The Multi-institutional Medullary Thyroid Cancer Collaborative Registry (MTCCoRe): Can a rare tumor registry accurately represent the real-world patient population?

BACKGROUND: Large population-based registries, such as the Surveillance, Epidemiology and End Results (SEER) Registry help in the study of rare tumors, including medullary thyroid cancer (MTC), but lack data to understand the natural history of the disease. The Medullary Thyroid Cancer Collaborative Registry (MTCCoRe) is an exhaustive multi-institutional collection of demographic, clinical, and pathologic data. To determine the extent to which MTCCoRe represents the real-world MTC population, we compared characteristics of patients enrolled in MTCCoRe with patients enrolled in population-based cancer registries. METHODS: Comparison of demographic and clinical characteristics of MTC patients who were enrolled in MTCCoRe, Texas Cancer Registry (TCR), California Cancer Registry (CCR), and SEER between 1995-2018. RESULTS: 1,416 patients were identified in MTCCoRe, 329 in TCR, 2,105 in CCR, and 3,820 in SEER. Percentages of patients 20-54 years in MTCCoRe were 58.0%, 50.2% in TCR, 47.2% in CCR, and 44.8% in SEER (p < 0.0001). About half of the patients were female (55.9% in MTCCoRe, 61.4% in TCR, 59% in CCR, and 57.5% in SEER (p=0.3). Percentages of Hispanic and Black patients differed among cohorts (10.1% and 3.8% for MTCCoRe, 23.7% and 8.2% for TCR, 24.8% and 4.9% in CCR, and 15.9% and 8.2% for SEER, respectively; p<0.001). MTCCoRe patients presented with more advanced T and N classifications than patients in the other registries (MTCCoRe, 28.6% T3-4 and 49.4% N1; TCR, 12.7% and 32.2%; CCR, 18.6% and 32.4%; and SEER, 24% and 37.8%; p < 0.0001). Prevalence of M1 disease was 10% in MTCCoRe, 11.9% in TCR, 14.1% in CCR, and 9.5% in SEER (p < 0.0001). In the MTCCoRe, 11.4% underwent systemic therapy (compared to 0.3% in TCR, 5.6% in CCR). CONCLUSIONS: The clinico-demographic profile of patients with MTC enrolled in a multi-institutional registry differs from those enrolled in population-based databases, with lower proportions of Hispanic and Black patients but additive data on treatment modalities. Moving forward, MTCCoRe and other registry and clinical trial enrollment efforts should intentionally include underrepresented groups via community engagement techniques, patient stakeholder involvement, and inclusion of languages other than English in study materials to yield more generalizable results and conclusions.

Translational and oncologic significance of tertiary lymphoid structures in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with poor survival and limited treatment options. PDAC resistance to immunotherapeutic strategies is multifactorial, but partially owed to an immunosuppressive tumor immune microenvironment (TiME). However, the PDAC TiME is heterogeneous and harbors favorable tumor-infiltrating lymphocyte (TIL) populations. Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop within non-lymphoid tissue under chronic inflammation in multiple contexts, including cancers. Our current understanding of their role within the PDAC TiME remains limited; TLS are complex structures with multiple anatomic features such as location, density, and maturity that may impact clinical outcomes such as survival and therapy response in PDAC. Similarly, our understanding of methods to manipulate TLS is an actively developing field of research. TLS may function as anti-tumoral immune niches that can be leveraged as a therapeutic strategy to potentiate both existing chemotherapeutic regimens and potentiate future immune-based therapeutic strategies to improve patient outcomes. This review seeks to cover anatomy, relevant features, immune effects, translational significance, and future directions of understanding TLS within the context of PDAC.

A Unique Patient Presentation of Disseminated Strongyloidiasis: Unraveling the Clinical Complexity of an Immunocompromised Patient.

Strongyloidiasis is a rare parasitic disease that can remain dormant and asymptomatic in many individuals. However, in cases of immunosuppression, the motility rate of the Strongyloides parasite increases significantly. This case study presents a unique clinical scenario involving an 88-year-old Hispanic male with a disseminated Strongyloidesinfection. The patient's medical history includes coronary artery disease, a history of percutaneous coronary intervention, heart failure with reduced ejection fraction and subsequent recovery of left ventricular function, hypertension, dyslipidemia, mantle cell lymphoma being treated with rituximab every two months since 2019, and chronic anemia. This case emphasizes the importance for physicians to consider strongyloidiasis when faced with a diverse range of symptoms, including syndrome of inappropriate antidiuretic hormone secretion (SIADH), rash, gastrointestinal upset, urinary retention, chronic anemia, and chronic eosinophilia, as these manifestations may share a common origin.

U.S. mothers' appraisals of the race-related events of 2020: Implications for the course of maternal posttraumatic stress disorder symptoms.

For parents of color, publicized racial violence can heighten concerns about their children's safety. The goal of this study was to test whether this form of race-related stress exacerbates maternal posttraumatic stress disorder (PTSD) symptoms over a 4-month period in families of color. Participants included 262 U.S. mothers with a lifetime mental health diagnosis (67.6% non-Hispanic White, 15.6% African-American/Black, 16.8% other family of color). Mothers completed online surveys and open-ended questions, including appraisals of the meaning of the 2020 race-related events (i.e., George Floyd's death, subsequent protests) in relation to their children's future. Open-ended responses were quantified using LIWC15 text analysis for emotion word frequency and thematic coding for perceived implications. In ANCOVA, there were significant racial group differences in appraisals, ds = 0.09-0.57. The responses from mothers of Black children included fewer positive and more negative emotion words than mothers of White children; they also included more perceived negative implications than all other mothers but did not vary on perceived positive implications. In regression analyses, there were significant moderating effects of race/ethnicity in the association between appraisals and PTSD symptom course such that negative appraisals predicted a subsequent increase in PTSD symptoms only for mothers of Black children, ßs = .26-.37. Variations in event appraisals were unrelated to PTSD symptom course for other mothers. These findings provide longitudinal support for the link between vicarious racism exposure and PTSD symptoms and highlight one potential form of racism-related stress for parents of Black children.

Neuropsychological and Neuroanatomical Features of Patients with Behavioral/Dysexecutive Variant Alzheimer's Disease (AD): A Comparison to Behavioral Variant Frontotemporal Dementia and Amnestic AD Groups.

BACKGROUND: An understudied variant of Alzheimer's disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. OBJECTIVE: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. METHODS: Subjects included 16 bvAD, 67 bvFTD, 18 aAD patients, and 26 healthy controls. Neuropsychological assessment and MRI data were compared between these groups. RESULTS: Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. CONCLUSION: Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

Understanding Children's Emotions: Differences in Mothers With a History of Childhood Maltreatment.

Experiencing maltreatment in childhood can have a lasting impact on how individuals identify and understand emotions in others. Research in this area has not examined parents' understanding of children's emotions, although emotion processing deficits may be one mechanism linking childhood maltreatment to subsequent parenting problems. In a matched case-control design, we test whether mothers with (n = 50) and without (n = 96) childhood maltreatment differ in their understanding of children's emotions on self-report measures and computer-based tasks. Compared to the control group, mothers who experienced maltreatment labeled more children with sad or angry emotions when given limited facial information and made different interpersonal inferences about children they labeled angry. They also reported more subjective difficulty interpreting emotions in unknown children and their own child. Results provide further evidence of emotion processing biases associated with childhood maltreatment. Interventions aimed at improving parental emotion understanding and mentalization may be particularly useful for mothers with a history of childhood maltreatment.

Admission Lymphopenia Predicts Infectious Complications and Mortality in Traumatic Brain Injury Victims.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of mortality and disability associated with increased risk of secondary infections. Identifying a readily available biomarker may help direct TBI patient care. Herein, we evaluated whether admission lymphopenia could predict outcomes of TBI patients. METHODS: This is a 10-year retrospective review of TBI patients with a head Abbreviated Injury Score 2 to 6 and absolute lymphocyte counts (ALC) collected within 24 h of admission. Exclusion criteria were death within 24 h of admission and presence of bowel perforation on admission. Demographics, admission data, injury severity score, mechanism of injury, and outcomes were collected. Association between baseline variables and outcomes was analyzed. RESULTS: We included 2,570 patients; 946 (36.8%) presented an ALC ≤1,000 on admission (lymphopenic group). Lymphopenic patients were significantly older, less likely to smoke, and more likely to have heart failure, hypertension, or chronic kidney disease. Lymphopenia was associated with increased risks of mortality (OR = 1.903 [1.389-2.608]; P < 0.001) and pneumonia (OR = 1.510 [1.081-2.111]; P = 0.016), increased LOS (OR = 1.337 [1.217-1.469]; P < 0.001), and likelihood of requiring additional healthcare resources at discharge (OR = 1.669 [1.344-2.073], P < 0.001). Additionally, lymphopenia increased the risk of early in-hospital death (OR = 1.459 [1.097-1.941]; P = 0.009). Subgroup analysis showed that lymphopenia was associated with mortality in polytrauma patients and those who presented with two or more concurrent types of TBI. In all subgroup analyses, lymphopenia was associated with longer length of stay and discharge requiring higher level of care. CONCLUSION: A routine complete blood count with differential for all TBI patients may help predict patient outcomes and direct care accordingly.

Modeling the Effects of Hemodynamic Stress on Circulating Tumor Cells using a Syringe and Needle.

During metastasis, cancer cells from solid tissues, including epithelia, gain access to the lymphatic and hematogenous circulation where they are exposed to mechanical stress due to hemodynamic flow. One of these stresses that circulating tumor cells (CTCs) experience is fluid shear stress (FSS). While cancer cells may experience low levels of FSS within the tumor due to interstitial flow, CTCs are exposed, without extracellular matrix attachment, to much greater levels of FSS. Physiologically, FSS ranges over 3-4 orders of magnitude, with low levels present in lymphatics (<1 dyne/cm2) and the highest levels present briefly as cells pass through the heart and around heart valves (>500 dynes/cm2). There are a few in vitro models designed to model different ranges of physiological shear stress over various time frames. This paper describes a model to investigate the consequences of brief (millisecond) pulses of high-level FSS on cancer cell biology using a simple syringe and needle system.

Body surveillance as a prospective risk factor for depressive symptoms in low-income adolescent girls from the United States.

Adolescent girls who engage in frequent self-objectification often report a greater number of depressive symptoms. Although concurrent associations between self-objectification and depression are well-documented, it is less clear if objectification contributes to the course of symptoms. The current study examined: (a) whether body surveillance is prospectively related to depressive symptoms over a 1-month period in a sample of 150 low-income adolescent girls in the United States, and; (b) whether receiving certain types of weight-relevant information (i.e., learning one's weight is much higher than estimated) moderates this association. Heightened body surveillance at baseline predicted greater symptom severity one month later, but the strength of this relationship depended on what type of weight information girls received. Among girls high in body surveillance, those who found out their actual weight was much higher than they estimated subsequently reported more severe depressive symptoms; those who learned their actual weight was consistent or lower than they estimated reported fewer depressive symptoms. For girls low in body surveillance, weight-relevant information was not significantly related to the subsequent severity of depressive symptoms. Findings highlight the potential utility of assessing and addressing heightened body surveillance in depression interventions for adolescent girls.

Cancer Cells Resist Mechanical Destruction in Circulation via RhoA/Actomyosin-Dependent Mechano-Adaptation.

During metastasis, cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level FSS in vitro relative to non-transformed epithelial cells. Herein, we identify a mechano-adaptive mechanism of FSS resistance in cancer cells. Our findings demonstrate that cancer cells activate RhoA in response to FSS, which protects them from FSS-induced plasma membrane damage. We show that cancer cells freshly isolated from mouse and human tumors are resistant to FSS, that formin and myosin II activity protects circulating tumor cells (CTCs) from destruction, and that short-term inhibition of myosin II delays metastasis in mouse models. Collectively, our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.

Persistent and Progressive Outer Retina Thinning in Frontotemporal Degeneration.

OBJECTIVE: While Alzheimer's disease is associated with inner retina thinning measured by spectral-domain optical coherence tomography (SD-OCT), our previous cross-sectional study suggested outer retina thinning in frontotemporal degeneration (FTD) patients compared to controls without neurodegenerative disease; we sought to evaluate longitudinal changes of this potential biomarker. METHODS: SD-OCT retinal layer thicknesses were measured at baseline and after 1-2 years. Clinical criteria, genetic analysis, and a cerebrospinal fluid biomarker (total tau: ß-amyloid) to exclude likely underlying Alzheimer's disease pathology were used to define a subgroup of predicted molecular pathology (i.e., tauopathy). Retinal layer thicknesses and rates of change in all FTD patients (n = 16 patients, 30 eyes) and the tauopathy subgroup (n = 9 patients,16 eyes) were compared to controls (n = 30 controls, 47 eyes) using a generalized linear model accounting for inter-eye correlation and adjusting for age, sex, and race. Correlations between retinal layer thicknesses and Mini-Mental State Examinations (MMSE) were assessed. RESULTS: Compared to controls, returning FTD patients (143 vs. 130 µm, p = 0.005) and the tauopathy subgroup (143 vs. 128 µm, p = 0.03) had thinner outer retinas but similar inner layer thicknesses. Compared to controls, the outer retina thinning rate was not significant for all FTD patients (p = 0.34), but was significant for the tauopathy subgroup (-3.9 vs. 0.4 µm/year, p = 0.03). Outer retina thickness change correlated with MMSE change in FTD patients (Spearman rho = 0.60, p = 0.02) and the tauopathy subgroup (rho = 0.73, p = 0.04). CONCLUSION: Our finding of FTD outer retina thinning persists and longitudinally correlates with disease progression. These findings were especially seen in probable tauopathy patients, which showed progressive outer retina thinning.

Longitudinal decline in speech production in Parkinson's disease spectrum disorders.

We examined narrative speech production longitudinally in non-demented (n=15) and mildly demented (n=8) patients with Parkinson's disease spectrum disorder (PDSD), and we related increasing impairment to structural brain changes in specific language and motor regions. Patients provided semi-structured speech samples, describing a standardized picture at two time points (mean±SD interval=38±24months). The recorded speech samples were analyzed for fluency, grammar, and informativeness. PDSD patients with dementia exhibited significant decline in their speech, unrelated to changes in overall cognitive or motor functioning. Regression analysis in a subset of patients with MRI scans (n=11) revealed that impaired language performance at Time 2 was associated with reduced gray matter (GM) volume at Time 1 in regions of interest important for language functioning but not with reduced GM volume in motor brain areas. These results dissociate language and motor systems and highlight the importance of non-motor brain regions for declining language in PDSD.

Arg188 drives RhoC membrane binding.

RhoA and RhoC GTPases are 92% identical but demonstrate unique regulation and function. Phosphorylation of Ser188 has widely been reported to inhibit RhoA activity. RhoC possesses Arg188 in place of Ser188 but retains a canonical upstream PKA recognition sequence. We report here that RhoC-R188S was a PKA substrate in vitro and exhibited less GTP loading compared to wild-type RhoC when expressed in cells. Transiently expressed RhoC was found to be significantly more membrane associated than RhoA. Membrane association of RhoC-R188S and RhoC-R188A were similar to each other and wild-type RhoA, suggesting that Arg188 directly promotes RhoC membrane binding. The positive influence of Arg188 on RhoC membrane association was evident in a constitutively active (Q63L) background. In accordance, RhoA-S188R was significantly more membrane associated than either RhoA or RhoA-S188A. Altogether, these data suggest that swapping residue 188 identity effectively flips the membrane binding profile of wild-type RhoA and RhoC through positive arginine contribution rather than negative phosphoserine regulation.