Citations

Abstract This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

BACKGROUND Limited data exist on sentinel lymph node biopsy (SLNB) for cutaneous squamous cell carcinoma (cSCC) of the head and neck. OBJECTIVE To review the results of SLNB for patients with cSCC of the head and neck at the authors’ institution. MATERIALS AND METHODS A retrospective review was completed for patients who underwent SLNB for cSCC of the head and neck over 19 years. Patient demographics, immune status, tumor stage, total patients with positive SLNB, local recurrence, nodal recurrence, in-transit metastasis, and disease-specific death were recorded. RESULTS Sixty patients underwent lymphoscintigraphy, and an SLN was identified in 58 patients. The mean follow-up was 3.2 years (range, 15 days–16 years). Four patients (6.9%) had a positive SLNB. All were Brigham and Women's Hospital (BWH) stage T2b tumors. Three of these patients were immunosuppressed, 3 patients underwent neck dissection, and 2 patients received adjuvant radiation. None developed local or regional recurrence. Of the 53 patients with a negative SLNB, there were 4 local recurrences, 2 in-transit metastases, and no nodal recurrences. CONCLUSION Immunosuppressed patients with tumors BWH stage T2b or greater may be a reasonable cohort to focus future prospective studies on the utility of SLNB in cSCC of the head and neck.

Key Points Asymptomatic pyuria is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene and cystic growth. The eGFR decline occurred after detection of asymptomatic pyuria without significant changes in the rate of total kidney volume growth. This study supports the use of asymptomatic pyuria as an enriching prognostic biomarker to predict faster disease progression. Background Autosomal dominant polycystic kidney disease (ADPKD) has phenotypic variability only partially explained by established biomarkers that do not readily assess pathologically important factors of inflammation and kidney fibrosis. We evaluated asymptomatic pyuria (AP), a surrogate marker of inflammation, as a biomarker for disease progression. Methods We performed a retrospective cohort study of adult patients with ADPKD. Patients were divided into AP and no pyuria (NP) groups. We evaluated the effect of pyuria on kidney function and kidney volume. Longitudinal models evaluating kidney function and kidney volume rate of change with respect to incidences of AP were created. Results There were 687 included patients (347 AP, 340 NP). The AP group had more women (65% versus 49%). Median ages at kidney failure were 86 and 80 years in the NP and AP groups (log rank, P =0.49), respectively, for patients in Mayo Imaging Class (MIC) 1A–1B as compared with 59 and 55 years for patients in MIC 1C–1D–1E (log rank, P =0.02), respectively. Compared with the NP group, the rate of kidney function (ml/min per 1.73 m 2 per year) decline shifted significantly after detection of AP in the models, including all patients (−1.48; P <0.001), patients in MIC 1A–1B (−1.79; P <0.001), patients in MIC 1C–1D–1E (−1.18; P <0.001), and patients with PKD1 (−1.04; P <0.001). Models evaluating kidney volume rate of growth showed no change after incidence of AP as compared with the NP group. Conclusions AP is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene, cystic burden, and cystic growth. These results support AP as an enriching prognostic biomarker for the rate of disease progression.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]). Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

BACKGROUND: The diagnosis of isolated small bowel Crohn’s disease (CD) can be challenging. Symptoms are non-specific and both imaging and capsule endoscopy (CE) may be misleading as several diseases may mimic CD. Double balloon enteroscopy (DBE) allows a more extensive endoscopic and histologic evaluation of the small bowel. Our aim was to describe the diagnostic utility and impact of DBE on management of patients with known CD and in patients with suspected/rule-out CD. METHODS: Retrospective review of our institution’s DBE database from February 2009 to May 2013. Adult patients referred for DBE for further evaluation of known or suspected CD (due to symptoms, abnormal imaging and/or CE) were included. Patient demographics, clinical characteristics, imaging and CE results, prior DBE, indication for DBE, DBE findings, DBE adverse events, pathology findings, final diagnosis, treatment prior and post DBE and follow-up DBE were abstracted from the electronic medical record. RESULTS: A total of 108 patients were included, 61 (56%) females, mean age 52 years (range 20-83). Indications for DBE included: disease activity assessment/therapeutic in 10 patients with established diagnosis of CD and for diagnostic purposes in 98 patients with suspected CD (31 patients due to abnormal imaging, 29 due to abnormal CE and 26 due to both abnormal imaging and CE). Upper, lower, bidirectional upper and lower, and stomal DBE were performed in 21, 24, 62 and 1 patients, respectively. DBE revealed active disease in 8/10 patients with known CD with one patient undergoing dilation of a stricture. Changes in management were recommended for all patients with active disease – start thiopurine (2), optimize thiopurine dose (1), start biologics (3) change biologics (1), systemic steroids (1) and budesonide (1). The patient who underwent stricture dilation ultimately required surgery. A definitive diagnosis of CD (both endoscopic and histologic) was reached in only 39/98 (40%) patients who were referred for suspected CD. Changes in management were recommended in 32/39 (82%) patients. Interestingly, 24/98 patients had been diagnosed with CD at outside institutions and were recommended to initiate therapy for CD. Of these, CD was confirmed in only 15/24 (63%) patients. Adverse events included perforation in 1 patient (1%) who required surgical management and mouth swelling/abrasion in 3 patients (3%). Follow-up DBE to re-assess disease activity was performed in 10/49 (20%) patients with definitive diagnosis of CD, average time between procedures 4.5 years (range 0.7-11.6). One patient with CD was diagnosed with lymphoma 2.4 years after initial DBE. Changes in management were recommended in 6 patients: de-escalation of therapy (3, two underwent surgery), start thiopurine and/or biologic (2) and switch biologics (1). No complications were seen at follow-up DBE. CONCLUSION: DBE is a useful technique to confirm a diagnosis in patients who have suspected CD and can help establish a diagnosis of several diseases that may mimic CD on CT scan or CE. Additionally, DBE in patients with established diagnosis of small bowel CD is an effective tool to assess disease activity and guide therapy. Serious complications are infrequent.

Background Patients with single ventricle (SV) congenital heart disease (CHD) undergo several interventions in the first years of life. Advanced diagnostics are required for interstage assessment of anatomy, but are associated with significant diagnostic risk. We sought to evaluate image quality, risk, and accuracy of cardiac computed tomography (CCT) for evaluation of anatomy prior to superior cavopulmonary connection (SCPC) compared to surgical findings across 2 institutions. Methods A retrospective evaluation of image quality, risk, and accuracy of pre-SCPC CCT was performed at 2 institutions between January 1, 2010 and September 30, 2016. Results CCT was performed in 90 SV CHD patients with a median age of 4.03 months (interquartile range [IQR] 3.36, 5.33) prior to SCPC. Image quality was optimal (84%) or good (16%) in all patients, without significant discrepancy compared to surgical findings. 7 patients (8%) required interventional cardiac catheterization subsequent to CCT and before surgical intervention. 49% of scans were performed without sedation, 43% of scans were performed with mild to moderate sedation, and 8% of scans were performed with general anesthesia. The median total procedural dose-length product (DLP) was 18 (IQR 14, 26) mGy*cm, estimating an age adjusted radiation dose of 1.4 millisievert (mSv). One minor (1%) adverse event was reported within 24 h of the CCT. Surgical complications were unrelated to the presurgical findings. Conclusions CCT for pre-SCPC evaluation is safe, with excellent accuracy for anatomy at the time of surgical intervention across 2 institutions. In select patients, noninvasive evaluation with CCT may be indicated.

Abstract Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.