Citations

Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993–2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population.

Abstract Background: Obesity is a well established risk factor not only for increased prostate cancer incidence, but for poorer survival from prostate cancer. However, there is limited knowledge on the role of the circulating lipidome in prostate cancer. In order to target lipid metabolism optimally, it is critical to understand the spectrum of changes in circulating lipid profiles and the association with clinical outcome across the natural history of prostate cancer. Aim: To assess the relationship between the plasma lipidome and clinical outcome in localized and metastatic prostate cancer. Methods: Liquid chromatography-tandem mass spectrometry was used to quantitate over 500 lipid species in plasma samples from 3 cohorts (1) 389 men with localized prostate cancer, (2) 44 men with metastatic hormone-sensitive prostate cancer (mHSPC), and (3) 137 men with metastatic castration-resistant prostate cancer (CRPC). Associations between circulating lipids with metastatic relapse, androgen-deprivation therapy (ADT) failure or overall survival for each relevant disease stage were examined by latent class analysis and cox regression. Results: Circulating lipid profiles displaying elevated levels of ceramides were associated with metastatic relapse in localized prostate cancer (HR 5.8, 95% CI 3.0-11, P 1 × 10−6), early ADT failure in mHSPC (HR 2.4, 95% CI 1.1-5.3, P 0.03), and shorter overall survival in CRPC (HR 2.5, 95% CI 1.7-3.7, P 2 × 10−6). ADT failure in mHSPC and shorter overall survival in CRPC were also associated with elevated levels of other sphingolipids (sphingomyelins, hexosylceramides). The prognostic significance of the high risk lipid profiles in localized prostate cancer was independent of clinicopathological characteristics (lipid profile HR 4.7, 95%CI 2.4-9.3, P 7 × 10−6) when modeled with Gleason score (P<0.0001) and pathological stage (P<0.0001). Furthermore, the circulating lipid profiles were independent of metabolic factors (localized prostate cancer lipid profile HR 8.2, 95% CI 2.6-25, P 0.0003 when modeled with diabetes, statin, hypertension, body mass index [BMI]; CRPC lipid profile HR 2.6, 95% CI 1.7-3.8, P x10−6 when modeled with BMI). Conclusion: Elevated circulating ceramides are associated with poorer clinical outcomes across the natural history of prostate cancer (from localized to metastatic hormone-sensitive to metastatic castration resistant prostate cancer). This demonstrates that aberrant lipid metabolism in the patients occurs early in prostate cancer and could be therapeutically targeted in prospective clinical trials to improve prostate cancer outcomes. Citation Format: Lisa Glen Horvath, Hui-Ming Lin, Blossom Mak, Kate Mahon, Nicole Yeung, Maria Docanto, Peter Sutherland, andrew Shepherd, Winston Tan, Arun Azad, Manish Kohli, Peter Meikle, Lisa Butler. Lipidomic analysis of circulating lipids across the natural history of prostate cancer identifies aberrant ceramide metabolism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4761.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Abstract 17 year old female presented for evaluation of galactorrhea of 3 months duration. Patient was diagnosed with papillary thyroid cancer and underwent total thyroidectomy in 2011. She was prescribed Synthroid 175 mcg but was not compliant with taking her medicine. In April 2019 she developed bilateral galactorrhea for which she was evaluated at an outside facility and was found to have a prolactin 143.7ng/mL (n 7.2-63) and TSH 996 mIU/L (n 0.5 -4.0). Pituitary MRI revealed pituitary macroadenoma measuring 1.5 x 1.4 x 1.2 cm with slight elevation of the optic chiasm and infundibulum. She was advised to restart Synthroid and was referred for the neurosurgery team at our facility for surgical resection of pituitary macroadenoma. Over the same period of time, she gained 25 lbs, developed headaches, excessive fatigue, constipation, hair loss, lower extremity swelling, and puffiness of her face. Her menstrual cycles were regular but this was only after she was placed on norelgestromin/ ethinyl estradiol transdermal patch. She denied visual changes. By the time she was seen at our clinic in June 2019, she was taking Synthroid daily for 1 month. TSH decreased to 1.0 mIU/L and prolactin improved to 68 ng/mL. IGF-1 was low at 98 ng/mL (n 149-509). ACTH, morning cortisol, and 24 hour urine free cortisol were within reference range. Visual field testing showed no visual defects. We advised patient to continue taking Synthroid and to follow up in 1 month. On the follow up visit in July 2019, TSH was 0.2 mIU/L, prolactin was 52 ng/mL and IGF-1 was 105 ng/mL. Pituitary MRI showed pituitary hyperplasia that has decreased compared to previous MRI, now measuring around 1 cm at the largest dimension without contact with the optic chiasm and the Infundibulum was at midline. Galactorrhea and headaches resolved and fatigue significantly improved.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract Purpose: Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Patients and Methods: Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients. Results: Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs. Conclusions: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.

Background Aesthetic outcomes of unilateral cleft lip repairs have important psychosocial implications for patients who are heavily influenced by social perceptions. Online crowdsourcing offers the unique potential to efficiently recruit large numbers of laypeople to assess public perception. The aim of this study was to use the online crowdsourcing platform Mechanical Turk to compare the postoperative outcomes of Fisher, Millard, and Mohler cleft lip repair techniques. Methods Two hundred fifty-four participants were recruited through Mechanical Turk to evaluate 29 cropped and deidentified photographs of children, 8 photographs were controls without cleft lips and 21 were children with unilateral cleft lips who had undergone Fisher, Millard, or Mohler repairs (7 in each group). Respondents were asked whether a scar was present, whether they would be personally satisfied with the surgical result and used a Likert scale from 1 to 5 to rate overall appearance, scar severity, and nasal symmetry. Results Fewer respondents reported that a scar was present when assessing postoperative photographs of Fisher repairs (70.3 ± 8.6%) compared with Millard (92.0 ± 1.5%) or Mohler (88.8 ± 3.1%) repairs. Average rating of scar severity was also lower for Fisher (1.9) compared with Millard (2.6) or Mohler (2.6) repairs. Average ratings of nose symmetry, general appearance, and satisfaction with operative result were not statistically significantly different between the repair groups. Conclusions This study demonstrates the potential of online crowdsourcing to assess public perception of plastic surgery outcomes. The Mechanical Turk platform offers a reduction in selection bias, ease of study design, and enhanced efficiency of large-scale participant recruitment. Results indicate that the Fisher repair led to the most favored aesthetic outcomes compared with the Millard and Mohler techniques, particularly with regard to scar severity. Crowdsourcing is a powerful tool to assess layperson perception of plastic surgery outcomes and can be used to better guide surgical decision-making.

3539 Background: Therapy with decitabine and entinostat (ENT: HDAC inhibitor) shows synergistic effect in re-expression of tumor-suppressor genes and growth inhibition in CRC cell lines and in vivo studies. Methods: We conducted a phase II, multi-institutional study of SQ 5-azacitidine (AZA) and oral ENT in mCRC pts. A 28 day cycle included: AZA at 40 mg/m2 d1-5 and 8-10 with ENT 7 mg d3 and 10. Initial eligibility criteria included: ECOG PS 0-1, good end organ function, and biopsiable disease for cohort A (CoA). An interim analysis indicated that toxicity which crossed pre-specified safety boundary was secondary to disease. A 2nd cohort B (CoB) with eligibility restrictions: <2 prior regimens in KRAS-mutated CRC pts, <3 prior regimens if KRAS wild-type, and liver disease limited to <30% of volume was accrued. Serial tumor biopsies and research blood were collected to assess for methylation/expression changes in circulating tumor DNA and biopsies, respectively. The primary endpoint was response as measured by RECIST criteria using a 2-stage Simon design. Results: 47 pts were initially enrolled (24 CoA, 23 CoB). Pts received a median of 2 cycles on both cohorts (1-16 CoA, 2-6 CoB). Pts had a median of 4 prior therapies for CoA (range 2-9) and 3 for CoB (range 2-6). Gr 4 AEs attributable to treatment for CoA included hyperglycemia (1) and hypokalemia (1); other common Gr 3 AEs included anemia (3), decreased lymphocytes (7), fatigue (3), and nausea (3). CoB pts experienced grade 3 chest pain (1), neutropenia (2), leucopenia (2), urinary tract obstruction (1), and hypophosphatemia (1). No responses have been observed. Results of translational objectives will be presented at the meeting. Conclusions: SQ AZA and ENT therapy does not have clinical activity as defined by confirmed response in aCRC. Follow-up for survival, response to subsequent therapy, and correlative analysis are ongoing. Supported in part by N01-CM-2011-00099. Clinical trial information: NCT01105377. [Table: see text]

Background and Aims In cholestatic liver diseases, ductular reactive (DR) cells extend into the hepatic parenchyma and promote inflammation and fibrosis. We have previously observed that multidrug‐resistant 2 (Mdr2−/− ) double knockout (DKO) mice lacking tumor necrosis factor–related apoptosis‐inducing ligand receptor (Tr−/− ) display a more extensive ductular reaction and hepatic fibrosis compared to Mdr2−/− mice. This observation suggests that the magnitude of the DR‐cell population may be regulated by apoptosis. Approach and Results To examine this concept, we cultured epithelial cell adhesion molecule–positive reactive cholangioids (ERCs) obtained from wild‐type (WT), Tr−/− , Mdr2−/− and DKO mice. Single‐cell transcriptomics and immunostaining of both WT and DKO ERCs confirmed their DR‐cell phenotype. Moreover, DKO ERCs displayed a unique translational cluster with expression of chemokines, indicating a reactive state. Incubation with the myeloid cell leukemia 1 (MCL1) inhibitor S63845, a proapoptotic BH3‐mimetic therapy, significantly decreased DKO and Mdr2−/− ERC viability compared to WT. Intravenous administration of S63845 significantly reduced the DR‐cell population and markers of inflammation and liver fibrosis in Mdr2−/− and DKO mice. Furthermore, DKO mice treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high‐definition mass cytometry by time‐of‐flight. Coculture of bone marrow–derived macrophages with ERCs from DKO mouse livers up‐regulated expression of the B cell–directed chemokine (C‐C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl‐2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens. Conclusions DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR‐cell and B‐cell populations and hepatic fibrosis.