Citations

Background: Diagnosis and treatment of posterior shoulder instability (PSI) has improved with advances in imaging and surgical technique. However, the relationship between PSI and osteoarthritis (OA) remains unclear. Purpose: To evaluate a population-based cohort to (1) determine the rate of symptomatic OA, (2) identify patient characteristic risk factors for OA, and (3) evaluate the effect of posterior capsulolabral repair on OA progression. Study Design: Case-control study; Level of evidence, 3. Methods: After review of 324 patient records, we included 115 patients (14 female, 101 male) diagnosed with PSI between January 1994 and July 2012 with an average follow-up of 12.5 years (range, 5-23 years). Medical records were reviewed for patient characteristics, injury characteristics, surgical details (if any), and radiographic progression of OA. Kaplan-Meier survival was used to estimate survival free of OA; characteristics associated with OA progression were determined via univariate Cox regression models, and associated 95% CIs and hazard ratios (HRs) are presented. Results: Overall, 14% (16/115) of patients had radiographic progression of symptomatic glenohumeral arthritis, with 5-year survival of 88.3% (95% CI, 79.7%-97.3%). Older age at the time of instability diagnosis was associated with arthritis progression (10-year unit HR, 1.95; 95% CI, 1.26-3.03). Patients who underwent surgery demonstrated increased radiographic progression of OA (HR, 4.03; 95% CI, 1.23-13.23). There was a trend of increased OA in patients treated with labral debridement compared with repair despite lower baseline levels of OA; however, this difference was not statistically significant ( P = .09). Conclusion: Symptomatic glenohumeral arthritis is not seen routinely in patients with PSI. Although uncommon, an age of at least 30 years at the time of diagnosis and surgical intervention were identified as risk factors for developing symptomatic arthritis at long-term follow-up.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. Subjects: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19–1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03–1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81–0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20–1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.

AbstractObjectivesDrug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well‐controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age.MethodsThe RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population.ResultsAfter reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children.SignificanceThese recommendations should result in more rapid accessibility of antiseizure medications for infants.

Abstract Research on the care of inflammatory bowel disease (IBD) patients has been primarily in populations of European ancestry. However, the incidence of IBD, which comprises Crohn’s disease and ulcerative colitis, is increasing in different populations around the world. In this comprehensive review, we examine the epidemiology, clinical presentations, disease phenotypes, treatment outcomes, social determinants of health, and genetic and environmental factors in the pathogenesis of IBD in Black and Hispanic patients in the United States. To improve health equity of underserved minorities with IBD, we identified the following priority areas: access to care, accurate assessment of treatment outcomes, incorporation of Black and Hispanic patients in therapeutic clinical trials, and investigation of environmental factors that lead to the increase in disease incidence.

AbstractLafora disease is a rare inherited neurodegenerative disease with onset in adolescence. Patients present with progressive myoclonic seizures and cognitive decline. The disease is linked to mutations in either of the two genes encoding malin and laforin, and it is associated with the accumulation of polyglucosan inclusions (Lafora bodies [LBs]) in various tissues, such as brain, liver, muscle, and skin, with the skin being particularly accessible for biopsy. Histopathologic examination of affected tissue with demonstration of LBs, together with the presence of pathologic mutation in EPM2A or NHLRC1 genes, is sufficient for diagnosis of this neurologic disorder when clinically suspected. Here, we report the case of a 16‐year‐old female with progressive neurologic symptoms and homozygous mutation in the NHLRC1 gene encoding malin. The skin biopsy was instrumental in reaching the final diagnosis by showing LBs in sweat glands by histopathologic and electron microscopic examination.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A medically supervised ketogenic diet (MSKD) defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies. A ketogenic diet combined with triplet chemotherapy (gemcitabine, nab-paclitaxel, cisplatin) was shown to inhibit murine pancreatic KPC tumor growth and to triple the survival benefit of chemotherapy alone. The ketogenic diet combined with triple chemotherapy was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Citation Format: Diana Hanna, Gayle S. Jameson, Drew W. Rasco, Angela Alistar, Richard C. Frank, Anthony B. El-Khoueiry, Julia E. Wiedmeier, Caroline Roberts, Brandon Fell, Sarah Hallberg, Denise Roe, Derek Cridebring, Joshua Rabinowitz, Stephen Thomas Gately, Daniel D. Von Hoff. Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT549.

Abstract Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number abnormalities (CNVs) with prognostic value. Identifying these structural variations is central to defining CLL pathogenesis, risk stratification, and therapeutic approaches. Fluorescence in situ hybridization (FISH) is the clinical gold standard in detecting prognostic CNVs in CLL. However, next-generation sequencing (NGS) techniques have become more readily available for clinical genomic applications and can also be used to identify CNVs. Here we present bioinformatic methods to accurately identify CNVs in CLL using NGS data. We used the CNV-calling algorithm PatternCNV to detect clinically relevant CNVs: deletion 17p13 [del(17p)], deletion 11q23 [del(11q)], deletion 13q14 [del(13q)], and trisomy 12. PatternCNV was run on 2274 samples (1500 somatic and 774 germline samples) from six different sequencing batches, screened using a targeted sequencing panel that covers all exons of 59 recurrently CLL mutated genes and additional amplicons covering the minimal affected regions of relevant CNVs. To correct for potential batch effects, PatternCNV was initially run to quantify exon coverage behavior without the chromosomes containing recurrent CNV events, 11, 12, 13, and 17. Principal component analyses and correlation matrices were analyzed, grouping the samples into four distinct clusters that contain similar exon coverage patterns. Samples in each of the four clusters were then independently re-run through PatternCNV using all chromosomes. Visual analysis of CNV plots revealed a bias in normalization. To correct this, the log2ratios were corrected to center the log ratio on the median coverage. Sample noisiness was calculated from the difference in the median absolute deviation (DiffMAD) and samples with a DiffMAD score greater than 0.3 were excluded. All CNV analyses were blinded to clinical FISH results. The effectiveness of our CNV calling was evaluated in 522 CLL patients who had FISH conducted within three months of the sample date. We excluded samples with low tumor metrics identified by FISH (less than 20% of cells with either del(17p), del(11q), trisomy 12 or del(13q)). When we compared our CNV analyses with the FISH data, we found high concordance 99.6% for del(17p), 97.5% for del(11p), 99.1% for trisomy 12, and 93.7% for del(13q). N=46 total discordant pairs were identified, with the highest discordance for del(13q), N=28, followed by del(11q), N=12. These novel bioinformatic methods allow for accurate detection of CNVs across NGS sequencing batches. The high concordance in detecting CNVs between targeted NGS and the gold standard of FISH, suggest NGS is an accurate tool for calling CNVs in CLL. Further, NGS can infer clinically relevant CNVs in genomic locations not targeted by FISH. Citation Format: Chantal E. McCabe, Erik Jessen, Daniel R. O'Brien, Julia E. Wiedmeier-Nutor, Susan L. Slager, Esteban Braggio. Identifying copy number variations in chronic lymphocytic leukemia using targeted next generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3352.

Abstract In drug-resistant focal epilepsy, interictal high-frequency oscillations (HFOs) recorded from intracranial EEG (iEEG) may provide clinical information for delineating epileptogenic brain tissue. The iEEG electrode contacts that contain HFO are hypothesized to delineate the epileptogenic zone; their resection should then lead to postsurgical seizure freedom. We test whether our prospective definition of clinically relevant HFO is in agreement with postsurgical seizure outcome. The algorithm is fully automated and is equally applied to all data sets. The aim is to assess the reliability of the proposed detector and analysis approach. We use an automated data-independent prospective definition of clinically relevant HFO that has been validated in data from two independent epilepsy centres. In this study, we combine retrospectively collected data sets from nine independent epilepsy centres. The analysis is blinded to clinical outcome. We use iEEG recordings during NREM sleep with a minimum of 12 epochs of 5 min of NREM sleep. We automatically detect HFO in the ripple (80–250 Hz) and in the fast ripple (250–500 Hz) band. There is no manual rejection of events in this fully automated algorithm. The type of HFO that we consider clinically relevant is defined as the simultaneous occurrence of a fast ripple and a ripple. We calculate the temporal consistency of each patient’s HFO rates over several data epochs within and between nights. Patients with temporal consistency &lt;50% are excluded from further analysis. We determine whether all electrode contacts with high HFO rate are included in the resection volume and whether seizure freedom (ILAE 1) was achieved at ≥2 years follow-up. Applying a previously validated algorithm to a large cohort from several independent epilepsy centres may advance the clinical relevance and the generalizability of HFO analysis as essential next step for use of HFO in clinical practice.