Publications by authors named "David Geller"

415 Publications

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Gut 2021 Apr 13. Epub 2021 Apr 13.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
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http://dx.doi.org/10.1136/gutjnl-2020-322595DOI Listing
April 2021

Laparoscopic versus open hepatectomy for intrahepatic cholangiocarcinoma: An individual patient data survival meta-analysis.

Am J Surg 2021 Mar 26. Epub 2021 Mar 26.

Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Background: We compared the outcomes of laparoscopic hepatectomy (LH) vs. open hepatectomy (OH) for intrahepatic cholangiocarcinoma (iCCA).

Methods: A systematic review of the MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed using PRISMA guidelines (end-of-search date: 08-June-2020). Individual patient data on overall survival (OS) and recurrence-free survival (RFS) were extracted. Random-effects meta-analyses, and one- and two-stage survival analyses were conducted.

Results: Eight retrospective cohort studies comparing LH (n = 544) vs. OH (n = 2256) were identified. LH demonstrated lower overall complication (Risk ratio [RR] = 0.64, 95% confidence interval [CI]: 0.46-0.90; p = 0.01), surgical lymphadenectomy (RR = 0.74, 95% CI: 0.58-0.93; p = 0.01) and margin-positive resection (RR = 0.78, 95% CI: 0.62-0.99; p = 0.04) rates, and higher recurrence-free rate (RR = 1.24, 95% CI: 1.01-1.51; p = 0.04) vs. OH. In Cox regression, no difference was observed regarding OS (Hazard Ratio [HR] = 1.11, 95% CI: 0.65-1.91; p = 0.70) and RFS (HR = 1.19, 95% CI: 0.74-1.90; p = 0.47).

Conclusion: The use of LH should be considered when feasible in well-selected iCCA patients by hepatobiliary surgeons with experience in minimally-invasive surgery.
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http://dx.doi.org/10.1016/j.amjsurg.2021.03.052DOI Listing
March 2021

A Snapshot of the 2020 Conception of Anatomic Liver Resections and Their Applicability on Minimally Invasive Liver Surgery. A preparatory survey for the Expert Consensus Meeting on Precision Anatomy for Minimally Invasive HBP Surgery.

J Hepatobiliary Pancreat Sci 2021 Mar 31. Epub 2021 Mar 31.

Center for Advanced Treatment of Hepatobiliary and Pancreatic Diseases, Ageo Central General Hospital, Saitama, Japan.

Background: The main aim of this survey was to analyze how liver surgeons perform liver resections and to define their conception of anatomic procedures within the incorporation of minimally invasive liver surgery (MILS).

Methods: The survey was distributed among liver surgeons. It mainly focused on personal experience on open and MILS, methods and landmarks, and experience on anatomic resections and Glissonean approach.

Results: A total of 445 valid answers from 54 countries was obtained. Surgeons performing MILS mainly has below 10 years of experience (81.8% of responders) and one third has never done complex MILS. New techniques, including indocyanine green demarcation are marginally used (<25%). More than 60% of surgeons do not make a full exposure of hepatic veins during MILS, mainly due to the risk of injury or not considering it of any utility. Although 88% of responders agreed with the conception of anatomic resection as the "resection along the border/watersheds of each order division identified by the portal vein flow", only 55% of surgeons have ever performed MILS Glissonean approaches.

Conclusions: Liver anatomy is not a static concept. Anatomic resections need training and precision. Standardization of complex anatomic resections by minimally invasive approach should be encouraged.
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http://dx.doi.org/10.1002/jhbp.959DOI Listing
March 2021

Interferon regulatory factor 1 (IRF-1) downregulates Checkpoint kinase 1 (CHK1) through miR-195 to upregulate apoptosis and PD-L1 expression in Hepatocellular carcinoma (HCC) cells.

Br J Cancer 2021 Mar 26. Epub 2021 Mar 26.

Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Background: CHK1 is considered an oncogene with overexpression in numerous cancers. However, CHK1 signalling regulation in hepatocellular carcinoma (HCC) remains unclear.

Methods: CHEK1 mRNA, protein, pri-miR-195 and miR-195 expression in HCC tissue was determined by qPCR, WB and IF staining assay. Survival analyses in HCC with high- and low-CHEK1 mRNA expression was performed using TCGA database. Relative luciferase activity was investigated in HCC cells transfected with p-CHEK1 3'UTR. Apoptosis was detected by TUNEL assay. NK and CD8+ T cells were analysed by flow cytometry.

Results: CHK1 is increased in human HCC tumours compared with non-cancerous liver. High CHK1 predicts worse prognosis. IFN-γ suppresses CHK1 via IRF-1 in HCC cells. The molecular mechanism of IRF-1 suppressing CHK1 is post-transcriptional by promoting miR-195 binding to CHEK1 mRNA 3'UTR, which exerts a translational blockade. Upregulated IRF-1 inhibits CHK1, which induces apoptosis of HCC cells. Likewise, CHK1 inhibition augments cellular apoptosis in HCC tumours. This effect may be a result of increased tumour NK cell infiltration. However, IRF-1 expression or CHK1 inhibition also upregulates PD-L1 expression via increased STAT3 phosphorylation.

Conclusions: IRF-1 induces miR-195 to suppress CHK1 protein expression. Both increased IRF-1 and decreased CHK1 upregulate cellular apoptosis and PD-L1 expression in HCC.
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http://dx.doi.org/10.1038/s41416-021-01337-6DOI Listing
March 2021

Economic analysis of open versus laparoscopic versus robotic hepatectomy: a systematic review and meta-analysis.

Eur J Health Econ 2021 Mar 19. Epub 2021 Mar 19.

Department of Transplant Surgery, Aristotle University of Thessaloniki School of Medicine, Thessaloníki, Greece.

Background: Following the publication of reports from landmark international consensuses (Louisville 2008 and Morioka 2014), minimally invasive hepatectomy became widely accepted as a legitimate alternative to open surgery. We aimed to compare the operative, hospitalization, and total economic costs of open (OLR) vs. laparoscopic (LLR) vs. robotic liver resection (RLR).

Methods: We performed a systematic literature review (end-of-search date: July 3, 2020) according to the PRISMA statement. Random-effects meta-analyses were conducted. Quality assessment was performed with the Cochrane Risk of Bias tool for randomized controlled trials, and the Newcastle-Ottawa Scale for non-randomized studies.

Results: Thirty-eight studies reporting on 3847 patients (1783 OLR; 1674 LLR; 390 RLR) were included. The operative costs of LLR were significantly higher than those of OLR, while subgroup analysis also showed higher operative costs in the LLR group for major hepatectomy, but no statistically significant difference for minor hepatectomy. Hospitalization costs were significantly lower in the LLR group, with subgroup analyses indicating lower costs for LLR in both major and minor hepatectomy series. No statistically significant difference was observed regarding total costs between LLR and OLR both overall and on subgroup analyses in either major or minor hepatectomy series. Meta-analyses showed higher operative, hospitalization, and total costs for RLR vs. LLR, but no statistically significant difference regarding total costs for RLR vs. OLR.

Conclusion: LLR's higher operative costs are offset by lower hospitalization costs compared to OLR leading to no statistically significant difference in total costs, while RLR appears to be a more expensive alternative approach.
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http://dx.doi.org/10.1007/s10198-021-01277-1DOI Listing
March 2021

IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating β-catenin.

Transl Oncol 2021 Mar 15;14(6):101059. Epub 2021 Mar 15.

Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, United States. Electronic address:

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Lenvatinib oral chemotherapy is approved as a first-line treatment of patients with unresectable HCC. The efficacy and therapeutic duration of lenvatinib are limited by drug resistance, and the mechanism is unclear. IRF2 is a constitutive transcription factor associated with the development of various cancers by regulating cancer cell growth, apoptosis, and drug resistance. However, the potential role of IRF2 in lenvatinib resistance in HCC has not been explored. In this study, we found that IRF2 promoted proliferation, inhibited apoptosis, and increased lenvatinib resistance of HCC cells by regulating β-catenin expression. Silencing IRF2 downregulated the expression of β-catenin, while overexpressing IRF2 upregulated β-catenin. Moreover, the expression of β-catenin and IRF2 was positively correlated in HCC tissues. Inhibiting β-catenin with XAV-939 effectively abrogated β-catenin expression caused by lenvatinib treatment. These findings identify an important function of IRF2 in HCC and demonstrate a mechanism of lenvatinib resistance of HCC cells. Targeting IRF2 may be a potential strategy to improve the therapeutic effect of lenvatinib on HCC.
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http://dx.doi.org/10.1016/j.tranon.2021.101059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988337PMC
March 2021

Interferon regulatory factor 1(IRF-1) activates anti-tumor immunity via CXCL10/CXCR3 axis in hepatocellular carcinoma (HCC).

Cancer Lett 2021 May 6;506:95-106. Epub 2021 Mar 6.

Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA. Electronic address:

Interferon regulatory factor 1 (IRF-1) is a tumor suppressor gene in cancer biology with anti-proliferative and pro-apoptotic effect on cancer cells, however mechanisms of IRF-1 regulating tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remain only partially characterized. Here, we investigated that IRF-1 regulates C-X-C motif chemokine 10 (CXCL10) and chemokine receptor 3 (CXCR3) to activate anti-tumor immunity in HCC. We found that IRF-1 mRNA expression was positively correlated with CXCL10 and CXCR3 through qRT-PCR assay in HCC tumors and in analysis of the TCGA database. IRF-1 response elements were identified in the CXCL10 promoter region, and ChIP-qPCR confirmed IRF-1 binding to promote CXCL10 transcription. IRF-2 is a competitive antagonist for IRF-1 mediated transcriptional effects, and overexpression of IRF-2 decreased basal and IFN-γ induced CXCL10 expression. Although IRF-1 upregulated CXCR3 expression in HCC cells, it inhibited proliferation and exerted pro-apoptotic effects, which overcome proliferation partly mediated by activating the CXCL10/CXCR3 autocrine axis. In vitro and in vivo studies showed that IRF-1 increased CD8 T cells, NK and NKT cells migration, and activated IFN-γ secretion in NK and NKT cells to induce tumor apoptosis through the CXCL10/CXCR3 paracrine axis. Conversely, this effect was markedly abrogated in HCC tumor bearing mice deficient in CXCR3. Therefore, the IRF-1/CXCL10/CXCR3 axis contributes to the anti-tumor microenvironment in HCC.
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http://dx.doi.org/10.1016/j.canlet.2021.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009854PMC
May 2021

Proposal of a New Comprehensive Notation for Hepatectomy: The "New World" Terminology.

Ann Surg 2021 Feb 12. Epub 2021 Feb 12.

*Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan †Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA ‡Department of General, Visceral and Transplant Surgery, University Hospital Mainz, Mainz, Germany §Hôpital Paul Brousse, APHP - Université Paris - Saclay, Villejuif, France ¶Department of HPB- and Liver Transplantation Surgery, University College London, Royal Free Hospitals, London, UK ||Department of Surgery & Transplantation, University Hospital Zurich, Zurich, Switzerland **Hepatobiliary Surgery Division, Department of Surgery, IRCCS San Raffaele Hospital, School of Medicine, Milan, Italy ††Department of Hepatobiliary and Digestive Surgery, Rennes University Hospital, Rennes, France ‡‡Section of Transplantation Surgery, Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, USA §§Department of Surgery, University of California at San Diego, San Diego, USA ¶¶Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina ||||Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China ***Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan †††Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan ‡‡‡Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA §§§Department of Surgery, General and Hepatobiliary Surgery, University of Verona, Verona, Italy ¶¶¶Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, USA ||||||HepatoBiliary Surgery & Liver Transplantation, Asan Medical Center, Ulsan University, Seoul, Republic of Korea ****HPB and Transplant Unit, St. James's University Hospital, Leeds, UK ††††Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany ‡‡‡‡Center for Abdominal Transplantation Weston, Cleveland Clinic Florida, Weston, USA §§§§Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands ¶¶¶¶Department of HPB Surgery and Liver Transplant, Beaujon Hospital, Clichy, France.

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http://dx.doi.org/10.1097/SLA.0000000000004808DOI Listing
February 2021

Prognostic and Therapeutic Utility of Variably Expressed Cell Surface Receptors in Osteosarcoma.

Sarcoma 2021 2;2021:8324348. Epub 2021 Feb 2.

Department of Orthopaedic Surgery, Montefiore Medical Center, The Children's Hospital at Montefiore, Bronx, NY, USA.

Background: Six cell surface receptors, human epidermal growth factor receptor-2 (Her-2), platelet-derived growth factor receptor- (PDGFR-), insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR), c-Met, and vascular endothelial growth factor receptor-3 (VEGFR-3), previously demonstrated variable expression across varying patient-derived and standard osteosarcoma (OS) cell lines. The current study sought to validate previous expression patterns and evaluate whether these receptors offer prognostic and/or therapeutic value.

Methods: Patient-derived OS cell lines ( = 52) were labeled with antibodies to Her-2, PDGFR-, IGF-1R, IR, c-Met, and VEGFR-3. Expression was characterized using flow cytometry. The difference in geometric mean fluorescent intensity (geoMFI = geoMFI - geoMFI) was calculated for each receptor across all cell lines. Receptor expression was categorized as low (Q1), intermediate (Q2, Q3), or high (Q4). The event-free survival (EFS) and overall survival for the six cell surface receptors were estimated by the Kaplan-Meier method. Differences in hazard for EFS event and overall survival event for patients in each of the three expression levels in each of the six cell surface receptors were assessed using the log-rank test.

Results: All 6 receptors were variably expressed in the majority of cell lines. IR and PDGFR- expressions were found to be significant predictors for EFS amongst patients with nonmetastatic disease (=0.02 and 0.01, respectively). The hazard ratio for EFS was significantly higher between high IR and intermediate IR expression (HR = 2.66, =0.02), as well as between high PDGFR- and intermediate PDGFR- expression (HR = 5.68, =0.002). Her-2, c-Met, IGF-1R, and VEGFR-3 were not found to be significant predictors for either EFS or overall survival.

Conclusion: The six cell surface receptors demonstrated variable expression across the majority of patient-derived OS cell lines tested. Limited prognostic value was offered by IR and PDGFR- expression within nonmetastatic patients. The remaining receptors do not provide clear prognostic utility. Nevertheless, their consistent, albeit variable, surface expression across a large panel of patient-derived OS cell lines maintains their potential use as future therapeutic targets.
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http://dx.doi.org/10.1155/2021/8324348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872755PMC
February 2021

The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma.

Ann N Y Acad Sci 2021 Feb 16. Epub 2021 Feb 16.

Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.

Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene; p27 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCF E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27 KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27 KI mice were crossed on to the DKO background, p27 protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27 promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCF -p27 axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2-p27 axis may represent a desirable therapeutic strategy for this cancer.
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http://dx.doi.org/10.1111/nyas.14578DOI Listing
February 2021

The next generation of collaborative care: The design of a novel web-based stepped collaborative care intervention delivered via telemedicine for people diagnosed with cancer.

Contemp Clin Trials 2021 Feb 5:106295. Epub 2021 Feb 5.

University of Pittsburgh, United States of America.

Background: The NIH consensus statement on cancer-related symptoms concluded the most common and debilitating were depression, pain and fatigue (American Cancer Society, 2019; Qaseem et al., 2008; Meijer et al., 2013; Meijer, 2011 [1-6]). Although the comorbidity of these symptoms is well known and may have similar underlying biological mechanisms; yet no intervention has been developed to reduce these symptoms concurrently. The novel web-based stepped collaborative care intervention delivered by telemedicine is the first to be tested in people diagnosed with cancer.

Methods: We plan to test a web-based stepped collaborative care intervention with 450 cancer patients and 200 caregivers in the context of a randomized controlled trial. The primary outcomes include the assessment of patient-reported depression, pain, fatigue and quality of life. Secondary outcome include patient serum levels of pro-inflammatory cytokines and disease progression. We also will assess informal caregiver stress, depression, and metabolic syndrome to determine if improvements in patients' symptoms also result in improvement in caregiver outcomes.

Results: The trial is ongoing and a total of 370 patient have been randomized. Preliminary analyses of the screening tools used for study entry suggest that Center for Epidemiological Studies-Depression (CESD) scale has good sensitivity and specificity (0.77 and 0.85) whereas the scale used to assess pain (0.47 and 0.91) and fatigue (0.11 and 0.91) had poor sensitivity but excellent specificity. Using the AUROC, the best cut point for the CES-D was 15.5, for pain was 4.5; and for fatigue was 2.5. Outcomes not originally proposed included health care utilization and healthcare charges. For the first 100 patients who have been followed a year post-treatment, and who were less than 75 years and randomized to the web-based stepped collaborative care intervention, had lower rates of complications after surgery [χ = 5.45, p = 0.02]. For patients who survived 6 months or less and were randomized to the web-based stepped collaborative care intervention, had lower rates of 90-day readmissions when compared to patients randomized to the screening and referral arm [χ = 4.0, p = 0.046]. Patients randomized to the collaborative care intervention arm had lower mean overall health care charges of $19,546 per patient per year when compared to the screening and referral arm. In a separate analyses focused on the caregivers, we found that after adjusting for age, gender, and race; low levels of caregiver quality of life (HR = 1.067, 95% CI = 1.019-1.117, p = 0.006), high levels of hostility (HR = 1.142, 95% CI = 1.030-1.267, p = 0.012), and alcohol use (HR = 4.193, 95% CI = 1.174-14.978, p = 0.027) were significant predictors of metabolic syndrome.

Discussion: This novel web-based stepped stepped collaborative care intervention, delivered via telemedicine, is expected to provide a new strategy to improve the quality of life in those diagnosed with cancer and their caregivers.

Trial Registration: ClinicalTrials.gov NCT02939755.
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http://dx.doi.org/10.1016/j.cct.2021.106295DOI Listing
February 2021

Nrf2 and β-catenin coactivation in hepatocellular cancer: Biological and therapeutic implications.

Hepatology 2021 Feb 2. Epub 2021 Feb 2.

Department of Pathology, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.

Background: Hepatocellular cancer (HCC) remains a major unmet clinical need. Although activating CTNNB1 mutations are seen in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Co-expression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between β-catenin and Nrf2 signaling in HCC.

Methods: Public HCC datasets were assessed for concomitant presence of CTNNB1 mutations and either mutations in NFE2L2 or KEAP1, or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following co-expression of T41A-CTNNB1 with either WT-, G31A- or T80K-NFE2L2. Based on mTORC1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mTOR inhibitor was investigated.

Results: Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were due to mutations in NFE2L2/KEAP1. Co-expression of mutated-CTNNB1 with mutant-NFE2L2 but not WT-NFE2L2 led to HCC development and mortality by 12-14 weeks. These HCCs were positive for β-catenin targets like Glutamine synthetase and Cyclin-D1, and Nrf2 targets like NAD(P)H Quinone Dehydrogenase 1 and peroxiredoxin 1. RNA-seq and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (Iron Homeostasis and Glioblastoma Multiforme signaling) and expected (Glutamine Metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5mg/kg diet ad libitum), which led to >50% decrease in tumor burden. Conclusion Co-activation of β-catenin and Nrf2 is evident in 9% of all human HCCs. Co-expression of mutant-NFE2L2 and mutant-CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.
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http://dx.doi.org/10.1002/hep.31730DOI Listing
February 2021

A graphic guide to the percutaneous tripod acetabular reconstruction for metastatic cancer.

J Surg Oncol 2021 Apr 1;123(5):1316-1327. Epub 2021 Feb 1.

Department of Orthopaedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.

Symptomatic peri-acetabular metastatic lesions are often treated with open surgery such as modified Harrington procedures. In an effort to avoid surgical complications inherently associated with open surgical approaches, we developed and recently reported a novel Tripod percutaneous screw technique. The tripod technique is minimally invasive and was found to yield excellent outcomes regarding both pain control and functionality. The procedure is performed in a standard operative theater using fluoroscopic guided percutaneous screws. Despite the simplicity of intraoperative set-up and instrumentation, it is technically demanding. Obtaining the correct fluoroscopic views and troubleshooting intraoperative hurdles can be challenging for even an experienced orthopedic surgeon. The technique and bony conduits were previously described in the trauma literature, however, there are key points of difference in the setting of metastatic disease. Here we provide a compilation of a stepwise graphic guide for the tripod model in the setting of metastatic peri-acetabular lesions, as well as the tips and tricks based on our own experience. These encompass preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, postoperative care, and subsequent conversion to a cemented total hip arthroplasty, if needed.
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http://dx.doi.org/10.1002/jso.26409DOI Listing
April 2021

Definitions of Computer-Assisted Surgery and Intervention, Image-Guided Surgery and Intervention, Hybrid Operating Room, and Guidance Systems: Strasbourg International Consensus Study.

Ann Surg Open 2020 Dec 20;1(2):e021. Epub 2020 Nov 20.

Research Institute against Cancer of the Digestive System (IRCAD), Strasbourg, France.

Objective: To develop consensus definitions of image-guided surgery, computer-assisted surgery, hybrid operating room, and surgical navigation systems.

Summary Background Data: The use of minimally invasive procedures has increased tremendously over the past 2 decades, but terminology related to image-guided minimally invasive procedures has not been standardized, which is a barrier to clear communication.

Methods: Experts in image-guided techniques and specialized engineers were invited to engage in a systematic process to develop consensus definitions of the key terms listed above. The process was designed following review of common consensus-development methodologies and included participation in 4 online surveys and a post-surveys face-to-face panel meeting held in Strasbourg, France.

Results: The experts settled on the terms computer-assisted surgery and intervention, image-guided surgery and intervention, hybrid operating room, and guidance systems and agreed-upon definitions of these terms, with rates of consensus of more than 80% for each term. The methodology used proved to be a compelling strategy to overcome the current difficulties related to data growth rates and technological convergence in this field.

Conclusions: Our multidisciplinary collaborative approach resulted in consensus definitions that may improve communication, knowledge transfer, collaboration, and research in the rapidly changing field of image-guided minimally invasive techniques.
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http://dx.doi.org/10.1097/AS9.0000000000000021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771637PMC
December 2020

Perioperative Management of Metastatic Paraganglioma-Pheochromocytoma of the Humerus with the Aid of Regional Anesthesia.

Case Rep Anesthesiol 2020 11;2020:2482793. Epub 2020 Dec 11.

Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.

A 38-year-old female with a past history of pheochromocytoma and subsequent malignant paraganglioma presented with right arm pain after a fall. Imaging demonstrated a malunited humeral shaft associated with a large cortical destructive lesion and extraosseous extension. Here, we report the use of a multidisciplinary team approach including an endocrinologist, anesthesiologist, and orthopedic surgeon in the perioperative management of a patient with metastatic paraganglioma undergoing a surgical resection of the humerus, internal fixation, reconstruction, and placement of endoprosthesis. The challenges of perioperative anesthetic management and the use of regional anesthesia, especially peripheral nerve block for perioperative pain management, are highlighted.
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http://dx.doi.org/10.1155/2020/2482793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748908PMC
December 2020

Readmission After Surgical Resection and Transplantation for Hepatocellular Carcinoma: A Retrospective Cohort Study.

Am Surg 2020 Dec 28:3134820973739. Epub 2020 Dec 28.

Department of Surgery, 6614University of Pittsburgh, Pittsburgh, PA, USA.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Liver resections and transplantations have increasingly become feasible options for potential cure. These complex surgeries are inherently associated with increased rates of readmission. In the meanwhile, hospital readmission rates are rapidly becoming an important quality of care metric. Therefore, it is very important to understand the effect of 30-day readmission on mortality and the factors associated with increased 30- and 90-day mortality rates.

Methods: This is a retrospective cohort study utilizing data from the National Cancer Database. Patients included were 18 years or older who underwent liver resection or liver transplantation for HCC between 2003 and 2011. Our primary outcomes of interest were 30- and 90-day mortality rates. Our primary independent variable of interest was 30-day readmission.

Results: 16 658 patients underwent either a liver resection or transplantation for HCC between 2003 and 2011. For patients with liver transplantations, increased readmission rates were associated with lower risks of 30-day mortality ( = .012) but a trend toward higher 90-day mortality ( = .057). Patients who underwent liver resection for HCC also demonstrated increased readmission rates to be associated with lower risk of 30-day mortality ( = .014) but higher 90-day mortality ( ≤ .001).

Conclusion: This is the only study to utilize a national database to investigate the association between readmission rates and mortality rates of both liver transplantations and resections for patients with HCC. We demonstrate 30-day readmission to show no increase in 30-day mortality, but rather higher 90-day mortality.
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http://dx.doi.org/10.1177/0003134820973739DOI Listing
December 2020

The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients.

Oncologist 2020 Dec 14. Epub 2020 Dec 14.

First Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background: Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced-stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs.

Methods: A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed.

Results: Sixty-three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15).

Conclusion: ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate.

Implications For Practice: This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced-stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence). Six of these patients experienced graft rejection (40.0%).
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http://dx.doi.org/10.1002/onco.13638DOI Listing
December 2020

Impact of Resection Margin Status in Patients with Pancreatic Cancer: a National Cohort Study.

J Gastrointest Surg 2020 Dec 2. Epub 2020 Dec 2.

Department of Surgery, University of Pittsburgh, 3459 Fifth Avenue, UPMC Montefiore, 7 South, Pittsburgh, PA, 15213-2582, USA.

Aim: To assess the predictors and influence of resection margins and the role of neoadjuvant and adjuvant therapy on survival for a national cohort of patients with resected pancreatic cancer.

Methods: Using the National Cancer Data Base between 2004 and 2016, 56,532 patients were identified who underwent surgical resection for pancreatic adenocarcinoma. Univariate and multivariate models were employed to identify factors predicting R0/R1 resection and assess the impact on survival.

Results: In total, 48,367 (85.6%) patients were found to have negative margins (R0) compared to 8165 (14.4%) who had microscopic residual tumor (R1). Factors predicting positive margin on univariate analysis included male gender, Medicare, advanced stage, moderately or poorly differentiated tumor, lymphovascular invasion, and tumors > 2 cm. Factors predicting R0 resection included receipt of neoadjuvant therapy and treatment at an Academic/Research Center. Following adjustment for other factors, margin status remained an independent predictor for overall survival (HR: 1.24; 95% CI 1.22-1.27, p < 0.001) (1-, 3-, and 5-year overall survival rates (R0: 77%, 37%, and 25% vs R1: 62%, 19%, and 10%).

Conclusions: A positive margin predicts a poorer survival than R0 resections regardless of stage and receipt of adjuvant therapy. Several modifiable factors significantly predict the likelihood of R0 resection including neoadjuvant treatment and treatment at Academic/Research Programs. Knowledge about these factors can help guide patient management by offering neoadjuvant treatment modalities at Academic as well as Community hospitals.
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http://dx.doi.org/10.1007/s11605-020-04870-6DOI Listing
December 2020

Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance.

Am J Transplant 2020 Nov 28. Epub 2020 Nov 28.

Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

We assessed the role of donor liver non-conventional plasmacytoid dendritic cells (pDCs) in spontaneous liver transplant tolerance in a fully MHC-mismatched (C57BL/6 (H2 ) to C3H (H2 )) mouse model. Compared with spleen pDCs, liver pDCs expressed higher levels of DNAX-activating protein of 12 kDa and its co-receptor, triggering receptor expressed by myeloid cells 2, and higher ratios of programed death ligand-1 (PD-L1):costimulatory CD80/CD86 in the steady state and after Toll-like receptor 9 ligation. Moreover, liver pDCs potently suppressed allogeneic CD4 and CD8 T cell proliferative responses. Survival of pDC-depleted livers was much poorer (median survival time: 25 days) than that of either untreated donor livers or pDC-depleted syngeneic donor livers that survived indefinitely. Numbers of forkhead box p3 (FoxP3) regulatory T cells in grafts and mesenteric lymph nodes of mice given pDC-depleted allogeneic livers were reduced significantly compared with those in recipients of untreated livers. Graft-infiltrating CD8 T cells with an exhausted phenotype (programed cell death protein 1 , T cell immunoglobulin and mucin domain-containing protein 3 ) were also reduced in recipients of pDC-depleted livers. PD1-PD-L1 pathway blockade reversed the reduction in exhausted T cells. These novel observations link immunoregulatory functions of liver interstitial pDCs, alloreactive T cell exhaustion, and spontaneous liver transplant tolerance.
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http://dx.doi.org/10.1111/ajt.16412DOI Listing
November 2020

The liver transplant risk score prognosticates the outcomes of liver transplant recipients at listing.

HPB (Oxford) 2020 Nov 11. Epub 2020 Nov 11.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: We assessed if the risk of post-liver transplant mortality within 24 h could be stratified at the time of listing using the liver transplant risk score (LTRS). Secondary aims were to assess if the LTRS could stratify the risk of 30-day, 1-year mortality, and survival beyond the first year.

Methods: MELD, BMI, age, diabetes, and the need for dialysis were the five variables used to calculate the LTRS during patients' evaluation for liver transplantation. Mortality rates at 24 h, 30 days, and 1-year were compared among groups of patients with different LTRS. Patients with ABO-incompatibility, redo, multivisceral, partial graft and malignancies except for hepatocellular carcinoma were excluded. Data of 48,616 adult liver transplant recipients were extracted from the Scientific Registry of Transplant Recipients between 2002 and 2017.

Results: 24-h mortality was 0.9%, 1.0%, 1.1%, 1.7%, 2.3%, 2.0% and 3.5% for patients with LTRS of 0,1,2,3,4, 5 and ≥ 6, respectively (P < 0.001). 30-day mortality was 3.5%, 4.2%, 4.9%, 6.2%, 7.6%, 7.2% and 10.1% respectively (P < 0.001). 1-year mortality was 8.6%, 10.8%, 12.9%, 13.9%, 18.5%, 20.3% and 28.6% respectively (P < 0.001). 10-year survival was 61%, 56%, 57%, 54%, 47%, and 31% for patients with 0, 1, 2, 3, 4, 5 and ≥ 6 points respectively (P < 0.001).

Conclusion: Perioperative mortality and long-term survival of patients undergoing LT can be accurately estimated at the time of listing by the LTRS.
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http://dx.doi.org/10.1016/j.hpb.2020.10.002DOI Listing
November 2020

Interferon Regulatory Factor-1 (IRF1) activates autophagy to promote liver ischemia/reperfusion injury by inhibiting β-catenin in mice.

PLoS One 2020 2;15(11):e0239119. Epub 2020 Nov 2.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.

Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). β-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and β-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of β-catenin. β-catenin inhibitor increased autophagy while β-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting β-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605671PMC
December 2020

Late-Onset Bartter Syndrome Type II Due to a Homozygous Mutation in KCNJ1 Gene: A Case Report and Literature Review.

Am J Case Rep 2020 Sep 30;21:e924527. Epub 2020 Sep 30.

Department of Nephrology, Hamad Medical Corporation, Doha, Qatar.

BACKGROUND Bartter syndrome is a rare genetic disease characterized by hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Five different subtypes have been described based on the genetic defect identified. Bartter syndrome type II is caused by homozygous or compound heterozygous loss-of-function mutations in the KCNJ1 gene encoding ROMK. This subtype is typically described as a severe antenatal form of the disease, often presenting with polyhydramnios before childbirth. CASE REPORT Here, we describe the case of a 26-year-old man who presented with generalized body weakness and hypokalemia and was ultimately diagnosed with Bartter syndrome type II based on his clinical features coupled with the identification of a homozygous missense mutation in KCNJ1. CONCLUSIONS To the best of our knowledge, this is the fifth case of late-onset Bartter syndrome type II. Interestingly, the mutation identified in our patient has been previously described in patients with antenatal Bartter's Syndrome. The late presentation in our patient suggests a surprising degree of phenotypic variability, even in patients carrying the identical disease-causing mutation.
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http://dx.doi.org/10.12659/AJCR.924527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534490PMC
September 2020

Laparoscopic versus robotic major hepatectomy: a systematic review and meta-analysis.

Surg Endosc 2021 Feb 28;35(2):524-535. Epub 2020 Sep 28.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Pittsburgh Medical Center, MUH 7 South, 3459 Fifth Avenue, Pittsburgh, PA, 15213, USA.

Background: The implementation of the laparoscopic and robotic approaches for major hepatectomy (LMH and RMH) was slower than that for minor hepatectomy, but has significantly increased over the past years. The role or advantages of RMH remains controversial, and we aimed to compare the peri-/postoperative outcomes of LMH versus RMH.

Methods: A systematic literature review was conducted using the MEDLINE and Cochrane Library databases according to the PRISMA guidelines (end-of-search date: March 16th, 2020). Only comparative studies (LMH vs. RMH) reporting on outcomes of interest were included. Meta-analysis was performed using the random-effects model when substantial heterogeneity was encountered; otherwise, the fixed-effects model was implemented. Quality of evidence assessment was performed using the Newcastle-Ottawa Scale.

Results: Seven retrospective cohort studies comparing LMH (n = 300) versus RMH (n = 225) were identified. No significant difference was observed between LMH and RMH regarding overall complications [odds ratio (OR) 1.42, 95% confidence interval (CI) 0.90-2.23; p = 0.13], severe complications (Clavien-Dindo grade ≥ 3) [risk difference (RD) 0.01, 95% CI - 0.03 to 0.05; p = 0.72], and overall mortality (RD 0.00, 95% CI - 0.02 to 0.03; p = 0.73). The two approaches were also equivalent regarding conversion to open hepatectomy (RD 0.03, 95% CI - 0.01 to 0.08; p = 0.15), margin-positive resection (OR 1.34, 95% CI 0.51-3.52; p = 0.55), and transfusion rate (RD - 0.03, 95% CI - 0.16 to 0.11; p = 0.67). No significant difference was observed for LMH versus RMH regarding blood loss [standardized mean difference (SMD) 0.27, 95% CI - 0.24 to 0.77; p = 0.30), operative time (SMD - 0.08, 95% CI - 0.51 to 0.34; p = 0.70), and length of stay (SMD 0.13, 95% CI - 0.58 to 0.84; p = 0.72).

Conclusion: LMH and RMH have equivalent peri-/postoperative outcomes when performed in select patients and high-volume centers.
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http://dx.doi.org/10.1007/s00464-020-08008-2DOI Listing
February 2021

Exercise Training Decreases Hepatic Injury and Metastases Through Changes in Immune Response to Liver Ischemia/Reperfusion in Mice.

Hepatology 2020 Sep 14. Epub 2020 Sep 14.

Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.

Background And Aims: Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown.

Approach And Results: Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment.

Conclusions: ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.
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http://dx.doi.org/10.1002/hep.31552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956053PMC
September 2020

Short-term Outcomes of "Difficult" Laparoscopic Liver Resection at Specialized Centers: Report From INSTALL (International Survey on Technical Aspects of Laparoscopic Liver Resection)-2 on 4478 Patients.

Ann Surg 2020 Sep 1. Epub 2020 Sep 1.

Department of Surgery, Ageo Central General Hospital, Ageo, Japan.

Objective: To define the current status of "difficult" LLR, a global database was created and investigated.

Background: In the Second International Consensus Conference in 2014, minor LLR was considered as a standard practice and major LLR remained an innovative procedure. Since then, no updates on worldwide trends have been available.

Methods: A questionnaire on all consecutive patients who underwent difficult LLR (major hepatectomy, posterosuperior segmentectomy, sectionectomy, living donor hepatectomy, tumor size ≥10 cm, Child-Pugh grade ≥B, combined with biliary reconstruction, and Iwate criteria difficulty score ≥7) in 2014-2018 was distributed via email to 65 high-volume LLR centers worldwide. Individual data on patient and tumor demographics, surgical information, and short-term outcomes were obtained to create a large-scale international registry for analyses.

Results: Overall, 58 centers in 19 countries performed 4478 difficult LLR (median, 58.5; range, 5-418) during the study period. Hepatocellular carcinoma accounted for ≥40% of all indications. Half of the patients underwent major hepatectomy, followed by sectionectomy, posterosuperior segmentectomy, and living donor hepatectomy. In the vast majority of procedures, Clavien-Dindo grade ≥IIIa complication rates of ≈10% and 90-day mortality rates of ≈1% were achieved. Left or right trisectionectomy had the worst Clavien-Dindo grade ≥IIIa complication rate of ≥10% and 90-day mortality rate of 5%-10%. No significant correlation was observed between center volume and short-term outcomes.

Conclusions: Total 4478 patients underwent difficult LLR worldwide in 2014-2018. Most procedures are safe and feasible when conducted in specialized centers.
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http://dx.doi.org/10.1097/SLA.0000000000004434DOI Listing
September 2020

Changes in Performance of More Than 1000 Minimally Invasive Liver Resections.

JAMA Surg 2020 Aug 26. Epub 2020 Aug 26.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1001/jamasurg.2020.2623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450397PMC
August 2020

The ILLS Laparoscopic Liver Surgery Fellow Skills Curriculum.

Ann Surg 2020 11;272(5):786-792

Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Introduction: Laparoscopy is becoming the standard approach in liver surgery. As the degree of difficulty varies greatly from core skills to advanced procedures, strategies for teaching young surgeons need to be reconsidered. We here aimed to design a skills curriculum for LLR.

Methods: Using the nominal group technique, 22 substeps of LLR were identified by 61 hepatobiliary surgeons. The raters were asked to rate (1) the difficulty of substeps and (2) the minimum number of times that the substep must be performed for mastery of the technique. According to the frequency of defined substeps, being estimated on the basis of high volume center experiences (n = 222 LLR; 1/2017-12/2018), the center's training capacity and defined goals for a 2-year fellowship were calculated.

Results: Ten surgical substeps (45%) are routinely performed and can thus be taught sufficiently at centers carrying out ≥50 LLR in 2 years. As the mobilization of the right liver lobe and the dissection of the hepatic artery or portal vein is performed in only 27% and 28% of all LLR, respectively, sufficient training can only be provided at centers with ≥100 LLRs in 2 years. Mastery of complex parenchymal dissection (19%) and hilar lymphadenectomy (8%) can only be achieved in center performing ≥200 LLR in 2 years.

Conclusion: We here suggest a stepwise approach for training of hepatobiliary fellows in LLR. Based on the estimated complexity of the substeps and the size of the center, not every substep can be learned within 2 years.
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http://dx.doi.org/10.1097/SLA.0000000000004175DOI Listing
November 2020

The Utility of 18FDG PET/CT Versus Bone Scan for Identification of Bone Metastases in a Pediatric Sarcoma Population and a Review of the Literature.

J Pediatr Hematol Oncol 2021 03;43(2):52-58

Department of Radiology, Division of Nuclear Medicine.

Background: Outcome of patients with osteosarcoma (OS) and Ewing sarcoma (EWS) is dependent on presence of metastases. Imaging guidelines for OS and EWS include radiographs, computed tomography (CT), and magnetic resonance imaging for primary tumor evaluation and CT chest and bone scintigraphy (BS) for metastatic detection. 18Fluorodeoxyglucose (18FDG) positron emission tomography (PET)/CT has become more common for disease evaluation, yet there is no consensus for its use in this population.

Objective: We aimed to compare identification of osseous metastases using BS versus 18FDG PET/CT in our patient population. We hypothesized that 18FDG PET/CT is more likely to detect osseous metastases both at diagnosis and relapse.

Materials And Methods: We performed retrospective chart reviews of pediatric sarcoma patients treated at our institution from 2008 to 2019. Paired BS and 18FDG PET/CT scans were reviewed. Review of the literature was also performed.

Results: Thirty-three patients had paired BS and 18FDG PET/CT during diagnosis or treatment. Fifteen patients had distant osseous metastases. In the OS cohort, 8/16 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 75% on BS. Thirty-one bony lesions were seen on imaging in OS patients; 100% of these were identified on 18FDG PET/CT but only 29% on BS. In the EWS cohort, 6/15 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 50% on BS. Eighteen bony lesions were seen on imaging in EWS patients; 94% of these were identified on 18FDG PET/CT, but only 28% on BS.

Conclusion: For patients in our institution with OS or EWS, osseous metastases were more likely detected using 18FDG PET/CT.
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http://dx.doi.org/10.1097/MPH.0000000000001917DOI Listing
March 2021

Neutrophil extracellular traps as a novel biomarker to predict recurrence-free and overall survival in patients with primary hepatic malignancies.

HPB (Oxford) 2021 Feb 15;23(2):309-320. Epub 2020 Aug 15.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: The incidence of primary hepatic malignancies including Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) is on the rise. (i) Surgery remains the mainstay of potential curative treatment, however the vast majority of patients will recur and not be amenable to curative therapy. (ii) Inflammation has been associated with poor prognosis, however there is no preoperative marker that can predict recurrence-free- or overall survival. Our aim is to correlate inflammation measured as neutrophil extracellular traps (NETs) with survival.

Methods: A retrospective analysis was performed using sera/tissue from patients with hepatic malignancies. NET levels were measured in the serum (MPO-DNA) or tumor (Cit-H3). Log rank analysis for RFS/OS was performed.

Results: Cancer patients had higher pre-surgery MPO-DNA levels compared to healthy individuals (healthy vs cancer: 2.6 ± 1.0 ng/ml vs 34.7 ± 2.13 ng/ml; p < 0.0001). High pre-surgery serum NET levels were associated with shorter RFS/OS compared to those with low levels (RFS-HCC: HR: 2.91, 95% CI: 1.61-5.26, p < 0.0001, RFS-CC: HR: 3.22, 95% CI: 1.33-7.77 p < 0.0093). High Cit-H3 tumor levels similarly predicted shorter RFS/OS.

Conclusion: The current study shows a correlation between pre-operative NET levels and survival. Studying NET formation as a biomarker pre-surgery can help identify patients that could benefit from closer follow-up due to higher risk for recurrence.
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http://dx.doi.org/10.1016/j.hpb.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958967PMC
February 2021