods: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching., Results: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004)., Conclusion: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers., (© 2024. The Author(s).)

Background: Extrahepatic biliary neuroendocrine tumors (EBNETs) are rare. We aimed to characterize EBNETs including factors associated with survival., Methods: The National Cancer Database was queried for patients with EBNETs from 2004 to 2016. Patients who underwent resection were examined using Cox proportional hazards regression and the Kaplan-Meier method. We compared overall survival (OS) among patients with EBNETs to those with NETs from other primary sites., Results: Overall, 223 patients with EBNETs were identified. Patients were predominantly male (n = 113, 50.7 %), white (n = 177, 79.4 %) and presented without distant metastasis (n = 182, 81.6 %). The majority underwent operation (n = 127, 57.9 %) with resection of the primary tumor (n = 89, 70 %). Among patients who underwent resection (n = 71), multivariable regression demonstrated older age (HR 1.11, 95 % C.I. 1.04-1.17), lymph node metastases (HR 1.19, 95 % C.I. 1.02-1.38) and poorly/undifferentiated tumors [HR 22.3, 95 % C.I. 3.78-131]) were associated with worse overall survival. Patients with EBNETs experienced abbreviated OS compared to patients with small bowel or pancreas NETs (p < 0.001), but improved OS when compared to patients with gallbladder NETs (p = 0.001)., Conclusions: Tumor differentiation and lymph node status significantly impact overall survival., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background and Objective: With the development of novel active systemic therapies, the landscape of hepatocellular carcinoma (HCC) management is rapidly changing. However, HCC lacks sensitive and specific biomarkers to predict prognosis, monitor for minimal residual disease after locoregional therapy, and predict treatment response. In this review, we aim to summarize the best supporting evidence for refining existing, and development of novel biomarkers for staging, prognosis, determination of minimal residual disease and monitoring treatment response in HCC, focusing on those with evidence in clinical trials., Methods: PubMed and Embase databases were searched using the keywords; hepatocellular carcinoma, biomarker, minimal residual disease, surveillance, prognosis, staging, alpha-fetoprotein (AFP), liquid biopsy, treatment response, adjuvant, immunotherapy. Relevant clinical studies were included., Key Content and Findings: AFP remains the major workhorse as the most widely used biomarker in HCC, however, its lack of wide applicability due to the high proportion of patients with HCC who are AFP negative, limits its value throughout all stages of HCC management. Significant work has been done to combine AFP with other clinical and serologic factors to increase its accuracy and utility as a biomarkers. However, it is likely that other more novel biomarkers such as those obtained through liquid biopsy will provide the prognostic power necessary for applications such as detecting recurrence and predicting treatment response. Liquid biopsy provides not only a wealth of potential biomarkers including circulating tumor cells and cell-free RNA/DNA, but also the ability to examine the mutational characteristics of the tumor with next generation sequencing. While early evidence supports the potential impact of many new biomarkers, validation in large clinical trials is lacking., Conclusions: This review highlights the paucity of sensitive and specific, widely applicable biomarkers, throughout all phases of management of HCC and summarizes evidence on biomarkers currently in use, as well as those in development and validation. Inclusion of biomarker analysis through clinical trials in HCC is critical to development of optimal therapeutic regimens, and improve patient outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-526/coif). The series “Molecular, Protein, and Cellular Markers for HPB Cancers” was commissioned by the editorial office without any funding or sponsorship. D.A.D. receives payments from Johnson & Johnson for surgical video annotation work not relevant to current work. The authors have no other conflicts of interest to declare., (2024 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Primary liver cancer (PLC) consists of two main histological subtypes; hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The role of transcription factors (TFs) in malignant hepatobiliary lineage commitment between HCC and iCCA remains underexplored. Here, we present genome-wide profiling of transcription regulatory elements of 16 PLC patients using single-cell assay for transposase accessible chromatin sequencing. Single-cell open chromatin profiles reflect the compositional diversity of liver cancer, identifying both malignant and microenvironment component cells. TF motif enrichment levels of 31 TFs strongly discriminate HCC from iCCA tumors. These TFs are members of the nuclear/retinoid receptor, POU, or ETS motif families. POU factors are associated with prognostic features in iCCA. Overall, nuclear receptors, ETS and POU TF motif families delineate transcription regulation between HCC and iCCA tumors, which may be relevant to development and selection of PLC subtype-specific therapeutics., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: A few observational studies have found that outcomes after esophagectomies by thoracic surgeons are better than those by general surgeons., Methods: Non-emergent esophagectomy cases were identified in the 2016-2017 American College of Surgeons NSQIP database. Associations between patient characteristics and outcomes by thoracic versus general surgeons were evaluated with univariate and multivariate logistic regression., Results: Of 1,606 cases, 886 (55.2%) were performed by thoracic surgeons. Those patients differed from patients treated by general surgeons in race (other/unknown 19.3% vs 7.8%; P<.001) but not in other baseline characteristics (age, sex, BMI, and comorbidities). Thoracic surgeons performed an open approach more frequently (48.9% vs 30.8%, P<.001) and had operative times that were 30 minutes shorter (P<.001). General surgeons had lower rates of reoperation (11.8% vs 17.2%; P=.003) and were more likely to treat postoperative leak with interventional means (6.3% vs 3.4%, P=.01). Thoracic surgeons were more likely to treat postoperative leak with reoperation (5.9% vs 3.6%, P=.01). There were no other differences in univariate comparison of outcomes between the two groups, including leak, readmission, and death. General surgery specialty was associated with lower risk of reoperation. Our multivariable model also found no relationship between general surgeon and risk of any complication (odds ratio 1.10; 95% CI .86 to 1.42)., Discussion: In our large, national database study, we found that outcomes of esophagectomies by general surgeons were comparable with those by thoracic surgeons. General surgeons managed postoperative leaks differently than thoracic surgeons.

Surgery is the cornerstone of treatment for retroperitoneal sarcoma (RPS). Surgery should be performed by a surgical oncologist with sub-specialization in this disease and in the context of a multidisciplinary team of sarcoma specialists. For primary RPS, the goal of surgery is to achieve the complete en bloc resection of the tumor along with involved organs and structures to maximize the clearance of the disease. The extent of resection also needs to consider the risk of complications. Unfortunately, the overarching challenge in primary RPS treatment is that even with optimal surgery, tumor recurrence occurs frequently. The pattern of recurrence after surgery (e.g., local versus distant) is strongly associated with the specific histologic type of RPS. Radiation and systemic therapy may improve outcomes in RPS and there is emerging data studying the benefit of non-surgical treatments in primary disease. Topics in need of further investigation include criteria for unresectability and management of locally recurrent disease. Moving forward, global collaboration among RPS specialists will be key for continuing to advance our understanding of this disease and find more effective treatments.

Objective: The aim of this study was to investigate whether our previously reported improvements in short-term cancer esophagectomy outcomes after large-scale regionalization in the United States translated to longer-term survival benefit., Background: Regionalization is associated with better early postoperative outcomes following cancer esophagectomy; however, data regarding its effect on long-term survival are mixed., Methods: We retrospectively reviewed 461 patients undergoing cancer esophagectomy before (2009-2013, N = 272) and after (2014-2016, N = 189) regionalization. Kaplan-Meier curves and chi-square tests were used to describe 1- and 3-year survival in each era. Hierarchical logistic regression models examined the adjusted effect of regionalization on mortality., Results: Compared to pre-regionalization patients, post-regionalization patients had significantly higher 1-year survival (83.1% vs 73.9%, P = 0.02) but not 3-year survival (52.9% vs 58.2%, P = 0.26).Subgroup analysis by cancer stage revealed that 1-year survival benefit was only significant among mid-stage (IIB-IIIB) patients, whereas differences in 3-year survival only approached significance among early-stage (IA-IIA) patients.In multivariable analysis, only regionalization was a predictor of lower mortality at 1 year [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.29-1.00], and only thoracic specialty at 3years (OR 0.62, 95% CI 0.38-0.99). Older age, more advanced stage, and complications were associated with higher 1- and 3-year mortality. Comorbidity, minimally invasive approach, surgeon volume, facility volume, and neoadjuvant treatment were not significant in this model., Conclusions: Regionalization was associated with improved 1-year survival after cancer esophagectomy, independent of factors such as morbidity or volume in our adjusted models. This survival benefit did not persist at 3 years, likely due to the aggressive nature of the disease., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) has been associated with soft gland texture and/or small pancreatic duct. We hypothesized that selective use of pancreaticogastrostomy (PG) over pancreaticojejunostomy (PJ) in those scenarios would decrease the rate of CR-POPF., Methods: Review of prospective database of all PD's performed at a single institution between 2009 and 2019 was performed. The pancreatic remnant was deemed "high risk" if soft gland and/or small duct were present., Results: PJ was performed in 199 (147 "low-risk" and 52 "high-risk") cases, and 110 patients (all "high-risk") had a PG. Overall CR-POPF rate was 11.9% with no difference between the groups. Risk-stratified analysis within PJ group showed CR-POPF rate of 5.4% versus 36% in "low-risk" versus "high risk" scenarios, respectively; the use of PG significantly decreased CR-POPF rate (9.1%, p < 0.0001). Gastrointestinal bleeding was more likely to occur following PG than PJ. Soft gland texture and gastrointestinal bleeding were the strongest predictors of CR-POPF in PJ and PG groups, respectively., Conclusion: Selective use of PG after PD in "high-risk" scenarios mitigates the risk of CR-POPF. Increased rate of gastrointestinal bleeding calls for further refinement of the technique and heightened postoperative vigilance., Competing Interests: Conflict of interest statement All contributing authors report no relevant conflicts of interest., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The role of adjuvant chemotherapy in resected stage II colon cancer remains controversial. Treatment recommendations rely largely on the presence of certain high-risk features for recurrence., Objective: We sought to define patient and clinicopathologic differences between early-onset and late-onset colorectal cancer and determine whether these differences impact treatment. We hypothesized that high-risk features in stage II colorectal cancer differed between age groups and would most strongly influence administration of adjuvant chemotherapy., Design: This was a retrospective cohort study., Setting: The study was conducted at a Commission on Cancer designated hospital as well as the National Cancer Institute Intramural Research Program., Patients: Patients with resected stage II colon cancer were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. Patients were stratified into young (≤45), middle-aged (50-75), and older (>75) age groups., Main Outcome Measures: Incidence of high-risk clinicopathologic features and receipt of adjuvant chemotherapy were measured., Results: A total of 14,966 patients met inclusion criteria. Young patients were found to have had at least one high-risk feature ( n = 489, 44%) slightly more often than both middle-aged ( n = 3734, 40%) and older patients ( n = 1890, 42%). A total of 332 (7%) older patients received adjuvant chemotherapy compared to 627 (56%) young patients and 2854 (30%) middle-aged patients. Age group was independently associated with receipt of adjuvant chemotherapy when controlling for relevant clinicopathologic factors., Limitations: This was a retrospective study without granular detail on treatment decisions., Conclusions: Young patients are frequently prescribed adjuvant chemotherapy for both high- and low-risk tumors despite questionable benefit in the latter. Older patients rarely receive adjuvant therapy. Both medical and surgical oncologists should be aware of disparities in cancer treatment and remain conscientious about making treatment decisions solely based on age. See Video Abstract at http://links.lww.com/DCR/B846 ., La Edad Determina El Uso De Quimioterapia Adyuvante En El Cncer De Colon Resecado En Estadio Ii: ANTECEDENTES:El papel de la quimioterapia adyuvante en el cáncer de colon resecado en estadio II sigue siendo controversial . Las recobmendaciones para el tratamiento dependen en gran medida de la presencia de ciertas características de alto riesgo de recurrencia.OBJETIVO:Buscamos definir las diferencias clínico-patológicas del paciente entre el CCR de inicio temprano y tardío; y determinar si estas diferencias afectan el tratamiento. Hipotetizamos que las características de alto riesgo del cáncer colorrectal en estadio II difieren entre los grupos de edad y que influyen fuertemente en la administración de quimioterapia adyuvante.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLINICO:El estudio se llevó a cabo en un hospital designado por la Comisión sobre el Cáncer, así como el Programa de Investigación Intramural del Instituto Nacional del Cáncer.PACIENTES:Se identificaron los pacientes con cáncer de colon resecado en estadio II en la Base de datos nacional del cáncer y se registraron las características clínico-patológicas. Los pacientes se estratificaron en grupos de edad jóvenes (≤45), de mediana edad (50-75) y mayores (> 75).PRINCIPALES MEDIDAS DE RESULTADO:Se estudiaron la incidencia de las características clínico-patológicas de alto riesgo y la recepción de quimioterapia adyuvante.RESULTADOS:Un total de 14.966 pacientes cumplieron con los criterios de inclusión. Se encontró que los pacientes jóvenes tenían al menos una característica de alto riesgo (n = 489, 44%) un poco más frecuente que los pacientes de mediana edad (n = 3734, 40%) y los pacientes mayores (n = 1890, 42%). Un total de 332 (7%) de los pacientes mayores recibieron quimioterapia adyuvante en comparación con 627 (56%) de los pacientes jóvenes y 2854 (30%) de los pacientes de mediana edad. El grupo de edad se asoció de forma independiente con la recepción de quimioterapia adyuvante al controlar los factores clínico-patológicos relevantes.LIMITACIONES:Este fue un estudio retrospectivo sin detalles granulares sobre las decisiones de tratamiento.CONCLUSIONES:A los pacientes jóvenes se les prescribe con frecuencia quimioterapia adyuvante para tumores de alto y bajo riesgo, a pesar de los cuestionables beneficios en estos últimos. Los pacientes de edad avanzada rara vez reciben terapia adyuvante. Tanto los oncólogos clínicos como los quirúrgicos deben ser conscientes de las disparidades en el tratamiento del cáncer y ser conscientes de tomar decisiones de tratamiento basadas únicamente en la edad. Consulte Video Resumen en http://links.lww.com/DCR/B846 . (Traducción- Dr. Francisco M. Abarca-Rendon )., (Copyright © The ASCRS 2021.)

Objective: Existing evidence demonstrates some benefit of regionalization on early postoperative outcomes following lung cancer resection, but data regarding the persistence of this effect in long-term mortality are lacking. We investigated whether previously reported improvements in short-term outcomes translated to long-term survival benefit., Methods: We retrospectively reviewed patients undergoing major pulmonary resection (lobectomy, bilobectomy, or pneumonectomy) for cancer within our integrated health care system before (2011-2013; n = 782) and after (2015-2017; n = 845) thoracic surgery regionalization. Overall survival was compared by Kaplan-Meier analysis, and 1- and 3-year mortality was compared by the by χ 2 or Fisher exact test. Multivariable Cox regression models evaluated the effect of regionalization on mortality adjusted for relevant factors., Results: Kaplan-Meier curves showed that overall survival was better among patients undergoing surgery postregionalization (log-rank test, P < .0001). Both 1- and 3-year mortality were decreased after regionalization: to 5.7% from 11.1% (P < .0001) for 1 year and to 17.0% from 25.5% (P = .0002) for 3 years. The multivariable adjusted Cox regression analysis revealed that only regionalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.42-0.76), age (HR, 1.03; 95% CI, 1.02-1.04), cancer stage (HR, 1.72, 1.83, and 2.56 for stages II, III, and IV, respectively), and Charlson comorbidity index (HR, 1.80 for 1-2; 2.05 for ≥3) were independent predictors of mortality., Conclusions: We found that overall mortality as well as 1- and 3-year mortality for lung cancer resection were lower after thoracic surgery regionalization. The association between regionalization and reduced mortality was significant even after adjusting for other related factors in a multivariable Cox analysis. Notably, surgeon volume, facility volume, surgeon specialty, neoadjuvant treatment, and video-assisted thoracoscopic surgery approach did not significantly affect mortality in the adjusted model., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Intercostal nerve blockade (INB) for thoracic surgery analgesia has gained popularity in practice, but evidence demonstrating its efficacy remains sparse and inconsistent. We investigated the effect of INB with standard bupivacaine (SB) with epinephrine versus liposomal bupivacaine (LB) versus a mixed solution of the two on postoperative pain control and outcomes in video assisted thoracoscopic lobectomy patients., Methods: Since 2014, our practice has shifted from using INBs with SB with epinephrine, to LB, to a mix of the two as the central component of multimodal analgesia after video assisted thoracoscopic surgery. The blocks are performed in a standardized fashion under thoracoscopic visualization consecutively from two rib spaces above to two below the outermost incisions. We retrospectively compared all minimally invasive lobectomies performed at our institution between January 2014 and July 2018 by type of local anesthetic used for INB. We examined median length of stay (LOS), opioid utilization, and subjective pain scores [0-10]., Results: Out of 302 minimally invasive lobectomy patients, 34 received SB with epinephrine, 222 received LB alone, and 46 received the mixed solution. LOS was almost a full day shorter in the LB group than in the SB group (34.8 vs. 56.5 hours, P=0.01). There was nearly 25% lower median total morphine equivalent utilization in the mixed solution cohort compared to the LB cohort (-7.1 mg, P=0.02). Additionally, IV morphine equivalent utilization was over 50% lower in the mixed solution group than in the SB with epinephrine group (-10.0 mg, P=0.03)., Conclusions: Our study is by far the largest (N=302) to compare types of local anesthetic used for INB within a uniform case population. The reductions in LOS and opiate utilization observed in our study among patients receiving LB-based formulations were both statistically and clinically significant., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1583/coif). The authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Background & Aims: Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis., Methods: We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA., Results: Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer., Conclusions: Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy., Lay Summary: Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Published by Elsevier B.V.)

Background: Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3' end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results., Results: We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients., Conclusions: Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer., (© 2021. The Author(s).)

Background: Adrenal venous sampling (AVS) is recommended before adrenalectomy for patients with primary aldosteronism (PA) over 35 years old. The literature examining contralateral suppression (CoS) on AVS in predicting surgical outcomes is conflicting. We examined the presence of CoS in patients who underwent adrenalectomy while adjusting for clinical and biochemical factors associated with a clinical cure of hypertension (ccHTN)., Methods: We performed a retrospective review of patients with successful AVS who underwent unilateral adrenalectomy for PA at a quaternary referral center. Patients were excluded if they had overt cortisol co-secretion, or inadequate follow-up. We first evaluated the aldosterone resolution score (ARS) in predicting ccHTN in our cohort. Next, the receiver-operator characteristic analysis (ROC) was used to determine the optimal contralateral suppression index (CSI) cutoff to define CoS. We performed univariable and multivariable analyses of factors associated with ccHTN. The primary outcome was ccHTN defined as blood pressure less than 140/90 mmHg, and off blood pressure medications., Results: Of the 102 patients on bivariable analysis, age, sex, duration of HTN, number of medications, preoperative systolic blood pressure, and creatinine level were associated with ccHTN. ROC analysis of ARS had an AUC of 0.850 (p < 0.001). On multivariable analysis, only ARS remained associated with ccHTN (OR 3.40, 95% CI 1.20-9.61, p = 0.021). CSI was not significantly associated with ccHTN on ROC, bivariable, or multivariable analyses., Conclusion: The presence of CoS was not useful in predicting ccHTN following unilateral adrenalectomy for PA in our cohort. After adjusting for clinical and biochemical factors, ARS remains a useful predictor for ccHTN., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Given the lack of consensus in the surgical treatment of anal adenocarcinoma, practice-patterns demonstrate utilization of organ-preserving techniques. The adequacy of local excision compared to abdominoperineal resection (APR) as a surgical approach for stage II disease is unknown. Our study examines the utilization of local excision in the treatment of stage II anal adenocarcinoma, rates of R0 resection, and differences in overall survival compared to APR., Materials and Methods: Using the National Cancer Database (2004-2016), we retrospectively analyzed patients diagnosed with clinical stage II anal adenocarcinoma who received chemoradiation and surgery. Patient cohorts were assigned based on the surgical procedure they received. Propensity score matching was used to offset selection bias and confounding factors. Treatment approach, pathologic margin status, and overall survival were assessed., Results: Overall, 359 patients underwent resection of clinical stage II anal adenocarcinoma and received chemoradiation therapy. Of these patients, 87 (24%) underwent local excision, whereas 272 (76%) received an abdominoperineal resection. In a propensity score-matched cohort, patients who underwent local excision were less likely to achieve an R0 resection (40% vs 90%), and more likely to receive adjuvant instead of neoadjuvant chemoradiation. Overall survival was not significantly different between the propensity-matched groups. Surgical approach and pathologic margin status were not independently associated with overall survival., Conclusions: Among patients with clinical stage II anal adenocarcinoma who received chemotherapy and radiation, complete resection was significantly less likely with local excision compared to abdominoperineal resection, however, overall survival was not affected. Prospective studies of neoadjuvant chemoradiation followed by local excision are warranted., (Published by Elsevier Ltd.)

Background: Locally advanced gastric cancer (LAGC) presents a therapeutic dilemma, particularly as it often involves adjacent organs through desmoplasia or true pathologic invasion. To obtain a margin-negative resection, these tumors require en bloc gastrectomy with multivisceral resection (G+MVR), and contention remains regarding its safety and oncologic benefit., Methods: We used the National Cancer Database to retrospectively evaluate the short- and long-term outcomes of patients with LAGC treated in the USA between 2004 and 2016. Associations with margin status and perioperative outcomes were calculated using logistic regression. Survival was estimated using Cox proportional hazards regression and the Kaplan-Meier method., Results: Overall, 785 pathologic stage T4b (pT4b) patients diagnosed with LAGC underwent gastrectomy (n = 438) or G+MVR (n = 347). There was no association between G+MVR and short- or long-term mortality. Positive resection margins (HR 1.68, 95% CI 1.40-2.03), the presence of nodal disease (HRs 1.46-1.50), treatment at a high-volume center (HR 0.76, 95% CI 0.68-0.85), and the receipt of adjuvant chemotherapy (HR 0.64, 95% CI 0.51-0.80) were independently associated with overall survival. Diffuse-type histology was associated with higher rates of an R1 resection (OR 3.60, 95% CI 2.20-5.87). Perioperative and long-term survival metrics were comparable between patients with pT4a and pT4b LAGC who underwent a margin-negative G+MVR. Undergoing a margin-negative G+MVR imparted a 6-month survival benefit over non-curative gastrectomy alone (p < 0.001)., Conclusions: Our study demonstrates the safety and long-term feasibility of G+MVR for disease clearance in well-selected patients with LAGC, and we advocate for their referral to high-volume centers for optimal care.

Background: Most gallbladder cancers are diagnosed after cholecystectomy for presumed benign disease, and nodal staging to inform subsequent treatment is therefore often lacking. We evaluated the association of lymphovascular invasion (LVI) with regional lymph node involvement in gallbladder adenocarcinoma and its impact on survival., Methods: The National Cancer Database was queried to identify patients with resected gallbladder adenocarcinoma and with available staging and LVI status. Patients with pT4 and M1 disease were excluded. Univariable and multivariable regression identified factors associated with positive lymph nodes. Cox proportional hazards model was used to evaluate overall survival (OS)., Results: Of 1649 patients with available LVI status, 1142 (69.7%) had at least one positive lymph node and 765 (46.4%) had LVI. On multivariable regression, presence of LVI was the strongest predictor of positive lymph nodes (odds ratio, 3.69; P < .001). The positive predictive value of LVI for positive lymph nodes in pT2 and pT3 tumors was 80.1% and 90.5%, respectively. LVI was independently associated with decreased OS (hazard ratio, 1.21; P = .001), as were node-positive disease and increasing T stage., Conclusion: In patients with gallbladder adenocarcinoma, LVI is independently associated with regional lymph node metastases and abbreviated OS. LVI status may help risk-stratify patients following initial cholecystectomy and inform subsequent treatment., (© 2020 Wiley Periodicals LLC.)

Background: Alveolar soft part sarcoma is a rare, histologic subtype of soft tissue sarcoma that remains poorly defined. We aimed to describe patient characteristics and treatment patterns and to examine factors associated with survival for patients with alveolar soft part sarcoma., Methods: After identifying patients with alveolar soft part sarcoma in the National Cancer Database, we recorded their clinicopathologic characteristics. Univariable log-rank survival analysis and Cox proportional hazards model were employed. For context, survival comparisons were included for patients with other sarcoma subtypes., Results: Overall, 293 patients with alveolar soft part sarcoma were identified. Interestingly, patients with head and neck tumors were least likely to present with distant disease (40%, P = .025). The majority of patients underwent resection (n = 183, 63%). Among those, no predictors of lesser survival were identified other than the presence of metastases (hazard ratio 6.04, P ≤ .001). Patients with stage IV alveolar soft part sarcoma who underwent resections experienced improved survival relative to similar patients with more common subtypes of soft tissue sarcomas (P ≤ .001)., Conclusion: Alveolar soft part sarcoma is exceedingly rare, and patients often present with metastases. Primary tumors can occur anywhere in the body, and location impacts the rates of metastases at presentation. Resection is associated with a favorable survival advantage when compared to other, more common histologic subtypes of soft tissue sarcomas., (Published by Elsevier Inc.)

Background: Granulomatous mastitis (GM) is a rare entity of benign origin. Multiple treatment strategies, including surgical procedures, can have sequelae of recurrence, nonhealing wounds, and protracted pain. Even after GM is diagnosed, the best management strategy remains controversial. We sought to evaluate intralesional steroid injection as a potential treatment for GM., Materials and Methods: Electronic medical records from 2003 to 2017 of patients diagnosed with benign breast lesions were retrospectively reviewed. Patients with pathologically confirmed GM were identified. All treatment methods were documented, which included observation, oral steroids, methotrexate, steroid injection, and surgical excision. Primary outcome was time to resolution. Effectiveness was based on relief of symptoms along with duration of symptoms from initial time of diagnosis to full relief. Analysis of variance was used to compare outcomes between groups., Results: Of the 49 patients with confirmed GM diagnoses, 57% had observation only, 24% had steroid injection, and 19% had surgical resection. The average time to resolution differed significantly among the three groups (11.5 mo from the start of observation, 2.0 mo from the time of steroid injection, and 0.5 mo from the time of surgical excision, P < 0.001)., Conclusions: Intralesional steroid injection is an effective treatment of GM. Selective management is appropriate for patients with GM, and surgical resection is not required for most patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME., (Copyright © 2020 Barry, Baldeosingh, Lamm, Patel, Zhang, Dominguez, Kirton, Shah and Dang.)

Background: Therapeutic options for patients with hepatocellular carcinoma (HCC) are limited. Transarterial chemoembolization (TACE) is an interventional procedure used to deliver chemotherapy and embolizing agents directly to the tumor and is the procedure of choice for patients with intermediate stage HCC. While effective, more than 40% of patients do not respond to therapy, highlighting the need to investigate possible mechanisms of resistance. We sought to evaluate mechanisms of TACE resistance and evaluate a potential therapeutic target to overcome this resistance., Methods: Using a prognostic gene signature which predicts TACE response (TACE Navigator) in a cohort of HCC patients who received TACE, patients were classified as responders and non-responders. Transcriptomic and gene pathway analysis were used to identify potential drivers of TACE resistance. Knockdown of the gene encoding rate limiting enzyme PKM2 using shRNA in HCC cell lines, as well as pharmacologic inhibition of PKM2 with shikonin using an in vitro TACE model measured response to chemotherapy under hypoxia. Finally, we replicated the TACE model with shikonin using patient derived cell line organoids (PDC). Functional studies were performed in vitro using immunoblotting, quantitative polymerase chain reaction, glycolysis and hypoxia assays., Results: In patient non-responders, we identified enrichment of the glycolysis pathway, specifically of the gene encoding the rate-limiting enzyme PKM2. We identified four HCC cell lines which recapitulated a TACE responder-like and non-responder-like phenotype. PKM2 knockdown in HCC cell lines demonstrated a less proliferative and aggressive phenotype as well as improved drug sensitivity to both doxorubicin and cisplatin. In vitro TACE model demonstrated that TACE non-responder-like cells overcame therapeutic resistance and rendered them susceptible to therapy through PKM2 knockdown. Lastly, we obtained similar results using a pharmacologic PKM2 inhibitor, shikonin in both cell lines, and PDC organoids., Conclusion: Elevated PKM2 is associated with treatment resistance and abbreviated survival in patients receiving TACE. Elevated PKM2 in vitro is associated with increased utilization of the glycolysis pathway, resulting in oxygen independent cell metabolism. Through PKM2 knockdown as well as with pharmacologic inhibition with shikonin, non-responder cells can be reprogrammed to act as responders and could improve TACE efficacy in patients.

Introduction: Guidelines for imaging anticoagulated patients following a traumatic injury are unclear. Interval CT head (CTH) is often routinely performed after initial negative CTH to assess for delayed intracranial hemorrhage (ICH-d). The rate of ICH-d for patients taking novel oral anticoagulants (NOACs) is unknown. We hypothesized that the incidence of ICH-d in patients on NOACs would be similar, if not lower to that of warfarin, and routine repeat CTH after initial negative would not change management, and thus, may not be indicated., Materials and Methods: Anticoagulated patients presenting with blunt trauma to a level I trauma center between 2016 and 2018 were evaluated. Exclusion criteria included: positive initial CTH and those taking nonoral anticoagulation or antiplatelet agents alone (without warfarin or NOAC). Outcomes included: ICH-d, discharge GCS, administration of reversal agents, neurosurgical intervention, readmission, and death. Multivariable regression was performed to evaluate patient factors associated with the development of ICH-d., Results: A total of 332 patients met the inclusion criteria. Patients were divided into a warfarin group (n = 191) and NOAC group (n = 141). The incidence of ICH-d in the warfarin group was 2.6% (5/191) and 2.1% (3/141) in the NOAC group (P = 0.77). There were no reversal agents administered, neurosurgical interventions, readmissions, or deaths in the NOAC group., Conclusions: Little is known about the impact of NOACs in the setting of trauma, especially regarding risks of ICH-d following traumatic injury. In the NOAC group, ICH-d occurred only 2.1% of the time. In addition, there were no reversal agents given, neurosurgical interventions, or deaths. These data, taken together, suggest the limited utility of repeat imaging in this patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Deregulated RNA-binding proteins (RBP), such as Argonaute 2 (AGO2), mediate tumor-promoting transcriptomic changes during carcinogenesis, including hepatocellular carcinoma (HCC). While AGO2 is well characterized as a member of the RNA-induced silencing complex (RISC), which represses gene expression through miRNAs, its role as a bona fide RBP remains unclear. In this study, we investigated AGO2's role as an RBP that regulates the MYC transcript to promote HCC. Using mRNA and miRNA arrays from patients with HCC, we demonstrate that HCCs with elevated AGO2 levels are more likely to have the mRNA transcriptome deregulated and are associated with poor survival. Moreover, AGO2 overexpression stabilizes the MYC transcript independent of miRNAs. These observations provide a novel mechanism of gene regulation by AGO2 and provide further insights into the potential functions of AGO2 as an RBP in addition to RISC. IMPLICATIONS: Authors demonstrate that the RBP Argonaute 2 stabilizes the MYC transcript to promote HCC., (©2020 American Association for Cancer Research.)

Background: Clinically lymph node positive (cLNP) intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, without clear management guidelines for the practicing clinician. We sought to evaluate current practice patterns for cLNP ICC, including associations with survival., Methods: The National Cancer Database was queried for patients with cLNP ICC, without extrahepatic metastases., Results: We identified 1023 patients with cLNP ICC, 77%% (n = 784) of whom received chemotherapy alone. Resection was undertaken in 23% (n = 239) of patients and was most commonly utilized in combination with chemotherapy (n = 150). Median survival for all patients was 13.6 months. Patients undergoing resection in combination with chemotherapy were associated with an improved survival (22.5 months) as compared to those patients receiving chemotherapy alone (11.9 months) or resection alone (12.4 months) (p < 0.01). Finally, we compared the survival of patients with cLNP ICC with that of patients with pathologically proved lymph node positive (pLNP) ICC, all of whom were treated with resection with chemotherapy, and found no difference in survival (22.5 months-19.3 months, p = 0.99, respectively)., Conclusions: While the decision to pursue resection for ICC is multifactorial and patient specific, the presence of clinically positive LNs should not represent a contraindication., (Copyright © 2019. Published by Elsevier Ltd.)

Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell-like EpCAM + AFP + HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM + AFP + HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM + HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM + HCC subpopulations. SIGNIFICANCE: This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM + HCC tumors by inactivating the Wnt/β-catenin signaling pathway., (©2019 American Association for Cancer Research.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The MYC oncogene is dysregulated in approximately 30% of liver cancer. In an effort to exploit MYC as a therapeutic target, including in hepatocellular carcinoma (HCC), strategies have been developed on the basis of MYC amplification or gene translocation. Due to the failure of these strategies to provide accurate diagnostics and prognostic value, we have developed a Negative Elongation Factor E (NELFE)-Dependent MYC Target (NDMT) gene signature. This signature, which consists of genes regulated by MYC and NELFE, an RNA binding protein that enhances MYC-induced hepatocarcinogenesis, is predictive of NELFE/MYC-driven tumors that would otherwise not be identified by gene amplification or translocation alone. We demonstrate the utility of the NDMT gene signature to predict a unique subtype of HCC, which is associated with a poor prognosis in three independent cohorts encompassing diverse etiologies, demographics, and viral status. The application of gene signatures, such as the NDMT signature, offers patients access to personalized risk assessments, which may be utilized to direct future care.

Introduction: Some patients with cardiac stents will need thoracic surgery during the dual antiplatelet therapy (DAPT) period. When surgery cannot be safely delayed to allow 1 year of uninterrupted DAPT, appropriate perioperative management of anticoagulation is critical., Case Presentation: A patient treated with new drug-eluting stents and DAPT was concomitantly diagnosed with lung cancer and required a lobectomy. We describe the novel addition of ticagrelor (a short-acting oral antiplatelet agent) to eptifibatide (a short-acting intravenous antiplatelet agent) to bridge DAPT for surgery., Discussion: This ticagrelor-eptifibatide perioperative bridge resulted in decreased preoperative hospitalization compared with eptifibatide alone. There were no associated perioperative cardiac or bleeding complications.

Background: Postsurgical pain control can have a significant impact on patient outcomes and hospital-associated costs. We sought to evaluate the effect of intercostal nerve blocks using liposomal bupivacaine on length of stay (LOS) in patients undergoing video-assisted thoracoscopic surgery (VATS)., Methods: We retrospectively reviewed outcomes in 80 patients undergoing VATS wedge resection, VATS lobectomy, or minimally-invasive esophagectomy (MIE). Patients received either liposomal bupivacaine (n=40) or standard-release bupivacaine with epinephrine (n=40) via intercostal nerve block. The LOS, 24-hour postoperative pain scores, overall opioid usage, and patient ambulation rates at 24 hours were compared for the two groups., Results: The median LOS was significantly shorter in patients receiving liposomal bupivacaine, at 1.35 days (IQR, 1.28 to 1.53 days) compared to 2.45 days (IQR, 2.08 to 3.51 days) in patients receiving standard-release bupivacaine (P<0.0001). Average post-operative pain score during the first 24 hours was 3.4±1.8 for the liposomal bupivacaine group and 2.3±1.2 for the control group (P=0.002). This difference, though statistically significant, is likely not clinically significant, as there was no difference in 24-hour postoperative intravenous morphine equivalent usage between the liposomal bupivacaine and control groups (29.8±21.0 vs. 31.9±20.9 mg, respectively, P=0.664). Interestingly, however, 93% (37/40) of patients receiving liposomal bupivacaine were able to ambulate within 24-hours after surgery, compared to 65% (26/40) of patients in the control group (P=0.003)., Conclusions: The use of liposomal bupivacaine is associated with decreased LOS in postoperative thoracic surgery patients and earlier return to ambulation. It does not, however, decrease 24-hour postoperative pain scores or opioid usage., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid. Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR ., (©2017 American Association for Cancer Research.)