Faculty Bibliography

Background Solid tumors comprise >90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively). 1Chimeric antigen receptor (CAR) T-cell therapy demonstrated clinical outcomes in hematologic malignancies.2 3 However, translating engineered T-cell therapies to solid tumors proves difficult due to a lack of tumor-specific targets that discriminate cancer cells from normal cells. In previous studies, the use of a carcinoembryonic antigen T-cell receptors and mesothelin CARs both resulted in dose-limiting on-target, off-tumor toxicities.4 5 TmodTM CAR T-cell therapy addresses these challenges by leveraging dual receptors to create a robust AND NOT signal integrator capable of killing tumor cells, while leaving healthy cells intact (figure 1).6 Tmod platform technology is a versatile system that may be applied to T cells and natural killer cells in autologous and allogeneic settings. HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy.6 7 The 2 receptors comprise an activator that recognizes an antigen present on the surface of normal and tumor cells and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. HLA LOH has been observed in ~13% across all solid tumors and up to 33% of pancreatic cancers.8 New technologies have shown higher HLA LOH rates; however, it is unclear whether patients with HLA LOH in their primary tumor tissues are at higher risk for recurrence. BASECAMP-1 is an observational study with key objectives: 1) To determine and identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) Subsequent leukapheresis and manufacturing feasibility for future Tmod CAR T-cell trials. Methods BASECAMP-1 (NCT04981119) patient eligibility has 2 parts (figure 2): 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central nextgeneration sequencing (NGS). If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed by xT-Onco NGS testing9 to determine if somatic tumor HLAA* 02 LOH is present; 2) If the tumor demonstrates HLAA* 02 LOH and the patient screens eligible, the patient will undergo leukapheresis. Patients enrolled in the study who undergo leukapheresis will be evaluated for safety 7 days post-leukapheresis and followed for relapsed status. Banked T cells will be available for subsequent autologous Tmod CAR T-cell therapy at the time of relapse

Primary vaginal cancer is rare, comprising 1% to 2% of gynecologic malignancies and 20% of all malignancies involving the vagina. More frequently, the vagina is involved secondarily by direct invasion from malignancies originating in adjacent organs or by metastases from other pelvic or extrapelvic primary malignancies. Data on the use of imaging in vaginal cancer are sparse. Insights are derived from the study of imaging in cervical cancer and have reasonable generalizability to vaginal cancer due to similar tumor biology. Given the trend toward definitive chemoradiation for both cancers in all but early stage lesions, principles of postchemoradiation tumor response evaluation are largely analogous. Accordingly, many of the recommendations outlined here are informed by principles translated from the literature on cervical cancer. For pretreatment assessment of local tumor burden and in the case of recurrent vaginal cancer, MRI is the preferred imaging modality. PET/CT has demonstrated utility for the detection of nodal metastatic and unexpected distant metastatic disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

BACKGROUND:Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. OBJECTIVE:We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. METHODS: RESULTS: DISCUSSION/CONCLUSIONS:Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178.

Introduction: Tracheostomy in COVID-19 patients is a controversial and difficult clinical decision. A recent COVID-19 Severity Score (CSS) was validated to identify high-risk patients requiring hospitalization. We hypothesized that the CSS would be associated with survival in patients considered for tracheostomy.
Method(s): We reviewed 77 mechanically ventilated COVID-19 patients evaluated for percutaneous dilational tracheostomy (PDT) from March-June 2020 at a public tertiary care center. Decision for PDT was based on clinical judgment of the screening surgeons. The CSS was retrospectively calculated using mean biomarker values from admission to time of PDT consult. Primary end point was survival to discharge. The Youden index identified an optimal CSS cut point for survival.
Result(s): Mean CSS for 42 survivors vs 35 nonsurvivors was significantly different (CSS 52 vs 66; p = 0.003). The Youden index returned an optimal CSS of 55 (area under the curve 0.7; 95% CI, 43 to 72). Median CSS was 40 (interquartile range 27 to 49) in the Low CSS (<55 group) and 72 (interquartile range 66 to 93) in the high CSS (>= 55) group (Fig. 1a). Eighty-seven percent of low CSS patients underwent PDT, with 74% survival, and 61% of high CSS patients underwent PDT with only 41% surviving (Fig. 1b). Patients with high CSS had 77% lower odds of survival (odds ratio 0.2; 95% CI, 0.1 to 0.7).
Conclusion(s): Higher CSS was associated with decreased survival to discharge in patients evaluated for PDT, with a score > 55 predictive of mortality. The novel CSS can be a useful adjunct in determining which COVID-19 patients will benefit from tracheostomy. Further prospective validation of this tool is warranted. [Formula presented]
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BACKGROUND AND AIMS:The ankle-brachial index (ABI) is a diagnostic test for screening and detecting peripheral artery disease (PAD), as well as a risk enhancer in the AHA/ACC guidelines on the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, our understanding of the association between ABI and cardiovascular risk in contemporary older populations is limited. Additionally, the prognostic value of ABI among individuals with prior ASCVD is not well understood. METHODS:Among 5,003 older adults at ARIC visit 5 (2011-2013) (4,160 without prior ASCVD [median age 74 years, 38% male], and 843 with ASCVD [median age 76 years, 65% male]), we quantified the association between ABI and the risk of heart failure (HF), and composite coronary heart disease and stroke (CHD/stroke) using multivariable Cox regression models. RESULTS:Over a median follow-up of 5.5 years, we observed 400 CHD/stroke events and 338 HF cases (242 and 199 cases in those without prior ASCVD, respectively). In participants without a history of ASCVD, a low ABI ≤0.9 (relative to ABI 1.11-1.20) was associated with both CHD/stroke and HF (adjusted hazard ratios 2.40 [95% CI: 1.55-3.71] and 2.23 [1.40-3.56], respectively). In those with prior ASCVD, low ABI was not significantly associated with CHD/stroke, but was with HF (7.12 [2.47-20.50]). The ABI categories of 0.9-1.2 and > 1.3 were also independently associated with increased HF risk. Beyond traditional risk factors, ABI significantly improved the risk discrimination of CHD/stroke in those without ASCVD and HF, regardless of baseline ASCVD. CONCLUSIONS:Low ABI was associated with CHD/stroke in those without prior ASCVD and higher risk of HF regardless of baseline ASCVD status. These results support ABI as a risk enhancer for guiding primary cardiovascular prevention and suggest its potential value in HF risk assessment for older adults.

BACKGROUND:Child appetite traits (ATs) are associated with later child weight and obesity risk. Less research has focused on ATs in low-income Hispanic children or included longitudinal associations with infant weight. OBJECTIVE:To determine stability of ATs during infancy and childhood and their relationship with subsequent weight and obesity risk at age 3 years among low-income Hispanic children. DESIGN/METHODS:A secondary longitudinal analysis of data from the Starting Early Program randomized controlled obesity prevention trial. PARTICIPANTS/SETTING/METHODS:Three hundred twenty-two low-income, Hispanic mother-child pairs enrolled between 2012 and 2014 in a public hospital in New York City. MAIN OUTCOME MEASURES/METHODS:ATs, including Slowness in Eating, Satiety Responsiveness, Food Responsiveness, and Enjoyment of Food were assessed using the Baby and Child Eating Behavior Questionnaires at ages 3 months, 2 years, and 3 years. Main outcome measures were child standardized weight-for-age z score (WFAz) and obesity risk (WFA≥95th percentile) at age 3 years. STATISTICAL ANALYSES PERFORMED/METHODS:AT stability was assessed using correlations and multilevel modeling. Linear and logistic regression analyses examined associations between ATs and child WFAz and obesity risk at age 3 years. RESULTS:There was limited stability for all ATs measured over time. During infancy, Slowness in Eating was associated with lower 3-year WFAz (B = -0.18, 95% CI -0.33 to -0.04; P = 0.01). At age 2 years, Slowness in Eating and Satiety Responsiveness were associated with lower WFAz (B = -0.29, 95% CI -0.47 to -0.12; P < 0.01; B = -0.36, 95% CI -0.55 to -0.17; P < 0.01) and obesity risk (adjusted odds ratio 0.49, 95% CI 0.28 to 0.85; adjusted odds ratio 0.61, 95% CI 0.38 to 0.99) at 3 years. Increased Slowness in Eating and Satiety Responsiveness over time were associated with lower 3-year WFAz (B = -0.74, 95% CI -1.18 to -0.2 [Slowness in Eating]; B = -1.19, 95% CI -1.87 to -0.52 [Satiety Responsiveness], both P values = 0.001). Higher Enjoyment of Food over time was associated with higher 3-year WFAz (B = 0.62, 95% CI 0.24 to 1.01; P = 0.002). CONCLUSIONS:Infants with lower Slowness in Eating and Satiety Responsiveness may have higher levels of obesity risk and need more tailored approaches to nutrition counseling and obesity prevention.

The present study investigated associations between prenatal mother-father cortisol linkage and infant executive functions. Data come from an international sample (N = 358) of predominantly white and middle- to upper-class first-time parents. During late pregnancy, parents collected diurnal salivary cortisol samples and reported on levels of psychological stress. At 24 months, children completed a battery of executive function tasks. Parent cortisol linkage was operationalized as the time-dependent, within-dyad association between maternal and paternal diurnal cortisol. Results indicated that prenatal linkage was positively related to infant executive functions, suggesting that stronger mother-father cortisol linkage was associated with higher executive function scores. Additionally, this relation was moderated by paternal average cortisol levels such that executive function scores were lower when fathers had higher average cortisol levels and linkage was weak. This association suggests that elevated paternal cortisol amplifies the negative relation between lower cortisol linkage and lower infant executive function scores. Importantly, these findings were observed while controlling for observational measures of caregiving and self-report measures of psychosocial functioning and infant social-emotional behavior. These results suggest that prenatal linkage of mother's and father's stress physiology plays a potentially important part in programming and regulating infant neurocognitive development.