Publications by authors named "John A Thompson"

191 Publications

Letter in response to Rivastigmine for the treatment of anticholinergic delirium following severe procyclidine intoxication.

Clin Toxicol (Phila) 2021 Feb 12:1-3. Epub 2021 Feb 12.

Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon, USA.

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http://dx.doi.org/10.1080/15563650.2020.1869757DOI Listing
February 2021

Retrospective analysis of hemispheric structural network change as a function of location and size of glioma.

Brain Commun 2021 17;3(1):fcaa216. Epub 2020 Dec 17.

Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA.

Gliomas are neoplasms that arise from glial cell origin and represent the largest fraction of primary malignant brain tumours (77%). These highly infiltrative malignant cell clusters modify brain structure and function through expansion, invasion and intratumoral modification. Depending on the growth rate of the tumour, location and degree of expansion, functional reorganization may not lead to overt changes in behaviour despite significant cerebral adaptation. Studies in simulated lesion models and in patients with stroke reveal both local and distal functional disturbances, using measures of anatomical brain networks. Investigations over the last two decades have sought to use diffusion tensor imaging tractography data in the context of intracranial tumours to improve surgical planning, intraoperative functional localization, and post-operative interpretation of functional change. In this study, we used diffusion tensor imaging tractography to assess the impact of tumour location on the white matter structural network. To better understand how various lobe localized gliomas impact the topology underlying efficiency of information transfer between brain regions, we identified the major alterations in brain network connectivity patterns between the ipsilesional versus contralesional hemispheres in patients with gliomas localized to the frontal, parietal or temporal lobe. Results were indicative of altered network efficiency and the role of specific brain regions unique to different lobe localized gliomas. This work draws attention to connections and brain regions which have shared structural susceptibility in frontal, parietal and temporal lobe glioma cases. This study also provides a preliminary anatomical basis for understanding which affected white matter pathways may contribute to preoperative patient symptomology.
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http://dx.doi.org/10.1093/braincomms/fcaa216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811759PMC
December 2020

Fecal calprotectin concentration to assess endoscopic and histologic remission in patients with cancer with immune-mediated diarrhea and colitis.

J Immunother Cancer 2021 Jan;9(1)

Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Immune-mediated diarrhea and colitis (IMDC) is currently diagnosed and monitored by evaluating clinical symptoms. Deep remission is determined by endoscopic and histologic evaluation of the disease process. However, repeating these invasive procedures frequently can become cumbersome. We sought to assess the role of fecal calprotectin (FC) concentration as a non-invasive biomarker of endoscopic or histologic remission.

Methods: We performed a retrospective study of patients with IMDC who were tested for FC at IMDC onset and after IMDC treatment between June 2016 and March 2020. Patient demographics, clinical variables, and FC data were collected and analyzed to determine the optimal cut-off FC concentration to predict endoscopic and histologic remission.

Results: Our sample comprised 77 patients with a median age of 62 years; 66% were male and 94% were Caucasian. Sixty-five patients (84%) achieved clinical remission, 46 (60%) achieved endoscopic remission, and 24 (31%) achieved histologic remission after IMDC treatment. FC concentrations decreased from the time of IMDC onset to the end of treatment (p0.001). High FC concentrations were associated with evident endoscopic inflammation (p=0.003) and acute/chronic active colitis (p=0.025) which positively correlated with the Mayo Endoscopic Subscore (r=0.615, p0.001) at the time of IMDC onset. In patients who achieved endoscopic remission after treatment, a significantly lower FC concentration was observed at IMDC onset (p=0.006) and after treatment (p<0.001) compared with those without endoscopic remission. The cut-off FC concentration to predict endoscopic remission was ≤116 μg/g and for histologic remission ≤80 μg/g; these cut-offs had optimal specificity (94% and 85%, respectively) and positive predictive value (0.91 and 0.38, respectively).

Conclusions: FC concentration may serve as a non-invasive biomarker to predict endoscopic and histologic remission in patients receiving treatment for IMDC, minimizing the need for frequent invasive endoscopies. Future prospective studies are needed to provide further insight on the role of this marker in disease surveillance.
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http://dx.doi.org/10.1136/jitc-2020-002058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805368PMC
January 2021

Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary.

Future Oncol 2021 Feb 5;17(4):363-369. Epub 2021 Jan 5.

Department of Epidemiology, University of Washington School of Public Health, Seattle, WA 98195, USA.

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.
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http://dx.doi.org/10.2217/fon-2020-0730DOI Listing
February 2021

"Pressed" Etizolam.

J Pediatr 2021 Jan 1. Epub 2021 Jan 1.

Department of Emergency Medicine, Oregon Poison Center, Oregon Health & Science University, Portland, Oregon.

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http://dx.doi.org/10.1016/j.jpeds.2020.12.075DOI Listing
January 2021

Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response.

J Natl Compr Canc Netw 2020 Dec 14:1-9. Epub 2020 Dec 14.

2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes.

Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis.

Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018).

Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.
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http://dx.doi.org/10.6004/jnccn.2020.7647DOI Listing
December 2020

A Randomized Phase II Study of AGS-16C3F Versus Axitinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma.

Oncologist 2021 Mar 19;26(3):182-e361. Epub 2021 Jan 19.

University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Lessons Learned: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. Median progression-free survival, the primary endpoint, was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107-2.537; p = .015), per investigator assessment The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.

Background: AGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC).

Methods: Patients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST version 1.1).

Results: In the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107-2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681-1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%).

Conclusion: The investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.
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http://dx.doi.org/10.1002/onco.13628DOI Listing
March 2021

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

Melanoma Res 2021 02;31(1):67-75

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.
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http://dx.doi.org/10.1097/CMR.0000000000000708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757740PMC
February 2021

Constant Current versus Constant Voltage: Clinical Evidence Supporting a Fundamental Difference in the Modalities.

Stereotact Funct Neurosurg 2020 Nov 23:1-5. Epub 2020 Nov 23.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada.

Background: Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Early versions of implantable systems delivered stimulation with constant voltage (CV); however, advances in available and newer platforms have permitted programming in constant current (CC). From a treatment management perspective, there are theoretical advantages of CC stimulation. In this case series, we present clinical evidence supporting the maintenance of current regardless of changes to impedance.

Materials And Methods: This case series included 3 patients with Parkinson's disease status post-bilateral subthalamic nucleus DBS. Patients in this series self-reported intermittent diplopia with pressure applied to the scalp. Patients were subsequently examined and converted from CV to CC and re-examined. Impedances were checked prior to and after conversion from CV to CC as well as while applying pressure to the scalp that induced the adverse effects.

Results: Across patients, we observed that compression of the scalp overlying the connector, while patients were maintained in CV, consistently and objectively induced unilateral adduction of an eye. In addition, during scalp compression, while in CV, impedance was reduced, which would increase current delivery. Converting the patients to CC stimulation without changing other stimulation parameters eliminated diplopia and objective findings of eye deviation with compression of the scalp overlying the hardware despite changes in impedance.

Conclusions: In this case series, we provide clinical support for the principal differences between CV and CC stimulation.
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http://dx.doi.org/10.1159/000510803DOI Listing
November 2020

Prognostic Gene Expression Profiling in Cutaneous Melanoma: Identifying the Knowledge Gaps and Assessing the Clinical Benefit.

JAMA Dermatol 2020 09;156(9):1004-1011

Stanford University Medical Center and Cancer Institute, Stanford, California.

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.

Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.

Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.

Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.

Conclusions And Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.
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http://dx.doi.org/10.1001/jamadermatol.2020.1729DOI Listing
September 2020

Untangling the Multidisciplinary Care Web: Streamlining Care Through an Immune-Related Adverse Events (IRAE) Tumor Board.

Target Oncol 2020 Aug;15(4):541-548

Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA.

Immune-related adverse events (IRAEs) are becoming increasingly common as the use of immune checkpoint inhibitors expands into more tumor types and treatment settings. Although the majority of IRAEs are mild and can be managed in the outpatient setting by the medical oncologist, severe IRAEs can be life threatening and often require complex care coordination among multiple providers. These providers include a variety of non-oncology specialists who have interest and expertise in managing IRAEs. Multiple systems-based solutions have been proposed in the literature, but these need to be tailored to the needs and resources of each practice setting. In this article, we highlight the challenges of IRAE care by presenting an illustrative case from our institution. We then describe the format and structure of the IRAE Tumor Board established at the University of Washington/Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Finally, we discuss how this tumor board attempts to address clinical issues related to complex IRAE presentations and provide IRAE education.
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http://dx.doi.org/10.1007/s11523-020-00739-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489785PMC
August 2020

Discrete changes in brain volume after deep brain stimulation in patients with Parkinson's disease.

J Neurol Neurosurg Psychiatry 2020 09 10;91(9):928-937. Epub 2020 Jul 10.

Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Objectives: Deep brain stimulation (DBS), targeting the subthalamic nucleus (STN) and globus pallidus interna, is a surgical therapy with class 1 evidence for Parkinson's disease (PD). Bilateral DBS electrodes may be implanted within a single operation or in separate staged surgeries with an interval of time that varies patient by patient. In this study, we used the variation in the timing of implantation from the first to the second implantation allowing for examination of potential volumetric changes of the basal ganglia in patients with PD who underwent staged STN DBS.

Methods: Thirty-two patients with a mean time interval between implantations of 141.8 (±209.1; range: 7-700) days and mean duration of unilateral stimulation of 244.7 (±227.7; range: 20-672) days were included in this study. Using volumetric analysis of whole hemisphere and subcortical structures, we observed whether implantation or stimulation affected structural volume.

Results: We observed that DBS implantation, but not the duration of stimulation, induced a significant reduction of volume in the caudate, pallidum, putamen and thalamus ipsilateral to the implanted hemisphere. These findings were not dependent on the trajectory of the implanted electrode nor on first surgery pneumocephalus (0.07%: %Δ for intracranial volume between first and second surgery). In addition, unique regional atrophy differences were evident in each of the structures.

Conclusion: Our results demonstrate that DBS implantation surgery may affect hemisphere volume at the level of subcortical structures connected to the surgical target.
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http://dx.doi.org/10.1136/jnnp-2019-322688DOI Listing
September 2020

Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B.

Clin Cancer Res 2020 Oct 30;26(19):5086-5091. Epub 2020 Jun 30.

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

Purpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte-associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma.

Patients And Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

Results: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively.

Conclusions: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0177DOI Listing
October 2020

The Combined Endoscopic Endonasal Far Medial and Open Postauricular Transtemporal Approaches As a Lesser Invasive Approach to the Jugular Foramen: Anatomic Morphometric Study With Case Illustration.

Oper Neurosurg (Hagerstown) 2020 09;19(4):471-479

Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona.

Background: Access to the jugular foramen (JF) requires extensive approaches. An endoscopic endonasal far medial (EEFM) approach combined with a postauricular transtemporal (PTT) approach may provide adequate exposure with limited morbidities.

Objective: To provide a quantitative anatomic comparison of the EEFM, the PTT, and the combined EEFM/PTT approaches. A clinical case of the combined approach is presented.

Methods: Five cadaveric heads were dissected. Each specimen received PTT and EEFM approaches on opposite sides followed by an EEFM approach on the side of the PTT approach. Morphometric and quadrant analyses were conducted. Three groups were obtained and compared: PTT (group A), EEFM (group B), and combined (group C).

Results: Group B had a significantly higher area of exposure of the JF as compared to group A (112.3 and 225 mm2, respectively, P = .004). The average degree of freedom (DOF) in the cranio-caudal plane for groups A and B was 63.6 and 12.6 degrees, respectively (P < .00001). Group A had a higher DOF in the medial-lateral plane than group B (49 vs 13.4 degrees, respectively, P < .00001. The average volume of exposure in groups A and B was 1469.2 and 1897.4 mm3, respectively (P = .02). By adding an EEFM approach to the PTT approach, an additional 56.1% of the anterior quadrant was exposed, representing a 584.4% increase in the anterior exposure.

Conclusion: The PTT and EEFM approaches provide optimal exposures to different aspects of the JF and in combination may constitute a less invasive alternative to the more extensive approaches.
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http://dx.doi.org/10.1093/ons/opaa080DOI Listing
September 2020

Stimulation Mapping Using Stereoelectroencephalography: Current and Future Directions.

Front Neurol 2020 12;11:320. Epub 2020 May 12.

Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, United States.

Electrical stimulation mapping (ESM) using stereoelectroencephalography (SEEG) is an essential component in the workup of surgical epilepsy. Since the initial application of ESM in the mid-1960s, it remains unparalleled in defining eloquent brain areas and delimiting seizure foci for the purposes of surgical planning. Here, we briefly review the current state of SEEG stimulation, with a focus on the techniques used for identifying the epileptogenic zone and eloquent cortex. We also summarize clinical data on the efficacy of SEEG stimulation in surgical outcomes and functional mapping. Finally, we briefly highlight future applications of SEEG ESM, including novel functional mapping approaches, identifying rare seizure semiologies, neurophysiologic investigations for understanding cognitive function, and its role in SEEG-guided radiofrequency thermal coagulation.
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http://dx.doi.org/10.3389/fneur.2020.00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238877PMC
May 2020

Immunologic adverse events from immune checkpoint therapy.

Best Pract Res Clin Rheumatol 2020 08 13;34(4):101511. Epub 2020 Apr 13.

Seattle Cancer Care Alliance, Fred Hutch Clinical Research Division, 825 Eastlake Ave E, Seattle, WA 98109, United States.

The growth of cancer immunotherapy has led to an urgent need for a multispecialty approach to treating patients with advanced malignancies. Checkpoint inhibitor therapies cause a wide range of toxicities termed immune-related adverse events (irAEs) that can affect any organ system. Similar to the anti-tumor responses induced by these medications, irAEs represent an interruption of self-tolerance that results in T cell-driven cytotoxicity, the exact mechanisms of which are likely heterogeneous. This review describes the various immunologic pathways that may lead to irAEs along with the diverse clinical manifestations seen in clinical practice. Treatment based on the severity and specific organ involvement will also be discussed, along with an overview of current guidelines and potential challenges that arise with immunosuppressive medications.
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http://dx.doi.org/10.1016/j.berh.2020.101511DOI Listing
August 2020

NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020.

J Natl Compr Canc Netw 2020 03;18(3):230-241

National Comprehensive Cancer Network.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.
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http://dx.doi.org/10.6004/jnccn.2020.0012DOI Listing
March 2020

NCCN Guidelines Insights: Uveal Melanoma, Version 1.2019.

J Natl Compr Canc Netw 2020 02;18(2):120-131

National Comprehensive Cancer Network.

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.
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http://dx.doi.org/10.6004/jnccn.2020.0007DOI Listing
February 2020

Striatal and Thalamic Auditory Response During Deep Brain Stimulation for Essential Tremor: Implications for Psychosis.

Neuromodulation 2020 Jun 5;23(4):478-488. Epub 2020 Feb 5.

Department of Neurosurgery, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.

Introduction: The P50, a positive auditory-evoked potential occurring 50 msec after an auditory click, has been characterized extensively with electroencephalography (EEG) to detect aberrant auditory electrophysiology in disorders like schizophrenia (SZ) where 61-74% have an auditory gating deficit. The P50 response occurs in primary auditory cortex and several thalamocortical regions. In rodents, the gated P50 response has been identified in the reticular thalamic nucleus (RT)-a deep brain structure traversed during deep brain stimulation (DBS) targeting of the ventral intermediate nucleus (VIM) of the thalamus to treat essential tremor (ET) allowing for interspecies comparison. The goal was to utilize the unique opportunity provided by DBS surgery for ET to map the P50 response in multiple deep brain structures in order to determine the utility of intraoperative P50 detection for facilitating DBS targeting of auditory responsive subterritories.

Materials And Methods: We developed a method to assess P50 response intraoperatively with local field potentials (LFP) using microelectrode recording during routine clinical electrophysiologic mapping for awake DBS surgery in seven ET patients. Recording sites were mapped into a common stereotactic space.

Results: Forty significant P50 responses of 155 recordings mapped to the ventral thalamus, RT and CN head/body interface at similar rates of 22.7-26.7%. P50 response exhibited anatomic specificity based on distinct positions of centroids of positive and negative responses within brain regions and the fact that P50 response was not identified in the recordings from either the internal capsule or the dorsal thalamus.

Conclusions: Detection of P50 response intraoperatively may guide DBS targeting RT and subterritories within CN head/body interface-DBS targets with the potential to treat psychosis and shown to modulate schizophrenia-like aberrancies in mouse models.
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http://dx.doi.org/10.1111/ner.13101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299762PMC
June 2020

Automatic detection and quantification of hand movements toward development of an objective assessment of tremor and bradykinesia in Parkinson's disease.

J Neurosci Methods 2020 03 7;333:108576. Epub 2020 Jan 7.

Department of Electrical Engineering, University of Colorado Denver, Denver, Colorado, USA. Electronic address:

Background: Classification of parkinsonian symptoms, including tremor and bradykinesia, require the application of validated clinical rating scales which are inherently subjective. In this study, we assessed an objective measure of parkinsonian symptomology using automated analysis of hand gestures.

New Method: We constructed and evaluated a hand and finger motion capture apparatus and analysis pipeline that recorded hand/finger motion of control subjects and patients with Parkinson's disease. The detailed three-dimensional (3D) motion features of each finger joint was extracted by using Discrete Wavelet Transform (DWT). The severity of tremor for each finger joint was quantitated by analyzing the motion changes in the frequency domain on four types of motion from five patients and twenty-two control subjects.

Results: The proposed approach could distinguish the behavior of patients with Parkinson's disease and control subjects by analyzing the detailed motion features of their hands/fingers.

Comparison With Existing Methods: Previously established methods to quantitate finger movement dynamics focus on speed and amplitude. In contrast, our approach measures unsupervised motion features, in real-time, using wavelet analysis, of each individual finger joint during active free movement.

Conclusions: The proposed study provides an objective assessment of tremor and bradykinesia in Parkinson's disease. Accordingly, this may help movement disorder clinicians to detect, diagnose and monitor treatment efficacy in Parkinson's disease.
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http://dx.doi.org/10.1016/j.jneumeth.2019.108576DOI Listing
March 2020

Fiber-tract localized diffusion coefficients highlight patterns of white matter disruption induced by proximity to glioma.

PLoS One 2019 21;14(11):e0225323. Epub 2019 Nov 21.

Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.

Gliomas account for 26.5% of all primary central nervous system tumors. Recent studies have used diffusion tensor imaging (DTI) to extract white matter fibers and the diffusion coefficients derived from MR processing to provide useful, non-invasive insights into the extent of tumor invasion, axonal integrity, and gross differentiation of glioma from metastasis. Here, we extend this work by examining whether a tract-based analysis can improve non-invasive localization of tumor impact on white matter integrity. This study retrospectively analyzed preoperative magnetic resonance sequences highlighting contrast enhancement and DTI scans of 13 subjects that were biopsy-confirmed to have either high or low-grade glioma. We reconstructed the corticospinal tract and superior longitudinal fasciculus by applying atlas-based regions of interest to fibers derived from whole-brain deterministic streamline tractography. Within-subject comparison of hemispheric diffusion coefficients (e.g., fractional anisotropy and mean diffusivity) indicated higher levels of white matter degradation in the ipsilesional hemisphere. Novel application of along-tract analyses revealed that tracts traversing the tumor region showed significant white matter degradation compared to the contralesional hemisphere and ipsilesional tracts displaced by the tumor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225323PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874090PMC
March 2020

Age-Specific Incidence of Melanoma in the United States.

JAMA Dermatol 2020 01;156(1):57-64

Melanoma and Skin Oncology, Seattle Cancer Care Alliance, Seattle, Washington.

Importance: Melanoma is epidemiologically linked to UV exposure, particularly childhood sunburn. Public health campaigns are increasing sun-protective behavior in the United States, but the effect on melanoma incidence is unknown.

Objective: To examine the incidence of melanoma in the United States and whether any age-specific differences are present.

Design, Setting, And Participants: Observational, population-based registry data were extracted on July 3, 2018, from the combined National Program of Cancer Registries-Surveillance Epidemiology and End Results United States Cancer Statistics database for 2001-2015. Deidentified data for 988 103 cases of invasive melanoma, with International Classification of Diseases for Oncology histologic categorization codes 8720 to 8790, were used for analysis. Data analysis was performed from July 1, 2018, to March 1, 2019.

Main Outcomes And Measures: The annual rates of melanoma in pediatric, adolescent, young adult, and adult age groups were determined. Analyses were stratified by sex, and incidence rates were age-adjusted to the 2000 US standard population. Annual percentage change (APC) in incidence rate was calculated over the most recent decade for which data were available (2006-2015) using the weighted least squares method.

Results: In 2015, 83 362 cases of invasive melanoma were reported in the United States, including 67 in children younger than 10 years, 251 in adolescents (10-19 years), and 1973 in young adults (20-29 years). Between 2006 and 2015, the overall incidence rate increased from 200.1 to 229.1 cases per million person-years. In adults aged 40 years or older, melanoma rates increased by an APC of 1.8% in both men (95% CI, 1.4%-2.1%) and women (95% CI, 1.4%-2.2%). In contrast, clinically and statistically significant decreases were seen in melanoma incidence for adolescents and young adults. Specifically, incidence rates decreased by an APC of -4.4% for male adolescents (95% CI, -1.7% to -7.0%), -5.4% for female adolescents (95% CI, -3.3% to -7.4%), -3.7% for male young adults (95% CI, -2.5% to -4.8%), and -3.6% for female young adults (95% CI, -2.8% to -4.5%). Data on skin pigmentation and sun protection history were unavailable; similar trends were observed with data limited to non-Hispanic whites. Young adult women appeared to have twice the risk of melanoma as young adult men.

Conclusions And Relevance: The incidence of invasive melanoma in the United States appeared to decrease in adolescents and young adults from 2006 to 2015, and this finding contrasted with increases in older populations. These incidence trends suggest that public health efforts may be favorably influencing melanoma incidence in the United States.
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http://dx.doi.org/10.1001/jamadermatol.2019.3353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865303PMC
January 2020

Biopsy Confirmed Glioma Recurrence Predicted by Multi-Modal Neuroimaging Metrics.

J Clin Med 2019 Aug 23;8(9). Epub 2019 Aug 23.

Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Histopathological verification is currently required to differentiate tumor recurrence from treatment effects related to adjuvant therapy in patients with glioma. To bypass the complications associated with collecting neural tissue samples, non-invasive classification methods are needed to alleviate the burden on patients while providing vital information to clinicians. However, uncertainty remains as to which tissue features on magnetic resonance imaging (MRI) are useful. The primary objective of this study was to quantitatively assess the reliability of combining MRI and diffusion tensor imaging metrics to discriminate between tumor recurrence and treatment effects in histopathologically identified biopsy samples. Additionally, this study investigates the noise adjuvant radiation therapy introduces when discriminating between tissue types. In a sample of 41 biopsy specimens, from a total of 10 patients, we derived region-of-interest samples from MRI data in the ipsilateral hemisphere that encompassed biopsies obtained during resective surgery. This study compares normalized intensity values across histopathology classifications and contralesional volumes reflected across the midline. Radiation makes noninvasive differentiation of abnormal-nontumor tissue to tumor recurrence much more difficult. This is because radiation exhibits opposing behavior on key MRI modalities: specifically, on post-contrast T1, FLAIR, and GFA. While radiation makes noninvasive differentiation of tumor recurrence more difficult, using a novel analysis of combined MRI metrics combined with clinical annotation and histopathological correlation, we observed that it is possible to successfully differentiate tumor tissue from other tissue types. Additional work will be required to expand upon these findings.
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http://dx.doi.org/10.3390/jcm8091287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780506PMC
August 2019

Neural Circuit and Clinical Insights from Intraoperative Recordings During Deep Brain Stimulation Surgery.

Brain Sci 2019 Jul 20;9(7). Epub 2019 Jul 20.

Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO 80203, USA.

Observations using invasive neural recordings from patient populations undergoing neurosurgical interventions have led to critical breakthroughs in our understanding of human neural circuit function and malfunction. The opportunity to interact with patients during neurophysiological mapping allowed for early insights in functional localization to improve surgical outcomes, but has since expanded into exploring fundamental aspects of human cognition including reward processing, language, the storage and retrieval of memory, decision-making, as well as sensory and motor processing. The increasing use of chronic neuromodulation, via deep brain stimulation, for a spectrum of neurological and psychiatric conditions has in tandem led to increased opportunity for linking theories of cognitive processing and neural circuit function. Our purpose here is to motivate the neuroscience and neurosurgical community to capitalize on the opportunities that this next decade will bring. To this end, we will highlight recent studies that have successfully leveraged invasive recordings during deep brain stimulation surgery to advance our understanding of human cognition with an emphasis on reward processing, improving clinical outcomes, and informing advances in neuromodulatory interventions.
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http://dx.doi.org/10.3390/brainsci9070173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681002PMC
July 2019

Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors.

J Natl Compr Canc Netw 2019 06;17(6):750-757

Department of Medicine, Division of Oncology, University of Washington, and.

The use of immune checkpoint inhibitors (ICIs) is rapidly expanding to the treatment of many cancer types, both in the metastatic setting and as an adjuvant to other therapies. Clinical trials using ICIs have largely excluded patients with preexisting autoimmune diseases due to concerns for increased toxicity. However, emerging evidence shows that ICIs may be considered in some patients with autoimmunity. This review discusses the commonalities between clinical autoimmune diseases and ICI-induced immunotherapy-related adverse events, and summarizes the existing case series that describes patients with solid tumors who have a preexisting autoimmune disease. This review also discusses which patients with autoimmunity could be considered reasonable candidates for ICI therapy.
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http://dx.doi.org/10.6004/jnccn.2019.7310DOI Listing
June 2019

Current Applications of Diffusion Tensor Imaging and Tractography in Intracranial Tumor Resection.

Front Oncol 2019 29;9:426. Epub 2019 May 29.

Department of Neurosurgery, School of Medicine, University of Colorado, Aurora, CO, United States.

In the treatment of brain tumors, surgical intervention remains a common and effective therapeutic option. Recent advances in neuroimaging have provided neurosurgeons with new tools to overcome the challenge of differentiating healthy tissue from tumor-infiltrated tissue, with the aim of increasing the likelihood of maximizing the extent of resection volume while minimizing injury to functionally important regions. Novel applications of diffusion tensor imaging (DTI), and DTI-derived tractography (DDT) have demonstrated that preoperative, non-invasive mapping of eloquent cortical regions and functionally relevant white matter tracts (WMT) is critical during surgical planning to reduce postoperative deficits, which can decrease quality of life and overall survival. In this review, we summarize the latest developments of applying DTI and tractography in the context of resective surgery and highlight its utility within each stage of the neurosurgical workflow: preoperative planning and intraoperative management to improve postoperative outcomes.
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http://dx.doi.org/10.3389/fonc.2019.00426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549594PMC
May 2019

Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.

Nat Rev Clin Oncol 2019 09;16(9):563-580

Service Immunologie et Allergie, CHUV, Lausanne, Switzerland.

Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.
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http://dx.doi.org/10.1038/s41571-019-0218-0DOI Listing
September 2019

Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2019 04;17(4):367-402

27National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.
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http://dx.doi.org/10.6004/jnccn.2019.0018DOI Listing
April 2019

Analysis of Coronavirus Temperature-Sensitive Mutants Reveals an Interplay between the Macrodomain and Papain-Like Protease Impacting Replication and Pathogenesis.

J Virol 2019 06 29;93(12). Epub 2019 May 29.

Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA

Analysis of temperature-sensitive (ts) mutant viruses is a classic method allowing researchers to identify genetic loci involved in viral replication and pathogenesis. Here, we report genetic analysis of a ts strain of mouse hepatitis virus (MHV), tsNC11, focusing on the role of mutations in the macrodomain (MAC) and the papain-like protease 2 (PLP2) domain of nonstructural protein 3 (nsp3), a component of the viral replication complex. Using MHV reverse genetics, we generated a series of mutant viruses to define the contributions of macrodomain- and PLP2-specific mutations to the ts phenotype. Viral replication kinetics and efficiency-of-plating analysis performed at permissive and nonpermissive temperatures revealed that changes in the macrodomain alone were both necessary and sufficient for the ts phenotype. Interestingly, mutations in the PLP2 domain were not responsible for the temperature sensitivity but did reduce the frequency of reversion of macrodomain mutants. Coimmunoprecipitation studies are consistent with an interaction between the macrodomain and PLP2. Expression studies of the macrodomain-PLP2 portion of nsp3 indicate that the ts mutations enhance proteasome-mediated degradation of the protein. Furthermore, we found that during virus infection, the replicase proteins containing the MAC and PLP2 mutations were more rapidly degraded at the nonpermissive temperature than were the wild-type proteins. Importantly, we show that the macrodomain and PLP2 mutant viruses trigger production of type I interferon and are attenuated in mice, further highlighting the importance of the macrodomain-PLP2 interplay in viral pathogenesis. Coronaviruses (CoVs) are emerging human and veterinary pathogens with pandemic potential. Despite the established and predicted threat these viruses pose to human health, there are currently no approved countermeasures to control infections with these viruses in humans. Viral macrodomains, enzymes that remove posttranslational ADP-ribosylation of proteins, and viral multifunctional papain-like proteases, enzymes that cleave polyproteins and remove polyubiquitin chains via deubiquitinating activity, are two important virulence factors. Here, we reveal an unanticipated interplay between the macrodomain and the PLP2 domain that is important for replication and antagonizing the host innate immune response. Targeting the interaction of these enzymes may provide new therapeutic opportunities to treat CoV disease.
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http://dx.doi.org/10.1128/JVI.02140-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613754PMC
June 2019

Management of Immunotherapy-Related Toxicities, Version 1.2019.

J Natl Compr Canc Netw 2019 03;17(3):255-289

National Comprehensive Cancer Network.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.
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http://dx.doi.org/10.6004/jnccn.2019.0013DOI Listing
March 2019