Citations

Background: Whether a significant proportion of cryptogenic stroke (CS) is caused by under-detected paroxysmal atrial fibrillation (PAF) is not known. Prolonged ambulatory cardiac monitoring may detect episodes of PAF in patients with stroke of unknown cause (cryptogenic stroke, CS). However, it is unclear whether PAF is more common in patients wtih CS compared with patients with stroke of known cause (SKC). We performed a case control study to compare the rates of detection of PAF in CS vs SKC using prolonged ambulatory cardiac rhythm monitoring. Methods and Results: We prospectively enrolled 132 patients within 3 months of a stroke (66 with CS and 66 with SKC) to undergo 3-week ambulatory cardiac rhythm monitoring using the CardioNet MCOT system. Stroke group was assigned by consensus between two vascular neurologists upon enrollment based on the Causative Classification of Stroke system. Primary endpoint was detection of PAF of any duration independently confirmed by two cardiologists blinded to the stroke group. The groups were well balanced except that patients with CS tended to be older and to have less hypertension and diabetes. Four patients (2 in each group) were excluded because of insufficient stroke evaluation or early discontinuation of monitoring. Episodes of PAF were detected in 16/64 (25%) patients with CS and 9/64 (14%) patients with SKC (p=0.12). Only 5 patients had episodes of PAF lasting > 30 seconds (3 with CS and 2 with SKC). Six of the 9 patients from the SKC group with PAF had small subcortical infarctions; the other 3 had cortical strokes ascribed to artery-to-artery embolism (2 with complex aortic plaques, 1 with severe vertebrobasilar stenosis). In patients under age 65, episodes of PAF were more common in the CS group (22% vs 3; p=0.07) while in patients age 65 or older the rates of detection were very similar (29% in CS vs 28% in SKC; p=0.9). Conclusions: Very short episodes of PAF are relatively common in patients with CS and with SKC, and their pathogenic significance is unclear. However, considering only patients under 65, a greater proportion of cryptogenic stroke patients had PAF, suggesting it might be pathogenic.

AbstractBackgroundThe optimal analgesic strategy for patients undergoing donor hepatectomy is not known and the potential short‐ and long‐term physical and psychological consequences of complications are significant.ObjectivesTo identify whether a multimodal approach to pain of the donor intraoperatively enhances immediate and short‐term outcomes after living liver donation, and to provide international expert panel recommendations.Data sourcesOvid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central.MethodsSystematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. PROSPERO 2021 CRD42021260699.ResultsNine studies assessing multi‐modal analgesia strategies were included in a qualitative assessment. Interventions included local, regional, and neuro‐axial anesthetic techniques, pharmacological intervention (NSAIDs, COX‐2 inhibitors, ketamine, dexmedetomidine, and lidocaine), and acupuncture. Overall, there was a significant (40%) reduction in opioid requirement on day 1 and a significant reduction in pain scores in the intervention vs control groups. Significant reductions in either length of stay or post‐operative complications were demonstrated in four of nine studies.ConclusionsOpioid use for patients undergoing donor hepatectomy is likely to impact both their short‐ and long‐term outcomes. To reduce post‐operative pain scores, shorten length of hospital stay, and promote earlier post‐operative return of bowel function, we recommend that multi‐modal analgesia be offered to patients undergoing living donor hepatectomy. Further research is required to confirm which multi‐modal techniques are most associated with enhanced recovery in living liver donors.

SummaryBackground and aimsExtra‐intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited.MethodsAs a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty‐four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds.ResultsFor use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence.ConclusionsConsensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician‐reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.

Abstract Background: Cyclin dependent kinase (CDK) 4/6 inhibitors (CDK 4/6i) can improve outcomes in ER-positive/HER2-negative (ER+/HER2-) breast cancer. The choice of CDK 4/6i selection and dose depends on clinical context and/or potential side effect of profile of each unique CDK 4/6i. The objective of this study was to evaluate practice patterns in patients initiated on CDK 4/6i and assess adherence to recommended laboratory monitoring in breast cancer patients in both an institutional and national dataset. Methods: The institutional cohort (IC) involved a retrospective chart review of patients newly initiated on palbociclib between May 8, 2018 - June 4, 2019 at Mayo Clinic, Rochester. The national cohort (NC) reviewed medical and pharmacy claims data from the OptumLabs Data Warehouse (OLDW) and included patients who were initiated on palbociclib (P), ribociclib (R) or abemaciclib (A) between February 6, 2015 - September 30, 2019. NC patients were required to have a minimum of 6 months baseline coverage, 6 months coverage after first prescription and Day 1 labs drawn. For both cohorts, patients were ≥18 years old with metastatic ER+/HER2- breast cancer. Data was collected for up to 6 cycles of treatment and included cycle start dates, doses, dates of lab draws and dose changes. Laboratory adherence was defined as a complete blood count being drawn +/- 3 days of the defined timepoint for the IC and +/- 5 days for the NC with a l4-day window for Cycle 1, Day 1 labs. Results: The IC included 81 patients and the NC 2600. In the NC, the most prescribed CDK 4/6i was P (90%), followed by A (6%) and R (4%). Prescription breakdown by geographic region was Midwest (26%), Northeast (14%), South (47%), West (13%). Ethnic breakdown of the group was White (68%), Black (15%), Hispanic (8%), Asian (3%) and unknown (6%). P practice pattern data were available for both the IC and NC, but R and A data in the NC only. In the IC, the initial P dose was 125 mg (95%), 100 mg (1%) and 75 mg (4%). In the NC, P (n=2329) dose was 125 mg (81%), 100 mg (15%) and 75 mg (4%). Dose reductions were common with 25% and 28% of patients requiring one dose reduction and 16% and 9% of patients requiring two dose reductions in the IC and NC, respectively. In NC patients initially treated with P, 5% were subsequently treated with A and 2% with R. In the NC, A (n=163) was initiated at 200 mg (7%), 150 mg (79%), 100 mg (10%) and 50 mg (4%). One dose reduction was required in 25% of patients and 6% required two dose reductions. Of those initially treated with A, 16% were subsequently treated with P and 1% with R. In the NC, R (n=108) was initiated at 600 mg (81%), 400 mg (8%) and 200 mg (11%). One dose reduction was required in 17% of patients and 2% required two dose reductions. Of those initially treated with R, 7% each were subsequently treated with P and 10% with A. Laboratory adherence was assessed for P only. For the IC, a total of 81 patients were included (mean age 61±13 years, 98% female and 95% White). The NC included 2329 patients (mean age 66±12 years, 99% female and 69% White). Laboratory adherence is listed in the table below: Conclusions: P was the most commonly prescribed CDK 4/6i. Dose reductions were less common with R. Adherence to laboratory monitoring was higher in our institutional cohort than in a national administrative claims database. Initiatives to ensure that labs are drawn at recommended timepoints during P therapy will be important for safety. ICNCC1D193%100%C1D1589%61%C2D191%71%C2D1558%55%C3D199%62%C4D190%55%C5D184%53%C6D178%50%C = cycle, D = day. Citation Format: Jodi Taraba, Kavya Swarna, Allison Golbach, Lindsey Sangaralingham, Kathryn Ruddy, Kristin Mara, Matthew Smith, Tufia Haddad, Karthik Giridhar. Evaluation of CDK 4/6 inhibitor practice patterns and institutional versus national adherence to palbociclib laboratory monitoring in breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-23-05.

AbstractObjectiveCarpal tunnel syndrome (CTS) is the most common peripheral entrapment mononeuropathy. The purpose of this systematic review is to evaluate the reported clinical effectiveness and safety of ultrasound‐guided percutaneous carpal tunnel release (USCTR) for the treatment of CTS.Literature SurveyPubMed, EMBASE, and ScienceDirect databases were queried from database inception to February 20, 2021, to identify clinical studies on USCTR.MethodologyTwo reviewers independently completed title, abstract, and full‐text screening, and they extracted data in duplicate for analysis. Procedure techniques, outcome measures, and complications were descriptively analyzed.SynthesisEighty‐seven studies were eligible for screening. Twenty studies (three randomized controlled trials, three prospective cohort studies, and 14 case series) met inclusion criteria, with a total of 1772 USCTR cases. The overall level of evidence was very low, with seven studies with at least moderate risk of bias. Thirteen studies exceeded the minimal clinically important difference (MCID) for the Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ‐SS) and Boston Carpal Tunnel Questionnaire Functional Status Scale (BCTQ‐FS), and six studies exceeded the MCID for the Quick Disabilities of Arm, Shoulder & Hand (QDASH). Five studies reported statistically significant improvement in these functional outcome measures as early as the first week post‐procedure. A major complication occurred in one patient who developed suspected compartment syndrome, and minor complications were reported in 24 patients.ConclusionsBased on very low level of evidence, early studies suggest that USCTR may be an effective treatment for CTS, with potential for short post‐procedure recovery times.

AbstractFor many years, Neuromuscular Medicine programs lacked a standardized means of handling fellowship applications and offering positions. Programs interviewed applicants and made offers as early as the first half of Post Graduate Year 3 (PGY3), a suboptimal timeline for applicants who may have had little prior exposure to neuromuscular or electrodiagnostic medicine. In 2021, the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) developed the Neuromuscular Fellowship Portal to standardize a later timeline and establish a process for fellowship applications and offers. In its first year, the Neuromuscular Fellowship Portal used a unique one‐way match, in which the portal released serial offers to applicants based on rank order lists submitted by programs. Fifty‐two Neuromuscular Medicine programs and seven electromyography (EMG)‐focused Clinical Neurophysiology programs participated. Sixty‐eight positions were filled, a similar number to previous years. A survey of fellowship directors and applicants following this process showed overwhelming support for the standardized timeline and application portal, but all program directors and most applicants favored moving to a traditional match. To maintain the existing application timeline and minimize costs for all parties, the AANEM Neuromuscular Fellowship Portal will host a two‐way match, based on existing commercial match algorithms, in 2022. A match will afford a fair and efficient process for all involved. Both Neuromuscular Medicine and EMG‐focused Clinical Neurophysiology programs will be encouraged to participate. The process undertaken by the AANEM can stand as an example for other neurologic subspecialties who are interested in standardizing their application timeline.

Abstract Background:Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described.Methods: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors <45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean “capillary” area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher’s exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [ recent birth: ≤5 years versus remote birth: >5 years]) using multivariable regression models.Results:Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p<0.001). Differences in TDLU counts and average acini size persisted for >5 years postpartum whereas increases in immune cells were most marked <5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions:Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

AbstractBackgroundCenters discard high kidney donor profile index (KDPI) allografts, potentially related to delayed graft function and prolonged hospital use by kidney transplant recipients (KTR). We sought to determine whether high KDPI KTRs have excess health care utilization.MethodsWe conducted a retrospective cohort study from a high‐volume center analyzing KTRs from January 3, 2011 to April 12, 2015 (n = 652). We measured differences in hospital use, emergency visits, and outpatient visits within the first 90 days between low (≤85%) versus high KDPI (>85%) KTRs, as well as long‐term graft function and patient survival.ResultsHigh (n = 107) and low KDPI (n = 545) KTRs had similar length of stay (median = 3 days, P = .66), and readmission rates at 7, 30, and 90 days after surgery (all, P > .05). High KDPI kidneys were not associated with excess utilization of the hospital, emergency services, outpatient transplant clinics, or ambulatory infusion visits on univariate or multivariate analysis (all, P > .05). Low KDPI KTRs had significantly better eGFR at 2 years (Low vs. High KDPI: 60.35 vs. 41.54 ml/min, P < .001), but similar 3‐year patient and graft survival (both, P > .09).ConclusionsHigh and low KDPI KTRs demonstrated similar 90‐day risk‐adjusted health care utilization, which should encourage use of high KDPI kidneys.

Direct interactions between tumor and immune cells mediate the antitumor effect of all modern cancer immunotherapeutic agents. Simultaneously, tumor cells have evolved mechanisms of evasion, including the downregulation of HLA-I, potentially disrupting the mechanism of action employed by many immune checkpoint inhibitors. And yet, the in situ interplay between these cells within the tumor immune microenvironment (TIME) remains elusive. Recent advances in histologic multiplex bioimaging platforms have enabled in-depth molecular characterization of single cells within spatially preserved and clinically archived tumor tissues. Herein, we applied multiplex immunofluorescence to excisional lymph node biopsies from 14 patients with metastatic melanoma who experienced clear objective responses to immunotherapy (7 complete response; 7 progressive disease) to determine distinguishing features of the TIME in the pretreatment setting. Distinct regions of the TIME were evaluated using 35 proteins probing tumor, immune, and vasculature components across 323 fields of view. Single-cell compositional analysis confirmed established prognostic immune cell types including increased prevalence of cytotoxic T cells within the tumor core fields of view of responders. Integrating single-cell quantification with the spatial arrangement of cellular neighborhoods surrounding tumor cells revealed novel, spatial immune signatures capable of stratifying TIME based on clinical response. Our analysis revealed dynamic cellular composition of the tumor-centric cellular neighborhood (TCCN) based on anatomic subregion, functional expression of HLA-I by the index tumor cell and ultimately clinical response to immunotherapy. Overall, this study provides an analytic framework to resolve the cellular complexity of the TIME, increasingly relevant to the outcomes of modern cancer immunotherapy. Significance: Findings from this work propose a novel approach to resolving clinical heterogeneity of the TIME by objectively quantifying the cellular interactions occurring in metastatic melanoma lymph node tissue utilizing multiplex immunofluorescence. This study provides an analytic and biologically derived unit of measure, the TCCN which is customizable for studying critical paracrine interactions within spatially preserved tissue of various cancers and across the spectrum of multiplex imaging modalities.