Origins of cancer: ain't it just mature cells misbehaving?

A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.

A new role for IFRD1 in regulation of ER stress in bladder epithelial homeostasis.

A healthy bladder requires the homeostatic maintenance of and rapid regeneration of urothelium upon stress/injury/infection. Several factors have been identified to play important roles in urothelial development, injury and disease response, however, little is known about urothelial regulation at homeostasis. Here, we identify a new role for IFRD1, a stress-induced gene that has recently been demonstrated to play a critical role in adult tissue proliferation and regeneration, in maintenance of urothelial function/ homeostasis in a mouse model. We show that the mouse bladder expresses IFRD1 at homeostasis and its loss alters the global transcriptome of the bladder with significant accumulation of cellular organelles including multivesicular bodies with undigested cargo, lysosomes and mitochondria. We demonstrate that IFRD1 interacts with several mRNA-translation-regulating factors in human urothelial cells and that the urothelium of Ifrd1-/- mice reveal decreased global translation and enhanced endoplasmic reticulum (ER) stress response. Ifrd1-/- bladders have activation of the unfolded protein response (UPR) pathway, specifically the PERK arm, with a concomitant increase in oxidative stress and spontaneous exfoliation of urothelial cells. Further, we show that such increase in cell shedding is associated with a compensatory proliferation of the basal cells but impaired regeneration of superficial cells. Finally, we show that upon loss of IFRD1, mice display aberrant voiding behavior. Thus, we propose that IFRD1 is at the center of many crucial cellular pathways that work together to maintain urothelial homeostasis, highlighting its importance as a target for diagnosis and/or therapy in bladder conditions.

Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

The coordinated management of ribosome and translation during injury and regeneration.

Diverse acute and chronic injuries induce damage responses in the gastrointestinal (GI) system, and numerous cell types in the gastrointestinal tract demonstrate remarkable resilience, adaptability, and regenerative capacity in response to stress. Metaplasias, such as columnar and secretory cell metaplasia, are well-known adaptations that these cells make, the majority of which are epidemiologically associated with an elevated cancer risk. On a number of fronts, it is now being investigated how cells respond to injury at the tissue level, where diverse cell types that differ in proliferation capacity and differentiation state cooperate and compete with one another to participate in regeneration. In addition, the cascades or series of molecular responses that cells show are just beginning to be understood. Notably, the ribosome, a ribonucleoprotein complex that is essential for translation on the endoplasmic reticulum (ER) and in the cytoplasm, is recognized as the central organelle during this process. The highly regulated management of ribosomes as key translational machinery, and their platform, rough endoplasmic reticulum, are not only essential for maintaining differentiated cell identity, but also for achieving successful cell regeneration after injury. This review will cover in depth how ribosomes, the endoplasmic reticulum, and translation are regulated and managed in response to injury (e.g., paligenosis), as well as why this is essential for the proper adaptation of a cell to stress. For this, we will first discuss how multiple gastrointestinal organs respond to stress through metaplasia. Next, we will cover how ribosomes are generated, maintained, and degraded, in addition to the factors that govern translation. Finally, we will investigate how ribosomes and translation machinery are dynamically regulated in response to injury. Our increased understanding of this overlooked cell fate decision mechanism will facilitate the discovery of novel therapeutic targets for gastrointestinal tract tumors, focusing on ribosomes and translation machinery.

Bringing Excitement to Empirical Business Ethics Research: Thoughts on the Future of Business Ethics.

To commemorate 40 years since the founding of the Journal of Business Ethics, the editors-in-chief of the journal have invited the editors to provide commentaries on the future of business ethics. This essay comprises a selection of commentaries aimed at creating dialog around the theme Bringing Excitement to Empirical Business Ethics Research (inspired by the title of the commentary by Babalola and van Gils). These editors, considering the diversity of empirical approaches in business ethics, envisage a future in which quantitative business ethics research is more bold and innovative, as well as reflexive about its techniques, and dialog between quantitative and qualitative research nourishes the enrichment of both. In their commentary, Babalola and van Gils argue that leadership research has stagnated with the use of too narrow a range of perspectives and methods and too many overlapping concepts. They propose that novel insights could be achieved by investigating the lived experience of leadership (through interviews, document analysis, archival data); by focusing on topics of concern to society; by employing different personal, philosophical, or cultural perspectives; and by turning the lens on the heroic leader (through "dark-side" and follower studies). Taking a provocative stance, Bal and Garcia-Lorenzo argue that we need radical voices in current times to enable a better understanding of the psychology underlying ethical transformations. Psychology can support business ethics by not shying away from grander ideas, going beyond the margins of "unethical behaviors harming the organization" and expanding the range of lenses used to studying behavior in context. In the arena of finance and business ethics, Guedhami, Liang, and Shailer emphasize novel data sets and innovative methods. Significantly, they stress that an understanding the intersection of finance and ethics is central to business ethics; financial equality and inclusion are persistent socio-economic and political concerns that are not always framed as ethics issues, yet relevant business policies and practices manifest ethical values. Finally, Charles Cho offers his opinion on the blurry line between the "ethical" versus "social" or "critical" aspects of accounting papers. The Journal of Business Ethics provides fertile ground for innovative, even radical, approaches to quantitative methods (see Zyphur and Pierides in J Bus Ethics 143(1):1-16, 10.1007/s10551-017-3549-8, 2017), as part of a broad goal of ethically reflecting on empirical research.

Models of Follow-Up Care and Secondary Prevention Measures for Survivors of Colorectal Cancer: Evidence-Based Guidelines and Systematic Review.

OBJECTIVE: To provide recommendations for preferred models of follow-up care for stage I-IV colorectal (CRC) cancer survivors in Ontario; to identify signs and symptoms of potential recurrence and when to investigate; and to evaluate patient information and support needs during the post-treatment survivorship period. METHODS: Consistent with the Program in Evidence-Based Medicine's standardized approach, MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO databases were systematically searched. The authors drafted recommendations and revised them based on the comments from internal and external reviewers. RESULTS: Four guidelines, three systematic reviews, three randomized controlled trials, and three cohort studies provided evidence to develop recommendations. CONCLUSIONS: Colorectal cancer follow-up care is complex and requires multidisciplinary, coordinated care delivered by the cancer specialist, primary care provider, and allied health professionals. While there is limited evidence to support a shared care model for follow-up, this approach is deemed to be best suited to meet patient needs; however, the roles and responsibilities of care providers need to be clearly defined, and patients need to know when and how to contact them. Although there is insufficient evidence to recommend any individual or combination of signs or symptoms as strong predictor(s) of recurrence, patients should be educated about these and know which care provider to contact if they develop any new or concerning symptoms. Psychosocial support and empathetic, effective, and coordinated communication are most valued by patients for their post-treatment follow-up care. Continuing professional education should emphasize the importance of communication skills and coordination of communication between the patient, family, and healthcare providers.

An Evidence-Based Guideline for Surveillance of Patients after Curative Treatment for Colon and Rectal Cancer.

OBJECTIVE: To provide recommendations for a surveillance regimen that leads to the largest overall survival benefit for patients after curative treatment for Stage I-IV colon and rectal cancer. METHODS: Consistent with the Program in Evidence-Based Care's standard approach, guideline databases, i.e., MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO, were systematically searched. Then, we drafted recommendations and methodology experts performed an internal review of the resulting draft recommendations, which was followed by an external review by targeted experts and intended users. RESULTS: Four systematic reviews and two randomized controlled trials were identified that provided evidence for recommendations. CONCLUSIONS: For patients with stage I-III colon cancer, a medical history and physical examination should be performed every six months for three years; computed tomography (CT) of the chest-abdomen-pelvis (CT CAP) should be performed at one and three years, or one CT CAP could be performed at 18 months; the use of carcinoembryonic antigen (CEA) is optional if CT imaging is being performed; and surveillance colonoscopy should be performed one year after the initial surgery. The frequency of subsequent surveillance colonoscopy should be dictated by previous findings, but generally, colonoscopies should be performed every five years if the findings are normal. There was insufficient evidence to support these recommendations for patients with rectal cancer, Stage IV colon cancer, and patients over the age of 75 years. Patients should be informed of current recommendations and the treating physician should discuss the specific risks and benefits of each recommendation with their patients.

Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium.

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling-independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.

Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury.

BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.

Paligenosis: Cellular Remodeling During Tissue Repair.

Complex multicellular organisms have evolved specific mechanisms to replenish cells in homeostasis and during repair. Here, we discuss how emerging technologies (e.g., single-cell RNA sequencing) challenge the concept that tissue renewal is fueled by unidirectional differentiation from a resident stem cell. We now understand that cell plasticity, i.e., cells adaptively changing differentiation state or identity, is a central tissue renewal mechanism. For example, mature cells can access an evolutionarily conserved program (paligenosis) to reenter the cell cycle and regenerate damaged tissue. Most tissues lack dedicated stem cells and rely on plasticity to regenerate lost cells. Plasticity benefits multicellular organisms, yet it also carries risks. For one, when long-lived cells undergo paligenotic, cyclical proliferation and redif-ferentiation, they can accumulate and propagate acquired mutations that activate oncogenes and increase the potential for developing cancer. Lastly, we propose a new framework for classifying patterns of cell proliferation in homeostasis and regeneration, with stem cells representing just one of the diverse methods that adult tissues employ.

ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis.

A single transcription factor, MIST1 (BHLHA15), maximizes secretory function in diverse secretory cells (like pancreatic acinar cells) by transcriptionally upregulating genes that elaborate secretory architecture. Here, we show that the scantly studied MIST1 target, ELAPOR1 (endosome/lysosome-associated apoptosis and autophagy regulator 1), is an evolutionarily conserved, novel mannose-6-phosphate receptor (M6PR) domain-containing protein. ELAPOR1 expression was specific to zymogenic cells (ZCs, the MIST1-expressing population in the stomach). ELAPOR1 expression was lost as tissue injury caused ZCs to undergo paligenosis (i.e., to become metaplastic and reenter the cell cycle). In cultured cells, ELAPOR1 trafficked with cis-Golgi resident proteins and with the trans-Golgi and late endosome protein: cation-independent M6PR. Secretory vesicle trafficking was disrupted by expression of ELAPOR1 truncation mutants. Mass spectrometric analysis of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR shared many binding partners. However, CI-M6PR and ELAPOR1 must function differently, as CI-M6PR co-immunoprecipitated more lysosomal proteins and was not decreased during paligenosis in vivo. We generated Elapor1-/- mice to determine ELAPOR1 function in vivo. Consistent with in vitro findings, secretory granule maturation was defective in Elapor1-/- ZCs. Our results identify a role for ELAPOR1 in secretory granule maturation and help clarify how a single transcription factor maintains mature exocrine cell architecture in homeostasis and helps dismantle it during paligenosis.NEW & NOTEWORTHY Here, we find the MIST1 (BHLHA15) transcriptional target ELAPOR1 is an evolutionarily conserved, trans-Golgi/late endosome M6PR domain-containing protein that is specific to gastric zymogenic cells and required for normal secretory granule maturation in human cell lines and in mouse stomach.

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program.

Differentiated cells across multiple species and organs can re-enter the cell cycle to aid in injury-induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive-enzyme-secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3-/- mice fail to induce RAB7-positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.

Close Observation versus Additional Surgery after Noncurative Endoscopic Resection of Esophageal Squamous Cell Carcinoma.

INTRODUCTION: After noncurative endoscopic submucosal dissection (ESD) of superficial esophageal squamous cell carcinoma (SESCC), additional esophagectomy is generally recommended. However, considering its high mortality and morbidity, it is uncertain if additional surgery improves the clinical outcomes. This study aimed to compare the clinical outcomes between patients who were observed without additional treatment and those who underwent radical esophagectomy. METHODS: A total of 52 patients with SESCC who underwent complete but noncurative ESD from January 2008 to December 2016 at the Samsung Medical Center and Asan Medical Center in Korea were retrospectively analyzed. Clinicopathologic characteristics and oncologic outcomes were compared between the observation group (n = 23) and the additional surgery group (n = 29). RESULTS: During a mean follow-up of 34.4 and 41.7 months, respectively, the rates of death (observation vs. surgery, 17.4 vs. 10.3%; p = 0.686), recurrence (observation vs. surgery, 13 vs. 17.2%; p = 1.000), and disease-specific death (observation vs. surgery, 4.3 vs. 6.9%; p = 1.000) did not significantly differ between the 2 groups. The 3-year overall survival was 86.3 and 96.4%, respectively (p = 0.776). The 3-year recurrence-free survival (observation vs. surgery, 85.0 vs. 88.7%; p = 0.960) and disease-specific survival (observation vs. surgery, 95.2 vs. 96.4%; p = 0.564) also did not significantly differ. CONCLUSIONS: The clinical outcomes of close observation of noncuratively resected SESCC are comparable to those of additional surgery, at least in the midterm. The wait-and-see strategy could be a feasible management option after noncurative ESD of SESCC in selected patients.

Patterns of Interaction Between Diffuse Low-Grade Glioma and Pregnancy: An Institutional Case Series.

BACKGROUND: The occurrence of pregnancy in patients with low-grade glioma (LGG) constitutes a unique therapeutic challenge. Owing to the rarity of cases, there is a dearth of information in existing literature. METHODS: We retrospectively identified all patients with a diagnosis of LGG and pregnancy at some point during their illness. Clinical course and obstetrical outcomes were reviewed. A volumetric analysis of tumor growth rate in association with pregnancy was performed. RESULTS: Of 15 women identified, 13 (86.7%) had a prepregnancy LGG diagnosis. Of the 2 patients in whom LGG was diagnosed during pregnancy, one underwent upfront surgery, and the other had watchful waiting with resection after 60 weeks. Nine patients (60.0%) remained asymptomatic during pregnancy, while 5 (33.3%) experienced recurrence of seizures. There was one case of transformation of an astrocytoma to glioblastoma during the third trimester, which was resected emergently. In 10 cases, progression occurred after pregnancy at a median interval of 24.2 months (interquartile range 6.6-37.5 months), with progression within 6 months of delivery in 2 cases. Mean (SD) growth rate during pregnancy was 7.8 (22.2) mm/year compared with 0.62 (1.12) mm/year before pregnancy and 0.29 (1.18) mm/year after pregnancy; the difference did not reach statistical significance (P = 0.306). CONCLUSIONS: Pregnancy was associated with clinical deterioration in one third of patients. No significant change in growth rate was identified. Time to progression and malignant dedifferentiation were unaffected. Patients with LGG wishing to pursue pregnancy should be counseled regarding the risk of complications, and if pregnancy is pursued, close neurological and obstetrical follow-up is recommended.

Management of degenerative spondylolisthesis: development of appropriate use criteria.

BACKGROUND CONTEXT: Outcomes of treatment in care of patients with spinal disorders are directly related to patient selection and treatment indications. However, for many disorders, there is absence of consensus for precise indications. With the increasing emphasis on quality and value in spine care, it is essential that treatment recommendations and decisions are optimized. PURPOSE: The purpose of the North American Spine Society Appropriate Use Criteria was to determine the appropriate (ie reasonable) multidisciplinary treatment recommendations for patients with degenerative spondylolisthesis across a spectrum of more common clinical scenarios. STUDY DESIGN: A Modified Delphi process was used. METHODS: The methodology was based on the Appropriate Use Criteria development process established by the Research AND Development Corporation. The topic of degenerative spondylolisthesis was selected by the committee, key modifiers determined, and consensus reached on standard definitions. A literature search and evidence analysis were completed by one work group simultaneously as scenarios were written, reviewed, and finalized by another work group. A separate multidisciplinary rating group was assembled. Based on the literature, provider experience, and group discussion, each scenario was scored on a nine-point scale on two separate occasions, once without discussion and then a second time following discussion based on the initial responses. The median rating for each scenario was then used to determine if indications were rarely appropriate (1 - 3), uncertain (4-6), or appropriate (7-9). Consensus was not mandatory. RESULTS: There were 131 discrete scenarios. These addressed questions on bone grafting, imaging, mechanical instability, radiculopathy with or without neurological deficits, obesity, and yellow flags consisting of psychosocial and medical comorbidities. For most of these, appropriateness was established for physical therapy, injections, and various forms of surgical intervention. The diagnosis of spondylolisthesis should be determined by an upright x-ray. Scenarios pertaining to bone grafting suggested that patients should quit smoking prior to surgery, and that use of BMP should be reserved for patients who had risk factors for non-union. Across all clinical scenarios, physical therapy (PT) had an adjusted mean of 7.66, epidural steroid injections 5.76, and surgery 4.52. Physical therapy was appropriate in most scenarios, and most appropriate in patients with back pain and no neurological deficits. Epidural steroid injections were most appropriate in patients with radiculopathy. Surgery was generally more appropriate for patients with neurological deficits, higher disability scores, and dynamic spondylolisthesis. Mechanical back pain and presence of yellow flags tended to be less appropriate, and obesity in general had relatively little influence on decision making. Decompression alone was more strongly considered in the presence of static versus dynamic spondylolisthesis. On average, posterior fusion with or without interbody fusion was similarly appropriate, and generally more appropriate than stand-alone interbody fusion which was in turn more appropriate than interspinous spacers. CONCLUSIONS: Multidisciplinary appropriate treatment criteria were generated based on the Research AND Development methodology. While there were consistent and significant differences between surgeons and non-surgeons, these differences were generally very small. This document provides comprehensive evidence-based recommendations for evaluation and treatment of degenerative spondylolisthesis. The document in its entirety will be found on the North American Spine Society website (https://www.spine.org/Research-Clinical-Care/Quality-Improvement/Appropriate-Use-Criteria).

Intraoperative Transcranial Motor-evoked Potential Stimulation Does Not Seem to Cause Seizures.

BACKGROUND: Intraoperative neurophysiological monitoring is of critical importance in evaluating the functional integrity of the central nervous system during surgery of the central or peripheral nervous system. In a large recent study, transcranial motor-evoked potentials (TcMEPs) were found to be associated with a 0.7% risk of inducing a seizure as diagnosed by clinical observation and electromyography in patients having general anesthesia with intravenous anesthetics. The gold standard for seizure diagnosis, however, is electroencephalography (EEG). The aim of this single-institution retrospective study is to ascertain the risk of intraoperative seizures detected using EEG during surgeries in adult patients undergoing intraoperative monitoring with TcMEPs. METHODS: The authors retrospectively reviewed the intraoperative EEG records of 1175 patients anesthetized with a variety of anesthetic agents, including volatile and intravenous anesthetics, to ascertain the rate of EEG-diagnosed seizures attributable to TcMEPs. RESULT: Our analysis did not reveal a single seizure event attributable to TcMEPs in 1175 patients. CONCLUSION: The intraoperative use of TcMEPs does not seem to cause seizures.

Stereotactic body radiation therapy for hepatocellular carcinoma with Macrovascular invasion.

BACKGROUND: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MVI) is associated with a poor prognosis. The purpose of this study is to describe long-term outcomes of patients with HCC and MVI treated with stereotactic body radiation therapy (SBRT). METHODS: Patients with HCC and MVI who were treated with SBRT from January 2003 to December 2016 were analyzed. Patients who had extrahepatic disease or previous liver transplant were excluded. Demographical, clinical, and treatment variables were analyzed. RESULTS: 128 eligible patients with HCC and MVI were treated with SBRT. Median age was 60.5 years (39 to 90 years). Baseline Child-Pugh (CP) score was A5 in 67%, A6 in 20%. Median SBRT dose was 33.3 Gy (range: 27 to 54 Gy) in 5 fractions. Local control at 1 year was 87.4% (95% CI 78.6 to 96.1%). Median overall survival (OS) was 18.3 months (95% CI 11.2 to 21.4 months); ECOG performance status > 1 (HR:1.85, p = 0.0138) and earlier treatment era (HR: 2.20, p = 0.0015) were associated with worsening OS. In 43 patients who received sorafenib following SBRT, median OS was 37.9 months (95% CI 19.5 to 54.4 months). Four patients developed GI bleeding possibly related to SBRT at 2 to 8 months, and 27% (31/112 evaluable patients) had worsening of CP class at three months after SBRT. CONCLUSIONS: SBRT was associated with encouraging outcomes for patients with HCC and MVI, especially in those patients who received sorafenib after SBRT. Randomized phase III trials of SBRT with systemic and/or regional therapy are warranted and ongoing.