Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma.

PURPOSE: To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. PATIENTS AND METHODS: We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. RESULTS: Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively (P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% (P < .001), respectively, the latter persisting on multivariable analyses. CONCLUSION: Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.

Clinical Trial Laboratory Data Nested With in Subject: Components of Variance, Sample Size and Cost.

Nesting of experimental factors is well established in statistical design literature related to agricultural, environmental and engineering studies. It is perhaps not sufficiently discussed in biological and laboratory experiments stemming from the use of human bio-specimens, where sample size considerations are often provided a priori on subject level, but there is little advice regarding the needed number of units at lower levels. Motivated by an example from spectroscopic microscopy and lung cancer, we revisit the experimental nesting frame work and discuss how variability, cost of sampling and sample size at lower levels may be coherently utilized. We show how the number of subjects may have to be adjusted to account for inadequate sampling decisions made at lower levels.

Adverse Events During Hematopoietic Stem Cell Infusion: Analysis of the Infusion Product.

BACKGROUND: Stem cell transplantation is a treatment option for patients with cancer. However, a risk of adverse events might be associated with the infusion itself. An understanding of the types and grades of adverse events occurring during infusion and the patient and infusion characteristics that might be associated with these events could allow for interventions to minimize these complications. The risk factors associated with transplant-related adverse events are not well understood. MATERIALS AND METHODS: We retrospectively analyzed the adverse events occurring within 1 hour after infusion in 460 patients with cancer undergoing stem cell transplantation at the Northwestern University Robert H. Lurie Comprehensive Cancer Center from January 1, 2008 and May 1, 2011. Of the 460 patients, 382 received autologous transplants and 78 allogeneic transplants. The incidence, types, and National Cancer Institute Common Terminology Criteria grade of toxicity for adverse events were noted (primary objective). Univariate analyses were performed to study which patient and infusion characteristics might be associated with the occurrence of adverse events (secondary objectives). RESULTS: Of the 460 patients, 261 (56.7%) experienced adverse events (66.7% during allogeneic infusion and 54.7% during autologous infusion). Most events were cardiopulmonary. Univariate analysis of the infusion and patient characteristics revealed that a second transplant (P = .005) was associated with more adverse events for autologous transplant patients. For allogeneic transplant patients, a higher infusion red blood cell volume (P = .01) was associated with more adverse events. CONCLUSION: Adverse events are common during stem cell infusion and are generally cardiopulmonary.

The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients.

OBJECTIVE: To evaluate the impact and burden of the new National Healthcare Safety Network surveillance definition, mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI), in hematology, oncology, and stem cell transplant populations. DESIGN: Retrospective cohort study. SETTING: Two hematology, oncology, and stem cell transplant units at a large academic medical center. METHODS: Central line-associated bloodstream infections (CLABSIs) identified during a 14-month period were reviewed and classified as MBI-LCBI or non-MBI-LCBI (MBI-LCBI criteria not met). During this period, interventions to improve central line maintenance were implemented. Characteristics of patients with MBI-LCBI and non-MBI-LCBI were compared. Total CLABSI, MBI-LCBI, and non-MBI-LCBI rates were compared between baseline and postintervention phases of the study period. RESULTS: Among 66 total CLABSI cases, 47 (71%) met MBI-LCBI criteria. Patients with MBI-LCBI and non-MBI-LCBI were similar in regard to most clinical and demographic characteristics. Between the baseline and postintervention study periods, the overall CLABSI rate decreased from 3.37 to 3.21 infections per 1,000 line-days (incidence rate ratio, 0.95; 4.7% reduction, P=.84), the MBI-LCBI rate increased from 2.08 to 2.61 infections per 1,000 line-days (incidence rate ratio, 1.25; 25.3% increase, P=.44), and the non-MBI-LCBI rate decreased from 1.29 to 0.60 infections per 1,000 line-days (incidence rate ratio, 0.47; 53.3% reduction, P=.12). CONCLUSIONS: Most CLABSIs identified among hematology, oncology, and stem cell transplant patients met MBI-LCBI criteria, and CLABSI prevention efforts did not reduce these infections. Further review of the MBI-LCBI definition and impact is necessary to direct future definition changes and reporting mandates.

Characteristics of Certifying Urologists Performing Cystectomies in the United States.

INTRODUCTION: The surgical volume and training of the surgeon performing radical cystectomy can have a significant impact on bladder cancer outcomes. We hypothesize significant variability in the training and volume of surgeons performing radical cystectomy in the United States. METHODS: The 6-month case log data of urologists certifying between 2003 and 2013 were obtained from the American Board of Urology. Cases specifying an ICD-9 code for bladder cancer and a CPT code for radical cystectomy were analyzed for surgeon specific variables. RESULTS: A total of 5,335 radical cystectomies in the case log system were performed by 2,102 urologists, with 289 (5.4%) performed laparoscopically or robotically. Median urologist age was 42 years (range 36 to 50). Median number of cystectomies performed was 2 (IQR 1-3) with the top 10% of urologists performing 5 or more cystectomies. Half of cystectomies were performed by a urologist who performed only 1 during the certification period. On multivariable analysis stated specialty of oncology and nonprivate practice type were associated with top 10% cystectomy volume. For minimally invasive cystectomy 54% of surgeons logged only a single minimally invasive cystectomy. Factors predictive of performing minimally invasive cystectomy on multivariable analysis were male gender, more recent certifying year and original certification year, endourology and urolithiasis specialization, and Northeast practice region. CONCLUSIONS: Despite the high level of complexity associated with the surgical management of bladder cancer with radical cystectomy, the majority of cystectomies seem to be performed by low volume surgeons who have most often applied for their first certification with the American Board of Urology.

Assessing statistical competencies in clinical and translational science education: one size does not fit all.

INTRODUCTION: Statistics is an essential training component for a career in clinical and translational science (CTS). Given the increasing complexity of statistics, learners may have difficulty selecting appropriate courses. Our question was: what depth of statistical knowledge do different CTS learners require? METHODS: For three types of CTS learners (principal investigator, co-investigator, informed reader of the literature), each with different backgrounds in research (no previous research experience, reader of the research literature, previous research experience), 18 experts in biostatistics, epidemiology, and research design proposed levels for 21 statistical competencies. RESULTS: Statistical competencies were categorized as fundamental, intermediate, or specialized. CTS learners who intend to become independent principal investigators require more specialized training, while those intending to become informed consumers of the medical literature require more fundamental education. For most competencies, less training was proposed for those with more research background. DISCUSSION: When selecting statistical coursework, the learner's research background and career goal should guide the decision. Some statistical competencies are considered to be more important than others. Baseline knowledge assessments may help learners identify appropriate coursework. CONCLUSION: Rather than one size fits all, tailoring education to baseline knowledge, learner background, and future goals increases learning potential while minimizing classroom time.

Clinical outcomes with the MammoSite radiation therapy system: results of a prospective trial.

OBJECTIVE: The purpose of this study was to report the treatment-induced adverse events and cosmetic and treatment outcomes of accelerated partial breast irradiation (APBI) delivered with the MammoSite radiation therapy system (RTS) in breast cancer patients undergoing breast-conserving therapy (BCT). METHODS: This is a prospective clinical trial that was approved by the institutional review board. The study included female breast cancer patients undergoing breast-conserving therapy in the form of surgery and APBI delivered with the MammoSite RTS. Patients and tumor characteristics, treatment-induced acute adverse events based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0, chronic AEs according to Radiation Therapy Oncology Group (RTOG) scale, treatment outcomes (including local control, disease-free survival, and overall survival), and cosmetic outcomes are reported. RESULTS: The study included 36 eligible patients treated consecutively in our institution between November 2003 and August 2009. The age range was 45-83 years. A total of 29 patients had invasive disease (median size 1.1 cm), while 7 patients had in situ disease only (median size 0.8 cm). The skin distance in most of the patients (91.7 %) was ≥1 cm; only three patients (8.3 %) had skin distance <1 cm. The median balloon diameter was 5 cm (range 4-6 cm). At a median follow-up of 42 months (range 4-65 months), local control, disease-free survival, and overall survival were 100 %. None of the patients experienced any grade 3 or 4 toxicities; 16.7 and 5.6 % of the patients had late grade 2 fibrosis and telangiectasia, respectively. At last follow-up, cosmetic outcome was rated as good or excellent in 94 % of the patients. CONCLUSION: APBI delivered with the MammoSite RTS is a feasible, tolerable, and effective treatment modality. Multicenter, randomized, controlled clinical trials with a larger number of patients are required for verification.

Patterns of performance of retroperitoneal lymph node dissections by American urologists: most retroperitoneal lymph node dissections in the United States are performed by low-volume surgeons.

OBJECTIVE: To characterize the current patterns of retroperitoneal lymph node dissection (RPLND) performance among practicing US urologists. METHODS: Six-month case log data of urologists certifying between 2003 and 2013 were obtained from the American Board of Urology. Cases specifying both an International Classification of Diseases, Ninth Revision code for testis cancer and a Current Procedural Terminology code for RPLND were analyzed for surgeon-specific variables. RESULTS: Among 8545 certifying urologists, 290 (3.4% of all) urologists logged 553 RPLNDs in the case log system with 21 (3.6%) performed laparoscopically. Median number of RPLNDs logged annually was 1 (range, 1-59; interquartile range, 1-1) with 3 urologists performing 23% of all RPLNDs. Seventy-five percent of urologists logged a single RPLND. Urologists who logged 2 RPLNDs in a year were in the top 25% of performers with over half (52%) of all RPLNDs performed by urologists who logged 1 or 2 RPLND. On univariate regression analysis, oncology specialization (odds ratio, 5.1 [95% confidence interval, 2.2-11.6; P = .0001]) and non-private practice type (odds ratio, 2.8 [95% confidence interval, 1.1-7.1; P = .03]) were predictive of top 10% (≥ 3 cases) surgeon RPLND volume. CONCLUSION: Despite the critical importance of the surgical quality for outcomes of patients with testis cancer, the majority of surgeons performing RPLND are certifying for the first time and log only 1 RPLND.

Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression.

Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase human PCa cell invasion and its overexpression is associated with metastatic disease. The role of HSP27 in driving PCa cell movement from the prostate to distant metastatic sites is unknown. Increased HSP27 expression increased metastasis as well as primary tumor mass. In vitro studies further examined the mechanism of HSP27-induced metastatic behavior. HSP27 did not affect cell detachment, adhesion, or migration, but did increase cell invasion. Cell invasion was dependent upon matrix metalloproteinase 2 (MMP-2), whose expression was increased by HSP27. In vivo, HSP27 induced commensurate changes in MMP-2 expression in tumors. These findings demonstrate that HSP27 drives metastatic spread of cancer cells from the prostate to distant sites, does so across a continuum of expression levels, and identifies HSP27-driven increases in MMP-2 expression as functionally relevant. These findings add to prior studies demonstrating that HSP27 increases PCa cell motility, growth and survival. Together, they demonstrate that HSP27 plays an important role in PCa progression.

Error augmentation enhancing arm recovery in individuals with chronic stroke: a randomized crossover design.

BACKGROUND: Neurorehabilitation studies suggest that manipulation of error signals during practice can stimulate improvement in coordination after stroke. OBJECTIVE: To test visual display and robotic technology that delivers augmented error signals during training, in participants with stroke. METHODS: A total of 26 participants with chronic hemiparesis were trained with haptic (via robot-rendered forces) and graphic (via a virtual environment) distortions to amplify upper-extremity (UE) tracking error. In a randomized crossover design, the intervention was compared with an equivalent amount of practice without error augmentation (EA). Interventions involved three 45-minute sessions per week for 2 weeks, then 1 week of no treatment, and then 2 additional weeks of the alternate treatment. A therapist provided a visual cursor using a tracking device, and participants were instructed to match it with their hand. Haptic and visual EA was used with blinding of participant, therapist, technician-operator, and evaluator. Clinical measures of impairment were obtained at the beginning and end of each 2-week treatment phase as well as at 1 week and at 45 days after the last treatment. RESULTS: Outcomes showed a small, but significant benefit to EA training over simple repetitive practice, with a mean 2-week improvement in Fugl-Meyer UE motor score of 2.08 and Wolf Motor Function Test of timed tasks of 1.48 s. CONCLUSIONS: This interactive technology may improve UE motor recovery of stroke-related hemiparesis.

Patient knowledge and recall of health information following exposure to "facts and myths" message format variations.

OBJECTIVE: To assess if exposure to varying "facts and myths" message formats affected participant knowledge and recall accuracy of information related to influenza vaccination. METHODS: Consenting patients (N=125) were randomized to receive one of four influenza related messages (Facts Only; Facts and Myths; Facts, Myths, and Refutations; or CDC Control), mailed one week prior to a scheduled physician visit. Knowledge was measured using 15 true/false items at pretest and posttest; recall accuracy was assessed using eight items at posttest. RESULTS: All participants' knowledge scores increased significantly (p<0.05); those exposed to the CDC Control message had a higher posttest knowledge score (adjusted mean=11.18) than those in the Facts Only condition (adjusted mean 9.61, p=<0.02). Participants accurately recalled a mean of 4.49 statements (SD=1.98). ANOVA demonstrated significant differences in recall accuracy by condition [F(3, 83)=7.74, p<.001, η(2)=0.22]. CONCLUSION: Messages that include facts, myths, and evidence to counteract myths appear to be effective in increasing participants' knowledge. We found no evidence that presenting both facts and myths is counterproductive to recall accuracy. PRACTICE IMPLICATIONS: Use of messages containing facts and myths may engage the reader and lead to knowledge gain. Recall accuracy is not assured by merely presenting factual information.

A phase I trial of aminolevulinic acid-photodynamic therapy for treatment of oral leukoplakia.

BACKGROUND: Photodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia. METHODS: Patients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585nm). Clinical, histologic, and biologic markers were assessed. RESULTS: Analysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4J/cm(2). One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study. CONCLUSIONS: ALA PDT could be safely administered with a light dose up to 4J/cm(2) and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT.

Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial.

Soy isoflavone consumption may protect against breast cancer development. We conducted a phase IIB trial of soy isoflavone supplementation to examine its effect on breast epithelial proliferation and other biomarkers in the healthy high-risk breast. One hundred and twenty-six consented women underwent a random fine-needle aspiration (rFNA); those with 4,000 or more epithelial cells were randomized to a double-blind 6-month intervention of mixed soy isoflavones (PTIG-2535) or placebo, followed by repeat rFNA. Cells were examined for Ki-67 labeling index and atypia. Expression of 28 genes related to proliferation, apoptosis, and estrogenic effect was measured using quantitative reverse transcriptase PCR. Hormone and protein levels were measured in nipple aspirate fluid (NAF). All statistical tests were two-sided. Ninety-eight women were evaluable for Ki-67 labeling index. In 49 treated women, the median Ki-67 labeling index was 1.18 at entry and 1.12 post intervention, whereas in 49 placebo subjects, it was 0.97 and 0.92 (P for between-group change: 0.32). Menopausal stratification yielded similar results between groups, but within premenopausal soy-treated women, Ki-67 labeling index increased from 1.71 to 2.18 (P = 0.04). We saw no treatment effect on cytologic atypia or NAF parameters. There were significant increases in the expression of 14 of 28 genes within the soy, but not the control group, without significant between-group differences. Plasma genistein values showed excellent compliance. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women.

Analysis of pressure, angle and temporal effects on tissue optical properties from polarization-gated spectroscopic probe measurements.

Noninvasive optical techniques for tissue characterization, in particular, light scattering properties and blood supply quantification of mucosa, is useful in a wide variety of applications. However, fiber-optic probes that require contact with the tissue surface can present a challenging problem in the variability of in vivo measurements due the nature of interactions, for example affects due to variations in pressure applied to the probe tip. We present an in vivo evaluation of pressure, angle, and temporal effects on tissue properties for polarization-gated spectroscopy at superficial depths (within 100 to 200 microns of tissue surface) for oral mucosa.

Prolongation of off-cycle interval by finasteride is not associated with survival improvement in intermittent androgen deprivation therapy in LNCaP tumor model.

BACKGROUND: We have previously reported that finasteride administration in intermittent androgen deprivation therapy (IADT) can improve survival of nude mice bearing LNCaP xenograft tumors when the duration of off-cycle in IADT was fixed. A recent retrospective study showed that addition of finasteride doubled the duration of the off-cycle, without changing progression to castration resistance. In view of the above difference, we attempted to investigate the relationship of 5alpha-reductase inhibition with the off-cycle interval and overall survival in a murine model. METHODS: Subcutaneous LNCaP tumors were established in nude mice (Balb/C-Nu). After the tumors reached a size of 0.5 cm in diameter, the mice were castrated and followed up for 2 weeks after which they were randomized to continuous androgen deprivation (CAD), CAD plus finasteride, IADT, and IADT plus finasteride. The off-cycle was discontinued when the tumor volume was doubled. Subsequent cycles were carried out similarly. RESULTS: Use of finasteride during the off-cycle of IADT doubled the first off-cycle duration. However, prolongation of the off-cycle by finasteride did not translate into an increase in overall survival. CONCLUSIONS: The survival advantage of IADT + finasteride over IADT that we previously reported was lost when the off-cycle prolongation by finasteride was allowed. Maximum possible lengthening of the off-cycle by 5alpha-reductase inhibition is not associated with survival improvement in this animal model.

The novel expanded porphyrin, motexafin gadolinium, combined with [90Y]ibritumomab tiuxetan for relapsed/refractory non-Hodgkin's lymphoma: preclinical findings and results of a phase I trial.

PURPOSE: Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation. EXPERIMENTAL DESIGN: We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [(90)Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma. RESULTS: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time-to-treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time-to-treatment failure of 14 months (2-48+ months). CONCLUSIONS: This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [(90)Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.

Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family.

Hypoxia inducible factors (HIFs) activate oncogenic pathways, while thioredoxins (Trx), including Trx1 and Trx reductases-1 and -2 (TrxR1 and TrxR2), promote HIF-alpha stabilization. In immunoblotting studies in lymphoma cell lines we found that Raji and SUDHL4 cells exhibited normoxic HIF-2alpha protein stabilization. Five cell lines showed increased TrxR1 expression, while only Namalwa, HF1 and SUDHL4 had Trx1 and TrxR2 activation. Tissue microarrays in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) identified different HIF expression among histological subgroups (e.g. 44% DLBCL vs. 11% of FL cases with moderate-to-high expression of HIF-1alpha and HIF-2alpha, P = 0.0017). These data demonstrate that HIF and the thioredoxin family are abnormally activated in lymphoma.

Acanthosis nigricans: a common finding in overweight youth.

We evaluated the prevalence of acanthosis nigricans among urban youth. Youth (7-17 years) at nine pediatric practices completed surveys on demographics and family history of diabetes and had weight and height measured. Acanthosis nigricans was scored and digital photography of the neck performed. A total of 618 youth were included in the analysis: mean age 11.5 years; 51% female; 61% African American, 27% Hispanic, 12% Caucasian, and 32% with body mass index >or=95th percentile. Acanthosis was found in 19%, 23%, and 4% of the African American, Hispanic, and Caucasian youth, respectively, and in 62% of youth with a body mass index >or=98 th percentile. Using multiple logistic regression, we found increasing body mass index z-score, presence of maternal gestational diabetes, female gender, and not being Caucasian each were independently associated with acanthosis nigricans. Acanthosis was common among overweight youth and was associated with risk factors for glucose homeostasis abnormalities. Acanthosis nigricans can be a trigger to counsel families on its causes and consequences; and thus motivate them to make healthy lifestyle changes that can decrease the risk of developing cardiovascular disease or diabetes.

Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases.

Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation (LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-treated patients as compared to 88% in the untreated subjects (P=0.03). Variables on presentation associated with death or need for LT compared to spontaneous survival: male gender, age>40 yr, immunocompromised state, ALT>5,000 U/L, platelet count<75x10(3)/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded.