Citations

This article reviews a systematic approach to implementation of telemedicine services in a large integrated multispecialty health care system. Eight components of operational infrastructure have been identified as essential to effective program deployment and sustainability. These components include (1) dedicated telemedicine staffing infrastructure, (2) functional support partnerships, (3) standardized systems of deployment, (4) refined operational processes and procedures, (5) data analytics, (6) practice partnerships, (7) performance reporting, and (8) provider instruction. Mayo Clinic Center for Connected Care endeavors to share its practice and its learning.

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Abstract Context Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. Objective To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. Design Open-label extension study; 5-year interim analysis. Setting 12 US centers. Patients Adults (N = 49) with chronic hypoparathyroidism. Intervention(s) rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. Main Outcome Measure(s) Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. Results Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. Conclusion Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.

Correct diagnosis of seizure type and epilepsy syndrome is the foundation for appropriate antiepileptic drug selection. Inappropriate medication choices occur in the treatment of generalized epilepsy and may aggravate some seizure types, including absence seizures, potentially leading to pseudo‐drug resistance. Fortunately, a correct diagnosis of absence seizures is usually not difficult, though rarely demonstrates electroclinical overlap with focal seizures. EEG can be especially misleading when secondary bilateral synchronous discharges occur in patients with focal seizures. However, the semiology of focal seizures associated with mesial temporal lobe epilepsy has a characteristic and consistent semiology that is the mark of this common epilepsy syndrome in adulthood. We recently encountered a 53‐year‐old female with refractory seizures and a semiology strongly suggesting mesial temporal lobe epilepsy. Instead of focal seizures, prolonged absence seizures were validated by video‐EEG monitoring and she became seizure‐free after a change to broad‐spectrum antiepileptic drugs. This case further expands our understanding of the complexity of semiology in electroclinical classification and the spectrum that may occur in adult absence seizures. It serves to underscore the need for ictal EEG recordings and the importance of concordance with the clinical course during the pre‐surgical evaluation of patients with lesions and drug‐resistant epilepsy. [Published with video sequences]

Abstract Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management.

Abstract Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Background:Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the US FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. Moreover, CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor‐promoting role.1,2,3 Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor, associated with rapid disease progression and shortened survival, suggesting an accelerated disease phase in MF.4 As such, tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, including patients with monocytosis.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with MF who were relapsed, refractory, or unable to tolerate JAKi.Methods:This multicenter, open‐label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), 28 days (cycles 5–7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the RP2D (12 mcg/kg).Results:23 patients with MF received tagraxofusp, including 12 patients who received ≥ 3 prior lines of therapy. Median age 69 years (range 55–81), 61% were female, and 30% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate‐1, 12 patients (52%) with intermediate‐2, and 10 patients (44%) with high‐risk. At study entry, the median platelet count was 59 K/uL with 71% of patients had baseline platelets <100 K/uL, of which 8 patients had platelets <50 K/uL. 87% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin [LCM]). Most common treatment‐related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, alanine aminotransferase increased and thrombocytopenia. The most common ≥ grade 3 TRAE was thrombocytopenia (8%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of > 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of > 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets <100 K/uL, had treatment duration of 6 months or more.Summary/Conclusion:Tagraxofusp demonstrated single agent activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor, both constituting potential areas of unmet medical need. Enrollment continues, and updated trial data will be presented. Registrational trial designs are being evaluated. Trial information: NCT02268253.

Background:Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ∼6–7 month median overall survival (OS) in the relapsed/refractory (r/r) setting. Splenomegaly is a major cause of morbidity, is a poor prognostic factor and has emerged as a potential therapeutic target in CMML. Tagraxofusp (SL‐401) is a targeted therapy directed to CD123, a target expressed on CMML blasts, monocytes and neoplastic microenvironmental plasmacytoid dendritic cells (pDCs) that are part of the CMML malignant clone, as well as on a variety of additional malignancies. Tagraxofusp was approved by the US FDA for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is being investigated in other CD123‐expressing malignancies.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with CMML.Methods:This multicenter, open‐label, Phase 1/2 clinical trial is enrolling patients with CMML. In Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), every 28 days (cycles 5–7), and every 42 days (cycles 8 and beyond). In Stage 2 (expansion), patients receive the RP2D (12 mcg/kg).Results:20 patients with CMML (CMML‐1 [n = 12]; CMML‐2 [n = 8]) were treated with tagraxofusp, including 18 in the relapsed/refractory setting, with hypomethylating agents (HMAs) being the most commonly administered prior therapy. Median age was 69 years (range 43–80) and 80% were male. 10 patients (50%) had baseline splenomegaly (defined as spleen palpable below the left costal margin [BCM]), of which 6 had baseline splenomegaly ≥ 5 cm BCM. Most common treatment‐related adverse events (TRAEs, incidence ≥ 20%) were hypoalbuminaemia, thrombocytopenia, nausea, vomiting and fatigue. Most common ≥ grade 3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome was reported in 3 patients (grade 1–2). 100% (10/10) of patients with baseline splenomegaly had a spleen response by physical exam: 80% (8/10) had spleen size reduction of ≥ 50% and 67% (4/6) with baseline spleen size ≥ 5 cm had spleen size reduction of ≥ 50%. Three patients treated with tagraxofusp achieved bone marrow complete responses (BMCRs), including 1 patient who was bridged to stem cell transplant in remission on tagraxofusp.Summary/Conclusion:Tagraxofusp demonstrated single agent activity in patients with CMML and splenomegaly, an area of potential unmet medical need. Given the expression of CD123 in CMML, tagraxofusp represents a rational therapeutic approach in this disease. Updated data will be presented, and a registrational trial is planned. Trial information: NCT02268253.