The evolution of clinical outcomes in metastatic pancreatic adenocarcinoma: a 10-year experience at a tertiary referral center.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the US. Recent studies have demonstrated survival benefits for FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) and Gem/nab-P (gemcitabine/nab-paclitaxel) over gemcitabine. We aimed to evaluate the clinical outcomes of mPDAC before and after incorporating these newer regimens into the clinical practice. METHODS: A retrospective study of patients with mPDAC at our institution between 2009 and 2018, who were followed up until December 2019. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier survival analysis. Univariate and multivariable Cox regression analyses were used to explore predictors of survival. RESULTS: A total of 394 patients with mPDAC were included: 122 (31%) were diagnosed 2009-2013 and 272 (69%) 2014-2018. In 2009-2013 cohort vs. 2014-2018 cohort, the median OS and PFS were similar (4 vs. 3.6 months, P = 0.5) and (2.3 vs. 2.5 months, P = 0.41), respectively. Age, ECOG-PS >1, serum albumin, neutrophil-to-lymphocyte ratio, and platelets-to-lymphocyte ratio were independent predictors of better OS. CONCLUSIONS: In this study of real-world data, the median OS and PFS for all patients with mPDAC were equivalent before and after incorporating newer treatment regimens into the clinical practice.

Metastatic tumors to the pancreas: Balancing clinical impression with cytology findings.

BACKGROUNDS/AIMS: Metastatic lesions of the pancreas (PMET) account for 1%-5% of all malignant solid pancreatic lesions (SPL). In this study we evaluated the utility of endoscopic ultrasonography with fine needle aspiration (EUS-FNA) in diagnosing PMET. METHODS: Patients who underwent EUS-FNA at a community referral center between 2011-2017 for SPL were identified. Clinical, radiologic, and EUS-FNA features of those with PMET were compared to those with primary solid tumors of the pancreas: pancreatic adenocarcinoma (PDAC) and neuroendocrine tumors (PNET). RESULTS: A total of 191 patients were diagnosed with solid pancreatic malignancy using EUS-FNA: 156 PDAC, 27 PNET, and eight (4.2%) had PMET. Patients with PMET were less likely to have abdominal pain (25.0% vs. 76.3% vs. 48.2%; p < 0.01) or obstructive jaundice (37.5% vs. 58.3% vs. 0%; p < 0.01) compared to PDAC and PNET. Those with PMET were more likely to have mass lesions with/without biliary or pancreatic ductal dilatations (100% vs. 86.5% vs. 85.2%; p < 0.01) and lower CA19-9 (82.5 ± 43.21 U/mL vs. 4,639.30 ± 11,489.68 U/mL vs. 10.50 ± 10.89 U/mL; p < 0.01) compared to PDAC and PNET. Endosonographic features were similar among all groups. Seven (87.5%) patients with PMET had a personal history of malignancy prior to PMET diagnosis. The primary malignancy was renal cell carcinoma in five PMET. CONCLUSIONS: PMET are exceedingly rare, comprising less than 5% of SLP. Patients with PMET are less likely to present with symptoms and mostly identified by surveillance imaging for the primary malignancy.

Effects of Prenatal Exposure to Alcohol and Smoking on Fetal Heart Rate and Movement Regulation.

Negative associations of prenatal tobacco and alcohol exposure (PTE and PAE) on birth outcomes and childhood development have been well documented, but less is known about underlying mechanisms. A possible pathway for the adverse fetal outcomes associated with PTE and PAE is the alteration of fetal autonomic nervous system development. This study assessed PTE and PAE effects on measures of fetal autonomic regulation, as quantified by heart rate (HR), heart rate variability (SD-HR), movement, and HR-movement coupling in a population of fetuses at ≥ 34 weeks gestational age. Participants are a subset of the Safe Passage Study, a prospective cohort study that enrolled pregnant women from clinical sites in Cape Town, South Africa, and the Northern Plains region, United States. PAE was defined by six levels: no alcohol, low quit early, high quit early, low continuous, moderate continuous, and high continuous; while PTE by 4 levels: no smoking, quit early, low continuous, and moderate/high continuous. Linear regression analyses of autonomic measures were employed controlling for fetal sex, gestational age at assessment, site, maternal education, household crowding, and depression. Analyses were also stratified by sleep state (1F and 2F) and site (South Africa, N = 4025, Northern Plains, N = 2466). The final sample included 6491 maternal-fetal-dyad assessed in the third trimester [35.21 ± 1.26 (mean ± SD) weeks gestation]. PTE was associated with a decrease in mean HR in state 2F, in a dose dependent fashion, only for fetuses of mothers who continued smoking after the first trimester. In state 1F, there was a significant increase in mean HR in fetuses whose mother quit during the first trimester. This effect was driven by the Norther Plains cohort. PTE was also associated with a significant reduction in fetal movement in the most highly exposed group. In South Africa a significant increase in mean HR both for the high quit early and the high continuous group was observed. In conclusion, this investigation addresses a critical knowledge gap regarding the relationship between PTE and PAE and fetal autonomic regulation. We believe these results can contribute to elucidating mechanisms underlying risk for adverse outcomes.

Kidney Transplant Outcomes in Indigenous People of the Northern Great Plains of the United States.

BACKGROUND: Indigenous people experience higher rates of end-stage renal disease as well as negative predictive factors that undermine kidney transplantation (KT) success. Despite these inequalities, data suggest that short-term outcomes are comparable to those of other groups, but few studies have examined this effect in the Northern Great Plains (NGP) region. METHODS: We performed a retrospective database review to determine outcomes of KT in Indigenous people of the NGP. White and Indigenous people receiving a KT between 2000 and 2018 at a single center were examined. RESULTS: A total of 622 KT recipients were included (117 Indigenous and 505 White). Indigenous patients were more likely to smoke, have diabetes, have higher immunologic risk, receive fewer living donor kidneys, and have longer waitlist times. In the 5 years after KT there were no significant differences in renal function, rejection events, cancer, graft failure, or patient survival. At 10 years posttransplant, Indigenous patients had twice the all-cause graft failure (odds ratio = 2.06; 95% confidence interval, 1.25-3.39) and half the survival rate (odds ratio = 0.47; 95% confidence interval, 0.29-0.76); however, this effect was not maintained once the effects of race, sex, smoking status, diabetes, preemptive transplant, high panel reactive antibody status, and transplant type were adjusted for. CONCLUSIONS: KT outcomes in Indigenous patients in the NGP region are similar to those of White patients 5 years posttransplant, with differences emerging at 10 years that could be diminished with greater emphasis on correcting modifiable risk factors.

Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers.

Targeting the ubiquitin-proteasome system (UPS) - in particular, the proteasome complex - has emerged as an attractive novel cancer therapy. While several proteasome inhibitors have been successfully approved by the Food and Drug Administration for the treatment of hematological malignancies, the clinical efficacy of these inhibitors is unexpectedly lower in the treatment of solid tumors due to the functional and structural heterogeneity of proteasomes in solid tumors. There are ongoing trials to examine the effectiveness of compound and novel proteasome inhibitors that can target solid tumors either alone or in combination with conventional chemotherapeutic agents. The modest therapeutic efficacy of proteasome inhibitors such as bortezomib in solid malignancies demands further research to clarify the exact effects of these proteasome inhibitors on different proteasomes present in cancer cells. The structural, cellular localization and functional analysis of the proteasome complexes in solid tumors originated from different tissues provides new insights into the diversity of proteasomes' responses to inhibitors. In this study, we used an optimized iodixanol gradient ultracentrifugation to purify a native form of proteasome complexes with their intact associated protein partners enriched within distinct cellular compartments. It is therefore possible to isolate proteasome subcomplexes with far greater resolution than sucrose or glycerol fractionations. We have identified differences in the catalytic activities, subcellular distribution, and inhibitor sensitivity of cytoplasmic proteasomes isolated from human colon, breast, and pancreatic cancer cell lines. Our developed techniques and generated results will serve as a valuable guideline for investigators developing a new generation of proteasome inhibitors as an effective targeted therapy for solid tumors.

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Finding a needle in a haystack: Endoscopic ultrasound-guided fine-needle aspiration for solid pancreatic masses in the setting of chronic pancreatitis.

BACKGROUND: The mainstay for the definitive diagnosis of pancreatic lesions is endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). However, there is evidence that EUS-FNA has low sensitivity in the setting of chronic pancreatitis (CP). This single-center retrospective study aimed to compare and analyze the diagnostic yield of EUS-FNA for solid pancreatic lesions in the presence and absence of CP, and to further investigate strategies for overcoming the low diagnostic yield in the setting of CP. METHODS: This study identified patients who underwent EUS-FNA at Sanford USD Medical Center (SD, USA) for a solid pancreatic lesion between July 15, 2011, and November 30, 2017. Data on demographics, clinical features, cross-sectional imaging findings, EUS findings, cytology/pathology, and clinical follow up were collected. RESULTS: The final diagnosis was adenocarcinoma in 156 patients (67%), neuroendocrine tumor in 27 (12%), lymphoma in 6 (3%), metastatic malignancy in 8 (4%), and benign etiologies in 35 (15%). CP was identified in 44/234 (19%) patients. The overall diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for EUS-FNA were 92.9%, 97.1%, 99.5%, 70.8%, and 93.5%, respectively. The sensitivity (80% vs. 95%, P=0.020) and accuracy (86% vs. 95%, P=0.043) were significantly lower in patients with CP compared to those without CP. CONCLUSION: CP can significantly affect the EUS-FNA diagnostic yield of solid pancreatic neoplasms. A high index of clinical suspicion is required in these cases to make a definitive diagnosis.

Association Between Prenatal Exposure to Alcohol and Tobacco and Neonatal Brain Activity: Results From the Safe Passage Study.

Importance: Research to date has not determined a safe level of alcohol or tobacco use during pregnancy. Electroencephalography (EEG) is a noninvasive measure of cortical function that has previously been used to examine effects of in utero exposures and associations with neurodevelopment. Objective: To examine the association of prenatal exposure to alcohol (PAE) and tobacco smoking (PTE) with brain activity in newborns. Design, Setting, and Participants: This prospective cohort study enrolled mother-newborn dyads from December 2011 through August 2015, with data analyzed from June 2018 through June 2019. Pregnant women were recruited from clinical sites in Cape Town, South Africa, and the Northern Plains region of the US. Participants were a subset of newborns enrolled in the Safe Passage Study. Exclusions included birth at less than 37 or more than 41 weeks' gestation, multiple birth, or maternal use of psychiatric medication during pregnancy. Exposures: PAE and PTE groups were determined by cluster analysis. Main Outcomes and Measures: Analyses of covariance were run on EEG spectral power at 12 scalp locations across the frequency spectrum from 1 to 45 Hz in 3-Hz bins by sleep state. Results: The final sample consisted of 1739 newborns (median [interquartile range] gestational age at birth, 39.29 [1.57] weeks; 886 [50.9%] were female; median [interquartile range] newborn age at assessment, 48.53 [44.96] hours). Newborns whose mothers were in the low continuous (95% CI, -0.379 to -0.031; P < .05; 95% CI, -0.379 to -0.045; P < .05), quit (95% CI, -0.419 to -0.127; P < .001; 95% CI, -0.398 to -0.106; P < .005), and moderate or high continuous (95% CI, -0.430 to -0.124; P < .001; 95% CI, -0.420 to -0.119; P < .005) PAE clusters had increased 4- to 6-Hz and 7- to 9-Hz left-temporal EEG power. Newborns with moderate or high continuous PTE had decreased 19- to 21-Hz (95% CI, 0.034 to 0.327; P < .05) and 22- to 24-Hz (95% CI, 0.022 to 0.316; P < .05) right-central EEG compared with newborns with no PTE. Newborns with moderate or high continuous PTE had significantly decreased 22- to 36-Hz right-central EEG power compared with the quit smoking group (22-24 Hz, 95% CI, 0.001 to 0.579; P < .05; 25-27 Hz, 95% CI, 0.008 to 0.586; P < .05; 28-30 Hz, 95% CI, 0.028 to 0.607; P < .05; 31-33 Hz, 95% CI, 0.038 to 0.617; P < .05; 34-36 Hz, 95% CI, 0.057 to 0.636; P < .05). Conclusions and Relevance: These findings suggest that even low levels of PAE or PTE are associated with changes in offspring brain development.

Delivering Precision Oncology in a Community Cancer Program: Results From a Prospective Observational Study.

INTRODUCTION: Precision oncology (PO) is a growing treatment approach in the era of next-generation sequencing (NGS) and matched therapies. Effective delivery of PO in the community has not been extensively studied. Our program developed a virtual molecular tumor board (MTB) strategy to help guide PO care. MATERIALS AND METHODS: Over 18 months, eligible adult patients with advanced, incurable solid tumor malignancies were enrolled in a molecular profiling (MP) study using the Foundation Medicine NGS panel. Results were reviewed through a weekly, videoconferenced MTB conducted across our largely rural integrated health system. Recommendations from the MTB were used to identify actionable alterations (AAs). Feasibility of PO care delivery was assessed as the primary outcome. Secondary outcomes included the frequency of AAs, genomic matched treatments, genomic matched clinical trial enrollment, and clinical outcomes. RESULTS: A total of 120 participants with a variety of advanced tumor types were enrolled. Of these, 109 (90.8%) had successful MP. Treatment on the basis of an AA was recommended by the MTB in 58% of patients (63 of 109) who had a successful MP result. For those completing MP, treatments included enrollment in a genomic matched clinical trial (n = 16; 14.6%) and genomic matched treatment with a Food and Drug Administration-approved agent (n = 23; 21.1%). Response and survival data were similar regardless of the matched treatment option chosen. CONCLUSION: A video-conferenced MTB-facilitated NGS testing and treatment delivery system was implemented in our integrated community oncology program. Continued use of this model aims to increase understanding of the impact of PO in this setting.

Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy.

Overexpression of the oncoprotein mortalin in cancer cells and its protein partners enables mortalin to promote multiple oncogenic signaling pathways and effectively antagonize chemotherapy-induced cell death. A UBX-domain-containing protein, UBXN2A, acts as a potential mortalin inhibitor. This current study determines whether UBXN2A effectively binds to and occupies mortalin's binding pocket, resulting in a direct improvement in the tumor's sensitivity to chemotherapy. Molecular modeling of human mortalin's binding pocket and its binding to the SEP domain of UBXN2A followed by yeast two-hybrid and His-tag pull-down assays revealed that three amino acids (PRO442, ILE558, and LYS555) within the substrate-binding domain of mortalin are crucial for UBXN2A binding to mortalin. As revealed by chase experiments in the presence of cycloheximide, overexpression of UBXN2A seems to interfere with the mortalin-CHIP E3 ubiquitin ligase and consequently suppresses the C-terminus of the HSC70-interacting protein (CHIP)-mediated destabilization of p53, resulting in its stabilization in the cytoplasm and upregulation in the nucleus. Overexpression of UBXN2A causes a significant inhibition of cell proliferation and the migration of colon cancer cells. We silenced UBXN2A in the human osteosarcoma U2OS cell line, an enriched mortalin cancer cell, followed by a clinical dosage of the chemotherapeutic agent 5-fluorouracil (5-FU). The UBXN2A knockout U2OS cells revealed that UBXNA is essential for the cytotoxic effect achieved by 5-FU. UBXN2A overexpression markedly increased the apoptotic response of U2OS cells to the 5-FU. In addition, silencing of UBXN2A protein suppresses apoptosis enhanced by UBXN2A overexpression in U2OS. The knowledge gained from this study provides insights into the mechanistic role of UBXN2A as a potent mortalin inhibitor and as a potential chemotherapy sensitizer for clinical application.