Missense Mutations in Myc Box I Influence Nucleocytoplasmic Transport to Promote Leukemogenesis.

PURPOSE: Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of patients with acute myeloid leukemia (AML), but the mechanisms by which they contribute to AML are unknown. EXPERIMENTAL DESIGN: To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc gene. RESULTS: Both wild-type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared with their wild-type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML-bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNA profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors. CONCLUSIONS: This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies.

PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA. These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.

Understanding baseline levels of physiological stress tolerance from excessive exercise in a holobenthic octopus species, Octopus pallidus.

Cephalopods receive a great deal of attention due to their socioeconomically important fisheries and aquaculture industries as well their unique biological features. However, basic information about their physiological responses under stress conditions is lacking. This study investigated the impact of a simple stressor, exercise to exhaustion, on the activity levels of antioxidant enzymes and the concentrations of molecules involved in oxidative stress response in the pale octopus (Octopus pallidus). Eight biochemical assays were measured in the humoral (plasma) and cellular (hemocyte) components of O. pallidus haemolymph, the invertebrate analogue to vertebrate blood. Overall, exercise resulted in an increase in activity of plasma catalase (CAT) and glutathione-S-transferase (GST) and the decrease in activity of plasms glutathione reductase (GR). In the hemocytes, the exercise elicited a different response, with a reduction in the activity of superoxide dismutase (SOD), GR, and glutathione peroxidase (GPX) and a reduction in nitric oxide (NO) concentration. Malondialdehyde (MDA) activity was similar in the plasma and haemocytes in control and exercised treatments, indicating that exercise did not induce lipid peroxidation. These results provide an important baseline for understanding oxidative stress in octopus, with exercise to exhaustion serving as a simple stressor which will ultimately inform our ability to detect and understand physiological responses to more complex stressors.

Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein.

Several canonical translocations produce oncofusion genes that can initiate acute myeloid leukemia (AML). Although each translocation is associated with unique features, the mechanisms responsible remain unclear. While proteins interacting with each oncofusion are known to be relevant for how they act, these interactions have not yet been systematically defined. To address this issue in an unbiased fashion, we fused a promiscuous biotin ligase (TurboID) in-frame with 3 favorable-risk AML oncofusion cDNAs (PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11) and identified their interacting proteins in primary murine hematopoietic cells. The PML::RARA- and RUNX1::RUNX1T1-TurboID fusion proteins labeled common and unique nuclear repressor complexes, implying their nuclear localization. However, CBFB::MYH11-TurboID-interacting proteins were largely cytoplasmic, probably because of an interaction of the MYH11 domain with several cytoplasmic myosin-related proteins. Using a variety of methods, we showed that the CBFB domain of CBFB::MYH11 sequesters RUNX1 in cytoplasmic aggregates; these findings were confirmed in primary human AML cells. Paradoxically, CBFB::MYH11 expression was associated with increased RUNX1/2 expression, suggesting the presence of a sensor for reduced functional RUNX1 protein, and a feedback loop that may attempt to compensate by increasing RUNX1/2 transcription. These findings may have broad implications for AML pathogenesis.

Missense mutations in Myc Box I influence MYC cellular localization, mRNA partitioning and turnover to promote leukemogenesis.

Somatic missense mutations in the phosphodegron domain of the MYC gene ( M YC Box I) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. To unveil unique proprieties of MBI MYC mutant proteins, we systematically compared the cellular and molecular consequences of expressing similar oncogenic levels of wild type and MBI mutant MYC. We found that MBI MYC mutants can accelerate leukemia by driving unique transcriptional signatures in highly selected, myeloid progenitor subpopulations. Although these mutations increase MYC stability, they overall dampen MYC chromatin localization and lead to a cytoplasmic accumulation of the mutant proteins. This phenotype is coupled with increased translation of RNA binding proteins and nuclear export machinery, which results in altered RNA partitioning and accelerated decay of select transcripts encoding proapoptotic and proinflammatory genes. Heterozygous knockin mice harboring the germline MBI mutation Myc p.T73N exhibit cytoplasmic MYC localization, myeloid progenitors' expansion with similar transcriptional signatures to the overexpression model, and eventually develop hematological malignancies. This study uncovers that MBI MYC mutations alter MYC localization and disrupt mRNA subcellular distribution and turnover of select transcripts to accelerate tumor initiation and growth.

Genomic landscape of TP53-mutated myeloid malignancies.

TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance.

Communication Frameworks for Palliative Surgical Consultations: A Randomized Study of Advanced Cancer Patients.

OBJECTIVE: To evaluate whether patients with advanced cancer prefer surgeons to use the best case/worst case (BC/WC) communication framework over the traditional risk/benefit (R/B) framework in the context of palliative surgical scenarios. BACKGROUND: Identifying the patient's preferred communication frameworks may improve satisfaction and outcome measures during difficult clinical decision-making. METHODS: In a video-vignette-based randomized, double-blinded study from November 2020 to May 2021, patients with advanced cancer viewed 2 videos depicting a physician-patient encounter in a palliative surgical scenario, in which the surgeon uses either the BC/WC or the R/B framework to discuss treatment options. The primary outcome was the patients' preferred video surgeon. RESULTS: One hundred fifty-five patients were approached to participate; 66 were randomized and 58 completed the study (mean age 55.8 ± 13.8 years, 60.3% males). 22 patients (37.9%, 95% CI: 25.4%-50.4%) preferred the surgeon using the BC/WC framework, 21 (36.2%, 95% CI: 23.8%-48.6%) preferred the surgeon using the R/B framework, and 15 (25.9%, 95% CI: 14.6%-37.2%) indicated no preference. High trust in the medical profession was inversely associated with a preference for the surgeon using BC/WC framework (odds ratio: 0.83, 95% CI: 0.70-0.98, P = 0.03). The BC/WC framework rated higher for perceived surgeon's listening (4.6 ± 0.7 vs 4.3±0.9, P = 0.03) and confidence in the surgeon's trustworthiness (4.3 ± 0.8 vs 4.0 ± 0.9, P = 0.04). CONCLUSIONS: Surgeon use of the BC/WC communication framework was not universally preferred but was as acceptable to patients as the traditional R/B framework and rated higher in certain aspects of communication. A preference for a surgeon using BC/WC was associated with lower trust in the medical profession. Surgeons should consider the BC/WC framework to individualize their approach to challenging clinical discussions.

Genomic landscape of TP53 -mutated myeloid malignancies.

TP53 -mutated myeloid malignancies are most frequently associated with complex cytogenetics. The presence of complex and extensive structural variants complicates detailed genomic analysis by conventional clinical techniques. We performed whole genome sequencing of 42 AML/MDS cases with paired normal tissue to characterize the genomic landscape of TP53 -mutated myeloid malignancies. The vast majority of cases had multi-hit involvement at the TP53 genetic locus (94%), as well as aneuploidy and chromothripsis. Chromosomal patterns of aneuploidy differed significantly from TP53 -mutated cancers arising in other tissues. Recurrent structural variants affected regions that include ETV6 on chr12p, RUNX1 on chr21, and NF1 on chr17q. Most notably for ETV6 , transcript expression was low in cases of TP53 -mutated myeloid malignancies both with and without structural rearrangements involving chromosome 12p. Telomeric content is increased in TP53 -mutated AML/MDS compared other AML subtypes, and telomeric content was detected adjacent to interstitial regions of chromosomes. The genomic landscape of TP53 -mutated myeloid malignancies reveals recurrent structural variants affecting key hematopoietic transcription factors and telomeric repeats that are generally not detected by panel sequencing or conventional cytogenetic analyses. Key Points: WGS comprehensively determines TP53 mutation status, resulting in the reclassification of 12% of cases from mono-allelic to multi-hit Chromothripsis is more frequent than previously appreciated, with a preference for specific chromosomes ETV6 is deleted in 45% of cases, with evidence for epigenetic suppression in non-deleted cases NF1 is mutated in 48% of cases, with multi-hit mutations in 17% of these cases TP53 -mutated AML/MDS is associated with altered telomere content compared with other AMLs.

Proteomic and phosphoproteomic landscapes of acute myeloid leukemia.

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.

A prospective feasibility study evaluating the 5x-multiplier to standardize discharge prescriptions in cancer surgery patients.

Background: We designed a prospective feasibility study to assess the 5x-multiplier (5x) calculation (eg, 3 pills in last 24 hours × 5 = 15) to standardize discharge opioid prescriptions compared to usual care. Methods: Faculty-based surgical teams volunteered for either 5x or usual care arms. Patients undergoing inpatient (≥ 48 hours) surgery and discharged by surgical teams were included. The primary end point was discharge oral morphine equivalents. Secondary end points were opioid-free discharges and 30-day refill rates. Results: Median last 24-hour oral morphine equivalents was similar between arms (7.5 mg 5x vs 10 mg usual care, P = .830). Median discharge oral morphine equivalents were less in the 5x arm (50 mg 5x vs 75 mg usual care, P < .001). Opioid-free discharges included 33.5% 5x vs 18.0% usual care arm patients (P < .001). Thirty-day refill rates were similar (15.3% 5x vs 16.5% usual care, P = .742). Conclusion: The 5x-multiplier was associated with reduced opioid prescriptions without increased refills and can be feasibly implemented across a diverse surgical practice.

Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes.

Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

Cavin4 interacts with Bin1 to promote T-tubule formation and stability in developing skeletal muscle.

The cavin proteins are essential for caveola biogenesis and function. Here, we identify a role for the muscle-specific component, Cavin4, in skeletal muscle T-tubule development by analyzing two vertebrate systems, mouse and zebrafish. In both models, Cavin4 localized to T-tubules, and loss of Cavin4 resulted in aberrant T-tubule maturation. In zebrafish, which possess duplicated cavin4 paralogs, Cavin4b was shown to directly interact with the T-tubule-associated BAR domain protein Bin1. Loss of both Cavin4a and Cavin4b caused aberrant accumulation of interconnected caveolae within the T-tubules, a fragmented T-tubule network enriched in Caveolin-3, and an impaired Ca2+ response upon mechanical stimulation. We propose a role for Cavin4 in remodeling the T-tubule membrane early in development by recycling caveolar components from the T-tubule to the sarcolemma. This generates a stable T-tubule domain lacking caveolae that is essential for T-tubule function.

Tumor suppressor function of Gata2 in acute promyelocytic leukemia.

Most patients with acute promyelocytic leukemia (APL) can be cured with combined all-trans retinoic acid (ATRA) and arsenic trioxide therapy, which induces the destruction of PML-RARA, the initiating fusion protein for this disease. However, the underlying mechanisms by which PML-RARA initiates and maintains APL cells are still not clear. Therefore, we identified genes that are dysregulated by PML-RARA in mouse and human APL cells and prioritized GATA2 for functional studies because it is highly expressed in preleukemic cells expressing PML-RARA, its high expression persists in transformed APL cells, and spontaneous somatic mutations of GATA2 occur during APL progression in mice and humans. These and other findings suggested that GATA2 may be upregulated to thwart the proliferative signal generated by PML-RARA and that its inactivation by mutation (and/or epigenetic silencing) may accelerate disease progression in APL and other forms of acute myeloid leukemia (AML). Indeed, biallelic knockout of Gata2 with CRISPR/Cas9-mediated gene editing increased the serial replating efficiency of PML-RARA-expressing myeloid progenitors (as well as progenitors expressing RUNX1-RUNX1T1, or deficient for Cebpa), increased mouse APL penetrance, and decreased latency. Restoration of Gata2 expression suppressed PML-RARA-driven aberrant self-renewal and leukemogenesis. Conversely, addback of a mutant GATA2R362G protein associated with APL and AML minimally suppressed PML-RARA-induced aberrant self-renewal, suggesting that it is a loss-of-function mutation. These studies reveal a potential role for Gata2 as a tumor suppressor in AML and suggest that restoration of its function (when inactivated) may provide benefit for AML patients.

A Predictive Model for Nodal Metastases in Patients With Appendiceal Cancers.

BACKGROUND: Histologic subtypes of appendiceal cancer vary in their propensity for metastases to regional lymph nodes (LN). A predictive model would help direct subsequent surgical therapy. METHODS: The National Cancer Database was queried for patients with appendiceal cancer undergoing surgery between 1998 and 2012. Multivariable logistic regression was used to develop a predictive model of LN metastases which was internally validated using Brier score and Area under the Curve (AUC). RESULTS: A total of 21,647 patients were identified, of whom 9079 (41.9%) had node negative disease, 4575 (21.1%) node positive disease, and 7993 (36.9%) unknown LN status. The strongest predictors of LN positivity were histology (carcinoid tumors OR 12.78, 95% CI 9.01-18.12), increasing T Stage (T3 OR 3.36, 95% CI 2.52-4.50, T4 OR 6.30, 95% CI 4.71-8.42), and tumor grade (G3 OR 5.55, 95% CI 4.78-6.45, G4 OR 5.98, 95% CI 4.30-8.31). The coefficients from the regression analysis were used to construct a calculator that generated predicted probabilities of LN metastases given certain inputs. Internal validation of the overall model showed an AUC of 0.75 (95% CI 0.74-0.76) and Brier score of 0.188. Histology-specific predictive models were also constructed with an AUC that varied from 0.669 for signet cell to 0.75 for goblet cell tumors. CONCLUSIONS: The risk for nodal metastases in patients with appendiceal cancers can be quantified with reasonable accuracy using a predictive model incorporating patient age, sex, tumor histology, T-stage, and grade. This can help inform clinical decision making regarding the need for a right hemicolectomy following appendectomy.

Comparative Effectiveness of Pylorus-Preserving Versus Standard Pancreaticoduodenectomy in Clinical Practice.

OBJECTIVES: We compared risk-adjusted short- and long-term outcomes between standard pancreaticoduodenectomy (SPD) and a pylorus-preserving pancreaticoduodenectomy (PPPD). METHODS: The National Cancer Database was queried for the years 2004 to 2014 to identify patients with adenocarcinoma of the pancreatic head undergoing SPD and PPD. Margin status, lymph node yield, length of stay (LOS), 30- and 90-day mortality, and overall survival were compared. RESULTS: A total of 11,172 patients were identified, of whom 9332 (83.5%) underwent SPD and 1840 (16.5%) PPPD. There was no difference in patient age, sex, stage, tumor grade, radiation treatment, and chemotherapy treatment between the 2 groups. Total number of regional lymph nodes was examined, and surgical margin status and overall survival were also comparable. However, patients undergoing PPPD had a shorter LOS (11.3 vs 12.3 days, P < 0.001), lower 30-day mortality (2.5% vs 3.7%, P = 0.02), and 90-day mortality (5.5% vs 6.9%, P = 0.03). On multivariate analyses, patients undergoing SPD were at higher risk for 30-day mortality compared with PPPD (odds ratio, 1.51; 95% confidence interval, 1.07-2.13). CONCLUSIONS: Standard pancreaticoduodenectomy and PPPD are oncologically equivalent, yet PPPD is associated with a reduction in postoperative mortality and shorter LOS.

Implementation of an Enhanced Recovery After Surgery (ERAS) Program is Associated with Improved Outcomes in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with increased postoperative complications and a prolonged length of stay (LOS). We report on our experience following implementation of an Enhanced Recovery After Surgery (ERAS) program for CRS and HIPEC. METHODS: Patients were divided into pre- and post-ERAS groups. Modifications in the ERAS group included routine use of transversus abdominis plane blocks, intra- and postoperative fluid restriction, and minimizing the use of narcotics, drains, and nasogastric tubes. RESULTS: Of a total of 130 procedures, 49 (38%) were in the pre-ERAS group and 81 (62%) were in the ERAS group. Mean LOS was reduced from 10.3 ± 8.9 days to 6.9 ± 5.0 days (p = 0.007) and the rate of grade III/IV complications was reduced from 24 to 15% (p = 0.243) following ERAS implementation. The ERAS group received less intravenous fluid during hospitalization (19.2 ± 18.7 L vs. 32.8 ± 32.5 L, p = 0.003) and used less opioids than the pre-ERAS group (median of 159.7 mg of oral morphine equivalents vs. 272.6 mg). There were no significant changes in the rates of 30-day readmission or acute kidney injury between the two groups (p = non-significant). On multivariable analyses, ERAS was significantly associated with a reduction in LOS (- 2.89 days, 95% CI - 4.84 to - 0.94) and complication rates (odds ratio 0.22, 95% CI 0.08-0.57). CONCLUSIONS: Implementation of an ERAS program for CRS and HIPEC is associated with a reduction in overall intravenous fluids, postoperative narcotic use, complication rates, and LOS.

Giant hepatic cyst as a cause of gastric outlet obstruction.

We describe the case of a 58-year-old female who presented to her primary care provider with lifelong anorexia, 6-week history of liquid only diet and new onset epigastric abdominal pain radiating to the back accompanied by nausea and abdominal distension. An initial computed tomography scan with contrast demonstrated a massive simple hepatic cyst with mass effect compression of the duodenal sweep. Repetitive treatment with aspiration sclerotherapy using hypertonic saline provided initial resolution of symptoms and led to substantial reduction of cyst diameter. Repeat imaging demonstrated complete drainage of the cyst and decompression of the duodenum. Ultimately, the patient's symptoms returned 6 weeks later at which time she opted for surgical deroofing of the cyst. Surgery provided for complete resolution. This case appears to be the first to document the compression of second portion of the duodenum by a massive simple hepatic cyst causing anorexia and mimicking gastric outlet obstruction.