Citations

Abstract Introduction Skull base neuroanatomy is classically taught using surgical atlases. Although these texts are critical and rich resources for learning three-dimensional (3D) relationships between key structures, we believe they could be optimized and complemented with step-by-step anatomical dissections to fully meet the learning needs of trainees. Methods Six sides of three formalin-fixed latex-injected specimens were dissected under microscopic magnification. A far lateral craniotomy was performed by each of three neurosurgery resident/fellow at varying stages of training. The study objective was the completion and photodocumentation of the craniotomy to accompany a stepwise description of the exposure to provide a comprehensive, intelligible, and anatomically oriented resource for trainees at any level. Illustrative case examples were prepared to supplement approach dissections. Results The far lateral approach provides a wide and versatile corridor for posterior fossa operation, with access spanning the entire cerebellopontine angle (CPA), foramen magnum, and upper cervical region. Key Steps Include The study includes the following steps: positioning and skin incision, myocutaneous flap, placement of burr holes and sigmoid trough, fashioning of the craniotomy bone flap, bilateral C1 laminectomy, occipital condyle/jugular tubercle drilling, and dural opening. Conclusion Although more cumbersome than the retrosigmoid approach, a far lateral craniotomy offers unparalleled access to lesions centered lower or more medially in the CPA, as well as those with significant extension into the clival or foramen magnum regions. Dissection-based neuroanatomic guides to operative approaches provide a unique and rich resource for trainees to comprehend, prepare for, practice, and perform complex cranial operations, such as the far lateral craniotomy.

Objective: To analyze insulin delivery and glycemic metrics throughout the menstrual cycle for women with type 1 diabetes using closed loop control (CLC) insulin delivery. Methods: Menstruating women using a CLC system in a clinical trial were invited to record their menstrual cycles through a cycle-tracking application. Sixteen participants provided data for this secondary analysis over three or more complete cycles. Insulin delivery and continuous glucose monitoring (CGM) data were analyzed in relation to reported cycle phases. Results: Insulin delivery and CGM metrics remained consistent during cycle phases. Intraparticipant variability of CGM metrics and weight-based insulin delivery did not change through cycle phases. Conclusions: For this sample of menstruating women with type 1 diabetes using a CLC system, insulin delivery and glycemic metrics remained stable throughout menstrual cycle phases. Additional studies in this population are needed, particularly among women who report variable glycemic control during their cycles. Trial Registration: NCT03591354.

Abstract Introduction Although endonasal endoscopic approaches (EEA) to the orbit have been previously reported, a didactic resource for educating neurosurgery and otolaryngology trainees regarding the pertinent anatomy, techniques, and decision-making pearls is lacking. Methods Six sides of three formalin-fixed, color latex–injected cadaveric specimens were dissected using 4-mm 0- and 30-degree rigid endoscopes, as well as standard endoscopic equipment, and a high-speed surgical drill. The anatomical dissection was documented in stepwise three-dimensional (3D) endoscopic images. Following dissection, representative case applications were reviewed. Results EEA to the orbit provides excellent access to the medial and inferior orbital regions. Key steps include positioning and preoperative considerations, middle turbinate medialization, uncinate process and ethmoid bulla removal, complete ethmoidectomy, sphenoidotomy, maxillary antrostomy, lamina papyracea resection, orbital apex and optic canal decompression, orbital floor resection, periorbita opening, dissection of the extraconal fat, and final exposure of the orbit contents via the medial-inferior recti corridor. Conclusion EEA to the orbit is challenging, in particular for trainees unfamiliar with nasal and paranasal sinus anatomy. Operatively oriented neuroanatomy dissections are crucial didactic resources in preparation for practical endonasal applications in the operating room (OR). This approach provides optimal exposure to the inferior and medial orbit to treat a wide variety of pathologies. We describe a comprehensive step-by-step curriculum directed to any audience willing to master this endoscopic skull base approach.

Abstract Introduction: TP53 aberrations, including mutations and deletion of 17p (del17p), are important adverse prognostic markers in chronic lymphocytic leukemia (CLL). Prevalence of TP53 aberrations ranges from 7-11% in untreated CLL and increases with disease progression and treatment. Among CLL patients with TP53 aberrations, co-occurrence of TP53 mutations with del(17p) is common. CLL patients with TP53 mutations or del(17p) have significantly worse outcomes when compared to wild-type patients. Previous studies, focusing on CLL patients at time of treatment, are mixed as to whether a single or more than one TP53 aberration impacts outcomes. TP53 is less well studied in monoclonal B-cell lymphocytosis (MBL), an asymptomatic pre-malignant state of CLL. Del(17p) occurs in 3-4% of MBL individuals, and a study of 54 MBL individuals reported a 2% mutation frequency in TP53. Here we estimated prevalence and evaluated the impact of TP53 aberrations in a large cohort MBL or untreated CLL individuals. Methods : Patients with CLL or MBL diagnosed between 2000 and 2019 from the Mayo Clinic CLL Resource with pre-treatment peripheral blood mononuclear cells (PBMC) collected within two years of diagnosis were considered. DNA was extracted from PBMCs with purity >80% or with sorted CD5+/CD19+ clonal cells. The entire coding regions of 59 CLL driver genes were paired end sequenced. Median coverage depth was >1000x per nucleotide, allowing for detection of mutations with variant allelic fraction (VAF) as low as 1%. Somatic mutations were called using MuTect2 in tumor-only mode, and high impact mutations (frameshift, nonsense, and splicing variants) and missense mutations in CLL hot spots were selected. Somatic mutations and FISH del(17p) were used to define TP53 state for each patient: 1) wild-type [no TP53 mutations and normal del(17p)], 2) single-hit [one TP53 mutation or del(17p)], or 3) multi-hit [multiple TP53 mutations or TP53 mutation and del(17p)]. Time to first treatment (TTFT) and overall survival (OS) were analyzed by TP53 state. TTFT and OS were defined as time from sample collection to first treatment or death, respectively, or last follow-up date. Median TTFT and OS was estimated by the Kaplan-Meier method. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for TTFT and OS associations. The models were adjusted for known adverse prognostic factors including clinical diagnosis (CLL or MBL), age at diagnosis, Rai stage, b2 microglobulin, and IGHV mutation status. Results: Individuals with CLL (N=597) or MBL (N=285) were analyzed for prevalence of TP53 mutations and del(17p). We found 58 CLL patients (9.7%) and 15 MBL individuals (5.3%) had TP53 mutations. The median VAF in CLL was 30.9% (<10% VAF, n=21) and in MBL was 13.5% (<10% VAF, n=7). Del(17p) was present in 37 patients with CLL (6.2%) and 7 individuals with MBL (2.7%). In total, 86 CLL/MBL patients had a TP53 mutation and/or del(17p): 56.8% (48 patients) were single-hit and 44.2% (38 patients) were multi-hit (Fig. 1a). Patients with any TP53 aberration had shorter TTFT than wild-type patients (median 2.3 vs 9.4 years). Among patients with TP53 aberrations, median TTFT was shorter in multi-hit patients (20 events, 1.8 years) compared to single-hit patients (24 events, 3.2 years) (Fig. 1b). In Cox regression, single-hit (HR = 1.7 [1.1-2.6]) and multi-hit (HR = 1.8 [1.1-2.9]) patients had shorter TTFT compared to wild-type patients after adjusting for covariates (Fig. 1c). Multi-hit patients also had shorter OS compared to wild-type patients, while OS in single-hit patients did not significantly differ from wild-type patients (Fig. 1d). Median OS was 5.5 years in multi-hit patients (22 deaths) compared to 15.1 years in wild-type patients (196 deaths) and 14.3 years in single-hit patients (15 deaths). In the OS model adjusted for covariates, multi-hit patients had a significant increased risk (HR = 2.6 [1.6-4.1]), but single-hit patients did not (HR = 1.4 [0.8-2.5]) compared with wild-type patients (Fig. 1e). OS HRs remained stable after censoring at time of treatment. Both TTFT and OS HRs were consistent when mutations with VAF < 10% were excluded. Conclusions: This study suggests single versus multi-hit TP53 aberrations may be important for prognostic outcomes in untreated CLL and MBL patients. Prognostic metrics may need to consider single versus multi-hit TP53 aberrations and include TP53 mutations with low VAF. Figure 1 Figure 1. Disclosures Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Genentech: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: MEI Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees.

Abstract Venetoclax (VTX) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells presenting lymphoid features and those with translocation t(11;14). Despite its impressive clinical activity, VTX therapy for a prolonged duration can lead to drug resistance. Therefore, it is important to understand the underlying mechanisms of resistance in order to develop strategies to prevent or overcome resistance. In the present study, we established four VTX resistant human myeloma cell lines (HMCLs) from four sensitive HMCLs, including three with t(11;14), in culture with a stepwise increase in treatment dose with VTX. To identify the molecular basis of acquired VTX resistance, whole exon sequencing (WES), mRNA-sequencing (mRNAseq), and protein expression assays were performed in the four isogenic VTX-sensitive/resistant HMCLs and three MM patients with samples collected before VTX administration and after clinical resistance to the drug. Compared with sensitive cell lines and patient samples collected before VTX administration, mRNAseq analysis identified downregulation of BIM and upregulation of BCLXL in both resistant cell lines and MM cells from relapse patients. Other transcriptional changes detected included upregulation of AURKA, BIRC3, BIRC5, and IL32. Enrichment analysis of differentially expressed genes suggested involvement of PI3K and MAPK signaling, likely associated with cytokines, growth factors (EGF, FGF and IGF family members), and receptor tyrosine kinase (EGF and FGF). Western blot analysis was performed to compare BCL2 family expression in resistant cell lines versus sensitive cell lines and it showed upregulation of BCL2 survival members (such as MCL-1 and BCLXL), and downregulation of pro-apoptotic BH3 members (such as BIM and PUMA). BIM expression was completely lost in one resistant cell line, and introduction of exogenous BIM into this cell line enhanced VTX sensitivity. Interestingly, BCL2 was upregulated in some resistant cell lines generated after a long-term treatment with VTX, suggesting BCL2 expression level may not be suitable as a marker of VTX sensitivity for acquired resistance. Unlike in CLL, BCL2 mutations were not identified through WES in any resistant cell lines or primary patient sample harvested after relapse. While 8 genes were mutated in two resistant samples , no clear mutational pattern emerged . Based on the above, we further tested some specific inhibitors in in vitro or ex vivo cell models to help understanding resistant mechanism and identify strategies to overcome VTX resistance. We found that inhibition of MCL-1, with the compound S68345, substantially enhanced VTX sensitivity in three resistant HMCLs and in primary cells from one relapsed MM patient. A BCLXL inhibitor (A155463) only significantly enhanced VTX sensitivity in one resistant cell line after co-treatment with VTX. Co-treatment of the other three resistant cell lines with VTX, S68345 and A155463 resulted in the most synergistic anti-myeloma activity, suggesting those cell lines are co-dependent on MCL-1, BCLXL, and BCL2 for survival, although they are more dependent on MCL-1. We also found that inhibition of PI3K signaling, IGF1, RTK (EGF and FGF) and AURKA significantly increased VTX sensitivity, partially through downregulation of MCL-1, and BCLXL, and upregulation of BIM. Conventional anti-MM drugs such as dexamethasone, bortezomib and lenalidomide, were shown to have little activity on augmenting VTX sensitivity in most resistant cell lines. In summary, we find that acquired resistance to VTX in MM is largely associated with BCL2 family regulation, including upregulation of survival members such as MCL-1, BCLXL, BCL2, and downregulation of pro-apoptotic members, especially BIM. Our study also indicates that upstream signaling involved in BCL2 family regulation during acquired resistance is likely related to cytokine, growth factor, and/or RTK-induced cell signaling such as PI3K. Co-inhibition of MCL-1, or BCLXL, as well as the upstream PI3K, RTK (FGF and EGF), IGF-1 mediated signaling were effective in overcoming VTX resistance. Disclosures Fonseca: Mayo Clinic in Arizona: Current Employment; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNA) and mutations that are central to disease pathogenesis, prognosis, risk-stratification, and identification of response or resistance to therapies. Fluorescence in situ hybridization (FISH) is gold standard in the clinical laboratory for detecting prognostic CNAs in CLL (e.g. deletion 17p13 (del(17p), deletion 11q23 (del(11q), deletion 13q14 (del(13q), and trisomy 12). Most clinical FISH assays have high specificity and sensitivity, but the technique can detect a limited number of alterations per assay. Importantly, next-generation sequencing (NGS) techniques have become more readily available for clinical applications and are increasingly being used for screening not only mutations, but also copy number abnormalities in multiple genes and chromosomal regions of interest in hematologic malignancies. Here, we evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using a custom targeted NGS assay for detecting common prognostic chromosomal alterations in CLL and high-count monoclonal B-cell lymphocytosis (MBL), the precursor to CLL. Methods : We designed a SureSelect DNA targeted sequencing panel, covering all exons of 59 recurrently CLL mutated genes and additional amplicons across regions affected by clinically relevant CNAs. All CLL (N=534) and MBL (N=162) patients had pre-treatment peripheral blood mononuclear cells (PBMC) collected within two years of diagnosis. DNA was extracted in cases with purity >80% of CD5+/CD19+ cells. Clinical FISH data was available within 100 days of NGS in all untreated CLL and MBL cases. PatternCNV was used to detect clinically relevant CNAs in chromosomes 11, 12, 13 and 17. We performed a principal component analysis on the CNA calls, excluding chromosomes 11, 12, 13, and 17 to identify clusters of samples. Each cluster was then independently rerun with PatternCNV and the results from chromosomes 11, 12, 13, and 17 were extracted and further analyzed. We excluded samples with low tumor metrics identified by FISH (less than 20% of cells with del(17p), del(11q), trisomy 12 and del(13q)). Results: We sequenced a total of 696 patients of whom 162 were MBL and 534 were untreated CLL. The most commonly mutated genes were NOTCH1 (11.0%), TP53 (8.7%), SF3B1 (7.7%), ATM (4.1%), and CHD2 (3.8%). Based on CNA analyses from the NGS data, we identified 59 (9.1%) individuals with del(17p), 88 (13.4%) individuals with del(11q), 128 (20.0%) individuals with trisomy 12, and 329 (53.0%) individuals with del(13q). All 696 individuals had FISH panels conducted, with 39 (5.6%) individuals with del(17p), 68 (9.8%) individuals with (11q), 119 (17.1%) with trisomy 12, and 295 (42.4%) with del(13q). When we compared our CNA analyses with the FISH data, we found high concordance 95.0% for del(17p), 92.7% del(11p), 94.3% for trisomy 12, and 88.2% for del(13q). For del(17p) we found a sensitivity of 93.9%, specificity of 95.4%, PPV of 52.5%, and NPV of 99.7%. Del(11q) revealed a sensitivity of 88.1%, specificity of 94.0%, PPV of 59.1%, and NPV 98.8%. We found a sensitivity of 93.8%, specificity of 95.6%, PPV 82.0%, and NPV of 98.6% for trisomy 12 and for del(13q) we found a sensitivity of 92.6%, specificity of 90.9%, PPV of 91.7%, and NPV of 93.8%. We found lower PPVs in del(17p) and del(11q) likely due to lower prevalence of these chromosomal abnormalities. Conclusion: Here we show a high sensitivity, specificity, and NPV when comparing targeted sequencing with FISH. FISH panel testing is widely used in clinical practice to characterize highly prognostic chromosomal abnormalities in CLL. Comprehensive genetic profiling with NGS has become increasingly important in the work up of hematologic malignancies and provides additional prognostic and predictive information, including clinically relevant mutations such as TP53, SF3B1, and NOTCH1, tumor mutation load and mutations associated with resistance to chemo-immunotherapy and targeted therapies, such as BTK or BCL2 inhibitors, that FISH cannot offer. We show that NGS can infer clinically relevant CNA in cases without FISH testing while also providing additional clinically relevant information. Figure 1 Figure 1. Disclosures Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Genentech: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: Genentech: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Acerta Pharma: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees.

Abstract Background Individuals increasingly want to access, contribute to, and share their personal health information to improve outcomes, such as through shared decision-making (SDM) with their care teams. Health systems' growing capacity to use person-generated health data (PGHD) expands the opportunities for SDM. However, SDM not only lacks organizational and information infrastructure support but also is actively undermined, despite public interest in it. Objectives This work sought to identify challenges to individual–clinician SDM and policy changes needed to mitigate barriers to SDM. Methods Two multi-stakeholder group of consumers, patients, caregivers; health services researchers; and experts in health policy, informatics, social media, and user experience used a consensus process based on Bardach's policy analysis framework to identify barriers to SDM and develop recommendations to reduce these barriers. Results Technical, legal, organizational, cultural, and logistical obstacles make data sharing difficult, thereby undermining use of PGHD and realization of SDM. Stronger privacy, security, and ethical protections, including informed consent; promoting better consumer access to their data; and easier donation of personal data for research are the most crucial policy changes needed to facilitate an environment that supports SDM. Conclusion Data protection policy lags far behind the technical capacity for third parties to share and reuse electronic information without appropriate permissions, while individuals' right to access their own health information is often restricted unnecessarily, poorly understood, and poorly communicated. Sharing of personal information in a private, secure environment in which data are shared only with individuals' knowledge and consent can be achieved through policy changes.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.

AbstractObjectiveSatiety, defined as the duration of the sensation of fullness, is usually measured by validated visual analog scales (VAS) for appetite. Gastric function plays a key role in food intake regulation. However, the association between gastric emptying (GE) and VAS appetite is unknown.MethodsIn this cross‐sectional study, 134 participants (mean [SEM] age = 39 [0.8] years, mean [SEM] BMI = 38 [0.5] kg/m2, 67% females) completed simultaneous measurements of GE and VAS appetite. After a 320‐kcal meal, GE was measured by scintigraphy and appetite by validated 100‐mm VAS for 240 minutes. Satiation was defined as calories consumed to terminate meal and was measured by an ad libitum meal. GE, VAS, and ad libitum meal tests were measured on the same day. Percent of meal retention in the stomach, VAS area under curve (AUC0‐240 min), and overall appetite score (OAS) were calculated. Pearson correlation (ρ) determined the association of GE with VAS appetite and satiation. Appetite components were also analyzed by quartiles based on GE120 min.ResultsGE120 min was correlated with sensation of VAS hungerAUC(0‐240 min) (ρ = 0.24, p = 0.004), fullnessAUC(0‐240 min) (ρ = 0.16, p = 0.05), and OASAUC(0‐240 min) (ρ = 0.20, p = 0.02). Patients with rapid GE120 min had a mean increase in VAS hungerAUC(0‐240 min) by 32 mm/min (15.62%, p = 0.03) compared with normal/slow GE120 min.ConclusionsGE is associated with the sensations of appetite, and rapid GE is associated with increased appetite, which may contribute to weight gain.