Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

Novel Surface Topographic Assessment of Lung Volume and Pulmonary Function Tests in Idiopathic Scoliosis: A Preliminary Study.

OBJECTIVE: Severe spinal deformity results in restrictive pulmonary disease from thoracic distortions and lung-volume limitations. Though spirometry and body plethysmography are widely accepted tests for pulmonary function tests (PFTs), they are time-consuming and require patient compliance. This study investigates whether surface topographic [surface topography (ST)] measurements of body volume difference (BVD) and torso volume difference between maximum inhale and exhale correlate to values determined on PFTs. METHODS: This study included patients with idiopathic scoliosis and thoracic/thoracolumbar curves ≥40 degrees. Patients received ST scans, clinical examinations, and EOS biplanar radiographs on the same day. PFTs were performed within 3 months of ST/radiographic analysis. Univariate linear regression analysis was used to examine relationships between BVD, PFT values, and mean curves. RESULTS: Sixteen patients (14.6 ± 2.2 y, 69% females) with idiopathic scoliosis and mean thoracic/thoracolumbar curves of 62 degrees ± 15˚ degrees (45 degrees to 93 degrees) were assessed. BVD displayed statistically high-positive positive correlations with forced vital capacity (R= 0.863, P< 0.0001), forced expiratory volume in 1 second (R= 0.870, P< 0.001), vital capacity (R= 0.802, P< 0.0001), and TLC (R= 0.831, P< 0.0001. Torso volume difference showed similarly high positive correlations to forced vital capacity, forced expiratory volume in 1 second, vital capacity, and TLC, but not residual volume. No correlations emerged between the mean thoracic/thoracolumbar curve and BVD or PFT values. CONCLUSION: This study strongly endorses further investigation into ST scanning as an alternative to traditional PFTs for assessing pulmonary volumes. The noncontact and noninvasive nature of ST scanning presents a valuable alternative method for analyzing thoracic volume, particularly beneficial for patients unable to cooperate with standard PFTs. LEVEL OF EVIDENCE: Level II-prognostic.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Side scatter ratio of the CD105-positive and CD105-negative red blood cell fractions is useful for the detection of low-grade myelodysplastic neoplasms by flow cytometry.

OBJECTIVES: We assessed the utility of red blood cell (RBC) CD105 and side scatter (SSC) parameters by flow cytometry for the detection of low-grade myelodysplastic neoplasms (MDS) in bone marrow specimens. METHODS: Ten RBC parameters incorporating CD105 or SSC combined with the Meyerson-Alayed scoring system (MASS) metrics were retrospectively evaluated by flow cytometry for utility in detecting low-grade MDS (n = 56) compared with cytopenic controls (n = 86). RESULTS: Myelodysplastic neoplasms were associated with 7 of the RBC parameters in univariate analysis. Multivariate analysis using cutoff values based on optimal and 95% specificity levels of the RBC metrics and the MASS parameters revealed the SSC ratio of CD105-positive and CD105-negative RBC fractions (CD105+/- SSC); the percentage and coefficient of variation of the CD105-positive fraction of RBCs (CD105%, CD105+CV) emerged as significant RBC variables. Two simple scoring schemes using these RBC values along with MASS parameters were identified: 1 using CD105+/- SSC, CD105%, and CD105+CV combined with the percentage of CD177-positive granulocytes (CD177%), myeloblast percentage (CD34%), and granulocyte SSC (GranSSC), and the other incorporating CD105+/- SSC, CD105+CV, CD177%, CD34%, GranSSC, and B-cell progenitor percentage. Both demonstrated a sensitivity of approximately 80%, with a specificity of roughly 90% for the detection of MDS compared with cytopenic controls. CONCLUSIONS: The red blood cell parameter, CD105+/- SSC, appears to be beneficial in the evaluation of low-grade MDS by flow cytometry.

Impact of the New Heart Allocation System on the Medium-Term Outcomes in Patients With Hypertrophic Cardiomyopathy.

The introduction of the new heart allocation system in the United States in 2018 resulted in an increase in the number of heart transplants (HT) performed among patients with hypertrophic cardiomyopathy (HCM). However, whether that affected medium-term post-HT outcomes in this group of patients remains unknown. We conducted an analysis of the United Network for Organ Sharing Transplant Database, including adults with HCM who underwent heart transplantation between 2015 and 2021. Patients were divided into two equal-duration eras: Era 1 (October 17, 2015, to October 17, 2018) and Era 2 (October 18, 2018, to October 18, 2021). In the studied period, 444 patients with HCM underwent HT: 204 in Era 1 and 240 in Era 2. In Era 2, the waitlist time was shorter, transplant rates were higher, patients were less frequently supported with inotropes but more often with an IABP, ischemic time was longer, and donor-to-recipient distance larger. Pre- and post-transplant functional status was comparable across the two eras, while the pre-HT employment rate was higher in the new system. The 3 year survival was unchanged across eras. In the new allocation system, despite more frequent mechanical circulatory support (MCS) use and increased ischemic time, the medium-term outcomes of patients with HCM remained favorable.

Co-Morbidities of Irritable Bowel Syndrome in a Racially and Ethnically Diverse Population.

Introduction: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI), and associated co-morbidities worsen quality of life. Research concerning IBS co-morbidities in different racial/ethnic groups is very sparse. This study aimed to determine the prevalence rates of co-morbidities and possible differences in a multiracial/ethnic IBS cohort. Methods: Based on ICD-9-coded IBS diagnosis, 740 outpatients (≥18 years) were included in this retrospective study at Boston Medical Center. Demographics and ICD-9-coded co-morbidities were extracted from electronic records. Descriptive statistics and multiple logistic regression were used for data analyses. Results: The most prevalent co-morbidities in this IBS cohort included gastroesophageal reflux disorder (GERD) (30%), depression (27%), anxiety (23%), (chronic obstructive pulmonary disease) COPD/asthma (16%), and obesity (10%). GERD was more prevalent in Hispanics and Blacks (p = 0.0005), and non-ulcer dyspepsia (NUD) was more prevalent in Blacks and Asians (p = 0.003). Higher rates of diabetes mellitus type 2 (DMT2) (p = 0.0003) and depression (p = 0.03), but not anxiety (p = 0.9), were present in Blacks and Hispanics. GERD was significantly associated with Hispanics (p = 0.003), dependent on age, overweight, and obesity. NUD was significantly associated with Blacks (p = 0.01) and Asians (p = 0.006), independent of sex, age, and BMI. Cancer of the thyroid, ovaries, and testis occurred at a five-fold higher rate than expected. Conclusions: Significant racial/ethnic differences exist for IBS co-morbidities in this study cohort, including depression, DMT2, GERD, and NUD. Certain cancers were found to be more frequent in this IBS sample as compared with the general population.

Association of multiple metabolic and cardiovascular markers with the risk of cognitive decline and mortality in adults with Alzheimer's disease and AD-related dementia or cognitive decline: a prospective cohort study.

Background and objectives: There is a scarcity of data stemming from large-scale epidemiological longitudinal studies focusing on potentially preventable and controllable risk factors for Alzheimer's disease (AD) and AD-related dementia (ADRD). This study aimed to examine the effect of multiple metabolic factors and cardiovascular disorders on the risk of cognitive decline and AD/ADRD. Methods: We analyzed a cohort of 6,440 participants aged 45-84 years at baseline. Multiple metabolic and cardiovascular disorder factors included the five components of the metabolic syndrome [waist circumference, high blood pressure (HBP), elevated glucose and triglyceride (TG) concentrations, and reduced high-density lipoprotein cholesterol (HDL-C) concentrations], C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), factor VIII, D-dimer, and homocysteine concentrations, carotid intimal-medial thickness (CIMT), and urine albumin-to-creatinine ratio (ACR). Cognitive decline was defined using the Cognitive Abilities Screening Instrument (CASI) score, and AD/ADRD cases were classified using clinical diagnoses. Results: Over an average follow-up period of 13 years, HBP and elevated glucose, CRP, homocysteine, IL-6, and ACR concentrations were significantly associated with the risk of mortality in the individuals with incident AD/ADRD or cognitive decline. Elevated D-dimer and homocysteine concentrations, as well as elevated ACR were significantly associated with incident AD/ADRD. Elevated homocysteine and ACR were significantly associated with cognitive decline. A dose-response association was observed, indicating that an increased number of exposures to multiple risk factors corresponded to a higher risk of mortality in individuals with cognitive decline or with AD/ADRD. Conclusion: Findings from our study reaffirm the significance of preventable and controllable factors, including HBP, hyperglycemia, elevated CRP, D-dimer, and homocysteine concentrations, as well as, ACR, as potential risk factors for cognitive decline and AD/ADRD.

mTOR Inhibition Prolongs Survival and Has Beneficial Effects on Heart Function After Onset of Lamin A/C Gene Mutation Cardiomyopathy in Mice.

BACKGROUND: Mutations in LMNA encoding nuclear envelope proteins lamin A/C cause dilated cardiomyopathy. Activation of the AKT/mTOR (RAC-α serine/threonine-protein kinase/mammalian target of rapamycin) pathway is implicated as a potential pathophysiologic mechanism. The aim of this study was to assess whether pharmacological inhibition of mTOR signaling has beneficial effects on heart function and prolongs survival in a mouse model of the disease, after onset of heart failure. METHODS: We treated male LmnaH222P/H222P mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival. RESULTS: Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% (P=0.018) reduction in left ventricular end-diastolic diameter and a 39% (P=0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in LmnaH222P/H222P mice, by 9% (P=0.0348) and 11% (P=0.0206), respectively, compared with placebo (n=20). CONCLUSIONS: These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by LMNA mutations and that further study is warranted.

Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.52, P = 0.02), Mini-Mental State Examination score (ß = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (ß = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (ß = -0.0007, P < 0.01) and Mini-Mental State Examination score (ß = -0.02, P < 0.01) and increased Trail Making Test B completion time (ß = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Geriatric chronic recurrent multifocal osteomyelitis (CRMO) mimicking multifocal multiple myeloma: a first in an octogenarian.

Chronic recurrent multifocal osteomyelitis (CRMO), an autoinflammatory bone disorder characterized by non-bacterial osteomyelitis causing recurrent multifocal bone lesions, is a well-known, yet uncommon pediatric condition that rarely affects adults; to date, it has never been diagnosed over the age of 75. The following report will discuss the first octogenarian diagnosed with CRMO and therefore represents an exceptionally rare presentation of a rare disease. An 83-year-old woman presented with progressive right shoulder, forearm, and hip pain, with associated weight loss and global weakness, requiring a wheelchair for mobility. Imaging revealed a pathologic right ulna fracture in addition to lytic lesions of the right proximal humerus and proximal femur. The clinical picture was thus that of a patient with probable multiple myeloma versus metastatic disease. After an extensive workup, however, the lesions were not malignant; histologic findings were instead suggestive of chronic osteomyelitis with negative cultures. Given the multifocal nature of this condition, combined with a lack of clinical symptoms of infection, a diagnosis of CRMO was rendered. The patient underwent intramedullary nailing of the right femur and splinting of the ulna, with a subsequent remarkable recovery to painless ambulation, complete union of the right ulna fracture, and resolution of the lytic lesions without receiving any targeted medical treatment. This case highlights the importance of maintaining CRMO on the differential for multifocal skeletal lesions, regardless of age. Performing a thorough workup with necessary imaging, biopsy, and culture are critical to establishing this diagnosis, which can only made as a diagnosis of exclusion.

Sensing and Imaging Molecular Oxygen in Mammals with Spin Lattice Relaxation Electron Paramagnetic Resonance.

Molecular oxygen and its thermodynamic transformation drive nearly all life processes. Quantitative measurement and imaging of oxygen in living systems is of fundamental importance for the study of life processes and their aberrations-disease- many of which are affected by hypoxia, or low levels of oxygen. Cancer is among the disease processes profoundly affected by hypoxia. Electron paramagnetic resonance has been shown to provide remarkably accurate images of normal and cancerous tissue. In this review, we emphasize the reactivity of molecular oxygen particularly highlighting the metabolic processes of living systems to store free energy in the reactants. The history of hypoxic resistance of living systems to cytotoxic therapy, particularly radiation therapy is also reviewed. The measurement and imaging of molecular oxygen with pulse spin lattice relaxation (SLR) electron paramagnetic resonance (EPR) is reviewed briefly. This emphasizes the advantages of the spin lattice relaxation based measurement paradigm to reduce the sensitivity of the measurement to the presence of the oxygen sensing probe itself. The involvement of a novel small mammal external beam radiation delivery system is described. This enables an experimental paradigm based on control by radiation of the last resistant clonogen. This is much more specific for tumor cure than growth delay assays which primarily reflects control of tumor cells most sensitive to therapy.

Stage-Based Detection Methods and Recurrence Patterns for Cutaneous Melanoma.

Melanoma surveillance guidelines vary. Melanoma recurrence patterns and detection methods were examined. Resected melanoma patients were reviewed. Recurrence detection included patient complaint (PC), physical exam (PE), cross-sectional imaging (CSI), and ultrasound (US). 276 patients were included: 131 stage I, 83 stage II, and 62 stage III. Recurrence rates were 8%, 24%, and 27%, respectively. For stage I patients, 46% of recurrences were local, 18% regional, and 36% distant. Patient complaint identified 55% of recurrences, PE 36%, and CSI 9%. For stage II, 20% of recurrences were local, 20% regional, and 60% distant. Patient complaint identified 35% of recurrences, PE 20%, and CSI 45%. For stage III, 6% of recurrences were local, 53% regional, and 41% distant. Patient complaint identified 17% of recurrences, PE 12%, CSI 59%, and US 12%. Average time to recurrence by stage was 23.7, 24.6, and 17.7 months, respectively. H&P for all melanoma patients and CSI for higher stages are effective surveillance strategies.

Enhanced recovery after surgery may mitigate the risks associated with robotic-assisted fundoplication in lung transplant patients.

INTRODUCTION: A history of lung transplantation is a risk factor for poor outcomes in patients undergoing laparoscopic fundoplication. We wanted to determine whether enhanced recovery after a robotic-assisted surgery program would mitigate these risks. METHODS: We performed a single-center retrospective analysis of the Society of Thoracic Surgery database for patients who underwent elective antireflux procedures from 1/2018 to 2/2021 under the enhanced recovery after surgery program using robotic assistance. We identified the patient and surgical characteristics, morbidity, length of stay, and 30-day readmission rates. RESULTS: Among 386 patients who underwent barrier creation, 41 had previously undergone a lung transplant, either bilateral (n = 28) or single (n = 13). There were no significant differences in postoperative complications (9.8% vs. 5.2%, p = 0.27), median hospital length of stay (1 d vs. 1 d, p = 0.28), or 30-day readmission (7.3% vs. 4.9%, p = 0.46). Bivariate analysis showed that older age (p = 0.03), history of DVT/PE (p < 0.001), history of cerebrovascular events (p = 0.03), opioid dependence (p = 0.02), neurocognitive dysfunction (p < 0.001), and dependent functional status (p = 0.02) were associated with postoperative complications. However, lung transplantation was not associated with an increased risk of postoperative complications (p = 0.28). DISCUSSION: The risk of surgical complications in patients with a history of lung transplantation may be mitigated by the combination of ERAS and minimally invasive surgery such as robot-assisted surgery.

Voxel-wise hemispheric Amyloid Asymmetry and its association with cerebral metabolism and grey matter density in cognitively normal older adults.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by changes in beta amyloid (Aß) and tau as well as changes in cerebral glucose metabolism and gray matter volume. This has been categorized as three distinct stages of amyloid, tau, and neurodegeneration. Past studies have shown asymmetric Aß accumulation and its association with asymmetric cerebral metabolism in preclinical AD. We analyzed data to replicate these findings and extend them to associations with gray matter volume and cognitive function. Methods: We recruited 93 (mean age = 76.4±6.1 years) cognitively normal adults who underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) with Pittsburgh compound B (PiB) and Fluorodeoxyglucose (FDG) tracers (to estimate Aß and glucose metabolism, respectively). We conducted voxel-wise paired t-test on PiB (left vs. right hemispheres) to identify regions that differ in Aß between the left and right cortex. We identified whether these regions showed asymmetry in FDG and gray matter volume using paired t-tests on each region. We then conducted correlations between asymmetry indices for each region that had significant asymmetry in PiB, FDG, and gray matter volume. We ran a group regression analysis on cognitive functions. Results: We found 26 regions that had significant rightward asymmetry in PiB including prefrontal cortex, temporal cortex, insula, parahippocampus, caudate, and putamen. All these regions showed significant gray matter rightward asymmetry, and most of these regions showed significant FDG asymmetry except the caudate, orbital cortex, medial frontal gyrus, and superior temporal gyrus. Only in the superior frontal gyrus, we found that greater rightward asymmetry in PiB was associated with greater rightward asymmetry in FDG, r(82) =0.38, p<0.005 (FDR corrected) - no other regions showed significant Aß asymmetry correlation with either FDG or gray matter volume asymmetry. We found that greater rightward FDG asymmetry in the superior frontal gyrus was associated with greater visuospatial processing scores in our cognitive domain group regression analysis. Discussion: AD has previously been modeled in three-stages: however, our results indicate that cerebral glucose metabolism may be dynamic throughout the disease progression and may serve as a compensatory pathway for maintaining cognitive functioning.

Linking Type and Extent of Head Trauma to Cavum Septum Pellucidum in Older Adults With and Without Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

Long-Term Satisfaction of Oral Sedation versus Standard-of-Care Intravenous Sedation for Ocular Surgery.

Purpose: Long-term patient satisfaction may influence patients' perspectives of the quality of care and their relationship with their providers. This is a follow up to a comparative effectiveness study investigating oral to intravenous sedation (OIV study). The OIV study found that oral sedation was noninferior in patient satisfaction to standard intravenous (IV) sedation for anterior segment and vitreoretinal surgeries. This study aims to determine if patient satisfaction with oral sedation remained noninferior long term. Patients and Methods: Patients were re-interviewed using the same satisfaction survey given during the OIV study. Statistical analysis involved t-tests for noninferiority of the long-term mean satisfaction score of oral and IV sedation. We also compared the original mean satisfaction score and the follow-up mean satisfaction score for each type of sedation and for both groups combined. Results: Participants were interviewed at a median of 1225.5 days (range 754-1675 days) from their surgery. The original mean satisfaction score was 5.26 ± 0.79 for the oral treatment group (n = 52) and 5.27 ± 0.64 for the intravenous treatment group (n = 46), demonstrating noninferiority with a difference in mean satisfaction score of 0.015 (p < 0.0001). The follow-up mean satisfaction score was 5.23 ± 0.90 for oral sedation and 5.60 ± 0.61 for IV sedation, with a difference in the mean satisfaction score of 0.371 (p = 0.2071). Satisfaction scores did not differ between the original mean satisfaction score and the follow-up mean satisfaction score for the oral treatment group alone (p = 0.8367), but scores in the intravenous treatment group increased longitudinally (p = 0.0004). Conclusion: In this study, long-term patient satisfaction with oral sedation was not noninferior to satisfaction with IV sedation, unlike our findings with short-term patient satisfaction in our original study. Patient satisfaction also remained unchanged over time for the oral treatment group, but patients in the intravenous treatment group reported higher long-term satisfaction with their anesthesia experience compared to the immediate post-operative period.

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia.

Background: Frontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes: GRN, C9orf72, or MAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage. Methods: We conducted a comprehensive investigation of biomarkers indicative of lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations in GRN, C9orf72, or MAPT, as well as asymptomatic GRN mutation carriers. We also assessed the longitudinal changes of biomarkers in GRN mutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomatic GRN carriers. Results: We confirmed glucosylsphingosine (GlcSph), a lysosomal biomarker regulated by progranulin, was elevated in the plasma from GRN mutation carriers, both symptomatic and asymptomatic. GlcSph and other lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomatic GRN carriers, and all symptomatic groups, except the symptomatic C9orf72 mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomatic MAPT mutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD SB in symptomatic GRN and MAPT mutation carriers. Conclusions: In conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients with GRN mutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.