Association between tooth extraction during radiotherapy and the risk of osteoradionecrosis in patients with head and neck cancers.

PURPOSE: It is commonly recommended that tooth extraction should be performed prior to radiotherapy (RT) in patients with head neck cancer to prevent osteoradionecrosis (ORN). However, doctors still occasionally encounter patients who require tooth extraction during RT. This study aimed to determine the risk of ORN in patients who undergo tooth extraction during RT. METHODS: Data were collected from Taiwan's National Health Insurance Research Database. We retrospectively enrolled 24,412 patients with head and neck cancer treated with radiotherapy between 2011 and 2017. The associations between ORN and demographic characteristics, timing of tooth extraction, and treatments were examined using univariate and multivariable Cox proportional hazards regression models. RESULTS: A total of 24,412 head and neck cancer patients were enrolled; 133 patients underwent tooth extraction during RT and 24,279 patients did not undergo tooth extraction during RT. Tooth extraction during RT was not associated with a significantly higher risk of ORN (hazard ratio [HR] = 1.303, P = 0.4862). Tumor site, RT dose ≥ 60 Gy, age < 55 y/o, mandibulectomy, chronic periodontitis, and chemotherapy were significantly associated with a higher risk of ORN. CONCLUSION: The risk of ORN in head and neck cancer is not significantly different between patients who undergo tooth extraction during RT and patients who do not undergo tooth extraction during RT.

Suicide risk after head and neck cancer diagnosis in Taiwan: A retrospective cohort study.

BACKGROUND: The diagnosis of head and neck cancer (HNC) may lead to exhaustion and depression. Therefore, the suicide risk of patients with HNC is high. This study aimed to understand the suicide risk of patients with HNC in Taiwan compared with patients with other-cancer and general population during the period from 2010 to 2019. METHODS: A total of 74,495 patients with HNC were compared against the other two cohort consisting 148,878 patients with other-cancer and 595,512 individual without cancer by age, sex, and index year from the Taiwan National Health Insurance Research Database. The multivariate Cox proportional hazard regression analysis was performed to estimate the risk of all-cause or suicide mortality. RESULTS: Compared to the non-cancer group, the all-cause mortality risk of the HNC group (the adjusted hazard ratio (aHR), 7.72; 95 % confidence interval (CI), 7.60-7.83) is lower than that of the other-cancer group (aHR, 8.87; 95 % CI, 8.77-8.98). However, the suicide mortality risk compared with non-cancer group in the HNC group (aHR, 3.89; 95 % CI, 3.46-4.37) is much higher than other-cancer group (aHR, 1.86; 95 % CI, 1.64-2.10). HNC only has the seventh highest all-cause mortality risk, but HNC has the second highest suicide mortality risk. Men always have a higher suicide mortality risk than women. Middle-aged patients (age 50-60 years) have the highest suicide mortality risk, whereas younger patients (age < 40 years) have the lowest suicide mortality risk. LIMITATIONS: In this study, some factors and information needed were limited to the existing database; thus, preventing recall bias was difficult. CONCLUSIONS: This study indicates that patients with HNC did not have a higher risk of all-cause mortality than patients with other cancers. However, the risk of suicide mortality in patients with HNC was higher than that of patients without cancer and patients with other cancers in Taiwan.

Stellettin B-Induced Oral Cancer Cell Death via Endoplasmic Reticulum Stress-Mitochondrial Apoptotic and Autophagic Signaling Pathway.

Oral squamous cell carcinoma (OSCC) affects tens of thousands of people worldwide. Despite advances in cancer treatment, the 5-year survival rate of patients with late-stage OSCC is low at 50-60%. Therefore, the development of anti-OSCC therapy is necessary. We evaluated the effects of marine-derived triterpene stellettin B in human OC2 and SCC4 cells. Stellettin B dose-dependently decreased the viability of both cell lines, with a significant reduction in OC2 cells at ≥0.1 µM at 24 and 48 h, and in SCC4 cells at ≥1 µM at 24 and 48 h. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells were significantly observed at 20 µM of stellettin B at 48 h, with the overexpression of cleaved caspase3 and cleaved poly(ADP-ribose) polymerase (PARP). Moreover, mitochondrial respiratory functions were ablated by stellettin B. Autophagy-related LC3-II/LC3-I ratio and Beclin-1 proteins were increased, whereas p62 was decreased. At 20 µM at 48 h, the expression levels of the endoplasmic reticulum (ER) stress biomarkers calnexin and BiP/GRP78 were significantly increased and mitogen-activated protein kinase (MAPK) signaling pathways were activated. Further investigation using the autophagy inhibitor 3-methyladenine (3-MA) demonstrated that it alleviated stellettin B-induced cell death and autophagy. Overall, our findings show that stellettin B induces the ER stress, mitochondrial stress, apoptosis, and autophagy, causing cell death of OSCC cells.

Tooth extraction within 2 weeks before radiotherapy and osteoradionecrosis: A nationwide cohort study.

OBJECTIVES: The theory of at least 2-week waiting period between tooth extraction and head and neck radiotherapy could reduce osteoradionecrosis remains controversial. Thus, this study examined the theory and associated factors. MATERIALS AND METHODS: Data were retrieved from the National Health Insurance Research Database, Taiwan Cancer Registry Database, and Cause of Death Statistics. We included 24,353 patients with head and neck cancer who received radiotherapy from 2011 to 2017 and were followed up until 2019. The patients were divided into three groups: those undergoing tooth removal 2-8 weeks before radiotherapy, those undergoing tooth removal within 2 weeks before radiotherapy, and others. Confounding factors were clinical information, physical conditions, and risky habits. We used the Cox regression model to assess osteoradionecrosis risk. RESULTS: No significant difference in osteoradionecrosis risk was observed between those undergoing tooth extraction within 2 weeks before radiotherapy and the other groups. An irradiation dose of ≥60 Gy, chemotherapy, tumor excision, post-radiotherapy tooth extraction, mandibulectomy, hyperlipidemia, and oral cavity as the tumor subsite were significantly positively associated with osteoradionecrosis risk. CONCLUSION: A waiting period of ≥2 weeks between tooth extraction and radiotherapy did not significantly reduce osteoradionecrosis risk.

Impact of Rehabilitation Intensity on 3-Year Mortality among Children with Moderate to Severe Cerebral Palsy: A Population-Based Cohort Study.

Though numerous studies demonstrated the positive effect of rehabilitation on cerebral palsy (CP) children, there was no literature addressing the role of rehabilitation on mortality among children with CP. Therefore, we aimed to evaluate the impact of rehabilitation intensity on mortality among children with moderate to severe CP. This retrospective cohort study was conducted by National Health Insurance Research Database in Taiwan. Children (<12 years) with newly diagnosed moderate to severe CP between 1 January 2000 and 31 December 2013 were included. All patients were followed up for 3 years after CP diagnosis or death or until 31 December 2013. The intensity of rehabilitation therapy within 6 months after CP diagnosis was categorized into <6 times and ≥6 times. The Cox proportional hazard analysis was used to determine the association between rehabilitation intensity and all-cause mortality after adjusting age, sex, other demographic factors and comorbidities. Among 3936 severe CP children, 164 (4.2%) died during the 3-year follow-up period. The mortality rate was higher among patients receiving rehabilitation < 6 times within 6 months than those ≥6 times within 6 months after adjusting demographic profile and comorbidities (adjust HR (aHR): 1.96, 95% CI 1.33-2.89, p < 0.001). We found that patients who were younger (aHR: 0.84, 95% CI 0.76-0.92, p < 0.001), who were receiving inpatient care more than twice in 1 year before their CP diagnosis (aHR: 2.88; 95% CI: 1.96-4.23; p < 0.001), and who have pneumonia (aHR: 1.41, 95% CI 1.00-1.96, p = 0.047), epilepsy (aHR: 1.41, 95% CI: 1.02-1.95, p = 0.039) and dysphagia (aHR: 1.55, 95% CI: 1.06-2.26, p = 0.024) have higher risk of mortality. Rehabilitation ≥ 6 times within 6 months has a potentially positive impact on pediatric CP survival. Besides having a younger age, being hospitalized more than twice within a year before diagnosis and having pneumonia, epilepsy and dysphagia were modifiable risk factors in clinical practice for these children.

Tumor subsites and risk of osteoradionecrosis of the jaw in patients with oral cavity cancer: a national-based cohort study.

PURPOSE: The association between the tumor subsites of the oral cavity and the risk of osteoradionecrosis of the jaw (ORNJ) remains unclear. We study the correlation between oral cavity tumor subsites and the risk of ORNJ in a nationwide population-based database. METHODS: We enrolled 16,701 adult patients with oral cavity cancers who were treated with radiotherapy between 2000 and 2013. The subsites of the oral tumor, treatments of oral cavity cancers, and the timing of tooth extraction were examined for their association with ORNJ in oral cancer patients. RESULTS: 903 patients (5.40%) developed ORNJ. Of the relevant variables, pre-RT mandible surgery, tooth extraction either before or after RT, and tumor sites were associated with the risk of ORNJ. The adjusted HRs for ORNJ in the mouth floor, gums, retromolar, and buccal cancer were 2.056 (1.490-2.837), 1.909 (1.552-2.349), 1.683 (1.105-2.562), and 1.303 (1.111-1.528), respectively, compared with the risk of tongue cancer. There was no significant difference in the risk of ORNJ between the pre-RT extraction group, the during-RT extraction group, and the post-RT extraction (less than 6 months) group; the post-RT extraction (more than 6 months) group had a significantly higher risk of ORNJ. CONCLUSIONS: This study demonstrated that oral cavity tumor subsite is an independent risk factor of ORNJ after RT. Post-RT extraction (less than 6 months) group did not carry a significantly higher risk of ORNJ compared with pre-RT extraction group or during RT extraction group.

Risk factors of strabismus surgery among pediatric cerebral palsy population with strabismus in Taiwan: A population-based cohort study.

BACKGROUND: To identify the risk factors of strabismus surgery among Taiwanese children with severe cerebral palsy (CP) and strabismus. METHODS: This retrospective nationwide population-based cohort study examined a cohort of newly diagnosed pediatric CP patients (age ≤ 10 y) between 1997 and 2013 with strabismus. The primary endpoint was strabismus surgery. A stepwise logistic regression was applied to determine the demographic factors, ophthalmic conditions, and comorbidities associated with strabismus surgery. RESULTS: Out of 808 patients, 115 had received strabismus surgery. The significant factors correlated to strabismus surgery in pediatric patients with severe CP and strabismus were CP diagnosis age < 4 years, residency in a suburban/rural area, low birth weight, and strabismic amblyopia. CONCLUSION: In CP children with strabismus who have risk factors of younger CP diagnosis age (age < 4 y), residency in a suburban/rural area, a low birthweight, and the presence of strabismic amblyopia, strabismus surgery should be considered.

Preradiation tooth extraction and jaw osteoradionecrosis: Nationwide population-based retrospective study in Taiwan.

OBJECTIVE: Radiotherapy (RT) for head and neck cancer (HNC) within 7 days of tooth extraction is contraindicated because it may increase the risk of osteoradionecrosis of the jaw (ORNJ). However, delayed RT could compromise survival in patients with HNC. By using a national healthcare database, we reviewed the contraindications and analysed other risk factors for ORNJ. DESIGN: A retrospective cohort study. SETTING: By using Taiwan's National Health Insurance Research Database, 5,062 HNC patients with at least one tooth extraction 1-21 days before the first RT day (index day) and without any extractions during or after RT from 2000 to 2013 were included. The patients were divided into two groups according to the time of tooth extraction before the index day: 1-7 days and 8-21 days. PARTICIPANTS: Taiwanese patients with head and neck cancer. MAIN OUTCOMES MEASURE: Univariate and multivariate Cox proportional hazard regression models were used to evaluate the risk factors of ORNJ. RESULTS: The overall incidence of ORNJ in the included patients was 1.03% (mean follow-up duration, 4.07 ± 3.01 years; range, 1.00-13.99 years). Tooth extraction within 7 days before RT was not associated with increased ORNJ risk (hazard ratio [HR] =0.734; P = .312). Significant risk factors for ORNJ included oral cancer (adjusted HR = 3.961), tumour excision surgery within 3 months before RT (adjusted HR = 3.488) and mandibulectomy within 3 months before RT (adjusted HR = 5.985; all P < .001). CONCLUSION: In a mean follow-up of 4 years, tooth extraction within 7 days before RT for HNC treatment did not increase the ORNJ risk compared with tooth extraction 7-21 days before RT.

Nomogram for pneumonia prediction among children and young people with cerebral palsy: A population-based cohort study.

BACKGROUND: Pneumonia is the leading cause of death among children and young people (CYP) with severe cerebral palsy (CP). Only a few studies used nomogram for assessing risk factors and the probability of pneumonia. Therefore, we aimed to identify risk factors and devise a nomogram for identifying the probability of severe pneumonia in CYP with severe CP. METHODS: This retrospective nationwide population-based cohort study examined CYP with newly diagnosed severe CP before 18 years old between January 1st, 1997 and December 31st, 2013 and followed them up through December 31st, 2013. The primary endpoint was defined as the occurrence of severe pneumonia with ≥ 5 days of hospitalization. Logistic regression analysis was used for determining demographic factors and comorbidities associated with severe pneumonia. These factors were assigned integer points to create a scoring system to identify children at high risk for severe pneumonia. RESULTS: Among 6,356 CYP with newly diagnosed severe CP, 2,135 (33.59%) had severe pneumonia. Multivariable logistic regression analysis revealed that seven independent predictive factors, namely age <3 years, male sex, and comorbidities of pressure ulcer, gastroesophageal reflux, asthma, seizures, and perinatal complications. A nomogram was devised by employing these seven significant predictive factors. The prediction model presented favorable discrimination performance. CONCLUSIONS: The nomogram revealed that age, male sex, history of pressure ulcer, gastroesophageal reflux, asthma, seizures, and perinatal complications were potential risk factors for severe pneumonia among CYP with severe CP.

Continuity of Care Is Associated with Medical Costs and Inpatient Days in Children with Cerebral Palsy.

Background: Children with cerebral palsy (CP) place a considerable burden on medical costs and add to an increased number of inpatient days in Taiwan. Continuity of care (COC) has not been investigated in this population thus far. Materials and Methods: We designed a retrospective population-based cohort study using Taiwan's National Health Insurance Research Database. Patients aged 0 to 18 years with CP catastrophic illness certificates were enrolled. We investigated the association of COC index (COCI) with medical costs and inpatient days. We also investigated the possible clinical characteristics affecting the outcome. Results: Over five years, children with CP with low COCI levels had higher medical costs and more inpatient days than did those with high COCI levels. Younger age at CP diagnosis, more inpatient visits one year before obtaining a catastrophic illness certificate, pneumonia, and nasogastric tube use increased medical expenses and length of hospital stay. Conclusions: Improving COC reduces medical costs and the number of inpatient days in children with CP. Certain characteristics also influence these outcomes.

11ß,20ß-Epoxybriaranes from the Gorgonian Coral Junceella fragilis (Ellisellidae).

Two 11,20-epoxybriaranes, including a known compound, juncenolide K (1), as well as a new metabolite, fragilide X (2), have been isolated from gorgonian Junceella fragilis collected off the waters of Taiwan. The absolute configuration of juncenolide K (1) was determined by single-crystal X-ray diffraction analysis for the first time in this study and the structure, including the absolute configuration of briarane 2 was established on the basis of spectroscopic analysis and compared with that of model compound 1. One aspect of the stereochemistry of the known compound 1 was revised. Briarane 2 was found to enhance the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) release from RAW 264.7 cells.

Etoricoxib prevents progression of osteolysis in repeated intra-articular monosodium urate-induced gouty arthritis in rats.

Deposition of monosodium urate (MSU) crystals in the joint or synovium is the major factor in Gouty arthritis (GA). The clinical features of chronic and recurrent GA include pain and the subsequent development of chronic tophaceous GA with multiple tophi deposits accompanied by osteolysis. The majority of previous animal studies have focused on MSU-induced acute GA without making observations regarding osteolysis. In the study, intra-articular injections of MSU into the knee (2 times/week for 10 weeks) was used to induce chronic and recurrent attacks of GA that in turn induced progressive osteolysis. Moreover, we also evaluated whether the clinical, nonsteroidal anti-inflammatory drug (NSAID) etoricoxib attenuated the osteoclastogenesis of progressive osteolysis. The knee morphometry and the expression of osteoclastogenesis-related proteins (cathepsin K and matrix metalloproteinase-9 and -13) in the knee were examined by micro-CT and immunohistochemistry, respectively. Results showed that oral etoricoxib not only significantly attenuated the nociceptive behaviors of the rats but that it also inhibited the expression of osteoclastogenesis-related proteins in their knee joints in chronic and recurrent attacks of GA. Our findings thus suggest that NSAIDs not only inhibit nociception but also prevent the progression of osteolysis in chronic and repeated attacks of GA.

Postanesthesia alternation of lower limb contractures in children with spastic cerebral palsy.

The aim of this study was to clarify the effects of general anesthesia (GA) on joint range of motion (ROM) in children with spastic cerebral palsy (SCP). Eighty-four SCP cases (mean age 8.4 years) admitted for first corrective surgery were retrospectively reviewed. Lower limb ROM were measured 1 day before operation and immediately after GA. Contracture of hip, knee, and ankle joints decreased significantly after GA, with + 11.1° (39.5%) for the hip abduction angle, -3.7° (18.0%) for the Thomas test, -15.0° (19.1%) for the popliteal angle, + 6.6° (39.8%) and 7.0° (109%) for ankle dorsiflexion with knee flexion and extension, respectively (all P < 0.001). These changes were correlated positively to pre-GA contracture and body weight, negatively to age, but independent of preoperative functional level, geographic classification of SCP, or modified Ashworth scale. On the basis of these findings, routine post-GA reassessments of joint ROM before corrective surgeries were recommended for pediatric SCP cases.

Effects of continuity of care on the postradiotherapy survival of working-age patients with oral cavity cancer: A nationwide population-based cohort study in Taiwan.

OBJECTIVES: Cancer of the oral cavity, a well-known global health concern, remains one of most common causes of cancer mortality. Continuity of care (COC), a measurement of the extent to which an individual patient receives care from a given provider over a specified period of time, can help cancer survivors process their experiences of dealing with the illness and recuperation; however, limited research has focused on the survival rate of working-age patients with oral cancer. METHODS: A total of 14,240 working-age patients (20 0.38) and non-high COC (COCI ≤ 0.38) groups. After propensity-score matching, the mortality risk in the low and intermediate COC groups was also found to be significantly higher than that in the high COC group (aHR = 1.178, 95% CI = 1.074-1.292, p < 0.001 and aHR = 1.189, 95% CI = 1.107-1.277, p = 0.001, respectively). CONCLUSIONS: In Taiwan, COC and prior dental treatment before RT significantly affected the survival rate of working-age patients with oral cancer. This result merits policymakers' attention.

Rhodoptilometrin, a Crinoid-Derived Anthraquinone, Induces Cell Regeneration by Promoting Wound Healing and Oxidative Phosphorylation in Human Gingival Fibroblast Cells.

Gingival recession (GR) potentially leads to the exposure of tooth root to the oral cavity microenvironment and increases susceptibility to dental caries, dentin hypersensitivity, and other dental diseases. Even though many etiological factors were reported, the specific mechanism of GR is yet to be elucidated. Given the species richness concerning marine biodiversity, it could be a treasure trove for drug discovery. In this study, we demonstrate the effects of a marine compound, (+)-rhodoptilometrin from crinoid, on gingival cell migration, wound healing, and oxidative phosphorylation (OXPHOS). Experimental results showed that (+)-rhodoptilometrin can significantly increase wound healing, migration, and proliferation of human gingival fibroblast cells, and it does not have effects on oral mucosa fibroblast cells. In addition, (+)-rhodoptilometrin increases the gene and protein expression levels of focal adhesion kinase (FAK), fibronectin, and type I collagen, changes the intracellular distribution of FAK and F-actin, and increases OXPHOS and the expression levels of complexes I~V in the mitochondria. Based on our results, we believe that (+)-rhodoptilometrin might increase FAK expression and promote mitochondrial function to affect cell migration and promote gingival regeneration. Therefore, (+)-rhodoptilometrin may be a promising therapeutic agent for GR.

Effects of income and residential area on survival of patients with head and neck cancers following radiotherapy: working age individuals in Taiwan.

OBJECTIVES: The five-year survival rate of head and neck cancer (HNC) after radiotherapy (RT) varies widely from 35% to 89%. Many studies have addressed the effect of socioeconomic status and urban dwelling on the survival of HNC, but a limited number of studies have focused on the survival rate of HNC patients after RT. MATERIALS AND METHODS: During the period of 2000-2013, 40,985 working age individuals (20 < age < 65 years) with HNC patients treated with RT were included in this study from a registry of patients with catastrophic illnesses maintained by the Taiwan National Health Insurance Research Database (NHIRD). RESULTS: The cumulative survival rate of HNC following RT in Taiwan was 53.2% (mean follow-up period, 3.75 ± 3.31 years). The combined effects of income and geographic effect on cumulative survival rates were as follows: high income group > medium income group > low income group and northern > central > southern > eastern Taiwan. Patients with moderate income levels had a 36.9% higher risk of mortality as compared with patients with high income levels (hazard ratio (HR) = 1.369; p < 0.001). Patients with low income levels had a 51.4% greater risk of mortality than patients with high income levels (HR = 1.514, p < 0.001). CONCLUSION: In Taiwan, income and residential area significantly affected the survival rate of HNC patients receiving RT. The highest income level group had the best survival rate, regardless of the geographic area. The difference in survival between the low and high income groups was still pronounced in more deprived areas.

Different impacts of dementia on two-year mortality after osteosynthesis and hemiarthroplasty in treating geriatric hip fractures.

BACKGROUND: Geriatric hip fractures are mostly managed by internal fixation (IF) or hemiarthroplasty (HA). Survivorship of dementia patients following these surgeries has not been extensively compared in literature. By analysis of nationwide database, this study aimed to investigate the impact of dementia on two-year mortality after IF and HA in treating geriatric hip fractures. METHOD: From retrospective review of Taiwan's National Health Insurance Research Database, we enrolled 153,623 subjects aged 65 years and older with hospitalization for first hip fracture operated by IF (93,029 cases) or HA (60,594 cases) between 2000 and 2011. Postoperative mortality was compared between subjects with and without dementia after adjustments of age, gender, Charlson comorbidity index and hospital level. RESULTS: The prevalence of dementia was 5.24% in the IF and 5.29% in the HA group. In the IF group, dementia increased adjusted hazard ratio of one-year (1.06, 95%CI:1.00-1.13) and two-year mortality (1.10, 95%CI:1.05-1.16). However, short and long-term mortality following HA was not significantly impacted by dementia (in-hospital OR:0.79, 95%CI:0.60-1.03; three-month HR:0.99, 95%CI:0.87-1.12; one-year HR:1.01, 95%CI:0.93-1.10; two-year HR:1.03, 95%CI:0.96-1.09). In a subgroup of dementia patients, mortality following IF was 15% higher than HA in one (p = 0.004) and two years (p < 0.001). The negative prognostic factors included female (HR:1.10; 95%CI:1.03-1.18) and aging 65-84 years (HR:1.15; 95%CI:1.00-1.32). CONCLUSION: Dementia increased one and two-year mortality following geriatric hip fracture treated by IF, rather than HA. Dementia patients undergoing HA, especially female or 65-84 years old, sustained better one and two-year survival than those receiving IF.