Protocol for a feasibility randomized controlled trial of gentle yoga in older patients discharged from phase II cardiac rehabilitation.

Background: Physical activity (PA) is essential following an acute cardiac event. Cardiac rehabilitation (CR) is commonly prescribed, and PA after CR is recommended. Because of age-related changes in functional ability and multi-comorbidity, many older cardiac patients struggle to continue performing PA at home after CR. Depressive symptoms and anxiety are prevalent in cardiac patients and associated with poor self-care, including lack of daily PA. Yoga has been demonstrated to improve psychological and physical health outcomes in cardiac patients, but it is unknown whether yoga, modified for older CR patients - Gentle Yoga - is beneficial in managing psychological distress and maintaining PA following phase II CR. Our specific aims are to:1) determine the feasibility and acceptability of a modified gentle yoga intervention delivered via video conferencing for older cardiac patients; 2) compare, at 3-month follow-up, the effects and determine effect sizes of a gentle yoga intervention versus control on psychological health and physical health. Methods: We are conducting a 2-group (intervention versus control) randomized controlled pilot study. The intervention is a 12-week gentle yoga program delivered via video conference. Short-term effects will be evaluated at 3-month. Conclusion: This study is designed to be suited for older cardiac patients who would not have access to supervised PA opportunities after facility-based CR to enhance PA. This study will provide data about the feasibility and acceptability of the protocol for older cardiac patients and will offer effect sizes to determine sample size for a fully powered randomized controlled trial.

Adapting the serious illness conversation guide for unhoused older adults: a rapid qualitative study.

BACKGROUND: Older adults experiencing homelessness (OAEH) age quickly and die earlier than their housed counterparts. Illness-related decisions are best guided by patients' values, but healthcare and homelessness service providers need support in facilitating these discussions. The Serious Illness Conversation Guide (SICG) is a communication tool to guide discussions but has not yet been adapted for OAEH. METHODS: We aimed to adapt the SICG for use with OAEH by nurses, social workers, and other homelessness service providers. We conducted semi-structured interviews with homelessness service providers and cognitive interviews with OAEH using the SICG. Service providers included nurses, social workers, or others working in homeless settings. OAEH were at least 50 years old and diagnosed with a serious illness. Interviews were conducted and audio recorded in shelters, transitional housing, a hospital, public spaces, and over Zoom. The research team reviewed transcripts, identifying common themes across transcripts and applying analytic notetaking. We summarized transcripts from each participant group, applying rapid qualitative analysis. For OAEH, data that referenced proposed adaptations or feedback about the SICG tool were grouped into two domains: "SICG interpretation" and "SICG feedback". For providers, we used domains from the Toolkit of Adaptation Approaches: "collaborative working", "team", "endorsement", "materials", "messages", and "delivery". Summaries were grouped into matrices to help visualize themes to inform adaptations. The adapted guide was then reviewed by expert palliative care clinicians for further refinement. RESULTS: The final sample included 11 OAEH (45% Black, 61 ± 7 years old) and 10 providers (80% White, 8.9 ± years practice). Adaptation themes included changing words and phrases to (1) increase transparency about the purpose of the conversation, (2) promote OAEH autonomy and empowerment, (3) align with nurses' and social workers' scope of practice regarding facilitating diagnostic and prognostic awareness, and (4) be sensitive to the realities of fragmented healthcare. Responses also revealed training and implementation considerations. CONCLUSIONS: The adapted SICG is a promising clinical tool to aid in the delivery of serious illness conversations with OAEH. Future research should use this updated guide for implementation planning. Additional adaptations may be dependent on specific settings where the SICG will be delivered.

The relationship of health activation with risk of future cardiovascular disease among rural family caregivers of patients with chronic illnesses.

BACKGROUND: Family caregivers are at higher risk for developing cardiovascular disease (CVD) than non-caregivers. This risk is worse for those who live in rural compared to urban areas. Health activation, an indicator of engagement in self-care, is predictive of health outcomes and CVD risk in several populations. However, it is not known whether health activation is associated with CVD risk in rural caregivers of patients with chronic illnesses nor is it clear whether sex moderates any association. OBJECTIVES: Our aims were to determine (1) whether health activation independently predicts 10-year CVD risk; and (2) whether sex interacts with health activation in the prediction of 10-year CVD risk among rural family caregivers (N = 247) of patients with chronic illnesses. METHODS: Health activation was measured using the Patient Activation Measure. The predicted 10-year risk of CVD was assessed using the Framingham Risk Score. Data were analyzed using nonlinear regression analysis. RESULTS: Higher levels of health activation were significantly associated with decreased risk of developing CVD (p < 0.028). There was no interaction of sex with health activation on future CVD risk. However, male caregivers had greater risk of developing CVD in the next 10 years than female caregivers (p < 0.001). CONCLUSIONS: We demonstrated the importance of health activation to future CVD risk in rural family caregivers of patients with chronic illnesses. We also demonstrated that despite the higher risk of future CVD among male, the degree of association between health activation and CVD risk did not differ by sex.

An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier. BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40 to 50 times greater reporter expression in the CNS of human TFRC knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared with AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.

Perceived Control, Functional Status, Depressive Symptoms, and Anxiety: Mediating and Moderating Influences on Health-Related Quality of Life in Patients With Heart Failure.

BACKGROUND: Health-related quality of life (HRQoL) is poor in patients with heart failure. Psychological (ie, depressive symptoms [DS], anxiety, and perceived control) and physical (ie, functional status) factors are associated with HRQoL. The dynamic relationships among these variables and their impact on HRQoL remain unclear, limiting the ability to design effective interventions. PURPOSE: Our aim was to evaluate a moderated mediation model, in which the association between perceived control and HRQoL was hypothesized to be mediated by DS and anxiety in the presence of a moderator, functional status. METHODS: Patients (N = 426) with heart failure completed the Control Attitudes Scale-Revised to measure perceived control, Duke Activity Status Index for functional status, Patient Health Questionnaire-9 for DS, Brief Symptom Inventory for anxiety, and Minnesota Living with Heart Failure Questionnaire for HRQoL. We performed a moderated parallel mediation analysis. RESULTS: Higher levels of perceived control were associated with better HRQoL through lower levels of anxiety and DS in the presence of functional status (index of moderated mediation for DS, b = 0.029; 95% confidence interval, 0.016-0.045; for anxiety: b = 0.009, 95% confidence interval, 0.002-0.018). The effect of perceived control on psychological symptoms was stronger at low and moderate functional statuses; however, this effect diminished with increasing functional status. CONCLUSION: Functional status moderated the indirect effects of perceived control on HRQoL through DS and anxiety in patients with heart failure. Efforts to improve HRQoL by targeting perceived control may be more effective when considering DS and anxiety in patients with low to moderate levels of functional status.

Depressive Symptoms and Sleep Quality Mediate the Relationship Between Race and Quality of Life Among Patients With Heart Failure: A Serial Multiple Mediator Model.

BACKGROUND: Black patients with heart failure (HF) report worse quality of life (QoL) than White patients. Few investigators have examined mediators of the association between race and QoL, but depressive symptoms and sleep quality are associated with QoL. OBJECTIVE: The aim of this study was to determine whether depressive symptoms and sleep quality are mediators of the relationship between race and QoL among patients with HF. METHODS: This was a cross-sectional study. We included 271 outpatients with HF. Self-reported race (White/Black), depressive symptoms (Patient Health Questionnaire), sleep quality (Pittsburgh Sleep Quality Index), and QoL (Kansas City Cardiomyopathy Questionnaire) were collected at baseline. A serial multiple mediator analysis was conducted using the PROCESS macro for SPSS. RESULTS: Ninety-six patients (35.4%) were Black. Black participants reported higher levels of depressive symptoms and poorer sleep quality than White participants. Race was not directly associated with QoL but indirectly associated with QoL through depressive symptoms and poorer sleep quality. Because of higher levels of depressive symptoms and poorer sleep quality, Black participants reported poorer QoL than White participants. CONCLUSIONS: Depressive symptoms and sleep quality together mediated the relationship between race and QoL. These findings suggest that screening for depressive symptoms and sleep quality could identify patients at risk for poor QoL, especially in Black patients.

Mediators of the Association Between Cognitive Function and Self-care Behaviors in Patients Hospitalized With an Exacerbation of Heart Failure.

BACKGROUND: Patients with heart failure (HF) must engage in self-care, yet their self-care is often poor. Cognitive function commonly is impaired in HF and is associated with poor self-care. Heart failure knowledge and self-care confidence also are needed to preform self-care. Few investigators have examined mediators of the association of cognitive function with self-care. OBJECTIVES: The aim of this study was to determine whether HF knowledge and self-care confidence mediated the association of cognitive function with self-care maintenance and management among patients with HF. METHODS: This was a cross-sectional observational study of 164 patients with HF. Cognitive function was assessed using the Montreal Cognitive Assessment. Self-care maintenance and self-care management behaviors and self-care confidence were measured using the Self-care of Heart Failure Index. Heart failure knowledge was measured using the Dutch Heart Failure Knowledge Scale. We conducted 2 parallel mediation analyses using the PROCESS macro in SPSS, one for self-care maintenance and one for self-care management. RESULTS: Cognitive function was indirectly associated with self-care maintenance through HF knowledge (indirect effect, 0.54; 95% confidence interval, 0.10-1.02) and self-care confidence (indirect effect, 0.26; 95% confidence interval, 0.04-0.54). Those with better cognitive function had more HF knowledge and self-care confidence. Better cognitive function was not directly associated with self-care management but indirectly associated with better self-care management through higher self-care confidence (indirect effect, 0.50; 95% confidence interval, 0.04-1.05). CONCLUSIONS: Both HF knowledge and self-care confidence mediated the association of cognitive function with self-care maintenance, and only self-care confidence mediated the association between cognitive function and self-care management. Interventions targeting HF knowledge and self-care confidence may improve self-care even for those with lower cognitive function and need to be developed and tested.

A Biomarker of Stress and Self-reported Caregiving Distress Predict Poor Quality of Life in Family Caregivers of Patients With Heart Failure.

BACKGROUND: Family caregivers are at a high risk for low quality of life due to caregiving-related stress. Caregivers' stress is commonly assessed using self-reported measures, which reflect relatively subjective and long-term stress related to caregiving, but objective biological markers of stress are rarely used for caregivers. The purposes of this study were (1) to determine whether caregiver characteristics were associated with stress assessed using a stress biomarker (serum cortisol) and a self-reported caregiving distress measure (Caregiver Burden Inventory) and (2) to determine the predictability of both stress measures for quality of life in caregivers of patients with heart failure. METHODS: Taiwanese family caregivers (N = 113; mean age, 54.5 years; 70.8% female) of patients with heart failure completed surveys including caregiving distress and quality of life measured by the Caregiver Burden Inventory and the Short Form-36 (physical and psychological well-being subscales), respectively, and provided blood samples for serum cortisol. Independent t tests, correlation, and hierarchical regression were conducted. RESULTS: Single caregivers had higher serum cortisol levels than married caregivers (P = .002). Men had significantly higher serum cortisol levels than women (P = .010), but men reported lower caregiving distress than women (P = .049). Both serum cortisol (ß = -0.32, P = .012) and caregiving distress (ß = -0.29, P = .018) were significant predictors of quality of life in the physical well-being scale while controlling for caregivers' characteristics and depressive symptoms. Serum cortisol (ß = -0.28, P = .026) and caregiving distress (ß = -0.25, P = .027) also predicted quality of life in the psychological well-being scale. CONCLUSIONS: Serum cortisol and self-reported caregiving distress have similar predictability for quality of life in family caregivers of patients with heart failure. Reducing stress and caregiving distress is critical to improving quality of life in this population.

Mediation by Fatalism of the Association Between Symptom Burden and Self-care Management in Patients With Heart Failure.

BACKGROUND: Clinicians and researchers often assume that symptom burden is associated with self-care management (SCM) in patients with heart failure (HF). However, that association is often not borne out in simple regression analyses and may be because another variable mediates the association. Fatalism is an appropriate candidate for mediation and is the belief that circumstances are predetermined without opportunity for control by individuals. OBJECTIVE: Our objective was to determine whether fatalism mediated the relationship of symptom burden with SCM among adults with HF. METHODS: We conducted a secondary analysis (N = 95) from a clinical trial. We used Self-care of HF Index to measure SCM, the Memorial Symptom Assessment Scale-HF for symptom burden, and the Cardiovascular Disease Fatalism Instrument to measure fatalism. We used the PROCESS macro to evaluate mediation. RESULTS: Symptom burden was not directly associated with SCM (effect coefficient [C'] = 0.0805; 95% confidence interval, -0.048 to 0.209; P = .217). There was, however, an indirect pathway between symptom burden and SCM through fatalism (ab = -0.040; 95% confidence interval, -0.097 to -0.002). Those with higher symptom burden were more fatalistic (a = 0.004, P = .015), and greater fatalism was associated with worse SCM (b = -9.132, P = .007). CONCLUSION: Symptom burden, not directly associated with SCM, is associated through the mediator of fatalism. Interventions to improve SCM should include strategies to mitigate fatalistic views. Self-care management interventions should focus on promoting internal locus of control or increasing perceptions of perceived control to decrease fatalism and improve engagement in self-care.

Psychometric Properties of the Patient Activation Measure in Family Caregivers of Patients With Chronic Illnesses.

BACKGROUND: The Patient Activation Measure (PAM) is used clinically and in research to measure an individual's knowledge, skills, and confidence related to their health management engagement. Despite the use of "patient" in the title, the instrument can be used in nonpatient populations. A group at high risk for low activation concerning their own health is family caregivers of patients with chronic illnesses. The psychometric properties of the PAM have not been established in family caregivers. OBJECTIVES: This study aimed to examine the psychometric properties of the PAM 10-item version (PAM-10) in a sample of family caregivers of patients with chronic illnesses. Our focus was on family caregivers' health activation of their own healthcare needs. METHODS: We evaluated the internal consistency reliability of the PAM-10 in a sample of 277 family caregivers. Item-total correlations and interitem correlations were used to assess item homogeneity. Construct validity of the PAM-10 was examined using exploratory factor analysis and testing hypotheses on known relationships. RESULTS: The PAM-10 demonstrated adequate internal consistency. Item-total correlation coefficients and interitem correlation coefficients were acceptable. Construct validity of the instrument was supported. Factor analysis yielded two factors that explained 62.3% of the variance in the model. Lower levels of depressive symptoms were significantly associated with better activation, providing evidence of construct validity. Caregivers with high activation levels were significantly more likely to engage in and adhere to self-care behaviors such as regular exercise, eating a healthy diet, and engaging in stress reduction strategies. DISCUSSION: This study demonstrated that the PAM-10 is a reliable and valid measure for family caregivers of patients with chronic illnesses to measure caregivers' health activation of their own healthcare needs.

Heart Failure Knowledge, Symptom Perception, and Symptom Management in Patients With Heart Failure.

BACKGROUND: Prevention of heart failure (HF) exacerbations requires that patients carefully self-manage their condition. Symptom perception is a key component in self-care for patients with HF that involves monitoring for HF symptoms and recognizing symptom changes. Heart failure knowledge is a prerequisite for better symptom perception and symptom management. However, the relationships among HF knowledge, symptom perception, and symptom management remain unclear. OBJECTIVE: The aim of this study was to explore the inter-relationships among HF knowledge, symptom monitoring, symptom recognition, and symptom response in patients with HF. METHOD: We included 185 patients with HF in this study. Heart failure knowledge was measured using the Dutch HF Knowledge Scale. Symptom monitoring, symptom recognition, and symptom response were measured using the Self-care of HF Index. Structural equation modeling was used for data analyses. RESULTS: Heart failure knowledge was associated with symptom monitoring (ß = .357, P < .001). Symptom monitoring was directly associated with both symptom recognition (ß = .371, P < .001) and symptom response (ß = .499, P < .001). Symptom recognition was directly associated with symptom response (ß = .274, P < .001). Heart failure knowledge was not directly associated with symptom recognition, nor with symptom response. Heart failure knowledge was indirectly associated with symptom recognition and symptom response through symptom monitoring. CONCLUSION: Symptom monitoring is associated with both symptom recognition and symptom response and is a mediator between HF knowledge and symptom recognition and between HF knowledge and symptom response. This finding suggests that it is important for clinicians not just to increase patients' HF knowledge but also to enhance their skills of symptom monitoring and symptom recognition and promote symptom monitoring among patients to improve symptom response in self-care.

Association of psychological distress with reasons for delay in seeking medical care in rural patients with worsening heart failure symptoms.

BACKGROUND: The impact of depressive symptoms and anxiety on rural patients' decisions to seek care for worsening heart failure (HF) symptoms remains unknown. The purposes of this study were (1) to describe rural patients' reasons for delay in seeking care for HF, and (2) to determine whether depressive symptoms or anxiety was associated with patients' reasons for delay in seeking medical care for worsening symptoms. METHODS: A total of 611 rural HF patients were included. Data on reasons for patient delay in seeking medical care (The Reasons for Delay Questionnaire), depressive symptoms (PHQ-9), and anxiety (BSI-ANX) were collected. Statistical analyses included chi-square and multiple regression. RESULTS: A total of 85.4% of patients reported at least 1 reason for delay. Patients with higher levels of depressive symptoms were more likely to cite embarrassment, problems with transportation, and financial concerns as a reason for delay. Patients with anxiety not only cited nonsymptom-related reasons but also reported symptom-related reasons for delay in seeking care (ie, symptoms seemed vague, not sure of symptoms, symptoms didn't seem to be serious enough, and symptoms were different from the last episode). In multiple regression, patients with greater depressive symptoms and anxiety had a greater number of reasons for delay in seeking care (P = .003 and P = .023, respectively). CONCLUSIONS: Our findings suggest that enhancement of patients' symptom appraisal abilities and improvement in psychological distress may result in a reduction in delay in seeking medical care for worsening symptoms in rural patients with HF.

Older and younger patients' perceptions, evaluations, and responses to worsening heart failure symptoms.

BACKGROUND: Whether recognition and prompt response to worsening symptoms are worse in older compared with younger patients with heart failure (HF) is unclear. OBJECTIVES: The aims of this study were to compare older and younger patients (1) perceptions, evaluations, and responses to worsening HF symptoms, and (2) responses once worsening symptoms were perceived. METHODS: A mixed-methods study was conducted and to compare data between older (≥ 65) and younger (< 65) in 185 patients hospitalized with HF. RESULTS: There were few differences attributed to age. In response to higher perceived symptom distress, patients in both groups did nothing and hoped their symptoms would go away (p = 0.004), ignored symptoms and continued doing what they were doing (p = 0.002), or laid down to relax (p < 0.001). CONCLUSIONS: The majority of patients, regardless of age, did not recognize, interpret, and respond appropriately to HF symptoms. Interventions should be tested that target better symptom appraisal and promote appropriate symptom responses in patients with HF across all ages.

Delay in seeking medical care for worsening heart failure symptoms: predictors and association with cardiac events.

AIMS: The association of delay in seeking medical care to subsequent cardiac events remains unknown in patients with worsening heart failure (HF) symptoms. The aims of this study were to (i) identify factors predicting care-seeking delay and (ii) examine the impact of care-seeking delay on subsequent cardiac rehospitalization or death. METHODS AND RESULTS: We studied 153 patients hospitalized with an exacerbation of HF. Potential predictors of delay including demographic, clinical, psychosocial, cognitive, and behavioural variables were collected. Patients were followed for 3 months after discharge to determine time to the first cardiac rehospitalization or death. The median delay time was 134 h (25th and 75th percentiles 49 and 364 h). Non-linear regression showed that New York Heart Association functional class III/IV (P = 0.001), worse depressive symptoms (P = 0.004), better HF knowledge (P = 0.003), and lower perceived somatic awareness (P = 0.033) were predictors of delay time from patient perception of worsening HF to subsequent hospital admission. Cox regression revealed that patients who delayed longer (more than 134 h) had a 1.93-fold higher risk of experiencing cardiac events (P = 0.044) compared to non-delayers. CONCLUSIONS: Care-seeking delay in patients with worsening HF symptoms was significantly associated with an increased risk of rehospitalization and mortality after discharge. Intervention strategies addressing functional status, psychological state, cognitive and behavioural factors are essential to reduce delay and thereby improve outcomes.

Perceived Control Predicts Symptom Status in Patients With Heart Failure.

BACKGROUND: Symptom status is an important indicator of disease progression in patients with heart failure (HF). Perceived control is a target of most self-care interventions and is associated with better outcomes in HF; however, little is known about the relationship between perceived control and symptom status in patients with HF. OBJECTIVE: The aims of this study were to (1) determine the relationship of perceived control to HF symptom status and (2) examine the associations of perceived control to self-care and of self-care to symptom status. METHODS: A total of 115 patients with HF were included. Data on symptom status (Memorial Symptom Assessment Scale-HF), perceived control (Control Attitudes Scale-Revised), and self-care (Self-Care of Heart Failure Index) were collected. Other covariates included were age, gender, New York Heart Association class, comorbidity burden, and depressive symptoms. Multiple regression analyses were performed to analyze the data. RESULTS: Lower perceived control predicted worse symptom status after controlling for covariates (P = .009). Other covariates predictive of worse symptom status were younger age, New York Heart Association class III/IV, and higher levels of depressive symptoms. Higher levels of perceived control were associated with better self-care (P = .044). Better self-care was associated with better symptom status (P = .038). CONCLUSIONS: Lower levels of perceived control were independently associated with worse symptom status in patients with HF. Intervention strategies targeting perceived control should be tested to determine whether they could improve symptom status.

Beyond social support: Self-care confidence is key for adherence in patients with heart failure.

BACKGROUND: Adherence to treatment is crucial to improve outcomes in patients with heart failure. Good social support is associated with better adherence, but the mechanism for this association has not been well-explored. AIMS: The aim of this secondary analysis was to examine whether self-care confidence mediates the relationship between social support and treatment adherence in heart failure patients hospitalized with acute exacerbation. METHODS: A total of 157 inpatients with heart failure (63.5±13 years, 73% New York Heart Association class III/IV) were recruited from two hospitals located in urban areas in the USA. Participants completed the Self-Care of Heart Failure Index, the Multidimensional Perceived Social Support Scale, and the Medical Outcomes Study Specific Adherence Scale. A series of regression models were used to determine the mediation relationship. RESULTS: Controlling for marital status and hospital site, social support was associated with adherence ( p=0.03). When self-confidence was included in the model, the effect of social support became non-significant, indicating full mediation of the relationship between social support and adherence by self-care confidence. The indirect effect (0.04) of social support on adherence through self-confidence was significant (95% confidence interval: 0.01-0.09). CONCLUSION: Heart failure self-care confidence mediated the relationship between social support and treatment adherence. Thus interventions targeting patients' self-care confidence is essential to maximize patients' treatment adherence.

Prognostic significance of parapharyngeal space venous plexus and marrow involvement: potential landmarks of dissemination for stage I-III nasopharyngeal carcinoma.

PURPOSE: To determine whether the parapharyngeal space venous plexus and marrow of the skull base bones are anatomic landmarks of the potential routes for the spread of disease for Stage I-III (American Joint Commission on Cancer 1997 staging system) nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: A total of 364 patients with NPC were enrolled in this study. The selection criteria were Stage I-III disease and primary radiotherapy at our hospital between 1990 and 2001. All patients had undergone MRI to evaluate the head-and-neck tumors. Patients who had undergone inadequate radiotherapy at a dose of <60 Gy and/or preradiotherapy chemotherapy before the imaging evaluation were excluded from the study. RESULTS: Of the 364 patients treated between 1990 and 2001, 163 (44.8%) had low-risk Stage I-III NPC (without parapharyngeal space extension or T3 disease). The 5-year distant metastasis-free survival rate, with and without adjuvant chemotherapy, was 97% and 96%, respectively. The remaining 201 patients had Stage II-III with parapharyngeal space extension or T3 disease. Their 5-year recurrence-free survival rate, with and without adjuvant chemotherapy, was 76.8% and 53.2% (p = 0.01), respectively. CONCLUSION: Our findings suggest that the risk of distant metastasis in Stage I-III NPC patients without parapharyngeal space extension or T3 disease is extremely low. Invasion into the parapharyngeal space venous plexus and marrow of the skull base bones is associated with distant metastasis, and involvement of these anatomic sites is considered a potential route for hematogenous disease spread in patients with Stage I-III NPC.