Connectivity-based segmentation of the thalamic motor region for deep brain stimulation in essential tremor: A comparison of deterministic and probabilistic tractography.

OBJECTIVE: Deep brain stimulation (DBS) studies have shown that stimulation of the motor segment of the thalamus based on probabilistic tractography is predictive of improvement in essential tremor (ET). However, probabilistic methods are computationally demanding, requiring the need for alternative tractography methods for use in the clinical setting. The purpose of this study was to compare probabilistic vs deterministic tractography methods for connectivity-based targeting in patients with ET. METHODS: Probabilistic and deterministic tractography methods were retrospectively applied to diffusion-weighted data sets in 36 patients with refractory ET. The thalamus and precentral gyrus were selected as regions of interest and fiber tracking was performed between these regions to produce connectivity-based thalamic segmentations, per prior methods. The resultant deterministic target maps were compared with those of thresholded probabilistic maps. The center of gravity (CG) of each connectivity map was determined and the differences in spatial distribution between the tractography methods were characterized. Furthermore, the intersection between the connectivity maps and CGs with the therapeutic volume of tissue activated (VTA) was calculated. A mixed linear model was then used to assess clinical improvement in tremor with volume of overlap. RESULTS: Both tractography methods delineated the region of the thalamus with connectivity to the precentral gyrus to be within the posterolateral aspect of the thalamus. The average CG of deterministic maps was more medial-posterior in both the left (3.7 ± 1.3 mm3) and the right (3.5 ± 2.2 mm3) hemispheres when compared to 30 %-thresholded probabilistic maps. Mixed linear model showed that the volume of overlap between CGs of deterministic and probabilistic targeting maps and therapeutic VTAs were significant predictors of clinical improvement. CONCLUSIONS: Deterministic tractography can reconstruct DBS thalamic target maps in approximately 5 min comparable to those produced by probabilistic methods that require > 12 h to generate. Despite differences in CG between the methods, both deterministic-based and probabilistic targeting were predictive of clinical improvement in ET.

Clinical, economic, and health-related quality of life outcomes in patients with overweight or obesity in the United States: 2016-2018.

Objectives: This study aimed to estimate clinical, economic (including productivity), and health-related quality of life (HRQoL) outcomes and associated individual characteristics among adults with overweight (OW) or obesity in the United States. Methods: This study included adult respondents with body mass index (BMI) ≥18.5 kg/m2 in the 2017-2018 National Health and Nutrition Examination Survey (NHANES) and 2016 Medical Expenditure Panel Survey. Respondents were classified according to BMI. Individual characteristics were described by BMI categories. Multivariable regression models estimated the association between BMI categories and outcomes, adjusting for individual characteristics. Results: Nearly three-quarters (73.7%) of NHANES participants were OW or obese. Relative to Normal weight (NW), respondents with Class 3 obesity had more obesity-related complications (2.07 vs. 4.62, p < 0.001). Higher BMI was associated with significantly lower HRQoL, lower productivity, and higher healthcare expenditures as well as more frequent weight loss attempts in the previous 12 months. Weight loss surgery and prescription anti-obesity medications (AOMs) were used only by a very small proportion of individuals. Despite frequent weight loss attempts, most respondents did not achieve clinically meaningful weight loss. Conclusions: Adults with OW or obesity experienced worse clinical, economic and HRQoL outcomes than those with NW. Better use of evidence-based obesity treatments, including prescription AOMs, should be considered to achieve more clinically meaningful weight reduction and improved outcomes in individuals with OW or obesity.

Deep Learning Provides Rapid Screen for Breast Cancer Metastasis with Sentinel Lymph Nodes.

OBJECTIVE: Deep learning has been shown to be useful in detecting breast cancer metastases by analyzing whole slide images (WSI) of sentinel lymph nodes; however, it requires extensive analysis of all the lymph node slides. Our deep learning study attempts to provide a rapid screen for metastasis by analyzing only a small set of image patches to detect changes in tumor environment. METHODS: We designed a convolutional neural network to build a diagnostic model for metastasis detection. We obtained WSIs of Hematoxylin and Eosin-stained slides from 34 cases with equal distribution in positive/negative categories. Two WSIs were selected from each case for a total of 69 WSIs. From each WSI, 40 image patches (100x100 pixels) were obtained to yield 2720 image patches, from which 2160 (79%) were used for training, 240 (9%) for validation, and 320 (12%) for testing. Interobserver variation was also examined among 3 users. RESULTS: The test results showed excellent diagnostic results: accuracy (91.15%), sensitivity (77.92%), and specificity (92.09%). No significant variation in results was observed among the 3 observers. CONCLUSION: This preliminary study provided a proof of concept for conducting a rapid screen for metastasis rather than an exhaustive search for tumors in all fields of all sentinel lymph nodes.

Preferences for first-line treatment of advanced urothelial carcinoma among US practicing oncologists and patients.

Aim: Investigate oncologist and patient preferences for the first-line treatment of advanced urothelial carcinoma. Materials & methods: A discrete-choice experiment was used to elicit treatment attribute preferences, including patient treatment experience (number and duration of treatments and grade 3/4 treatment-related adverse events), overall survival and treatment administration frequency. Results: The study included 151 eligible medical oncologists and 150 patients with urothelial carcinoma. Both physicians and patients appeared to prefer treatment attributes related to overall survival, treatment-related adverse events and the number and duration of the medications in a regimen over frequency of administration. Overall survival had the most influence in driving oncologists' treatment preferences, followed by the patient's treatment experience. Patients found the treatment experience the most important attribute when considering options, followed by overall survival. Conclusion: Patient preferences were based on treatment experience, while oncologists preferred treatments that prolong overall survival. These results help to direct clinical conversations, treatment recommendations and clinical guideline development.

Different treatments are available for people with urothelial cancer that has spread to other parts of the body. Researchers wanted to find out what specialist cancer doctors and people with urothelial cancer think is important when choosing the first treatment. To do this, researchers asked 150 cancer specialists and 150 people with urothelial cancer to complete an internet questionnaire. It included questions about side effects, if treatment could help people live longer, and how often people would need to be treated. Researchers found that cancer specialists think that helping people live longer is the most important. However, people with advanced urothelial cancer think that having fewer severe side effects is the most important.

Estimating Productivity Loss from Breast and Non-Small-Cell Lung Cancer among Working-Age Patients and Unpaid Caregivers: A Survey Study Using the Multiplier Method.

Background. Traditional approaches to capturing health-related productivity loss (e.g., the human capital method) focus only on the foregone wages of affected patients, overlooking the losses caregivers can incur. This study estimated the burden of productivity loss among breast cancer (BC) and non-small-cell lung cancer (NSCLC) patients and individuals caring for such patients using an augmented multiplier method. Design. A cross-sectional survey of BC and NSCLC patients and caregivers measured loss associated with time absent from work (absenteeism) and reduced effectiveness (presenteeism). Respondents reported pre- and postcancer diagnosis income, hours worked, and time to complete tasks. Exploratory multivariable analyses examined correlations between respondents' clinical/demographic characteristics-including industry of employment-and postdiagnosis productivity. Results. Of 204 patients (104 BC, 100 NSCLC) and 200 caregivers (100 BC, 100 NSCLC) who completed the survey, 319 participants (162 BC, 157 NSCLC) working ≥40 wk/y prediagnosis were included in the analysis. More than one-third of the NSCLC (33%) and BC (43%) patients left the workforce postdiagnosis, whereas only 15% of caregivers did. The traditional estimate for the burden of productivity loss was 66% lower on average than the augmented estimate (NSCLC patients: 60%, BC patients: 69%, NSCLC caregivers: 59%, and BC caregivers: 73%). Conclusions. Although patients typically experience greater absenteeism, productivity loss incurred by caregivers is also substantial. Failure to account for such impacts can result in substantial underestimation of productivity gains novel cancer treatments may confer by enabling patients and caregivers to remain in the workforce longer. Our results underscore the importance of holistic approaches to understanding this impact on both patients and their caregivers and accounting for such considerations when making decisions about treatment and treatment value. Highlights: Cancer can have a profound impact on productivity. This study demonstrates how the disease affects not only patients but also the informal or unpaid individuals who care for patients.An augmented approach to calculating health-related productivity loss suggests that productivity impacts are much larger than previously understood.A more comprehensive understanding of the economic burden of cancer for both patients and their caregivers suggests the need for more support in the workplace for these individuals and a holistic approach to accounting for these impacts in treatment decision making.

Real-world clinical outcomes with avelumab in patients with Merkel cell carcinoma treated in the USA: a multicenter chart review study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neuroendocrine neoplasm with annual incidence rates of 0.13-1.6 cases/100,000/year worldwide as of 2018. Chemotherapy for metastatic MCC (mMCC) has high objective response rates (ORRs), but responses are not durable and overall survival (OS) is poor. Avelumab (anti-programmed death-ligand 1) has demonstrated meaningful survival benefit and durable responses in clinical trials for mMCC. This study investigated real-world clinical outcomes in avelumab-treated patients with advanced (stage IIIB/IV) MCC in US academic medical centers. METHODS: We conducted a retrospective chart review of patients with advanced MCC who initiated avelumab between March 1, 2017, and July 31, 2019, at six US academic centers. Data were requested for eligible patients from index date through December 31, 2020. Descriptive analyses were conducted to assess demographic and clinical characteristics, real-world ORR (rwORR), real-world duration of response, real-world progression-free survival (rwPFS), and OS. RESULTS: Ninety patients with advanced MCC (82%, stage IV; 18%, stage IIIB) received avelumab. Median follow-up was 20.8 months (95% CI: 19.1 to 24.2). Median age was 68 years (range, 48-83), and the majority of patients were men (58%) and white (93%). The primary tumor was most commonly located on the lower limb (38%), with metastases mostly located in lymph nodes (68%), lung (52%), and viscera (52%). Approximately 42% and 26% of patients had an Eastern Cooperative Oncology Group performance status of 2 and 3, respectively. Seventy-three patients (81%) received avelumab as first-line treatment of advanced MCC, while 17 (19%) received avelumab as second-line or later treatment. The median duration of avelumab treatment was 13.5 months (95% CI: 6.4 to 30.6), with 42% of patients still receiving avelumab by the end of follow-up. Patients with avelumab treatment had an rwORR of 73% (95% CI: 64 to 83), median rwPFS of 24.4 months (95% CI: 8.31 to not estimable (NE)), and median OS of 30.7 months (95% CI: 11.2 to NE). CONCLUSIONS: This real-world study of patients with advanced MCC demonstrated that avelumab treatment resulted in a high response rate with durable responses and prolonged survival. The study findings validate the results demonstrated in prospective clinical trials and other observational studies.

Automated optimization of deep brain stimulation parameters for modulating neuroimaging-based targets.

Objective.Therapeutic efficacy of deep brain stimulation (DBS) in both established and emerging indications, is highly dependent on accurate lead placement and optimized clinical programming. The latter relies on clinicians' experience to search among available sets of stimulation parameters and can be limited by the time constraints of clinical practice. Recent innovations in device technology have expanded the number of possible electrode configurations and parameter sets available to clinicians, amplifying the challenge of time constraints. We hypothesize that patient specific neuroimaging data can effectively assist the clinical programming using automated algorithms.Approach.This paper introduces the DBS Illumina 3D algorithm as a tool which uses patient-specific imaging to find stimulation settings that optimizes activating a target area while minimizing the stimulation of areas outside the target that could result in unknown or undesired side effects. This approach utilizes preoperative neuroimaging data paired with the postoperative reconstruction of the lead trajectory to search the available stimulation space and identify optimized stimulation parameters. We describe the application of this algorithm in three patients with treatment-resistant depression who underwent bilateral implantation of DBS in subcallosal cingulate cortex and ventral capsule/ventral striatum using tractography optimized targeting with an imaging defined target previously described.Main results.Compared to the stimulation settings selected by the clinicians (informed by anatomy), stimulation settings produced by the algorithm that achieved similar or greater target coverage, produced a significantly smaller stimulation area that spilled outside the target (P= 0.002).Significance. The DBS Illumina 3D algorithm is seamlessly integrated with the clinician programmer software and effectively and rapidly assists clinicians with the analysis of image based anatomy, and provides a starting point to search the highly complex stimulation parameter space and arrive at the stimulation settings that optimize activating a target area.

Patient preferences for treatment in relapsed/refractory diffuse large B-cell lymphoma: a discrete choice experiment.

Aim: We quantified patient preferences for second-line diffuse large B-cell lymphoma therapies, including attributes of chimeric antigen receptor (CAR) T-cell therapy. Materials & methods: Using a discrete choice experiment, we surveyed 224 diffuse large B-cell lymphoma patients from the USA and Europe. Patients chose between two treatment options defined by six attributes with predefined levels for overall survival, adverse events (severe cytokine-release syndrome, severe neurological toxicities, severe infection) and time to return to pre-treatment functioning. Results: Increasing the probability of 1-year survival was most important to patients, followed by avoiding risks of cytokine-release syndrome and neurological toxicities. Respondents required a 13-14 percentage point increased 1-year survival probability to accept risks of treatment-associated adverse events. Conclusion: Patients prioritize survival and will accept certain adverse event risks to gain survival improvements.

Chimeric antigen receptor (CAR) T-cell therapy is a new treatment for patients with diffuse large B-cell lymphoma. CAR T-cell therapies are made from a patient's own cells, modified in a laboratory and used to attack cancer cells. While CAR T-cell therapies may increase long-term survival, they can also cause temporary but serious side effects, including neurological issues (e.g., headache, confusion, brain swelling) and cytokine-release syndrome (CRS), an inflammatory condition that can cause fever, breathing difficulties and organ dysfunction. To understand how patients' perspectives of CAR T-cell therapy compared with their perspectives on other treatments for diffuse large B-cell lymphoma, we surveyed 224 patients in the USA and Europe. They were asked to choose between two treatments in a series of choice sets, each displaying varying levels of aspects of cancer therapies, including survival and risks of serious side effects. Their choices allowed us to measure which factors were most important to patients when making decisions about treatment. We found that increasing the probability of survival was most important, followed by avoiding risks of neurological complications and CRS. Patients were willing to accept increased risks of neurological toxicities and CRS if they could obtain a 13­14 percentage point increase in the probability of surviving for at least 1 year after treatment.

Are caregivers ready for digital? Caregiver preferences for health technology tools to monitor medication adherence among patients with serious mental illness.

Background: Adherence to antipsychotic medication is critical for bipolar disorder (BPD), major depression (MDD) and schizophrenia (SCZ) patients. Digital tools have emerged to monitor medication adherence along with tracking general health. Evidence on physician or patient preferences for such tools exists but is limited among caregivers. The study objective was to assess preferences and willingness-to-pay (WTP) for medication adherence monitoring tools among caregivers of SMI patients. Methods: A web-based survey was administered to caregivers of adult SMI patients. Twelve discrete choice questions comparing adherence monitoring tools that varied across two attribute bundles: (1) tool attributes including source of medication adherence information, frequency of information updates, access to adherence information, and physical activity, mood, and rest tracking, and (2) caregiver monthly out-of-pocket cost attribute were administered to caregiver respondents. Attributes were parameterized for both digital and non-digital tools. Random utility models were used to estimate caregivers' preferences and WTP. Results: Among 184 study-eligible caregivers, 57, 61 and 66 participants cared for BPD, MDD, and SCZ patients, respectively. Caregivers highly preferred (odds ratio (OR): 7.34, 95% confidence interval (CI): 5.00-10.79) a tool that tracked medication ingestion using a pill embedded with an ingestible event market (IEM) sensor and tracked patients' physical activity, mood, and rest than a non-digital pill organizer. Additionally, caregivers were willing to pay $255 per month (95% CI: $123-$387) more for this tool compared to a pill organizer. Conclusion: Caregivers of SMI patients highly preferred and were willing to pay more for digital tools that not only measures medication ingestion but also tracks general health.

Imaging versus electrographic connectivity in human mood-related fronto-temporal networks.

BACKGROUND: The efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography. OBJECTIVE: Leverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses. METHODS: Evoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression - the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) - in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography. RESULTS: Evoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials. CONCLUSION: The two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation.

The quantitative impact of joint peer review with a specialist radiologist in head and neck cancer radiotherapy planning.

OBJECTIVES: Radiologist input in peer review of head and neck radiotherapy has been introduced as a routine departmental approach. The aim was to evaluate this practice and to quantitatively analyse the changes made. METHODS: Patients treated with radical-dose radiotherapy between August and November 2020 were reviewed. The incidence of major and minor changes, as defined by The Royal College of Radiologists guidance, was prospectively recorded. The amended radiotherapy volumes were compared with the original volumes using Jaccard Index (JI) to assess conformity; Geographical Miss Index (GMI) for undercontouring; and Hausdorff Distance (HD) between the volumes. RESULTS: In total, 73 out of 87 (84%) patients were discussed. Changes were recommended in 38 (52%) patients: 30 had ≥1 major change, eight had minor changes only. There were 99 amended volumes: The overall median JI, GMI and HD was 0.91 (interquartile range [IQR]=0.80-0.97), 0.06 (IQR = 0.02-0.18) and 0.42 cm (IQR = 0.20-1.17 cm), respectively. The nodal gross-tumour-volume (GTVn) and therapeutic high-dose nodal clinical-target-volume (CTVn) had the biggest magnitude of changes: The median JI, GMI and HD of GTVn was 0.89 (IQR = 0.44-0.95), 0.11 (IQR = 0.05-0.51), 3.71 cm (IQR = 0.31-6.93 cm); high-dose CTVn was 0.78 (IQR = 0.59-0.90), 0.20 (IQR = 0.07-0.31) and 3.28 cm (IQR = 1.22-6.18 cm), respectively. There was no observed difference in the quantitative indices of the 85 'major' and 14 'minor' volumes (p = 0.5). CONCLUSIONS: Routine head and neck radiologist input in radiotherapy peer review is feasible and can help avoid gross error in contouring. ADVANCES IN KNOWLEDGE: The major and minor classifications may benefit from differentiation with quantitative indices but requires correlation from clinical outcomes.

The impact of certificate of need laws on heart attack mortality: Evidence from county borders.

Certificate of need (CON) regulations requires that health care providers obtain state approval before offering a new service or expanding existing facilities. The purported goal of CON regulations is to reduce health care costs by generating regional economies of scale and reducing redundant investments resulting from excessive competition. Critics of CON regulations note that the regulatory environment increases the costs of expansion and may incentivize health care providers to forgo capital investment, which can have a negative effect on health outcomes. To estimate the net effect of CON regulations, I use a border discontinuity design to measure within-regional heart attack mortality spanning 1968 to 1982. I estimate that CON regulations led to an increase in heart attack deaths, by 6%-10%, three years after the policy was enacted.

Antiobesity Medication Use Among Overweight and Obese Adults in the United States: 2015-2018.

OBJECTIVE: To estimate the utilization of U.S. Food and Drug Administration- approved prescription antiobesity medications (AOMs) and to identify factors associated with AOM use in the United States. METHODS: Respondents aged ≥18 years meeting AOM eligibility criteria in the 2015-2016 and 2017-2018 National Health and Nutrition Examination Survey and the 2016 Medical Expenditure Panel Survey were included in the study. AOM eligibility was defined as having a body mass index (BMI) of ≥30 kg/m2 or having a BMI between 27 and 29.9 kg/m2 and at least 1 obesity-related comorbidity. Demographic, socioeconomic, and clinical characteristics, economic outcomes, and health-related quality of life were summarized and compared between AOM users and nonusers. Multivariable logistic regression was used to identify factors that were associated with AOM use. RESULTS: Only 0.80% of eligible adults reported using AOMs in the past 30 days in 2015-2016 and 2017-2018 National Health and Nutrition Examination Survey. A greater proportion of current AOM users previously tried dietary changes compared with nonusers. They also reported an average weight loss of 3.1 kg over the previous year compared with a 1.5-kg gain among the nonusers. The total health care costs trended higher among AOM users, driven mostly by higher outpatient service costs. A BMI of ≥30 kg/m2, depression, dyslipidemia, and infertility predicted AOM use, whereas Medicare and being at risk of sleep apnea were associated with lower odds of AOM use. CONCLUSION: Despite the availability of newer AOMs and their inclusion in medical treatment guidelines, the utilization of AOMs remains low. This may reflect under-prescribing of and/or restricted patient access to approved evidence-based pharmacotherapy for obesity.

Non-operative management for oral cavity carcinoma: Definitive radiation therapy as a potential alternative treatment approach.

PURPOSE: To determine the outcomes of oral cavity squamous cell cancer (OSCC) patients treated with non-surgical approach i.e. definitive intensity-modulated radiation therapy (IMRT). METHODS: All OSCC patients treated radically with IMRT (without primary surgery) between 2005-2014 were reviewed in a prospectively collected database. OSCC patients treated with definitive RT received concurrent chemotherapy except for early stage patients or those who declined or were unfit for chemotherapy. The 5-year local, and regional, distant control rates, disease-free, overall, and cancer-specific survival, and late toxicity were analyzed. RESULTS: Among 1316 OSCC patients treated with curative-intent; 108 patients (8%) received non-operative management due to: medical inoperability (n = 14, 13%), surgical unresectability (n = 8, 7%), patient declined surgery (n = 15, 14%), attempted preservation of oral structure/function in view of required extensive surgery (n = 53, 49%) or extensive oropharyngeal involvement (n = 18, 17%). Sixty-eight (63%) were cT3-4, 38 (35%) were cN2-3, and 38 (35%) received concurrent chemotherapy. With a median follow-up of 52 months, the 5-year local, regional, distant control rate, disease-free, overall, and cancer-specific survival were 78%, 92%, 90%, 42%, 50%, and 76% respectively. Patients with cN2-3 had higher rate of 5-year distant metastasis (24% vs 3%, p = 0.001), with detrimental impact on DFS (p = 0.03) and OS (p < 0.02) on multivariable analysis. Grade ≥ 3 late toxicity was reported in 9% of patients (most common: grade 3 osteoradionecrosis in 6%). CONCLUSIONS: Non-operative management of OSCC resulted in a meaningful rate of locoregional control, and could be an alternative curative approach when primary surgery would be declined, unsuitable or unacceptably delayed.

SM04755, a small-molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy.

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small-molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro-inflammatory cytokines in human mesenchymal stem cells, rat tendon-derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight-bearing function in rat collagenase-induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy.

The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models.

The Wnt/ß-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).

Validation of distant metastases risk-groups in oral cavity squamous cell carcinoma patients treated with postoperative intensity-modulated radiotherapy.

BACKGROUND: This study aimed to derive distant metastases (DM) risk-groups in oral cavity squamous cell carcinoma (OSCC) patients treated with postoperative intensity-modulated radiation therapy (PO-IMRT). METHODS: OSCC patients treated with PO-IMRT were divided into discovery (2005-2012) and validation (2013-2014) cohorts. DM predictors were identified from multivariable analysis (MVA) to derive low- and high-risk groups in the discovery-cohort. The result was subsequently evaluated in validation-cohort. RESULTS: Overall 447 patients were included (discovery-cohort: n = 300, and validation-cohort: n = 147). Between the two cohorts, there were no significant differences in DM (p = 0.16) or OS (p = 0.26). MVA identified pN2-3 and histological grade 2-3 (G2-3) as DM predictors. High-risk group included patients who had both poor predictors (pN2-3 and G2-3), while low-risk group included patients with no or only one poor predictor. In discovery-cohort, 3-year distant control (DC) was 78% and 97% in high- and low-risk groups respectively (p < 0.001, concordance index = 0.72). In validation-cohort, risk-group classification performed similarly (concordance index = 0.73). The 3-year OS for high- versus low-risk group was 85% versus 95% in discovery-cohort (p < 0.001), and 74% versus 93% in validation-cohort (p < 0.001). CONCLUSION: A model (G2-3/pN2-3) which identifies high DM risk was validated internally. This model might be used to design future prospective studies investigating treatment intensification and/or DM surveillance.

A Method to Investigate Astrocyte and Microglial Morphological Changes in the Aging Brain of the Rhesus Macaque.

With a rapidly aging population, studies of neuroinflammation and degeneration associated with eugeric aging are becoming critical. Using the unique archive at the Tulane National Primate Research Center as a resource, we have developed tools to quantify morphological changes in astrocytes and microglia across the life span of monkeys. This method can be used for morphometric studies of multiple parameters simultaneously in an unbiased manner.

Predictors of Early Recurrence Prior to Planned Postoperative Radiation Therapy for Oral Cavity Squamous Cell Carcinoma and Outcomes Following Salvage Intensified Radiation Therapy.

PURPOSE: To determine predictors and outcomes for oral squamous cell carcinoma (OSCC) patients who had early recurrence before commencement of postoperative radiation therapy (PORT). METHODS: Retrospective review was performed for patients with OSCC treated with PORT between 2003 and 2015 after curative-intent surgery. Early recurrence was defined as tumor recurrence after surgical resection and before initiating planned PORT. Patients were classified into the following groups: (1) adjuvant PORT group (no early recurrence), (2) salvage PORT group (locoregional early recurrence), and (3) palliative PORT group (locoregional and distant early recurrence). For the whole cohort, multivariable analysis (MVA) was applied to identify predictors of early recurrence. In the salvage group, the post-PORT recurrence-free rate was estimated, and MVA was used to identify predictors of recurrence-free rate, disease-free survival, and overall survival (OS). RESULTS: Six hundred and one patients were identified, of whom 513 (85%) were treated with adjuvant PORT. Eighty-eight patients (15%) had early recurrence (28 of 88; 32% were biopsy proven) before PORT (70 in the salvage group and 18 in the palliative group). On MVA, oral tongue subsite, microscopic positive resection margin, pT3-4, and pN2-3 were associated with the development of early recurrence (P < .05 for all). The 3-year OS rates for patients with OSCC treated with adjuvant and salvage PORT were 71% (95% confidence interval [CI], 67%-75%) and 41% (95% CI, 30%-56%), respectively (P < .001; median follow-up was 3.4 and 2.9 years, respectively). After salvage PORT, the 3-year recurrence-free rate was 36% (95% CI, 23%-47%). On MVA, extranodal extension and volume of early recurrent gross disease were associated with poor recurrence-free rate, disease-free survival, and OS (P < .05 for all). CONCLUSION: Early recurrences are not uncommon in patients with high-risk features, Further study is required to improve prediction and outcomes of this very high-risk group.

Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells.

Increased protein translation in cells and various factors in the tumor microenvironment can induce endoplasmic reticulum (ER) stress, which initiates the unfolded protein response (UPR). We have previously reported that factors released from cancer cells mounting a UPR induce a de novo UPR in bone marrow-derived myeloid cells, macrophages, and dendritic cells that facilitates protumorigenic characteristics in culture and tumor growth in vivo. We investigated whether this intercellular signaling, which we have termed transmissible ER stress (TERS), also operates between cancer cells and what its functional consequences were within the tumor. We found that TERS signaling induced a UPR in recipient human prostate cancer cells that included the cell surface expression of the chaperone GRP78. TERS also activated Wnt signaling in recipient cancer cells and enhanced resistance to nutrient starvation and common chemotherapies such as the proteasome inhibitor bortezomib and the microtubule inhibitor paclitaxel. TERS-induced activation of Wnt signaling required the UPR kinase and endonuclease IRE1. However, TERS-induced enhancement of cell survival was predominantly mediated by the UPR kinase PERK and a reduction in the abundance of the transcription factor ATF4, which prevented the activation of the transcription factor CHOP and, consequently, the induction of apoptosis. When implanted in mice, TERS-primed cancer cells gave rise to faster growing tumors than did vehicle-primed cancer cells. Collectively, our data demonstrate that TERS is a mechanism of intercellular communication through which tumor cells can adapt to stressful environments.