Functionality of bone marrow mesenchymal stromal cells derived from head and neck cancer patients - A FDA-IND enabling study regarding MSC-based treatments for radiation-induced xerostomia.

PURPOSE: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs [MSC(M)] from HNC patients could be used for the treatment of RT-induced salivary dysfunction. METHODS: An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined. RESULTS: A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFNγ-stimulated MSC(M) acquired an immunosuppressive phenotype. IFNγ-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production. CONCLUSIONS: MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFNγ-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction.

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): A pilot, first-in-human study of interferon gamma-stimulated marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia.

BACKGROUND AIMS: Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for patients with head and neck cancer (HNC). Preliminary data suggest that mesenchymal stromal/stem cells (MSCs) can improve salivary function. We performed a first-in-human pilot study of interferon gamma (IFNγ)-stimulated autologous bone marrow-derived MSCs, or MSC(M), for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints. METHODS: A single-center pilot clinical trial was conducted investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M). The study was conducted under an approved Food and Drug Administration Investigational New Drug application using an institutional review board-approved protocol (NCT04489732). Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated, cultured, stimulated with IFNγ and cryopreserved for later use. Banked cells were thawed and allowed to recover in culture before patients received a single injection of 10 × 106 MSC(M) into the right submandibular gland under ultrasound guidance. The primary objective was determination of safety and tolerability by evaluating dose-limiting toxicity (DLT). A DLT was defined as submandibular pain >5 on a standard 10-point pain scale or any serious adverse event (SAE) within 1 month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using three validated quality of life instruments. Quantitative results are reported as mean and standard deviation. RESULTS: Six patients with radiation-induced xerostomia who had completed radiation at least 2 years previously (average 7.8 years previously) were enrolled in the pilot study. The median age was 71 (61-74) years. Five (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. Grade 1 pain was seen in 50% of patients after submandibular gland injection; all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAE or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. Three patients (50%) had an increase in unstimulated saliva at 1 and 3 months after MSC(M) injection. Quality of life surveys also showed a trend toward improvement. CONCLUSIONS: Injection of autologous IFNγ-stimulated MSC(M) into a singular submandibular gland of patients with RIX is safe and well tolerated in this pilot study. A trend toward an improvement in secondary endpoints of salivary quantity and quality of life was observed. This first-in-human study provides support for further investigation into IFNγ-stimulated MSC(M) injected in both submandibular glands as an innovative approach to treat RIX and improve quality of life for patients with HNC.

Effects of Food and Liquid Properties on Swallowing Physiology and Function in Adults.

Foods and liquids have properties that are often modified as part of clinical dysphagia management to promote safe and efficient swallowing. However, recent studies have questioned whether this practice is supported by the evidence. To address this, a scoping review was conducted to answer the question: "Can properties of food and liquids modify swallowing physiology and function in adults?" Online search in six databases yielded a set of 4235 non-duplicate articles. Using COVIDENCE software, two independent reviewers screened the articles by title and abstract, and 229 full-text articles were selected for full-text review. One-hundred eleven studies met the inclusion criteria for qualitative synthesis and assessment of risk of bias. Three randomized controlled trials and 108 non-randomized studies were analyzed. Large amounts of variability in instrumental assessment, properties of food and liquids, and swallowing measures were found across studies. Sour, sweet, and salty taste, odor, carbonation, capsaicin, viscosity, hardness, adhesiveness, and cohesiveness were reported to modify the oral and pharyngeal phase of swallowing in both healthy participants and patients with dysphagia. Main swallow measures modified by properties of food and liquids were penetration/aspiration, oral transit time, lingual pressures, submental muscle contraction, oral and pharyngeal residue, hyoid and laryngeal movement, pharyngeal and upper esophageal sphincter pressures, and total swallow duration. The evidence pooled in this review supports the clinical practice of food texture and liquid consistency modification in the management of dysphagia with the caveat that all clinical endeavors must be undertaken with a clear rationale and patient-specific evidence that modifying food or liquid benefits swallow safety and efficiency while maintaining quality of life.

Quantification of very late xerostomia in head and neck cancer patients after irradiation.

Objective: Radiation therapy (RT) for head and neck cancer (HNC) can result in severe xerostomia, or the subjective feeling of dry mouth. Characterizing xerostomia is critical to designing future clinical trials investigating how to improve HNC patients' quality of life (QoL). Few studies have investigated the very late (>5 years post-RT) effects of RT for HNC. We undertook preliminary studies quantifying very late xerostomia. Methods: Six adults who underwent RT for HNC at least 5 years prior and reported xerostomia were enrolled. Five healthy adults without a self-reported history of HNC or xerostomia were enrolled as controls. All participants completed three validated surveys to measure xerostomia-related QoL. Salivary production rates were measured and compositional analysis of the saliva and oral microbiome was completed. Results: The QoL survey scores for the HNC participants were significantly worse as compared to the control participants. The HNC participants produced less unstimulated saliva (p = .02) but not less stimulated saliva. The median salivary mucin significantly higher in HNC participants than in control participants (p = .02). There was no significant difference between the pH, amylase, or total protein. Microbiome analysis revealed alpha diversity to be significantly lower in the HNC participants. Conclusion: In the survivors of HNC who suffer from late toxicities, multiple means of measuring toxicity may be useful. We found that in patients with radiation-induced xerostomia over 5 years after therapy, not only were the QoL surveys significantly worse, as expected, but other measurements such as mucin and oral microbiome diversity were also significantly different. Level of evidence: 3.

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study protocol for a phase 1 dose-escalation trial of patients with xerostomia after radiation therapy for head and neck cancer: MARSH: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction.

BACKGROUND: Xerostomia, or dry mouth, is a common side effect of head and neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Adult stem cells are the ultimate source for replenishment of salivary gland tissue. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. We have undertaken studies enabling U.S. Food and Drug Administration Investigational New Drug status, demonstrating the normal phenotype, intact functionality, and pro-growth secretome of interferon-γ (IFNγ)-stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation ± chemotherapy. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow-derived, IFNγ-activated BM-MSCs for the treatment of radiation-induced xerostomia. METHODS: This single-center phase 1 dose-escalation with expansion cohort, non-placebo-controlled study will assess the safety and tolerability of BM-MSCs for the treatment of radiation-induced xerostomia in patients who had head and neck cancer. The phase 1 dose-escalation study will be a 3 + 3 design with staggered enrollment. A total of 21 to 30 subjects (9 to 18 in phase 1 study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of IFNγ-stimulated BM-MSCs to enable further studies on the efficacy of BM-MSCs. Patients' bone marrow will be aspirated, and BM-MSCs will be expanded, stimulated with IFNγ, and injected into the submandibular gland. The RP2D will be determined by dose-limiting toxicities occurring within 1 month of BM-MSC injection. Secondary outcomes of saliva amounts and composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3-, 6-, 12-, and 24-month visits. DISCUSSION: Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands after radiation therapy or chemoradiation therapy may provide an innovative remedy to treat xerostomia and restore quality of life. This is the first therapy for radiation-induced xerostomia that may be curative. TRIAL REGISTRATION: World Health Organization International Clinical Trials Registry Platform: NCT04489732.

New Antipsychotic Prescribing Continued into Skilled Nursing Facilities Following a Heart Failure Hospitalization: a Retrospective Cohort Study.

BACKGROUND: Multimorbidity and polypharmacy are common among individuals hospitalized for heart failure (HF). Initiating high-risk medications such as antipsychotics may increase the risk of poor clinical outcomes, especially if these medications are continued unnecessarily into skilled nursing facilities (SNFs) after hospital discharge. OBJECTIVE: Examine how often older adults hospitalized with HF were initiated on antipsychotics and characteristics associated with antipsychotic continuation into SNFs after hospital discharge. DESIGN: Retrospective cohort. PARTICIPANTS: Veterans without prior outpatient antipsychotic use, who were hospitalized with HF between October 1, 2010, and September 30, 2015, and were subsequently discharged to a SNF. MAIN MEASURES: Demographics, clinical conditions, prior healthcare utilization, and antipsychotic use data were ascertained from Veterans Administration records, Minimum Data Set assessments, and Medicare claims. The outcome of interest was continuation of antipsychotics into SNFs after hospital discharge. KEY RESULTS: Among 18,008 Veterans, antipsychotics were newly prescribed for 1931 (10.7%) Veterans during the index hospitalization. Among new antipsychotic users, 415 (21.5%) continued antipsychotics in skilled nursing facilities after discharge. Dementia (adjusted OR (aOR) 1.48, 95% CI 1.11-1.98), psychosis (aOR 1.62, 95% CI 1.11-2.38), proportion of inpatient days with antipsychotic use (aOR 1.08, 95% CI 1.07-1.09, per 10% increase), inpatient use of only typical (aOR 0.47, 95% CI 0.30-0.72) or parenteral antipsychotics (aOR 0.39, 95% CI 0.20-0.78), and the day of hospital admission that antipsychotics were started (day 0-4 aOR 0.36, 95% CI 0.23-0.56; day 5-7 aOR 0.54, 95% CI 0.35-0.84 (reference: day > 7 of hospital admission)) were significant predictors of continuing antipsychotics into SNFs after hospital discharge. CONCLUSIONS: Antipsychotics are initiated fairly often during HF admissions and are commonly continued into SNFs after discharge. Hospital providers should review antipsychotic indications and doses throughout admission and communicate a clear plan to SNFs if antipsychotics are continued after discharge.

Shifting Tides Toward a Proactive Patient-Centered Approach in Dysphagia Management of Neurodegenerative Disease.

Purpose Persons with neurodegenerative disease frequently develop comorbid dysphagia as part of their disease process. Current "reactive" approaches to dysphagia management address dysphagia once it manifests clinically and consist of compensatory approaches. The purpose of this article is to propose a paradigm shift in dysphagia management of patients with neurodegenerative disease from a "reactive to proactive" approach by highlighting amyotrophic lateral sclerosis (ALS) and dementia as case examples. Method The authors present several areas of special consideration for speech-language pathologists (SLPs) treating dysphagia in patients with neurodegenerative disease. The drawbacks of historical "reactive" approaches to dysphagia management are described. Concepts of functional reserve for swallowing and homeostenosis are discussed. A "proactive" patient-centered paradigm of care for these patients is proposed with evidence to support its importance. A rationale for use of this approach in patients with ALS and dementia is provided with strategies for implementation. Results When treating dysphagia in patients with neurodegenerative disease, SLPs must balance a variety of factors in their decision making, including disease severity and expected progression, cultural considerations, goals of care, patient empowerment, and caregiver support. Reactive approaches to dysphagia management in these populations are problematic in that they disempower patients by focusing on use of compensatory techniques (e.g., diet modification, postural changes, feeding tube placement). Proactive approaches that employ rehabilitative interventions to increase functional reserve, such as resistance training, may result in improvement or maintenance of swallowing function longer into disease progression. An interdisciplinary team with early SLP involvement is necessary. Conclusions SLPs play a critical role in the management of dysphagia in patients with neurodegenerative disease and should be integrated early in the care of these patients. By focusing on a proactive patient-centered approach, patients with neurodegenerative conditions, such as ALS and dementia, will experience improved quality of life and health outcomes for a longer time.

Perceived Professional and Institutional Factors Influencing Clinical Adoption of Pharyngeal High-Resolution Manometry.

Purpose We assessed experienced clinicians' perceptions of benefits and drawbacks to the clinical adoption of pharyngeal high-resolution manometry (HRM). This article focuses on the professional and institutional factors that influence the clinical adoption of pharyngeal HRM by speech-language pathologists (SLPs). Method Two surveys (closed- and open-ended questions) and a series of focus groups were completed with SLP members of both the American Speech-Language-Hearing Association and the Dysphagia Research Society (DRS). Transcripts were inductively coded for emergent themes. Results Thirteen SLPs were recruited to attend focus group sessions at the American Speech-Language-Hearing Association. Eighty-seven SLPs responded to the DRS open-set response survey. Two additional focus groups of 11 SLPs were convened at the DRS meeting. Conventional content analysis revealed overall SLP enthusiasm for the clinical use of HRM, with some concerns about the technology adoption process. The following themes related to the professional and institutional factors influencing clinical adoption were identified: (a) scope of practice, (b) access, (c) clinical workflow, and (d) reimbursement. Conclusion These data serve to elucidate the most salient factors relating to the clinical adoption of pharyngeal HRM into routine speech-language pathology clinical practice. While enthusiasm exists, a variety of systems-level issues must be addressed to support this process.

Correlates of Early Pharyngeal High-Resolution Manometry Adoption in Expert Speech-Language Pathologists.

Pharyngeal high-resolution manometry (HRM) is at a point of entry into speech-language pathologist (SLP) clinical practice. However, the demographic characteristics of SLPs who are early adopters of HRM are unclear; perspectives of early adopters may shape how the technology is received by the field at large. We hypothesized that younger SLPs, those working in outpatient settings, those with a strong knowledge base in HRM, and those with experience in other types of instrumentation are more likely to have interest in adopting HRM. We surveyed the population of board-certified SLPs (BCS-S; n = 262) with a 33% response rate (n = 78). Firth logistic regression was used to determine differences in those expressing interest in adopting HRM into future practice (n = 28) and those who did not (n = 45) from the analytic sample of 73 respondents. The best fitting model predicted that SLPs: (1) with training in more types of instrumentation; and (2) believing they could explain the HRM procedure to a patient were more likely to plan to adopt pharyngeal HRM into regular clinical practice. Experience with a variety of instrumentation techniques may encourage SLPs to use new forms of technology. Knowledge of early adopter demographics will allow for development of targeted trainings and determination of HRM implementation barriers. Identification of a clinician sub-group more likely to adopt other new technologies in the future may also be possible.

SLP-Perceived Technical and Patient-Centered Factors Associated with Pharyngeal High-Resolution Manometry.

High-resolution manometry (HRM) objectively measures swallowing-related pressures in the pharynx and esophagus. It has been used in many research applications, but it is unclear how HRM is perceived amongst speech-language pathologists (SLP) as it enters into clinical practice. The purpose of this study was to explore SLP perceptions of clinical HRM use. Based on qualitative data collected at four focus groups held at two national conferences and a survey based on open-ended questions, we found broad consensus among those queried regarding how HRM's objective and targeted data could enhance diagnosis and drive treatments. However, we found less consensus among SLPs regarding which patients may and may not benefit, as well as when in the clinical process HRM would best supplement existing technologies, showing a need for further research. These findings highlight how SLPs can be motivated to adopt new clinical technologies if they see a patient-centered benefit and underscore the need for continued SLP education on pharyngeal HRM.

A Pilot Study of Perceived Mouth Dryness, Perceived Swallowing Effort, and Saliva Substitute Effects in Healthy Adults Across the Age Range.

Xerostomia, or perceived mouth dryness, increases with advancing age, but its influence on swallowing effort is unknown. This study: (1) quantified relationships among age, perceived sense of swallowing effort, and ratings of perceived mouth dryness, and (2) examined changes in swallowing effort following application of a gel-based saliva substitute in healthy participants. This was a cross-sectional observational study and data were collected from attendees of a community healthy aging fair. Forty-two healthy participants (mean age = 65 years; 20 female) were enrolled. Each participant rated perceived effort with swallowing and perceived mouth dryness on a 10-cm horizontal, undifferentiated line. After participants applied a gel-based saliva substitute (Biotene® Oral Balance) to their tongue and oral mucosa, they rated perceived effort with swallowing again. Age was associated with greater perceived mouth dryness (r = 0.37, p < 0.03) but not with perceived swallowing effort (r = 0.16, p = 0.32). Perceived mouth dryness was associated with greater perceived swallowing effort (r = 0.62, p < 0.001). Perceived swallowing effort declined following application of the salivary substitute (mean difference = 9.39 mm, p < 0.002). Age was found to be a significant predictor of perceived mouth dryness (p < .02); and perceived mouth dryness was found to significantly predict perceived swallow effort (p < .001). Perceived mouth dryness increased with advancing age, but perceived swallowing effort did not. Regardless of age, participants with higher levels of perceived mouth dryness also reported more perceived effort with swallowing suggesting a role for adequate oral lubrication in this perception. Even in healthy participants, use of a gel-based saliva substitute lowered perceived swallowing effort.

Effects of Change in Tongue Pressure and Salivary Flow Rate on Swallow Efficiency Following Chemoradiation Treatment for Head and Neck Cancer.

Patients treated with chemoradiation for head and neck cancer frequently develop dysphagia. Tissue damage to the oral tongue causing weakness along with decreases in saliva production may contribute to dysphagia. Yet, effects of these variables on swallowing-related measures are unclear. The purpose of this study was (1) to determine effects of chemoradiation on tongue pressures, as a surrogate for strength, and salivary flow rates and (2) to elucidate relationships among tongue pressures, saliva production, and swallowing efficiency by bolus type. Twenty-one patients with head and neck cancer treated with chemoradiation were assessed before and after treatment and matched with 21 healthy control participants who did not receive chemoradiation. Each participant was given a questionnaire to rate dysphagia symptoms. Videofluoroscopic Evaluation of Swallowing (VFES) was used to determine swallowing efficiency; the Saxon test measured salivary flow rate; and the Iowa Oral Performance Instrument (IOPI) was used for oral tongue maximum and endurance measures. Results revealed significantly lower tongue endurance measures for patients post-treatment as compared to controls (p = .012). Salivary flow rates also were lower compared to pre-treatment (p = .000) and controls (p = .000). Simple linear regression analyses showed that change in salivary flow rate was predictive of change in swallow efficiency measures from pre- to post-treatment for 1 mL thin liquid (p = .017), 3 mL nectar-thick liquid (p = .026), and 3 mL standard barium pudding (p = .011) boluses. Based on these findings, it appears that chemoradiation treatment affects tongue endurance and salivary flow rate, and these changes may impact swallow efficiency. These factors should be considered when planning treatment for dysphagia.

Bolus effects on patient awareness of swallowing difficulty and swallow physiology after chemoradiation for head and neck cancer.

BACKGROUND: Patients treated for head and neck cancer frequently develop dysphagia. Bolus characteristics are altered during fluoroscopic swallowing studies to observe the impact on swallowing function. The purpose of this study was to determine bolus volume and consistency effects on oropharyngeal swallowing physiology and patient awareness of swallowing difficulty. METHODS: Twenty-one patients with head and neck cancer were assessed pre-chemoradiation and post-chemoradiation. The Modified Barium Swallow Study (MBSS) was utilized to examine swallow physiology. Each patient provided perceptual ratings of swallowing difficulty after each swallow of varying bolus types. RESULTS: Oral transit times were significantly longer with pudding boluses. There were trends for higher residue percentages as well as perceptual ratings for pudding and cookie boluses. One correlation between perceptual ratings and physiology was significant. CONCLUSION: Patient awareness of swallowing difficulty and aspects of swallowing physiology vary with bolus consistency. Patient awareness does not correlate with observed changes in swallowing physiology.

Changes in swallowing physiology and patient perception of swallowing function following chemoradiation for head and neck cancer.

Patients treated with chemoradiation for head and neck cancer often report difficulty with swallowing and are frequently diagnosed with dysphagia. The extent to which patient awareness of dysphagia corresponds to observed physiologic changes in swallowing is unclear. The purpose of this study was to determine how both patient awareness of swallowing function and swallowing physiology individually change following chemoradiation and then to clarify the relationship between them. Twenty-one patients with head and neck cancer treated with chemoradiation were assessed before and after treatment and matched with twenty-one control subjects. The modified barium swallow test was utilized to examine swallowing physiology. Each subject was also given a series of items regarding awareness of specific dysphagia symptoms. Results showed decreased swallow efficiencies, higher percentages of residue, and more occurrences of penetration and aspiration following chemoradiation. Patients also had significantly higher ratings for 4 of the 12 items ("dry mouth," "food sticking in my mouth," "need water to help food go down," and "change in sense of taste"). Only one strong and significant correlation was found between ratings for "I have difficulty swallowing" and swallow efficiency values. Based on these findings, it appears that patients sense a general difficulty with swallowing but have less awareness of specific symptoms of dysphagia.

Effects of reduced saliva production on swallowing in patients with Sjogren's syndrome.

This study aimed to further characterize the nature of swallowing dysfunction in patients with Sjogren's syndrome (SS). Subjects filled out a perception of swallow function form. Measures of stimulated salivary flow rate were also taken, and videofluoroscopic evaluation of swallowing was completed. The amount of saliva produced by patients with SS was significantly less than that produced by normal age-matched controls, and these patients perceived their swallowing to be impaired. Few statistically significant differences were found between the SS group and normal age-matched controls on temporal measures of swallowing, and 96% of swallows in the SS group were judged to be functional. There was no correlation between perception of swallowing and amount of saliva produced. No strong correlations were found between temporal measures of swallowing and salivary flow rate. Results indicated that patients with SS tend to perceive their swallowing to be worse than physiologic swallowing measures indicate. The decreased saliva production in these patients does not appear to be the cause of their perceived swallowing difficulty but may affect their sensory judgment of swallow function. Future studies will focus on how quality of saliva affects swallowing in these patients.