Citations

Abstract Purpose Many women are employed at the time of breast cancer (BC) diagnosis. Pre-diagnosis psychological distress is prevalent among early-stage BC patients. We prospectively evaluated return to work (RTW) in BC patients with and without reported pre-diagnosis psychological distress over a 15-month period to determine if such distress affects workforce participation and mental health status after curative treatment. Methods 188 patients with newly diagnosed stage 0-III BC and working 35-plus hours/week participated at Mayo Clinic in Minnesota and Florida. Patients received an email survey at diagnosis and 3 and 15 months later. Incidence of severe psychological distress (SPD) per the Kessler Psychological Distress Scale (K6, score ≥ 13) was assessed at each timepoint. Results 77/188 survey respondents (41%) reported pre-diagnosis psychological distress, with 23.5% noting job-related stress. 59/188 patients (31%) had SPD at diagnosis, with similar incidence in the group that had pre-diagnosis distress (+ stress) and the non-stressed group (no-stress). The sample was highly educated and well salaried. The + stress group worked more hours on average at diagnosis (41.3 vs. 39.3 hours, p = 0.034). At 3 months, 83/141 respondents (60.1%) reported taking time off work after diagnosis, with 46.6% returning within 2 weeks and 42.5% requiring > 4 weeks’ break. More + stress patients reported RTW to maintain health insurance (13/56 vs. 6/85, p = 0.006), although this difference resolved by 15 months. SPD rates decreased over time but affected 17/104 respondents (16.3%) at 15 months. Conclusion Job-related stress is a primary driver of pre-diagnosis psychological distress. Three months after BC diagnosis, many women with pre-diagnosis psychological distress were motivated to RTW to keep employer-linked health insurance. SPD is prominent in BC patients; while SPD declined over time, it did not resolve completely.

Analgesia in liver transplantation patients has been traditionally considered a secondary priority where perioperative management principally focused on survival rates in these critically ill patients. With recent advancements in both surgical and medical management, posttransplant survival rates have steadily improved. Outcome measurements are no longer limited to short-term mortality rates and hospital length of stay but are also measured by patient-centered outcomes, such as pain control and quality of life. As living donor liver transplantation has increased access to transplantation, it has also added a different patient population to manage in the perioperative period. For healthy patients undergoing living donor hepatectomies, it is important to reduce the impact of the surgery with proper perioperative pain management. We performed a literature search for articles related to perioperative pain management for liver transplantation living donors and recipients to identify current practices and recent advances. Neuraxial techniques, peripheral nerve blocks, and enteral and parenteral medications were all found to be feasible analgesia modalities for patients undergoing either liver transplant or donor hepatectomy. Patients may also benefit from nonpharmacological interventions and preoperative counseling. No particular perioperative analgesic modality was deemed superior to any other. For liver transplant living donors and recipients, perioperative pain management should emphasize the application of sustainable patient-centered pain control protocols.

Background: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor–positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. Patients and Methods: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. Results: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12–1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98–1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09–3.17; P=.02) compared with N0–N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50–1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. Conclusions: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. ClinicalTrials.gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).

AbstractPrior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5‐year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere—winter (December–February); spring (March–May); summer (June–August); autumn (September–November) and Southern Hemisphere—winter (June–August); spring (September–November); summer (December–February); autumn (March–May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%–31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

The nonalcoholic steatohepatitis clinical research network (NASH-CRN) system is commonly used for histologic assessment of disease activity and fibrosis in NASH. Despite this, the system does not fully capture the range of disease activity and fibrosis. As such, an expanded NAS (E-NAS) grading and staging system with a calculated E-NAS index was developed by our group. In this follow up study, we aim to revalidate the E-NAS system and compare its reliability to existing systems. Hematoxylin and eosin and trichrome stained sections from 40 liver biopsies were reviewed digitally by four hepatopathologists and assessed using the NASH-CRN and E-NAS systems as well as a modified Ishak fibrosis stage. The pathologist's gestalt impression of disease activity and fibrosis was scored on a Visual Analogue Scale (VAS), which ranged from 0 (no activity/fibrosis) to 100 (the worst activity/fibrosis ever seen). Inter-rater reliability was assessed, and Spearman correlation coefficients were calculated. The E-NAS index had higher inter-rater agreement versus the NAS score (ICC 0.70 vs 0.61). The inter-rater agreement for ballooning in the E-NAS system was also higher at 0.67 compared to the NAS (ICC 0.60). ICCs for fibrosis were comparable between all the systems assessed (0.78 to 0.88). Finally, the calculated E-NAS index was higher with increasing stage of fibrosis compared to the NAS suggesting that it associates better with fibrosis. In summary, the E-NAS system demonstrates substantial inter-rater reliability as well as improved correlation with disease activity VAS and fibrosis compared to the NAS score.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

NGS used to diagnose and treat NSCLC patient with initial concern for metaplastic breast cancer

4107 Background: Aberrant Wnt/β-catenin activation has been implicated in tumor formation and progression in BTC. CTNNB1 is a key transcriptional co-activator in Wnt signaling. The impact of CTNNB1 alterations on outcomes in intrahepatic (IHCC) vs extrahepatic (EHCC) vs gallbladder (GB) tumors and patterns of gene co-expression is unclear. We examined the molecular correlates and predictive and prognostic significance of CTNNB1 expression in a real-world cohort of pts with BTC. Methods: 7450 BTC tumors were analyzed using Next Generation Sequencing (NextSeq), Whole Exome and Whole Transcriptome Sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ). Top quartile transcripts per million (TPM) expression was considered high expressors (Q4), bottom quartile was considered low expressors (Q1) within each subtype. Real-world overall survival (OS) data was obtained from insurance claims. Hazard ratio (HR) was calculated using Cox proportional hazards model, P values were calculated using log-rank test. Significance was determined to be p <0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q<0.05). Results: The cohort was comprised of 61% IHCC, 14% EHCC, 23% GB, 2% NOS. CTNNB1 mutations are rare in BTC (1.3%). Pts with CTNNB1-wt tumors had significantly better OS vs CTNNB1-mt (13.6 vs 10.2 mo, HR 0.74, p=0.008). This association remained significant in IHCC (13.2 vs 4.5 mo, HR 0.64, p=0.031) but not EHCC (18.0 vs 11.8 mo, HR 0.87, p=0.64) or GB (12.9 vs 11.0 mo, HR 0.75, p=0.071). CTNNB1-mt tumors were more frequently TP53-mt (63% vs 41%), ERBB2-mt (9% vs 2%) and ATM-mt (9% vs 3%). CTNNB1-wt tumors were more likely BAP-mt (9% vs 0%) and IDH1-mt (10% vs 0%) (all q<0.05). CTNNB1-mt tumors had higher median CTNNB1 expression vs wt (154.9 vs 113.4, q<0.009). Pts with CTNNB1 Q1 expression had significantly better OS vs Q4 (14.5 vs 12.4 mo, HR 0.88, p=0.007). This association held in IHCC (15.0 vs 10.6 mo, HR 0.77, p<0.00001) but not EHCC (17.5 vs 19.9 mo, HR 1.05, p=0.70) or GB (12.4 vs 12.8 mo, HR 1.05, p=0.63). CTNNB1 Q4 expressing tumors were more likely to be TP53-mt (55% vs 34%), PIK3CA-mt (9% vs 5%), KRAS-mt (23% vs 12%) and less likely IDH1-mt (4% vs 14%) compared to Q1 (all q<0.05). CTNNB1 Q4 pts had higher ARID1A, CTLA4, LAG3, HIF1A, TGFB1/2/3, EPHB4, EPHA2, VEGFA expression (FC: 2.1-4.2, all q<0.05) and higher T-cell inflamed score vs Q1. There was a trend towards improved OS in pts with IHCC CTNNB1 Q1 tumors receiving gemcitabine or fluorouracil (17.5 vs 15.0 mo, HR 0.86, p=0.064); no difference in outcomes by CTNNB1 expression in pts receiving immunotherapy. Conclusions: CTNNB1 mutations and mRNA expression levels impact survival in BTC, especially IHCC, and may be associated with benefit from chemotherapy. CTNBB1 alterations are associated with immunogenic, DNA repair and angiogenic pathways and may help identify novel therapeutic strategies for BTC.

4106 Background: The WNT/beta catenin (CTNNB1) pathway plays an integral role in the development of HCC. CTNNB1 has been implicated in HCC progression, metastasis, and drug resistance. We examined associations between CTNNB1 mutations and mRNA expression and clinical outcomes in a real-world cohort of patients with HCC. Methods: 1652 HCC tumors were tested at Caris Life Sciences (Phoenix, AZ) and analyzed with Whole Transcriptome Sequencing (WTS; Illumina Novaseq), Whole Exome Sequencing (NovaSeq,WES) and NextGen DNA sequencing (NextSeq, 592 genes). mRNA expression (transcripts per million) was further stratified into top (Q4) and bottom quartiles (Q1). Kaplan Meier estimates were calculated for overall survival (OS) in the molecularly defined cohorts and estimated from time of tissue collection to last contact. Significance was determined to be p <0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q<0.05). Results: Pathogenic CTNNB1 mutations were present in 32% of HCC and mutation status was not associated with CTNNB1 expression level. Pts whose tumors had lower CTNNB1 expression had significantly improved OS, 17.9 vs 12.4 months, Q1 vs Q4, HR 0.72, CI: 0.58-0.89 p=0.002. This association remained significant in patients who received first-line IO (Q1 vs Q4: OS 16.7 vs 10.6 mo, HR 0.54, CI: 0.32-0.94, p=0.025) or TKI (Q1 vs Q4: OS 27.1 vs 17.6 mo, HR 0.60, CI: 0.38-0.94, p=0.025). Low CTNNB1-expressing tumors (Q1) had more frequent ARID1A mutations (15% vs 8%); less frequent TP53 mutations (31% vs 42%); lower VEGFA, EPHB4, EPHA2, HIF1A, TGFB1/2/3 expression, lower MAPK activation and lower T-cell inflamed scores vs Q4 tumors (all q < 0.05). All tumors were MSS. CTNNB1 mutation status (MT vs WT) did not impact survival (OS 17.6 vs 15.3 mo, CTNNB1-MT vs CTNNB1-WT, HR 1.05, CI: 0.91-1.20, p=0.55). Similarly, CTNNB1 mutation status (MT vs WT) did not impact OS in pts treated with IO (19.8 vs 19.6 mo, HR 0.99, p=0.94) or TKI (23.0 vs 22.0 mo, HR 0.86, p=0.33). Conclusions: CTNNB1 mRNA expression, but not CTNNB1 mutation status, is associated with survival in HCC. Patients whose tumors had lower CTNNB1 expression appeared to derive more benefit from immune checkpoint inhibitors and TKI therapy in first line. CTNNB1 expression is associated with DNA repair, immune, neuronal and angiogenic pathways which may pave the way for potential therapeutic opportunities. Further studies are needed to prospectively evaluate CTNNB1 as a biomarker for treatment selection in HCC.