Hepatocytes direct the formation of a pro-metastatic niche in the liver.

The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study.

PURPOSE: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. METHODS: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. RESULTS: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years). CONCLUSION: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Feeling offended by clients: The experiences of doctoral student therapists.

Ten doctoral student therapists (8 White, 5 female) in 1 counseling psychology doctoral program located in the Mid-Atlantic United States were interviewed for approximately 1 hour each about their experiences of feeling offended by a client during an individual psychotherapy session. Interview data were analyzed with consensual qualitative research (CQR). Trainee therapists typically felt offended related to their sociocultural identities (e.g., being a woman, LGBTQ+, racial-ethnic minority), felt frozen after the events and uncertain about how to respond, wished they had handled the events differently, and struggled when clients expressed opinions or beliefs that ran counter to their own values. Trainees had difficulty maintaining an empathic, nonjudgmental therapeutic stance where they could both value the client and maintain their own sense of integrity and beliefs about social justice and multiculturalism. Implications for training, practice, and research are provided. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Autism-related deficits via dysregulated eIF4E-dependent translational control.

Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.

An integrated enrichment system to facilitate isolation and molecular characterization of single cancer cells from whole blood.

Circulating tumor cells (CTCs) carry valuable biological information. While enumeration of CTCs in peripheral blood is an FDA-approved prognostic indicator of survival in metastatic prostate and other cancers, analysis of CTC phenotypic and genomic markers is needed to identify cancer origin and elucidate pathways that can guide therapeutic selection for personalized medicine. Given the emergence of single-cell mRNA sequencing technologies, a method is needed to isolate CTCs with high sensitivity and specificity as well as compatibility with downstream genomic analysis. Flow cytometry is a powerful tool to analyze and sort single cells, but pre-enrichment is required prior to flow sorting for efficient isolation of CTCs due to the extreme low frequency of CTCs in blood (one in billions of blood cells). While current enrichment technologies often require many steps and result in poor recovery, we demonstrate a magnetic separator and acoustic microfluidic focusing chip integrated system that enriches rare cells in-line with FACS™ (fluorescent activated cell sorting) and single-cell sequencing. This system analyzes, isolates, and index sorts single cells directly into 96-well plates containing reagents for Molecular Indexing (MI) and transcriptional profiling of single cells. With an optimized workflow using the integrated enrichment-FACS system, we performed a proof-of-concept experiment with spiked prostate cancer cells in peripheral blood and achieved: (i) a rapid one-step process to isolate rare cancer cells from lysed whole blood; (ii) an average of 92% post-enrichment cancer cell recovery (R2 = 0.9998) as compared with 55% recovery for a traditional benchtop workflow; and (iii) detection of differentially expressed genes at a single cell level that are consistent with reported cell-type dependent expression signatures for prostate cancer cells. These model system results lay the groundwork for applying our approach to human blood samples from prostate and other cancer patients, and support the enrichment-FACS system as a flexible solution for isolation and characterization of CTCs for cancer diagnosis. © 2018 International Society for Advancement of Cytometry.

The development and validation of the Contemporary Critical Consciousness Measure II.

Critical consciousness (CC) has been heralded as an antidote to oppression. Developed by the Brazilian educator, Paulo Freire, CC represents the process by which individuals gain awareness of societal inequities and subsequently take action to dismantle the systems and institutions that sustain them. Empirically supported instruments intended to assess this important construct have only been recently introduced to the literature and have focused specifically on racism, classism, and heterosexism. The purpose of this project was to develop a psychometrically sound measure of CC that expands assessment into sexism, cissexism (genderism/transphobia), and ableism. Two studies with a total of 569 observations provided initial reliability and validity evidence on the Contemporary Critical Consciousness Measure II (CCCMII). Results from exploratory and confirmatory factor analyses suggest that the final 37-item CCCMII provides a general index of CC as well as assesses CC associated with sexism and ableism above and beyond the general factor. Results support the internal consistency and factor structure of the measure. Expected relationships between the CCCMII and existing measures of sexism, cissexism, and ableism provide evidence for the validity of the instrument. Limitations, future directions for research, and counseling implications are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Comparative clinical utility of tumor genomic testing and cell-free DNA in metastatic breast cancer.

PURPOSE: Breast cancer metastases differ biologically from primary disease; therefore, metastatic biopsies may assist in treatment decision making. Commercial genomic testing of both tumor and circulating tumor DNA have become available clinically, but utility of these tests in breast cancer management remains unclear. METHODS: Patients undergoing a clinically indicated metastatic tumor biopsy were consented to the ongoing METAMORPH registry. Tumor and blood were collected at the time of disease progression before subsequent therapy, and patients were followed for response on subsequent treatment. Tumor testing (n = 53) and concurrent cell-free DNA (n = 32) in a subset of patients was performed using CLIA-approved assays. RESULTS: The proportion of patients with a genomic alteration was lower in tumor than in blood (69 vs. 91%; p = 0.06). After restricting analysis to alterations covered on both platforms, 83% of tumor alterations were detected in blood, while 90% of blood alterations were detected in tumor. Mutational load specific for the panel genes was calculated for both tumor and blood. Time to progression on subsequent treatment was significantly shorter for patients whose tumors had high panel-specific mutational load (HR 0.31, 95% CI 0.12-0.78) or a TP53 mutation (HR 0.35, 95% CI 0.20-0.79), after adjusting for stage at presentation, hormone receptor status, prior treatment type, and number of lines of metastatic treatment. CONCLUSIONS: Treating oncologists must distinguish platform differences from true biological heterogeneity when comparing tumor and cfDNA genomic testing results. Tumor and concurrent cfDNA contribute unique genomic information in metastatic breast cancer patients, providing potentially useful biomarkers for aggressive metastatic disease.

The intersectionality framework and identity intersections in the Journal of Counseling Psychology and The Counseling Psychologist: A content analysis.

The framework of intersectionality is a powerful analytical tool for making sense of how interlocking systems of privilege and oppression are experienced by individuals and groups. Despite the long history of the concept, intersectionality has only recently gained attention in psychology. We conducted a content analysis to assess counseling psychology's engagement with an intersectional perspective. All articles published in the Journal of Counseling Psychology (n = 4,800) and The Counseling Psychologist (n = 1,915) from their first issues until July 2016 were reviewed to identify conceptual and empirical work focused on intersectionality. A total of 40 articles were identified and examined for themes. Limitations and future directions are discussed. (PsycINFO Database Record

Comprehensive analysis of gene expression in human retina and supporting tissues.

Understanding the influence of gene expression on the molecular mechanisms underpinning human phenotypic diversity is fundamental to being able to predict health outcomes and treat disease. We have carried out whole transcriptome expression analysis on a series of eight normal human postmortem eyes by RNA sequencing. Here we present data showing that ∼80% of the transcriptome is expressed in the posterior layers of the eye and that there is significant differential expression not only between the layers of the posterior part of the eye but also between locations of a tissue layer. These differences in expression also extend to alternative splicing and splicing factors. Differentially expressed genes are enriched for genes associated with psychiatric, immune and cardiovascular disorders. Enrichment categories for gene ontology included ion transport, synaptic transmission and visual and sensory perception. Lastly, allele-specific expression was found to be significant for CFH, C3 and CFB, which are known risk genes for age-related macular degeneration. These expression differences should be useful in determining the underlying biology of associations with common diseases of the human retina, retinal pigment epithelium and choroid and in guiding the analysis of the genomic regions involved in the control of normal gene expression.

Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies.

BACKGROUND: Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. METHODS: Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1(+/+)) with tumours carrying a mutation in both alleles (RB1(-/-)). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. FINDINGS: No RB1 mutations (RB1(+/+)) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1(+/+) tumours had high-level MYCN oncogene amplification (28-121 copies; RB1(+/+)MYCN(A)), whereas none of 93 RB1(-/-) primary tumours tested showed MYCN amplification (p<0·0001). RB1(+/+)MYCN(A) tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1(-/-) tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1(+/+)MYCN(A) retinoblastoma. One additional MYCN(A) tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1(+/+)MYCN(A) tumours was 4·5 months (IQR 3·5-10), compared with 24 months (15-37) for 79 children with non-familial unilateral RB1(-/-) retinoblastoma. INTERPRETATION: Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1(+/+)MYCN(A) retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. FUNDING: National Cancer Institute-National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.

Regional replication of association with refractive error on 15q14 and 15q25 in the Age-Related Eye Disease Study cohort.

PURPOSE: Refractive error is a complex trait with multiple genetic and environmental risk factors, and is the most common cause of preventable blindness worldwide. The common nature of the trait suggests the presence of many genetic factors that individually may have modest effects. To achieve an adequate sample size to detect these common variants, large, international collaborations have formed. These consortia typically use meta-analysis to combine multiple studies from many different populations. This approach is robust to differences between populations; however, it does not compensate for the different haplotypes in each genetic background evidenced by different alleles in linkage disequilibrium with the causative variant. We used the Age-Related Eye Disease Study (AREDS) cohort to replicate published significant associations at two loci on chromosome 15 from two genome-wide association studies (GWASs). The single nucleotide polymorphisms (SNPs) that exhibited association on chromosome 15 in the original studies did not show evidence of association with refractive error in the AREDS cohort. This paper seeks to determine whether the non-replication in this AREDS sample may be due to the limited number of SNPs chosen for replication. METHODS: We selected all SNPs genotyped on the Illumina Omni2.5v1_B array or custom TaqMan assays or imputed from the GWAS data, in the region surrounding the SNPs from the Consortium for Refractive Error and Myopia study. We analyzed the SNPs for association with refractive error using standard regression methods in PLINK. The effective number of tests was calculated using the Genetic Type I Error Calculator. RESULTS: Although use of the same SNPs used in the Consortium for Refractive Error and Myopia study did not show any evidence of association with refractive error in this AREDS sample, other SNPs within the candidate regions demonstrated an association with refractive error. Significant evidence of association was found using the hyperopia categorical trait, with the most significant SNPs rs1357179 on 15q14 (p=1.69×10⁻³) and rs7164400 on 15q25 (p=8.39×10⁻4), which passed the replication thresholds. CONCLUSIONS: This study adds to the growing body of evidence that attempting to replicate the most significant SNPs found in one population may not be significant in another population due to differences in the linkage disequilibrium structure and/or allele frequency. This suggests that replication studies should include less significant SNPs in an associated region rather than only a few selected SNPs chosen by a significance threshold.

Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the Age-Related Eye Disease Study.

PURPOSE: A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted. DESIGN: Candidate gene genetic association study. PARTICIPANTS: Two thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis. METHODS: Microarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P(emp)) and multiple-test study-wise (P(multi)) significance levels were calculated empirically through permutation. MAIN OUTCOME MEASURES: Mean spherical equivalent refraction was used as a quantitative measure of ocular refraction. RESULTS: The mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 (P(emp) = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P(emp)<0.01 in the lower-education stratum of AREDS participants. CONCLUSIONS: This study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. Evidence of a gene-environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development.

Opioid Prescribing at Discharge in Opioid-Naïve Trauma Patients.

BACKGROUND: Opioid analgesics remain mainstay of treatment for trauma-related pain despite growing concerns for opioid dependency or misuse. The purpose of this study was to evaluate opioid prescribing at hospital discharge after traumatic injury. METHODS: This is a single-center, retrospective analysis of patients ≥18 years of age admitted for ≥24 hours with a primary diagnosis of traumatic injury. Those with alcohol use disorder, polysubstance abuse, chronic opioid use, or in-hospital mortality were excluded. The primary outcome was the incidence of patients prescribed opioids at discharge. Secondary outcomes included percent of patients who received nonopioids, intensive care unit (ICU) admission, and hospital length of stay (LOS). RESULTS: Of the 927 encounters, 471 were included. The mean age was 60 ± 23 years, and 62.0% were male. The majority were blunt trauma, and 49.9% were falls. Mean initial injury severity score (ISS) was 9 ± 7.2. Of the 70.4% of patients prescribed opioids, 39.4% were discharged on opioids. Age ≥30 years, ICU admission, ISS <9, or Charlson Comorbidity Index >1 was less likely to have opioids prescribed at discharge. Most received nonopioids (93.6%) and multimodal analgesia (84.3%). The median hospital and ICU LOS were 5 (3-9) and 2 (0-4) days, respectively. DISCUSSION: Only 39.4% had opioids prescribed at discharge. Opioid-reductive strategies may decrease in-hospital and discharge opioid prescribing. While opioid analgesics remain a mainstay of trauma-associated pain management, institution-wide opioid-sparing strategies can further reduce discharge opioid prescribing after trauma.

Decreased sensory responses in osteocalcin null mutant mice imply neuropeptide function.

Osteocalcin, the most abundant member of the family of extracellular mineral binding gamma-carboxyglutamic acid proteins is synthesized primarily by osteoblasts. Its affinity for calcium ions is believed to limit bone mineralization. Several of the numerous hormones that regulate synthesis of osteocalcin, including glucocorticoids and parathyroid hormone, are also affected by stressful stimuli that require energy for an appropriate response. Based on our observations of OC responding to stressful sensory stimuli, the expression of OC in mouse and rat sensory ganglia was confirmed. It was thus hypothesized that the behavioral responses of the OC knockout mouse to stressful sensory stimuli would be abnormal. To test this hypothesis, behaviors related to sensory aspects of the stress response were quantified in nine groups of mice, aged 4-14 months, comparing knockout with their wild-type counterparts in six distinctly different behavioral tests. Resulting data indicated the following statistically significant differences: open field grooming frequency following saline injection, wild-type > knockout; paw stimulation with Von Frey fibers, knockout < wild-type; balance beam, knockout mobility < WT; thermal sensitivity to heat (tail flick), knockout < wild-type; and cold, knockout < wild-type. Insignificant differences in hanging wire test indicate that these responses are unrelated to reduced muscle strength. Each of these disparate environmental stimuli provided data indicating alterations of responses in knockout mice that suggest participation of osteocalcin in transmission of information about those sensory stimuli.

Association of women leaders in the C-suite with hospital performance.

BACKGROUND: Women comprise 50% of the healthcare workforce, but only about 25% of senior leadership positions in the USA. No studies to our knowledge have investigated the performance of hospitals led by women versus those led by men to evaluate the potential explanation that the inequity reflects appropriate selection due to skill or performance differences. METHODS: We conducted a descriptive analysis of the gender composition of hospital senior leadership (C-suite) teams and cross-sectional, regression-based analyses of the relationship between gender composition, hospital characteristics (eg, location, size, ownership), and financial, clinical, safety, patient experience and innovation performance metrics using 2018 data for US adult medical/surgical hospitals with >200 beds. C-suite positions examined included chief executive officer (CEO), chief financial officer (CFO) and chief operating officer (COO). Gender was obtained from hospital web pages and LinkedIn. Hospital characteristics and performance were obtained from American Hospital Directory, American Hospital Association Annual Hospital Survey, Healthcare Cost Report Information System and Hospital Consumer Assessment of Healthcare Providers and Systems surveys. RESULTS: Of the 526 hospitals studied, 22% had a woman CEO, 26% a woman CFO and 36% a woman COO. While 55% had at least one woman in the C-suite, only 15.6% had more than one. Of the 1362 individuals who held one of the three C-suite positions, 378 were women (27%). Hospital performance on 27 of 28 measures (p>0.05) was similar between women and men-led hospitals. Hospitals with a woman CEO performed significantly better than men-led hospitals on one financial metric, days in accounts receivable (p=0.04). CONCLUSION: Hospitals with women in the C-suite have comparable performance to those without, yet inequity in the gender distribution of leaders remains. Barriers to women's advancement should be recognised and efforts made to rectify this inequity, rather than underusing an equally skilled pool of potential women leaders.

Comparative Analysis of Patients with Robotic Hiatal Hernia Repairs with and without Collis Gastroplasty.

INTRODUCTION: After extensive mediastinal dissection fails to achieve adequate intra-abdominal esophageal length, a Collis gastroplasty(CG) is recommended to decrease axial tension and reduce hiatal hernia recurrence. However, concerns exist about staple line leak, and long-term symptoms of heartburn and dysphagia due to the acid-producing neoesophagus which lacks peristaltic activity. This study aimed to assess long-term satisfaction and GERD-related quality of life after robotic fundoplication with CG (wedge fundectomy technique) and to compare outcomes to patients who underwent fundoplication without CG. Outcomes studied included patient satisfaction, resumption of proton pump inhibitors (PPI), length of surgery (LOS), hospital stay, and reintervention. METHODS: This was a single-center retrospective analysis of patients from January 2017 through December 2018 undergoing elective robotic hiatal hernia repair and fundoplication. 61 patients were contacted for follow-up, of which 20 responded. Of those 20 patients, 7 had a CG performed during surgery while 13 did not. There was no significant difference in size and type of hiatal hernias in the 2 groups. These patients agreed to give their feedback via a GERD health-related quality of life (GERD HRQL) questionnaire. Their medical records were reviewed for LOS, length of hospital stay (LOH), and reintervention needed. Statistical analysis was performed using SPSS v 25. Satisfaction and need for PPIs were compared between the treatment and control groups using the chi-square test of independence. RESULTS: Statistical analysis showed that satisfaction with outcome and PPI resumption was not significantly different between both groups (P > .05). There was a significant difference in the average ranks between the 2 groups for the question on postoperative dysphagia on the follow-up GERD HRQL questionnaire, with the group with CG reporting no dysphagia. There were no significant differences in the average ranks between the 2 groups for the remaining 15 questions (P > .05). The median LOS was longer in patients who had a CG compared to patients who did not (250 vs. 148 min) (P = .01). The LOH stay was not significantly different (P > .05) with a median length of stay of 2 days observed in both groups. There were no leaks in the Collis group and no reoperations, conversions, or blood transfusions needed in either group. CONCLUSION: Collis gastroplasty is a safe option to utilize for short esophagus noted despite extensive mediastinal mobilization and does not adversely affect the LOH stay, need for reoperation, or patient long-term satisfaction.

Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

PSMA-targeting TGFß-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-ß. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-ß receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-ß-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

Pseudoaneurysm of the Abdominal Aorta at the Celiac Trunk After Penetrating Trauma.

We report the case of a 33-year-old man who had received multiple gunshot wounds to the abdomen; consequently, he was diagnosed with a traumatic dissection of the abdominal aorta at the level of the superior mesenteric artery (SMA) extending to just below the renal arteries with a posterior pseudoaneurysm of the aorta. He had wounds in the right upper quadrant and in the left lower back. He demonstrated signs of peritonitis for which he was taken to the operating room for exploratory laparotomy. A right common iliac to SMA bypass with a 7-mm ringed polytetrafluoroethylene (PTFE) graft was created. The celiac trunk was then ligated, and through the right groin sheath, a thoracic endograft stent (Cook Medical, Bloomington, IN) was inserted at the level of the thoracic aorta with resolution of the blood flow to the aorta, visceral and iliac arteries, as well as retrograde flow into the bypass graft. The literature on traumatic abdominal aortic pseudoaneurysm was reviewed, and based on that, we believe this report describes a unique case of a traumatic aortic pseudoaneurysm at the level of the celiac trunk, as well as our operative approach.