Mayo Clinic Rochester Research Articles

NCMP-16. MANAGEMENT AND LONG-TERM OUTCOMES OF PATIENTS WITH RECURRENT STROKE-LIKE EPISODES AFTER CRANIAL RADIOTHERAPY

Abstract Stroke-Like Migraine Attacks after Radiation Therapy (SMART) is a descriptive clinical entity consisting of transient hemispheric dysfunction. We were interested in pragmatic management patterns for patients with Recurrent Stroke-Like Episodes (R-SLE) of transient negative neurologic symptoms after cranial radiotherapy (RT) to define optimal management strategy and assess long-term outcomes. We conducted a retrospective review of all patients with recurrent negative neurologic symptoms after cranial RT who were treated at Mayo Clinic (Rochester), with follow-up extending until February 2021. Descriptive statistics and Chi-Square analysis was performed to assess for differences between patients with clinical cessation of symptoms, death, progressive encephalopathy and therapeutic class, patient and primary treatment characteristics (i.e. whole brain RT). We identified 27 patients with R-SLE after RT. 25 patients were included in analyses. Median age at diagnosis was 28.7 years (3.0-65.8 years, SD: 15.0 years). Median time from RT to symptom onset was 14.6 years (3.3-30.5 years, SD: 8.9 years). The most common presentations included hemiparesis (55.6%), hemisensory loss (22.2%), transient visual field loss (33.3%), encephalopathy (18.5%), and aphasia (22.2%). Antiseizure medications were most used for management of R-SLE (92%) followed by anti-platelets (68%), verapamil (52%), statins (48%), glucocorticoids (24%), antivirals (20%), and ACE inhibitors/angiotensin receptor blockers (16%). Beta blockers were not used. Verapamil use was frequently associated with clinical cessation of recurrent events with cessation being achieved in 64.7% of patients on verapamil versus 35.3% not on verapamil (p=0.0638). Other medical interventions did not approach clinical or statistical significance. Progressive encephalopathy was more common in patients without clinical cessation (87.5% vs. 23.5%, p=0.0026). All patients who died at last follow-up had progressive encephalopathy. We found cessation of recurrent negative neurologic symptoms after cranial RT in most patients. Verapamil use was associated with clinical cessation. Progressive encephalopathy was more common in patients without clinical cessation of recurrent events.

Mortality Trends in Multiple Myeloma after the Introduction of Novel Therapies in the United States

Mortality Trends in Multiple Myeloma after the Introduction of Novel Therapies in the United States

Pilot Implementation of Remote Patient Monitoring Program for Outpatient Management of CAR-T Cell Therapy

Pilot Implementation of Remote Patient Monitoring Program for Outpatient Management of CAR-T Cell Therapy

Metabolic PET/CT Analysis of Aggressive Non-Hodgkin Lymphoma Prior to Axicabtagene Ciloleucel CAR-T Infusion: Predictors of Progressive Disease, Survival, and Toxicity

Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion.Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use.Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD.Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each).While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2).Additional patients and follow-up will be presented.Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. [Display omitted] DisclosuresBennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

Time to Refractory Status Defines Subsets of Primary Refractory Diffuse Large B-Cell Lymphoma with Distinct Outcomes

Time to Refractory Status Defines Subsets of Primary Refractory Diffuse Large B-Cell Lymphoma with Distinct Outcomes

Barriers to Enrollment in Clinical Trials in Patients with Aggressive B-Cell Non-Hodgkin Lymphoma That Progressed after Anti-CD19 CART Cell Therapy

Barriers to Enrollment in Clinical Trials in Patients with Aggressive B-Cell Non-Hodgkin Lymphoma That Progressed after Anti-CD19 CART Cell Therapy

The role research gap years play in a successful dermatology match.

A new trend includes taking a dedicated year away from medical school to complete a research fellowship. There is minimal data on the benefit of a gap year. We aimed to identify if a gap year makes a dermatology applicant more successful in The Match. Dermatology applicants who applied to Mayo Clinic Arizona for the 2018-2019 application cycle and Mayo Clinic Rochester, Arizona, and Florida for the 2019-2020 application cycle were surveyed. In total, 291 dermatology applicants completed the initial survey, and 236 completed the follow-up survey. Ninety applicants took a gap year, 198 applicants did not. There was no significant difference in match rates. When comparing match rates at top dermatology residency programs, 40.6% of gap-year applicants matched to these residencies versus 19.0% of no gap-year applicants (P < 0.01). Applicants should weigh the opportunity costs before pursuing research gap years as they may not be universally helpful. Applicants who want to match at a top dermatology program may benefit from a research gap year. This data may have limited generalizability outside of the United States.

Investigation of the correlation between immature reticulocyte fraction and reticulocyte hemoglobin content with common tests for iron deficiency anemia

Abstract Reticulocyte hemoglobin content (Ret-He, the hemoglobin within reticulocytes or immature red blood cells) and immature reticulocyte fraction (IRF, the immature fraction of the absolute-reticulocyte-count) are tests that provide insight into erythropoiesis and iron status earlier than conventional iron studies offering the added benefit of not being acute-phase-reactants. Studies have shown that Ret-He is a diagnostic marker for iron-deficiency-anemia (IDA), but fewer studies have investigated IRF. Our laboratory is currently planning to report these parameters when reticulocyte is ordered. Since these are new parameters, we wanted to investigate their overall correlation with complete blood count (CBC) and other iron studies to gain a better appreciation of their utility in our patient population. The aim of this study was to compare the overall correlation of Ret-He and IRF with seven tests used in the evaluation of IDA. To our knowledge these parameters have not all been directly correlated within a single study. CBC and reticulocytes were quantified using XN 9000 hematology analyzers (Sysmex Corporation), ferritin (DXI 800, Beckman Coulter Inc.), and % iron-saturation (measured using total iron-binding-capacity (TIBC)=transferrin*1.18 on Cobas 6000, Roche Diagnostics). Two de-identified cohorts of patients undergoing physician-ordered reticulocyte testing were used for this analysis. Dataset 1 (DS1): (N=2026 from Mayo Clinic Florida) had Ret-He and IRF compared to absolute-reticulocyte-count (Ret), ferritin and % iron saturation. Dataset 2 (DS2): (N=3990 from Mayo Clinic Rochester) had Ret-He and IRF compared to the red-cell-indices of the CBC including hemoglobin (Hgb), mean-corpuscular-volume (MCV), mean-corpuscular-hemoglobin (MCH), and mean-corpuscular-hemoglobin-concentration (MCHC). Correlation coefficients were calculated using Spearman rank-order (ρ) wherein values below +/-0.39 are weak, between +/-0.40-0.59 are considered moderate, and values above +/-0.60 are considered strong. For DS1, Ret-He demonstrated the following correlations: Ret (ρ=0.01), ferritin (ρ=0.33), % iron saturation (ρ=0.63). IRF demonstrated: Ret (ρ=0.46), ferritin (ρ=-0.05), % iron saturation (ρ=-0.22). For DS2, Ret-He demonstrated the following correlations: Hgb (ρ=0.17), MCV (ρ=0.64), MCH (ρ=0.74), MCHC (ρ=0.56). IRF demonstrated Hgb (ρ=-0.41), MCV (ρ=0.10), MCH (ρ=0.04), MCHC (ρ=-0.11). Ret-He and IRF demonstrated different correlative profiles suggesting they may have differing uses. Ret-He was strongly positively-correlated with % iron saturation, MCV, MCH and moderately positively-correlated with MCHC. These positive-correlations are consistent with relationships established in the literature. Interestingly, Ret-He was only weakly correlated with ferritin, possibly owing to ferritin being an acute-phase-reactant. IRF had a moderate positive correlation with Ret and moderate inverse correlation with Hgb. Both of these IRF relationships are consistent with other reports, but both relationships have not been shown in the same study before, preventing direct comparison until now. The literature suggests IRF may have more potential in monitoring treatment than in diagnosis. One limitation of these datasets is their lack of clinical correlation such as established iron-deficiency, anemia status, or treatment information.

Autoimmune Encephalitis After SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes.

Background and ObjectivesAutoimmune encephalitis (AE) cases after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, but the frequency is unknown. We aimed to determine the frequency and diagnostic features of coronavirus disease 2019 (COVID-19)–related AE.MethodsResidual sera from 556 consecutive Mayo Clinic Rochester patients (laboratory cohort) who underwent autoimmune encephalopathy neural immunoglobulin G (IgG) evaluation were tested for total antibodies against the SARS-CoV-2 spike glycoprotein using a Food and Drug Administration–authorized chemiluminescence assay (October 2019–December 2020). Clinical records from patients with a positive SARS-CoV-2 antibody result and available research consent were reviewed. This laboratory cohort was cross-referenced with the Department of Neurology's COVID-19–related consultative experience (encephalopathy cohort, n = 31).ResultsEighteen of the laboratory cohort (3%) were SARS-CoV-2 antibody positive (April–December 2020). Diagnoses were as follows: AE, 2; postacute sequelae of SARS CoV-2 infection (PASC), 3; toxic-metabolic encephalopathy during COVID-19 pneumonia, 2; diverse non–COVID-19 relatable neurologic diagnoses, 9; unavailable, 2. Five of the encephalopathy cohort had AE (16%, including the 2 laboratory cohort cases that overlapped), representing 0.05% of 10,384 patients diagnosed and cared for with any COVID-19 illness at Mayo Clinic Rochester in 2020. The 5 patients met definite (n = 1), probable (n = 1), or possible (n = 3) AE diagnostic criteria; median symptom onset age was 61 years (range, 46–63); 3 were women. All 5 were neural IgG negative and 4 tested were SARS-CoV-2 PCR/IgG index negative in CSF. Phenotypes (and accompanying MRI and EEG findings) were diverse (delirium [n = 5], seizures [n = 2], rhombencephalitis [n = 1], aphasia [n = 1], and ataxia [n = 1]). No acute disseminated encephalomyelitis cases were encountered. The 3 patients with possible AE had spontaneously resolving syndromes. One with definite limbic encephalitis was immune therapy responsive but had residual mood and memory problems. One patient with probable autoimmune rhombencephalitis died despite immune therapy. The remaining 26 encephalopathy cohort patients had toxic-metabolic diagnoses.DiscussionWe encountered occasional cases of AE in our 2020 COVID-19 experience. Consistent with sporadic reports and small case series during the COVID-19 pandemic, and prior experience of postinfectious AE, our cases had diverse clinical presentations and were neural IgG and CSF viral particle negative. Application of diagnostic criteria assists in differentiation of AE from toxic-metabolic causes arising in the setting of systemic infection.

DIAGNOSTIC YIELD OF NEXT GENERATION SEQUENCING IN THE EVALUATION OF PLEURAL EFFUSIONS

TOPIC: Disorders of the Pleura TYPE: Original Investigations PURPOSE: Next Generation Sequencing (NGS) is a massive parallel sequencing technology that is becoming increasingly important in clinical microbiology. Its use has the potential to change workflows in the evaluation of multiple infectious syndromes, particularly those that have been historically difficult to diagnose based on conventional culture. This retrospective study aimed to compare the diagnostic yield of NGS and bacterial culture in the evaluation of pleural effusions. METHODS: Subjects were recruited from the Pleural practice at Mayo Clinic Rochester from January 2017 to August 2019 with IRB approval. Pleural fluid aliquots were collected at the time of thoracentesis or thoracostomy tube placement. Clinical characteristics, including patient demographics, pleural fluid chemistries, Gram stain and culture results, and antimicrobial usage patterns prior to pleural fluid sampling, were obtained from the electronic medical record. NGS was performed by microbiology laboratory personnel blinded to the clinical data.Subjects were stratified into groups based on the likelihood that the sampled pleural effusion was secondary to empyema. We defined proven cases as those having a consistent clinical presentation with empyema in addition to either positive Gram stain or bacterial culture and/or the presence of frank pus at the time of pleural fluid aspiration. Probable cases were defined as exudates by Light’s criteria, with a pH less than 7.2 in association with clinical evidence of infection (fever, leukocytosis, and/or elevated CRP). Unlikely cases did not meet the proven or probable criteria. Unclassifiable cases were missing information needed to determine whether they qualified as proven or probable cases. Proven and probable cases were considered to be true empyemas when calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NGS.Agreement between NGS and bacterial culture data was categorized as total agreement (negative testing or same organism detected by both methods), partial agreement (single organism detected by one method and multiple organisms detected by other method), or no agreement. RESULTS: Our study included 47 patients with a mean age of 70 and majority male population. The breakdown of cases included 9 proven empyemas, 3 probable empyemas, 17 unlikely empyemas, and 18 cases that were unclassifiable. The diagnostic yield of NGS in diagnosing empyemas was as follows: sensitivity 92%, specificity 74%, PPV 55%, and NPV 96%. The diagnostic yield of bacterial culture was not able to be characterized to the same degree, as bacterial culture was not ordered on all effusions included in our study. However, we were able to determine that the sensitivity of bacterial culture in diagnosing empyema was 58%. Of the 34 cases that had available culture and NGS data, there was total agreement between the two methods in 67.7% of cases, partial agreement in 8.8% of cases, and discordance in 23.5% of cases. CONCLUSIONS: The diagnostic evaluation of pleural effusions that are potentially infectious in nature can be augmented by NGS given its high NPV. CLINICAL IMPLICATIONS: Further study is needed to determine the most appropriate patient population in whom NGS will enhance the diagnosis and management of pleural effusions without overly increasing the detection of clinically insignificant bacterial burden in the pleural space. DISCLOSURES: No relevant relationships by Dagny Anderson, source=Web Response No relevant relationships by Eva Carmona, source=Web Response

Single-Dose Intraprocedural Steroid Administration Does Not Impact Early Atrial Fibrillation Recurrence.

To evaluate the effect of single-dose intravenous dexamethasone on atrial fibrillation (AF) recurrence following radiofrequency catheter ablation. A cohort of 84 adult patients (> 18years) underwent catheter ablation at Mayo Clinic Rochester from January to March 2019. Only first-time ablation patients were included, with all re-do ablations excluded to minimize heterogeneity. Administration of intraoperative dexamethasone 4mg or 8mg was determined by chart review from the procedure. At our institution, intraoperative intravenous steroids are administered for postoperative nausea and vomiting (PONV) prophylaxis at the discretion of the anesthesiologist. AF recurrence was determined by ECG or cardiac monitoring within 3months or between 3 and 12months post-ablation with an in-person follow-up visit. A total of 31 (36.9%) patients received intravenous dexamethasone compared to 54 (63.1%) who did not (approximating a 2:1 comparison group). The incidence of documented AF or atrial flutter, lasting greater than 30s, within the first 3months post-ablation was 29.0% in the dexamethasone group versus 24.5% in the non-dexamethasone group (p value 0.80). AF or atrial flutter recurrence at 3-12months post-ablation was 3.2% in the dexamethasone group compared to 9.4% in the non-dexamethasone group (p value 0.41). These data suggest that intraoperative intravenous dexamethasone administered during AF ablation for postoperative nausea and vomiting prophylaxis may not have a significant effect on AF recurrence rates.

Diamond-Forrester classification using echocardiography haemodynamic assessment in cardiac intensive care unit patients.

AimsWe sought to determine whether the Diamond–Forrester classification using non‐invasive haemodynamic measurements by 2‐D and Doppler echocardiography would predict hospital mortality in cardiac intensive care unit (CICU) patients.Methods and resultsWe retrospectively analysed unique patients admitted to the CICU at Mayo Clinic Rochester from 2007 to 2018. Doppler‐derived cardiac index (CI) and ratio of mitral valve E velocity to medial mitral annulus e′ velocity (E/e′ ratio) were used to classify patients into four profiles: Profile I (warm/dry), Profile II (warm/wet), Profile III (cold/dry), and Profile IV (cold/wet). Logistic regression was used to determine predictors of hospital mortality, and Cox proportional‐hazards analysis was used to determine predictors of mortality during one year of follow‐up. We included 4563 patients with a mean age of 68.3 ± 14.3 years, including 36.2% female patients. The distribution of each profile was as follows: I, 47.4%; II, 36.2%; III, 7.9%; IV, 8.5%. A total of 5.8% patients died during hospitalization, and 18.1% died by 1 year. Patients with either low CI or elevated E/e′ ratio had higher in‐hospital and 1 year mortality. Patients with elevated E/e′ ratio (i.e. Profiles II and IV) had an increased risk of death during hospitalization and at 1 year after multivariate adjustment (adjusted hazard ratio 1.72 and 2.17 for 1 year mortality, respectively, compared with Profile I, P < 0.01).ConclusionsSimple Doppler echocardiographic assessment can be used to identify haemodynamic profiles defined by the Diamond–Forester classification in patients admitted in CICU. These profiles predict outcomes and may be used to guide therapy in critically ill patients.

Improving time to palliative care review with predictive modeling in an inpatient adult population: study protocol for a stepped-wedge, pragmatic randomized controlled trial

BackgroundPalliative care is a medical specialty centered on improving the quality of life (QOL) of patients with complex or life-threatening illnesses. The need for palliative care is increasing and with that the rigorous testing of triage tools that can be used quickly and reliably to identify patients that may benefit from palliative care.MethodsTo that aim, we will conduct a two-armed stepped-wedge cluster randomized trial rolled out to two inpatient hospitals to evaluate whether a machine learning algorithm accurately identifies patients who may benefit from a comprehensive review by a palliative care specialist and decreases time to receiving a palliative care consult in hospital. This is a single-center study which will be conducted from August 2019 to November 2020 at Saint Mary’s Hospital & Methodist Hospital both within Mayo Clinic Rochester in Minnesota. Clusters will be nursing units which will be chosen to be a mix of complex patients from Cardiology, Critical Care, and Oncology and had previously established relationships with palliative medicine. The stepped wedge design will have 12 units allocated to a design matrix of 5 treatment wedges. Each wedge will last 75 days resulting in a study period of 12 months of recruitment unless otherwise specified. Data will be analyzed with Bayesian hierarchical models with credible intervals denoting statistical significance.DiscussionThis intervention offers a pragmatic approach to delivering specialty palliative care to hospital patients in need using machine learning, thereby leading to high value care and improved outcomes. It is not enough for AI to be utilized by simply publishing research showing predictive performance; clinical trials demonstrating better outcomes are critically needed. Furthermore, the deployment of an AI algorithm is a complex process that requires multiple teams with varying skill sets. To evaluate a deployed AI, a pragmatic clinical trial can accommodate the difficulties of clinical practice while retaining scientific rigor.Trial registrationClinicalTrials.gov NCT03976297. Registered on 6 June 2019, prior to trial start.

IBCL-085: Assessment of Fixed-Duration Therapies for Treatment-Naïve Waldenström Macroglobulinemia

Context Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Objective To compare the efficacy of the most frequently used rituximab-based fixed-duration anti-WM regimens in routine practice [rituximab, bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR)] to inform clinicians about the benefits/limitations of choosing one regimen over the other. Design A retrospective cohort study. Participants Patients with active WM seen at Mayo Clinic Rochester, Arizona, and Florida campuses between 10/01/2000 and 10/31/2019 who received R-Benda, DRC, or BDR as primary therapy were included. Outcomes Measures Overall response rate (ORR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), time-to-next therapy (TTNT) and treatment related adverse-effects (AEs) based on the three treatment regimens. The MYD88L265P mutation status was assessed using allele-specific polymerase-chain-reaction (sensitivity 1%). Response rates were assessed by Consensus Criteria. Time-to-event analyses were performed from the frontline therapy, using Kaplan-Meier method. CTCAE v4.03 was used to grade toxicities. Results The study included 220 patients with active WM who were treated with R-Benda (n=83), DRC (n=92) or BDR (n=45). The median follow-up was 4.5 (95% CI: 4-5) years. The R-Benda cohort demonstrated superior ORR (98%), in comparison to DRC (78%) or BDR (84%) cohorts, p=0.003. Similarly, longer PFS was evident with R-Benda use [median 5.2 versus 4.3 (DRC) and 1.8 years (BDR), p=0.0003]. The TTNT favored R-Benda [median, not-reached, versus 4.4 (DRC) and 2.6 years (BDR), p=0.0002]. These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p=0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the MYD88 signature within each cohort. Toxicity profiles across the three groups were comparable, barring a higher incidence of neutropenia and neuropathy in patients who received R-Benda and BDR regimens, respectively. Conclusions The ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naive patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status.

The Addition of C-Reactive Protein and von Willebrand Factor to Model for End-Stage Liver Disease-Sodium Improves Prediction of Waitlist Mortality.

Background and AimsPatients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF‐Ag) and C‐reactive protein (CRP) are simple, broadly available markers of these processes.Approach and ResultsWe determined whether addition of vWF‐Ag and CRP to the Model for End‐Stage Liver Disease‐Sodium (MELD‐Na) score improves risk stratification of patients awaiting LT. CRP and vWF‐Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD‐Na, and mortality on the waiting list were recorded. Prediction of 3‐month waiting list mortality was assessed by receiver operating characteristics curve (ROC‐AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF‐Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF‐Ag and CRP both improved the predictive value of MELD‐Na for 3‐month waitlist mortality and showed the highest predictive value when combined (AUC: MELD‐Na, 0.764; MELD‐Na + CRP, 0.790; MELD‐Na + vWF, 0.803; MELD‐Na + CRP + vWF‐Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD‐Na, 0.677; MELD‐Na + CRP + vWF‐Ag, 0.882). vWF‐Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation.ConclusionsThe addition of vWF‐Ag and CRP—reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT—to the MELD‐Na score improves prediction of waitlist mortality. Using the vWFAg‐CRP‐MELD‐Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Mapping of critical events in disease progression through binary classification: Application to amyotrophic lateral sclerosis

BackgroundThe progression of many degenerative diseases is tracked periodically using scales evaluating functionality in daily activities. Although estimating the timing of critical events (i.e., disease tollgates) during degenerative disease progression is desirable, the necessary data may not be readily available in scale records. Further, analysis of disease progression poses data challenges, such as censoring and misclassification errors, which need to be addressed to provide meaningful research findings and inform patients. MethodsWe developed a novel binary classification approach to map scale scores into disease tollgates to describe disease progression leveraging standard/modified Kaplan-Meier analyses. The approach is demonstrated by estimating progression pathways in amyotrophic lateral sclerosis (ALS). Tollgate-based ALS Staging System (TASS) specifies the critical events (i.e., tollgates) in ALS progression. We first developed a binary classification predicting whether each TASS tollgate was passed given the itemized ALSFRS-R scores using 514 ALS patients’ data from Mayo Clinic-Rochester. Then, we utilized the binary classification to translate/map the ALSFRS-R data of 3,264 patients from the PRO-ACT database into TASS. We derived the time trajectories of ALS progression through tollgates from the augmented PRO-ACT data using Kaplan-Meier analyses. The effects of misclassification errors, condition-dependent dropouts, and censored data in trajectory estimations were evaluated with Interval Censored Kaplan Meier Analysis and Multistate Model for Panel Data. ResultsThe approach using Mayo Clinic data accurately estimated tollgate-passed states of patients given their itemized ALSFRS-R scores (AUCs > 0.90). The tollgate time trajectories derived from the augmented PRO-ACT dataset provide valuable insights; we predicted that the majority of the ALS patients would have modified arm function (67%) and require assistive devices for walking (53%) by the second year after ALS onset. By the third year, most (74%) ALS patients would occasionally use a wheelchair, while 48% of the ALS patients would be wheelchair-dependent by the fourth year. Assistive speech devices and feeding tubes were needed in 49% and 30% of the patients by the third year after ALS onset, respectively. The onset body region alters some tollgate passage time estimations by 1–2 years. ConclusionsThe estimated tollgate-based time trajectories inform patients and clinicians about prospective assistive device needs and life changes. More research is needed to personalize these estimations according to prognostic factors. Further, the approach can be leveraged in the progression of other diseases.

Analyzing Patient Secure Messages Using a Fast Health Care Interoperability Resources (FIHR)-Based Data Model: Development and Topic Modeling Study.

BackgroundPatient portals tethered to electronic health records systems have become attractive web platforms since the enacting of the Medicare Access and Children’s Health Insurance Program Reauthorization Act and the introduction of the Meaningful Use program in the United States. Patients can conveniently access their health records and seek consultation from providers through secure web portals. With increasing adoption and patient engagement, the volume of patient secure messages has risen substantially, which opens up new research and development opportunities for patient-centered care.ObjectiveThis study aims to develop a data model for patient secure messages based on the Fast Healthcare Interoperability Resources (FHIR) standard to identify and extract significant information.MethodsWe initiated the first draft of the data model by analyzing FHIR and manually reviewing 100 sentences randomly sampled from more than 2 million patient-generated secure messages obtained from the online patient portal at the Mayo Clinic Rochester between February 18, 2010, and December 31, 2017. We then annotated additional sets of 100 randomly selected sentences using the Multi-purpose Annotation Environment tool and updated the data model and annotation guideline iteratively until the interannotator agreement was satisfactory. We then created a larger corpus by annotating 1200 randomly selected sentences and calculated the frequency of the identified medical concepts in these sentences. Finally, we performed topic modeling analysis to learn the hidden topics of patient secure messages related to 3 highly mentioned microconcepts, namely, fatigue, prednisone, and patient visit, and to evaluate the proposed data model independently.ResultsThe proposed data model has a 3-level hierarchical structure of health system concepts, including 3 macroconcepts, 28 mesoconcepts, and 85 microconcepts. Foundation and base macroconcepts comprise 33.99% (841/2474), clinical macroconcepts comprise 64.38% (1593/2474), and financial macroconcepts comprise 1.61% (40/2474) of the annotated corpus. The top 3 mesoconcepts among the 28 mesoconcepts are condition (505/2474, 20.41%), medication (424/2474, 17.13%), and practitioner (243/2474, 9.82%). Topic modeling identified hidden topics of patient secure messages related to fatigue, prednisone, and patient visit. A total of 89.2% (107/120) of the top-ranked topic keywords are actually the health concepts of the data model.ConclusionsOur data model and annotated corpus enable us to identify and understand important medical concepts in patient secure messages and prepare us for further natural language processing analysis of such free texts. The data model could be potentially used to automatically identify other types of patient narratives, such as those in various social media and patient forums. In the future, we plan to develop a machine learning and natural language processing solution to enable automatic triaging solutions to reduce the workload of clinicians and perform more granular content analysis to understand patients’ needs and improve patient-centered care.

Increased short-term and long-term mortality in community- and hospital-acquired hypernatraemia and in patients with delayed serum sodium correction.

This study examined the short-term and long-term mortality of community- and hospital-acquired hypernatraemia in a large cohort of general hospitalised patients, and the impact of delayed serum sodium correction in hypernatraemic patients. Adult patients admitted to Mayo Clinic Rochester from 2011 to 2013 were examined. The patients with admission serum sodium ≥138mEq/L and at least 2 serum sodium measurements during hospitalisation were included. Hypernatraemia was defined as serum sodium ≥143mEq/L. The patients were categorised into three groups based on serum sodium at admission and during hospitalisation: (a) normal serum sodium, (b) community-acquired hypernatraemia and (c) hospital-acquired hypernatraemia. Outcomes included hospital mortality and 1-year mortality after hospital discharge amongst hospital survivors. Of 25781 eligible patients, 45% had normal serum sodium, 20% had community-acquired hypernatraemia and 35% had hospital-acquired hypernatraemia. In adjusted analysis, odds ratios (ORs) of community- and hospital-acquired hypernatraemia for hospital mortality were 4.91 (95% CI 3.47-6.94) and 4.11 (95% CI 2.94-5.73), whereas hazard ratio (HR) for 1-year mortality was 1.76 (95% CI 1.56-1.98) and 1.61 (95% CI 1.45-1.79), respectively. Hospital-acquired hypernatraemia had a higher hospital mortality but not 1-year mortality than community-acquired hypernatraemia. In patients with community-acquired hypernatraemia, 36% remained hypernatraemic by hospital day 3. Hospital mortality (OR 3.01; 95% CI 2.71-5.83) and 1-year mortality (HR 1.51; 95% CI 1.26-1.81) were significantly increased in patients with persistent hypernatraemia, compared with those with serum sodium correction into optimal range of 138-142mEq/L. Hypernatraemia, regardless of acquisition origin, is associated with elevated short-term and long-term mortality. Hospital-acquired hypernatraemia was more common and had a higher short-term mortality than community-acquired hypernatraemia. Failure to correct hypernatraemia by hospital day 3 is associated with increased mortality.

Acute Lymphoblastic Leukemia/Lymphoma in the Elderly: The Mayo Clinic Experience

IntroductionElderly patients (≥60 years of age) with acute lymphoblastic leukemia/lymphoma (ALL) have a poor prognosis compared to younger adults. This is thought to be due to comorbidities, treatment-related mortality, adverse disease biology, low rates of complete remission (CR), high risk of relapse, and ineligibility for allogeneic hematopoietic stem cell transplantation (HSCT). Since it is unclear how all these factors play into the poor prognosis of elderly ALL, we sought to describe the presentation, treatment outcomes, and predictors of survival at our multi-site institution.MethodsAfter IRB approval, we performed a retrospective study of patients (pts) ≥60 years old diagnosed with ALL from 2000-2017 at Mayo Clinic Rochester, Arizona, and Florida. Statistical analysis was performed using JMP 10.0 software.ResultsBaseline characteristicsWe identified 124 consecutive pts with elderly ALL. The median age at time of diagnosis was 67 (60-86) and 74 (60%) were male. Median time of follow-up was 15.6 months (range 0.2-132). 77 (62%) were deceased at the time of last follow-up: 37 deaths related to disease, 24 due to infection or other causes, and 16 unknown.At time of diagnosis, 108 (87%) pts had B-cell ALL, of which 40 (37%) were Philadelphia chromosome positive (Ph+). Only 16 (13%) pts had T-cell ALL. Overall, 24 (19%) had an ECOG performance status (PS) ≥2, and 22 (18%) had a Charlson Comorbidity Index (CCI) ≥3. Further baseline characteristics including cytogenetics and FISH studies are detailed in Table 1.Treatment and Outcomes102/124 (82%) elected to undergo induction. Of these, 19 (19%) had an up-front dose reduction. The most common induction regimen was Hyper-CVAD, which was used in 62 (61%), concomitantly with rituximab in 21, and tyrosine kinase inhibitors (TKIs) in 17. Asparaginase-based chemotherapy was used in 27 (26%) pts. The remaining 13 (13%) received other regimens. Complete remission (CR/CRi) was achieved in 92 (90%) pts. 11 (11%) had primary refractory disease, of which 7 were refractory to multiple lines of therapy. Median time to CR was 30 days (range 10-352), requiring a median of 1 cycle (range 1-8) of chemotherapy. 5 (5%) died within 60 days of starting treatment, and by Day 100 there were a total of 10 (10%) deaths; these were related to subdural hematoma (3), infection (2), treatment discontinuation (1), and unknown causes (4).Palliative therapy up-front was chosen in 22/124 (18%), which included chemotherapy (e.g. vincristine and steroids), TKIs or hospice. 7 (32%) of these pts achieved CR within a median time of 54 days (range 23-128). The median overall survival (mOS) in the palliative group was 5.7 months (interquartile range [IQR] 1.7-12.1).Relapse occurred in 42 (42%) pts within a median time of 9.9 months (range 0-71.5); 10 (24%) of these pts had an extramedullary relapse, including 3 with CNS leukemia. 31 (74%) were treated with salvage chemotherapy, while 10 (21%) chose palliative care. Median survival from the time of relapse was 5.7 months (IQR 2-18).Overall, 34 (27%) underwent HSCT: allogeneic HSCT in 33, and autologous HSCT in 1. Of these, 29 (85%) were in CR1, and 5 (15%) were in CR2. The median age at time of HSCT was 65 (range 60-73). 3 (9%) died within 100 days of HSCT, due to early relapse (2; both were in CR1) and acute graft-versus-host disease (1). 11 (31%) relapsed after HSCT, within a median time of 9 months (range 1-30). Median survival after HSCT was 27.4 months (IQR 0.7-not reached [NR]).Predictors of SurvivalElderly ALL across the three Mayo Clinic campuses had a mOS of 20.8 months (IQR 9.4-87.3), which was inferior compared to our adult ALL (age 18-59) cohort in Rochester, who had a mOS of 51.1 months (IQR 15.3-NR) (Figure 1). In univariate analysis, which included the presenting variables shown in Table 1, only age, ECOG PS, CCI, and LDH negatively influenced survival (P <0.05). These factors continued to significantly predict for poor survival in multivariate analysis (Table 2).ConclusionsALL has worse outcomes in elderly pts compared to younger adults. However, treatment-related mortality was relatively low in our cohort even though the majority of pts underwent induction. Interestingly, we found that survival was influenced by age, ECOG PS, CCI, and LDH at time of diagnosis, rather than by cytogenetics or other biological features. Our data needs to be verified in a larger cohort. Nevertheless, this could be the first step toward a prognostic model in elderly ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Therapy-Related Acute Lymphoblastic Leukemia/Lymphoma in the Elderly

IntroductionTherapy-related ALL (t-ALL) is a rare entity. It was recently estimated to occur in about 4.7%-6.9% of adult ALL cases and has been associated with a worse prognosis(Aldoss et al ., 2017; Abdulwahab et al ., 2012). However, these studies included very few patients over the age of 60. Since t-ALL specifically in the elderly has never been described, we sought to characterize its clinical features and treatment outcomes.MethodsAfter IRB approval, we performed a retrospective study of patients (pts) ≥60 years old diagnosed with ALL from 2000-2017 at Mayo Clinic Rochester, Arizona, and Florida. We included pts who received known leukemogenic chemotherapy prior to being diagnosed with ALL. We excluded pts with malignancies who were not exposed to leukemogenic chemotherapy. We also excluded pts diagnosed with chronic myeloid leukemia (CML) with blast crisis. Moreover, we excluded pts treated with radiation therapy other than to the whole pelvic region. Statistical analysis was performed using JMP 10.0 software.ResultsBaseline characteristicsOut of 124 consecutive pts with elderly ALL, we identified 20 (16%) pts who fit our inclusion criteria. 16 (80%) were female. The median latent time to developing ALL was 9.25 years (range 0.26-28.67). The median time of follow-up was 12.6 months (range 0.9-63.2). 11 (55%) were deceased at the time of follow-up: 3 deaths related to disease, 6 from infection or other causes, and 2 unknown.Of the 20 pts with t-ALL, 13 (65%) had been treated for hematological malignancies prior to ALL, which included multiple myeloma (3), acute myeloid leukemia in remission (2), diffuse large B-cell lymphoma (2), myelofibrosis (2), myelodysplastic syndrome (1), MALT lymphoma (1), hairy cell leukemia (1), chronic lymphocytic leukemia (1), and light-chain (AL) amyloidosis (1). Additionally, 6 pts had prior treatment for breast cancer; 1 of these was the pt who also had AL amyloidosis. Finally, 1 pt had a history of receiving cyclophosphamide for bronchiolitis obliterans with organizing pneumonia and myositis.Median age at time of ALL diagnosis was 67 (60-82). 19 (95%) had B-cell ALL, of which 5 (26%) were positive for the Philadelphia chromosome. Only 1 (5%) pt had T-cell ALL.Cytogenetics and FISH studies18 pts had available cytogenetic data at time of diagnosis. 8 (44%) had complex cytogenetics (≥5 abnormalities), 7 (39%) had a monosomal karyotype, 4 (22%) were hyperdiploid, 2 (11%) were hypodiploid, 1 (6%) was a mixture of hyper- and hypo-diploid. Furthermore, FISH analysis was available in 10 pts: 3 had CDKN2A deletion, 2 had a duplication of 1q, 2 had a TCF3-PBX1 translocation, 1 had a MLL rearrangement, and 1 had a deletion of IKZF1 .Treatment and Outcomes15/20 (75%) underwent induction chemotherapy. 6 of them received Hyper-CVAD. The other 9 received various regimens, including asparaginase-based chemotherapy in 6 (67%). 13 (87%) had a complete remission (CR/CRi), within a median time of 32 days (range 19-128). 1 (7%) had primary refractory disease. The other 5 (25%) pts chose palliative treatment up-front; this included chemotherapy (e.g. vincristine and steroids), tyrosine kinase inhibitors, or hospice. 3 (60%) of these pts got into CR.Of the 16 total pts who achieved CR, 5 (31%) relapsed within a median time of 20.67 months (range 9-22.3). All of them were treated with salvage chemotherapy. Median survival after relapse was 4.8 months (range 0.1-42.2). Overall, 7/20 (35%) underwent allogeneic HSCT; all were in CR1. Median survival after HSCT was not reached (IQR 7.6-NR). Only 2 (29%) relapsed after HSCT within a median time of 6.4 months (range 3.1-9.6).The median overall survival (mOS) in patients with t-ALL was 13.83 months (interquartile range [IQR] 11.73-not reached), which was not significantly different (P=0.9935) from elderly patients without t-ALL, who had a mOS of 20.93 months (IQR 8.73-56.63) (Figure 1).ConclusionsTherapy-related ALL (t-ALL) seems to be relatively more common in the elderly compared to younger adults, with an incidence of 16% in our elderly ALL cohort. Almost all cases were B-cell ALL. In addition, MLL rearrangements appeared to be less frequent in our elderly cohort (7%), in contrast to what has been reported in younger adults (25-35%). Moreover, the overall survival in elderly t-ALL was not significantly different compared to elderly ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.