Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

OBJECTIVES: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth but current evidence on dosing, candidacy, and outcomes are limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. METHODS: This single-centre, open-label, pilot phase 1 safety and feasibility clinical trial included 25 pregnant individuals with a fetal diagnosis of SVP. Participants self-administered continuous supplemental oxygen using medical-grade oxygen concentrators for up to 24 hours per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation by echocardiography and late-gestational cardiovascular magnetic resonance, early outcomes including brain growth and pre-operative brain injury, and 18-month neurodevelopmental outcomes by the Bayley Scales of Infant and Toddler Development 3rd Edition compared to a contemporary fetal SVP cohort that received standard of care (SOC). RESULTS: Among 25 participants, the average maternal age at conception was 35 years, and fetal SVP diagnoses included 16 right ventricle dominant, 8 left ventricle dominant, and 1 indeterminant ventricular morphology. Participants started the trial at approximately 29.3 gestational weeks and took MSO for a median 16.1 hours per day for 63 days, cumulating a median 1029 hours of oxygen intake from enrollment until delivery. The only treatment-associated adverse events were nasal complications that were typically resolved by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio, nor head circumference to abdominal circumference ratio Z-scores over gestation compared to SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over gestation compared to SOC (p=0.02), this was likely due to initial baseline differences in placental resistance. At late-gestational cardiovascular magnetic resonance, MSO was not associated with any significant increase in umbilical vein oxygen saturation, fetal oxygen delivery, or fetal cerebral oxygen delivery. Similarly, we observed no differences in newborn outcomes including brain volume and pre-operative brain injury, nor mortality by 18 months of age, nor neurodevelopmental outcomes at 18 months of age. CONCLUSIONS: This pilot phase 1 clinical trial indicates low-dose maternal supplemental oxygen therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with any significant changes in fetal circulatory physiology or improvements in early neurologic or neurodevelopmental outcomes. This article is protected by copyright. All rights reserved.

How phenotype guides management of the neuroendocrine carcinomas of the larynx.

OBJECTIVE: This review aimed to critically analyse data pertaining to the clinical presentation and treatment of neuroendocrine carcinomas of the larynx. METHOD: A PubMed search was performed using the term 'neuroendocrine carcinoma'. English-language articles on neuroendocrine carcinoma of the larynx were reviewed in detail.Results and conclusionWhile many historical classifications have been proposed, in contemporary practice these tumours are sub-classified into four subtypes: carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. These tumours exhibit a wide range of biological behaviour, ranging from the extremely aggressive nature of small and large cell neuroendocrine carcinomas, which usually have a fatal prognosis, to the less aggressive course of carcinoid tumours. In small and large cell neuroendocrine carcinomas, a combination of irradiation and chemotherapy is indicated, while carcinoid and atypical carcinoid tumour management entails conservation surgery.

Role of ancillary techniques in profiling unclassified laryngeal malignancies.

Laryngeal biopsies, contrary to biopsies from many other sites of the body, very often contain minute amounts of tumour tissue that may consist of morphologically undifferentiated tumour only. In haematoxylin- and eosin-stained sections, there may be no indicative features of what specific tumour entity that is present. In the larynx, particularly small round cell neoplasms, primary or metastatic, often cause a diagnostic dilemma and where an incorrect diagnosis can induce substantial clinical consequences for the patient (e.g., primary neuroendocrine carcinomas vs metastatic variants, certain sarcomas). If sufficient/representative material has been obtained, the application of immunohistochemistry and/or molecular techniques should in virtually every case reveal the true nature of the malignancy. In cases with sparse amount of material, and therefore a limited number of sections to be cut, a careful and thoughtful stepwise approach is necessary to ascertain a reliable diagnosis, or at least guide the clinician to the most likely diagnoses. With today's advanced and widely available technology with an abundance of markers to discriminate different tumours, the use of the term "undifferentiated" should be largely unnecessary. In the exceptional, and indeed exceedingly rare cases, when a classification is not possible, even after repeat biopsy, we suggest that the laryngeal neoplasm is better termed "unclassified malignant neoplasm" rather than "undifferentiated malignant neoplasm".

The Chernobyl thyroid cancer experience: pathology.

The Chernobyl accident was followed by a large increase in the incidence of thyroid carcinoma in the areas exposed to high levels of fallout. The Chernobyl Tumor Bank was set up in 1998 to make tumours available for study internationally, and a pathology panel reviewed all the tumours and established an agreed diagnosis. The thyroid tumours that were discovered after the Chernobyl nuclear accident were virtually all (95%) of the papillary carcinoma type. Rare examples of other tumour types were identified. Within the papillary group, several subtypes were noted, including classical or usual type, follicular variant, solid variant and mixed patterns Diffuse sclerosis variant, cribriform/morular type and Warthin-like variant were rare. No tall cell or columnar cell variants were identified. The tumours examined by the Pathology Panel of the Chernobyl Tumor Bank constitute a large representative sample (estimated at about 50%) of the tumours that developed in this population. This overview describes the method adopted by the panel and the different diagnostic categories adopted; illustrates the pathology of these neoplasms; compares the pathological characteristics of the early lesions with those identified after long latency periods and the institution of screening programmes and outlines the possible associated causes for the various morphological patterns seen.

Mucoepidermoid carcinoma of upper aerodigestive tract: clinicopathologic study of 78 cases with immunohistochemical analysis of Dicer expression.

MicroRNAs (miR) are small noncoding RNAs that are predicted to regulate up to 30% of protein-encoding genes. miR maturation requires functional microRNA machinery, including the Dicer protein. We review our experience with mucoepidermoid carcinoma (MEC) and characterize the prognostic value of Dicer expression. Expression of Dicer was assessed in 78 MEC by immunohistochemistry. Dicer expression was scored semiquantitatively and relative to the internal controls: large excretory/striated ducts or basal/parabasal layers of normal squamous epithelium (mucosa). Dicer scores were then correlated with clinical and pathologic parameters. Dicer over- and/or under-expression were more commonly seen in high-grade MEC (83%) than in low/intermediate grade MEC (35%; p=0.002) and in stage III/IV MEC (80%) than in stage I/II MEC (41%; p=0.04). Abnormal Dicer expression correlates with high-grade and advanced stage, acting as a univariate predictor of poor disease-specific survival (DSS) in MEC. Age and stage were independent predictors of poor DSS on multivariate analysis. Abnormal immunoexpression of Dicer in aggressive MEC suggests a role for miR and miR machinery in tumor progression.

Detecting genetic predisposition for complicated clinical outcomes after burn injury.

Sepsis, septic shock and organ failure are common among patients with moderate to severe burns. The inability of demographic and clinical factors to identify patients at high risk for such complications suggests that genetic variation may influence clinical outcome. Moreover, the genetic predisposition to death from infection has been estimated to be greater than for cardiovascular disease or cancer . While it is widely accepted that genetic factors influence many complex disease processes, controversy has emerged regarding the most appropriate methods for detection and even the validity of many published allelic associations . This article will review the few studies of genetic predisposition that have been conducted in the setting of burn injury, then discuss some of the obstacles and potential approaches for the discovery of additional allelic associations.

TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury.

CONTEXT: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries. The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury. OBJECTIVE: Resolution of genetic variants associated with severe sepsis following burn injury. PATIENTS: A total of 159 patients with burns > or =20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)> or =16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission. METHODS: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 -159) and inflammatory response (TNF-alpha -308, IL-1beta -31, IL-6 -174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality. RESULTS: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2). Carriage of the TNF-alpha -308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0). None of the SNPs examined were significantly associated with mortality. CONCLUSIONS: The TLR4 +896 and TNF-alpha -308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

Sentinel lymph node biopsy identifies occult nodal metastases in patients with Marjolin's ulcer.

Since Marjolin's description, the management of burn scar carcinoma has remained controversial. A multitude of options and recommendations exist for the management of both primary lesions and regional nodal metastasis. This work reviews six cases of Marjolin's ulcer staged using sentinel lymph node biopsy. All primary lesions were confirmed to be squamous cell carcinoma and occurred a median of 29.5 years after burn. No patient had clinically detectable lymphadenopathy. In all cases, preoperative lymphoscintigraphy successfully identified a single draining regional nodal basin. Subsequent intraoperative lymphatic mapping/sentinel lymph node (SLN) biopsy was successful in five of six cases (83%). A successful intraoperative lymphatic mapping/SLN biopsy was defined as the identification of blue (uptake of isosulfan blue dye) or "hot" (uptake of radiolabeled sulfur colloid as measured with a handheld gamma counter) node(s) and subsequent excision. Four of five SLN biopsies identified previously occult nodal metastasis. SLN biopsy represents a minimally invasive and accurate staging procedure for Marjolin's ulcer.

Serial measurements increase the accuracy of laser Doppler assessment of burn wounds.

Traditional methods of judging burn depth by clinical evaluation of the wound based on appearance and sensation remain in wide use but are subject to individual variation by examiner. In addition to the clinical difficulties with burn wound management, observer dependency of wound assessment complicates clinical trials of burn wound therapy. A laser Doppler flowmeter with a multichannel probe was used to measure burn wound perfusion as a tool to predict wound outcome. Serial measurement with laser Doppler flowmetry had an 88% specificity and a positive predictive value of 81% for identifying nonhealing wounds. These results suggest that laser Doppler flowmetry is a potentially useful tool for burn wound assessment.

A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century.

Toxic epidermal necrolysis (TEN) is a potentially fatal disorder that involves large areas of skin desquamation. Patients with TEN are often referred to burn centers for expert wound management and comprehensive care. The purpose of this study was to define the presenting characteristics and treatment of TEN before and after admission to regional burn centers and to evaluate the efficacy of burn center treatment for this disorder. A retrospective multicenter chart review was completed for patients admitted with TEN to 15 burn centers from 1995 to 2000. Charts were reviewed for patient characteristics, non-burn hospital and burn center treatment, and outcome. A total of 199 patients were admitted. Patients had a mean age of 47 years, mean 67.7% total body surface area skin slough, and mean Acute Physiology and Chronic Health Evaluation (APACHE II) score of 10. Sixty-four patients died, for a mortality rate of 32%. Mortality increased to 51% for patients transferred to a burn center more than one week after onset of disease. Burn centers and non-burn hospitals differed in their use of enteral nutrition (70 vs 12%, respectively, P < 0.05), prophylactic antibiotics (22 vs 37.9%, P < 0.05), corticosteroid use (22 vs 51%, P < 0.05), and wound management. Age, body surface area involvement, APACHE II score, complications, and parenteral nutrition before transfer correlated with increased mortality. The treatment of TEN differs markedly between burn centers and non-burn centers. Early transport to a burn unit is warranted to improve patient outcome.

Repeated injury to the lumbar nerve roots produces enhanced mechanical allodynia and persistent spinal neuroinflammation.

STUDY DESIGN: A lumbar radiculopathy model investigated pain behavioral responses after nerve root reinjury. OBJECTIVES: To gain a further understanding of central sensitization and neuroinflammation associated with chronic lumbar radiculopathy after repeated nerve root injury. SUMMARY OF BACKGROUND DATA: The pathophysiologic mechanisms associated with chronic radicular pain remain obscure. It has been hypothesized that lumbar root injury produces neuroimmunologic and neurochemical changes, sensitizing the spinal cord and causing pain responses to manifest with greater intensity and longer duration after reinjury. However, this remains untested experimentally. METHODS: Male Holtzman rats were divided into two groups: a sham group having only nerve root exposure, and a chromic group in which the nerve root was ligated loosely with chromic gut suture. Animals underwent a second procedure at 42 days. The chromic group was further divided into a reinjury group and a chromic-sham group, in which the lumbar roots were only re-exposed. Bilateral mechanical allodynia was continuously assessed throughout the study. Qualitative assessment of spinal cord glial activation and IL-beta expression was performed. RESULTS: Mechanical allodynia was significantly greater on both the ipsilateral and contralateral sides after reinjury (P < 0.001), and the response did not return to baseline after reinjury, as it did with the initial injury. There were also persistent spinal astrocytic and microglial activation and interleukin-1beta expression. CONCLUSIONS: The bilateral responses support central modulation of radicular pain after nerve root injury. An exaggerated and more prolonged response bilaterally after reinjury suggests central sensitization after initial injury. Neuroinflammatory activation in the spinal cord further supports the hypothesis that central neuroinflammation plays an important role in chronic radicular pain.

Differential activation of coronary and pulmonary endothelial cells by thermal injury.

Remote organ dysfunction during resuscitation of severe thermal injury is characterized by early, transient pulmonary insufficiency and cardiac contractile dysfunction. Thermal injury is typified by profound systemic alterations of endothelial immunological, vasoactive, and barrier functions. The unique location of this ubiquitous, fragile monolayer makes it vulnerable to circulating serum factors created at remote cutaneous wounds. We examined endothelial "activation" in 2 distinct cell types, human coronary and pulmonary endothelial cells (EC), after severe thermal injury. By using human serum isolated at specific times after thermal injury ("early" [2 h post-burn] or "late" [26 h post-burn]), the endothelial release of vasoactive mediators, ICAM-1 expression, and monolayer permeability were assessed in vitro. Early burn serum enhanced coronary EC vasoconstrictor (ET-1) release and ICAM expression, inhibited vasodilator (PGI2) release, but had no effect on permeability. Conversely, under similar conditions, pulmonary EC PGI2 release and permeability were enhanced, ET-1 release was diminished, but ICAM was unaffected. Late burn serum enhanced vasodilator (NO) release and permeability to albumin in both coronary and pulmonary EC, whereas ET-1 release was inhibited. Under these conditions, only pulmonary ICAM expression was significantly enhanced. These data suggest that human endothelium isolated from divergent vascular beds are activated by burn injury in a unique manner for time post-burn and vascular site of cell origin.

Magnetic resonance imaging of the ovary.

Magnetic resonance imaging (MRI) of the pelvis can characterize a wide variety of ovarian lesions. We discuss MRI strategies for identification and characterization of ovarian neoplasms and correlate MRI findings with lesion gross pathological and histopathological structure.

Objective estimates of the incidence and consequences of multiple organ dysfunction and sepsis after burn trauma.

BACKGROUND: Organ dysfunction and sepsis are frequent after major burn trauma, represent quantifiable consequences of the systemic response to injury, and may be important end points by which to measure treatment effectiveness. However, standard and widely applied methods for their measurement have not been applied to burn trauma victims. Therefore, the purpose of this study was to quantify these complications after burn trauma. METHODS: Patients with > or = 20% total body surface area burns admitted to a single center were prospectively enrolled. Standard sepsis criteria and multiple organ dysfunction (MOD) scores for the pulmonary, renal, cardiovascular, hepatic, and hematologic systems were determined. The incidence and risk factors for severe MOD (cumulative MOD score > or = 6) and severe sepsis were determined. The relationships between these complications and mortality and resource utilization were examined by univariate and multivariate analyses. RESULTS: A total of 85 patients were enrolled over 1 year. Severe MOD developed in 24 (28%) and severe sepsis or septic shock developed in 12 (14%). Both were associated with increasing age and burn size and were more likely to occur in men. Most patients who developed severe MOD or severe sepsis survived (71% and 67%, respectively), and both were associated with longer intensive care unit stays and duration of mechanical ventilation. CONCLUSION: According to simple and objective scoring systems, severe MOD and severe sepsis/septic shock are both related to burn size, age, and male sex. Both are related to intensive care unit length of stay and duration of mechanical ventilation.

Ovarian teratomas: tumor types and imaging characteristics.

Ovarian teratomas include mature cystic teratomas (dermoid cysts), immature teratomas, and monodermal teratomas (eg, struma ovarii, carcinoid tumors, neural tumors). Most mature cystic teratomas can be diagnosed at ultrasonography (US) but may have a variety of appearances, characterized by echogenic sebaceous material and calcification. At computed tomography (CT), fat attenuation within a cyst is diagnostic. At magnetic resonance (MR) imaging, the sebaceous component is specifically identified with fat-saturation techniques. The US appearances of immature teratoma are nonspecific, although the tumors are typically heterogeneous, partially solid lesions, usually with scattered calcifications. At CT and MR imaging, immature teratomas characteristically have a large, irregular solid component containing coarse calcifications. Small foci of fat help identify these tumors. The US features of struma ovarii are also nonspecific, but a heterogeneous, predominantly solid mass may be seen. On T1- and T2-weighted images, the cystic spaces demonstrate both high and low signal intensity. Familiarity with the US, CT, and MR imaging features of ovarian teratomas can aid in differentiation and diagnosis.

An evaluation of risk factors for mortality after burn trauma and the identification of gender-dependent differences in outcomes.

BACKGROUND: The primary objective of this study was to determine an objective method for estimating the risk of mortality after burn trauma, and secondarily, to evaluate the relationship between gender and mortality, in the setting of a quantifiable inflammatory stimulus. Previously reported estimates of mortality risk after burn trauma may no longer be applicable, given the overall reduction in case-fatality rates after burn trauma. We expect that future advances in burn trauma research will require careful and ongoing quantification of mortality risk factors to measure the importance of newly identified factors and to determine the impact of new therapies. Conflicting clinical reports regarding the impact of gender on survival after sepsis and critical illness may in part, be from different study designs, patient samples, or failure to adequately control for additional factors contributing to the development ofsepsis and mortality. STUDY DESIGN: Data from the prospectively maintained burn registry for patients admitted to the Parkland Memorial Hospital burn unit between January 1, 1989 and December 31, 1998 were analyzed. Logistic regression was used to generate estimates of the probability of death in half of the study sample, and this model was validated on the second half of the sample. Risk factors evaluated for their relationship with mortality were: age, inhalation injury, burn size, body mass (weight), preexisting medical conditions, nonburn injuries, and gender. RESULTS: Of 4,927 patients, 5.3% died. The best model for estimating mortality included the percent of total body surface area burned; the percent of full-thickness burn size; the presence of an inhalation injury; age categories of: < 30 years, 30 to 59 years, > or = 60 years; and gender. The risk of death was approximately two-fold higher in women aged 30 to 59 years compared with men of the same age. CONCLUSIONS: We have provided a detailed method for estimating the risk of mortality after burn trauma, based on a large, contemporary cohort of patients. These estimates were validated on a second sample and proved to predict mortality accurately. We have identified an increased mortality risk in women of 30 to 59 years of age.

The fate of the coracoacromial ligament in arthroscopic acromioplasty: an anatomical study.

This study defines the normal anatomical relationships among the coracoacromial ligament, the deltoid, and the acromion in cadavers. The effect of arthroscopic acromioplasty on the acromial attachments of the coracoacromial ligament and the anterior fibers of the deltoid was also studied. After arthroscopic acromioplasty, the fibers of coracoacromial ligament and overlying deltoid inserting into the anterior part of the acromion remained attached to the acromion by a bridge of tissue composed of periosteum and collagen fibers of the coracoacromial ligament and deltoid tendon. We have called this the coracoacromial-deltoid-periosteal complex; it has not previously been described. This study demonstrates that arthroscopic acromioplasty preserves the acromial attachment of the coracoacromial ligament and the anterior fibers of the deltoid.

Cardiovascular effect of 7.5% sodium chloride-dextran infusion after thermal injury.

HYPOTHESIS: Clinical study can help determine the safety and cardiovascular and systemic effects of an early infusion of 7.5% sodium chloride in 6% dextran-70 (hypertonic saline-dextran-70 [HSD]) given as an adjuvant to a standard resuscitation with lactated Ringer (RL) solution following severe thermal injury. DESIGN: Prospective clinical study. SETTING: Intensive care unit of tertiary referral burn care center. PATIENTS: Eighteen patients with thermal injury over more than 35% of the total body surface area (TBSA) (range, 36%-71%) were studied. INTERVENTIONS: Eight patients (mean +/- SEM, 48.2% +/- 2% TBSA) received a 4-mL/kg HSD infusion approximately 3.5 hours (range, 1.5-5.0 hours) after thermal injury in addition to routine RL resuscitation. Ten patients (46.0% +/- 6% TBSA) received RL resuscitation alone. MAIN OUTCOME MEASURES: Pulmonary artery catheters were employed to monitor cardiac function, while hemodynamic, metabolic, and biochemical measurements were taken for 24 hours. RESULTS: Serum troponin I levels, while detectable in all patients, were significantly lower after HSD compared with RL alone (mean +/- SEM, 0.45 +/- 0.32 vs 1.35 +/- 0.35 microg/L at 8 hours, 0.88 +/- 0.55 vs 2.21 +/- 0.35 microg/L at 12 hours). While cardiac output increased proportionately between 4 and 24 hours in both groups (from 5.79 +/- 0.8 to 9.45 +/- 1.1 L/min [mean +/- SEM] for HSD vs from 5.4 +/- 0.4 to 9.46 +/- 1.22 L/min for RL), filling pressure (central venous pressure and pulmonary capillary wedge pressure) remained low for 12 hours after HSD infusion (P = .048). Total fluid requirements at 8 hours (2.76 +/- 0.7 mL/kg per each 1% TBSA burned [mean +/- SEM] for HSD vs 2.67 +/- 0.24 mL/kg per each 1% TBSA burned for RL) and 24 hours (6.11 +/- 4.4 vs 6.76 +/- 0.75 mL/kg per each 1% TBSA burned) were similar. Blood pressure remained unchanged, and serum sodium levels did not exceed 150 +/- 2 mmol/L (mean +/- SD) in either group. CONCLUSIONS: The absence of deleterious hemodynamic or metabolic side effects following HSD infusion in patients with major thermal injury confirms the safety of this resuscitation strategy. Postburn cardiac dysfunction was demonstrated in all burn patients through the use of cardiospecific serum markers and pulmonary artery catheter monitoring. Early administration of HSD after a severe thermal injury may reduce burn-related cardiac dysfunction, but it had no effect on the volume of resuscitation or serum biochemistry values.