A protocol for stakeholder engagement in head and neck cancer pragmatic trials.

Meaningful engagement with stakeholders in research demands intentional approaches. This paper describes the development of a framework to guide stakeholder engagement as research partners in a pragmatic trial proposed to evaluate behavioral interventions for dysphagia in head and neck cancer patients. We highlight the core principles of stakeholder engagement including representation of all perspectives, meaningful participation, respectful partnership with stakeholders, and accountability to stakeholders; and describe how these principles were operationalized to engage relevant stakeholders throughout the course of a large clinical trial.

In situ-gelling hydrophobized starch nanoparticle-based nanoparticle network hydrogels for the effective delivery of intranasal olanzapine to treat brain disorders.

Intranasal (IN) delivery offers potential to deliver antipsychotic drugs with improved efficacy to the brain. However, the solubilization of such drugs and the frequency of required re-application both represent challenges to its practical implementation in treating various mental illnesses including schizophrenia. Herein, we report a sprayable nanoparticle network hydrogel (NNH) consisting of hydrophobically-modified starch nanoparticles (SNPs) and mucoadhesive chitosan oligosaccharide lactate (COL) that can gel in situ within the nasal cavity and release ultra-small penetrative SNPs over time. Hydrophobization of the SNPs enables enhanced uptake and prolonged release of poorly water soluble drugs such as olanzapine from the NNH depot through mucous and ultimately into the brain via the nose-to-brain (N2B) pathway. The hydrogel shows high in vitro cytocompatibility in mouse striatal neuron and human primary nasal cell lines and in vivo efficacy in an amphetamine-induced pre-clinical rat schizophrenia model, with IN-delivered NNH hydrogels maintaining successful attenuation of locomotor activity for up to 4 h while all other tested treatments (drug-only IN or conventional intraperitoneal delivery) failed to attenuate at any time point past 0.5 h. As such, in situ-gelling NNHs represent a safe excipient for the IN delivery of hydrophobic drugs directly to the brain using customized SNPs that exhibit high penetration and drug complexing properties to maximize effective drug delivery.

Supramolecularly-Cross-Linked Nanogel Assemblies for On-Demand, Ultrasound-Triggered Chemotherapy.

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.

Clinical Implementation of DIGEST as an Evidence-Based Practice Tool for Videofluoroscopy in Oncology: A Six-Year Single Institution Implementation Evaluation.

Clinical implementation of evidence-based practice (EBP) tools is a healthcare priority. The Dynamic Grade of Swallowing Toxicity (DIGEST) is an EBP tool developed in 2016 for videofluoroscopy in head and neck (H&N) oncology with clinical implementation as a goal. We sought to examine: (1) feasibility of clinical implementation of DIGEST in a national comprehensive cancer center, and (2) fidelity of DIGEST adoption in real-world practice. A retrospective implementation evaluation was conducted in accordance with the STARI framework. Electronic health record (EHR) databases were queried for all consecutive modified barium swallow (MBS) studies conducted at MD Anderson Cancer Center from 2016 to 2021. Implementation outcomes included: feasibility as measured by DIGEST reporting in EHR (as a marker of clinical use) and fidelity as measured by accuracy of DIGEST reporting relative to the decision-tree logic (penetration-aspiration scale [PAS], residue, and Safety [S] and Efficiency [E] grades). Contextual factors examined included year, setting, cancer type, MBS indication, and provider. 13,055 MBS were conducted by 29 providers in 7,842 unique patients across the lifespan in diverse oncology populations (69% M; age 1-96 years; 58% H&N cancer; 10% inpatient, 90% outpatient). DIGEST was reported in 12,137/13,088 exams over the 6-year implementation period representing 93% (95% CI: 93-94%) adoption in all exams and 99% (95% CI: 98-99%) of exams excluding the total laryngectomy population (n = 730). DIGEST reporting varied modestly by year, cancer type, and setting/provider (> 91% in all subgroups, p < 0.001). Accuracy of DIGEST reporting was high for overall DIGEST (incorrect SE profile 1.6%, 200/12,137), DIGEST-safety (incorrect PAS 0.4% 51/12,137) and DIGEST-efficiency (incorrect residue 1.2%, 148/12,137). Clinical implementation of DIGEST was feasible with high fidelity in a busy oncology practice across a large number of providers. Adoption of the tool across the lifespan in diverse cancer diagnoses may motivate validation beyond H&N oncology.

Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via ß2-adrenergic receptor (ß2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using ß2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Profession-based manual therapy nomenclature: exploring history, limitations, and opportunities.

OBJECTIVE: The International Consortium on Manual Therapies (ICMT) is a grassroots interprofessional association open to any formally trained practitioner of manual therapy (MT) and basic scientists promoting research related to the practice of MT. Currently, MT research is impeded by professions' lack of communication with other MT professions, biases, and vernacular. Current ICMT goals are to minimize these barriers, compare MT techniques, and establish an interprofessional MT glossary. METHODS: Practitioners from all professions with training in manual therapies were encouraged by e-mail and website to participate (www.ICMTConferene.org). Video conferences were conducted at least bimonthly for 2.5 years by profession-specific and interprofessional focus groups (FGs). Members summarized scopes of practice, technique descriptions, associated mechanisms of action (MOA), and glossary terms. Each profession presented their work to the interprofessional FG to promote dialogue, understanding and consensus. Outcomes were reported and refined at numerous public events. RESULTS: Focus groups with representatives from 5 MT professions, chiropractic, massage therapy, osteopathic, physical therapy and structural integration identified 17 targeting osseous structures and 49 targeting nonosseous structures. Thirty-two techniques appeared distinct to a specific profession, and 13 were used by more than 1. Comparing descriptions identified additional commonalities. All professions agreed on 4 MOA categories for MT. A glossary of 280 terms and definitions was consolidated, representing key concepts in MT. Twenty-one terms were used by all MT professions and basic scientists. Five terms were used by MT professions exclusive of basic scientists. CONCLUSION: Outcomes suggested a third to a half of techniques used in MT are similar across professions. Additional research is needed to better define the extent of similarity and how to consistently identify those approaches. Ongoing expansion and refinement of the glossary is necessary to promote descriptive clarity and facilitate communication between practitioners and basic scientists.

Predicting health-related quality of life change using natural language processing in thyroid cancer.

Background: Patient-reported outcomes (PRO) allow clinicians to measure health-related quality of life (HRQOL) and understand patients' treatment priorities, but obtaining PRO requires surveys which are not part of routine care. We aimed to develop a preliminary natural language processing (NLP) pipeline to extract HRQOL trajectory based on deep learning models using patient language. Materials and methods: Our data consisted of transcribed interviews of 100 patients undergoing surgical intervention for low-risk thyroid cancer, paired with HRQOL assessments completed during the same visits. Our outcome measure was HRQOL trajectory measured by the SF-12 physical and mental component scores (PCS and MCS), and average THYCA-QoL score.We constructed an NLP pipeline based on BERT, a modern deep language model that captures context semantics, to predict HRQOL trajectory as measured by the above endpoints. We compared this to baseline models using logistic regression and support vector machines trained on bag-of-words representations of transcripts obtained using Linguistic Inquiry and Word Count (LIWC). Finally, given the modest dataset size, we implemented two data augmentation methods to improve performance: first by generating synthetic samples via GPT-2, and second by changing the representation of available data via sequence-by-sequence pairing, which is a novel approach. Results: A BERT-based deep learning model, with GPT-2 synthetic sample augmentation, demonstrated an area-under-curve of 76.3% in the classification of HRQOL accuracy as measured by PCS, compared to the baseline logistic regression and bag-of-words model, which had an AUC of 59.9%. The sequence-by-sequence pairing method for augmentation had an AUC of 71.2% when used with the BERT model. Conclusions: NLP methods show promise in extracting PRO from unstructured narrative data, and in the future may aid in assessing and forecasting patients' HRQOL in response to medical treatments. Our experiments with optimization methods suggest larger amounts of novel data would further improve performance of the classification model.

Consideration of the importance of measuring thermal discomfort in biomedical research.

Core temperature stability is the result of a dynamically regulated balance of heat loss and gain, which is not reflected by a simple thermometer reading. One way in which these changes manifest is in perceived thermal comfort, 'feeling too cold' or 'feeling too hot', which can activate stress pathways. Unfortunately, there is surprisingly little preclinical research that tracks changes in perceived thermal comfort in response to either disease progression or various treatments. Without measuring this endpoint, there may be missed opportunities to evaluate disease and therapy outcomes in murine models of human disease. Here, we discuss the possibility that changes in thermal comfort in mice could be a useful and physiologically relevant measure of energy trade-offs required under various physiological or pathological conditions.

Chronic adrenergic stress and generation of myeloid-derived suppressor cells: Implications for cancer immunotherapy in dogs.

Recent studies have highlighted a key role played by the sympathetic nervous system (SNS) and adrenergic stress in mediating immune suppression associated with chronic inflammation in cancer and other diseases. The connection between chronic SNS activation, adrenergic stress and immune suppression is linked in part to the ability of catecholamines to stimulate the bone marrow release and differentiation of myeloid-derived suppressor cells (MDSC). Rodent model studies have revealed an important role for ß-adrenergic receptor signalling in suppression of cancer immunity in mice subjected to chronic stresses, including thermal stress. Importantly, therapeutic blockade of beta-adrenergic responses by drugs such as propranolol can partially reverse the generation and differentiation of MDSC, and partly restore tumour immunity. Clinical trials in both humans and dogs with cancer have demonstrated that propranolol blockade can improve responses to radiation therapy, cancer vaccines and immune checkpoint inhibitors. Thus, the SNS stress response has become an important new target to relieve immune suppression in cancer and other chronic inflammatory conditions.

Galectin-3 expression in donor T cells reduces GvHD severity and lethality after allogeneic hematopoietic cell transplantation.

Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD.

Modelling growth of Bacillus cereus in paneer by one-step parameter estimation.

Bacillus cereus phylogenetic group III and IV strains are commonly associated with food products and cause toxin mediated foodborne diseases. These pathogenic strains have been identified from milk and dairy products, such as reconstituted infant formula and several cheeses. Paneer is a fresh, soft cheese originating from India that is prone to foodborne pathogen contamination, such as by Bacillus cereus. However, there are no reported studies of B. cereus toxin formation in paneer or predictive models quantifying growth of the pathogen in paneer under different environmental conditions. This study assessed enterotoxin-producing potential of B. cereus group III and IV strains, isolated from dairy farm environments, in fresh paneer. Growth of a four-strain cocktail of toxin-producing B. cereus strains was measured in freshly prepared paneer incubated at 5-55 °C and modelled using a one-step parameter estimation combined with bootstrap re-sampling to generate confidence intervals for model parameters. The pathogen grew in paneer between 10 and 50 °C and the developed model fit the observed data well (R2 = 0.972, RMSE = 0.321 log10 CFU/g). The cardinal parameters for B. cereus growth in paneer along with the 95% confidence intervals were: µopt 0.812 log10 CFU/g/h (0.742, 0.917); Topt is 44.177 °C (43.16, 45.49); Tmin is 4.405 °C (3.973, 4.829); Tmax is 50.676 °C (50.367, 51.144). The model developed can be used in food safety management plans and risk assessments to improve safety of paneer while also adding to limited information on B. cereus growth kinetics in dairy products.

Circadian Rhythm Disruption Increases Tumor Growth Rate and Accumulation of Myeloid-Derived Suppressor Cells.

Circadian rhythm disruption is implicated in the initiation and progression of many diseases, including cancer. External stimuli, such as sunlight, serve to synchronize physiological processes and cellular functions to a 24-h cycle. The immune system is controlled by circadian rhythms, and perturbation of these rhythms can potentially alter the immune response to infections and tumors. The effect of circadian rhythm disruption on the immune response to tumors remains unclear. Specifically, the effects of circadian disruption (CD) on immunosuppressive cell types within the tumor, such as myeloid-derived suppressor cells (MDSCs), are unknown. In this study, a shifting lighting schedule is used to disrupt the circadian rhythm of mice. After acclimation to lighting schedules, mice are inoculated with 4T1 or B16-F10 tumors. Tumor growth is increased in mice housed under circadian disrupting lighting conditions compared to standard lighting conditions. Analysis of immune populations within the spleen and tumor shows an increased accumulation of MDSCs within these tissues, suggesting that MDSC mediated immunosuppression plays a role in the enhanced tumor growth caused by circadian disruption. This paves the way for future studies of the effects of CD on immunosuppression in cancer.

Isolation of human and mouse myeloid-derived suppressor cells for metabolic analysis.

Metabolic reprogramming is associated with myeloid-derived suppressor cell (MDSC) immunosuppressive function. Here, we outline the process for acquiring MDSCs from human and murine sources for subsequent analysis of fatty acid oxidation, oxidative phosphorylation, and glycolysis using the Seahorse XFe 96 Analyzer. Murine MDSCs can be isolated directly from tumor-bearing mice or derived through IL-6 and GM-CSF culture of bone marrow cells from non-tumor-bearing mice. To generate human MDSCs, peripheral blood mononuclear cells (PBMCs) can be cultured with IL-6 and GM-CSF. For complete details on the use and execution of this protocol, please refer to Mohammadpour et al. (2021).

An Implementation Assessment of the Virtual Acute Care for Elders Program From the Perspective of Key Stakeholders.

OBJECTIVE: The aim of this study was to obtain feedback from key stakeholders and end users to identify program strengths and weaknesses to plan for wider dissemination and implementation of the Virtual Acute Care for Elders (Virtual ACE) program, a novel intervention that improves outcomes for older surgical patients. BACKGROUND: Virtual ACE was developed to deliver evidence-based geriatric care without requiring daily presence of a geriatrician. Previous work demonstrated that Virtual ACE increased mobility and decreased delirium rates for surgical patients. METHODS: We conducted semi-structured interviews with 30 key stakeholders (physicians, nurses, hospital leadership, nurse managers, information technology staff, and physical/occupational therapists) involved in the implementation and use of the program. RESULTS: Our stakeholders indicated that Virtual ACE was extremely empowering for bedside nurses. The program helped nurses identify older patients who were at risk for a difficult postoperative recovery. Virtual ACE also gave them skills to manage complex older patients and more effectively communicate their needs to surgeons and other providers. Nurse managers felt that Virtual ACE helped them allocate limited resources and plan their unit staffing assignments to better manage the needs of older patients. The main criticism was that the Virtual ACE Tracker that displayed patient status was difficult to interpret and could be improved by a better design interface. Stakeholders also felt that program training needed to be improved to accommodate staff turnover. CONCLUSIONS: Although respondents identified areas for improvement, our stakeholders felt that Virtual ACE empowered them and provided effective tools to improve outcomes for older surgical patients.

Conservative management of De Quervain's tendinopathy with an orthopedic manual physical therapy approach emphasizing first CMC manipulation: a retrospective case series.

De Quervain's tendinopathy (DQT) is a musculoskeletal disorder that limits hand function of affected individuals. Management of DQT can include splinting, activity modification, medications, corticosteroid injections, physical therapist management, and surgery. There is limited evidence to support the combination of manual therapy and exercise interventions within an Orthopedic Manual Physical Therapy (OMPT) approach when managing patients with DQT. Three patients identified with DQT underwent a multi-modal treatment regimen including carpometacarpal (CMC) thrust and non-thrust manipulation, end range radiocarpal mobilization, mobilization with movement (MWM), strengthening exercises, and grip proprioception training. Outcomes were assessed using the numeric pain rating scale (NPRS), Jamar hand dynamometer grip strength, and the Quick Disabilities of the Arm, Shoulder, and Hand (Quick DASH) questionnaire. These measures were administered at baseline and discharge. Each patient demonstrated improvements in all outcome measures and required ten visits or less to reach a satisfactory outcome. The NPRS improved by a mean of 7.1 points on a 0-10 scale, Quick DASH improved by an average of 37.1%, and grip strength improved by a mean of 27.6 pounds. Each patient was able to return to daily tasks without pain and all improvements were maintained at six month follow-up. An impairment based OMPT management approach was effective in managing three patients with DQT. The inclusion of first CMC manipulation within this multi-modal approach may enhance conservative management of patients with DQT. Because a cause and effect relationship cannot be inferred from a case series, further research is recommended to investigate the efficacy of this management approach.

Time Heals Most Wounds - Perceptions of Thyroidectomy Scars in Patients With Thyroid Cancer.

BACKGROUND: Patients understandably have concerns about thyroidectomy scars. This study aimed to characterize patients' perceptions of their thyroidectomy scar before and up to 1-y after surgery. METHODS: Patients with papillary thyroid cancer (n = 83) completed semi-structured interviews before and at 2-wks, 6-Wk, 6-mo, and 1-y post-thyroidectomy. Interviews probed about scar concerns and appearance. Content analysis was used to identify themes. RESULTS: The majority of participants did not express concerns about scar appearance. When expressed, preoperative concerns often stemmed from previous surgery experiences or unease with neck incisions. Postoperatively, concerns about scar appearance decreased over time throughout the healing period with most patients being satisfied with their scar appearance by 6-mo after surgery. CONCLUSIONS: Patients with papillary thyroid cancer express few concerns about scar thyroidectomy appearance. Surgeons can reassure patients who have preoperative concerns that most patients are satisfied with their scar appearance by 6-mo after surgery.

Ultrasonographic Validation for Needle Placement in the Tibialis Posterior Muscle.

BACKGROUND: The tibialis posterior (TP) muscle plays an important role in normal foot function. Safe, efficacious therapeutic approaches addressing this muscle are necessary; however, the location of the muscle in the deep posterior compartment can create challenges. PURPOSE: The purpose of this study was to assess the accuracy of needle placement in the TP muscle and determine the needle placement in relation to the neurovascular structures located within the deep compartment. DESIGN: Cross Sectional Study. METHODS: Needle placement and ultrasound imaging were performed on 20 healthy individuals. A 50 mm or 60 mm needle was inserted between 30 - 50% of the tibial length measured from the medial tibiofemoral joint. The needle was inserted in a medial to lateral direction into the right extremity with the patient in right side lying. Placement of the needle into the TP muscle was verified with ultrasound imaging, and the shortest distance from the needle to the posterior tibial artery and tibial nerve was measured. The depth from the skin to the superficial border of the TP muscle was also measured. RESULTS: Ultrasonography confirmed the needle filament was inserted into the TP muscle in all 20 individuals and did not penetrate the neurovascular bundle in any individual. The mean distance from the needle to the tibial nerve and posterior tibial artery was 10.0 + 4.7 mm and 10.2 + 4.7 mm respectively. The superficial border of the TP muscle from the skin was at a mean depth of 25.8 + 4.9 mm. CONCLUSION: This ultrasound imaging needle placement study supports placement of a solid filament needle into the TP muscle with avoidance of the neurovascular structures of the deep posterior compartment when placed from a medial to lateral direction at 30-50% of the tibial length. LEVEL OF EVIDENCE: 2b.

ß2-adrenergic receptor signaling regulates metabolic pathways critical to myeloid-derived suppressor cell function within the TME.

Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that ß2 adrenergic receptor (ß2-AR) expression on MDSCs increases with tumor growth and that the ß2-AR stress pathway drives the immune suppressive activity of MDSCs by altering their metabolism. We show that ß2-AR signaling decreases glycolysis and increases oxidative phosphorylation and fatty acid oxidation (FAO). It also increases expression of the fatty acid transporter CPT1A, which is necessary for the FAO-mediated immunosuppressive function of MDSCs. Moreover, we show that ß2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2. Our data reveal that ß2-AR signaling triggered by stress is an important physiological regulator of key metabolic pathways in MDSCs, driving their immunosuppressive function.