Publications by authors named "Kenneth K Tanabe"

171 Publications

Quantitative, noninvasive MRI characterization of disease progression in a mouse model of non-alcoholic steatohepatitis.

Sci Rep 2021 Mar 17;11(1):6105. Epub 2021 Mar 17.

Department of Radiology, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging, Harvard Medical School, 149 13th St., Boston, MA, 02129, USA.

Non-alcoholic steatohepatitis (NASH) is an increasing cause of chronic liver disease characterized by steatosis, inflammation, and fibrosis which can lead to cirrhosis, hepatocellular carcinoma, and mortality. Quantitative, noninvasive methods for characterizing the pathophysiology of NASH at both the preclinical and clinical level are sorely needed. We report here a multiparametric magnetic resonance imaging (MRI) protocol with the fibrogenesis probe Gd-Hyd to characterize fibrotic disease activity and steatosis in a common mouse model of NASH. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with advanced fibrosis. Mice fed normal chow and CDAHFD underwent MRI after 2, 6, 10 and 14 weeks to measure liver T1, T2*, fat fraction, and dynamic T1-weighted Gd-Hyd enhanced imaging of the liver. Steatosis, inflammation, and fibrosis were then quantified by histology. NASH and fibrosis developed quickly in CDAHFD fed mice with strong correlation between morphometric steatosis quantification and liver fat estimated by MRI (r = 0.90). Sirius red histology and collagen quantification confirmed increasing fibrosis over time (r = 0.82). Though baseline T1 and T2* measurements did not correlate with fibrosis, Gd-Hyd signal enhancement provided a measure of the extent of active fibrotic disease progression and correlated strongly with lysyl oxidase expression. Gd-Hyd MRI accurately detects fibrogenesis in a mouse model of NASH with advanced fibrosis and can be combined with other MR measures, like fat imaging, to more accurately assess disease burden.
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http://dx.doi.org/10.1038/s41598-021-85679-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971064PMC
March 2021

ASO Author Reflections: Variations and Inconsistencies in the Guidelines for the Clinical Management of Cholangiocarcinoma.

Ann Surg Oncol 2021 Mar 6. Epub 2021 Mar 6.

Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1245/s10434-021-09703-7DOI Listing
March 2021

The Clinical Management of Cholangiocarcinoma in the United States and Europe: A Comprehensive and Evidence-Based Comparison of Guidelines.

Ann Surg Oncol 2021 May 1;28(5):2660-2674. Epub 2021 Mar 1.

Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: The incidence of cholangiocarcinoma has doubled over the last 15 years with a similar rise in mortality, which provides the impetus for standardization of evidence-based care through the establishment of guidelines.

Methods: We compared available guidelines on the clinical management of cholangiocarcinoma in the United States and Europe, which included the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), British Society of Gastroenterology (BSG) and the International Liver Cancer Association (ILCA) guidelines.

Results: There is discordance in the recommendation for biopsy in patients with potentially resectable cholangiocarcinoma and in the recommendation for use of fluorodeoxyglucose positron emission tomography scans. Similarly, the recommendation for preoperative biliary drainage for extrahepatic and perihilar cholangiocarcinoma in the setting of jaundice is inconsistent across all four guidelines. The BILCAP (capecitabine) and ABC-02 trials (gemcitabine with cisplatin) have provided the strongest evidence for systemic therapy in the adjuvant and palliative settings, respectively, but all guidelines have refrained from setting them as standard of care, given heterogeneity in the study cohorts and ABC-02's negative intention-to-treat results.

Conclusions: Future progress in enhancing survivorship of patients with cholangiocarcinoma would likely entail improvements in diagnostic biomarkers and novel systemic therapies. Based on recent results from studies of targeted therapy, future iterations of the guidelines will likely incorporate molecular profiling.
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http://dx.doi.org/10.1245/s10434-021-09671-yDOI Listing
May 2021

Open hepatic resection in the elderly at two tertiary referral centers.

Am J Surg 2021 Jan 21. Epub 2021 Jan 21.

Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: Surgeons are being increasingly called upon to operate on the very elderly. This study aimed to evaluate outcomes following hepatectomy in patients ≥80 years of age at two tertiary care centers.

Methods: All adult patients who underwent liver resection from 2001 to 2017 were included. Primary outcome was 90-day postoperative mortality. Secondary outcomes included 30-day postoperative mortality and postoperative complications.

Results: Between 2001 and 2017, 2397 patients underwent liver resection. On unadjusted analysis, patients ≥80 years of age had higher rates of 90-day mortality (13.3% vs. 3.6%, p < 0.001), 30-day mortality (5.6% vs. 1.8%, p = 0.01), MI (7.9% vs. 3.5%, p = 0.04), and UTI (10.0% vs. 4.5%, p = 0.02). On multivariable analysis, age ≥80 years was significantly associated with 90-day postoperative mortality (OR 4.51, 95%CI 2.11-9.67, p < 0.001).

Conclusions: Across these two major referral tertiary care centers, very elderly patients had higher rates of 90-day and 30-day postoperative mortality on both unadjusted and adjusted analyses.
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http://dx.doi.org/10.1016/j.amjsurg.2021.01.024DOI Listing
January 2021

Risk Factors, Pathogenesis, and Strategies for Hepatocellular Carcinoma Prevention: Emphasis on Secondary Prevention and Its Translational Challenges.

J Clin Med 2020 Nov 25;9(12). Epub 2020 Nov 25.

Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.
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http://dx.doi.org/10.3390/jcm9123817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760293PMC
November 2020

Size of the Largest Colorectal Liver Metastasis Is an Independent Prognostic Factor in the Neoadjuvant Setting.

J Surg Res 2021 Mar 5;259:253-260. Epub 2020 Nov 5.

Harvard Medical School, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Up to 50% of patients diagnosed with colorectal cancer develop metastases during the course of their disease. Surgical resection remains the only curative treatment option for colorectal liver metastases (CRLM), frequently in conjunction with neoadjuvant chemotherapy. This study sought to determine if the pathologic size of the largest CRLM impacted disease-free survival (DFS) and disease-specific survival (DSS) in the setting of neoadjuvant chemotherapy.

Methods: All patients diagnosed with CRLM who underwent neoadjuvant chemotherapy for liver resection at the Massachusetts General Hospital between 2004 and 2016 were reviewed. The median size of the largest liver lesion was used as the cutoff for grouped evaluation.

Results: A total of 214 patients were included. Median follow-up was 100.0 mo (interquartile range 68.9-133.8 mo). The median size of the largest lesion was 21 mm. Patients with lesions ≥21 mm exhibited significantly worse median DFS (12.5 mo versus 16.6 mo; P = 0.033) and median DSS (71.3 mo versus 103.5 mo; P = 0.038). CRLM lesions ≥21 mm were associated with poorer DFS on univariate analysis (hazard ratio (HR) = 1.42, 95% confidence interval (CI) 1.03-1.95 P = 0.033) and multivariable analysis (HR = 1.58, 95% CI 1.07-2.35, P = 0.023). CRLM lesions ≥21 mm were also independently associated with poorer DSS after liver resection on univariate analysis (HR = 1.51, 95% CI 1.02-2.24; P = 0.037) and multivariable analysis (HR = 1.98, 95% CI: 1.27-3.07; P = 0.002).

Conclusions: The size of the largest CRLM is an important prognostic factor for both DFS and DSS after neoadjuvant therapy and serves as a useful indicator of tumor biology.
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http://dx.doi.org/10.1016/j.jss.2020.09.039DOI Listing
March 2021

Molecular Magnetic Resonance Imaging of Liver Fibrosis and Fibrogenesis Is Not Altered by Inflammation.

Invest Radiol 2021 Apr;56(4):244-251

Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.

Methods: Three groups of mice that develop either mild type 2 inflammation and fibrosis (wild type), severe fibrosis with exacerbated type 2 inflammation (Il10-/-Il12b-/-Il13ra2-/-), or minimal fibrosis with marked type 1 inflammation (Il4ra∂/∂) after infection with S. mansoni were imaged using both probes for determination of signal enhancement. Schistosoma mansoni-infected wild-type mice developed chronic liver fibrosis.

Results: The liver MR signal enhancement after either probe administration was significantly higher in S. mansoni-infected wild-type mice compared with naive animals. The S. mansoni-infected Il4ra∂/∂ mice presented with little liver signal enhancement after probe injection despite the presence of substantial inflammation. Schistosoma mansoni-infected Il10-/-Il12b-/-Il13ra2-/- mice presented with marked fibrosis, which correlated to increased signal enhancement after injection of either probe.

Conclusions: Both MR probes, EP-3533 and Gd-Hyd, were specific for fibrosis in this model of chronic liver disease regardless of the presence or severity of the underlying inflammation. These results, in addition to previous findings, show the potential application of both molecular MR probes for detection and quantification of fibrosis from various etiologies.
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http://dx.doi.org/10.1097/RLI.0000000000000737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956154PMC
April 2021

Choices of Therapeutic Strategies for Colorectal Liver Metastases Among Expert Liver Surgeons: A Throw of the Dice?

Ann Surg 2020 11;272(5):715-722

Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.

Objective: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe.

Summary/background: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients.

Methods: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers.

Results: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries.

Conclusions: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.
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http://dx.doi.org/10.1097/SLA.0000000000004331DOI Listing
November 2020

Hepatectomy for Solitary Hepatocellular Carcinoma: Resection Margin Width Does Not Predict Survival.

J Gastrointest Surg 2020 Aug 10. Epub 2020 Aug 10.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Background: The survival benefit of negative margins for hepatocellular carcinoma (HCC) has been demonstrated. However, there is no consensus regarding the optimal resection margin width. We assessed the impact of hepatic resection margin width for solitary HCC on overall (OS), recurrence-free (RFS), and liver-specific recurrence-free survival (LSRFS).

Methods: Clinicopathologic data were retrospectively collected for solitary HCC patients who underwent a negative margin hepatectomy (1992-2015). Margin width was categorized in tertiles as "narrow" (≤ 0.3 cm), "intermediate" (0.31-1.0 cm), or "wide" (> 1.0 cm). Survival was compared among groups.

Results: Of the 178 included patients, most were male (76%); median age, MELD score, and tumor size were 63 years, 8, and 5.2 cm, respectively; 93% were Child-Pugh class A. Median margin width was 0.5 cm. Median follow-up and OS were 47.8 months and 76.7 months, respectively. There was no significant survival difference among narrow, intermediate, and wide margin groups with a median OS of 53 months (IQR 21-not reached [NR]), 74 months (IQR 14-138), and 97 months (IQR 37-142) (p = 0.87), respectively. Median RFS was 33.0 months; again, there was no difference among narrow, intermediate, and wide margin groups with a median of 31 months (IQR 18-NR), 45 months (IQR 14-NR), and 27 months (IQR 11-NR), respectively (p = 0.66). Median LSRFS was 63.0 months (IQR 14-NR) with no difference among groups (p = 0.87). In multivariate analyses, margin width was not associated with OS (p = 0.77), RFS (p = 0.74), or LSRFS (p = 0.92). Findings were similar in all subgroups analyzed (≤ 5 cm, > 5 cm, microvascular invasion, T1, T2/T3, anatomical or non-anatomical resection, major or minor hepatectomy).

Conclusions: Narrow margins appear to be oncologically safe and the feasibility of achieving wide margins should not determine resectability.
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http://dx.doi.org/10.1007/s11605-020-04765-6DOI Listing
August 2020

Patterns of Failure and the Need for Biliary Intervention in Resected Biliary Tract Cancers After Chemoradiation.

Ann Surg Oncol 2020 Dec 1;27(13):5161-5172. Epub 2020 Aug 1.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: This study assessed patterns of failure and rates of subsequent biliary intervention among patients with resected biliary tract cancers (BTCs) including gallbladder carcinoma (GBC) and extra- and intrahepatic cholangiocarcinoma (eCCA and iCCA) treated with adjuvant chemoradiation therapy (CRT).

Methods: In this single-institution retrospective analysis of 80 patients who had GBC (n = 29), eCCA (n = 43), or iCCA (n = 8) treated with curative-intent resection and adjuvant CRT from 2007 to 2017, the median radiation dose was 50.4 Gy (range 36-65 Gy) with concurrent 5-fluorouracil (5-FU) chemotherapy. All but two of the patients received adjuvant chemotherapy. The 2-year locoregional failure (LRF), 2-year recurrence-free survival (RFS), and 2-year overall survival (OS), and univariate predictors of LRF, RFS, and OS were calculated for the entire cohort and for a subgroup excluding patients with iCCA (n = 72). The predictors of biliary interventions also were assessed.

Results: Of the 80 patients (median follow-up period, 30.5 months; median OS, 33.9 months), 54.4% had American Joint Committee on Cancer (AJCC) stage 1 or 2 disease, 57.1% were lymph node-positive, and 66.3% underwent margin-negative resection. For the entire cohort, 2-year LRF was 23.8%, 2-year RFS was  43.7%, and 2-year OS was 62.1%.  When patients with iCCA were excluded, the 2-year LRF was 22.6%, the 2-year RFS was 43.9%, and the 2-year OS was 59.2%. In the overall and subgroup univariate analyses, lymph node positivity was associated with greater LRF, whereas resection margin was not. Biliary intervention was required for 12 (63.2%) of the 19 patients with LRF versus 11 (18%) of the 61 patients without LRF (P < 0.001). Of the 12 patients with LRF who required biliary intervention, 4 died of biliary complications.

Conclusions: The LRF rates remained significant despite adjuvant CRT. Lymph node positivity may be associated with increased risk of LRF. Positive margins were not associated with greater LRF, suggesting that CRT may mitigate LRF risk for this group. An association between LRF and higher rates of subsequent biliary interventions was observed, which may yield significant morbidity. Novel strategies to decrease the rates of LRF should be considered.
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http://dx.doi.org/10.1245/s10434-020-08967-9DOI Listing
December 2020

Collagen-targeted molecular imaging in diffuse liver diseases.

Abdom Radiol (NY) 2020 11 31;45(11):3545-3556. Epub 2020 Jul 31.

Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA.

Liver fibrosis is a common pathway shared by all progressive chronic liver diseases (CLD) regardless of the underlying etiologies. With liver biopsy being the gold standard in assessing fibrosis degree, there is a large unmet clinical need to develop non-invasive imaging tools that can directly and repeatedly quantify fibrosis throughout the liver for a more accurate assessment of disease burden, progression, and treatment response. Type I collagen is a particularly attractive target for molecular imaging as its excessive deposition is specific to fibrosis, and it is present in concentrations suitable for many imaging modalities. Novel molecular MRI contrast agents designed to bind with collagen provide direct quantification of collagen deposition, which have been validated across animal species and liver injury models. Collagen-targeted molecular imaging probes hold great promise not only as a tool for initial staging and surveillance of fibrosis progression, but also as a marker of fibrosis regression in drug trials.
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http://dx.doi.org/10.1007/s00261-020-02677-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606709PMC
November 2020

Fibrotic Response to Neoadjuvant Therapy Predicts Survival in Pancreatic Cancer and Is Measurable with Collagen-Targeted Molecular MRI.

Clin Cancer Res 2020 Sep 1;26(18):5007-5018. Epub 2020 Jul 1.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC.

Experimental Design: Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101.

Results: In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS = 0.028, DFS = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established PDAC risk factors [AUC CPA (-) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight ( < 0.05) and increased tumor fibrosis by collagen staining ( < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls ( = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging.

Conclusions: In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980315PMC
September 2020

Platelet and neutrophil to lymphocyte ratios predict survival in patients with resectable colorectal liver metastases.

Am J Surg 2020 12 14;220(6):1579-1585. Epub 2020 May 14.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. Electronic address:

Background: The prognostic significance of the platelet (PLR) and neutrophil (NLR) to lymphocyte ratios for patients with resectable colorectal cancer liver metastases (CLM) was evaluated.

Methods: Clinicopathologic data from patients who underwent hepatectomy for CLM at two tertiary care hospitals between 1995 and 2017 were collected. Blood counts were evaluated for prognostic significance.

Results: 151 patients met inclusion criteria. The median age was 58 years, 44% were female, and 58% had synchronous metastases. Median number of liver metastases was 2, and 59% of patients underwent lobectomy or extended lobectomy. On multivariable analysis, NLR ≥5 (HR 2.46 [1.08-5.60 CI], p = 0.032), PLR ≥ 220 (HR 2.10 [1.04-4.23 CI], p = 0.037), and greater than 2 liver metastases (HR 2.41 [1.06-5.45 CI], p = 0.035) were associated with reduced overall survival.

Conclusions: PLR ≥ 220 and NLR ≥ 5 may have utility as preoperative prognostic markers for overall survival in patients with resectable CLM.
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http://dx.doi.org/10.1016/j.amjsurg.2020.05.003DOI Listing
December 2020

ASO Author Reflections: Developing Personalized Care for Hepatocellular Adenoma Based on Subtype Classification.

Ann Surg Oncol 2020 Sep 16;27(9):3339-3340. Epub 2020 Jun 16.

Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1245/s10434-020-08681-6DOI Listing
September 2020

A Shifting Paradigm in Diagnosis and Management of Hepatic Adenoma.

Ann Surg Oncol 2020 Sep 15;27(9):3330-3338. Epub 2020 Jun 15.

Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: New insights into molecular pathogenesis of hepatocellular adenomas (HCA) have allowed sub-classification based on distinct genetic alterations and a fresh look at characterizations of natural history. Clinically, this is important in understanding risk factors for two feared complications: malignant transformation and hemorrhage.

Methods: PubMed literature search for hepatocellular adenoma over all years, excluding case reports and articles focusing on multiple adenomas or adenomatosis.

Results: The β-catenin exon 3 mutated HCA accounts for about 10% of all HCAs and is associated with the highest risk of malignant transformation. The HF1α subtype accounts for 30-40% of all HCAs and has the lowest risk of malignant transformation. Gender has also emerged as an increasingly important risk factor and males with HCA are at considerably higher risk of malignant transformation, regardless of tumor size. The increasing use of gadoxetic-enhanced MRI has allowed for improved differentiation of HCAs from focal nodular hyperplasia, as well as the identification of specific radiologic features of some subtypes, particularly the inflammatory and HF1α HCAs.

Conclusions: Classification of HCA by subtype has important implications for patient counseling and treatment given variable risks of malignant transformation and hemorrhage. Males and those with β-catenin exon 3 mutated HCAs are two groups who should always be counselled to undergo surgical resection. On the other hand, in the lower risk HF1α subtype observation is appropriate in lesions < 5 cm and may even be considered in larger lesions as longer follow-up data is aggregated and tumorigenesis is better understood.
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http://dx.doi.org/10.1245/s10434-020-08580-wDOI Listing
September 2020

Surgical Oncologists and the COVID-19 Pandemic: Guiding Cancer Patients Effectively through Turbulence and Change.

Ann Surg Oncol 2020 Aug 14;27(8):2600-2613. Epub 2020 Jun 14.

Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

Background: The COVID-19 pandemic has posed extraordinary demands from patients, providers, and health care systems. Despite this, surgical oncologists must maintain focus on providing high-quality, empathetic care for the almost 2 million patients nationally who will be diagnosed with operable cancer this year. The focus of hospitals is transitioning from initial COVID-19 preparedness activities to a more sustained approach to cancer care.

Methods: Editorial Board members provided observations of the implications of the pandemic on providing care to surgical oncology patients.

Results: Strategies are presented that have allowed institutions to successfully prepare for cancer care during COVID-19, as well as other strategies that will help hospitals and surgical oncologists manage anticipated challenges in the near term. Perspectives are provided on: (1) maintaining a safe environment for surgical oncology care; (2) redirecting the multidisciplinary model to guide surgical decisions; (3) harnessing telemedicine to accommodate requisite physical distancing; (4) understanding interactions between SARS CoV-2 and cancer therapy; (5) considering the ethical impact of professional guidelines for surgery prioritization; and (6) advocating for our patients who require oncologic surgery in the midst of the COVID-19 pandemic.

Conclusions: Until an effective vaccine becomes available for widespread use, it is imperative that surgical oncologists remain focused on providing optimal care for our cancer patients while managing the demands that the COVID-19 pandemic will continue to impose on all of us.
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http://dx.doi.org/10.1245/s10434-020-08673-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293588PMC
August 2020

COVID-19 Pandemic and Surgical Oncology: Preserving the Academic Mission.

Ann Surg Oncol 2020 Aug 29;27(8):2591-2599. Epub 2020 May 29.

Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., Boston, MA, USA.

Background: The global pandemic of respiratory disease cause by the novel human coronavirus (SARS-CoV-2) has caused untold suffering, loss of life and upheaval in society. The pandemic has lead to massive redirection of health care resources to treat the surge of COVID-19 patients, and enforcement of social distancing to reduce the rate of transmission.

Methods: Editorial Board members provided observations of the implications of the pandemic on academic surgical oncology.

Results: Delivery of health care to other populations including cancer patients has been significantly disrupted. The implications both short term and long term threaten preservation of the academic mission in medicine at large, and certainly in the field of surgical oncology.

Conclusions: The effects on surgical oncology training, research and clinical trials are major.
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http://dx.doi.org/10.1245/s10434-020-08563-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257352PMC
August 2020

Advanced MRI of Liver Fibrosis and Treatment Response in a Rat Model of Nonalcoholic Steatohepatitis.

Radiology 2020 07 28;296(1):67-75. Epub 2020 Apr 28.

From the Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (I.Y.Z., V.C.J., N.J.R., E.A., H.K., H.S., N.W., C.T.F., P.C.), Division of Surgical Oncology (S.K., G.A., K.K.T., B.C.F.), and Institute for Technology Assessment, Department of Radiology (N.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, 149 13th St, Boston, MA 02129; and Pfizer, Cambridge, Mass (J.W., R.M., F.S.).

Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats age- and weight-matched animals received standard chow ( = 12 per group); received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or 9 weeks ( = 8 per group); were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks ( = 12); were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 ( = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020192118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325703PMC
July 2020

Epigallocatechin Gallate Induces Hepatic Stellate Cell Senescence and Attenuates Development of Hepatocellular Carcinoma.

Cancer Prev Res (Phila) 2020 06 6;13(6):497-508. Epub 2020 Apr 6.

Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.

Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue; therefore, chemoprevention may be a useful strategy to reduce HCC incidence. Several reports suggest that epigallocatechin gallate (EGCG), extracted from green tea, can suppress liver inflammation and fibrosis in animal models, but its role in HCC chemoprevention is not well established. In this study, male Wistar rats were injected with diethylnitrosamine at 50 mg/kg for 18 weeks to induce cirrhosis and HCC, and EGCG was given in drinking water at a concentration of 0.02%. Clinically achievable dosing of EGCG was well-tolerated in diethylnitrosamine-injured rats and was associated with improved serum liver markers including alanine transaminase, aspartate transaminase, and total bilirubin, and reduced HCC tumor formation. Transcriptomic analysis of diethylnitrosamine-injured hepatic tissue was notable for increased expression of genes associated with the Hoshida high risk HCC gene signature, which was prevented with EGCG treatment. EGCG treatment also inhibited fibrosis progression, which was associated with inactivation of hepatic stellate cells and induction of the senescence-associated secretory phenotype. In conclusion, EGCG administered at clinically safe doses exhibited both chemopreventive and antifibrotic effects in a rat diethylnitrosamine liver injury model.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0383DOI Listing
June 2020

Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma.

Gut 2021 Jan 26;70(1):157-169. Epub 2020 Mar 26.

Université de Strasbourg, Strasbourg, France

Objective: Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.

Design: Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by i and validation were used to identify chromatin modifiers and readers for HCC chemoprevention.

Results: In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.

Conclusion: Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.
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http://dx.doi.org/10.1136/gutjnl-2019-318918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116473PMC
January 2021

Socioeconomic determinants of the surgical treatment of colorectal liver metastases.

Am J Surg 2020 10 21;220(4):952-957. Epub 2020 Feb 21.

Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA; Newton-Wellesley Hospital, 2014 Washington Street, Newton, MA, 02462, USA. Electronic address:

Objective: We hypothesized that differences in resection rates of colorectal liver metastases exist based on socioeconomic status (SES) inequalities.

Methods: The NCDB was utilized to study patients of different median household income diagnosed with colon adenocarcinoma from 2010 to 2015.

Results: A total of 21,258 patients met inclusion criteria, of whom 3,587 (16.9%) underwent metastasectomy. Patients of the highest income quartile were more likely to undergo metastasectomy compared to the lowest quartile (OR 1.20, CI 1.07-1.37, p = 0.003). Overall, patients in the highest income quartile had a median OS of 17.1 months compared with 13.0 months for the lowest quartile (HR 0.85, CI 0.81-0.90, p < 0.001). While metastasectomy was associated with improved OS across all groups, the disparity by income quartile widened (29.2 vs. 22.0 months, respectively; HR 0.51, CI 0.49-0.54, p < 0.001).

Conclusion: Higher income patients were more likely to undergo metastasectomy compared with lower income patients and were associated with longer OS.
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http://dx.doi.org/10.1016/j.amjsurg.2020.02.019DOI Listing
October 2020

Palliative External Beam Radiation Therapy for Hepatocellular Carcinoma With Right Atrial Tumor Thrombus.

Pract Radiat Oncol 2020 May - Jun;10(3):e183-e187. Epub 2020 Jan 10.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.prro.2019.12.010DOI Listing
March 2021

Molecular Magnetic Resonance Imaging of Fibrin Deposition in the Liver as an Indicator of Tissue Injury and Inflammation.

Invest Radiol 2020 04;55(4):209-216

Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

Rationale And Objectives: Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation.

Methods: Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation.

Results: After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis.

Conclusions: EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.
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http://dx.doi.org/10.1097/RLI.0000000000000631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935409PMC
April 2020

Hypofractionated Radiation Therapy for Unresectable/Locally Recurrent Intrahepatic Cholangiocarcinoma.

Ann Surg Oncol 2020 Apr 23;27(4):1122-1129. Epub 2019 Dec 23.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

Objective: The aim of this study was to evaluate outcomes for patients with unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT).

Methods: We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008 to 2018. Median age at RT was 76 years (range 30-92), including 27 patients (41%) aged ≥ 80 years. Median RT dose was 58.05 Gy (range 37.5-67.5), all delivered in 15 daily fractions. Thirty-two patients received proton RT and 34 patients received photon RT.

Results: Median follow-up times from diagnosis and RT start were 21 months and 14 months, respectively. In total, five patients (7.6%) developed local failure. The 2-year outcomes were 84% local control (LC) and 58% OS. Among the 51 patients treated with definitive intent, the 2-year LC rate was 93% and the OS rate was 62%. On multivariate analysis for LC, older age was associated with a lower risk of local failure [hazard ratio (HR) 0.91; p = 0.02], while prior surgery (HR 16.5; p = 0.04) and macrovascular invasion (HR 123.93; p = 0.02) were independently associated with an increased risk of local failure. On multivariate analysis for OS, female sex (HR 0.33; p = 0.001) and prior chemotherapy (HR 0.38; p = 0.003) remained significantly associated with OS. On multivariate analysis for OS, compared with photon RT, there was a trend towards improved survival with proton RT (HR 0.50; p = 0.05). The rate of overall grade 3 + toxicity was 11%. One patient developed radiation-induced liver disease and was treated with corticosteroids.

Conclusions: HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC.
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http://dx.doi.org/10.1245/s10434-019-08142-9DOI Listing
April 2020

Management implications of fluorodeoxyglucose positron emission tomography/magnetic resonance in untreated intrahepatic cholangiocarcinoma.

Eur J Nucl Med Mol Imaging 2020 07 8;47(8):1871-1884. Epub 2019 Nov 8.

Department of Radiology, Massachusetts General Hospital, Harvard Medical School, WHT 270, 55 Fruit St., Boston, MA, 02114, USA.

Purpose: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosis with surgical resection offering the best chance for long-term survival and potential cure. However, in up to 36% of patients who undergo surgery, more extensive disease is found at time of operation requiring cancellation of surgery. PET/MR is a novel hybrid technology that might improve local and whole-body staging in ICC patients, potentially influencing clinical management. This study was aimed to investigate the possible management implications of PET/MR, relative to conventional imaging, in patients affected by untreated intrahepatic cholangiocarcinoma.

Methods: Retrospective review of the clinicopathologic features of 37 patients with iCCC, who underwent PET/MR between September 2015 and August 2018, was performed to investigate the management implications that PET/MR had exerted on the affected patients, relative to conventional imaging.

Results: Of the 37 patients enrolled, median age 63.5 years, 20 (54%) were female. The same day PET/CT was performed in 26 patients. All patients were iCCC-treatment-naïve. Conventional imaging obtained as part of routine clinical care demonstrated early-stage resectable disease for 15 patients and advanced stage disease beyond the scope of surgical resection for 22. PET/MR modified the clinical management of 11/37 (29.7%) patients: for 5 patients (13.5%), the operation was cancelled due to identification of additional disease, while 4 "inoperable" patients (10.8%) underwent an operation. An additional 2 patients (5.4%) had a significant change in their operative plan based on PET/MR.

Conclusions: When compared with standard imaging, PET/MR significantly influenced the treatment plan in 29.7% of patients with iCCC.

Trial Registration: 2018P001334.
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http://dx.doi.org/10.1007/s00259-019-04558-3DOI Listing
July 2020

Using Smartphones to Capture Novel Recovery Metrics After Cancer Surgery.

JAMA Surg 2020 02;155(2):123-129

Ariadne Labs, Brigham and Women's Hospital, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: Patient-generated health data captured from smartphone sensors have the potential to better quantify the physical outcomes of surgery. The ability of these data to discriminate between postoperative trends in physical activity remains unknown.

Objective: To assess whether physical activity captured from smartphone accelerometer data can be used to describe postoperative recovery among patients undergoing cancer operations.

Design, Setting, And Participants: This prospective observational cohort study was conducted from July 2017 to April 2019 in a single academic tertiary care hospital in the United States. Preoperatively, adults (age ≥18 years) who spoke English and were undergoing elective operations for skin, soft tissue, head, neck, and abdominal cancers were approached. Patients were excluded if they did not own a smartphone.

Exposures: Study participants downloaded an application that collected smartphone accelerometer data continuously for 1 week preoperatively and 6 months postoperatively.

Main Outcomes And Measures: The primary end points were trends in daily exertional activity and the ability to achieve at least 60 minutes of daily exertional activity after surgery among patients with vs without a clinically significant postoperative event. Postoperative events were defined as complications, emergency department presentations, readmissions, reoperations, and mortality.

Results: A total of 139 individuals were approached. In the 62 enrolled patients, who were followed up for a median (interquartile range [IQR]) of 147 (77-179) days, there were no preprocedural differences between patients with vs without a postoperative event. Seventeen patients (27%) experienced a postoperative event. These patients had longer operations than those without a postoperative event (median [IQR], 225 [152-402] minutes vs 107 [68-174] minutes; P < .001), as well as greater blood loss (median [IQR], 200 [35-515] mL vs 25 [5-100] mL; P = .006) and more follow-up visits (median [IQR], 2 [2-4] visits vs 1 [1-2] visits; P = .002). Compared with mean baseline daily exertional activity, patients with a postoperative event had lower activity at week 1 (difference, -41.6 [95% CI, -75.1 to -8.0] minutes; P = .02), week 3 (difference, -40.0 [95% CI, -72.3 to -3.6] minutes; P = .03), week 5 (difference, -39.6 [95% CI, -69.1 to -10.1] minutes; P = .01), and week 6 (difference, -36.2 [95% CI, -64.5 to -7.8] minutes; P = .01) postoperatively. Fewer of these patients were able to achieve 60 minutes of daily exertional activity in the 6 weeks postoperatively (proportions: week 1, 0.40 [95% CI, 0.31-0.49]; P < .001; week 2, 0.49 [95% CI, 0.40-0.58]; P = .003; week 3, 0.39 [95% CI, 0.30-0.48]; P < .001; week 4, 0.47 [95% CI, 0.38-0.57]; P < .001; week 5, 0.51 [95% CI, 0.42-0.60]; P < .001; week 6, 0.73 [95% CI, 0.68-0.79] vs 0.43 [95% CI, 0.33-0.52]; P < .001).

Conclusions And Relevance: Smartphone accelerometer data can describe differences in postoperative physical activity among patients with vs without a postoperative event. These data help objectively quantify patient-centered surgical recovery, which have the potential to improve and promote shared decision-making, recovery monitoring, and patient engagement.
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http://dx.doi.org/10.1001/jamasurg.2019.4702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820047PMC
February 2020

Recent Developments and Therapeutic Strategies against Hepatocellular Carcinoma.

Cancer Res 2019 09;79(17):4326-4330

Division of Cancer Treatment and Diagnosis, Molecular Radiation Therapeutics, Radiation Research Program, NCI, Rockville, Maryland.

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2-5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0803DOI Listing
September 2019

Exploring donor demographics effects on hepatocyte yield and viability: Results of whole human liver isolation from one center.

Technology (Singap World Sci) 2019 Mar-Jun;7(1-2):1-11. Epub 2019 Apr 26.

Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Due to the growth of cell-based therapeutic alternatives addressing the shortage of livers for transplant, there is necessity for a reliable source of human hepatocytes. In addition, pharmaceutical research often requires human hepatocytes to assess new drug therapies during development or to achieve FDA approval. Whole human livers producing large quantities of cells from the same donor are ideal, enhancing reproducibility for all purposes, while also allowing for capturing variances in drug-metabolism across different demographics for pharmaceutical testing and development but are limited in availability and quality for research purposes. The present study investigates the effect of donor and liver procurement factors of 16 human livers on cell viability and yield, showing that typical exclusion criteria for transplant still produce viable hepatocytes with significant yields. Although limited in number of data points, which should be taken into consideration, the conclusions of this study could be utilized as indications, allowing for expansion of liver selection criteria for hepatocyte isolation and provide the necessary quality hepatocytes in large quantities for the growing pharmaceutical, biomedical, and therapeutic research fields.
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http://dx.doi.org/10.1142/S2339547819500018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693938PMC
April 2019