University of North Carolina Hospitals

Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription factor nuclear factor kappa B (NF-kappaB), which suppresses apoptosis by an unknown mechanism. The activation of NF-kappaB was found to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kappaB transcriptional activity. In cells in which NF-kappaB was inactive, all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kappaB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and that function more distally to suppress genotoxic agent-mediated apoptosis.

Clostridium difficile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratified depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mild-to-moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classification of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI.

Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

BACKGROUND: Numerous studies have associated bladder cancer with exposure to carcinogens present in tobacco smoke and other environmental or occupational exposures. Approximately 50% of all humans inherit two deleted copies of the GSTM1 gene which encodes for the carcinogen-detoxification enzyme glutathione S-transferase M1. Recent findings suggest that the GSTM1 gene may modulate the internal dose of environmental carcinogens and thereby affect the risk of developing bladder cancer. PURPOSE: We investigated whether the absence of the GSTM1 gene affects bladder cancer risk and whether there are racial differences in GSTM1 genotype frequency. METHODS: Using a polymerase chain reaction (PCR)-based method, we examined the frequency of the homozygous deleted genotype (GSTM1 0/0) in 229 patients with transitional cell carcinoma of the bladder and 211 control subjects who were enrolled from the Urology Clinics at Duke University Medical Center and the University of North Carolina Hospitals. Control subjects were urology clinic patients who primarily presented with benign prostatic hypertrophy or impotence, who had no history of any cancer other than nonmelanoma skin cancer, and who were frequency matched to case patients on race, sex, and age (10-year age intervals). In order to explore racial differences in GSTM1 gene frequency, genotype was also determined in a community-based sample of 466 paid, healthy, unrelated volunteers from Durham and Chapel Hill, N.C. The presence or absence of the GSTM1 gene locus was determined by using a differential PCR, a semiquantitative technique in which multiple genes are coamplified. RESULTS: Overall, the GSTM1 0/0 genotype conferred a 70% increased risk of bladder cancer (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.2-2.5; P = .004). Absence of the GSTM1 gene encoding the glutathione S-transferase M1 enzyme significantly increased risk to persons with exposure to the carcinogens in tobacco smoke (OR = 1.8; 95% CI = 1.2-3.0; P = .01) but poses little increased risk to persons without such exposure. Persons with smoking exposure of more than 50 pack-years who had the GSTM1 0/0 genotype had a sixfold greater risk relative to persons in the lowest risk group (i.e., nonsmokers who were GSTM1 +/+ or +/0). In the pooled clinic control and community sample groups (677 individuals), the GSTM1 0/0 genotype occurred less frequently among Blacks (35%) than among Whites (49%, P < .001). CONCLUSIONS: These findings support a protective role for the GSTM1 gene in bladder cancer. From these findings, it is estimated that 25% of all bladder cancer may be attributable to the at-risk GSTM1 0/0 genotype.

BACKGROUND AND PURPOSE: The extent of a patient's impairment can be established by comparing measurements of that patient's performance with normative values obtained from apparently unimpaired individuals. Only a few studies have described normative values for muscle strength measured by hand-held dynamometry. The purpose of this study of older adults, therefore, was to obtain normative values of maximum voluntary isometric force using hand-held dynamometers. SUBJECTS: One hundred fifty-six asymptomatic adults (77 men, 70 women) participated in this study. The subjects' mean age was 64.4 years (SD=8.3, range=50-79). The male subjects' mean age was 64.5 years (SD=8.4, range=50-79), and the female subjects' mean age was 64.3 years (SD=8.2, range=50-79). METHODS: Gender, age, dominant side, height, weight, and activity level were recorded. Eight upper-extremity movements (shoulder flexion, extension, abduction, and medial and lateral rotation; elbow flexion and extension; and wrist extension) and five lower-extremity movements (hip flexion and abduction, knee flexion and extension, and ankle dorsiflexion) were resisted by one of three experienced testers using a strain-gauge hand-held dynamometer. RESULTS: Gender, age, and weight were identified as independent predictors of force for all muscle actions on both the dominant and nondominant sides. These variables were used, therefore, to create regression equations and normative values for the force of each muscle action. CONCLUSION AND DISCUSSION: The reference values provided may allow clinicians who follow the described testing protocol to estimate the severity of force-generating impairments in patients aged 50 to 79 years.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

BACKGROUND: Falls and their consequences are significant concerns for older adults, caregivers, and health care providers. Identification of fall risk is crucial for appropriate referral to preventive interventions. Falls are multifactorial; no single measure is an accurate diagnostic tool. There is limited information on which history question, self-report measure, or performance-based measure, or combination of measures, best predicts future falls. PURPOSE: First, to evaluate the predictive ability of history questions, self-report measures, and performance-based measures for assessing fall risk of community-dwelling older adults by calculating and comparing posttest probability (PoTP) values for individual test/measures. Second, to evaluate usefulness of cumulative PoTP for measures in combination. DATA SOURCES: To be included, a study must have used fall status as an outcome or classification variable, have a sample size of at least 30 ambulatory community-living older adults (≥65 years), and track falls occurrence for a minimum of 6 months. Studies in acute or long-term care settings, as well as those including participants with significant cognitive or neuromuscular conditions related to increased fall risk, were excluded. Searches of Medline/PubMED and Cumulative Index of Nursing and Allied Health (CINAHL) from January 1990 through September 2013 identified 2294 abstracts concerned with fall risk assessment in community-dwelling older adults. STUDY SELECTION: Because the number of prospective studies of fall risk assessment was limited, retrospective studies that classified participants (faller/nonfallers) were also included. Ninety-five full-text articles met inclusion criteria; 59 contained necessary data for calculation of PoTP. The Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) was used to assess each study's methodological quality. DATA EXTRACTION: Study design and QUADAS score determined the level of evidence. Data for calculation of sensitivity (Sn), specificity (Sp), likelihood ratios (LR), and PoTP values were available for 21 of 46 measures used as search terms. An additional 73 history questions, self-report measures, and performance-based measures were used in included articles; PoTP values could be calculated for 35. DATA SYNTHESIS: Evidence tables including PoTP values were constructed for 15 history questions, 15 self-report measures, and 26 performance-based measures. Recommendations for clinical practice were based on consensus. LIMITATIONS: Variations in study quality, procedures, and statistical analyses challenged data extraction, interpretation, and synthesis. There was insufficient data for calculation of PoTP values for 63 of 119 tests. CONCLUSIONS: No single test/measure demonstrated strong PoTP values. Five history questions, 2 self-report measures, and 5 performance-based measures may have clinical usefulness in assessing risk of falling on the basis of cumulative PoTP. Berg Balance Scale score (≤50 points), Timed Up and Go times (≥12 seconds), and 5 times sit-to-stand times (≥12) seconds are currently the most evidence-supported functional measures to determine individual risk of future falls. Shortfalls identified during review will direct researchers to address knowledge gaps.

PURPOSE OF REVIEW: This article reviews the evidence demonstrating the importance of contamination of hospital surfaces in the transmission of healthcare-associated pathogens and interventions scientifically demonstrated to reduce the levels of microbial contamination and decrease healthcare-associated infections. RECENT FINDINGS: The contaminated surface environment in hospitals plays an important role in the transmission of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), Clostridium difficile, Acinetobacter spp., and norovirus. Improved surface cleaning and disinfection can reduce transmission of these pathogens. 'No-touch' methods of room disinfection (i.e., devices which produce ultraviolet light or hydrogen peroxide) and 'self-disinfecting' surfaces (e.g., copper) also show promise to decrease contamination and reduce healthcare-associated infections. SUMMARY: Hospital surfaces are frequently contaminated with important healthcare-associated pathogens. Contact with the contaminated environment by healthcare personnel is equally as likely as direct contact with a patient to lead to contamination of the healthcare provider's hands or gloves that may result in patient-to-patient transmission of nosocomial pathogens. Admission to a room previously occupied by a patient with MRSA, VRE, Acinetobacter, or C. difficile increases the risk for the subsequent patient admitted to the room to acquire the pathogen. Improved cleaning and disinfection of room surfaces decreases the risk of healthcare-associated infections.

The American Society for Apheresis (ASFA) Apheresis Applications Committee is charged with a review and categorization of indications for therapeutic apheresis. This elaborate process had been undertaken every 7 years resulting in three prior publications in 1986, 1993, and 2000 of "The ASFA Special Issues." This article is the integral part of the Fourth ASFA Special Issue. The Fourth ASFA Special Issue is significantly modified in comparison to the previous editions. A new concept of a fact sheet has been introduced. The fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis. A detailed description of the fact sheet is provided. The article consists of 53 fact sheets devoted to each disease entity currently categorized by the ASFA. Categories I, II, and III are defined as previously in the Third Special Issue. However, a few new therapeutic apheresis modalities, not yet approved in the United States or are currently in clinical trials, have been assigned category P (pending) by the ASFA Clinical Categories Subcommittee. The diseases assigned to category IV are discussed in a separate article in this issue.

Epidermolysis bullosa acquisita is an acquired chronic blistering disease of the skin, in which separation of the skin occurs in the basement-membrane zone between the epidermis and the dermis. There is evidence that blistering is initiated by an immune process. Using serum samples from nine patients as a source of antibodies, we have identified a major protein of the basement membrane of human skin that serves as the antigen (or target) for autoantibodies in this disorder. This previously unrecognized protein, which consists of two components of 290,000 and 145,000 daltons, is distinct from other known components of the basement membrane. These studies provide evidence that epidermolysis bullosa acquisita is a specific disease that is different from other primary bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, and suggest that the basement-membrane component that has been identified may have a role in normal epidermal–dermal adherence. (N Engl J Med 1984; 310:1007–13.)

In current practice, gadolinium-based contrast agents have been considered safe when used at clinically recommended doses in patients without severe renal insufficiency. The causal relationship between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency resulted in new policies regarding the administration of these agents. After an effective screening of patients with renal disease by performing either unenhanced or reduced-dose-enhanced studies in these patients and by using the most stable contrast agents, nephrogenic systemic fibrosis has been largely eliminated since 2009. Evidence of in vivo gadolinium deposition in bone tissue in patients with normal renal function is well-established, but recent literature showing that gadolinium might also deposit in the brain in patients with intact blood-brain barriers caught many individuals in the imaging community by surprise. The purpose of this review was to summarize the literature on gadolinium-based contrast agents, tying together information on agent stability and animal and human studies, and to emphasize that low-stability agents are the ones most often associated with brain deposition.

OBJECTIVES: To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A(1C)) achieved during therapy. DESIGN: Post hoc epidemiological analysis of a double 2x2 factorial, randomised, controlled trial. SETTING: Diabetes clinics, research clinics, and primary care clinics. PARTICIPANTS: 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A(1C) concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control. MAIN OUTCOME MEASURES: Severe hypoglycaemia was defined as episodes of "low blood glucose" requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon. RESULTS: The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A(1C) concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A(1C) concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21). CONCLUSIONS: A greater drop in haemoglobin A(1C) concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00000620.

Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.

INTRODUCTION: Cisplatin, a platinum-based antineoplastic agent, is the cornerstone for the treatment of many malignancies. Nephrotoxicity is the primary dose-limiting toxicity, and various hydration regimens and supplementation strategies are used to prevent cisplatin-induced kidney injury. However, evidence-based recommendations on specific hydration regimens are limited. A systematic review was performed to evaluate clinical studies that have examined hydration and supplementation strategies to prevent cisplatin-induced nephrotoxicity. MATERIALS AND METHODS: PubMed and Excerpta Medica databases were searched from 1966 through October 2015 for clinical trials and other studies focused on hydration regimens to prevent nephrotoxicity in cancer patients treated with cisplatin. The University of Oxford Centre for Evidence-Based Medicine criteria were used to grade level of evidence. RESULTS: Among the 1,407 identified studies, 24 were included in this systematic review. All studies differed on type, volume, and duration of hydration. Among the 24 studies, 5 evaluated short-duration hydration, 4 evaluated low-volume hydration, 4 investigated magnesium supplementation, and 7 reviewed forced diuresis with hydration. Short-duration and lower-volume hydration regimens are effective in preventing cisplatin-induced nephrotoxicity. Magnesium supplementation may have a role as a nephroprotectant, and forced diuresis may be appropriate in some patients receiving cisplatin. CONCLUSION: 2017;22:609-619 IMPLICATIONS FOR PRACTICE: The findings contained within this systematic review show that (a) hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity, (b) short-duration, low-volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate- to high-dose cisplatin, (c) magnesium supplementation (8-16 milliequivalents) may limit cisplatin-induced nephrotoxicity, and (d) mannitol may be considered for high-dose cisplatin and/or patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin-induced nephrotoxicity.

PURPOSE: Plasma circulating tumor human papillomavirus DNA (ctHPVDNA) is a sensitive and specific biomarker of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We investigated whether longitudinal monitoring of ctHPVDNA during post-treatment surveillance could accurately detect clinical disease recurrence. METHODS AND MATERIALS: A prospective biomarker clinical trial was conducted among patients with nonmetastatic HPV-associated (p16-positive) OPSCC. All patients were treated with curative-intent chemoradiotherapy (CRT). Patients underwent a 3-month post-CRT positron emission tomography/computed tomography scan and were thereafter clinically evaluated every 2-4 months (years 1-2), then every 6 months (years 3-5). Chest imaging was performed every 6 months. Blood specimens were collected every 6-9 months for analysis of plasma ctHPVDNA using a multianalyte digital polymerase chain reaction assay. The primary endpoint was to estimate the negative predictive value (NPV) and positive predictive value (PPV) of ctHPVDNA surveillance. RESULTS: One hundred fifteen patients were enrolled, and 1,006 blood samples were analyzed. After a median follow-up time of 23 months (range, 6.1-54.7 months), 15 patients (13%) developed disease recurrence. Eighty-seven patients had undetectable ctHPVDNA at all post-treatment time points, and none developed recurrence (NPV, 100%; 95% CI, 96% to 100%). Twenty-eight patients developed a positive ctHPVDNA during post-treatment surveillance, 15 of whom were diagnosed with biopsy-proven recurrence. Sixteen patients had 2 consecutively positive ctHPVDNA blood tests, 15 of whom developed biopsy-proven recurrence. Two consecutively positive ctHPVDNA blood tests had a PPV of 94% (95% CI, 70% to 99%). Median lead time between ctHPVDNA positivity and biopsy-proven recurrence was 3.9 months (range, 0.37-12.9 months). CONCLUSION: Detection of ctHPVDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence in patients with HPV-associated oropharyngeal cancer and may facilitate earlier initiation of salvage therapy.

PURPOSE: To retrospectively evaluate the prevalence of neonatal intracranial hemorrhage (ICH) and its relationship to obstetric and neonatal risk factors. MATERIALS AND METHODS: Pregnant women were recruited for a prospective study of neonatal brain development; the study was approved by the institutional review board and complied with HIPAA regulations. After informed consent was obtained from a parent, neonates were imaged with 3.0-T magnetic resonance (MR) imaging without sedation. The images were reviewed by a neuroradiologist with 12 years of experience for the presence of ICH. Medical records were prospectively and retrospectively reviewed for selected risk factors, which included method of delivery, duration of labor, and evidence of maternal or neonatal birth trauma. Risk factors were assessed for relationship to ICH by using Fisher exact test statistics. RESULTS: Ninety-seven neonates (mean age at MR imaging, 20.8 days +/- 6.9 [standard deviation]) underwent MR imaging between the ages of 1 and 5 weeks. Eighty-eight (44 male and 44 female) neonates (65 with vaginal delivery and 23 with cesarean delivery) completed the MR imaging evaluation. Seventeen neonates with ICHs (16 subdural, two subarachnoid, and six parenchymal hemorrhages) were identified. Seven infants had two or more types of hemorrhages. All neonates with ICH were delivered vaginally, with a prevalence of 26% in vaginal births. ICH was significantly associated with vaginal birth (P < .005) but not with prolonged duration of labor or with traumatic or assisted vaginal birth. CONCLUSION: Asymptomatic ICH following vaginal birth in full-term neonates appears to be common, with a prevalence of 26% in this study.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

Abstract Purpose: To identify a profile of circulating tumor human papilloma virus (HPV) DNA (ctHPVDNA) clearance kinetics that is associated with disease control after chemoradiotherapy (CRT) for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Experimental Design: A multi-institutional prospective biomarker trial was conducted in 103 patients with (i) p16-positive OPSCC, (ii) M0 disease, and (iii) receipt of definitive CRT. Blood specimens were collected at baseline, weekly during CRT, and at follow-up visits. Optimized multianalyte digital PCR assays were used to quantify ctHPVDNA (types 16/18/31/33/35) in plasma. A control cohort of 55 healthy volunteers and 60 patients with non–HPV-associated malignancy was also analyzed. Results: Baseline plasma ctHPVDNA had high specificity (97%) and high sensitivity (89%) for detecting newly diagnosed HPV-associated OPSCC. Pretreatment ctHPV16DNA copy number correlated with disease burden, tumor HPV copy number, and HPV integration status. We define a ctHPV16DNA favorable clearance profile as having high baseline copy number (&amp;gt;200 copies/mL) and &amp;gt;95% clearance of ctHPV16DNA by day 28 of CRT. Nineteen of 67 evaluable patients had a ctHPV16DNA favorable clearance profile, and none had persistent or recurrent regional disease after CRT. In contrast, patients with adverse clinical risk factors (T4 or &amp;gt;10 pack years) and an unfavorable ctHPV16DNA clearance profile had a 35% actuarial rate of persistent or recurrent regional disease after CRT (P = 0.0049). Conclusions: A rapid clearance profile of ctHPVDNA may predict likelihood of disease control in patients with HPV-associated OPSCC patients treated with definitive CRT and may be useful in selecting patients for deintensified therapy.

The relative impact of inhalation injury, burn size, and age on overall outcome following burn injury was examined in 1447 consecutive burn patients over a five and a half year period. The overall mortality for all patients was 9.5% (138 of 1447). The presence of inhalation injury, increasing burn size, and advancing age were all associated with an increased mortality (p < 0.01). The incidence of inhalation injury was 19.6% (284 of 1447) and correlated with increasing percent total body surface area (%TBSA) burn (r = 0.41, p < 0.01) and advancing age (r = 0.15, p < 0.01). The overall mortality for patients with inhalation injury was 31% (88 of 284) compared with 4.3% (50 of 1163) for those without inhalation injury. Using multivariate analysis inhalation injury was found to be an important variable in determining outcome, but the most important factor in predicting mortality was %TBSA burn (accuracy = 92.8%) or a combination of %TBSA burn and patient age (accuracy = 93.0%). Adding inhalation injury only slightly improved the ability to predict mortality (accuracy = 93.3%). The presence of inhalation injury is significantly associated with mortality after thermal injury but adds little to the prediction of mortality using %TBSA and age alone.