The human neonatal cerebellum is one-fourth of its adult size yet contains the blueprint required to integrate environmental cues with developing motor, cognitive and emotional skills into adulthood. ...Although mature cerebellar neuroanatomy is well studied, understanding of its developmental origins is limited. In this study, we systematically mapped the molecular, cellular and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics. We profiled functionally distinct regions and gene expression dynamics within cell types and across development. The resulting cell atlas demonstrates that the molecular organization of the cerebellar anlage recapitulates cytoarchitecturally distinct regions and developmentally transient cell types that are distinct from the mouse cerebellum. By mapping genes dominant for pediatric and adult neurological disorders onto our dataset, we identify relevant cell types underlying disease mechanisms. These data provide a resource for probing the cellular basis of human cerebellar development and disease.
Initiation of the antiarrhythmic medication dofetilide requires an FDA-mandated 3 days of telemetry monitoring due to heightened risk of toxicity within this time period. Although a recommended dose ...management algorithm for dofetilide exists, there is a range of real-world approaches to dosing the medication.
In this multicenter investigation, clinical data from the Antiarrhythmic Drug Genetic (AADGEN) study was examined for 354 patients undergoing dofetilide initiation. Univariate logistic regression identified a starting dofetilide dose of 500 mcg (OR 5.0, 95%CI 2.5-10.0, p<0.001) and sinus rhythm at the start of dofetilide loading (OR 2.8, 95%CI 1.8-4.2, p<0.001) as strong positive predictors of successful loading. Any dose-adjustment during loading (OR 0.19, 95%CI 0.12-0.31, p<0.001) and a history coronary artery disease (OR 0.33, 95%CI 0.19-0.59, p<0.001) were strong negative predictors of successful dofetilide loading. Based on the observation that any dose adjustment was a significant negative predictor of successful initiation, we applied multiple supervised approaches to attempt to predict the dose adjustment decision, but none of these approaches identified dose adjustments better than a probabilistic guess. Principal component analysis and cluster analysis identified 8 clusters as a reasonable data reduction method. These 8 clusters were then used to define patient states in a tabular reinforcement learning model trained on 80% of dosing decisions. Testing of this model on the remaining 20% of dosing decisions revealed good accuracy of the reinforcement learning model, with only 16/410 (3.9%) instances of disagreement.
Dose adjustments are a strong determinant of whether patients are able to successfully initiate dofetilide. A reinforcement learning algorithm informed by unsupervised learning was able to predict dosing decisions with 96.1% accuracy. Future studies will apply this algorithm prospectively as a data-driven decision aid.
The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene fusion rearrangements that determine diagnosis, behavior, and ...response to therapy. We present herein 4 new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes. We studied the clinical presentation, pathologic features, genetics (FISH, targeted RNA sequencing) and outcome in these 4 patients. We also reviewed the literature describing similar cases. All our patients were male. The median age at diagnosis was 33.5 years. All tumors presented in long bones of the extremities as a large destructive mass with a mean size of 12.5 cm. All cases were hypercellular with prominent collagenous stroma and consisted of small to medium size round cells arranged in cords, thin trabeculae, and pseudoacinar structures. Most cases showed focal or diffuse membrane staining for CD99; whereas S100, synaptophysin and chromogranin were negative. EMA showed cytoplasmic staining in one case. Genetic studies identified EWSR1-NFATc2 fusion in 3 cases, and FUS-NFATc2 fusion in one case. Two patients were treated with neoadjuvant chemotherapy using Ewing sarcoma regimens, and surgical excision was performed on 3 patients; necrosis was minimal. Follow-up is limited; after a median follow-up of 8.7 months, one patient developed local recurrence and metastases to the lungs. Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon. The tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma. Importantly, these tumors do not respond to Ewing sarcoma chemotherapy regimens.
•The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene-fusion rearrangements that determine diagnosis, behavior, and response to therapy.•Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon.•EWSR1/FUS-NFATc2 tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma.•EWSR1/FUS-NFATc2 tumors do not respond to Ewing sarcoma chemotherapy regimens.
VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor ...axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.
This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0–1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2–10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.
Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1–19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6–79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1–90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five 15% of 33 patients), autoimmune toxicities (five 15%), nausea or vomiting (two 6%), and seizures (two 6%). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.
Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.
Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. ...Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas.
We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue.
We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4). Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities.
This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.
Primary malignant bone tumors are uncommon and their accurate classification requires careful correlation of clinical, radiological, and pathologic findings. It is a heterogeneous group of tumors ...with a wide spectrum of morphology and their biological potential can be of low- or high-grade, depending on their risk for developing metastases. Over the past several decades, the classification of bone sarcomas has remained largely constant. However, some of the tumors have been reclassified and several new entities have emerged. In this review, we will focus on pleomorphic fibrosarcoma/UPS and dedifferentiated bone tumors, discuss their key diagnostic features, differential diagnosis, and their relation to prognosis.
Spinal chordomas can have high local recurrence rates after surgery with or without conventional dose radiation therapy (RT). Treatment outcomes and prognostic factors after high-dose proton-based RT ...with or without surgery were assessed.
The authors conducted a retrospective review of 126 treated patients (127 lesions) categorized according to disease status (primary vs recurrent), resection (en bloc vs intralesional), margin status, and RT timing.
Seventy-one sacrococcygeal, 40 lumbar, and 16 thoracic chordomas were analyzed. Mean RT dose was 72.4 GyRBE (relative biological effectiveness). With median follow-up of 41 months, the 5-year overall survival (OS), local control (LC), locoregional control (LRC), and distant control (DC) for the entire cohort were 81%, 62%, 60%, and 77%, respectively. LC for primary chordoma was 68% versus 49% for recurrent lesions (p = 0.058). LC if treated with a component of preoperative RT was 72% versus 54% without this treatment (p = 0.113). Among primary tumors, LC and LRC were higher with preoperative RT, 85% (p = 0.019) and 79% (0.034), respectively, versus 56% and 56% if no preoperative RT was provided. Overall LC was significantly improved with en bloc versus intralesional resection (72% vs 55%, p = 0.016), as was LRC (70% vs 53%, p = 0.035). A trend was noted toward improved LC and LRC for R0/R1 margins and the absence of intralesional procedures.
High-dose proton-based RT in the management of spinal chordomas can be effective treatment. In patients undergoing surgery, those with primary chordomas undergoing preoperative RT, en bloc resection, and postoperative RT boost have the highest rate of local tumor control; among 28 patients with primary chordomas who underwent preoperative RT and en bloc resection, no local recurrences were seen. Intralesional and incomplete resections are associated with higher local failure rates and are to be avoided.
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