Active Surveillance of Engineered Stone Workers Facilitates Early Identification of Silicosis: A Discussion of Surveillance of Occupational Lung Diseases.

Silicosis in workers exposed to respirable crystalline silica while fabricating engineered stone products is an emerging respiratory health issue. We describe silicosis in engineered stone workers in California and examine clinical features by the source of identification. Cases were identified passively using hospital-based patient discharge data or actively through outreach and medical testing following enforcement investigation. Outcomes were examined based on the source of case identification. We identified 18 cases diagnosed between 2006 and 2020. Cases identified passively compared to other identification methods were associated with lower percent predicted forced vital capacity (FVC) (P ≤ .01), forced expiratory volume in 1 s (FEV1) (P ≤ .01), and diffusing capacity of the lungs for carbon monoxide (DLCO) (P < .01) at the time of diagnosis and were more likely to be identified following death or lung transplant (P = .01). Our experience demonstrates delays in diagnosis and case identification when relying on passive surveillance methods. Enhanced public health surveillance systems can improve the early detection of occupational lung disease and inform future prevention policies.

Tranexamic acid for the prevention of postpartum haemorrhage: the TAPPH-1 pilot randomized trial and lessons learned for trials in Canadian obstetrics.

Postpartum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality. While tranexamic acid (TXA) reduces bleeding and transfusion requirements in established PPH, we sought to determine the feasibility of conducting a fully powered trial assessing the effect of prophylactic tranexamic acid, prior to PPH onset, in a Canadian Obstetric setting. With institutional and Health Canada approval, consenting, eligible parturients (singleton, > 32 weeks gestation, vaginal or caesarian delivery) were randomly assigned to receive TXA (1 g intravenously) or placebo (0.9% saline) prior to delivery. Participants, investigators, data collectors/adjudicators, and analysis was blinded. The primary outcome was administration of study intervention to > 85% of randomized individuals. Secondary outcomes included recruitment rate (feasibility) and safety outcomes. Over 8 months, 611 were approached, 35 consented, and 27 randomized (14 TXA, 13 placebo). 89% of randomized participants received the assigned intervention. Recruitment fell below feasibility (23% target). No serious adverse outcomes occurred. Our pilot trial in a Canadian Obstetric setting was unable to demonstrate feasibility to conduct a large, multicentre trial to examine prophylactic use of tranexamic for PPH secondary to the complex regulatory requirements associated with a trial for an off-label, but commonly utilized intervention. These challenges should inform stakeholders on the resources and challenges of conducting future trials using off-label interventions.Trial registration: www.clinicaltrials.gov , NCT03069859 (03/03/2017).

Uncoupled nitric oxide synthase activity promotes colorectal cancer progression.

Increased levels of reactive oxygen/nitrogen species are one hallmark of chronic inflammation contributing to the activation of pro-inflammatory/proliferative pathways. In the cancers analyzed, the tetrahydrobiopterin:dihydrobiopterin ratio is lower than that of the corresponding normal tissue, leading to an uncoupled nitric oxide synthase activity and increased generation of reactive oxygen/nitrogen species. Previously, we demonstrated that prophylactic treatment with sepiapterin, a salvage pathway precursor of tetrahydrobiopterin, prevents dextran sodium sulfate-induced colitis in mice and associated azoxymethane-induced colorectal cancer. Herein, we report that increasing the tetrahydrobiopterin:dihydrobiopterin ratio and recoupling nitric oxide synthase with sepiapterin in the colon cancer cell lines, HCT116 and HT29, inhibit their proliferation and enhance cell death, in part, by Akt/GSK-3ß-mediated downregulation of ß-catenin. Therapeutic oral gavage with sepiapterin of mice bearing azoxymethane/dextran sodium sulfate-induced colorectal cancer decreased metabolic uptake of [18F]-fluorodeoxyglucose and enhanced apoptosis nine-fold in these tumors. Immunohistochemical analysis of both mouse and human tissues indicated downregulated expression of key enzymes in tetrahydrobiopterin biosynthesis in the colorectal cancer tumors. Human stage 1 colon tumors exhibited a significant decrease in the expression of quinoid dihydropteridine reductase, a key enzyme involved in recycling tetrahydrobiopterin suggesting a potential mechanism for the reduced tetrahydrobiopterin:dihydrobiopterin ratio in these tumors. In summary, sepiapterin treatment of colorectal cancer cells increases the tetrahydrobiopterin:dihydrobiopterin ratio, recouples nitric oxide synthase, and reduces tumor growth. We conclude that nitric oxide synthase coupling may provide a useful therapeutic target for treating patients with colorectal cancer.

Declining Colectomy Rates for Nonmalignant Colorectal Polyps in a Large, Ethnically Diverse, Community-Based Population.

INTRODUCTION: Despite studies showing improved safety, efficacy, and cost-effectiveness of endoscopic resection for nonmalignant colorectal polyps, colectomy rates for nonmalignant colorectal polyps have been increasing in the United States and Europe. Given this alarming trend, we aimed to investigate whether colectomy rates for nonmalignant colorectal polyps are increasing or declining in a large, integrated, community-based healthcare system with access to advanced endoscopic resection procedures. METHODS: We identified all individuals aged 50-85 years who underwent a colonoscopy between 2008 and 2018 and were diagnosed with a nonmalignant colorectal polyp(s) at the Kaiser Permanente Northern California integrated healthcare system. Among these individuals, we identified those who underwent a colectomy for nonmalignant colorectal polyps within 12 months after the colonoscopy. We calculated annual colectomy rates for nonmalignant colorectal polyps and stratified rates by age, sex, and race and ethnicity. Changes in rates over time were tested by the Cochran-Armitage test for a linear trend. RESULTS: Among 229,730 patients who were diagnosed with nonmalignant colorectal polyps between 2008 and 2018, 1,611 patients underwent a colectomy. Colectomy rates for nonmalignant colorectal polyps decreased significantly from 125 per 10,000 patients with nonmalignant polyps in 2008 to 12 per 10,000 patients with nonmalignant polyps in 2018 (P < 0.001 for trend). When stratified by age, sex, and race and ethnicity, colectomy rates for nonmalignant colorectal polyps also significantly declined from 2008 to 2018. DISCUSSION: In a large, ethnically diverse, community-based population in the United States, we found that colectomy rates for nonmalignant colorectal polyps declined significantly over the past decade likely because of the establishment of advanced endoscopy centers, improved care coordination, and an organized colorectal cancer screening program.

Pre-hospital hypothermia is associated with transfusion risk after traumatic injury.

OBJECTIVES: In traumatically injured patients, excessive blood loss necessitating the transfusion of red blood cell (RBC) units is common. Indicators of early RBC transfusion in the pre-hospital setting are needed. This study aims to evaluate the association between hypothermia (<36°C) and transfusion risk within the first 24 hours after arrival to hospital for a traumatic injury. METHODS: We completed an audit of all traumatically injured patients who had emergent surgery at a single tertiary care center between 2010 and 2014. Using multivariable logistic regression analysis, we evaluated the association between pre-hospital hypothermia and transfusion of ≥1 unit of RBC within 24 hours of arrival to the trauma bay. RESULTS: Of the 703 patients included to evaluate the association between hypothermia and RBC transfusion, 203 patients (29%) required a transfusion within 24 hours. After controlling for important confounding variables, including age, sex, coagulopathy (platelets and INR), hemoglobin, and vital signs (blood pressure and heart rate), hypothermia was associated with a 68% increased odds of transfusion in multivariable analysis (OR: 1.68; 95% CI: 1.11-2.56). CONCLUSIONS: Hypothermia is strongly associated with RBC transfusion in a cohort of trauma patients requiring emergent surgery. This finding highlights the importance of early measures of temperature after traumatic injury and the need for intervention trials to determine if strategies to mitigate the risk of hypothermia will decrease the risk of transfusion and other morbidities.

Association Between Web-Based Physician Ratings and Physician Disciplinary Convictions: Retrospective Observational Study.

BACKGROUND: Physician rating websites are commonly used by the public, yet the relationship between web-based physician ratings and health care quality is not well understood. OBJECTIVE: The objective of our study was to use physician disciplinary convictions as an extreme marker for poor physician quality and to investigate whether disciplined physicians have lower ratings than nondisciplined matched controls. METHODS: This was a retrospective national observational study of all disciplined physicians in Canada (751 physicians, 2000 to 2013). We searched ratings (2005-2015) from the country's leading online physician rating website for this group, and for 751 matched controls according to gender, specialty, practice years, and location. We compared overall ratings (out of a score of 5) as well as mean ratings by the type of misconduct. We also compared ratings for each type of misconduct and punishment. RESULTS: There were 62.7% (471/751) of convicted and disciplined physicians (cases) with web-based ratings and 64.6% (485/751) of nondisciplined physicians (controls) with ratings. Of 312 matched case-control pairs, disciplined physicians were rated lower than controls overall (3.62 vs 4.00; P<.001). Disciplined physicians had lower ratings for all types of misconduct and punishment-except for physicians disciplined for sexual offenses (n=90 pairs; 3.83 vs 3.86; P=.81). Sexual misconduct was the only category in which mean ratings for physicians were higher than those for other disciplined physicians (3.63 vs 3.35; P=.003). CONCLUSIONS: Physicians convicted for disciplinary misconduct generally had lower web-based ratings. Physicians convicted of sexual misconduct did not have lower ratings and were rated higher than other disciplined physicians. These findings may have future implications for the identification of physicians providing poor-quality care.

A regional massive hemorrhage protocol developed through a modified Delphi technique.

BACKGROUND: A massive hemorrhage protocol (MHP) enables rapid delivery of blood components in a patient who is exsanguinating pending definitive hemorrhage control, but there is variability in MHP implementation rates, content and compliance owing to challenges presented by infrequent activation, variable team performance and patient acuity. The goal of this project was to identify the key evidence-based principles and quality indicators required to develop a standardized regional MHP. METHODS: A modified Delphi consensus technique was performed in the spring and summer of 2018. Panellists used survey links to independently review and rate (on a 7-point Likert scale) 43 statements and 8 quality indicators drafted by a steering committee composed of transfusion medicine specialists and technologists, and trauma physicians. External stakeholder input from all hospitals in Ontario was sought. RESULTS: Three rounds were held with 36 experts from diverse clinical backgrounds. Consensus was reached for 42 statements and 8 quality indicators. Additional modifications from external stakeholders were incorporated to form the foundation for the proposed MHP. INTERPRETATION: This MHP template will provide the basis for the design of an MHP toolkit, including specific recommendations for pediatric and obstetrical patients, and for hospitals with limited availability of blood components or means to achieve definitive hemorrhage control. We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient comfort and safety, and, ultimately, improve patient outcomes.

Transfusion Camp: a prospective evaluation of a transfusion education program for multispecialty postgraduate trainees.

BACKGROUND: The optimal method of providing transfusion medicine (TM) education has not been determined. Transfusion Camp was established in 2012 at the University of Toronto as a centrally delivered TM education program for postgraduate trainees. The impact of Transfusion Camp on knowledge, attitudes, and self-reported behavior was evaluated. METHODS: Didactic lectures (delivered locally, by webinar, or recorded) and locally facilitated team-based learning seminars were delivered over 5 days during the academic year to 8 sites: 7 in Canada and 1 in the United Kingdom. Knowledge assessment using a validated 20-question multiple-choice exam was conducted before and after Transfusion Camp. Attitudes and self-reported behavior were collected through a survey. RESULTS: Over 2 academic years (July 2016 to June 2018), 390 trainees from 16 different specialties (predominantly anesthesia, 41%; hematology, 14%; and critical care, 7%) attended at least 1 day of Transfusion Camp. The mean pretest score was 10.3 of 20 (±2.9; n = 286) compared with posttest score of 13.0 (±2.8; n = 194; p < 0.0001). Lower pretest score and greater attendance (4-5 days compared with 1-3 days) were associated with larger improvement in posttest score; delivery format, specialty, and postgraduate year were not. Trainees reported an improvement in self-rated abilities to manage TM scenarios; 95% rated TM knowledge as very or extremely important in providing patient care; and 81% indicated that they had applied learning from Transfusion Camp into clinical practice. CONCLUSIONS: Transfusion Camp increased TM knowledge, fostered a positive attitude toward TM, and enabled a self-reported positive impact on transfusion practice in postgraduate trainees. It is a novel and scalable approach to delivering TM education.

Nitric oxide-donor/PARP-inhibitor combination: A new approach for sensitization to ionizing radiation.

Recently, clinical development of PARP inhibitors (PARPi) expanded from using them as a single agent to combining them with DNA-damaging therapy to derive additional therapeutic benefit from stimulated DNA damage. Furthermore, inhibiting PARP in cancers with BRCA1/2 mutations has been shown to be an effective synthetic lethality approach either as a single agent or in combination with the different DNA damaging agents: chemotherapy or ionizing radiation (IR). However, inherited BRCA1/2 mutations account only for 5-10% of breast cancers, 10-15% of ovarian cancers, and lesser for the other cancers. Hence, for most of the cancer patients with BRCA1/2-proficient tumors, sensitization to DNA-damaging agents with PARPi is significantly less effective. We recently demonstrated that moderate, non-toxic concentrations of NO-donors inhibited BRCA1 expression, with subsequent inhibition of error-free HRR and increase of error-prone non-homologous end joining (NHEJ). We also demonstrated that the effect of NO-dependent block of BRCA1 expression can only be achieved in the presence of oxidative stress, a condition that characterizes the tumor microenvironment and is also a potential effect of IR. Hence, NO-donors in combination with PARPi, with effects limited by tumor microenvironment and irradiated area, suggest a precise tumor-targeted approach for radio-sensitization of BRCA1/2-proficient tumors. The combination with NO-donors allows PARPi to be successfully applied to a wider variety of tumors. The present work demonstrates a new drug combination (NO-donors and PARP-inhibitors) which demonstrated a high potency in sensitization of wide variety of tumors to ionizing radiation treatment.

The Characteristics of Physicians Who are Re-Disciplined by Medical Boards: A Retrospective Cohort Study.

BACKGROUND: Physician misconduct adversely affects patient safety and is therefore of societal importance. Little work has specifically examined re-disciplined physicians. A study was conducted to compare the characteristics of re-disciplined to first-time disciplined physicians. METHODS: A retrospective review of Canadian physicians disciplined by medical boards between 2000 and 2015 was conducted. Physicians were divided into those disciplined once and those disciplined more than once. Differences in demographics, transgressions, and penalties were evaluated. RESULTS: There were 938 disciplinary events for 810 disciplined physicians with 1 in 8 (n = 101, 12.5%) being re-disciplined. Re-disciplined physicians had up to six disciplinary events in the study period and 4 (4.0%) had events in more than one jurisdiction. Among those re-disciplined, 94 (93.1%) were male, 34 (33.7%) were international medical graduates, and 88 (87.1%) practiced family medicine (n = 59, 58.4%), psychiatry (n = 11, 10.9%), surgery (n = 9, 8.9%), or obstetrics/gynecology (n = 9, 8.9%). The proportion of obstetrician/gynecologists was higher among re-disciplined physicians (8.9% vs. 4.2%, p = 0.048). Re-disciplined physicians had more mental illness (1.7% vs. 0.1%, p = 0.01), unlicensed activity (19.2% vs. 7.2%, p <0.01), and less sexual misconduct (20.1% vs. 27.9%, p = 0.02). License suspension occurred more frequently among those re-disciplined (56.8% vs. 48.0%, p = 0.02) as did license restriction (38.4% vs. 26.7%, p <0.01). License revocation was not different between cohorts (10.9% vs. 13.5%, p = 0.36). CONCLUSION: Re-discipline is not uncommon and underscores the need for better identification of at-risk individuals and optimization of remediation and penalties. The distribution of transgression argues for a national disciplinary database that could improve communication between jurisdictional medical boards.

Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization.

Previously, we demonstrated that nitric oxide (NO) synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor sepiapterin (SP) inhibits tumor progression. Endothelial dysfunction characterizes the poorly functional vasculature of solid tumors, and since NO is critical for regulation of endothelial function we asked whether SP, by recoupling NOS, improves tumor vasculature structure and function-enhancing chemotherapeutic delivery and response to radiotherapy. MMTV-neu mice with spontaneous breast tumors were treated with SP by oral gavage and evaluated by multispectral optoacoustic tomographic analysis of tumor HbO2 and by tissue staining for markers of hypoxia, blood perfusion, and markers of endothelial and smooth muscle proteins. Recoupling tumor NOS activity results in vascular normalization observed as reduced tumor hypoxia, improved tumor percentage of HbO2 and perfusion, as well as increased pericyte coverage of tumor blood vessels. The normalized vasculature and improved tumor oxygenation led to a greater than 2-fold increase in radiation-induced apoptosis compared with radiation or SP alone. High-performance liquid chromatography analysis of tumor doxorubicin levels showed a greater than 50% increase in doxorubicin uptake and a synergistic effect on tumor cell apoptosis. This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy.

Protocol for a pilot, randomised, double-blinded, placebo-controlled trial of prophylactic use of tranexamic acid for preventing postpartum haemorrhage (TAPPH-1).

INTRODUCTION: Postpartum haemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. Despite the availability of multiple uterotonic agents, the incidence of PPH continues to rise. Tranexamic acid (TXA) has been shown to be a safe, effective and inexpensive therapeutic option for the treatment of PPH, however, its use prophylactically in mitigating the risk of PPH is unknown. This pragmatic randomised prospective trial assesses the feasibility and safety of administering TXA at the time of delivery for the prevention of PPH. METHODS AND ANALYSIS: A pilot pragmatic randomised double-blinded placebo-controlled trial will be performed. 58 singleton parturients at term >32 weeks, undergoing either spontaneous vaginal delivery, or caesarean section will be randomised to receive 1 g of TXA or placebo (0.9% saline) intravenously. The primary outcome assessed will be the feasibility of administrating TXA, along with collecting data regarding safety of drug administration. The groups will also be analysed on efficacy of mitigating the onset of PPH and clinically relevant variables. Demographic, feasibility, safety and clinical endpoints will be summarised and the appropriate measures of central tendency and dispersion will be presented. ETHICS AND DISSEMINATION: This protocol was approved by the Sunnybrook Health Sciences Centre Research Ethics Board (number: 418-2016). The results will be disseminated in a peer-reviewed journal and at scientific meetings. TRIAL REGISTRATION NUMBER: NCT03069859; Pre-results.

The Characteristics of International Medical Graduates Who Have Been Disciplined by Professional Regulatory Colleges in Canada: A Retrospective Cohort Study.

PURPOSE: This study evaluated the proportion and characteristics of international medical graduates (IMGs) who have been disciplined by professional regulatory colleges in Canada in comparison with disciplined North American medical graduates (NAMGs). METHOD: The authors compiled a database of the nature of professional misconduct and penalties incurred by disciplined physicians from January 2000 to May 2015 using public records. They compared discipline data for IMGs versus those for NAMGs, and calculated risk ratios (RRs) and 95% confidence intervals (CIs) for select outcomes. RESULTS: There were 794 physicians disciplined; 922 disciplinary cases during the 15-year study period. IMGs composed an average of 23.4% (standard deviation = 1.1%) of the total physician population and represented one-third of disciplined physicians and discipline cases. The overall disciplinary rate for all Canadian physicians was 8.52 cases per 10,000 physician years (95% CI [7.77, 9.31]). This rate per group was higher for IMGs than for NAMGs (12.91 [95% CI (11.50, 14.43)] vs. 8.16 [95% CI (7.53, 8.82)] cases per 10,000 physician years, P < .01, and RR 1.58 (95% CI [1.38, 1.82]). IMGs were disciplined at significantly higher rates than NAMGs if they were trained in South Africa (RR 1.73 [95% CI (1.14, 2.51), P < .01), Egypt (RR 3.59 [95% CI (2.18, 5.52)], P < .01), or India (RR 1.66 [95% CI (1.01, 2.55)], P = .03). CONCLUSIONS: IMGs are disciplined at a higher rate than NAMGs. Future initiatives should be focused to delineate the exact cause of this observation.

C1-esterase inhibitor for short-term prophylaxis in a patient with hereditary angioedema with normal C1 inhibitor function.

Hereditary angioedema with normal C1-esterase inhibitor (HAE-nC1INH) perioperative is a rare condition which could have potential disastrous ramifications for the anesthesiologist in the perioperative period. However, there is limited evidence and/or guidelines on the optimal way to manage these patients. We present the case of a patient with HAE-nC1INH who was successfully managed in the perioperative period with plasma derived C1-esterase inhibitor (pdC1INH). A 29-year-old woman with a diagnosis of HAE-nC1INH presented to the preoperative consultation in preparation for an upcoming total thyroidectomy. She had a 14-year history of ongoing lip and facial edema sometimes necessitating emergency department visitation. Close consultation with her immunologist, transfusion medicine specialists, and anesthesia care providers allowed for a preoperative plan to provide the patient adequate prophylaxis. Both pdC1INH and tranexamic acid were given preoperatively. The patient underwent surgery with no complications. A multidisciplinary team of clinical immunologists, transfusion medicine specialists, and anesthesiologists facilitated the successful perioperative management of a patient with HAE-nC1INH; pdC1INH may a suitable prophylactic perioperative therapy for this rare patient population.

A recommended early goal-directed management guideline for the prevention of hypothermia-related transfusion, morbidity, and mortality in severely injured trauma patients.

Hypothermia is present in up to two-thirds of patients with severe injury, although it is often disregarded during the initial resuscitation. Studies have revealed that hypothermia is associated with mortality in a large percentage of trauma cases when the patient's temperature is below 32 °C. Risk factors include the severity of injury, wet clothing, low transport unit temperature, use of anesthesia, and prolonged surgery. Fortunately, associated coagulation disorders have been shown to completely resolve with aggressive warming. Selected passive and active warming techniques can be applied in damage control resuscitation. While treatment guidelines exist for acidosis and bleeding, there is no evidence-based approach to managing hypothermia in trauma patients. We synthesized a goal-directed algorithm for warming the severely injured patient that can be directly incorporated into current Advanced Trauma Life Support guidelines. This involves the early use of warming blankets and removal of wet clothing in the prehospital phase followed by aggressive rewarming on arrival at the hospital if the patient's injuries require damage control therapy. Future research in hypothermia management should concentrate on applying this treatment algorithm and should evaluate its influence on patient outcomes. This treatment strategy may help to reduce blood loss and improve morbidity and mortality in this population of patients.

The prescription opioid epidemic: an overview for anesthesiologists.

PURPOSE: The objectives for preparing this article were to review the historical context and epidemiology surrounding the North American prescription opioid crisis, to summarize the evidence regarding the benefits and harms of long-term opioid therapy for non-cancer pain, and to outline ways in which anesthesiologists may help ameliorate the problem. SOURCE: We searched PubMed, Google Scholar, and EMBASE™ for relevant articles using various search terms, including pain, opioid epidemic, history of opioid use, perioperative care, and addiction. Related citations were further explored and searched depending on the specific subtopic of interest. PRINCIPAL FINDINGS: In the 1980s and early 1990s, opioids were infrequently used for the treatment of chronic pain. Thereafter, however, physicians were gradually inculcated with the message that long-term opioid therapy was a safe and effective treatment option for patients with chronic non-cancer pain. Pharmaceutical companies supported this growing movement and employed aggressive and sometimes misleading marketing strategies for new opioid formulations. As a result, the practice of prescribing opioids flourished in the late 1990s. The surge in prescribing opioids was accompanied by a marked increase in opioid-related morbidity and mortality. This change in practice transpired despite the absence of randomized trials showing clinically significant benefit from the long-term use of opioids. Subsequently, however, a large and growing body of evidence has emerged quantifying the harms associated with long-term opioid therapy. Anesthesiologists widely prescribe opioids for acute and chronic pain; yet, as a group, they may be largely unaware of the current state of this growing epidemic and what role they can play to rectify this problem. CONCLUSION: Anesthesiologists are well positioned to take a leadership role in the management of postoperative discharge opioid therapy in an effort to curb the overutilization of opioids. Furthermore, anesthesiologists who regularly prescribe opioids for chronic pain patients should appreciate the limited evidence base for this practice and communicate the risks of opioid therapy to their patients.

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFß1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity.

PURPOSE: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. METHODS AND MATERIALS: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFß1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. RESULTS: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFß1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. CONCLUSIONS: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.