Faculty Bibliography

Background/Purpose: Previous studies on the association of dermatomyositis (DM) with cardiovascular (CV) disease have used combined idiopathic inflammatory myositis cohorts, included only non-United States (US) cohorts, included only inpatients, or have not included matched controls. We aimed to describe the burden and timing of CV disease in a demographically and geographically diverse sample of inpatients and outpatients with DM in the US. Table 1. All of Us Database Diagnosis Search Terms.
Method(s): We performed a nested, matched, case-control analysis based on diagnostic coding in the All of Us Registered Tier Dataset v5 (Table 1). We used nearest neighbor propensity score matching to select for age-, sex-, race-, and ethnicity-matched controls for each DM case. We compared CV comorbidities and their dates of diagnosis between cases and controls using Pearson's chi-squared test or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. A multivariable conditional logistic regression model was built by including comorbidities with significance of P < 0.1 in univariable analysis, followed by backward elimination of comorbidities with a significance of P > 0.1 or with evidence of collinearity. A sensitivity analysis was performed that excluded DM cases with comorbid systemic lupus Table 2. Demographic and clinical characteristics of DM cases versus age-, sex-, race-, and ethnicity-matched controls in All of Us. erythematosus (SLE), rheumatoid arthritis, psoriasis, or systemic sclerosis.
Result(s): Of the 214,206 All of Us participants with electronic health record data, we identified 248 DM cases and 992 controls (Table 2). The mean follow-up time for DM cases was 7.1 +/- 4.8 years. Compared to controls, DM cases were significantly associated with 14 of 14 tested CV comorbidities in univariable analysis: atrial fibrillation (AF), cerebrovascular disease (CVD), chronic kidney disease (CKD), chronic obstructive pulmonary disease, coronary artery disease, deep vein thrombosis, heart failure, hyperlipidemia, hypertensive disorder (HTN), myocardial infarction, peripheral artery disease, pulmonary embolism, type 2 diabetes (T2D), and valvular heart disease (VHD). Aside from HTN, which was diagnosed on average 3.6 years earlier in the DM cohort, comorbidities were diagnosed at similar ages between cases and controls. In multivariable analysis, CKD, CVD, T2D, and VHD remained significantly associated with DM (Table 3). In the sensitivity analysis, 154 cases and 616 controls were identified. Univariable analysis results were similar except AF was not a significant association. In multivariable analysis, CKD, T2D, and VHD remained significantly associated; the odds ratio for CVD was 2.11 (p = 0.086).
Conclusion(s): This study found an association between DM and T2D, which has been previously reported. Unique to this study is the strong association of DM with CKD and with VHD, which remained significant in multiple multivariable models. Elevated risk of CV disease has been established in chronic inflammatory states such as SLE. This study shows a similar association between CV disease and DM. It is necessary to establish if treatment of DM decreases risk of CV disease, as is the case in the treatment of other rheumatologic diseases. Our study is limited by ascertainment of diagnoses using electronic health records and a lack of data on clinical features of DM

This is a patient with multiple meningoencephaloceles which resulted in bacterial meningitis and subsequent status epilepticus. We identify impressive imaging findings demonstrating herniation of the meninges from nasal and bitemporal skull base defects possibly as a result of intracranial hypertension.

Radiation-induced meningiomas (RIMs) became more common as the use of ionizing radiation was adopted in the treatment of medical conditions, both benign and malignant. Currently, RIMs represent the most common radiation-induced tumors. They are heterogeneous in terms of patient characteristics, radiographic appearance, genetics, pathology, symptoms, and management strategies. They tend to occur in a younger population and are generally more aggressive in nature than their spontaneous counterparts. Their characteristics also vary based on the dose of radiation received, which is most commonly separated into low dose (<10Gy) and high dose (>10Gy). The importance of the dosing classification is that it can provide insight into the nature and biologic behavior of the tumor. Given their heterogeneity, RIMs pose significant challenges in management. While surgical resection remains the preferred treatment when feasible, recent data supports stereotactic radiosurgery (SRS) as a comparable alternative. Although there is more knowledge about the molecular pathways leading to RIMs, targeted drug therapy is still limited and is the focus of current research.

Background: T-DM1 is indicated for the treatment of HER2+ metastatic BC previously treated with trastuzumab and a taxane, separately or in combination. Atezo is an anti-PD-L1 antibody that inhibits PD-L1 binding to PD-1 and B7.1 thereby restoring antitumor immunity. In a phase 3 study, the addition of atezo to nab-paclitaxel significantly improved PFS in PD-L1+ pts with metastatic triple negative BC. In KATE2 (NCT02924883), adding atezo to T-DM1 in pts with HER2+ BC did not significantly increase PFS compared to T-DM1+pbo in the ITT population, but PFS was numerically longer in PD-L1+ pts. Here, we present OS and updated safety data from KATE2.
Method(s): Pts with advanced HER2-positive BC that had progressed after treatment with trastuzumab and a taxane were randomized 2:1 to atezo 1200 mg or pbo, +TDM1 3.6 mg/kg IV q3w. Pts were grouped by tumor infiltrating PD-L1+ immune cell (IC) status: IC0 vs IC1/2/3 (<1% vs>=1%, respectively) using VENTANA SP142. The preplanned OS analysis in the ITT population was a secondary endpoint with 30% power to detect an effect. OS in PD-L1 subgroups was analyzed post-hoc.
Result(s): As of the cutoff date (11 Dec 2018), median follow-up was 19.5 mo in the atezo+T-DM1 arm and 18.2 mo in the pbo+T-DM1 arm. With 52 OS events reported, median OS was not reached in either arm. In the ITT population, 1-year OS was similar in both arms. In the PD-L1+subgroup, 1-year OS was greater in the atezo+T-DM1 arm. The safety profile was consistent with the known safety profile of each drug. Grade >=3 AEs (52.6% vs 44.8%) and serious AEs (36.1% vs 20.9%)-primarily pyrexia- were more frequent in the atezo+T-DM1 arm than in the T-DM1+pbo arm.
Conclusion(s): These data suggest a possible OS benefit with atezo+T-DM1 in PD-L1+ pts. However, given the small number of OS events, the short follow-up and lack of statistical power, further study is necessary. (Table Presented)

GNE Myopathy (GNEM), also known as hereditary inclusion body myopathy (HIBM), is a severe progressive adult-onset myopathy caused by bi-allelic mutations of the GNE gene resulting in a defect in the sialic acid biosynthetic pathway. Aceneuramic acid extended release (Ace-ER) is being developed with the goal of replacing the deficient sialic acid. A phase 2 study demonstrated stabilization in the upper extremity (UE) with Ace-ER 6g/day over a 12-month period. This pivotal Phase 3 study is being conducted to further evaluate the efficacy and safety of Ace-ER 6g/day. The primary endpoint is the effect on UE muscle strength indicated by UE composite (UEC) score. In this double blind, placebo-controlled, multicenter, international study, 89 patients who could walk >= 200 meters in 6 minutes were randomized 1:1 to receive either Ace-ER 6g/day or placebo and assessed every 8 weeks over a 48-week treatment period. Patients were stratified by gender. The UEC is determined by dynamometry assessment of muscle strength bilaterally in gross grip, shoulder abductors, elbow flexors, and elbow extensors. The UEC is derived from the sum of the average of the right and left scores (in kg). The change from baseline in mean UEC score (Ace-ER vs placebo) will be tested using generalized estimating equation (GEE) repeated measures analysis. Key secondary endpoints include a lower extremity composite (LEC) score, knee extensor strength, and GNEM-Functional Activity Scale Upper Extremity and Mobility domain scores. Safety is being assessed by adverse events, vital signs and clinical laboratory results. The study will be completed by summer 2017 with data available for presentation in the second half of the year. This study, the first placebo-controlled Phase 3 study in GNEM, is being conducted to confirm the positive results of Ace-ER observed in the previously reported Phase 2 study.
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Stereotactic radiosurgery (SRS) to a surgical cavity after brain metastasis resection is a promising treatment for improving local control. The optimal timing of adjuvant SRS, however, has yet to be determined. Changes in resection cavity volume and local progression in the interval between surgery and SRS are likely important factors in deciding when to proceed with adjuvant SRS. We conducted a retrospective review of patients with a brain metastasis treated with surgical resection followed by SRS to the resection cavity. Post-operative and pre-radiosurgery magnetic resonance imaging (MRI) was reviewed for evidence of cavity volume changes, amount of edema, and local tumor progression. Resection cavity volume and edema volume were measured using volumetric analysis. We identified 21 consecutive patients with a brain metastasis treated with surgical resection and radiosurgery to the resection cavity. Mean age was 57 yrs. The most common site of metastasis was the frontal lobe (38%), and the most common primary neoplasms were lung adenocarcinoma and melanoma (24% each). The mean postoperative resection cavity volume was 7.8 cm(3) and shrank to a mean of 4.5 cm(3) at the time of repeat imaging for radiosurgical planning (median 41 days after initial post-operative MRI), resulting in a mean reduction in cavity volume of 43%. Patients who underwent pre-SRS imaging within 1 month of their initial post-operative MRI had a mean volume reduction of 13% compared to 61% in those whose pre-SRS imaging was >/=1 month (p=0.0003). Post-resection edema volume was not related to volume reduction (p=0.59). During the interval between MRIs, 52% of patients showed evidence of tumor progression within the resection cavity wall. There was no significant difference in local recurrence if the interval between resection and radiosurgery was <1 month (n=8) versus >/=1 month (n=13, p=0.46). These data suggest that the surgical cavity after brain metastasis resection constricts over time with greater constriction seen in patients whose pre-SRS imaging is >/=1 month after initial post-operative imaging. Given that there was no difference in local recurrence rate, the data suggest there is benefit in waiting in order to treat a smaller resection cavity.

The apical domain of embryonic (radial glia) and adult (B1 cells) neural stem cells (NSCs) contains a primary cilium. This organelle has been suggested to function as an antenna for the detection of morphogens or growth factors. In particular, primary cilia are essential for Hedgehog (Hh) signaling, which plays key roles in brain development. Their unique location facing the ventricular lumen suggests that primary cilia in NSCs could play an important role in reception of signals within the cerebrospinal fluid. Surprisingly, ablation of primary cilia using conditional alleles for genes essential for intraflagellar transport [kinesin family member 3A (Kif3a) and intraflagellar transport 88 (Ift88)] and Cre drivers that are activated at early [Nestin; embryonic day 10.5 (E10.5)] and late [human glial fibrillary acidic protein (hGFAP); E13.5] stages of mouse neural development resulted in no apparent developmental defects. Neurogenesis in the ventricular-subventricular zone (V-SVZ) shortly after birth was also largely unaffected, except for a restricted ventral domain previously known to be regulated by Hh signaling. However, Kif3a and Ift88 genetic ablation also disrupts ependymal cilia, resulting in hydrocephalus by postnatal day 4. To directly study the role of B1 cells' primary cilia without the confounding effects of hydrocephalus, we stereotaxically targeted elimination of Kif3a from a subpopulation of radial glia, which resulted in ablation of primary cilia in a subset of B1 cells. Again, this experiment resulted in decreased neurogenesis only in the ventral V-SVZ. Primary cilia ablation led to disruption of Hh signaling in this subdomain. We conclude that primary cilia are required in a specific Hh-regulated subregion of the postnatal V-SVZ.

The surgical management of Cushing's disease is often complicated by difficulties detecting corticotropic adenomas. Various diagnostic modalities are used when conventional magnetic resonance imaging (MRI) is negative or inconclusive. We sought to analyze our use of two such modalities in the surgical management of Cushing's disease: (1) cavernous/inferior petrosal sinus sampling (central venous sampling, CVS) for adrenocorticotropic hormone and (2) dynamic MRI (dMRI). We conducted a single-center, retrospective review of all patients with Cushing's disease treated by a single neurosurgeon with endonasal transsphenoidal surgery. Accuracy of adenoma localization with CVS and dMRI was analyzed. Ninety-one consecutive patients were included. Pathology confirmed an adenoma in 66. Preoperative dMRI and CVS were performed in 40 and 37 patients, respectively, with 20 undergoing both studies. Surgical pathology was positive for adenoma in 31 dMRI patients, 25 CVS patients, and 13 who underwent both. Among patients with pathology confirming an adenoma, dMRI identified a lesion in 96.8% and correctly lateralized the lesion in 89.7%, while CVS correctly lateralized in 52.2-65.2% (depending on location of sampling). Among patients with both studies, dMRI and CVS correctly lateralized in 76.9 and 61.5-69.2%, respectively. Accuracy of CVS improved if only patients with symmetric venous drainage were considered. In this mixed population of Cushing's disease patients, dMRI was more accurate than CVS at localizing adenomas, supporting the use of advance MRI techniques in the work-up of Cushing's disease. CVS, however, remains an important tool in the workup of Cushing's syndrome.

Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs.

BACKGROUND: Several investigators have recommended serial measurements of serum cortisol in the days following pituitary surgery to identify patients at risk of recurrence. OBJECTIVE: We systematically reviewed the literature on this topic and analyzed the usefulness of this test in our own patient population. METHODS: We identified studies publishing data regarding recurrence rates after transsphenoidal surgery for Cushing's disease, focusing on studies with data regarding patients with early postoperative cortisol levels. We determined a cumulative relative risk of having a subnormal vs normal cortisol level postoperatively using a fixed-effects meta-analysis model. Additionally, we analyzed our own patients with Cushing's disease undergoing transsphenoidal surgery and performed Kaplan-Meier analysis of recurrence-free survival for patients with undetectable, subnormal but detectable, and normal immediate 8 AM serum cortisol levels. RESULTS: Fourteen studies met inclusion criteria. The length of follow-up varied between 32 and 115 months. The cumulative rate of recurrence in the group of patients with subnormal cortisol levels was 9% (95% confidence interval: 6%-12%). The cumulative rate of recurrence in the group with normal cortisol levels was 24% (95% confidence interval: 17%-31%). We analyzed 73 of our own patients and found similar recurrence rates in patients with subnormal vs normal early postoperative cortisol levels (4% vs 22%, chi2 test, P < .05). CONCLUSION: Although a subnormal early postoperative cortisol level is predictive of improved outcome after transsphenoidal surgery for Cushing's disease, it is not analogous with cure, nor is a normal level completely predictive of future failure.