Feasibility and Impact of Integrating an Artificial Intelligence-Based Diagnosis Aid for Autism Into the Extension for Community Health Outcomes Autism Primary Care Model: Protocol for a Prospective Observational Study.

BACKGROUND: The Extension for Community Health Outcomes (ECHO) Autism Program trains clinicians to screen, diagnose, and care for children with autism spectrum disorder (ASD) in primary care settings. This study will assess the feasibility and impact of integrating an artificial intelligence (AI)-based ASD diagnosis aid (the device) into the existing ECHO Autism Screening Tool for Autism in Toddlers and Young Children (STAT) diagnosis model. The prescription-only Software as a Medical Device, designed for use in children aged 18 to 72 months at risk for developmental delay, produces ASD diagnostic recommendations after analyzing behavioral features from 3 distinct inputs: a caregiver questionnaire, 2 short home videos analyzed by trained video analysts, and a health care provider questionnaire. The device is not a stand-alone diagnostic and should be used in conjunction with clinical judgment. OBJECTIVE: This study aims to assess the feasibility and impact of integrating an AI-based ASD diagnosis aid into the ECHO Autism STAT diagnosis model. The time from initial ECHO Autism clinician concern to ASD diagnosis is the primary end point. Secondary end points include the time from initial caregiver concern to ASD diagnosis, time from diagnosis to treatment initiation, and clinician and caregiver experience of device use as part of the ASD diagnostic journey. METHODS: Research participants for this prospective observational study will be patients suspected of having ASD (aged 18-72 months) and their caregivers and up to 15 trained ECHO Autism clinicians recruited by the ECHO Autism Communities research team from across rural and suburban areas of the United States. Clinicians will provide routine clinical care and conduct best practice ECHO Autism diagnostic evaluations in addition to prescribing the device. Outcome data will be collected via a combination of electronic questionnaires, reviews of standard clinical care records, and analysis of device outputs. The expected study duration is no more than 12 months. The study was approved by the institutional review board of the University of Missouri-Columbia (institutional review board-assigned project number 2075722). RESULTS: Participant recruitment began in April 2022. As of June 2022, a total of 41 participants have been enrolled. CONCLUSIONS: This prospective observational study will be the first to evaluate the use of a novel AI-based ASD diagnosis aid as part of a real-world primary care diagnostic pathway. If device integration into primary care proves feasible and efficacious, prolonged delays between the first ASD concern and eventual diagnosis may be reduced. Streamlining primary care ASD diagnosis could potentially reduce the strain on specialty services and allow a greater proportion of children to commence early intervention during a critical neurodevelopmental window. TRIAL REGISTRATION: ClinicalTrials.gov NCT05223374; https://clinicaltrials.gov/ct2/show/NCT05223374. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37576.

Chromatin Accessibility Analysis from Fresh and Cryopreserved Human Ovarian Follicles.

Understanding how gene regulatory elements influence ovarian follicle development has important implications in clinically relevant settings. This includes understanding decreased fertility with age and understanding the short-lived graft function commonly observed after ovarian tissue cryopreservation and subsequent autologous transplantation as a fertility preservation treatment. The Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) is a powerful tool to identify distal and proximal regulatory elements important for activity-dependent gene regulation and hormonal and environmental responses such as those involved in germ cell maturation and human fertility. Original ATAC protocols were optimized for fresh cells, a major barrier to implementing this technique for clinical tissue samples which are more often than not frozen and stored. While recent advances have improved data obtained from stored samples, this technique has yet to be applied to human ovarian follicles, perhaps due to the difficulty in isolating follicles in sufficient quantities from stored clinical samples. Further, it remains unknown whether the process of cryopreservation affects the quality of the data obtained from ovarian follicles. Here, we generate ATAC-seq data sets from matched fresh and cryopreserved human ovarian follicles. We find that data obtained from cryopreserved samples are of reduced quality but consistent with data obtained from fresh samples, suggesting that the act of cryopreservation does not significantly affect biological interpretation of chromatin accessibility data. Our study encourages the use of this method to uncover the role of chromatin regulation in a number of clinical settings with the ultimate goal of improving fertility.

Evaluation of an artificial intelligence-based medical device for diagnosis of autism spectrum disorder.

Autism spectrum disorder (ASD) can be reliably diagnosed at 18 months, yet significant diagnostic delays persist in the United States. This double-blinded, multi-site, prospective, active comparator cohort study tested the accuracy of an artificial intelligence-based Software as a Medical Device designed to aid primary care healthcare providers (HCPs) in diagnosing ASD. The Device combines behavioral features from three distinct inputs (a caregiver questionnaire, analysis of two short home videos, and an HCP questionnaire) in a gradient boosted decision tree machine learning algorithm to produce either an ASD positive, ASD negative, or indeterminate output. This study compared Device outputs to diagnostic agreement by two or more independent specialists in a cohort of 18-72-month-olds with developmental delay concerns (425 study completers, 36% female, 29% ASD prevalence). Device output PPV for all study completers was 80.8% (95% confidence intervals (CI), 70.3%-88.8%) and NPV was 98.3% (90.6%-100%). For the 31.8% of participants who received a determinate output (ASD positive or negative) Device sensitivity was 98.4% (91.6%-100%) and specificity was 78.9% (67.6%-87.7%). The Device's indeterminate output acts as a risk control measure when inputs are insufficiently granular to make a determinate recommendation with confidence. If this risk control measure were removed, the sensitivity for all study completers would fall to 51.6% (63/122) (95% CI 42.4%, 60.8%), and specificity would fall to 18.5% (56/303) (95% CI 14.3%, 23.3%). Among participants for whom the Device abstained from providing a result, specialists identified that 91% had one or more complex neurodevelopmental disorders. No significant differences in Device performance were found across participants' sex, race/ethnicity, income, or education level. For nearly a third of this primary care sample, the Device enabled timely diagnostic evaluation with a high degree of accuracy. The Device shows promise to significantly increase the number of children able to be diagnosed with ASD in a primary care setting, potentially facilitating earlier intervention and more efficient use of specialist resources.

hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA.

Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG).

BACKGROUND: Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a "lighter" treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. METHODS/DESIGN: MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. DISCUSSION: MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12618000233224 , prospectively registered 14 February 2018.

Specialist physicians' referral behavior regarding preimplantation genetic testing for single-gene disorders: Is there room to grow?

OBJECTIVE: To assess whether primary care specialists' demographics, specialty, and knowledge of preimplantation genetic testing for monogenic disorders (PGT-M) influence their practice patterns. DESIGN: Cross-sectional survey study. SETTING: Academic medical center. PATIENTS: Not applicable. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Objective PGT-M knowledge, subjective comfort with PGT-related topics, PGT care practices (discussions/referrals), and PGT-M implementation barriers. RESULTS: Our survey had 145 respondents: 65 obstetrician/gynecologists, 36 internists, and 44 pediatricians. Overall, 88% believed that patients at a risk of passing on genetic disorders should be provided PGT-M information. However, few discussed PGT-M with their patients (24%) or referred them for testing (23%). Over half (63%) believed that the lack of physician knowledge was a barrier to PGT use. In terms of subjective comfort with PGT, only 1 in 5 physicians felt familiar enough with the topic to answer patient questions. There were higher odds of discussing (odds ratio, 3.21; 95% confidence interval, 1.75-5.87) or referring for PGT (odds ratio, 2.52; 95% confidence interval, 1.41-4.51) for each additional 0.5 correct answers to PGT knowledge-related questions. The odds of referring patients for PGT-M were the highest among obstetrician/gynecologists compared with those among the internists and pediatricians. CONCLUSIONS: Physician specialty and PGT knowledge were associated with PGT-M care delivery practices. Although most specialists believed in equipping at-risk patients with PGT-M information, <1 in 4 discussed or referred patients for PGT. The low levels of PGT-related care among providers may be owed to inadequate knowledge of and comfort with the topic. An opportunity to promote greater understanding of PGT-M among primary care specialists exists and can in turn improve the use of referrals to PGT-M services.

The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE AND BACKGROUND: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. METHODS: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. RESULTS: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence. CONCLUSIONS: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Peer support interventions seeking to improve physical health and lifestyle behaviours among people with serious mental illness: A systematic review.

People with serious mental illness (SMI) experience a premature mortality gap of between 10 and 20 years. Interest is growing in the potential for peer support interventions (PSI) to improve the physical health of people with SMI. We conducted a systematic review investigating if PSI can improve the physical health, lifestyle factors, and physical health appointment attendance among people with SMI. A systematic search of major electronic databases was conducted from inception until February 2016 for any article investigating PSI seeking to improve physical health, lifestyle, or physical health appointment attendance. From 1347 initial hits, seven articles were eligible, including three pilot randomized, control trials (interventions: n = 85, controls: n = 81), and four pretest and post-test studies (n = 54). There was considerable heterogeneity in the type of PSI, and the role of the peer support workers (PSW) varied considerably. Three studies found that PSI resulted in insignificant reductions in weight. Evidence from three studies considering the impact of PSI on lifestyle changes was equivocal, with only one study demonstrating that PSI improved self-report physical activity and diet. Evidence regarding physical health appointment attendance was also unclear across four studies. In conclusion, there is inconsistent evidence to support the use of PSW to improve the physical health and promote lifestyle change among people with SMI. The small sample sizes, heterogeneity of interventions, outcome measures, and lack of clarity about the unique contribution of PSW means no definitive conclusions can be made about the benefits of PSW and physical health in SMI.

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial.

IMPORTANCE: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE: To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS: LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS: Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS: In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE: Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02145468.

Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial.

BACKGROUND: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer. METHODS: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy. RESULTS: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively. CONCLUSIONS: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.

IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.

Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial.

BACKGROUND: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)1= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)1 = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)1 = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Darapladib effect on circulating high sensitive troponin in patients with acute coronary syndromes.

OBJECTIVES: We compared the incidence of late increase in hs-cTnI between ACS and non-ACS patients treated with standard of care with or without darapladib. METHODS: A total of 323 (161 ACS and 162 non-ACS patients) were included. High sensitivity troponin I was measured at baseline and at 4, 13, 26 and 52 weeks. RESULTS: ACS patients had statistically higher hs-cTnI values during longer term follow-up at which these patients were no longer in the acute setting of myocardial ischemia, but were regarded to have stable CAD (mean hsTnI value in ACS patients: 1.180 versus 0.886 ng/L in non-ACS patients, p = 0.02). Multivariate logistic regression revealed three predictors of any 2-fold increase in hs-cTnI levels compared to the previous visit when interactions were not considered. Treatment with darapladib (adjusted OR 0.53; 95% CI: 0.30-0.92) and initial presentation with ACS (adjusted OR 0.42; 95% CI: 0.23-0.77) were associated with less frequent occurrence of a 2-fold increase in hs-cTnI levels. In contrast, diabetes was associated with a higher incidence of 2-fold increases in hs-cTnI levels (adjusted OR 2.20; 95% CI: 1.04-4.64). Logistic regression to predict any 2-fold increase in hs-cTnI by ACS status showed that in the ACS group, treatment with darapladib decreased the risk of elevation of hs-cTnI (OR 0.219; 95% CI: 0.087, 0.553, p = 0.0013). CONCLUSION: In patients with ACS, treatment with darapladib is associated with less increase in cardiac troponin I compared to standard of care alone. This beneficial effect may be associated with darapladib's capability of reducing necrotic core in coronary plaques.

Pegloticase: a novel agent for treatment-refractory gout.

OBJECTIVE: To evaluate efficacy and safety of pegloticase, approved by the Food and Drug Administration in September 2010 for treatment of patients with chronic treatment-refractory gout. DATA SOURCES: Literature searches were conducted using PubMed (1948-January 2012), TOXLINE, International Pharmaceutical Abstracts (1970-January 2012), and Google Scholar using the terms pegloticase, puricase, PEG-uricase, gout, uricase, and Krystexxa. Results were limited to English-language publications. References from selected articles were reviewed to identify additional citations. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of pegloticase for the treatment of chronic treatment-refractory gout were included. DATA SYNTHESIS: Pegloticase represents a novel intravenous treatment option for patients who have chronic gout refractory to other available treatments. Pegloticase is a recombinant uricase and achieves therapeutic effects by catalyzing oxidation of uric acid to allantoin, resulting in decreased uric acid concentrations. Results of published trials demonstrate the ability of pegloticase to maintain uric acid concentrations below 7 mg/dL in patients with chronic gout. Data supporting reduction of gout flares are limited. Pegloticase is well tolerated but associated with gout flares and infusion reactions. Other adverse events include nausea, dizziness, and back pain. During Phase 3 trials, 2 patients in the pegloticase biweekly group and 1 in the monthly group experienced heart failure exacerbation; another patient in the monthly group experienced a nonfatal myocardial infarction. Providers should exercise caution before administering pegloticase to patients with cardiovascular disease. The cost burden and safety profile may limit its use in practice, in addition to limited data available to support decreases in patient-centered outcomes (eg, gouty attacks). CONCLUSIONS: Pegloticase is an effective option for patients with symptomatic gout for whom current uric acid-lowering therapies are ineffective or contraindicated.

Relationship between cardiovascular risk factors and biomarkers with necrotic core and atheroma size: a serial intravascular ultrasound radiofrequency data analysis.

We explored the impact of patient demographics, anthropometric measurements, cardiovascular risk factors, and soluble biomarkers on necrotic core and atheroma size in patients with coronary disease. The IBIS-2 trial enrolled 330 patients. In the multivariate analysis, at baseline, creatinine had a positive, whereas baseline mean lumen diameter and myeloperoxidase had a negative, independent association with percentage of necrotic core (PNC); while age, glomerular filtration rate <60, HbA1c, previous PCI or CABG and baseline % diameter stenosis were positively, and acute coronary syndromes (ACS) were negatively associated with baseline percentage atheroma volume (PAV). The variables associated with a decrease in PNC from baseline were darapladib, ACS and a large content of NC at baseline, while variables associated with an increase in PNC were previous stroke and % diameter stenosis at baseline. Those variables associated with a decrease in PAV from baseline were waist circumference, statin use, CD40L and baseline PAV, while the only variable associated with an increase in PAV was baseline diastolic blood pressure. Treatment with darapladib was associated with a decrease in necrotic core, but was not associated with a decrease in percentage atheroma volume. On the contrary, statin use was only associated with a decrease in percentage atheroma volume.

Metastatic cutaneous squamous cell carcinoma of the head and neck: the Immunosuppression, Treatment, Extranodal spread, and Margin status (ITEM) prognostic score to predict outcome and the need to improve survival.

BACKGROUND: : The authors propose a prognostic score model using a prospective study of patients with regional metastatic cutaneous squamous cell carcinoma of the head and neck. METHODS: : Two-hundred fifty patients were analyzed using a competing risks model to identify risk factors for survival. A risk score was obtained using the significant coefficients from the regression model, and cutoff points were determined that separated the score into 3 risk groups (low risk, moderate risk, and high risk). RESULTS: : At a median follow-up of 54 months (range, 1.3-212 months) 70 of 250 patients (28%) developed recurrent disease: Most were regional recurrences (51 of 70 patients; 73%) in the treated lymph node basin. After regional recurrence, a majority (73%) died of disease. The following 4 variables were associated significantly with survival: immunosuppression (hazard ratio [HR], 3.13; 95% confidence interval [CI], 1.39-7.05), treatment (HR, 0.32; 95% CI, 0.16-0.66), extranodal spread (HR, 9.92; 95% CI, 1.28-77.09), and margin status (HR, 1.85; 95% CI, 1.85-3.369); and those 4 variables (immuosuppression, treatment, extranodal spread, and margin status) were used to calculate the ITEM score. The 5-year risk of dying from disease for patients with high-risk (>3.0), moderate-risk (>2.6-3.0), and low-risk (< or =2.6) ITEM scores were 56%, 24%, and 6%, respectively. Fifty-six of 250 patients (22%) died from another cause. CONCLUSIONS: : Patients who underwent surgery and received adjuvant radiotherapy had a better outcome compared with patients who underwent surgery alone. Patients who had moderate- or high-risk ITEM scores, usually because of extranodal spread and involved excision margins, had a poor outcome. The authors recommend considering these patients for inclusion in adjuvant chemoradiotherapy trials. Cancer 2009. (c) 2009 American Cancer Society.

Effect of dutasteride on intraprostatic androgen levels in men with benign prostatic hyperplasia or prostate cancer.

OBJECTIVES: Dutasteride exerts its beneficial effects on the prostate through suppression of intraprostatic dihydrotestosterone (DHT). The aim of this analysis was to assess the effects of the approved dose of dutasteride (0.5 mg/d), given for 2 weeks to 4 months, on the serum and intraprostatic DHT and testosterone levels in 3 randomized studies. METHODS: Intraprostatic androgen levels were measured in benign prostatic tissue collected during transurethral resection of the prostate (benign prostatic hyperplasia studies, n = 256) or radical prostatectomy (prostate cancer study, n = 51), performed after 2 weeks, or 1, 3, or 4 months of treatment with dutasteride or with placebo or surgery alone. The serum androgen levels were assessed at the same points during treatment. Data from the control groups were pooled to provide 1 comparison group. RESULTS: Dutasteride reduced the intraprostatic DHT levels by 83%, 90%, 92%, and 93% after 2 weeks and 1, 3, and 4 months of treatment, respectively, compared with placebo/surgery alone. Dutasteride reduced the serum DHT levels from baseline by 84% at 2 weeks and by approximately 90% at 1, 2, 3, and 4 months compared with a 5.2% increase in the control group. The decrease in DHT levels with dutasteride was accompanied by a reciprocal increase in the serum and intraprostatic testosterone levels. However, the intraprostatic testosterone levels in the dutasteride groups generally remained lower than the intraprostatic DHT levels in the control group. CONCLUSIONS: The results of our study have shown that dutasteride provides near-maximal suppression of both serum and intraprostatic DHT levels in men with benign prostatic hyperplasia or prostate cancer at all points assessed.

Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy.

PURPOSE: Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)--containing the beta-emitter, yttrium-90--into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX). PATIENTS AND METHODS: A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m2) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity. RESULTS: Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months. CONCLUSION: The maximum-tolerated dose was 60 mg/m2 of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.

Merkel cell carcinoma: improved outcome with adjuvant radiotherapy.

BACKGROUND: Merkel cell carcinoma is an aggressive primary cutaneous neuroendocrine carcinoma. Patients remain at high risk of locoregional and distant relapse despite treatment. Most studies support the incorporation of locoregional adjuvant radiotherapy in reducing the risk of relapse. METHODS: Between 1980 and 2002, 86 patients diagnosed with Merkel cell carcinoma were treated with curative intent at Westmead Hospital, Sydney. Multivariate analysis was performed using Cox regression analysis. Disease-free survival and overall survival was calculated using Kaplan-Meier survival curves. RESULTS: Median age at diagnosis was 75 years (range 46-89 years) in 49 men and 37 women. Median duration of follow up was 31 months (range 6-153 months). Fifty-one (59%) patients presented with a primary lesion, 19 (22%) with a primary lesion and clinical nodal disease and 16 (19%) with lymph node metastases from an unknown primary. A total of 47 of 86 (55%) relapsed with regional nodal relapse, the commonest site of first relapse. Local relapse was similar for patients undergoing surgery (5/37; 14%) compared with surgery and adjuvant radiotherapy (3/25; 12%). Nodal relapse occurred in 14 of 36 (37%) treated with surgery compared with 7 of 38 (18%) patients treated with surgery and adjuvant radiotherapy. Patients treated with surgery and adjuvant radiotherapy experienced a better median disease free survival compared to those undergoing surgery alone (10.5 months vs 4 months; P < 0.01). The 5-year overall and disease-free survival rate for the entire study population was 47% and 25%, respectively. Twenty-six patients (30%) died as a result of Merkel cell carcinoma. CONCLUSION: Merkel cell carcinoma is an aggressive skin cancer. The addition of adjuvant radiotherapy markedly improves regional control rates and should be considered best practice.