Trade-off between pulse rate and radiation dose during modified barium swallow examination: what is the reality?

AIM: To evaluate the effect of modification of dose mode and frame rate on patient radiation dose during modified barium swallow (MBS) examinations. MATERIALS AND METHODS: A retrospective review was undertaken of consecutive MBS examinations performed over 6 months in the inpatient setting. Patients were divided into two cohorts: pre-implementation of the MBS Impairment Profile (MBSImP; low rate, normal dose) and post-implementation (high rate, low dose). Prior to implementation, pulse rate and dose testing were performed on multiple phantoms. RESULTS: Four hundred and forty-nine patients were included in the pre-implementation cohort and 378 in the post-implementation cohort. Phantom dose testing demonstrated no significant difference in dose on either phantom between low rate/normal dose and high rate/low dose modes. Prior to MBS standardisation, the mean radiation dose was 5.86 (±4.35) mGy. Following standardisation, the mean radiation dose was 4.72 (±3.77) mGy (p<0.0001). The mean fluoroscopy time for MBS prior to standardisation was 83.8 (±44.4) seconds and the mean fluoroscopy time for MBS after standardisation was 82.3 (±39.8) seconds (p=0.62). The dose rate for MBS prior to standardisation was 4.35 (±2.42) and the dose rate for MBS after standardisation was 3.55 (±2.41) mGy/s (p<0.0001). CONCLUSION: Adjustments made to lower the dose mode and the increase in fluoroscopy frame rate decreased the patient radiation dose and did not increase fluoroscopy time.

Anti-reflux procedures: complications, radiologic findings, and surgical and gastroenterologic perspectives.

This article provides an overview of the current surgical anti-reflux procedures and their imaging findings, as well as the surgical complications. Accurate and timely clinical assessment requires an engaged radiologist fluoroscopist who understands the perspectives of their interdisciplinary colleagues, including the surgeon and gastroenterologist. The complex pathophysiology calls for an interdisciplinary approach, and the radiologist needs to tailor their evaluation to answer the specific questions posed by their clinical colleagues and by the presenting symptomatology.

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.

White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy.

Therapeutic hypothermia is widely used to treat neonatal hypoxic ischemic (HI) brain injuries. However, potentially deleterious effects of delaying the induction of hypothermia and of rewarming on white matter injury remain unclear. We used a piglet model of HI to assess the effects of delayed hypothermia and rewarming on white matter apoptosis. Piglets underwent HI injury or sham surgery followed by normothermic or hypothermic recovery at 2h. Hypothermic groups were divided into those with no rewarming, slow rewarming at 0.5°C/h, or rapid rewarming at 4°C/h. Apoptotic cells in the subcortical white matter of the motor gyrus, corpus callosum, lateral olfactory tract, and internal capsule at 29h were identified morphologically and counted by hematoxylin & eosin staining. Cell death was verified by terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) assay. White matter neurons were also counted, and apoptotic cells were immunophenotyped with the oligodendrocyte marker 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase). Hypothermia, slow rewarming, and rapid rewarming increased apoptosis in the subcortical white matter relative to normothermia (p<0.05). The number of white matter neurons was not lower in groups with more apoptosis after hypothermia or rapid rewarming, indicating that the apoptosis occurred among glial cells. Hypothermic piglets had more apoptosis in the lateral olfactory tract than those that were rewarmed (p<0.05). The promotion of apoptosis by hypothermia and rewarming in these regions was independent of HI. In the corpus callosum, HI piglets had more apoptosis than shams after normothermia, slow rewarming, and rapid rewarming (p<0.05). Many apoptotic cells were myelinating oligodendrocytes identified by CNPase positivity. Our results indicate that delaying the induction of hypothermia and rewarming are associated with white matter apoptosis in a piglet model of HI; in some regions these temperature effects are independent of HI. Vulnerable cells include myelinating oligodendrocytes. This study identifies a deleterious effect of therapeutic hypothermia in the developing brain.

Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients.

Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.

[Molecular genetic detection of minimal residual disease (MRD) in children with acute lymphoblastic leukemia]. / Molekulargenetischer Nachweis minimaler Resterkrankung (minimal residual disease, MRD) bei Kindern mit akuter lymphoblastischer Leukämie.

The treatment of acute lymphoblastic leukemia (ALL) in childhood and adolescence achieves nowadays cure rates of more than 80%. The detection of minimal residual disease (MRD) via molecular genetic methods provides - in comparison with conventional clinical and biological parameters - much more sensitive approaches to monitor individual treatment response. Here we will discuss the molecular background and technical developments in the framework of the BFM-study group.

Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment.

Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL.

The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function.

Precursor T-cell acute lymphoblastic leukemia (T-ALL) remains an important challenge in pediatric oncology. Because of the particularly poor prognosis of relapses, it is vital to identify molecular risk factors allowing early and effective treatment stratification. Activating NOTCH1 mutations signify a favorable prognosis in patients treated on ALL-BFM protocols. We have now tested if NOTCH pathway activation at different steps has similar clinical effects and if multiple mutations in this pathway function synergistically. Analysis of a validation set of 151 T-ALL patients and of the total cohort of 301 patients confirms the low relapse rate generally and the overall favorable effect of activating NOTCH1 mutations. Subgroup analysis shows that the NOTCH1 effect in ALL-BFM is restricted to patients with rapid early treatment response. Inactivation of the ubiquitin ligase FBXW7 is associated with rapid early treatment response and synergizes with NOTCH1 receptor activation. However, the effect of FBXW7 inactivation is separable from NOTCH1 activation by not synergizing with NOTCH1 mutations in predicting favorable long-term outcome, which can probably be explained by the interaction of FBXW7 with other clients. Finally, the comparison with other European protocols suggests that the NOTCH effect is treatment dependent generally and may depend on the intensity of central nervous system-directed therapy specifically.

Prostacyclin receptor deletion aggravates hippocampal neuronal loss after bilateral common carotid artery occlusion in mouse.

Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an increase in cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including prostacyclin (PGI(2)). To determine the role of the PGI(2) receptor (IP) in post-ischemic delayed cell death, wild-type and IP knockout (IP(-/-)) C57Bl/6 mice were subjected to 12-min bilateral common carotid artery occlusion or sham surgery, followed by 7 days of reperfusion. In the sham-operated mice, no statistical difference in CA1 hippocampal neuronal density was observed between the wild-type (2836+/-18/mm(2)) and IP(-/-) (2793+/-43/mm(2)) mice. Interestingly, in animals subjected to ischemia, surviving neuronal density in wild-type mice decreased to 50.5+/-7.9% and that of IP(-/-) mice decreased to 23.0+/-4.5% of their respective sham-operated controls (P<0.05). The results establish a role for the IP receptor in protecting pyramidal hippocampal neurons after this global ischemic model and suggest that IP receptor agonists could be developed to prevent delayed pyramidal neuronal cell death.

Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia.

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (< or =10(-4)), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD > or =10(-3) at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.

Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus.

Translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus can play a major role in neuronal death elicited by oxidant stress. The time course of nuclear translocation of AIF after experimental stroke may vary with the severity of injury and may be accelerated by oxidant stress associated with reperfusion and nitric oxide (NO) production. Western immunoblots of AIF on nuclear fractions of ischemic hemisphere of male mice showed no significant increase with 1 h of middle cerebral artery occlusion and no reperfusion, whereas increases were detectable after 6 and 24 h of permanent ischemia. However, as little as 20 min of reperfusion after 1 h of middle cerebral artery occlusion resulted in an increase in nuclear AIF coincident with an increase in poly(ADP-ribose) polymer (PAR) formation. Further nuclear AIF accumulation was seen at 6 and 24 h of reperfusion. In contrast, 20 min of reperfusion after 2 h of occlusion did not increase nuclear AIF. In this case, nuclear AIF became detectable at 6 and 24 h of reperfusion. With brief occlusion of 30 min duration, nuclear AIF remained undetectable at both 20 min and 6 h and became evident only after 24 h of reperfusion. Inhibition of neuronal NO synthase attenuated formation of PAR and nuclear AIF accumulation. Gene deletion of neuronal NO synthase also attenuated nuclear AIF accumulation. Therefore, reperfusion accelerates AIF translocation to the nucleus when focal ischemia is of moderate duration (1 h), but is markedly delayed after brief ischemia (30 min). Nuclear translocation of AIF eventually occurs with prolonged focal ischemia with or without reperfusion. Neuronally-derived NO is a major factor contributing to nuclear AIF accumulation after stroke.

Minimal adhesions to ePTFE mesh after laparoscopic ventral incisional hernia repair: reoperative findings in 65 cases.

BACKGROUND AND OBJECTIVES: Laparoscopic ventral incisional hernia repair involves intraabdominal placement of a synthetic mesh, and the possibility of formation of severe visceral adhesions to the prosthesis is a principal concern. Little clinical information based on reoperative findings is available about adhesions to biomaterials placed intraabdominally. We conducted a multi-institutional study of adhesions to implanted expanded polytetrafluoroethylene (ePTFE) mesh at reoperation in patients who had previously undergone laparoscopic incisional hernia repair done with the same mesh implantation technique. METHODS: Nine surgeons retrospectively assessed the severity of adhesions to ePTFE mesh at reoperation in 65 patients. For each case, adhesions were assigned a score of 0 to 3, with 0 indicating no adhesions and 3 severe adhesions. RESULTS: The mean time from mesh implantation to reoperation was 420 days (range, 2-1 739 days). No adhesions were observed in 15 cases. Forty-four cases received an adhesion score of 1, and 6 cases a score of 2; no scores of 3 were assigned. Thus, 59 patients (91 %) had either no or filmy, avascular adhesions. No enterotomies occurred during adhesiolysis. CONCLUSIONS: In this large series of reoperations after laparoscopic incisional hernia repair, no or minimal formation of adhesions to implanted ePTFE mesh was observed in 91 % of cases, and no severe cohesive adhesions were found. Comparative analyses of newer materials based on clinical reoperative findings are warranted to assess the safety of intraabdominally placed meshes.

Diagnosing the occult contralateral inguinal hernia.

BACKGROUND: The incidence of bilateral inguinal hernias reported for total extra peritoneal (TEP) laparoscopic hernia repair, which reaches 45%, appears to be higher than that seen in studies of transabdominal laparoscopic and open repair. Given the unique ability of diagnostic laparoscopy to diagnose occult contralateral hernias (OCH) accurately, this study looked at how concurrent transabdominal diagnostic laparoscopy (TADL) would influence planned TEP repairs. METHODS: A prospective study oF 100 consecutive TEP cases was conducted. All patients had diagnostic laparoscopy via a 5-mm 45 degrees scope through an umbilical incision with 15 mmHg of pneumoperitoneum, followed by laparoscopic TEPrepair. A contralateral occult hernia was diagnosed and repaired if a true peritoneal eventration through the inguinal region was observed. RESULTS: Among the 100 patients, preoperative diagnosis suggested 31 bilateral hernias (31%), whereas TADL confirmed 25 bilateral hernias (25%). Of these 25 bilateral hernias, TADL confirmed 16 that had been diagnosed preoperatively (64%), but excluded 15 contralateral hernias that were incorrectly diagnosed (37%). Transabdominal diagnostic laparoscopy found nine OCHs, representing 36% of all bilateral hernias and 13% of the 69 preoperatively determined unilateral hernias. The preoperative physician examination false-negative rate for contralateral hernias was 36%, and the false-positive rate was 37%. In 26 cases (26%), TADL changed the operative approach. CONCLUSIONS: In this study, patients believed to have unilateral inguinal hernias had OCHs in 13% of cases when examined by TADL. The actual bilateral hernia incidence was 25%, with a 37% false-positive rate for preoperatively diagnosed bilateral hernias. The high rate of bilateral hernias reported by the TEP approach alone suggests that some OCH findings may be an artifact of the TEP dissection. However, failure to search for an OCH could result in up to 13% of patients subsequently requiring a second repair. Because some surgeons are concerned about unnecessary TEP dissection of the asymptomatic contralateral side, the approach described here may offer a solution to accurate diagnosis of the contralateral inguinal region during planned laparoscopic TEP hernia repair.

Advances in gastrointestinal intervention: the treatment of gastroduodenal and colorectal obstructions with metallic stents.

Metallic stents are currently an established component of the endoluminal treatment of stenoses within the blood vessels, bile ducts, esophagus, trachea, and bronchi. With the development of newer stent designs and delivery systems and the general momentum toward minimally invasive therapies, metallic stent placement has expanded into the nonsurgical therapy for gastroduodenal and colorectal obstructions. The use of metallic stents within the stomach, duodenum, or colon is intended not to be curative but to provide nonsurgical palliation for the symptoms of gastric or colonic obstruction. This palliation may be intended for the life of the patient in the case of unresectable disease or as a temporizing procedure prior to a definitive surgical procedure. In the latter clinical scenario, the benefits of a minimally invasive intestinal decompression procedure include (a) quick and noninvasive relief of the intestinal obstruction in an acutely ill patient that obviates a more extensive procedure; (b) allowance of time to improve a patient's overall medical condition and thus to allow a patient to better tolerate the definitive surgical procedure; and (c) reduction of the complexity of the definitive procedure by eliminating the need for staged procedures and allowing the definitive procedure to be performed at one setting.

Amino acid preferences of small, naturally occurring polypeptides.

An analysis of amino acid composition of small, naturally occurring peptides ranging in size from 3 to 50 residues has been carried out. The purpose of the study is to determine whether differential trends in amino acid usage exist for small peptides compared to larger polypeptides and proteins. Results indicate that Cys, Trp, and Phe are substantially more frequent in peptides compared to their abundance in proteins at large. Aliphatic hydrophobic residues, particularly Leu and Ile, are somewhat underrepresented, while the frequency of Glu is significantly reduced. The shorter peptides are also more frequently neutral and become increasingly charged as their size increases.

Effect of arrest time and cerebral perfusion pressure during cardiopulmonary resuscitation on cerebral blood flow, metabolism, adenosine triphosphate recovery, and pH in dogs.

OBJECTIVES: To test the hypothesis that greater cerebral perfusion pressure (CPP) is required to restore cerebral blood flow (CBF), oxygen metabolism, adenosine triphosphate (ATP), and intracellular pH (pHi) levels after variable periods of no-flow than to maintain them when cardiopulmonary resuscitation (CPR) is started immediately. DESIGN: Prospective, randomized, comparison of three arrest times and two perfusion pressures during CPR in 24 anesthetized dogs. SETTING: University cerebral resuscitation laboratory. INTERVENTIONS: We used radiolabeled microspheres to determine CBF and magnetic resonance spectroscopy to derive ATP and pHi levels before and during CPR. Ventricular fibrillation was induced, epinephrine administered, and thoracic vest CPR adjusted to provide a CPP of 25 or 35 mm Hg after arrest times of O, 6, or 12 mins. MEASUREMENTS AND MAIN RESULTS: When CPR was started immediately after arrest with a CPP of 25 mm Hg, CBF and ATP were 57 +/- 10% and 64 +/- 14% of prearrest (at 10 mins of CPR). In contrast, CBF and ATP were minimally restored with a CPP at 25 mm Hg after a 6-min arrest time (23 +/- 5%, 16 +/- 5%, respectively). With a CPP of 35 mm Hg, extending the no-flow arrest time from 6 to 12 mins reduced reflow from 71 +/- 11% to 37 +/- 7% of pre-arrest and reduced ATP recovery from 60 +/- 11% to 2 +/- 1% of pre-arrest. After 6- or 12-min arrest times, brainstem blood flow was restored more than supratentorial blood flow, but cerebral pHi was never restored. CONCLUSIONS: A CPP of 25 mm Hg maintains supratentorial blood flow and ATP at 60% to 70% when CPR starts immediately on arrest, but not after a 6-min delay. A higher CPP of 35 mm Hg is required to restore CBF and ATP when CPR is delayed for 6 mins. After a 12-min delay, even the CPP of 35 mm Hg is unable to restore CBF and ATP. Therefore, increasing the arrest time at these perfusion pressures increases the resistance to reflow sufficient to impair restoration of cerebral ATP.

Recurrences in laparoscopic incisional hernia repairs: a personal series and review of the literature.

OBJECTIVES: Laparoscopic repair of incisional ventral hernias with ePTFE mesh continues to evolve, with variable reporting of surgical techniques and outcomes. This report of 34 cases discusses, with a literature review of laparoscopic incisional hernia repair, specific factors associated with three recurrences. METHOD: Retrospective analysis and review of the literature. RESULTS: Thirty-two patients (16 female, 16 male), underwent 34 laparoscopic repairs: average age-54 years (27-80), average weight-207 lbs (100-300). Nineteen patients (62%) were undergoing first time repairs, 38% were redo cases and 5 cases (14%) involved previous mesh. Operating times averaged 101 minutes (45-220), and average length of stay was 1.9 days (0.6 days excluding 5 patients who required readmission), with 13 patients (38%) being discharged same-day. Two patients developed cellulitis (6%) treated without patch removal. Two enterotomies occurred (6%) both requiring patch removal. Five patients required readmission (14%), and one patient died postoperative day 29 secondary to end-stage liver disease. Three recurrences developed (9%): one secondary to missed enterotomy with reoperation, patch removal and hernia recurrence; one due to omission of suspension suture fixation; and one recurrence developed in a section of the intact old previous incision that extended beyond the original patch. Follow up has averaged 20 months (4-36). CONCLUSIONS: The laparoscopic repair of ventral and incisional hernias utilizing transabdominal placement of ePTFE patch can achieve excellent results with low morbidity in comparison with open surgical approaches. In reviewing the experience of other investigators, adequate fixation of the mesh, extension to cover the entire previous incision and standardizing the placement interval of the sutures are critical to the success of the repair.

Expandable metal stents for the treatment of colonic obstruction: techniques and outcomes.

BACKGROUND: Acute left-sided colonic obstruction is a surgical emergency whose management is controversial. Because experience using expandable metal stents for relief of this type of obstruction is limited, we evaluated their effectiveness, feasibility, safety, and outcome. METHODS: Twenty-five patients with acute colorectal obstruction underwent placement of various metal stents under fluoroscopic and endoscopic guidance. On an intent-to-treat basis, stents were placed for decompression before one-stage surgical resection in 10 patients and palliatively in 15 patients. Two preoperative patients had unresectable malignant disease, and stents were left for palliation resulting in 17 palliative and 10 preoperative patients for analysis. RESULTS: Stent placement was technically successful in 94% of patients. Overall effectiveness in relieving obstruction was 85% (palliative 82%, preoperative 90%). In the palliative group, stent duration ranged from 2 to 64 weeks (mean 17.3 weeks). Major complications occurred in 7 patients (30%). CONCLUSIONS: Expandable metal stents are a feasible, effective adjunct and alternative to surgery for acute colorectal obstruction.