Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Hysteroscopy and episiotomy in a rescued, cold-stressed Florida manatee (Trichechus manatus latirostris) for diagnosis and treatment of a retained fetal skeleton.

A rescued female manatee was observed expelling a fetal bone from the vulva. The manatee was anesthetized and diagnosed with uterine retention of a fetal skeleton by ultrasound and hysteroscopy. Episiotomy was performed to gain manual access to the vagina and uterus for removal of the skeleton. Second intention healing of the episiotomy site produced excellent results. Rescued female manatees should receive a thorough reproductive tract evaluation since presence of retained fetal tissues might not be evident in blood or hormone analyses. Retention of a whole or partial dead fetus can be life-threatening to manatees, and retained tissues should be removed as early as possible.

Accuracy of FAST scan in blunt abdominal trauma in a major London trauma centre.

INTRODUCTION: Blunt abdominal trauma (BAT) is a leading cause of morbidity and mortality. Rapid diagnosis and treatment with the Advanced Trauma Life Support guidelines are vital, leading to the development of Focused Assessment with Sonography in Trauma (FAST). METHODS: A retrospective study carried out from January 2007-2008 on all patients who presented with BAT and underwent FAST scan. All patients subsequently had a CT scan within 2 h of admission or a laparotomy within two days. The presence of intra-peritoneal free fluid was interpreted as positive. RESULTS: 100 patients with BAT presented; 71 had complete data. The accuracy of FAST in BAT was 59.2%; in these 31 (43.7%) were confirmed by CT and 11 (15%) by laparotomy. There were 29 (40.8%) inaccurate FAST scans, all confirmed by CT. FAST had a specificity of 94.7% (95% CI: 0.75-0.99) and sensitivity of 46.2% (95% CI: 0.33-0.60). Positive Predictive Value of 0.96 (0.81-0.99) and Negative Predictive Value of 0.39 (0.26-0.54). Fisher's exact test shows positive FAST is significantly associated with Intra-abdominal pathology (p=0.001). Cohen's chance corrected agreement was 0.3. 21 out of 28 who underwent laparotomies had positive FAST results indicating accuracy of 75% (95% CI: 57%-87%). CONCLUSION: Patients with false negative scans, requiring therapeutic laparotomy is concerning. In unstable patients FAST may help in triaging and identifying those requiring laparotomy. Negative FAST scans do not exclude abdominal injury. Further randomised control trials are recommended if the role of FAST is to be better understood.

Infection after spanning external fixation for high-energy tibial plateau fractures: is pin site-plate overlap a problem?

OBJECTIVES: The purpose of this study was to determine whether overlap between temporary external fixator pins and definitive plate fixation correlates with infection in high-energy tibial plateau fractures. DESIGN: Retrospective chart and radiographic review. SETTING: Academic medical center. PATIENTS: Seventy-nine patients with unilateral high-energy tibial plateau fractures formed the basis of this report. INTERVENTION: Placement of knee-spanning external fixation followed by delayed internal fixation for high-energy tibial plateau fractures treated at our institution between 2000 and 2008. METHODS: Demographic patient information was reviewed. Radiographs were reviewed to assess for the presence of overlap between the temporary external fixator pins and the definitive plate fixation. Fisher exact and t test analyses were performed to compare those patients who had overlap and those who did not and were used to determine whether this was a factor in the development of a postoperative infection. MAIN OUTCOME MEASUREMENTS: Development of infection in those whose external fixation pin sites overlapped with the definitive internal fixation device compared with those whose pin sites did not overlap with definitive plate and screws. RESULTS: Six knees in six patients developed deep infections requiring serial irrigation and débridement and intravenous antibiotics. Of these six infections, three were in patients with closed fractures and three in patients with open fractures. Two of these six infections followed definitive plate fixation that overlapped the external fixator pin sites with an average of 4.2 cm of overlap. In the four patients who developed an infection and had no overlap, the average distance between the tip of the plate to the first external fixator pin was 6.3 cm. There was no correlation seen between infection and distance from pin to plate, pin-plate overlap distance, time in the external fixator, open fracture, classification of fracture, sex of the patient, age of the patient, or healing status of the fracture. CONCLUSION: Fears of definitive fracture fixation site contamination from external fixator pins do not appear to be clinically grounded. When needed, we recommend the use of a temporary external fixation construct with pin placement that provides for the best reduction and stability of the fracture, regardless of plans for future surgery.

High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study.

OBJECTIVES: To determine the proportion of noncardiac surgery patients exceeding the published 99th percentile or change criteria with the high sensitivity Troponin T (hs-TnT) assay. DESIGN AND METHODS: We measured hs-TnT preoperatively and postoperatively on days 1, 2 and 3 in 325 adults. RESULTS: Postoperatively 45% (95% CI: 39-50%) of patients had hs-TnT≥14ng/L and 22% (95% CI:17-26%) had an elevation (≥14ng/L) and change (>85%) in hs-TnT. CONCLUSION: Further research is needed to inform the optimal hs-TnT threshold and change in this setting.

An international prospective cohort study evaluating major vascular complications among patients undergoing noncardiac surgery: the VISION Pilot Study.

OBJECTIVES: among patients undergoing noncardiac surgery, our objectives were to: (1) determine the feasibility of undertaking a large international cohort study; (2) estimate the current incidence of major perioperative vascular events; (3) compare the observed event rates to the expected event rates according to the Revised Cardiac Risk Index (RCRI); and (4) provide an estimate of the proportion of myocardial infarctions without ischemic symptoms that may go undetected without perioperative troponin monitoring. DESIGN: An international prospective cohort pilot study. PARTICIPANTS: Patients undergoing noncardiac surgery who were >45 years of age, receiving a general or regional anesthetic, and requiring hospital admission. MEASUREMENTS: Patients had a Roche fourth-generation Elecsys troponin T measurement collected 6 to 12 hours postoperatively and on the first, second, and third days after surgery. Our primary outcome was major vascular events (a composite of vascular death [i.e., death from vascular causes], nonfatal myocardial infarction, nonfatal cardiac arrest, and nonfatal stroke) at 30 days after surgery. Our definition for perioperative myocardial infarction included: (1) an elevated troponin T measurement with at least one of the following defining features: ischemic symptoms, development of pathologic Q waves, ischemic electrocardiogram changes, coronary artery intervention, or cardiac imaging evidence of myocardial infarction; or (2) autopsy findings of acute or healing myocardial infarction. RESULTS: We recruited 432 patients across 5 hospitals in Canada, China, Italy, Colombia, and Brazil. During the first 30 days after surgery, 6.3% (99% confidence interval 3.9-10.0) of the patients suffered a major vascular event (10 vascular deaths, 16 nonfatal myocardial infarctions, and 1 nonfatal stroke). The observed event rate was increased 6-fold compared with the event rate expected from the RCRI. Of the 18 patients who suffered a myocardial infarction, 12 (66.7%) had no ischemic symptoms to suggest myocardial infarction. CONCLUSIONS: This study suggests that major perioperative vascular events are common, that the RCRI underestimates risk, and that monitoring troponins after surgery can assist physicians to avoid missing myocardial infarction. These results underscore the need for a large international prospective cohort study.

Liquid nitrogen ingestion leading to massive pneumoperitoneum without identifiable gastrointestinal perforation.

BACKGROUND: Liquid nitrogen (LN) ingestion is unusual, but may be encountered by poison centers, emergency physicians, and general surgeons. Unique properties of LN produce a characteristic pattern of injury. CASE REPORT: A 19-year-old male college student presented to the Emergency Department complaining of abdominal pain and "bloating" after drinking LN. His presentation vital signs were remarkable only for mild tachypnea and tachycardia. On physical examination, he had mild respiratory difficulty due to abdominal distention. His abdomen was tense and distended. Abdominal X-ray studies revealed a massive pneumoperitoneum. At laparotomy, he was found to have a large amount of peritoneal gas. No perforation was identified. After surgery, the patient made an uneventful recovery and was discharged 5 days later. At 2-week clinic follow-up, he was doing well without complications. DISCUSSION: Nitrogen is a colorless, odorless gas at room temperature. Due to its low boiling point (-195 degrees C), LN rapidly evaporates when in contact with body surface temperatures. Therefore, ingested LN causes damage by two mechanisms: rapid freezing injury upon mucosal contact and rapid volume expansion as nitrogen gas is formed. Patients who ingest LN may develop gastrointestinal perforation and massive pneumoperitoneum. Because rapid gas formation may allow large volumes to escape from tiny perforations, the exact site of perforation may never be identified. CONCLUSION: In cases of LN ingestion, mucosal injury and rapid gas formation can cause massive pneumoperitoneum. Although laparotomy is recommended for all patients with signs of perforation, the site of injury may never be identified.

Sustained expression of human cytomegalovirus glycoprotein B (UL55) in the seeds of homozygous rice plants.

Production of recombinant subunit vaccines in transgenic plants may be a means of reducing vaccine costs while increasing availability and safety. A plant-derived product found safe and effective for oral administration would provide additional advantages when used as a vaccine. Outstanding issues with the technology include transgene stability through successive generations and consistent bioproduction. We previously reported expression of glycoprotein B (gB) of human cytomegalovirus in seeds of transgenic tobacco. Here the goal was to determine if gB could be similarly expressed in rice, and if so, to examine expression over several plant generations. Results show that immunoreactive gB was successfully expressed in transgenic rice seeds, with sustained expression over three generations. The gB contained several neutralizing epitopes and was stable over 27 months.

Evaluation of NO(x) flue gas analyzers for accuracy and their applicability for low-concentration measurements.

The requirements of the Texas State Implementation Plan of the U.S. Clean Air Act for the Houston-Galveston Ozone Nonattainment Area stipulate large reductions in oxides of nitrogen (NO(x)) emissions. A large number of sources at Dow Chemical Co. sites within the nonattainment area may require the addition of continuous emission monitoring systems (CEMS) for online analysis of NO(x), CO, and O2. At the outset of this work, it was not known whether the analyzers could accurately measure NO(x) as low as 2 ppm. Therefore, NO(x) CEMS analyzers from five different companies were evaluated for their ability to reliably measure NO(x) in the 2-20 ppm range. Testing was performed with a laboratory apparatus that accurately simulated different mixtures of flue gas and, on a limited basis, simulated a dual-train sampling system on a gas turbine. The results indicate that this method is a reasonable approach for analyzer testing and reveal important technical performance aspects for accurate NO(x) measurements. Several commercial analyzers, if installed in a CEMS application with sampling conditioning components similar to those used in this study, can meet the U.S. Environmental Protection Agency's measurement data quality requirements for accuracy.

Systemic evaluation: three flexible and inclusive approaches / Systemic evaluation: three flexible and inclusive approaches

Este artículo presenta tres diferentes enfoques para la evaluación, útiles para diversos propósitos, que pueden combinarse para producir un conjunto de instrumentos flexibles en respuesta a una amplia variedad de situaciones. Ofrece los argumentos que justifican la realización de evaluaciones sistémicas (holísticas) que son a la vez inclusivas y participativas