Wharton's jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury.

Wharton's jelly mesenchymal stem cells (WJ-MSCs) are gaining significant attention in regenerative medicine for their potential to treat degenerative diseases and mitigate radiation injuries. WJ-MSCs are more naïve and have a better safety profile, making them suitable for both autologous and allogeneic transplantations. This review highlights the regenerative potential of WJ-MSCs and their clinical applications in mitigating various types of radiation injuries. In this review, we will also describe why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine along with a balanced view on their strengths and weaknesses. Finally, the most updated literature related to both preclinical and clinical usage of WJ-MSCs for their potential application in the regeneration of tissues and organs will also be compiled.

Effect of dose to parotid ducts on Sticky Saliva and Xerostomia in radiotherapy of head and neck squamous cell carcinoma.

BACKGROUND: Radiotherapy (RT) in head and neck squamous cell cancer (HNSCC) often leads to sticky saliva and xerostomia (SSX). Dose sparing of salivary glands (SG) reduces occurrence of SSX but few studies investigated the relationship between RT dose to SG substructures and SSX. We therefore investigated this hypothesis, focusing on the parotid duct (PD). METHODS: Retrospective data was collected from 99 HNSCC patients treated at our center with (chemo-)radiotherapy (CRT). PD and other organs-at-risk (OAR) were (re-)contoured and DVHs were generated without re-planning. SSX was graded according to CTCAE v.4.03 and evaluated at acute, subacute, and two late timepoints. RESULTS: Most patients presented with loco-regionally advanced disease. In 47% of patients, up-front neck dissection preceded CRT. Weighted mean dose was 28.6 Gy for bilateral parotid glands (PG), and 32.0 Gy for PD. Acute SSX presented as grades 0 (35.3%), I (41.4%), II (21.2%) and III (2.0%). There was no association of OARs and SSX ≥ grade 2 in univariable logistic regression (LR). Multivariable LR showed statistically significant relationship of acute SSX with: PG weighted mean dose (OR 0.84, p = 0.004), contralateral PG mean dose (OR 1.14, p = 0.02) and contralateral PD planning OAR (PD PRV) mean dose (OR 1.84, p = 0.03). CONCLUSIONS: There was an association of acute SSX with dose exposure of PD PRV in multivariable regression, only. Due to statistical uncertainties and the retrospective nature of this analysis, further studies are required to confirm or reject the hypothesis.

MASCC/ISOO Clinical Practice Statement: Clinical assessment of salivary gland hypofunction and xerostomia in cancer patients.

PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the clinical assessment of salivary gland hypofunction and xerostomia in cancer patients. METHODS: This CPS was developed based on a critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care. RESULTS: The objective assessment of saliva secretion involves an extra- and intra-oral clinical examination while the subjective assessment involves eliciting information on the patient's complaint of xerostomia and its impact on daily functioning. This CPS summarizes the common investigator- and patient-reported instruments used in clinical practice for assessing salivary gland hypofunction and xerostomia in cancer patients. CONCLUSION: There is a range of tools to assess salivary gland function in patients undergoing cancer therapy, patients recovering from cancer therapy, or cancer survivors. Clinicians should ideally conduct both objective and subjective measurements to ensure a clear understanding about the status of the patients in order to provide the most appropriate treatment.

MASCC/ISOO Clinical Practice Statement: Management of salivary gland hypofunction and xerostomia in cancer patients.

PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the management of salivary gland hypofunction and xerostomia in cancer patients. METHODS: This CPS was developed based on critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care. RESULTS: Salivary gland hypofunction and xerostomia in cancer patients are managed by (i) stimulating saliva production of salivary glands with residual secretory capacity or (ii) artificial wetting of the oral and lip surfaces which can be achieved by pharmacological or non-pharmacological interventions. Pharmacological interventions encompass the use of sialagogues and sialolytics, while non-pharmacological interventions involve the use of moistening agents, mechanical, gustatory, or electrostimulation of the salivary glands. Additional treatment modalities may be incorporated in practice based on local availability and the clinician's experience. CONCLUSION: The information presented in this CPS offers clinicians convenient access to the dosages and regimens of different interventions for managing salivary gland hypofunction or xerostomia to facilitate clinical efficiency and conserve valuable time for clinicians.

Prevalence of Xerostomia and Hyposalivation Among Individuals Attending Oral Cancer Screening in Thailand: A Cross-Sectional Study.

Aim: It has been speculated that the prevalence of xerostomia and hyposalivation might be higher among individuals attending oral cancer screening than among members of the general population. Therefore, this study investigated the prevalence of these conditions and their associated factors among individuals taking part in oral cancer screening and residing in the northeastern provinces of Thailand. Materials and Methods: This cross-sectional study recruited convenient individuals aged ≥40 years with at least one oral cancer risk factor. In total, 561 participants were included. Demographic characteristics and relevant oral cancer risk factors were recorded. A questionnaire comprising five items was used to assess xerostomia. Participants were then categorized into two groups based on the absence or presence of xerostomia. Subsequently, the stimulated salivary flow rate was assessed using the spitting technique to identify hyposalivation. Participants were then separated into two groups depending on the absence or presence of hyposalivation. Univariate and multivariate logistic regression analyses were then performed to identify factors associated with xerostomia or hyposalivation. Results: The mean age of participants was 65.62 ± 9.70 years, and approximately 60% of participants were post-menopausal women. The prevalence of xerostomia was 43.85%, and the prevalence of hyposalivation was 61.50%. It was revealed that age ≥65 years (odds ratio [OR] = 1.57, P = 0.02) and burning sensation in the mouth (OR = 5.36, P < 0.001) were strongly associated with xerostomia. Female participants were more likely to exhibit hyposalivation (OR = 2.38, P = 0.001). Oral cancer risk factors were not associated with xerostomia or hyposalivation. Conclusions: In this study, age ≥65 years and burning sensation were identified as risk factors for xerostomia, whereas female sex was a risk factor for hyposalivation. Dentists should be aware of both conditions. Various interventions to alleviate dry mouth symptoms might be useful for individuals with these risk factors.

Considerations for oral and dental tissues in holistic care during long-haul space flights.

The health of astronauts during and after the return from long-haul space missions is paramount. There is plethora of research in the literature about the medical side of astronauts' health, however, the dental and oral health of the space crew seem to be overlooked with limited information in the literature about the effects of the space environment and microgravity on the oral and dental tissues. In this article, we shed some light on the latest available research related to space dentistry and provide some hypotheses that could guide the directions of future research and help maintain the oral health of space crews. We also promote for the importance of regenerative medicine and dentistry as well highlight the opportunities available in the expanding field of bioprinting/biomanufacturing through utilizing the effects of microgravity on stem cells culture techniques. Finally, we provide recommendations for adopting a multidisciplinary approach for oral healthcare during long-haul space flights.

Females have lower salivary flow than males, before and after radiation therapy for head/neck cancer.

OBJECTIVE: To compare salivary flow rates between females and males, before and after radiation therapy (RT) for head and neck cancer (HNC). METHODS: Prospective observational multicenter cohort study (OraRad). Stimulated whole salivary flow was measured before RT and at 6 and 18 months after RT. RESULTS: Mean (95% confidence interval) salivary flow in g/min before RT was 0.81 (0.71, 0.90) in females (n = 107) and 1.20 (1.15, 1.25) in males (n = 391) (p < 0.001); at 6 months was 0.34 (0.24, 0.44) in females and 0.50 (0.44, 0.55) in males (p = 0.01); at 18 months was 0.49 (0.38, 0.59) in females and 0.70 (0.64, 0.75) in males (p < 0.001). Median nadir salivary flow after RT was 0.22 in females and 0.35 in males (p < 0.001). A lower nadir salivary flow in females, but not males, was associated with an increased risk for tooth failure (p = 0.02). CONCLUSIONS: Females with HNC have lower stimulated whole salivary flow than males, before and after RT. Low salivary flow after RT may be a risk factor for tooth failure among females. The lower pre-RT salivary flow rates in females, combined with prior literature in other populations, indicates that, in general, females have lower stimulated salivary flow than males.

A new approach to prevent radiation-induced xerostomia using intraglandular injection of mitochondria-boosting agents.

Radiotherapy in patients with head and neck cancer fairly leads to xerostomia, profoundly affecting their quality of life. With limited effective preventive and therapeutic methods, attention has turned to exploring alternatives. This article outlines how intraglandular injection of mitochondria-boosting agents can serve as a potential strategy to reduce salivary acinar damage. This method can contribute to the thoughtful development of study protocols or medications to reduce radiation-induced salivary glands damage.

Diagnosis and Dental Management of a Patient With Forbes Albright Syndrome: A Report of a Rare Case.

Forbes Albright syndrome is a hyperprolactinemia syndrome linked to a pituitary tumor associated with galactorrhea and amenorrhea. Cabergoline, an ergot derivative, is its drug of choice. Here, we report the oral manifestations and management of a case of a 32-year-old female, diagnosed and treated with the same. The patient had an alarming increase in the incidence and progression of dental caries. Her diagnosis and management have been highlighted. This can have overbearing effects on the psychology and function of the individual, thus making early diagnosis and precise management important.

PIEZO1 activation may serve as an early tissue biomarker for the prediction of irradiation-induced salivary gland dysfunction.

Irradiation (IR)-induced xerostomia is the most common side effect of radiation therapy in patients with head and neck cancer (HNC). Xerostomia diagnosis is mainly based on the patient's medical history and symptoms. Currently, no direct biomarkers are available for the early prediction of IR-induced xerostomia. Here, we identified PIEZO1 as a novel predictive tissue biomarker for xerostomia. Our data demonstrate that PIEZO1 is significantly upregulated at the gene and protein levels during IR-induced salivary gland (SG) hypofunction. Notably, PIEZO1 upregulation coincided with that of inflammatory (F4/80) and fibrotic markers (fibronectin and collagen fibers accumulation). These findings suggest that PIEZO1 upregulation in SG tissue may serve as a novel predictive marker for IR-induced xerostomia.

Efficacy of lemon mouthwash in improving dry mouth symptoms and salivary flow in hemodialysis patients.

BACKGROUND/AIMS: Gargling mouthwash is a safe and convenient oral care intervention; it rinses the mouth and increases salivary flow rate. The effectiveness of lemon mouthwash in relieving xerostomia and increasing the salivary flow rate among hemodialysis patients has not been studied. Our study sought to analyze the effectiveness of varying concentrations of lemon in mouthwash solutions on xerostomia and salivary flow rate. METHODS: A multi-concentration test was used to assess lemon mouthwash at 20%, 15%, 10%, 5%, and 2.5% concentrations to determine the optimal concentration for relieving dry mouth and increasing salivary flow rate. Generalized estimating equations were used to analyze the differences between various concentrations of lemon mouthwash and bassline values. RESULTS: In total, 44 patients were recruited. The 10% lemon concentration mouthwash was the most effective for increasing salivary flow rate, but the 5% and 2.5% were better accepted by the participants. Our findings can help establish intervention guidelines to relieve xerostomia among hemodialysis patients. CONCLUSIONS: Our findings can help establish intervention guidelines to relieve xerostomia among hemodialysis patients.

Oral discomfort and health behavior of patients with typical vs. atypical antipsychotic drugs.

Introduction: Psychiatric patients suffer from oral diseases and side effects of antipsychotic medication. In particular, the typical antipsychotic drugs may cause severe hyposalivation with subsequent oral symptoms. We therefore aimed to compare oral health behavior and oral side effects of in-hospital patients taking typical vs. atypical antipsychotic drugs with the hypothesis that the former drugs cause more oral pain than the newer drugs. Methods: This cross-sectional questionnaire and interview study investigated subjective oral symptoms and their health behavior in 170 hospitalized psychiatric patients, comparing those taking typical vs. atypical antipsychotic drugs. Cross-tabulations and chi-square tests were used for analyses. Results: Persistent oral pain lasting throughout the day was reported by 46% in the typical, and 5% in the atypical antipsychotic group patients, respectively. In both groups, the pain was mainly in the tongue and buccal mucosa and was described as a burning sensation. A significantly higher prevalence of xerostomia was reported in the typical antipsychotic medication group (66%) compared with the atypical antipsychotic medication group (53%, p<0.01). Self-assessed dental health was assessed as poor by two-thirds of the patients of whom 69% reported toothbrushing once daily. Approximately half of them reported having had a visit to a dentist within the previous year. Of the women 28%, and of the men 17%, respectively, had received professional consultations for oral symptoms. Conclusion: The current results on psychiatrically hospitalized patients emphasize the need for awareness of oral discomfort and its subsequent effects on the quality of life in this challenging patient group. Focus should also be placed on a wide range of support encouraging the patients to maintain good daily oral hygiene and seek professional dental help when needed.

The use of stem cells in treating xerostomia: a systematic review.

INTRODUCTION: The complex nature of xerostomia prevents the establishment of a definite cure. Recently, research has pivoted towards stem cell transplantation for glandular reconstruction. The aim of this study is to provide an updated review of the existing research, to highlight the encountered challenges and research pathways, potentially enhancing the therapeutic applications of stem cell transplantation. METHODS: This is a systematic review according to PRISMA guidelines, using the following databases: PubMed (PMC), PMC Europe, Scopus, Medline, Research Gate, Elsevier. The main question was whether stem cell therapies can contribute to the treatment of xerostomia. RESULTS: 19 of 226 publications met the criteria for this review, including 'in vivo', 'in vitro' studies and clinical trials. All 19 studies described thoroughly the stem cell source and the transplantation method, and documented results based on analytical and statistical methods of confirmation. Data show that the various sources of stem cells play a significant role, with bone marrow or adipose tissue-derived pluripotent blasts being the most utilized. Human transplants in mice have also been accepted and reversed hyposalivation. The effects have been beneficial especially in models undergone radiotherapy (IR) or exhibit Sjogren Syndrome-like symptoms (SS), suggesting that with appropriate treatment and enrichment techniques, stem cell transplantation seems effective regardless of the cause of the disorder. Extracts and co-cultures of gland and stem cells also seem to improve gland function. CONCLUSION: Although in its initial stages, the use of stem cells seems to be a promising therapy to alleviate xerostomia regardless of its cause.

Oral Candida in post-radiotherapy patients with xerostomia/hyposalivation: A narrative review.

OBJECTIVE: Head and Neck Cancer (HNC) patients receiving radiotherapy (RT) often suffer from xerostomia and/or hyposalivation. As saliva plays an important antimicrobial and cleansing roles, these patients are at higher risks of opportunistic infections. This narrative review aims to provide an overview of current evidence on oral Candida colonisation and infection in these patients. METHODS: A literature review of clinical studies on oral Candida colonisation and candidiasis in HNC patients receiving radiotherapy/chemoradiotherapy was conducted. RESULTS: Many clinical studies found high levels of Candida colonisation and a substantial proportion of post-RT HNC patients suffering from oropharyngeal candidiasis (OPC). Importantly, oral Candida could be a reservoir for life-threatening systemic infection in immunocompromised patients. The rising prevalence of non-albicans Candida species and drug-resistant infections has made identification of Candida species and antifungal susceptibility more important. Recent advances in oral microbiome and its interactions with Candida are discussed. This review also offers perspectives on limitations of current evidence and suggestions for future research. CONCLUSION: Further research to better understand Candida carriage, microbiome, OPC, and xerostomia/hyposalivation post-RT would aid in devising a more comprehensive long-term management plan and novel therapeutic approaches for HNC patients to achieve the full benefits of RT while minimising side effects.

Therapy-Associated Saliva and Taste change Evaluation (TASTE) in head & neck cancer patients undergoing radiotherapy: a study protocol.

BACKGROUND: One of the main side effects of radiation therapy to the head and neck region is altered taste sensation. This causes significant morbidity and has profound effects on the quality of life (QoL) of patients. While radiation-associated toxicities like xerostomia and dysphagia are part of large investigations, data on taste impairment is sparse. Small cohort sizes in the majority of studies and a variety of analysis methods limit our current understanding of the underlying processes. None of the studies published to date used a taste-specific QoL questionnaire with differentiation of the different taste qualities (e.g. sour, bitter). Furthermore, data regarding the correlation of taste impairment with radiation-associated change in saliva composition is currently not available. The aim of the TASTE study is to fill this gap. Based on the acquired data, a normal tissue complication probability (NTCP) model for late radiation-associated taste impairment will be developed. METHODS: In this prospective, observational multicenter study 150 head and neck cancer patients undergoing radiation therapy will be recruited and undergo repetitive (semi-) objective and subjective assessment of their taste, smell and salivary function (questionnaires, taste and smell assessment, saliva analysis). Primary endpoint will be patient-reported taste impairment 12 months post radiation therapy using a standardized questionnaire. Secondary endpoints will include taste impairment measured using taste strips at 12 months and 2 years post radiation therapy. Differences between subgroups (radiation side, chemotherapy, etc.) and changes over time will be assessed while adjusting for confounding factors (e.g. age, sex, smoking history). DISCUSSION: This study sets out to further our understanding of taste impairment in patients undergoing radiation therapy to the head and neck region with the goal to prevent this common side effect in future patients. The results of the study may be used to evaluate taste-preserving radiotherapy for patients with head and neck cancer, which may significantly reduce the long-term burden in this patient cohort.

Endogenous IL-22 contributes to the pathogenesis of salivary gland dysfunction in the non-obese diabetic model of Sjögren's syndrome.

SjÓ§gren's syndrome is a systemic autoimmune disease primarily targeting the salivary and lacrimal glands. Our previous investigations have shown that administration of interleukin-22 (IL-22), an IL-10 family cytokine known for its complex and context-dependent effects on tissues, either protective- or detrimental, to salivary glands leads to hypofunction and pathological changes of salivary glands in C57BL/6 mice and in non-obese diabetic (NOD) mice, the latter being a commonly used model of SjÓ§gren's syndrome. This study aims to delineate the pathophysiological roles of endogenously produced IL-22 in the development of salivary gland pathologies and dysfunction associated with SjÓ§gren's disease in the NOD mouse model. Our results reveal that neutralizing IL-22 offered a protective effect on salivary gland function without significantly affecting the immune cell infiltration of salivary glands or the autoantibody production. Blockade of IL-22 reduced the levels of phosphorylated STAT3 in salivary gland tissues of NOD mice, while its administration to salivary glands had the opposite effect. Correspondingly, the detrimental impact of exogenously applied IL-22 on salivary glands was almost completely abrogated by a specific STAT3 inhibitor. Moreover, IL-22 blockade led to a downregulation of protein amounts of Ten-Eleven-Translocation 2, a methylcytosine dioxygenase critical for mediating interferon-induced responses, in salivary gland epithelial cells. IL-22 neutralization also exerted a protective effect on the salivary gland epithelial cells that express high levels of surface EpCAM and bear the stem cell potential, and IL-22 treatment in vitro hampered the survival/expansion of these salivary gland stem cells, indicating a direct negative impact of IL-22 on these cells. In summary, this study has uncovered a critical pathogenic role of the endogenous IL-22 in the pathogenesis of Sjögren's disease-characteristic salivary gland dysfunction and provided initial evidence that this effect is dependent on STAT3 activation and potentially achieved through fostering Tet2-mediated interferon responses in salivary gland epithelial cells and negatively affecting the EpCAMhigh salivary gland stem cells.

Validation of quantitative magnetic resonance imaging techniques in head and neck healthy structures involved in the salivary and swallowing function: Accuracy and repeatability.

Background and Purpose: Radiation-induced damage to the organs at risk (OARs) in head-and-neck cancer (HNC) patient can result in long-term complications. Quantitative magnetic resonance imaging (qMRI) techniques such as diffusion-weighted imaging (DWI), DIXON for fat fraction (FF) estimation and T2 mapping could potentially provide a spatial assessment of such damage. The goal of this study is to validate these qMRI techniques in terms of accuracy in phantoms and repeatability in-vivo across a broad selection of healthy OARs in the HN region. Materials and Methods: Scanning was performed at a 3 T diagnostic MRI scanner, including the calculation of apparent diffusion coefficient (ADC) from DWI, FF and T2 maps. Phantoms were scanned to estimate the qMRI techniques bias using Bland-Altman statistics. Twenty-six healthy subjects were scanned twice in a test-retest study to determine repeatability. Repeatability coefficients (RC) were calculated for the parotid, submandibular, sublingual and tubarial salivary glands, oral cavity, pharyngeal constrictor muscle and brainstem. Additionally, a linear mixed-effect model analysis was used to evaluate the effect of subject-specific characteristics on the qMRI values. Results: Bias was 0.009x10-3 mm2/s for ADC, -0.7 % for FF and -7.9 ms for T2. RCs ranged 0.11-0.25x10-3 mm2/s for ADC, 1.2-6.3 % for FF and 2.5-6.3 ms for T2. A significant positive linear relationship between age and the FF and T2 for some of the OARs was found. Conclusion: These qMRI techniques are feasible, accurate and repeatable, which is promising for treatment response monitoring and/or differentiating between healthy and unhealthy tissues due to radiation-induced damage in HNC patients.

Influence of two paraffin wax chewing gums with different con-sistencies on the stimulated salivary flow rate.

This study investigated and compared the consistency and compressive strength of two commercially available paraffin wax chewing gums (Aurosan (AU) and GC Europe (GC)), as well as their impact on stimulated salivary flow rate. Instrumental texture analysis was uti-lized to assess the consistency and compressive strength of AU and GC during a 7-min chewing period. Subsequently, stimulated salivary flow rate (sSFR) was evaluated in healthy subjects using AU and GC over a 7-minute period. The compressive strengths from the pre-liminary test were compared over time with the sialometry data. Eighty-one test subjects, comprising 33 men and 48 women, participated. Over the 7-min measurement period, dif-ferences were observed in the total amount of saliva accumulated per minute. Direct com-parison of AU and GC revealed that regardless of age and gender, the amount of saliva formed after 1 min was 0.63 times less with AU than with GC (95% CI: 0.56 - 0.70; P < 0.001). The accumulated saliva volume with AU was also significantly lower than that with GC in the first 4 min (P = 0.016). However, from minute 5 onwards, the two products no longer showed statistical differences in the total amount of saliva. Comparison of the com-pressive strength of AU and GC showed that the values after 1 and 2 min were significantly higher for AU than for GC (P < 0.05); for all other time points, the compressive strength was higher for GC. In the mixed-effects model after log-transformation of compressive strength and saliva volume, GC exhibited decreasing saliva volumes with increasing compressive strength (P <0.001). Conversely, the opposite was observed for AU (P = 0.019). The study suggests that the consistency or compressive strength of paraffin wax chewing gums from different manufacturers could impact sSFR.

Interventional Prospective Studies on Xerostomia in Patients Undergoing Palliative and End-of-Life Care: A Scoping Review.

Patients undergoing palliative care often develop debilitating oral conditions, including xerostomia. These conditions may significantly impact patients' quality of life. Despite the high prevalence and adverse impact of xerostomia, effective management strategies remain unclear. This scoping review was performed to elucidate effective interventions for xerostomia in patients undergoing palliative and end-of-life care. A comprehensive search strategy was employed to identify relevant studies up to August 2023. Full-text primary articles focusing on xerostomia in patients receiving palliative care were included in the review. Eleven articles were selected for analysis, and data were extracted by six reviewers. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among the 11 studies, interventions ranged from oral care to saliva substitutes and methods to stimulate saliva secretion. The primary method of assessing xerostomia was the performance of subjective evaluations using visual analog scale scores or numerical rating scale scores. Various interventions including oral care regimens, topical treatments, and mixed efficacy outcomes were reported. Notably, only one study directly measured the saliva volume, highlighting a reliance on subjective endpoints in most studies. Although no definitive conclusions can be drawn regarding the most effective intervention, oral care was a preferred option for managing xerostomia in patients undergoing palliative care. Additionally, adjunctive treatments such as ice cubes, saline, and moisturizers showed promise but require further investigation. Objective measures should be incorporated into future intervention trials to complement subjective assessments and provide a comprehensive evaluation of xerostomia management strategies in this patient population.