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Background: The aim of this study is to characterize the patterns of loco-regional progression (LRP) and outcomes after definitive-dose intensity modulated radiation therapy (IMRT) for anaplastic thyroid cancer (ATC) with macroscopic neck disease at the time of IMRT., Methods: Disease/treatment characteristics and outcomes for patients with unresected or incompletely resected ATC who received IMRT (≥45 Gy) were retrospectively reviewed. For those with LRP after IMRT, progressive/recurrent gross tumor volumes (rGTV) were contoured on diagnostic CTs and co-registered with initial planning CTs using deformable image registration. rGTVs were classified based on established spatial/dosimetric criteria., Results: Forty patients treated between 2010-2020 formed the cohort. Median IMRT dose was 66 Gy (45-70 Gy); altered fractionation (AF) was used in 24 (60 %). All received concurrent chemotherapy. In addition to areas of gross disease, target volumes (TVs) commonly included: central compartment/upper mediastinum (levels VI/VII), neck levels II-V in an involved, and levels III-IV in an uninvolved lateral neck. Median overall survival was 7.1 m. Median progression free survival was 7.4 m for patients with locoregional disease and 1.8 m for patients with distant metastasis at the time of IMRT. Twenty-one patients (53 %) developed LRP at median of 10.9 m; freedom from LRP at 3 m and 12 m was 71 % (95 %CI 58-87 %) and 47 % (95 %CI 32-68 %). Forty-one individual rGTVs were identified and most occurred within the high dose (HD) TVs: Type A/central HD (n = 29, 71 %) and B/peripheral HD (n = 3, 7 %)., Conclusions: Despite an intensive treatment schedule, including AF and concurrent chemotherapy, classic radio-resistant and rapid Type A failures predominated; isolated extraneous dose failures were rare. While these findings support the IMRT and TV delineation strategies described herein, they highlight the importance of identifying novel strategies to further improve LRC for patients with unresectable disease without targetable mutations for contemporary neo-adjuvant strategies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MZ has grant funding from Eli Lilly and Merck to MD Anderson Cancer Center for ongoing phase II clinical trials. RF: Consulting/advisory role in the past 2 years:Coherus Bioscience, Eisai Medical Research, Elevar Therapeutics, Prelude Therapeutics, Regeneron Pharmaceuticals, Remix Therapeutics, Sanofi-aventis, Answers in CME, Labcorp Drug Development. Research funding (institution):ISA Therapeutics, Merck, Ayala Pharmaceuticals, Viracta, Gilead, Seagen, Prelude Therapeutics in the past 2 years. MEC: Advisory boards/consulting: Bayer, Exelixis, Lilly, Novartis. Clinical trial funding Merck, Genentech. CDF received/receives related funding and salary support from: National Institutes of Health (NIH) National Cancer Institute (NCI) and National Institute of Dental and Craniofacial Research (NIDCR) Administrative Supplements to Support Collaborations to Improve AIML-Readiness of NIH-Supported Data (R01CA257814-02S3; R01DE028290-04S2); NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) Research Education Programs for Residents and Clinical Fellows Grant (R25EB025787); NIH/NCI Cancer Center Support Grant (CCSG) (P30CA016672); Patient-Centered Outcomes Research Institute (PCS-1609-36195; sub-award from Princess Margaret Hospital). Dr. Fuller receives grant and infrastructure support from MD Anderson Cancer Center via the Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program. Dr. Fuller has received NIH sub-award support from Oncospace, Inc. (R43CA254559, PI Lakshminarayanan) under a Small Business Innovation Research Grant Applications grant. Dr. Fuller has received direct industry grant/in-kind support, honoraria, and travel funding from Elekta AB. Dr. Fuller has served as a consulting capacity for Varian/Siemens Healthineers, Philips Medical Systems, and Oncospace, Inc. RD received research support from AstaZeneca, Merck, Eisai, Exellixis and serves in a cosulting role with Bayer, Novartis, Exelixis. NB: Honoraria: Eisai, Exelixis, Consulting or Advisory Role: Loxo, Eisai, Research Funding: GlaxoSmithKline/Novartis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease., Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making., Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Keam, Turner, Kugeratski, Rico, Colunga-Minutti, Poojary, Alekseev, Patel, Li, Sheshadri, Loghin, Woodman, Aaroe, Hamidi, Iyer, Palaskas, Wang and Nurieva.)

Context: Telomerase reverse transcriptase (TERT) promoter-mutated thyroid cancers are associated with a decreased rate of disease-free and disease-specific survival. High-quality analytical validation of a diagnostic test promotes confidence in the results that inform clinical decision-making., Objective: This work aimed to demonstrate the analytical validation of the Afirma TERT promoter mutation assay., Methods: TERT promoter C228T and C250T variant detection in genomic DNA (gDNA) was analyzed by assessing variable DNA input and the limit of detection (LOD) of variant allele frequency (VAF). The negative and positive percentage agreement (NPA and PPA) of the Afirma TERT test was examined against a reference primer pair as was the analytical specificity from potential interfering substances (RNA and blood gDNA). Further, the intrarun, interrun, and interlaboratory reproducibility of the assay were tested., Results: The Afirma TERT test is tolerant to variation in DNA input amount (7-13 ng) and can detect expected positive TERT promoter variants down to 5% VAF LOD at 7 ng DNA input with greater than 95% sensitivity. Both NPA and PPA were 100% against the reference primer pair. The test remains accurate in the presence of 20% RNA or 80% blood gDNA for an average patient sample that typically has 30% VAF. The test also demonstrated a 100% confirmation rate when compared with an external next-generation sequencing-based reference assay executed in a non-Veracyte laboratory., Conclusion: The analytical robustness and reproducibility of the Afirma TERT test support its routine clinical use among thyroid nodules with indeterminate cytology that are Afirma Genomic Sequencing Classifier suspicious or among Bethesda V/VI nodules., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAF V600E -mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n  = 23 in DT and n  = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment ( p  = 0.427) and prior treatments with surgery ( p  = 0.864) and radiation ( p  = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9-22.1]) compared with DT alone (9.0 months [CI, 4.5-13.5]), p  = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0-15.0]) compared with DT alone (4.0 months [CI, 0.7-7.3]), p  = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5-110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation.

The treatment of advanced, radioiodine refractory, differentiated thyroid cancers (RR-DTCs) has undergone major advancements in the last decade, causing a paradigm shift in the management and prognosis of these patients. Better understanding of the molecular drivers of tumorigenesis and access to next generation sequencing of tumors have led to the development and Food and Drug Administration (FDA)-approval of numerous targeted therapies for RR-DTCs, including antiangiogenic multikinase inhibitors, and more recently, fusion-specific kinase inhibitors such as RET inhibitors and NTRK inhibitors. BRAF + MEK inhibitors have also been approved for BRAF -mutated solid tumors and are routinely used in RR-DTCs in many centers. However, none of the currently available treatments are curative, and most patients will ultimately show progression. Current research efforts are therefore focused on identifying resistance mechanisms to tyrosine kinase inhibitors and ways to overcome them. Various novel treatment strategies are under investigation, including immunotherapy, redifferentiation therapy, and second-generation kinase inhibitors. In this review, we will discuss currently available drugs for advanced RR-DTCs, potential mechanisms of drug resistance and future therapeutic avenues., Competing Interests: RD has received grant funding from Eisai, Exelixis, AstraZeneca, and Merck and has participated in advisory boards for Exelixis and Bayer. MC has received grant funding from Genentech and Merck and has received consulting fees from Exelixis and Bayer. MH has received grant funding from Eli Lilly & Co. and has participated in a steering committee for Eli Lilly & Co. NB has received grant funding from GSK, has received consulting fees from Eisai and Loxo and has participated in advisory board for Exelixis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hamidi, Hofmann, Iyer, Cabanillas, Hu, Busaidy and Dadu.)

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients. Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020. Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients. Conclusion: Development of ICI-DM is associated with long-term insulin dependence and pancreatic atrophy; the use of diabetes technology in this patient population can help improve glycemic control.

Coccidioidomycosis, also known as Valley fever, is an endemic fungal infection commonly found in the southwestern parts of the United States. However, the disease has seen an increase in both in its area of residency and its prevalence. This review compiles some of the latest information on the epidemiology, current and in-development pharmaceutical approaches to treat the disease, trends and projections, diagnostic concerns, and the overlapping dynamics of coccidioidomycosis and COVID-19, including in special populations. This review provides an overview of the current diagnostic and therapeutic strategies and identifies areas of future development.

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6-3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

Objective: Cortical priming is an emerging strategy to enhance motor recovery after stroke, however, limited information exists on the neuromodulatory effects of lower limb movement-based priming to facilitate corticomotor excitability after stroke. In this study, we investigated the feasibility and effectiveness of game-based ankle movement priming using the DIG-I-PRIME™ on corticomotor excitability and motor performance in chronic stroke survivors., Methods: Nineteen stroke survivors participated in a 20-min session of game-based priming. A period of rest served as a control for the priming condition. Transcranial magnetic stimulation (TMS) was used to measure corticomotor excitability of the paretic and non-paretic tibialis anterior (TA) muscle representations. Motor performance was quantified by assessing the accuracy to track a sinusoidal target wave with paretic dorsiflexion and plantarflexion., Results: Ipsilesional corticomotor excitability increased by 25% after game-based movement priming ( p  = 0.02) while changes were not observed after the control condition. No change in motor performance was noted., Conclusion: Game-based ankle movement priming demonstrated a significant acute priming effect on the ipsilesional lower limb M1. These data provide preliminary evidence for the potential benefits of game-based priming to promote functional recovery after stroke.

Background: Stimulus response curves (SR curves), measured using transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEP), yield important information regarding corticomotor connectivity. Limited understanding of SR curve analyses techniques for leg muscles after stroke may limit the utility of TMS data for walking recovery., Objective: To compare linear and non-linear curve fitting for MEP responses from the non-paretic and paretic tibialis anterior (TA) muscles., Methods: Accuracy of fit was measured using coefficient of determination (R 2 ). Similarities of the fit were compared using slopes and area under the curve (AUC)., Results: The non-linear function demonstrated higher R 2 and slopes. The AUC was not significantly different between the two analyses approaches. The non-linear non-paretic SR slopes and paretic AUC had significant associations with walking speed., Conclusion: Our results highlight the differences between non-linear and linear approaches to best fit the SR curves from bilateral TA muscles in stroke survivors. Although the linear function can appropriately fit the SR curve of the paretic and non-paretic TA, the non-linear function estimated a higher slope. We found the AUC to be a more robust measure that was not affected by the type of curve-fitting approach and only the AUC of the paretic TA showed significant association with walking speeds. A better understanding of SR curve fitting approaches for the TA muscles in individuals with chronic stroke allows for their optimal use in interpretation of TMS data and literature., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The beneficial effects of transcranial direct current stimulation (tDCS) for stroke rehabilitation are limited by the variability in changes in corticomotor excitability (CME) after tDCS. Neuronal activity is closely related to cerebral blood flow; however, the cerebral hemodynamics of neuromodulation in relation to neural effects have been less explored. In this study, we examined the effects of tDCS on cerebral blood velocity (CBv) in chronic stroke survivors using transcranial Doppler (TCD) ultrasound in relation to changes in CME and described the neurovascular characteristics of tDCS responders. Middle cerebral artery (MCA) CBv, cerebrovascular resistance (CVRi) and other cerebral hemodynamics-related variables were continuously measured before and after 15 min of 1 mA anodal tDCS to the lesioned lower limb M1. tDCS did not modulate CBv in the whole group and upon TMS-based stratification of responders and non-responders. However, at baseline, responders demonstrated lower CME levels, lower CBv and higher CVRi as compared to non-responders. These results indicate a possible difference in baseline CME and CBv in tDCS responders that may influence their response to neuromodulation. Future trials with a large sample size and repeated baseline measurements may help validate these findings and establish a relationship between neuromodulation and neurovascular mechanisms in stroke.

Purpose: Anaplastic thyroid cancer (ATC) is a deadly form of thyroid cancer. BRAF V600E is the only actionable mutation for which there is a Food and Drug Administration-approved drug combination. Rapid detection of BRAF V600E and initiation of therapy is critical. We explored the ability of droplet digital polymerase chain reaction (ddPCR) to identify this mutation in circulating cell-free DNA (cfDNA) in plasma., Materials and Methods: The ddPCR assay was evaluated for its sensitivity, specificity for detection of BRAF V600E cfDNA, and concordance with tumor tissue. The assay also was used to evaluate its potential role as a biomarker of response., Results: Forty-four patients with ATC who were tested for the BRAF mutation by tumor tissue DNA sequencing or immunohistochemistry were included. Sixteen BRAF V600E-positive patients had treatment samples to evaluate cfDNA levels as a biomarker of response in correlation with restaging scans. Concordance of ddPCR with tumor tissue was 93%, with a sensitivity of 85% and specificity of 100%. Area under the curve by Wilcoxon rank sum test was 0.9 (95% CI, 0.80 to 0.99; P < .001). As a biomarker of response to treatment, 94% of ddPCR samples were concordant with tumor shrinkage in restaging scans, and 47% were concordant with tumor growth (Fisher's exact test P = .0061). In addition, cfDNA levels by ddPCR were predictive of treatment response in 71% of samples., Conclusion: cfDNA detection by ddPCR is highly sensitive, specific, and concordant with mutation status on ATC tumors. ddPCR also can be used for monitoring cfDNA levels in conjunction with imaging scans in patients with ATC., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Priyanka C. IyerNo relationship to discloseGilbert J. CoteNo relationship to discloseTao HaiNo relationship to discloseMaria Gule-MonroeNo relationship to discloseJacquelin Bui-GriffithNo relationship to discloseMichelle D. WilliamsNo relationship to discloseKenneth HessNo relationship to discloseMarie-Claude HofmannNo relationship to discloseRamona DaduResearch Funding: AstraZeneca, Merck, Eisai, Genentech, Bristol-Myers SquibbMark ZafereoNo relationship to discloseNaifa L. BusaidyConsulting or Advisory Role: Loxo Oncology, Eisai Research Funding: GlaxoSmithKline, NovartisRenata FerrarottoConsulting or Advisory Role: AYALA Research Funding: OncoMed Pharmaceuticals (Inst), G1 Therapeutics (Inst), AstraZeneca (Inst), MedImmune (Inst), EMD Serono (Inst), Genentech (Inst), Roche (Inst), Merck Serono (Inst)Vivek SubbiahConsulting or Advisory Role: MedImmune Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Roche (Inst), BERG (Inst), Bayer AG (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), MultiVir (Inst), Blueprint Medicines (Inst), Loxo Oncology (Inst), Vegenics (Inst), Takeda Pharmaceuticals (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst), Inhibrx (Inst), Exelixis (Inst) Travel, Accommodations, Expenses: PharmaMar, Bayer AGNeil GrossHonoraria: Intuitive Surgical Consulting or Advisory Role: PDS Biotechnology, Verb Surgical (Inst) Research Funding: Regeneron Pharmaceuticals, MedImmune (Inst), Genentech (Inst)Brandon G. GunnNo relationship to discloseHeath D. SkinnerNo relationship to discloseAdam S. GardenConsulting or Advisory Role: Galera TherapeuticsMaria E. CabanillasConsulting or Advisory Role: Loxo Oncology, Blueprint Medicines Research Funding: Kura Oncology, Eisai, Roche, Genentech, Exelixis, (© 2018 by American Society of Clinical Oncology.)

Objective: Non-invasive brain stimulation (NIBS), such as repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), are promising neuromodulatory priming techniques to promote task-specific functional recovery after stroke. Despite promising results, clinical application of NIBS has been limited by high inter-individual variability. We propose that there is a possible influence of neuromodulation on cerebral blood flow (CBF), as neurons are spatially and temporally related to blood vessels. Transcranial Doppler (TCD), a clinically available non-invasive diagnostic tool, allows for evaluation of CBF velocity (CBFv). However, little is known about the role of neuromodulation on CBFv., Methods: A systematic review of literature to understand the effects of NIBS on CBFv using TCD in stroke was conducted., Results: Twelve studies fit our inclusion criteria and are included in this review. Our review suggested that CBFv and/or vasomotor reactivity maybe influenced by rTMS dosage (intensity and frequency) and the type of tDCS electrode montage., Conclusion: There is limited evidence regarding the effects of NIBS on cerebral hemodynamics using TCD and the usefulness of TCD to capture changes in CBFv after NIBS is not evident from this review. We highlight the variability in the experimental protocols, differences in the applied neurostimulation protocols and discuss open questions that remain regarding CBF and neuromodulation., Significance: TCD, a clinically accessible tool, may potentially be useful to understand the interaction between cortical neuromodulation and CBFv., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae., Methods: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT., Results: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis., Conclusions: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.

Background: Anaplastic thyroid carcinoma (ATC) is a rare but deadly form of thyroid cancer. Kinase inhibitors kinase inhibitors have shown clinical efficacy in the management of ATC, however, eventually these tumors acquire resistance to KI and patients succumb to their disease. Salvage therapy in this setting is limited. As ATC tumors diffusely express the programmed cell death protein ligand (PD-L1), anti- programmed cell death protein (PD-1) drugs such as pembrolizumab offer therapeutic potential. We sought to explore the efficacy of adding pembrolizumab to kinase inhibitors at progression in ATC., Methods: We retrospectively reviewed the charts of ATC patients initiated on pembrolizumab in combination with KI at the time of progression on kinase inhibitors at MD Anderson Cancer Center between August 2016 and August 2017. Efficacy was evaluated with best overall response (BOR) using RECISTv1.1 criteria. Progression free survival (PFS) from the start of pembrolizumab and overall survival (OS) from the start of kinase inhibitors, as well as from the time of addition of pembrolizumab were calculated., Results: Twelve patients were treated with combination kinase inhibitors plus pembrolizumab at the time of progression on their KI therapy. Median age at initiation of pembrolizumab was 60 years (range 47-84 years). BOR was as follows: 5/12 (42%) had partial response, 4/12 (33%) had stable disease and 3/12 (25%) had progressive disease. Median OS from the start of kinase inhibitor was 10.43 months (95% CI = 6.02, 14.83, range 5.4-40 months). Median OS and PFS from the addition of pembrolizumab were 6.93 months (95% CI = 1.7, 12.15, range 3-15.9 months) and 2.96 months (95% CI = 2.2, 3.7, range 0.57-13.14 months), respectively. Fatigue, anemia and hypertension were the most common AEs encountered on these combinations. Therapy had to be discontinued in 2 patients due to drug induced rash and altered mental status likely from progression of disease., Conclusion: In a subset of ATC patients, pembrolizumab may be an effective salvage therapy added to kinase inhibitors at the time of progression on these drugs. However, better treatment strategies aimed at incorporating immunotherapy in patients with ATC should be explored. Frontline combination of KI with immunotherapy should be studied in prospective clinical trials.

Background: Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial., Methods: This is a retrospective review from April 2015 to May 2016 at a single academic institution where 16 ATC patients receiving targeted therapy outside of a clinical trial were studied. Ten patients (eight BRAF wild type and two BRAF V600E mutant tumors) were started on lenvatinib, and six with BRAF V600E -mutated tumors received a combination of dabrafenib plus trametinib. Best response evaluated by RECIST v1.1, progression-free survival, and overall survival were determined. Adverse events were evaluated for safety., Results: The majority of patients (63%) were men, and all had distant metastases or radiation-resistant primary disease at the time of treatment. In the entire cohort, 6/16 (38%) had a partial response, 6/16 (38%) had stable disease, and 2/16 (12%) had progressive disease. Two (12%) patients died before restaging. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months [confidence interval 1.8-7.6] in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months [confidence interval 1.8-7.6] for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib. Adverse events were as expected and manageable., Conclusions: Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAF V600E mutants) may provide clinical benefit in ATC patients who are unable to participate in clinical trials, and toxicities are manageable.

HIV-1 Nef is a critical AIDS progression factor yet underexplored target for antiretroviral drug discovery. A recent high-throughput screen for pharmacological inhibitors of Nef-dependent Src-family kinase activation identified a diphenylpyrazolodiazene hit compound with submicromolar potency in HIV-1 replication assays against a broad range of primary Nef variants. This compound, known as 'B9', binds directly to Nef and inhibits its dimerization in cells as a possible mechanism of action. Here were synthesized a diverse set of B9 analogs and identified structural features essential to antiretroviral activity. Chemical modifications to each of the three rings present in the parent compound were identified that did not compromise antiviral action. These analogs will guide the development of next-generation compounds with appropriate pharmacological profiles for assessment of antiretroviral activity in vivo., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A synthetic route to oligonucleotides containing N(2)-deoxyguanosine adducts at C-10 of the enantiomeric 7,8-diol 9,10-epoxides of 7,8,9,10-tetrahydrobenzo[a]pyrene in which the epoxide oxygen and the 7-hydroxyl group are trans is described. The present adducts result from the trans addition of N(2) of deoxyguanosine to the epoxide at C-10. Our synthesis proceeds via preparation of the 3'-H-phosphonate of a suitably protected deoxyguanosine N(2)-adduct. The blocking groups consisted of O(6)-allyl on the deoxyguanosine, acetates on the 7-, 8-, and 9-hydroxyl groups of the hydrocarbon moiety, and dimethoxytrityl on the 5'-hydroxyl group of the sugar. These blocking groups are well suited to oligonucleotide synthesis on solid supports. The free 3'-hydroxyl group of this nucleoside adduct was readily converted to its 3'-H-phosphonate with diphenyl phosphite in pyridine in high yield for both the 10R and 10S isomers. For synthesis of oligonucleotides, the first several nucleotides were incorporated onto the solid support with an automated synthesizer using standard phosphoramidite chemistry. The adducted deoxyguanilic acid residue was introduced as the H-phosphonate in a manual step (80% yield), followed by completion of the sequence on the synthesizer. Although a 10-fold excess of the 3'-H-phosphonate was used in the manual coupling step, as much as 70% of the reactant could be recovered. The 3'-H-phosphonate of the protected 10S nucleoside adduct was converted to the unblocked nucleotide adduct, various salts of which failed to form crystals suitable for X-ray analysis. Although submilligram quantities of this compound have been formed as mixed diastereomers by direct reaction of deoxyguanylic acid with racemic diol epoxide, the present study represents the first actual synthesis of the major DNA adduct formed from benzo[a]pyrene in mammals as its 3'-phosphate.