Measuring the Oxidation State and Enzymatic Activity of Glyceraldehyde Phosphate Dehydrogenase (GAPDH).

Glyceraldehyde phosphate dehydrogenase (GAPDH) is a highly conserved, essential, and abundant enzyme that catalyzes a rate-determining step of glycolysis. GAPDH catalyzes the nicotinamide adenine dinucleotide (NAD+)- and inorganic phosphate-dependent oxidation and phosphorylation of glyceraldehyde phosphate (GAP) to form 1,3-bisphosphoglycerate (BPG). As part of its mechanism of action, GAPDH employs a redox-sensitive cysteine that serves as a nucleophile to form a covalent adduct with GAP in order to set-up subsequent oxidation and phosphorylation steps. As a result of the redox sensitivity of the active site cysteine residue, GAPDH is susceptible to oxidative inactivation by oxidants such as hydrogen peroxide (H2O2). Indeed, numerous studies have demonstrated that oxidative inactivation of GAPDH has important metabolic consequences for adaptation to life in air and oxidative stress since decreased GAPDH activity results in the rerouting of carbon flux away from glycolysis and toward the pentose phosphate pathway to produce the key cellular reductant and antioxidant, NADPH. Thus, the ability to probe GAPDH oxidation and activity provides an important snapshot of the intracellular redox environment and glycolytic flux. Herein, we describe methods to measure reduced and oxidized GAPDH using thiol alkylation assays as well as GAPDH enzymatic activity.

Experiences of Young People and Their Carers with a Rural Mobile Mental Health Support Service: A Qualitative Study.

Mental health difficulties during teenage years are common. They are also a risk factor for later mental and physical health problems. Rural young people are at a greater risk for mental health difficulties and have less access to services than their urban counterparts. The purpose of this study was to explore the experiences of young people and their carers with mental health support provided by a rural mobile service, and to identify access enablers from the perspective of the service users. A qualitative descriptive approach was used to analyse twelve interviews with current service users and eight interviews with family members of young people who had accessed the service. Three main themes were identified: (a) access and flexibility, (b) the qualities and strategies of the clinicians, and (c) experiences of change. The mobile service was perceived to be effective in producing a positive change in mental health, relationships, and the attainment of life goals. Key enablers to access included the flexibility of the mobile service, the variety of service delivery modes and therapeutic methods offered, the ease of access facilitated by the location in schools, and the autonomy of young people in how they chose to utilise the service. This study provides information about what is important to rural young people and their families in the provision of mental health services. The findings have implications for changing the way services are organized and operated. Healthcare policies and services could support a user-led model design that incorporates access and use-enablers and removes barriers to rural mental health support.

Evaluation of independent risk factors associated with surgical site infections from caesarean section.

BACKGROUND: The present study assessed factors associated with the risk of surgical site infections (SSI) after a caesarean section (C-section). METHODS: Data were collected in 1682 women undergoing elective (53.9%) and emergency (46.1%) C-sections between 1st August 2020, and 30th December 2021, at a National Health Service hospital (Surrey, UK). RESULTS: At the time of C-section, the mean age was 33.1 yr (SD ± 5.2). Compared to women with BMI < 30 kg/m2, those with a BMI ≥ 35 kg/m2 had a greater risk of SSI, OR 4.07 (95%CI 2.48-6.69). Women with a history of smoking had a greater risk of SSI than those who had never smoked, OR 1.69 (95%CI 1.05-2.27). Women with a BMI ≥ 30 kg/m2 and had a smoking history or emergency C-section had 3- to tenfold increases for these adverse outcomes. Ethnic minority, diabetes or previous C-section did not associate with any of the outcomes. CONCLUSIONS: High BMI, smoking, and emergency C-section are independent risk factors for SSI from C-section. Women planning conception should avoid excess body weight and smoking. Women with diabetes and from ethnic minority backgrounds did not have increased risks of SSI, indicating a consistent standard of care for all patients.

TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

Reduction of adverse outcomes from cesarean section by surgical-site infection prevention care bundles in maternity.

OBJECTIVE: To reduce average surgical-site infection (SSI) rates to less than 7.5%, as well as other complications by incrementally implementing an SSI prevention care bundle in maternity: (1) ChloraPrep; (2) PICO dressings, performing elective cesarean sections in a main theater rather than a labor ward and warming blankets; (3) vaginal cleansing; and (4) Hibiscrub. METHODS: In this prospective cohort study, the association between categorical variables was assessed by χ2 tests, temporal trends in the monthly percentage change of SSI were measured using the Joinpoint Regression Program v4.7.0.0. RESULTS: In all, 1682 women (mean age 33.1 ± 5.2 years) underwent either elective (53.9%) or emergency (46.1%) cesarean section. After a small initial increase (10.0%-11.8%), SSI progressively declined to 4.4% (χ2  = 22.1, P < 0.001), as did sepsis, reoperation or readmission for SSI: from 12.5% to 0.5% (χ2  = 90.1, P < 0.001). The rates of SSI fell progressively with the cumulative introduction care bundle components. The average monthly percentage change was -14.0% (95% confidence interval -21.8% to -5.4%, P = 0.004), and the average SSI rate was kept below 7.5% for the last 12 months of the study. CONCLUSION: The maternal SSI prevention care bundle is simple and inexpensive; it effectively reduces SSI after a cesarean section and should be offered routinely to women undergoing cesarean section.

Barrett's oesophagus with indefinite for dysplasia shows high rates of prevalent and incident neoplasia in a UK multicentre cohort.

AIMS: Barrett's oesophagus with indefinite for dysplasia (IDD) carries a risk of prevalent and incident dysplasia and oesophageal adenocarcinoma. This study seeks to determine the risk of neoplasia in a multicentre prospective IDD cohort, along with determining adherence to British Society of Gastroenterology (BSG) guidelines for management and histology reporting. METHODS: This was a cohort study using prospectively collected data from pathology databases from two centres in the North West of England (UK). Cases with IDD were identified over a 10-year period. Data were obtained on patient demographics, Barrett's endoscopy findings and histology, outcomes and histological reporting. RESULTS: 102 biopsies with IDD diagnosis in 88 patients were identified. Endoscopy was repeated in 78/88 (88%) patients. 12/78 progressed to low-grade dysplasia (15% or 2.6 per 100 person years), 6/78 (7.7%, 1.3 per 100 person years) progressed to high-grade dysplasia and 6/78 (7.7%, 1.3 per 100 person years) progressed to oesophageal adenocarcinoma. The overall incidence rate for progression to any type of dysplasia was 5.1 per 100 person years. Cox regression analysis identified longer Barrett's segment, multifocal and persistent IDD as predictors of progression to dysplasia. Histology reporting did not meet 100% adherence to the BSG histology reporting minimum dataset prior to or after the introduction of the guidelines. CONCLUSIONS: IDD carries significant risk of progression to dysplasia or neoplasia. Therefore, careful diagnosis and management aided by clear histological reporting of these cases is required to diagnose prevalent and incident neoplasia.

Violence Exposure, Child Asthma Morbidity, and Maternal Depressive Symptoms: A Longitudinal Analysis of Cumulative Risk.

Low-income mothers of children with uncontrolled asthma are an underserved population at risk for psychological distress. We examined the impact of violence exposure and child asthma morbidity on depressive symptoms in mothers of youths with uncontrolled asthma. Asthma symptoms and health care utilization, socio-demographics, and standardized measures of depressive symptoms and violence exposure were ascertained by self-report. Latent Growth Curve Modeling tested the associations of violence and asthma morbidity with depressive symptoms. Participating mothers (N=276) reported high baseline violence exposure (59.5%) and depressive symptoms (34.4%); nearly a quarter had clinically significant depressive symptoms at 12 months. Violence exposure was consistently associated with maternal depressive symptoms. Individual indicators of asthma morbidity were nonsignificant, but the cumulative effect of asthma morbidity was predictive of higher depressive symptoms. Findings suggest holistic risk assessment and interventions may be needed to ameliorate the chronic distress observed in mothers of youths with uncontrolled asthma.

Feasibility and pilot efficacy of cognitive remediation for people in residential substance use treatment.

INTRODUCTION: There are high rates of cognitive impairment among people seeking treatment for problematic substance use, which is rarely addressed in treatment programs. The aim of this pilot study was to evaluate the feasibility and outcomes of the neuropsychological and educational approach to cognitive remediation (NEAR) in a residential substance treatment setting. METHODS: A non-randomised trial conducted between November 2018 and November 2019, compared outcomes for 34 residents who received cognitive remediation (CR) plus treatment as usual (TAU) to 31 residents who received TAU only. Number of groups and attendance, and a measure of client satisfaction assessed feasibility. Cognitive function was assessed at baseline (service admission), and at 2 and 6 months post-admission. RESULTS: A total of 95 CR groups were delivered over a 36-week time period with a high degree of treatment fidelity and acceptability to participants. Cognitive outcomes improved across both the CR+TAU and TAU groups by 2 months, which was maintained at 6 months for outcomes related to executive functioning. There were no significant differences between the CR+TAU and TAU groups at 2 or 6 months, although a large effect size and confidence intervals indicated a potentially larger change in cognitive flexibility after receiving CR. DISCUSSION AND CONCLUSIONS: This study contributes to our understanding of the implementation of CR in the alcohol and other drug rehabilitation setting. It is feasible to incorporate the NEAR program in treatment. The small sample size and lower than expected treatment dose likely contributed to the lack of significant findings.

Exploring Community Mental Health Systems - A Participatory Health Needs and Assets Assessment in the Yamuna Valley, North India.

BACKGROUND: In India and global mental health, a key component of the care gap for people with mental health problems is poor system engagement with the contexts and priorities of community members. This study aimed to explore the nature of community mental health systems by conducting a participatory community assessment of the assets and needs for mental health in Uttarkashi, a remote district in North India. METHODS: The data collection and analysis process were emergent, iterative, dialogic and participatory. Transcripts of 28 in-depth interviews (IDIs) with key informants such as traditional healers, people with lived experience and doctors at the government health centres (CHCs), as well as 10 participatory rural appraisal (PRA) meetings with 120 people in community and public health systems, were thematically analysed. The 753 codes were grouped into 93 categories and ultimately nine themes and three meta-themes (place, people, practices), paying attention to equity. RESULTS: Yamuna valley was described as both 'blessed' and limited by geography, with bountiful natural resources enhancing mental health, yet remoteness limiting access to care. The people described strong norms of social support, yet hierarchical with entrenched exclusions related to caste and gender, and social conformity that limited social accountability of services. Care practices were porous, pluralist and fragmented, with operational primary care services that acknowledged traditional care providers, and trusted resources for mental health such as traditional healers (malis) and government health workers (accredited social health activists. ASHAs). Yet care was often absent or limited by being experienced as disrespectful or of low quality. CONCLUSION: Findings support the value of participatory methods, and policy actions that address power relations as well as social determinants within community and public health systems. To improve mental health in this remote setting and other South Asian rural locations, community and public health systems must dialogue with the local context, assets and priorities and be socially accountable.

Sod1 integrates oxygen availability to redox regulate NADPH production and the thiol redoxome.

Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O2•-) by catalyzing its conversion to dioxygen (O2) and hydrogen peroxide (H2O2). Using Saccharomyces cerevisiae and mammalian cells, we discovered that a major aspect of the antioxidant function of Sod1 is to integrate O2 availability to promote NADPH production. The mechanism involves Sod1-derived H2O2 oxidatively inactivating the glycolytic enzyme, GAPDH, which in turn reroutes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH. The aerobic oxidation of GAPDH is dependent on and rate-limited by Sod1. Thus, Sod1 senses O2 via O2•- to balance glycolytic and oxPPP flux, through control of GAPDH activity, for adaptation to life in air. Importantly, this mechanism for Sod1 antioxidant activity requires the bulk of cellular Sod1, unlike for its role in protection against O2•- toxicity, which only requires <1% of total Sod1. Using mass spectrometry, we identified proteome-wide targets of Sod1-dependent redox signaling, including numerous metabolic enzymes. Altogether, Sod1-derived H2O2 is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.

Implementing cognitive remediation in substance use treatment: The impact of staff perceptions.

Cognitive remediation (CR) programs are new to substance treatment and research needs to evaluate their implementation. The context of implementation, specifically staff perceptions, is critical to changing practice. The aim of this study was to identify treatment staff members' perceptions about the benefits and challenges of a new CR intervention in their workplace. The study conducted semi-structured interviews with staff at a residential substance treatment center when the CR program was first being implemented and again six months later. The study interviewed eight staff members in each round (>50% of staff members in the unit) from all role designations. A critical perspective shaped a thematic analysis of challenges to implementation. The study identified benefits of the CR program to clients and staff. However, only one staff member participated in training to deliver the program. In principle, staff members support the program, but this does not necessarily translate into active involvement, even when the study conducted staff engagement activities. CR programs are likely to improve functional outcomes for people in substance rehabilitation programs. However, this study suggests that staff accepting and valuing a new intervention is not enough to sustain it. For CR programs to be feasible, management should schedule and support staff training, and facilitate staff participation in that training. Organizational factors are likely to play a significant role in implementation success or failure, and further research should explore how the organizational culture of alcohol and other drug services impacts the implementation of CR therapy.

Interstitial Cystitis or Painful Bladder Syndrome in a Premenopausal Female Precipitated by Oral Combined Contraceptives.

It has been well documented that female sex is a significant risk factor for the development of various autoimmune diseases. While the reason for this has been debated, one well-regarded theory is that increased estrogen and decreased testosterone play a role in this predisposition. Interstitial cystitis (IC), also known as painful bladder syndrome (PBS), is an autoimmune disorder that affects over nine million women in the United States. It presents with pelvic and bladder pain and urinary symptoms, both of which significantly and negatively affect the quality of life. Even so, very few studies have examined the pathophysiologic relationship between autoimmune disorders and hormonal contraceptives. In this report, we present a case of IC likely precipitated by oral contraceptives (OCPs) in a premenopausal female. Shortly after beginning OCPs, this patient developed symptoms of severe pelvic pain and increased urinary frequency. Over the course of a year, the patient was diagnosed and treated for a variety of conditions, such as urinary tract infection (UTI), fungal vaginitis, and nephrolithiasis. After consultation with a gynecologist, a normal abdominal CT scan, and unsuccessful cystoscopy due to pain, she was finally diagnosed with IC. The patient independently learned of a potential link between hormonal contraceptive pills and IC and decided to discontinue this method of birth control. Following this, her symptoms completely resolved within several months. The timing of her initiation and discontinuation of OCPs, alongside her symptomatology, suggest a connection to the development of IC. A literature review was performed, which supports this association. We, therefore, highlight this case as an important example of IC precipitated by OCPs.

Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix.

Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

Mammal decline, linked to invasive Burmese python, shifts host use of vector mosquito towards reservoir hosts of a zoonotic disease.

Invasive apex predators have profound impacts on natural communities, yet the consequences of these impacts on the transmission of zoonotic pathogens are unexplored. Collapse of large- and medium-sized mammal populations in the Florida Everglades has been linked to the invasive Burmese python, Python bivittatus Kuhl. We used historic and current data to investigate potential impacts of these community effects on contact between the reservoir hosts (certain rodents) and vectors of Everglades virus, a zoonotic mosquito-borne pathogen that circulates in southern Florida. The percentage of blood meals taken from the primary reservoir host, the hispid cotton rat, Sigmodon hispidus Say and Ord, increased dramatically (422.2%) from 1979 (14.7%) to 2016 (76.8%), while blood meals from deer, raccoons and opossums decreased by 98.2%, reflecting precipitous declines in relative abundance of these larger mammals, attributed to python predation. Overall species diversity of hosts detected in Culex cedecei blood meals from the Everglades declined by 40.2% over the same period (H(1979) = 1.68, H(2016) = 1.01). Predictions based upon the dilution effect theory suggest that increased relative feedings upon reservoir hosts translate into increased abundance of infectious vectors, and a corresponding upsurge of Everglades virus occurrence and risk of human exposure, although this was not tested in the current study. This work constitutes the first indication that an invasive predator can increase contact between vectors and reservoirs of a human pathogen and highlights unrecognized indirect impacts of invasive predators.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. Main Outcomes and Measures: The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Results: Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths. Conclusions and Relevance: Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing. Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

Maxillary and mandible contouring in patients with a head and neck area irradiation.

PURPOSE: Dental care is crucial after irradiation of the head and neck. This care may include dental restoration, extractions, and prosthetic implantation or prosthesis adjustment. To perform these procedures safely, dentists need to know the delivered radiation dose delivered to the relevant part of the mandible and/or maxilla. We propose a simple, fast, and useful contouring technique to aid accurate recording of radiation therapy dose to the mandible and maxilla. METHODS AND MATERIALS: The maxilla and mandible of 2 patients, 1 dentate and 1 edentulous, have been contoured on computed tomography planning scans. The jaw has been divided into sextants (3 segments in both the mandible and maxilla) using bony landmarks. RESULTS: We have developed a contouring atlas to aid radiation oncologists in delineating the maxilla and mandible allowing accurate recording of dose to each sextant and meaningful communication with their dental colleagues. CONCLUSION: Delineation of the maxilla and mandible is important if we are to improve communication between radiation oncologists and dentists regarding radiation and risk to these structures. Our method should not increase the time to delineate the organs at risk and target volumes in the head and neck area and could improve the safety of subsequent dental treatments.

Treatment planning constraints to avoid xerostomia in head-and-neck radiotherapy: an independent test of QUANTEC criteria using a prospectively collected dataset.

PURPOSE: The severe reduction of salivary function (xerostomia) is a common complication after radiation therapy for head-and-neck cancer. Consequently, guidelines to ensure adequate function based on parotid gland tolerance dose-volume parameters have been suggested by the QUANTEC group and by Ortholan et al. We perform a validation test of these guidelines against a prospectively collected dataset and compared with a previously published dataset. METHODS AND MATERIALS: Whole-mouth stimulated salivary flow data from 66 head-and-neck cancer patients treated with radiotherapy at the British Columbia Cancer Agency (BCCA) were measured, and treatment planning data were abstracted. Flow measurements were collected from 50 patients at 3 months, and 60 patients at 12-month follow-up. Previously published data from a second institution, Washington University in St. Louis (WUSTL), were used for comparison. A logistic model was used to describe the incidence of Grade 4 xerostomia as a function of the mean dose of the spared parotid gland. The rate of correctly predicting the lack of xerostomia (negative predictive value [NPV]) was computed for both the QUANTEC constraints and Ortholan et al. recommendation to constrain the total volume of both glands receiving more than 40 Gy to less than 33%. RESULTS: Both datasets showed a rate of xerostomia of less than 20% when the mean dose to the least-irradiated parotid gland is kept to less than 20 Gy. Logistic model parameters for the incidence of xerostomia at 12 months after therapy, based on the least-irradiated gland, were D(50) = 32.4 Gy and and γ = 0.97. NPVs for QUANTEC guideline were 94% (BCCA data), and 90% (WUSTL data). For Ortholan et al. guideline NPVs were 85% (BCCA) and 86% (WUSTL). CONCLUSION: These data confirm that the QUANTEC guideline effectively avoids xerostomia, and this is somewhat more effective than constraints on the volume receiving more than 40 Gy.