Citations

AbstractBackgroundPhosphomannomutase 2 deficiency (PMM2‐CDG) affects glycosylation pathways such as the N‐glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2‐CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy.Case PresentationOur patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2‐CDG.A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2‐CDG.ConclusionSince the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2‐CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counseling.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the “real world” of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

ObjectivesTo review our experience with secondary surgery for persistent nasal obstruction following successful septal perforation repair and describe the potential contribution of the nasal swell body (NSB) to obstruction.Study DesignRetrospective chart review.MethodsIRB‐approved retrospective chart review of perforation repairs utilizing bilateral mucosal flaps performed by the senior author from October 2008 through April 2019 was performed. Patients who underwent secondary surgery for persistent nasal obstruction were identified. Data regarding patient demographics, perforation characteristics, primary closure technique, and secondary surgical procedures for persistent postoperative obstruction were analyzed. Nasal Obstruction Symptom Evaluation (NOSE) scores were assessed pre and post revision surgery.ResultsThirty‐four patients (14.7% of 232 successful repairs) met study criteria. Of those, 30 patients underwent revision septal surgery. An inferiorly advanced NSB was surgically reduced in 9.9% (23/232) of patients following successful closure to improve persistent obstruction. There was no incidence of reperforation. All patients undergoing NSB reduction reported improved nasal airflow postoperatively and 13 completed the NOSE questionnaire. The mean preoperative NOSE score (95% CI) was 52.7 (42.2–63.2; median, 50). The mean postoperative NOSE score (95% CI) was 19.2 (12.8–25.6; median, 15). The difference between the preoperative and postoperative NOSE scores was statistically significant (P< .001).ConclusionsRepair of a septal perforation using a superior bipedicle flap carries the potential for the NSB to contribute to persistent postoperative nasal obstruction. The swell body can be surgically reduced, without re‐perforation, to relieve obstructive symptoms in the patient with a successful perforation repair.Level of EvidenceIVLaryngoscope, 2020

Abstract Purpose: Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits. Patients and Methods: We report the Southwest Oncology Group randomized phase II trial (S1304) comparing twice weekly low-dose (27 mg/m2; arm 1) to high-dose carfilzomib (56 mg/m2; arm 2), both with dexamethasone, administered for 12 cycles (11 months) for relapsed and/or refractory multiple myeloma with up to six prior lines of therapy (NCT01903811). The primary endpoint was progression-free survival (PFS), and patients on arm 1 could cross-over to arm 2 after progression on treatment. Results: Among 143 enrolled patients, of whom 121 were eligible and analyzable, the overall response rate was 42.8%, with no significant difference between the arms (P = 0.113). Also, neither the median PFS [5 months and 8 months, respectively; HR, 1.061; 80% Wald confidence interval (CI), 0.821–1.370; P = 0.384] nor the median overall survival were significantly different (26 and 22 months, respectively; HR, 1.149, 80% Wald CI, 0.841–.571; P = 0.284). Sixteen patients crossed over to arm 2 with a median PFS benefit of 3 months. Certain adverse events (AE) were more frequent in arm 2, including fatigue, thrombocytopenia, and peripheral neuropathy, but there was no significant difference in cardiopulmonary AEs. Conclusions: This randomized trial did not support a benefit of fixed duration, twice weekly 56 mg/m2 dosing of carfilzomib over the 27 mg/m2 dose for the treatment of relapsed and/or refractory multiple myeloma. However, treatment to progression in earlier patient populations with high-dose carfilzomib using different schedules should still be considered as part of the standard of care.

Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P <0.05 for each). Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Importance Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain. Objective To determine whether cumulative BP levels explain racial differences in cognitive decline. Design, Setting, and Participants Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018. Main Outcomes and Measures The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function. Exposures Race (black vs white). Results Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (−0.03 points per year faster [95% CI, −0.05 to −0.01]; P = .004) and memory (−0.08 points per year faster [95% CI, −0.11 to −0.06]; P &amp;lt; .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P &amp;lt; .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (−0.018 points per year faster per each 10–mm Hg increase [95% CI, −0.023 to −0.014]; P &amp;lt; .001), memory (−0.028 points per year faster per each 10–mm Hg increase [95% CI, −0.035 to −0.021]; P &amp;lt; .001), and executive function (−0.01 points per year faster per each 10–mm Hg increase [95% CI, −0.014 to −0.007]; P &amp;lt; .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (−0.01 points per year [95% CI, −0.03 to 0.01]; P = .56) and memory (−0.06 points per year [95% CI, −0.08 to −0.03]; P &amp;lt; .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P &amp;lt; .001). Conclusions and Relevance These results suggest that black individuals’ higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

AbstractBackgroundBody mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.MethodsTo improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.ResultsAmong 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5).ConclusionsAggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

Abstract Aims Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. Methods and results Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. Conclusions Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome. Trial registration ClinicalTrials.gov number: NCT01947621.

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]

8037 Background: Advances in the treatment of MM have greatly improved clinical outcomes for patients (pts). SPM occurrence has been observed in early and late stage MM as well as with increasing age. US SEER Cancer Registry reports a background incidence rate of SPM 2.1/100 person-yrs (PY) among persons ≥ 65 yrs of age. However, incidence of SPM in MM pts and the relationship to therapy still warrants further exploration. Methods: Connect MM is a US-based observational registry designed to characterize pts with newly diagnosed MM from 266 US sites. Initiated in Sep 2009, patient data were collected at baseline and each subsequent quarter with a standardized form. On Dec 14, 2011, Connect MM reached full enrollment at 1,500 pts. Results: As of Jan 13, 2012, preliminary retrospective SPM data is available for 1015 pts. Median age was 67 yrs, 56.8% male, and median follow-up was 10.6 mo (0.03-24.9 mo). 12 pts (7 male) with median age of 68.5 yrs developed SPM. Median time to SPM was 8.5 mo (0.8-17.7 mo) after treatment initiation. 11 invasive SPM were observed - 4 hematological (heme): 1 AML, 1 MDS, 1 CMML and 1 DLBCL, and 7 solid: 2 melanoma skin, 1 bronchus, 1 breast, 1 prostate, 1 tonsil, and 1 gastric carcinoid. Also, 1 pt had non-melanoma skin cancer (NMSC), and 1 pt with invasive skin cancer also had NMSC. Of the 4 pts developing heme SPM, 3 had bortezomib (BORT), 1 had thalidomide (THAL), 1 had lenalidomide (LEN), 2 had melphalan (MEL), and all 4 pts had steroids. Of the 7 pts who developed solid tumor SPM, 5 had BORT, 5 had LEN, 2 had doxorubicin, 1 had MEL, 5 had steroids, 1 had irradiation, and 1 had not received MM treatment. 2 pts with prior history of invasive malignancy developed solid tumor SPM (1 pt also developed NMSC).1 pt who received irradiation developed NMSC. Early overall incidence of invasive SPM was 1.21/100 PY (95% CI 0.60, 2.16) for all pts and 1.20/100 PY (95% CI 0.44,2.62) for pts ≥ 65 yrs of age. Conclusions: This preliminary analysis shows that SPM occurred at an expected rate in this disease specific registry of patients with NDMM and appeared to occur irrespective of MM treatment administered. Incidence rates of SPM may increase over time as patients receive transplantation and alkylators. Prospective observation will continue.