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Objective In this study, we aimed to determine the cause of death (COD) after the diagnosis of neuroendocrine tumors (NET). Methods We used the Surveillance, Epidemiology and End Results (SEER) Program to review patients diagnosed with NET during 2000 to 2016. Patients were followed until death, and different CODs were determined. Results Of 94,399 patients with NETs, 40.9% died during the study period. During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (4.6%). After more than 10 years, NET deaths decreased to 24.3%, whereas other cancers and cardiac disease became more common. Neuroendocrine tumors were responsible for 42.8%, 63.4%, and 81.2% of deaths in grade I, grade II, and grade III, respectively. For grade I localized NET, other cancers (22.2%) were the most common COD followed by NET (19.7%), whereas in grade 2 localized NET, NET was COD in 31.1% of cases followed by other cancers (22.4%). In metastatic disease, NET was the most common COD regardless of grade. Conclusions For low-grade localized NET, deaths were mostly secondary to non-NET causes. In contrast, NET is responsible for most of deaths in metastatic NET regardless of grade.

OBJECTIVE Investigations of the combined effects of neoadjuvant Onyx embolization and stereotactic radiosurgery (SRS) on brain arteriovenous malformations (AVMs) have not accounted for initial angioarchitectural features prior to neuroendovascular intervention. The aim of this retrospective, multicenter matched cohort study is to compare the outcomes of SRS with versus without upfront Onyx embolization for AVMs using de novo characteristics of the preembolized nidus. METHODS The International Radiosurgery Research Foundation AVM databases from 1987 to 2018 were retrospectively reviewed. Patients were categorized based on AVM treatment approach into Onyx embolization (OE) and SRS (OE+SRS) or SRS alone (SRS-only) cohorts and then propensity score matched in a 1:1 ratio. The primary outcome was AVM obliteration. Secondary outcomes were post-SRS hemorrhage, all-cause mortality, radiological and symptomatic radiation-induced changes (RICs), and cyst formation. Comparisons were analyzed using crude rates and cumulative probabilities adjusted for competing risk of death. RESULTS The matched OE+SRS and SRS-only cohorts each comprised 53 patients. Crude rates (37.7% vs 47.2% for the OE+SRS vs SRS-only cohorts, respectively; OR 0.679, p = 0.327) and cumulative probabilities at 3, 4, 5, and 6 years (33.7%, 44.1%, 57.5%, and 65.7% for the OE+SRS cohort vs 34.8%, 45.5%, 59.0%, and 67.1% for the SRS-only cohort, respectively; subhazard ratio 0.961, p = 0.896) of AVM obliteration were similar between the matched cohorts. The secondary outcomes of the matched cohorts were also similar. Asymptomatic and symptomatic embolization-related complication rates in the matched OE+SRS cohort were 18.9% and 9.4%, respectively. CONCLUSIONS Pre-SRS AVM embolization with Onyx does not appear to negatively influence outcomes after SRS. These analyses, based on de novo nidal characteristics, thereby refute previous studies that found detrimental effects of Onyx embolization on SRS-induced AVM obliteration. However, given the risks incurred by nidal embolization using Onyx, this neoadjuvant intervention should be used judiciously in multimodal treatment strategies involving SRS for appropriately selected large-volume or angioarchitecturally high-risk AVMs.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.

AbstractBackgroundAlzheimer’s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN‐TU APT) platform launched a double‐blind, randomized, placebo‐controlled, parallel group trial of two anti‐amyloid‐beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN‐TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top‐line results will be presented.MethodDIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN‐TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN‐TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer’s Association, philanthropic supporters, the DIAN‐TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid‐trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.ResultThe primary and key secondary outcomes of the DIAN‐TU trial will be presented for each therapy in the context of targeting amyloid‐beta at pre‐clinical and clinically symptomatic stages of disease.ConclusionThese results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.

AbstractBackgroundGantenerumab is a humanized anti‐amyloid‐beta monoclonal antibody in clinical development for the treatment of several stages of Alzheimer disease (AD). Gantenerumab was evaluated in a phase 2/3 clinical trial program designed to evaluate its efficacy in autosomal dominant AD based on a combination of clinical and biomarker evidence.MethodThe study enrolled both mutation carriers (n=69 with 3:1 randomization of treatment (n=52) vs placebo (n=17)) and non‐carriers (n=28, all on placebo) from 15 years before to 10 years after the expected age of onset inclusive. Patients were both asymptomatic (CDR 0 and MMSE >25) and symptomatic (CDR 0.5‐1 and MMSE >16). There were 41 asymptomatic and 28 symptomatic mutation carriers. The initial dose of gantenerumab was 225 mg monthly administered subcutaneously. The dose was titrated to 1200 mg/month following a protocol amendment based on the increased amyloid lowering seen at higher doses in the gantenerumab program in symptomatic AD. The treatment duration was a minimum of 4 years (range 48‐80 months). The primary outcome was change from baseline in the DIAN‐TU multivariate cognitive endpoint. Secondary clinical outcomes included the DIAN‐TU cognitive composite, Cogstate multivariate cognitive endpoint, CDR SB, and time to CDR progression of >0.5 points. Change from baseline in amyloid PET was the primary biomarker outcome. Other biomarker outcomes included MRI, tau PET, CSF amyloid, tau and phosphotau, and CSF and plasma neurofilament light (NfL). Safety outcomes including ARIA were compared between drug and placebo groups.ResultWe will report change from baseline on the DIAN‐TU multivariate cognitive endpoint, DIAN‐TU cognitive composite, CDR‐SB and other secondary efficacy endpoints. We expect significant lowering on amyloid PET with PIB and florbetapir based on the results from recent anti‐amyloid antibodies, including Gantenerumab, in sporadic AD. We will also present the results of change in other key imaging and fluid biomarkers. The frequency, duration, and severity of ARIA will be reported and compared with studies in sporadic AD.ConclusionThis clinical trial was designed to inform future for ADAD and will provide new insights on the role of amyloid reduction in both pre‐symptomatic and clinical AD.

AbstractBackgroundSolanezumab is a monoclonal antibody targeting soluble forms of β‐amyloid protein important in the pathogenesis of Alzheimer’s disease (AD). Three previous 18‐month double‐blind placebo‐controlled trials of low‐dose solanezumab in late‐onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly‐inherited mutation‐associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.MethodMutation‐carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 – 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double‐blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN‐MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale‐Revised, the Digit Symbol Substitution Test total score from the WAIS‐R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN‐MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β‐amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre‐specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.ResultThe topline efficacy, safety and biomarker results will be reported.ConclusionThis study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti‐amyloid therapy in sporadic AD.

Abstract Aims Cardiac scintigraphy, a non-invasive technique for diagnosing ATTR cardiac amyloidosis, lacks specificity in patients with concomitant monoclonal gammopathy (up to 40% of cases). For these patients, amyloid type is often established by endomyocardial biopsy (EMB), which has clinical risk. This study aimed to investigate the frequency of ATTR in amyloid-positive tendon/synovium, urinary bladder, and prostate biopsies, sites for which prior biopsy specimens might exist for patients suspected of having cardiac amyloidosis, and, when available, determine the amyloid type concordance rate with other anatomic sites and provide clinical data regarding subsequent development of cardiac amyloidosis. Methods and results We queried our reference laboratory database of 19,298 amyloid specimens from myriad anatomic sites typed by mass spectrometry-based proteomics (LC-MS/MS) to investigate the frequency of ATTR amyloid in tendon/synovium, urinary bladder, and prostate. The amyloid type was ATTR in 104/138 (75.4%) tendon/synovium, 173/453 (38.0%) urinary bladder, and 27/81 (33.3%) prostate samples. Of 62 patients with available clinical data, 12 (19%) had bona fide ATTR cardiac amyloidosis prior to/concomitant with the non-cardiac site biopsy. Of the remaining 14 with follow-up, 8 developed bona fide and 2 probable cardiac amyloidosis; at last follow-up 4 had no evidence of cardiac amyloidosis. Fourteen of 16 patients (87.5%) for whom we typed both non-cardiac and cardiac sites had concordant amyloid types. There were 2 discordant cases (prostate = ASem1/heart = AL and urinary bladder = AL/heart = ATTR); only the latter is potentially clinically consequential. Conclusions In patients suspected of having cardiac amyloidosis based on cardiac scintigraphy, LC-MS/MS typing of Congophilic deposits in pre-existing biopsy specimens from non-cardiac sites may help establish the cardiac amyloid type, obviating the need for EMB. However, if the amyloid type identified in the non-cardiac site is not in keeping with other clinical features, then EMB for typing the cardiac amyloid might be indicated.

Abstract BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.

Abstract Diffuse midline gliomas with the H3.3 K27M mutation are lethal brain tumors in children. H3 K27M causes global loss of Lys27 triple methylation (Lys27me3), inducing epigenetic reprograming. Here we show that H3.3 K27M also causes decreased H3.3 Ser31 phosphorylation on mitotic chromosomes. We show that H3.3 K27M DIPG cells have reduced pericentromeric phospho-Ser31 and increased rates of chromosome missegregation compared to normal, diploid human cells. CRISPR-editing K27M to M27K restored phospho-Ser31 to WT levels and dramatically decreased the rate of chromosome missegregation. We confirm that Chk1 is the H3.3 Ser31 kinase: K27M mutant H3.3 protein exhibits ~60% reduced Chk1 phosphorylation of Ser31 in vitro. Chk1 knockdown completely abolishes phospho-Ser31 in cells and these have increased rates of chromosome missegregation. In normal, diploid cells, expression of K27M or an S31A non-phosphorylatable mutant increased chromosome missegregation; this is suppressed by expressing a phosphomimetic double mutant (K27M/S31E) that restores phospho-Ser31. WT cells arrest following chromosome missegregation. However, cells expressing H3.3 K27M or S31A fail to arrest - despite having WT p53. Finally, we expressed H3F3AS31A and PDGFb in an RCAS/TVA mouse model of DIPG and ~80% developed diffuse high-grade brain tumors and show significantly decreased survival. Our results suggest that loss of phospho-Ser31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest – thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming.