Evolving indications and long-term oncological outcomes of risk-reducing bilateral nipple-sparing mastectomy.

Background: Bilateral nipple-sparing mastectomy (NSM) is a technically feasible operation and is associated with excellent cosmetic outcomes. The aim of this study was to evaluate trends in patient characteristics, indications for surgery and long-term outcomes of bilateral NSM for breast cancer risk reduction over time. Methods: A review of a single-centre experience with bilateral NSM performed between 2001 and 2017 for breast cancer risk reduction in patients without breast cancer was performed. Trends in patient characteristics and indications for surgery were evaluated over four time intervals: 2001-2005, 2006-2009, 2010-2013 and 2014-2017. Statistical analysis was performed using χ2 tests. Results: Over the study period, 272 NSMs were performed in 136 patients; their median age was 41 years. The number of bilateral NSMs performed increased over time. The most common indication was a mutation in breast cancer-associated genes (104 patients, 76·5 per cent), which included BRCA1 (62 patients), BRCA2 (35), PTEN (2), TP53 (3) and ATM (2). Other indications were family history of breast cancer (19 patients, 14·0 per cent), lobular carcinoma in situ (10, 7·4 per cent) and a history of mantle irradiation (3, 2·2 per cent). The proportion of patients having a bilateral NSM for mutation in a breast cancer-associated gene increased over time (2001-2005: 2 of 12; 2006-2009: 9 of 17; 2010-2013: 34 of 41; 2014-2017: 61 of 66; P < 0·001). Mean follow-up was 53 months; no breast cancers were found during follow-up. Conclusion: The use of bilateral NSM for breast cancer risk reduction is increasing and the indications have evolved over the past 16 years. These excellent long-term oncological results suggest that bilateral NSM is a good option for surgical breast cancer risk reduction.

Time to treatment and survival in triple negative breast cancer patients receiving trimodality treatment in the United States.

BACKGROUND: Time from diagnosis to treatment for breast cancer patients has been linked to outcomes. Our goal was to assess the relationship between survival, time to first treatment (TFT), and time to treatment completion (TTC) in Stage I-III triple negative breast cancer (TNBC) receiving trimodality therapy (surgery, chemotherapy, and radiation). METHODS: National Cancer Database (NCDB) was queried for TNBC patients diagnosed with Stage I-III disease from 2010 to 2011 who received all treatments (surgery, chemotherapy, radiation) within 18 months of diagnosis. Multivariate analysis controlled for age, stage, operation, neoadjuvant chemotherapy (NAC), and comorbidities. RESULTS: 17,717 women were included. Most had early stage disease (34.1% Stage 1; 48.2% Stage 2) treated with lumpectomy (69.2%) and adjuvant chemotherapy (63.3%). During follow-up (2.8 ±â€¯1.1 years), mortality was 11.4%. TFT was 34.8 days for NAC and 35.6 days for surgery. Multivariate analysis demonstrated no mortality difference when considering TFT in 30 day (p = 0.43) or 6 week (p = 0.91) intervals. When separating into NAC or surgery first, there remained no mortality difference when considering TFT in 30 day (NAC p = 0.96, surgery p = 0.26) or 6 week (NAC p = 0.91, surgery p = 0.91) intervals. Overall, TTC was 9.0 ±â€¯1.8 months. When dividing patients into tertiles by TTC, multivariate analysis demonstrated no survival difference between groups (p = 0.9). There was also no mortality difference for each 30 day increased TTC (p = 0.40). CONCLUSIONS: In Stage I-III TNBC patients receiving trimodality therapy, TFT (NAC or surgery) and TTC do not impact short-term survival if TTC is <18 months.

Use of an automated circuit for isolated limb infusion for malignancy.

BACKGROUND: Isolated limb infusion (ILI) for recurrent or in-transit melanoma is an accepted technique that allows high-dose chemotherapy to be delivered to an extremity with minimal systemic toxicity. Current infusion systems have relied on manual delivery of drugs and circulation of blood during the treatment. Herein, we document our initial results with an automated circuit for ILI as an alternative to the manual technique. METHODS: Patients undergoing ILI with an automated circuit for recurrent or advanced malignancy were identified. ILI was performed utilizing a Sarns 8000 roller pump attached to a Cobe 4:1 cardioplegia set with heat exchanger with a total priming volume of 80 ml. Melphalan (7.5 mg/L) and Dactinomycin (75 µg/L) doses which were corrected for ideal body weight were delivered via the infusion circuit after limb temperature reached 38 °C. RESULTS: Fourteen lower extremity infusion procedures were performed in 10 patients. Successful infusion procedures were completed in all patients using the automated circuit. Constant flow rates of 50-70 cc/minute were achievable with the automated circuit. Acute toxicity and clinical results were similar to that reported with manual delivery systems. CONCLUSION: ILI for advanced malignancy utilizing an automated circuit is feasible and safe. This automated system offers a safe and reliable alternative to the manual infusion technique.

Gold nanoparticles as a contrast agent for in vivo tumor imaging with photoacoustic tomography.

Photoacoustic tomography (PAT) is a rapidly emerging non-invasive imaging technology that integrates the merits of high optical contrast with high ultrasound resolution. The ability to quantitatively and non-invasively image nanoparticles has important implications for the development of nanoparticles as in vivo cancer diagnostic and therapeutic agents. In this study, the ability of systemically administered poly(ethylene glycol)-coated (PEGylated) gold nanoparticles as a contrast agent for in vivo tumor imaging with PAT has been evaluated. We demonstrate that gold nanoparticles (20 and 50 nm) have high photoacoustic contrast as compared to mouse tissue ex vivo. Gold nanoparticles can be visualized in mice in vivo following subcutaneous administration using PAT. Following intravenous administration of PEGylated gold nanoparticles to tumor-bearing mice, accumulation of gold nanoparticles in tumors can be effectively imaged with PAT. With gold nanoparticles as a contrast agent, PAT has important potential applications in the image guided therapy of superficial tumors such as breast cancer, melanoma and Merkel cell carcinoma.

Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma.

BACKGROUND: The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas. PATIENTS AND METHODS: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors. RESULTS: NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC. CONCLUSION: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.

Adult perineal sarcomas.

BACKGROUND AND OBJECTIVES: Primary perineal sarcoma in adults is a rare disease that has only been documented to occur in isolated case reports. METHODS: To better characterize and define the natural history of perineal sarcoma in adults (> or = 18 years), we reviewed our experience with treatment of perineal sarcoma between 1982 and 1999 (nine cases). RESULTS: Epithelioid sarcoma (n = 4) was the most common histologic subtype. Seven cases (78%) were histologically high grade, and lesions were most commonly < 5 cm. All patients were treated with wide local excision. External beam radiation was the most commonly used form of adjuvant therapy (n = 6). Recurrences were noted in five patients, and the recurrences were most commonly local (60%). Median time to first recurrence was 21 months. Six of nine patients are alive with a median follow-up of 54 months. Three died of recurrent/metastatic disease at 16, 51, and 54 months after initial surgery. CONCLUSIONS: Aggressive therapy and follow-up beginning with wide excision can be associated with long-term survival in adults with primary perineal sarcoma.

Malnutrition-induced macrophage apoptosis.

BACKGROUND: Human and murine studies suggest protein-calorie malnutrition (PCM) results in significant host immunosuppression resulting in increased morbidity and mortality. Apoptosis has been implicated as an important mediator in the immunosuppression observed in several disease states. This study was designed to characterize macrophage apoptosis in a murine model of PCM and investigate components that regulate the apoptotic process, such as protein kinase C (PKC) and Bcl-2 activity. METHODS: Swiss-Webster mice (n = 50) were randomly assigned to receive either a control (24% protein) or a PCM diet (0% protein) for 7 days. Peritoneal macrophages were harvested and detection of apoptosis was performed by terminal deoxy-transferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) and propidium iodide DNA staining under baseline and pro-apoptotic conditions. Pro-apoptotic conditions included cells treated with tumor necrosis factor-alpha (TNF-alpha) (10 ng/mL), interferon-gamma (IFN-gamma) (10 ng/mL), and a combination of both agents. In addition, levels of PKC activity and expression of Bcl-2 and p53 protein were measured. RESULTS: Peritoneal macrophages from PCM mice had a significantly greater amount of apoptosis at baseline and under stimulated conditions compared with controls. Levels of PCM apoptosis were elevated at baseline by TUNEL staining compared with macrophages from the control group (16.5% +/- 1.4%, versus 4.5% +/- 1.1%, P <.01). In addition, peritoneal macrophages from the malnourished animals were significantly more susceptible to the apoptotic effect of TNF-alpha and the effects of INF-gamma (27.3% +/- 2.1% and 31% +/- 1.4%) compared with control mice (5.5% +/- 0.7% and 7.2% +/- 0.5%, P <.01), respectively. Again, an increase in the baseline apoptosis rate was demonstrated in peritoneal macrophages from PCM mice compared with control fed mice (13.2% +/- 4.4% versus 4.3% +/- 3.1%, P <.01) as measured by propidium iodide staining. The combination of agents, TNF-alpha and INF-gamma, resulted in an additive apoptotic effect in the malnourished host compared with the control animals (43.4% +/- 4.7% versus 10.5% +/- 2.2%, P <.01), respectively. Furthermore, there was a significant decrease in the mean total PKC activity in the malnourished macrophages compared with results in controls (110,000 +/- 8000 versus 60,000 +/- 4000 cpm, P <.01). Similar changes were also observed in PKC cytosolic and membrane activity between both groups. In addition, Bcl-2 protein expression was significantly decreased in PCM animals compared with control animals. CONCLUSIONS: Thus, peritoneal macrophages from PCM mice exhibit significantly greater levels of apoptosis at baseline and when stimulated with pro-apoptotic agents compared with controls. The propensity of macrophages from PCM mice to undergo apoptosis may be attributable in part to decreased PKC activity and Bcl-2 protein expression. These findings may help to explain the associated immune dysfunction observed in malnutrition.

Pancreatic anastomotic failure after pancreaticoduodenectomy.

BACKGROUND: Pancreatic anastomotic failure has historically been regarded as one of the most feared complications after pancreaticoduodenectomy. METHODS: We reviewed our recent experience (59 cases), March 1994 to December 1998, with pancreaticoduodenectomy and compared preoperative and intraoperative characteristics as well as outcomes in those patients who experienced (n = 10) versus those who did not experience a postoperative pancreatic leak (n = 49). Information was retrospectively collected from hospital records, office records, and interviews with patients. RESULTS: The clinical leak rate in this series was 8.5%. There were no significant differences in preoperative or intraoperative characteristics comparing those with versus those without a postoperative pancreatic leak. Only 1 of 10 patients with a postoperative pancreatic leak required reoperation to manage the leak. Those with a pancreatic leak had more other postoperative complications (median 2 versus 0 complications per patient, P = 0.01) and longer hospital duration compared with those without a leak (median 13 versus 23 days, P<0.01). Overall mortality in the series was 3.4%; no mortalities occurred as a result of a pancreatic leak. CONCLUSIONS: In the 1990s pancreatic anastomotic leak remains a potentially lethal problem after pancreaticoduodenectomy. Pancreatic leakage after pancreaticoduodenectomy is associated with other postoperative complications and a longer hospital stay.

Interpretation of computed tomography does not correlate with laboratory or pathologic findings in surgically confirmed acute appendicitis.

BACKGROUND: Computed tomography (CT) is used increasingly to diagnose acute appendicitis, despite variable technique and interpretation. We hypothesized that CT interpretation would not reflect actual clinical-pathologic findings in all demographic patient groups. METHODS: A prospective university hospital database of 625 consecutive patients (1995-1999), all of whom were operated on for appendicitis (261, or 41.8%, within 24 hours of discretionary CT), was reviewed. CT and pathology data were obtained from final, written reports. CT criteria included free fluid or air, appendiceal visualization, mesenteric fat stranding, and blurred pericecal fat. Appendix pathology included acute, gangrenous, and perforated organs. Statistics were performed with the Fisher exact test (coordinate data) and univariate analysis of variance (continuous data); multivariate analysis of variance for independent effects on dependent variable (positive CT or pathology; P <.05). RESULTS: The mean age was 35 +/- 1 years with 46.6% being female patients. CT was done more often in women and after 1997 (both P <.05). The sensitivity and specificity of CT were 96.1% and 16.1%, respectively. The positive predictive value (PPV) and accuracy rate (A) were 90%, and 88%, respectively. After CT, the incidence of finding a normal appendix was lower (19.3% vs 12.3%, P <.05), especially if the white blood cell count (WBC) was normal (< or = 11K/microL, 6.1% vs 23.2%, P <.001). If the WBC was < or = 11K/microL with positive CT, PPV/A was 73. 7%/71.3%, whereas with WBC > 11K/microL and positive CT, PPV/A was 99.4%/93.3%. Multivariate analysis of variance showed that none of the individual variables used by the radiologist to determine a positive CT scan correlated with outcome determined by surgical pathology. A healthy appendix was predicted by a CT interpreted as negative and younger age (both P <.05), and especially by lower WBC (P <.0001), but not by gender or surgeon. CONCLUSIONS: Although the negative appendectomy rate was decreased by CT, there was no correlation between CT findings and pathologically proved disease. Other factors such as more precise patient selection by clinical criteria may also be improving outcome. A positive CT scan in a patient with a normal WBC should be interpreted with caution.

Elevation of IL-18 in human sepsis.

Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine that shares biochemical features with IL-1beta and acts in part by inducing interferon-gamma (IFN-gamma). Endotoxic bacterial lipopolysaccharide (LPS) (1 or 2 ng/kg) was insufficient to increase plasma IL-18 in five healthy adults measured 3, 12, and 24 hr following challenge. In contrast, in the first 96 hr of admission to the surgical intensive care unit, mean maximal serum IL-18 was elevated (1,122 +/- 259 pg/ml) in nine septic patients compared to six healthy adults (191 +/- 42 pg/ml), P < 0.01). Serum IL-18 concentrations in septic patients did not correlate with other measured inflammatory mediators: tumor necrosis factor, IL-6, IL-10, or secretory leukocyte protease inhibitor. Therefore, IL-18 circulates in healthy adults and is a component of the human systemic inflammatory response. Further, stimuli other than LPS may induce IL-18 production in vivo in human sepsis.

Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia.

OBJECTIVES: To document changes in serum secretory leukocyte protease inhibitor (SLPI) in human sepsis and in experimental endotoxemia in vivo. To compare changes in serum SLPI in human sepsis with changes in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. To determine whether or not changes in SLPI correlate with the severity of multiple organ dysfunction syndrome as measured by the maximal multiple organ dysfunction score. Finally, because neutrophils have been implicated in tissue injury associated with organ dysfunction, to determine whether recombinant human SLPI blocks activation of isolated human neutrophils. DESIGN: Case-control study and ex-vivo cellular assay. SETTING: Surgical intensive care unit and clinical research center of university hospitals; laboratory of a medical school. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There was a significant dose-dependent elevation (50.2+/-4.0 ng/mL, p = .01) in plasma SLPI 12 hrs after administration of lipopolysaccharide to seven healthy adults (36.4+/-2.3 ng/mL). Further, serum concentrations of SLPI (132+/-15 ng/mL) were elevated in septic surgical patients compared with healthy controls (43+/-2 ng/mL, p < .01) and nonseptic surgical controls (69+/-10 ng/mL, p = .01). Serum SLPI concentrations correlated (r2 = .71, p < .01) better with organ dysfunction as measured by maximal multiple organ dysfunction score than did serum IL-6 (r2 = .49, p < .01), IL-10 (r2 = .05, p = .22), or TNF-alpha (r2 = .02, p = .44). We found that recombinant human SLPI in vitro inhibits TNF-alpha-induced hydrogen peroxide production by human neutrophils (ID50 = 1-2 microg/mL). CONCLUSIONS: Serum SLPI is elevated in human sepsis and experimental endotoxemia. Maximal concentrations of serum SLPI correlate significantly with maximal multiple organ dysfunction scores in patients with sepsis. Secretory leukocyte protease inhibitor may function to limit ongoing neutrophil-mediated tissue injury associated with organ dysfunction.

Role of surgery in the management of postmastectomy extremity angiosarcoma (Stewart-Treves syndrome).

Stewart-Treves syndrome (STS) is the rare occurrence of angiosarcoma in a setting of postmastectomy upper extremity lymphedema. A collective comparison of outcomes following various initial treatment options in STS has not previously been reported. We reviewed 160 cases of STS reported in the literature since 1966. We analyzed the relationship between initial treatment and survival in all 92 of these patients for whom detailed treatment and outcome data had been reported. There was no significant difference in survival comparing those initially treated with wide excision (n = 16) and those treated with amputation (n = 45) (P = 0.40). Even in the setting of initial surgical treatment, overall long-term survival was poor (<40%). There have been even fewer long-term survivors among those treated initially with regional chemotherapy (n = 7) or radiation therapy (n = 24). An update on STS and a discussion of recent advances in the understanding of its molecular pathogenesis that may result in future treatment improvements are presented.

Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock.

BACKGROUND: Septic shock is a leading cause of mortality in intensive care units. No new interventions in the last 20 years have made a substantial impact on the outcome of patients with septic shock. Identification of inhibitable pathways that mediate death in shock is an important goal. MATERIALS AND METHODS: Two novel caspase inhibitors, (2-indolyl)-carbonyl-Ala-Asp-fluoromethylketone (IDN 1529) and (1-methyl-3-methyl-2-indolyl)-carbonyl-Val-Asp-fluoromethylketone (IDN 1965), were studied in a murine model of endotoxic shock. RESULTS: IDN 1529 prolonged survival when given before or up to 3 hr after high-dose LPS (p < 0.01) and increased by 2.2-fold the number of animals surviving longterm after a lower dose of LPS (p < 0.01). Despite its similar chemical structure, IDN 1965 lacked these protective effects. Both compounds inhibited caspases 1, 2, 3, 6, 8, and 9, and both afforded comparable reduction in Fas- and LPS-induced caspase 3-like activity and apoptosis. Paradoxically, administration of IDN 1529 but not IDN 1965 led to an increase in the LPS-induced elevation of serum cytokines related directly (IL-1beta, IL-18) or indirectly (IL-1alpha, IL-1Ra) to the action of caspase 1. CONCLUSIONS: A process that appears to be distinct from both apoptosis and the release of inflammatory cytokines is a late-acting requirement for lethality in endotoxic shock. Inhibition of this process can rescue mice even when therapy is initiated after LPS has made the mice severely ill.

Echocardiographic and survival studies in mice undergoing endotoxic shock: effects of genetic ablation of inducible nitric oxide synthase and pharmacologic antagonism of platelet-activating factor.

Evidence implicating inducible nitric oxide synthase (iNOS) in the alterations of cardiac function characteristic of septic shock has come mostly from studies on anesthetized animals, isolated hearts, cultured myocytes, or hosts treated with pharmacologic inhibitors that lack complete specificity for iNOS. Platelet-activating factor (PAF) can participate in the induction of iNOS and has also been implicated in cardiac dysfunction in sepsis. The present studies assessed cardiac function in a model of sepsis in awake mice in which the gene for iNOS was either normal or selectively disrupted. Mice of each genotype were treated with parenteral fluids or with a highly specific antagonist of PAF. Endotoxic shock was induced by challenge with bacterial lipopolysaccharide (LPS) after priming with heat-killed Propionobacterium acnes. Wild-type mice increased stroke volume and cardiac output in response to LPS. These changes were absent in iNOS-deficient mice. When treated with parenteral fluids, LPS-challenged wild-type and iNOS-deficient mice both had a marked reduction in cardiac output. Antagonism of PAF had no effect on echocardiographic indices in wild-type mice, but selectively overcame the bradycardia and reduced cardiac output elicited by fluid administration in LPS-shocked, iNOS-deficient mice. Thus, there are major cardiovascular effects of PAF that are shared by rather than mediated by iNOS. Neither complete iNOS deficiency nor antagonism of PAF improved survival, whether tested as single or combined intervention. On the contrary, complete deficiency of iNOS was detrimental to survival. Finally, we tested the hypothesis that iNOS deficiency might improve survival if the deficiency were specific but partial. For this, we used mice with one normal and one disrupted gene for iNOS. No survival advantage was evident for these iNOS heterozygotes. Thus, partial or complete inhibition of iNOS, with or without antagonism of PAF, afforded no evident benefit beyond the previously demonstrated reduction in hypotension. Finally, these studies demonstrate that echocardiography preceded by acclimatization is feasible in unanesthetized mice, a finding which should expand the value of genetically manipulated animals for analysis of cardiac function.

Colonic manifestations of multiple endocrine neoplasia type 2B: report of four cases.

Multiple endocrine neoplasia type 2B is best known for its endocrine manifestations and typical phenotype. The gastrointestinal manifestations, however, are also an important and commonly unrecognized component of the syndrome. We present four cases that demonstrate the varied presentation of patients with colonic manifestations of multiple endocrine neoplasia type 2B. We discuss the cause, diagnostic significance, and management of the colonic disease that is a component of multiple endocrine neoplasia type 2B.

Lethality of endotoxin in mice genetically deficient in the respiratory burst oxidase, inducible nitric oxide synthase, or both.

Two classes of oxidants are thought to play a critical role in tissue damage in septic shock: reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). Particular importance has been ascribed to peroxynitrite, a product arising from the reaction of nitric oxide with superoxide. A major source of ROI is the respiratory burst oxidase of neutrophils, eosinophils, monocytes, and macrophages. A major source of RNI is inducible nitric oxide synthase (iNOS), an enzyme expressed in leukocytes, hepatocytes, vascular smooth muscle cells, endothelium, and cardiac myocytes during inflammation. In previous studies using various mouse models of endotoxic shock, genetic deficiency of iNOS as a sole intervention did not consistently alter survival. Here, using Salmonella typhimurium endotoxic bacterial lipopolysaccharide (LPS) as a sole challenge, genetic deficiency of iNOS was associated with no protection or a reduction in survival, depending on the dose of LPS. Further, no protection from lethality was observed when LPS was injected into mice genetically deficient in the 91 kDa subunit of the respiratory burst oxidase (gp91phox) nor in mice genetically deficient in both gp91phox and iNOS (gp91phox-/-/NOS2-/- mice). For the latter experiments, mice were challenged either with S. typhimurium LPS alone or with inactivated bacille Calmette-Guerin (BCG) followed by Escherichia coli LPS. Deficiency of gp91phox impaired the inflammatory response to inactivated Propionobacterium acnes, rendering survival studies following priming with P. acnes difficult to interpret. Thus, in two models of endotoxic shock, major reductions in the ability to form nitric oxide or superoxide, alone or in combination, failed to improve survival.

Alcohol, drug intoxication, or both at the time of burn injury as a predictor of complications and mortality in hospitalized patients with burns.

The objective of this study was to characterize the association between drug and alcohol intoxication at the time of injury and subsequent complications and mortality in hospitalized patients with burns. A computerized burn database was used to analyze data on 3047 consecutive adult (21 to 75 years) hospitalized patients with burns admitted between January 1982 and August 1994. Data for intoxicated (by history, blood alcohol content, or positive drug screen) and nonintoxicated patients were compared. The same analysis was also conducted on 429 consecutive adolescent patients with burns (ages 14 to 20 years) admitted during the same time period. The incidence of intoxication at the time of burn was 6.9%. No significant differences in age, sex, race, or burn size were noted. Intoxicated patients had a higher incidence of associated injuries. Skin graft loss, cellulitis, donor site conversion, hypotension, and pneumonia were more common in the intoxicated group. They also had more intensive care unit admissions, ventilator days, operations, transfusions, and total hospital days. Intoxicated patients had a lower mortality (7.1%) than patients in the control group (10.9%). Intoxication at the time of burn injury is an important predictor of complications in adult patients with burns.

Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion.

Smooth muscle cell (SMC) migration is an early response to vascular injury and contributes to the development of intimal thickening. Upregulation of several components of the plasminogen activator (PA) system has been documented after vascular injury. Utilizing a Transwell filter assay system and human umbilical vein SMCs, we sought to define the role of four different PA system components on SMC migration and matrix invasion: (1) PAs, (2) plasmin, (3) PA receptors, and (4) PA clearance receptors (ie, low density lipoprotein receptor-related protein [LRP]). Addition of active two-chain urokinase-type PA (UPA) stimulated random migration (192 +/- 30% of control, 0.36 nmol/L, P < .001). The stimulation was inhibited by pretreatment with diisopropylfluorophosphate, PA inhibitor type 1 (PAI-1), or aprotinin, a plasmin inhibitor. Augmented migration was also observed with either low-molecular-weight UPA or the amino terminal fragment of UPA (ATF), with the effects being additive. Stimulation by ATF alone, however, was not inhibited by aprotinin. The stimulatory effect was not specific for UPA, in that tissue-type PA (TPA) also increased migration (169 +/- 9% of control, 10 nmol/L, P < .001); the augmentation was inhibited by pretreatment with DFP, PAI-1, or aprotinin and was additive to the UPA effect. Antibodies to the UPA receptor but not 5'-nucleotidase (another glycosylphosphatidylinositol-anchored cell surface protein) inhibited baseline and UPA-stimulated migration. Similarly, both UPA and TPA stimulated invasion of a collagen gel; this augmentation was inhibited by aprotinin, whereas antibodies to the UPA receptor reduced baseline invasion. Finally, we tested whether inhibition of LRP function, which mediates internalization of PA/inhibitor complexes, affected either process. Both antibodies to LRP and recombinant receptor associated protein, a known inhibitor of ligand binding to the LRP, significantly inhibited migration but did not affect collagen gel invasion. These data demonstrate the ability of several components of the PA system to modulate SMC migration and invasion in vitro via plasmin-dependent and -independent mechanisms.