Citations

Abstract Introduction The middle fossa (MF) approaches encompass a group of versatile surgical accesses to pathologies in the MF, internal auditory canal (IAC), and superomedial aspect of the posterior fossa. Although many descriptions of the MF approaches have been published, a practical surgical guide that allows an easy understanding for Skull Base trainees is needed. Methods Three formalin-fixed, colored-injected specimens were dissected under microscopic magnification (six sides). A MF craniotomy followed by IAC drilling was performed on three sides, and anterior petrosectomy (AP) was performed in the remaining three sides. The anatomical dissection was documented in stepwise three-dimensional photographic images. Following dissection, representative case applications were reviewed. Results The MF approach provides direct access to the MF structures and IAC. The AP provides excellent access to the superomedial aspect of the posterior fossa. Key common steps include: positioning and skin incision; scalp and muscle flaps; burr holes; craniotomy flap elevation; dural dissection along the petrous ridge; division of the middle meningeal artery; and exposure of the greater superficial petrosal nerve, tegmen tympani, and V3. Then, to approach the IAC: superior IAC drilling, and longitudinal dura opening. The area drilled in the AP approach forms a pentagon limited by the petrous internal carotid artery, cochlea, IAC, petrous ridge, and lateral border of V3. Conclusion The MF approaches are challenging. Operatively oriented skull base dissections provide a crucial foundation for learning these techniques. We describe comprehensive step-by-step approaches intended to develop familiarity in the cadaver laboratory and facilitate understanding of their potential for skull base disorders. Basic surgical principles are described to help in the operating room as well as illustrative cases.

Objective: To assess the efficacy and safety of closed-loop control (CLC) insulin delivery system in adolescents and young adults with type 1 diabetes. Research Design and Methods: Prespecified subanalysis of outcomes in adolescents and young adults aged 14–24 years old with type 1 diabetes in a previously published 6-month multicenter randomized trial. Participants were randomly assigned 2:1 to CLC (Tandem Control-IQ) or sensor augmented pump (SAP, various pumps+Dexcom G6 CGM) and followed for 6 months. Results: Mean age of the 63 participants was 17 years, median type 1 diabetes duration was 7 years, and mean baseline HbA1c was 8.1%. All 63 completed the trial. Time in range (TIR) increased by 13% with CLC versus decreasing by 1% with SAP (adjusted treatment group difference = +13% [+3.1 h/day]; 95% confidence interval [CI] 9–16, P < 0.001), which largely reflected a reduction in time >180 mg/dL (adjusted difference −12% [−2.9 h/day], P < 0.001). Time <70 mg/dL decreased by 1.6% with CLC versus 0.3% with SAP (adjusted difference −0.7% [−10 min/day], 95% CI −1.0% to −0.2%, P = 0.002). CLC use averaged 89% of the time for 6 months. The mean adjusted difference in HbA1c after 6 months was 0.30% in CLC versus SAP (95% CI −0.67 to +0.08, P = 0.13). There was one diabetic ketoacidosis episode in the CLC group. Conclusions: CLC use for 6 months was substantial and associated with improved TIR and reduced hypoglycemia in adolescents and young adults with type 1 diabetes. Thus, CLC has the potential to improve glycemic outcomes in this challenging age group. The clinical trial was registered with ClinicalTrials.gov (NCT03563313).

Background Migraine preventive medications are used to reduce headache frequency, severity, and duration. In patients with chronic migraine (CM), reversion to episodic migraine (EM) is an important treatment goal. Objective To evaluate the effect of fremanezumab on the rate of reversion from CM to EM. Methods This phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group trial included a 28‐day pretreatment period and a 3‐month treatment period. Patients with CM received subcutaneous fremanezumab quarterly (675 mg at baseline) or monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or placebo. Post hoc analyses evaluated the proportion of patients who reverted from CM to EM, defined as either a reduction to an average of <15 headache days per month during the 3‐month treatment period or a reduction to <15 headache days per month in all 3 months of the treatment period. Results This analysis included data from 1088 CM patients (quarterly, n = 366; monthly, n = 365; placebo, n = 357). More fremanezumab‐treated patients with CM reverted to EM using either the monthly average number of headache days criteria for reversion (quarterly: 50.5% [185/366], P = .108; monthly: 53.7% [196/365], P = .012; vs placebo: 44.5% [159/357]) or the monthly headache day count at Months 1, 2, and 3 criteria for reversion (quarterly: 31.2% [114/366], P = .008; monthly: 33.7% [123/365], P = .001; vs placebo: 22.4% [80/357]). Patients with CM who reported previous topiramate or onabotulinumtoxinA use, concomitant preventive medication use, or medication overuse were less likely to revert to EM. Conclusions Fremanezumab may offer the benefit of reversion from CM to EM, based on a reduction in the number of headache days over 3 months of treatment.

Background: Data are limited on the need for and benefits of pump setting optimization with automated insulin delivery. We examined clinical management of a closed-loop control (CLC) system and its relationship to glycemic outcomes. Materials and Methods: We analyzed personal parameter adjustments in 168 participants in a 6-month multicenter trial of CLC with Control-IQ versus sensor-augmented pump (SAP) therapy. Preset parameters (BR = basal rates, CF = correction factors, CR = carbohydrate ratios) were optimized at randomization, 2 and 13 weeks, for safety issues, participant concerns, or initiation by participants' usual diabetes care team. Time in range (TIR 70–180 mg/dL) was compared in the week before and after parameter changes. Results: In 607 encounters for parameter changes, there were fewer adjustments for CLC than SAP (3.4 vs. 4.1/participant). Adjustments involved BR (CLC 69%, SAP 80%), CR (CLC 68%, SAP 50%), CF (CLC 44%, SAP 41%), and overnight parameters (CLC 62%, SAP 75%). TIR before and after adjustments was 71.2% and 71.3% for CLC and 61.0% and 62.9% for SAP. The highest baseline HbA 1c CLC subgroup had the largest TIR improvement (51.2% vs. 57.7%). When a CR was made more aggressive in the CLC group, postprandial time >180 mg/dL was 43.1% before the change and 36.0% after the change. The median postprandial time <70 mg/dL before making CR less aggressive was 1.8%, and after the change was 0.7%. Conclusions: No difference in TIR was detected with parameter changes overall, but they may have an effect in higher HbA 1c subgroups or following user-directed boluses, suggesting that changes may matter more in suboptimal control or during discrete periods of the day. Clinical Trials Registration number: NCT03563313.

Background: Isolation measures used to contain epidemics generate social interaction restrictions and impose changes in routines of the public that increase negative psychological outcomes. Anxiety and depression are the most common symptoms. Objective: To evaluate the mental health of the Brazilian population during the SARs-CoV-2 pandemic and its relationship with demographic and health characteristics. Methods: Adults from all Brazilian States participated (n = 12,196; women: 69.8%, mean age = 35.2 years). The Depression, Anxiety and Stress Scale, and the Impact of Event Scale–revised were used (online survey). Data validity and reliability were verified by confirmatory factor analysis and ordinal alpha coefficient. The probability of presenting psychological symptoms was calculated by multiple logistic regression and odds ratio (OR) (0 = without symptoms, 1 = with mild, moderate, and severe levels of symptoms). Results: High prevalence of depression (61.3%), anxiety (44.2%), stress (50.8%), and psychological impact (54.9%) due to the isolation experienced from the pandemic was found. Younger individuals (OR = 1.58–3.58), those that felt unsafe (OR = 1.75–2.92), with a previous diagnosis of mental health (OR = 1.72–2.64) and/or had general health problems before the pandemic (OR = 1.17–1.51), who noticed changes in their mental state due to the pandemic context (OR = 2.53–9.07), and excessively exposed to the news (OR = 1.19–2.18) were at increased risk of developing symptoms. Women (OR = 1.35–1.65) and those with lower economic status (OR = 1.38–2.69) were more likely to develop psychological symptoms. Lower educational levels increased the likelihood of depressive (OR = 1.03–1.34) and intrusive symptoms (OR = 1.09–1.51). Conclusions: The pandemic and related factors can have a high impact on the mental health of the population. Demographic characteristics can influence the occurrence of psychological symptoms.

Abstract Immune dysfunction is a hallmark of CLL/MBL; ~25% individuals with newly diagnosed CLL have hypogammaglobulinemia at diagnosis. In this study of newly diagnosed CLL/MBL, we sought to a) investigate the association between serum immunoglobulins and specific mutations identified by next generation sequencing, and b) determine if serum immunoglobulin levels predict TFT, independent of the CLL-International Prognostic Index (CLL-IPI) and tumor mutational load (TML). We used the Mayo Clinic CLL Resource to identify newly diagnosed CLL/MBL individuals consented within 2 years of diagnosis. Baseline clinical characteristics and the CLL-IPI score was ascertained on all individuals. DNA was extracted from peripheral blood CD5+/CD19+ clonal B-cells; and the entire coding regions of 60 somatically recurring mutated CLL driver genes were enriched using a customized Agilent SureSelect gene panel and sequenced in Illumina Hiseq4000. Serum immunoglobulins were quantitated by radial immunodiffusion using Immunoplates. The relationship between serum immunoglobulins was assessed: a) with individual gene mutations (mutated vs. not); and b) using the TML score (using a value of 0, 1, and 2 or greater [2+] mutated genes). The impact of serum immunoglobulin levels on TFT was analyzed for all individuals. Of 356 individuals identified, 80 (22%) had MBL, median age was 63 years (28-87), 261 (73%) were male, and the CLL-IPI distribution was: low risk (n=149, 42%), intermediate risk (n=112, 32%), and high/very high risk (n=94, 26%). We observed 43%, 39%, and 18% individuals with 0, 1, or 2+ mutated genes, respectively. The most commonly mutated genes were NOTCH1 (13%), SF3B1 (13%), TP53 (8%), ATM (8%), BIRC3 (7%), and NFKBIE (7%). Using standard cutoffs, 135 (38%) individuals had low serum IgG, 73 (21%) had low serum IgA, and 154 (44%) had low serum IgM at diagnosis. There were no differences in individual gene mutation frequencies between individuals with low and normal serum IgG. In contrast, individuals with low serum IgA were more likely to have mutations in NOTCH1 (25% vs 10%) and ATM (14% vs 7%) compared to those with normal IgA, and individuals with low serum IgM were more likely to have mutations in NOTCH1 (19% vs 9%) and BIRC3 (11% vs 4%) compared to those with normal IgM (all p-values &lt;0.05). There were no significant differences in individuals with low serum IgG based on TML scores of 0, 1, and 2+ (31%, 35%, 40%, respectively, p=0.28). However, individuals with low serum IgA and low serum IgM were more likely to have a higher TML (8%, 20%, 36% for IgA, p&lt;0.0001; and 35%, 45%, 54% for IgM, p&lt;0.0001, for TML scores of 0, 1, and 2+, respectively). After a median follow-up of 6.9 years, 157 individuals required CLL therapy. After adjusting for CLL-IPI and TML, low serum IgG, low serum IgA, and low serum IgM (hazard ratio [HR]: 1.8, 2.3, and 2.4, respectively, all p-values &lt;0.05) were independently associated with a shorter TFT. Our study shows that individuals with CLL/MBL who harbor mutations in NOTCH1, ATM and BIRC3 are more likely to have low serum IgA and IgM at diagnosis. Serum IgA and IgM (but not serum IgG) levels decrease with an increase in the TML score. Finally, low serum immunoglobulins can predict TFT, independent of the CLL-IPI and TML, which has important implications for risk stratification in newly diagnosed CLL/MBL. Citation Format: Sameer A. Parikh, Cristine Allmer, Geffen Kleinstern, Nicholas J. Boddicker, Shulan Tian, Cecilia B. De Campos, Laura A. Bruins, Daniel R. o"brien, Brian F. Kabat, Kari G. Rabe, Aaron D. Norman, Huihuang Yan, Xing Li, Timothy G. Call, Wei Ding, Jose F. Leis, Saad J. Kenderian, Celine M. Vachon, James R. Cerhan, Neil E. Kay, Susan L. Slager, Esteban Braggio. Serum immunoglobulins are an independent prognostic marker of time to first therapy in newly diagnosed chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6466.

Abstract Context Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. Objective To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44. Design and Intervention FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. Settings and Participants Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Main Outcome Measures Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. Results The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (&gt;82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. Conclusions The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

AbstractObjectivesRenal development is impaired in fetal growth restriction (FGR). Renal size can be considered a surrogate of renal function in childhood, and could be impaired in that condition. Our aim was to evaluate the ratio of total renal volume, measured by three‐dimensional ultrasound, to estimated fetal weight (TRV/EFW) among fetuses with and without growth restriction. Furthermore, we correlated TRV/EFW with fetal Doppler velocimetry and renal vascularization indexes and evaluated the association of renal volume and vascular parameters with adverse neonatal events in growth‐restricted fetuses.MethodsIn a retrospective cohort, TRV and renal vascularization of growth‐restricted and normal fetuses were evaluated by three‐dimensional ultrasonography and VOCAL technique. Independent samples t‐tests and Mann‐Whitney test were used for comparisons between groups. Logistic regression model was applied to evaluate the association between renal characteristics and adverse neonatal events.ResultsSeventy‐one growth‐restricted fetuses were compared to 194 controls. The TRV/EFW was lower in the growth‐restricted group (P < .001). In our sample, this ratio did not correlate with Doppler velocimetry parameters, renal vascular indexes or any adverse neonatal events.ConclusionThe TRV/EFW ratio is decreased in FGR. Further studies are needed to investigate the association of this ratio with long‐term renal outcomes.

Abstract We generated eight multiple myeloma cell lines resistant to bortezomib; five acquired PSMB5 mutations. In 1,500 patients such mutations were rare clinically. To better understand disruption of proteasomes on multiple myeloma viability and drug sensitivity, we systematically deleted the major proteasome catalytic subunits. Multiple myeloma cells without PSMB5 were viable. Drug-resistant, PSMB5-mutated cell lines were resensitized to bortezomib by PSMB5 deletion, implying PSMB5 mutation is activating in its drug resistance function. In contrast, PSMB6 knockout was lethal to multiple myeloma cell lines. Depleting PSMB6 prevented splicing of the major catalytic subunits PSMB5, PSMB7, PSMB8, and PSMB10; however, PSMB6 engineered without splicing function or catalytic activity, also restored viability, inferring the contribution of PSMB6 to proteasome structure to be more important than functional activity. Supporting this, bortezomib sensitivity was restored in drug-resistant multiple myeloma cell lines by low level expression of mutated PSMB6 lacking splicing function. Loss of PSMB8 and PSMB9 was neither lethal nor restored bortezomib sensitivity. Significant codependency of PSMB5, PSMB6, and PSMB7 expression was observed. We demonstrated elevated levels of PSMB6 and 7, but not 8 and 9, in some, but not all, serial patient samples exposed to proteasome inhibitors. In summary, we show PSMB6 and PSMB7, but not PSMB5, to be essential for multiple myeloma cell survival, this dependency is structural and that upregulation or activating mutation of PSMB5, 6, and 7 confers proteasome inhibitor resistance, while depletion confers sensitivity. Implications: These findings support modulation of PSMB5, PSMB6, or PSMB7 expression as a new therapeutic strategy.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.