Prognosing post-treatment outcomes of head and neck cancer using structured data and machine learning: A systematic review.

BACKGROUND: This systematic review aimed to evaluate the performance of machine learning (ML) models in predicting post-treatment survival and disease progression outcomes, including recurrence and metastasis, in head and neck cancer (HNC) using clinicopathological structured data. METHODS: A systematic search was conducted across the Medline, Scopus, Embase, Web of Science, and Google Scholar databases. The methodological characteristics and performance metrics of studies that developed and validated ML models were assessed. The risk of bias was evaluated using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). RESULTS: Out of 5,560 unique records, 34 articles were included. For survival outcome, the ML model outperformed the Cox proportional hazards model in time-to-event analyses for HNC, with a concordance index of 0.70-0.79 vs. 0.66-0.76, and for all sub-sites including oral cavity (0.73-0.89 vs. 0.69-0.77) and larynx (0.71-0.85 vs. 0.57-0.74). In binary classification analysis, the area under the receiver operating characteristics (AUROC) of ML models ranged from 0.75-0.97, with an F1-score of 0.65-0.89 for HNC; AUROC of 0.61-0.91 and F1-score of 0.58-0.86 for the oral cavity; and AUROC of 0.76-0.97 and F1-score of 0.63-0.92 for the larynx. Disease-specific survival outcomes showed higher performance than overall survival outcomes, but the performance of ML models did not differ between three- and five-year follow-up durations. For disease progression outcomes, no time-to-event metrics were reported for ML models. For binary classification of the oral cavity, the only evaluated subsite, the AUROC ranged from 0.67 to 0.97, with F1-scores between 0.53 and 0.89. CONCLUSIONS: ML models have demonstrated considerable potential in predicting post-treatment survival and disease progression, consistently outperforming traditional linear models and their derived nomograms. Future research should incorporate more comprehensive treatment features, emphasize disease progression outcomes, and establish model generalizability through external validations and the use of multicenter datasets.

CBCT in Dental Implantology: A Key Tool for Preventing Peri-Implantitis and Enhancing Patient Outcomes.

(1) Introduction: Trust is a cornerstone of the patient-physician relationships. Unforeseen complications in the health care system could jeopardize patients' trust in their physicians. (2) Aim: This article presents a quantitative figure regarding foreseeing the necessity of a three-dimensional quantitative visualization of bone structure and concurrently preparing for an ancillary procedure by a dentist to successfully perform the surgery that could minimize unforeseen complications; (3) Materials and method: This retrospective study has been derived based on an analysis of 1134 patients who had received 4800 dental implants from January 2001 to August 2020, out of which 200 cases were randomly selected for this study. Each procedure during implant treatment was categorized as OPG (Orthopantomography) or OPG with CBCT as per all the procedures which included and were coded as follows, 1: Surgery & Restoration, 2: GBR (Guided Bone Regeneration), 3: GTR (Guided Tissue Regeneration), 4: Block Bone Graft, 5: Spreading, 6: Splitting, 7: Internal Sinus, 8: External Sinus, 9: PRF (Platelet Rich Fibrin). Any of the 200 cases in which implant placement could not have been performed for reasons related to a lack of CBCT were selected for this study. The surgery was aborted halfway through without implant placement in these cases due to a lack of bone quantity and/or lack of primary stability. These cases were registered for re-evaluation and statistical analysis; (4) Results: 7% of the cases that used OPG alone led the surgeon to unexpectedly abort in the middle of the surgery without implant placement. All (100%) of the patients who had CBCT during treatment planning were able to receive implants during the surgery. None of the patients left the surgery without receiving implants if CBCT was used (0%); (5) Discussion: Radiographic image quality is defined as the amount of information within the image that allows the radiologist to make a diagnostic decision with a particular level of certainty (Martin et al., 1999) and hence the importance of CBCT. The unexpected 7% of devastating situations for patients who started surgery but did not have implant placement led to [A] aborting the surgery, [B] procedural difficulties requiring an alternative treatment plan, [C] a negative impact on the patient's behavior, and [D] wanting to change doctor due to a lack of trust; (6) Conclusion: This study indicates that in implant dentistry patients' mistrust could be avoided by 7% if CBCT is obtained. It also shows the significance of cone-beam computed tomography as an adjunct to panoramic radiography during the diagnosis and treatment planning phase. The use of panoramic radiography alone can lead to a 7% likelihood of misdiagnosis. A lack of CBCT during treatment planning negatively affects the outcome of surgical procedures.

Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: Implementation of a Risk-Based Model.

PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

Practical 10-Color T-Cell Panel for Phenotyping Diverse Populations Using Spectral Flow Cytometry: A Beginner's Guide.

Flow cytometry stands as the most employed high-throughput single-cell analysis technique, facilitating the profiling of remarkably diverse samples, such as blood, bone marrow and body fluids. In addition, it allows for the discrimination of diverse immune cell subsets, including infrequently encountered types like T regulatory cells and exhausted CD28Null T cells. However, analyzing rare immune cell subsets with conventional flow cytometry poses challenges stemming from factors like fluorophore overlap, compensation issues, and limited flexibility in fluorophore selection. Therefore, spectral flow cytometry offers advantages over traditional flow cytometry. It measures the full emission spectrum and then separates it to identify different fluorochromes. This enables the use of fluorochromes with significant overlap in a single test, allowing for the analysis of more protein markers. Following this, spectral technology employs precise calculations to separate individual fluorochromes, thereby enabling the detection and elimination of autofluorescent signals originating from cells within the entire emission spectrum. This capability is pivotal in achieving deep phenotyping of immune cells with the requisite sensitivity and resolution essential for monitoring the immune systems of patients with compromised immunity, such as cancer and autoimmune disorders. Additionally, it allows for the exploration of interactions between distinct immune subsets. In this context, we introduce an optimized protocol utilizing spectral flow cytometry for precise T-cell characterization and differentiation, encompassing the assessment of their activation states. Furthermore, this protocol extends its applicability to the identification of less common circulating T-cell populations, notably T-regulatory and CD28Null T cells, following autofluorescence correction within the spectrum. This protocol provides a set of steps and reagents for the surface and intracellular staining of human T cells using whole peripheral blood. The spectral-based design of this panel allows for its applicability to other spectral machines, providing a versatile and efficient tool for T-cell analysis. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Achieving optimal staining through effective antibody titration Basic Protocol 2: Single-cell staining Basic Protocol 3: Comprehensive panel staining post-titration and spectral library integration.

Dental Extractions Before Radiation Therapy and the Risk of Osteoradionecrosis in Patients With Head and Neck Cancer.

Importance: Patients with head and neck cancer undergo extraction of teeth with poor prognoses to minimize post-radiation therapy (RT) extractions, which are known to cause osteoradionecrosis (ORN). However, many patients are required to start RT before the extraction sites are completely healed. The role of pre-RT extractions in the development of ORN has been disputed in literature. Objective: To determine whether the timing of pre-RT dental extractions is associated with ORN development in patients with head and neck cancer. Design, Setting, and Participants: This retrospective cohort study was conducted at a single institution (Princess Margaret Cancer Centre, Toronto, Canada) between January 1, 2011, and January 1, 2018, and included 879 patients with head and neck cancer who underwent pre-RT dental extractions before curative RT of 45 Gy or greater. Patient demographic information and clinical characteristics (eg, primary cancer site, nodal involvement, chemotherapy, smoking status, dental pathology) were considered. Data analyses were performed from July to December 2022. Main outcomes and measures: Timing (number of days) from dental extractions to RT start date and pre-RT extractions categorized as healed, minor bone spicules (MBS), or ORN. Results: The study population consisted of 879 patients with a median (range) age of 62 (20-96) years, with 685 men (78%) and 194 women (22%). Of these, 847 (96.3%) healed from pre-RT dental extractions, 16 (1.8%) developed MBS, and 16 (1.8%) developed ORN. The median (range) time in number of days from pre-RT extraction(s) to start of RT was 9 (0-98) days in the healed cohort, 6 (3-23) days in the MBS cohort, and 6 (0-12) days in the ORN cohort. There was a large difference in the timing of pre-RT extractions between the healed and the MBS cohorts (mean 11.9 vs 7.4 days to radiation; difference 4.4; 95% CI, 1.5-7.3), and the healed and the ORN cohorts (mean 11.9 vs 7.1 days; difference 4.8 days; 95% CI, 2.6-7.1). Conclusion: The findings of this retrospective cohort study suggest that there was an important association between the timing of pre-RT dental extractions and ORN when extractions occurred within 7 days of the RT start date. Despite this, ORN after pre-RT extractions is relatively rare. These findings indicate that patients with head and neck cancer who are to undergo RT should not delay treatment for extractions when it might compromise oncologic control.

Development and Standardization of a Classification System for Osteoradionecrosis: Implementation of a Risk-Based Model.

Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. Methods: Consecutive head-and-neck cancer (HNC) patients treated with curative-intent IMRT (≥ 45Gy) in 2011-2018 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared to fifteen existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). Results: ORN was identified in 219 out of 2732 (8%) consecutive HNC patients. Factors associated with high-risk of ORN were: oral-cavity or oropharyngeal primaries, received IMRT dose ≥60Gy, current/ex-smokers, and/or stage III-IV periodontal disease. The ORN rate for high-risk vs low-risk patients was 12.7% vs 3.1% (p<0.001) with an area-under-the-receiver-operating-curve (AUC) of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, RadORN, was proposed based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. Conclusion: We identified risk factors for ORN, and proposed a novel ORN classification system based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN, and may facilitate clinical care and clinical trials.

Implication of dental insurance status on patterns of pre-radiation dental extraction and risk of osteoradionecrosis of the jaw in head-and-neck cancer patients.

Oral toxicities such as osteoradionecrosis can be minimized by dental screening and prophylactic dental care prior to head and neck (HN) radiation therapy (RT). However, limited information is available about how dental insurance interacts with prophylactic dental care and osteoradionecrosis. To address this gap in knowledge, we conducted a cohort study of 2743 consecutive adult patients treated with curative radiation for HN malignancy who underwent pre-radiation dental assessment and where required, prophylactic dental treatment. Charts were reviewed to determine patient demographics, dental findings, dental treatment and development of osteoradionecrosis following radiation. Three insurance cohorts were identified: private-insured (50.4 %), public-insured (7.3 %), being patients with coverage through government-funded disability and welfare programs, and self-pay (42.4 %). More than half the public-insured patients underwent prophylactic pre-radiation dental extractions, followed by self-pay patients (44 %) and private-insured patients (26.6 %). After a median follow-up time of 4.23 years, 6.5 % of patients developed osteoradionecrosis. The actuarial rate of osteoradionecrosis in the public-insured patients was 14.7 % at 5-years post-RT, compared to 7.5 % in private-insured patients and 6.7 % in self-pay patients. On multivariable analysis, dental insurance status, DMFS160, age at diagnosis, sex, tumor site, nodal involvement, years smoked and gross income were all significant risk factors for tooth removal prior to HN radiation. However, only public-insured status, tumor site and years smoked were significant risk factors for development of osteoradionecrosis. Our findings demonstrate that lack of comprehensive dental coverage (patients who self-pay or who have limited coverage under public-insured programs) associates strongly with having teeth removed prior to HN RT. Nearly 1 in 6 patients covered under public-insurance developed osteoradionecrosis within 5 years of completing their treatment. Well-funded dental insurance programs for HN cancer patients might reduce the number of pre-RT extractions performed in these patients, improving quality of life post-RT.

Discovery of phosphorylated lantibiotics with proimmune activity that regulate the oral microbiome.

Lantibiotics are ribosomally synthesized and posttranslationally modified peptides (RiPPs) that are produced by bacteria. Interest in this group of natural products is increasing rapidly as alternatives to conventional antibiotics. Some human microbiome-derived commensals produce lantibiotics to impair pathogens' colonization and promote healthy microbiomes. Streptococcus salivarius is one of the first commensal microbes to colonize the human oral cavity and gastrointestinal tract, and its biosynthesis of RiPPs, called salivaricins, has been shown to inhibit the growth of oral pathogens. Herein, we report on a phosphorylated class of three related RiPPs, collectively referred to as salivaricin 10, that exhibit proimmune activity and targeted antimicrobial properties against known oral pathogens and multispecies biofilms. Strikingly, the immunomodulatory activities observed include upregulation of neutrophil-mediated phagocytosis, promotion of antiinflammatory M2 macrophage polarization, and stimulation of neutrophil chemotaxis-these activities have been attributed to the phosphorylation site identified on the N-terminal region of the peptides. Salivaricin 10 peptides were determined to be produced by S. salivarius strains found in healthy human subjects, and their dual bactericidal/antibiofilm and immunoregulatory activity may provide new means to effectively target infectious pathogens while maintaining important oral microbiota.

A Primed Neutrophil Subset Predicts the Risk of Bloodstream Infections in Allogeneic Hematopoietic Stem-Cell Transplant Patients: A Prospective Study.

BACKGROUND: Bloodstream infections (BSIs) are the most common infectious complication in patients who receive allogeneic hematopoietic stem-cell transplants (allo-HSCTs). Polymorphonuclear neutrophils (PMNs) are quantified to monitor the susceptibility to BSIs; however, their degree of activation is not. We previously identified a population of primed PMNs (pPMNs) with distinct markers of activation representing approximately 10% of PMNs in circulation. In this study, we investigate whether susceptibility to BSIs is related to the proportion of pPMNs rather than strictly PMN counts. METHODS: In this prospective observational study, we used flow cytometry to assess pPMNs in blood and oral rinse samples collected from patients receiving an allo-HSCT over the course of their treatment. We used the proportion of pPMNs in the blood on day 5 post-transplant to categorize patients into a high- or a low-pPMN group (>10% or <10% pPMNs). These groups were then used as a predictor of BSIs. RESULTS: A total of 76 patients were enrolled in the study with 36 in the high-pPMN group and 40 in the low-pPMN group. Patients in the low-pPMN group had lower expression of PMN activation and recruitment markers and displayed a delay in PMN repopulation of the oral cavity after the transplant. These patients were more susceptible to BSIs compared with patients in the high-pPMN group with an odds ratio of 6.5 (95% confidence interval, 2.110-25.07; P = .002). CONCLUSIONS: In patients who receive an allo-HSCT, having <10% pPMNs early in the post-transplant phase can be an independent predictor of BSI in allo-HSCT patients.

The Effect of Intensity-Modulated Radiotherapy to the Head and Neck Region on the Oral Innate Immune Response and Oral Microbiome: A Prospective Cohort Study of Head and Neck Tumour Patients.

Neutrophils, also known as polymorphonuclear leukocytes (PMNs), form a significant component of the innate host response, and the consequence of the interaction between the oral microbiota and PMNs is a crucial determinant of oral health status. The impact of radiation therapy (RT) for head and neck tumour (HNT) treatment on the oral innate immune system, neutrophils in particular, and the oral microbiome has not been thoroughly investigated. Therefore, the objective of this study was to characterize RT-mediated changes in oral neutrophils (oPMNs) and the oral microbiome in patients undergoing RT to treat HNTs. Oral rinse samples were collected prior to, during and post-RT from HNT patients receiving RT at Dental Oncology at Princess Margaret Cancer Centre. The oPMNs counts and activation states were analysed using flow cytometry, and the oral microbiome was analysed using 16S rRNA gene sequencing. Statistically significant (p < 0.05) drops in oPMN counts and the activation states of the CD11b, CD16, CD18, CD64 and H3Cit markers from pre-RT to post-RT were observed. Moreover, exposure to RT caused a significant reduction in the relative abundance of commensal Gram-negative bacteria and increased the commensal Gram-positive microbes. Ionizing radiation for the treatment of HNTs simultaneously decreased the recruitment of oPMNs into the oral cavity and suppressed their activation state. The oral microbiome composition post-RT was altered significantly due to RT which may favour the colonization of specific microbial communities unfavourable for the long-term development of a balanced oral microbiome.

THE PROCESS OF DEVELOPING CONSENSUS GUIDELINES BY DENTAL ONCOLOGISTS FOR PRE-RADIOTHERAPY DENTAL CARE IN HEAD AND NECK CANCER PATIENTS USING THE MODIFIED DELPHI TECHNIQUE.

BACKGROUND: There is a range of pre-radiation therapy (RT) dental care strategies used to prevent the side effects associated with the use of RT in the treatment of head and neck cancer. However, there is a paucity of evidence-based, prospectively tested clinical practice guidelines for dentists to utilize in the provision of care prior to RT. PURPOSE: The aim of this study is to describe the process of creating consensus guidelines for dental care in head and neck cancer patients undergoing RT using the Modified Delphi Technique. PROCEDURE: We invited 44 dental oncologists to participate as panelists in the study. Three rounds of iterative structured surveys were completed within eight months, followed by a virtual meeting to conclude the modified Delphi process. Questions were divided into six main domains and patients were categorized as low, moderate, and high-risk based on factors identified by panelists and agreed upon during the first round. The threshold value set for each round of the Delphi process was a 70% response rate and 75% Consensus level. FINDINGS: Eighteen panelists out of the forty-four (41% overall response rate) completed the study. The number of questions that achieved the set consensus level in rounds 1,2,3 and the virtual meeting were 24%, 62%,61% and 81%, respectively. A confidence level of 95% and a response rate of >75% were reached throughout the process. CONCLUSION: Consensus was attained in most of the questions in all domains, which will be utilized to develop guidelines for dental care in head and neck cancer patients before the commencement of RT.

Clinical practice guidelines for dental management prior to radiation for head and neck cancer.

PURPOSE: Limited evidence exists linking the specific preventative dental care provided prior to radiation therapy (RT) for head and neck cancer to outcomes like osteoradionecrosis (ORN). This study utilized expert consensus to develop tooth-specific dental treatment pathways for head and neck cancer patients prior to radiation. MATERIALS AND METHODS: Dental oncologists from across a single nation were engaged in a Modified Delphi process. Three rounds of questionnaires were performed followed by an in-person meeting. Domains included radiation dose, timing of dental treatment, and treatment of dental caries, periodontal disease and third molars. RESULTS: The response rate from the 32 participants between rounds was > 70%. Consensus was reached for all but 4 questions. The radiation dose at which participants would prophylactically remove teeth to prevent ORN was established as 70 Gy in the maxilla and 60 Gy in the mandible. Treatment pathways were developed for maxillary and mandibular anterior/premolar and molar teeth receiving a dose at or above this threshold. Risk factors were established for carious, periodontally involved and third molar teeth. In general, periodontally involved teeth and mandibular molars were most frequently recommended for extraction. Only symptomatic third molars were recommended for extraction when adequate healing time was available prior to commencement of RT. CONCLUSION: Tooth-level clinical practice guidelines were developed using expert consensus via the modified Delphi process. The treatment pathways developed in this study will be prospectively tested to evaluate the outcomes associated with tooth-specific dental treatments.

TNFα Signaling Is Increased in Progressing Oral Potentially Malignant Disorders and Regulates Malignant Transformation in an Oral Carcinogenesis Model.

Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management.

The neurorepellent, Slit2, prevents macrophage lipid loading by inhibiting CD36-dependent binding and internalization of oxidized low-density lipoprotein.

Atherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.

Short-term and long-term unstimulated saliva flow following unilateral vs bilateral radiotherapy for oropharyngeal carcinoma.

BACKGROUND: We aimed to compare unstimulated saliva flow using 3-minute modified Schirmer test (MST) following bilateral vs unilateral radiotherapy (RT) in oropharyngeal carcinoma (OPC). METHODS: We reviewed OPC patients treated with definitive intensity-modulated radiation therapy (IMRT) between 2011 and 2017. MST was measured at baseline, 1-/6-/12-/24-month post-RT. MST values were compared between bilateral-RT vs unilateral-RT groups. Multivariable logistic regression analysis (MVA) identified predictors of hyposalivation (MST < 25 mm). RESULTS: Total 498 bilateral-RT and 36 unilateral-RT patients were eligible. The MST values at 1-/6-/12-/24-month post-RT were all significantly reduced from baseline for the entire cohort. Baseline unilateral-RT and bilateral-RT MST values (in mm) were similar (P = .2), but much higher for unilateral-RT 1-month (mean: 19.1 vs 13.0, P = .03), 6-month (20.5 vs 9.3, P < .001), 12-month (20.1 vs 11.9, P < .01), and 24-month post-RT (22.2 vs 13.9, P = .04). MVA confirmed that unilateral RT reduced the likelihood of hyposalivation vs bilateral RT (OR 2.36, P = .006). CONCLUSION: Unilateral RT reduces unstimulated salivary flow in OPC patients.

Healthcare resource utilization following unilateral versus bilateral radiation therapy for oropharyngeal carcinoma.

PURPOSE: To describe differences in healthcare resource utilization between patients treated with bilateral vs. unilateral neck radiation therapy (RT) for lateralized oropharyngeal cancer. METHODS: A propensity score matching strategy was used to identify two otherwise clinically similar cohorts of tonsillar cancer patients treated with either bilateral or unilateral neck RT. Cohorts were matched based on similar propensity scores for age, sex, ECOG performance status, pack-year smoking history, cT-category, cN-category, HPV-status, and use of concurrent chemotherapy. Short term (from start of RT to 3 months following end of RT) resource utilization included: 1) outpatient supportive care visits, 2) hospital admission, and 3) interventions (feeding tube insertion and outpatient intravenous hydration). Long-term resource utilization included feeding tube dependency at 1-year. RESULTS: Among 559 patients with tonsillar cancer treated between 2004-2017, propensity score matching identified a unilateral neck RT cohort (n = 81) and bilateral neck RT cohort (n = 81) with similar clinical and treatment characteristics. Bilateral neck RT was associated with a higher likelihood of hospitalization (33% vs 12%, p < 0.01), outpatient IV hydration (33% vs 17%, p = 0.03), and feeding tube insertion (33% vs 10%, p < 0.001); a greater number of total days of hospitalization (110 vs 47 days, p < 0.01) and outpatient IV hydration (135 vs 72 days, p = 0.02); and higher total number of supportive clinic visits (1226 vs 1053 days, p = 0.04). In the long-term, bilateral RT was associated with higher rate of feeding tube dependency at 1-year (7% vs 0%, p < 0.001). CONCLUSION: Bilateral RT for tonsillar cancer resulted in significant increase in health resource utilization.

The effect of pamidronate delivery in bisphosphonate-naïve patients on neutrophil chemotaxis and oxidative burst.

The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ), a morbid condition associated with bisphosphonate administration, has not been fully elucidated. Recent research utilizing a murine model has revealed that the neutrophil becomes dysfunctional following exposure to bisphosphonates. Accordingly, the impairment of neutrophil function could play an important role in the pathogenesis of MRONJ via an infectious mechanism mediated by the suppression of the innate immune system. Currently, the existing human data are insufficient to substantiate this theory. To investigate, we isolated neutrophils from blood and oral rinse samples from bisphosphonate-naïve patients who were recently diagnosed with multiple myeloma both prior to and one month following their initial infusion of pamidronate, an intravenous bisphosphonate agent. Stimulated blood and oral neutrophil superoxide production and chemotactic capabilities were found to be impaired relative to baseline values. These results suggest that impaired neutrophil function may partially contribute to the aetiology underlying the pathophysiological processes linked to the development of MRONJ. Further, as the functional status of circulating neutrophils was reflected in the oral cavity where sampling can be accomplished in a non-invasive fashion, it is conceivable that neutrophil function could serve as a potential biomarker for MRONJ prognostication.

AP-002: A novel inhibitor of osteoclast differentiation and function without disruption of osteogenesis.

AP-002 is a novel, gallium-based, anti-cancer oral compound in clinical development for cancer patients with bone metastases. We examined the effects of AP-002 on osteoclastogenesis, fusion, and osteogenesis. AP-002 exhibited a dramatic effect on osteoclast function without causing osteoclast cell death. The expression of tartrate-resistant acid phosphatase and cathepsin K mRNA levels was down-regulated in RAW264.7 cells treated with AP-002 in the presence of soluble receptor activator of NF-κB ligand. AP-002 was also found to block the fusion of osteoclasts from RAW264.7 cells. AP-002 had a similar inhibitory effect on RANKL-induced mouse primary bone marrow monocytes fusion. Human blood monocytes treated with AP-002 failed to form TRAcP/ACP5-positive cells. AP-002 caused these inhibitory effects without causing osteoclast cell death, which was in contrast to zoledronic acid controls. Furthermore, unlike zoledronic acid, AP-002 did not inhibit Rac1 activation. Gene expression analysis by microarrays showed that AP-002 significantly reverses the effects of RANKL-induced gene expression. These include several key osteoclast-differentiation/function-associated genes such as: Scinderin, OCSTAMP, Atp6v0d2, OSCAR, RhoU, Usp18, MMP9, and Trim30. The difference between AP-002 and zoledronic acid is also seen in its effects on osteogenesis. Osteoblast mineralization was promoted by AP-002 (0.1-3.0 µM), whereas zoledronic acid showed toxicity to osteoblasts at the concentration >0.5 µM, in the same dose range where it causes osteoclast cell death. Zoledronic acid therefore has no therapeutic window in its toxic effect on osteoclasts and osteoblasts. AP-002 promotes osteogenesis in this therapeutic window, while blocking osteoclast development. We therefore conclude that AP-002 has potential as a new anti-bone resorption agent, with a mechanism of action different compared with other currently marketed anti-bone resorption agents.

The Neutrophil: Constant Defender and First Responder.

The role of polymorphonuclear neutrophils (PMNs) in biology is often recognized during pathogenesis associated with PMN hyper- or hypo-functionality in various disease states. However, in the vast majority of cases, PMNs contribute to resilience and tissue homeostasis, with continuous PMN-mediated actions required for the maintenance of health, particularly in mucosal tissues. PMNs are extraordinarily well-adapted to respond to and diminish the damaging effects of a vast repertoire of infectious agents and injurious processes that are encountered throughout life. The commensal biofilm, a symbiotic polymicrobial ecosystem that lines the mucosal surfaces, is the first line of defense against pathogenic strains that might otherwise dominate, and is therefore of critical importance for health. PMNs regularly interact with the commensal flora at the mucosal tissues in health and limit their growth without developing an overt inflammatory reaction to them. These PMNs exhibit what is called a para-inflammatory phenotype, and have reduced inflammatory output. When biofilm growth and makeup are disrupted (i.e., dysbiosis), clinical symptoms associated with acute and chronic inflammatory responses to these changes may include pain, erythema and swelling. However, in most cases, these responses indicate that the immune system is functioning properly to re-establish homeostasis and protect the status quo. Defects in this healthy everyday function occur as a result of PMN subversion by pathological microbial strains, genetic defects or crosstalk with other chronic inflammatory conditions, including cancer and rheumatic disease, and this can provide some avenues for therapeutic targeting of PMN function. In other cases, targeting PMN functions could worsen the disease state. Certain PMN-mediated responses to pathogens, for example Neutrophil Extracellular Traps (NETs), might lead to undesirable symptoms such as pain or swelling and tissue damage/fibrosis. Despite collateral damage, these PMN responses limit pathogen dissemination and more severe damage that would otherwise occur. New data suggests the existence of unique PMN subsets, commonly associated with functional diversification in response to particular inflammatory challenges. PMN-directed therapeutic approaches depend on a greater understanding of this diversity. Here we outline the current understanding of PMNs in health and disease, with an emphasis on the positive manifestations of tissue and organ-protective PMN-mediated inflammation.

Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way.

Periodontitis is a highly prevalent disease. As it progresses, it causes serious morbidity in the form of periodontal abscesses and tooth loss and, in the latter stages, pain. It is also now known that periodontitis is strongly associated with several nonoral diseases. Thus, patients with periodontitis are at greater risk for the development and/or exacerbation of diabetes, chronic obstructive pulmonary disease, and cardiovascular diseases, among other conditions. Although it is without question that specific groups of oral bacteria which populate dental plaque play a causative role in the development of periodontitis, it is now thought that once this disease has been triggered, other factors play an equal, and possibly more important, role in its progression, particularly in severe cases or in cases that prove difficult to treat. In this regard, we allude to the host response, specifically the notion that the host, once infected with oral periodontal pathogenic bacteria, will mount a defense response mediated largely through the innate immune system. The most abundant cell type of the innate immune system - polymorphonuclear neutrophils - can, when protecting the host from microbial invasion, mount a response that includes upregulation of proinflammatory cytokines, matrix metalloproteinases, and reactive oxygen species, all of which then contribute to the tissue damage and loss of teeth commonly associated with periodontitis. Of the mechanisms referred to here, we suggest that upregulation of reactive oxygen species might play one of the most important roles in the establishment and progression of periodontitis (as well as in other diseases of inflammation) through the development of oxidative stress. In this overview, we discuss both innate and epigenetic factors (eg, diabetes, smoking) that lead to the development of oxidative stress. This oxidative stress then provides an environment conducive to the destructive processes observed in periodontitis. Therefore, we shall describe some of the fundamental characteristics of oxidative stress and its effects on the periodontium, discuss the diseases and other factors that cause oxidative stress, and, finally, review potentially novel therapeutic approaches for the management (and possibly even the reversal) of periodontitis, which rely on the use of therapies, such as resveratrol and other antioxidants, that provide increased antioxidant activity in the host.