Effectiveness of Casirivimab-Imdevimab and Sotrovimab During a SARS-CoV-2 Delta Variant Surge: A Cohort Study and Randomized Comparative Effectiveness Trial.

Importance: The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant. Objective: To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab. Design, Setting, and Participants: This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria. Exposure: For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. Main Outcomes and Measures: For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. Results: A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence. Conclusions and Relevance: In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant. Trial Registration: ClinicalTrials.gov Identifier: NCT04790786.

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial.

BACKGROUND: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab. METHODS: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound. FINDINGS: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab. INTERPRETATION: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb. FUNDING AND REGISTRATION: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.

The UPMC OPTIMISE-C19 (OPtimizing Treatment and Impact of Monoclonal antIbodieS through Evaluation for COVID-19) trial: a structured summary of a study protocol for an open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization.

OBJECTIVES: The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. TRIAL DESIGN: Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization PARTICIPANTS: We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. INTERVENTION AND COMPARATOR: The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). MAIN OUTCOMES: The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable - e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. RANDOMISATION: We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. BLINDING (MASKING): This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. TRIAL STATUS: Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04790786 . Registered March 10, 2021 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Pediatric Early Warning Score and unplanned readmission to the pediatric intensive care unit.

BACKGROUND AND OBJECTIVES: Early unplanned Pediatric Intensive Care Unit (PICU) readmission is associated with greater length of stay and mortality. No tools exist to identify children at risk for PICU readmission. The Pediatric Early Warning Score (PEWS) currently identify children at risk for deterioration on the ward. Our primary objective was to evaluate the ability of PEWS to identify children at risk for unplanned PICU readmission. METHODS: A single-center case-control study of 189 children (38 cases and 151 age-matched controls) 18years or younger transferred from the PICU to the pediatric ward from January 1, 2010-March 30, 2013, at an urban tertiary care children's hospital was conducted. RESULTS: Thirty-eight cases had unplanned PICU readmission within 48hours of transfer to pediatric ward, whereas 151 controls were not readmitted. The PEWS assigned prior to PICU discharge and first PEWS assigned on the ward were collected for cases and controls. Each 1-point increase in the PEWS score significantly increased risk of PICU readmission (odds ratios [95% confidence intervals], 1.6 [1.12-2.27; P = .009] and 1.89 [1.33-2.69; P < .001], respectively). Discrimination ability of PEWS for PICU readmission improved when chronic diagnoses were included. CONCLUSIONS: Higher PEWS scores were associated with increased risk of unplanned PICU readmission. However, cutoff scores are not sensitive or specific enough to be clinically useful. Adding chronic disease variables may improve the clinical utility of cutoff PEWS scores.

Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit.

OBJECTIVE: To evaluate the ability of the RIFLE criteria to characterize acute kidney injury in critically ill children. DESIGN: Retrospective analysis of prospectively collected clinical data. SETTING: Multidisciplinary, tertiary care, 20-bed pediatric intensive care unit. PATIENTS: All 3396 admissions between July 2003 and March 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A RIFLE score was calculated for each patient based on percent change of serum creatinine from baseline (risk = serum creatinine x1.5; injury = serum creatinine x2; failure = serum creatinine x3). Primary outcome measures were mortality and intensive care unit length of stay. Logistic and linear regressions were performed to control for potential confounders and determine the association between RIFLE score and mortality and length of stay, respectively.One hundred ninety-four (5.7%) patients had some degree of acute kidney injury at the time of admission, and 339 (10%) patients had acute kidney injury develop during the pediatric intensive care unit course. Almost half of all patients with acute kidney injury had their maximum RIFLE score within 24 hrs of intensive care unit admission, and approximately 75% achieved their maximum RIFLE score by the seventh intensive care unit day. After regression analysis, any acute kidney injury on admission and any development of or worsening of acute kidney injury during the pediatric intensive care unit stay were independently associated with increased mortality, with the odds of mortality increasing with each grade increase in RIFLE score (p < .01). Patients with acute kidney injury at the time of admission had a length of stay twice that of those with normal renal function, and those who had any acute kidney injury develop during the pediatric intensive care unit course had a four-fold increase in pediatric intensive care unit length of stay. Also, other than being admitted with RIFLE risk score, an independent relationship between any acute kidney injury at the time of pediatric intensive care unit admission, any acute kidney injury present during the pediatric intensive care unit course, or any worsening RIFLE scores during the pediatric intensive care unit course and increased pediatric intensive care unit length of stay were identified after controlling for the same high-risk covariates (p < .01). CONCLUSIONS: RIFLE criteria serves well to describe acute kidney injury in critically ill pediatric patients.

Effect of tidal volume in children with acute hypoxemic respiratory failure.

OBJECTIVES: To determine if tidal volume (VT) between 6 and 10 ml/kg body weight using pressure control ventilation affects outcome for children with acute hypoxemic respiratory failure (AHRF) or acute lung injury (ALI). To validate lung injury severity markers such as oxygenation index (OI), PaO2/FiO2 (PF) ratio, and lung injury score (LIS). DESIGN: Retrospective, January 2000-July 2007. SETTING: Tertiary care, 20-bed PICU. PATIENTS: Three hundred and ninety-eight endotracheally intubated and mechanically ventilated children with PF ratio <300. Outcomes were mortality and 28-day ventilator free days. MEASUREMENTS AND MAIN RESULTS: Three hundred and ninety-eight children met study criteria, with 20% mortality. 192 children had ALI. Using >90% pressure control ventilation, 85% of patients achieved VT less than 10 ml/kg. Median VT was not significantly different between survivors and non-survivors during the first 3 days of mechanical ventilation. After controlling for diagnostic category, age, delta P (PIP-PEEP), PEEP, and severity of lung disease, VT was not associated with mortality (P > 0.1), but higher VT at baseline and on day 1 of mechanical ventilation was associated with more ventilator free days (P < 0.05). This was particularly seen in patients with better respiratory system compliance [Crs > 0.5 ml/cmH2O/kg, OR = 0.70 (0.52, 0.95)]. OI, PF ratio, and LIS were all associated with mortality (P < 0.05). CONCLUSIONS: When ventilating children using lung protective strategies with pressure control ventilation, observed VT is between 6 and 10 ml/kg and is not associated with increased mortality. Moreover, higher VT within this range is associated with more ventilator free days, particularly for patients with less severe disease.

Disseminated intravascular coagulation score is associated with mortality for children with shock.

OBJECTIVE: To evaluate the association between disseminated intravascular coagulation (DIC) score and mortality for children with shock. DESIGN: Retrospective. SETTING: Tertiary care, 20-bed pediatric intensive care unit. PATIENTS: A total of 132 children with sepsis or shock admitted from January 2003 to December 2005. MEASUREMENTS AND RESULTS: A total of 132 patients less than 18 years of age with a diagnosis of shock or sepsis were included in the analysis. Of these patients, 90 survived and 42 died (31.8%). Patients ranged from 6 days to 18 years (median 5.8 years), and were a majority male (63%). Variables associated with mortality included peak DIC score within 24 h of ICU admission, age, weight, volume of blood products transfused, inotrope score, pediatric index of mortality (PIM 2) score, 12-h pediatric risk of mortality (PRISM III) score and presence of mechanical ventilation (P < 0.05). Patients with DIC scores >or= 5 (overt DIC) had 50% mortality, compared to 20% for patients with DIC scores < 5. Overall, a one-point rise in DIC score was associated with an increased risk of mortality after adjusting for age, race, gender, hemodynamic instability, and PRISM III score [OR 1.35 (1.02, 1.78)]. Most patients achieve their peak DIC score within 2 h of ICU admission. CONCLUSIONS: This analysis suggests that DIC score, easily calculated early in ICU admission, is associated with mortality for children with sepsis and shock, regardless of initial severity of illness or inotrope use.

Comparison of the pulse oximetric saturation/fraction of inspired oxygen ratio and the PaO2/fraction of inspired oxygen ratio in children.

BACKGROUND: Although diagnostic criteria for acute lung injury (ALI) and ARDS are clear, invasive arterial sampling is required for computation of Pao(2)/fraction of inspired oxygen (Fio(2)) [PF] ratios. The pulse oximetric saturation (Spo(2))/Fio(2) (SF) ratio may be a reliable noninvasive alternative to the PF ratio for identifying children with lung injury. METHODS: We electronically queried blood gas measurements from two tertiary care pediatric ICUs (PICUs). Included in the analysis were corresponding measurements of Spo(2), Pao(2), and Fio(2) charted within 15 min of each other when Spo(2) values were between 80% and 97%. Computed PF and SF ratios were compared to identify threshold values for SF ratios that correspond to PF criteria for ALI (< or = 300) and ARDS (< or = 200). Data from one PICU were used for derivation and validated with measurements from the second PICU. RESULTS: From the 1,298 observations in the derivation data set, SF ratio could be predicted by the regression equation SF = 76 + 0.62 x PF (p < 0.0001, R(2) = 0.61). SF ratios of 263 and 201 corresponded to PF ratios of 300 and 200, respectively. The ALI SF cutoff of 263 had 93% sensitivity and 43% specificity, and the ARDS cutoff of 201 had 84% sensitivity and 78% specificity. Applying these values to the 1,845 observations in the validation data set yielded a sensitivity of 86% and specificity of 47% for ALI and a sensitivity of 68% and specificity of 84% for ARDS. CONCLUSION: SF ratio is a reliable noninvasive marker for PF ratio to identify children with ALI or ARDS.

Perioperative cyclooxygenase 2 inhibition to reduce tumor cell adhesion and metastatic potential of circulating tumor cells in non-small cell lung cancer.

OBJECTIVE: Surgical manipulation of lung cancers may increase circulating tumor cells and contribute to metastatic recurrence after resection. Cyclooxygenase 2 is overexpressed in most non-small cell lung cancer and upregulates the cell adhesion receptor CD44. Our goal was to examine the effects of perioperative cyclooxygenase blockade on the metastatic potential of circulating tumor cells, CD44 expression, and adhesion of cancer cells to extracellular matrix. METHODS: Human non-small cell lung cancer cells (A549) were injected through the lateral tail vein in an in vivo murine model of tumor metastasis with three random treatment groups: no treatment, perioperative selective cyclooxygenase 2 inhibition (celecoxib) only, and continuous celecoxib. Lung metastases were assessed at 6 weeks by a blinded observer. For in vitro experiments, cells were treated with celecoxib, and expression of CD44 was determined by Western blotting. Extracellular matrix adhesion was assessed by Matrigel (BD Labware, Bedford, Mass) assay. RESULTS: In vivo lung metastases were significantly decreased relative to control by both perioperative and continuous celecoxib (P = .0135). There was no significant difference in number of metastases between continuous and perioperative treatment groups. In vitro adhesion to the extracellular matrix was significantly inhibited by celecoxib in a dose-dependent manner (P < .01). A549 cells expressed high levels of CD44, upregulated by interleukin 1beta and downregulated by celecoxib. CONCLUSION: Celecoxib significantly reduced establishment of metastases by circulating tumor cells in a murine model. It also inhibited CD44 expression and extracellular matrix adhesion in vitro. Perioperative modulation of cyclooxygenase 2 may be a novel strategy to minimize metastases from circulating tumor cells during this high-risk period.

Dimethyl celecoxib as a novel non-cyclooxygenase 2 therapy in the treatment of non-small cell lung cancer.

OBJECTIVES: The cyclooxygenase 2 enzyme has become a therapeutic target in cancer treatment. Cyclooxygenase 2 blockade with selective inhibitors increases apoptosis and decreases the metastatic potential of lung cancer cells. Some of the antitumor effects of these inhibitors may occur through both cyclooxygenase 2-dependent and independent pathways. Our goal was to investigate these pathways using celecoxib (selective cyclooxygenase 2 inhibitor) and 2,5-dimethyl celecoxib, a structural analog modified to eliminate cyclooxygenase 2 inhibitory activity, while potentially maintaining antineoplastic properties. METHODS: 2,5-dimethyl celecoxib was synthesized in the Department of Chemistry at the University of Southern California. With the use of non-small cell lung cancer cells (A549), prostaglandin E2 production was quantified by enzyme-linked immunosorbent assay to assess cyclooxygenase 2 activity. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay. Cell migration was performed using transwell inserts that were matrigel coated for invasion experiments. Gelatin zymography was used to assess matrix-metalloproteinase activity. RESULTS: 2,5-dimethyl celecoxib did not inhibit interleukin-1beta-stimulated prostaglandin E2 production, whereas celecoxib did even at low doses. Both celecoxib and 2,5-dimethyl celecoxib decreased tumor cell viability and proliferation with IC50 for celecoxib and 2,5-dimethyl celecoxib of 73 and 53 micromol/L, respectively. Both drugs were also potent inducers of apoptosis, and both inhibited tumor cell migration and invasion. This was associated with down-regulation of matrix metalloproteinase activity. CONCLUSIONS: 2,5-dimethyl celecoxib is a structural analog of celecoxib that lacks cyclooxygenase 2 inhibitory activity but exhibits significant antineoplastic properties comparable to celecoxib. This suggests that the antineoplastic activities of celecoxib are, at least in part, cyclooxygenase independent and that therapeutic strategies can be developed without the side effects of global cyclooxygenase 2 blockade.

Proximal conduit obstruction after Sano modified Norwood procedure.

Sano and colleagues recently described a modification of first stage palliation for hypoplastic left heart syndrome utilizing a right ventricle to pulmonary artery conduit. Preliminary results are favorable, but experience with this technique is limited. We report a case of sudden death due to obstruction of the proximal conduit by fibrointimal hyperplasia. This case of lethal conduit obstruction presented 3 months after initial palliation. Early cardiac catheterization and second stage palliation may be necessary to minimize the risk of such adverse events after the Sano modification.

Evaluation of cyclooxygenase-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect.

OBJECTIVES: Cyclooxygenase-2 plays a role in growth, apoptosis, angiogenesis, and metastasis in lung cancer. Inhibition of cyclooxygenase-2 with celecoxib has been shown to inhibit tumor growth. We evaluated the effect of increasing doses of celecoxib in a murine model of human lung cancer. METHODS: Human lung adenocarcinoma cells (A549) were implanted in the left lung upper lobe of mice with severe combined immunodeficiency syndrome. Mice were randomly assigned to 4 groups at implantation (n = 10 per group): control, 125 mg/kg chow, 500 mg/kg chow, 1000 mg/kg chow. After 3 weeks, mice were killed, and a blinded observer measured total tumor volume. The dose effect of celecoxib was examined in vitro by studying cell proliferation, expression of cyclooxygenase-2 (mRNA and protein), and production of prostaglandin E 2 in unstimulated and interleukin 1beta-stimulated cells. RESULTS: All 40 mice survived for 3 weeks with no observed toxicities. Total tumor volume was inhibited in each celecoxib group ( P = .0038, Welch analysis of variance): 206.7 +/- 119.5 mm 3 (control group), 41.4 +/- 54.0 mm 3 (low-dose group), 34.5 +/- 39.3 mm 3 (medium-dose group), and 27.3 +/- 53.6 mm 3 (high-dose group). In vitro celecoxib was effective at inhibiting production of prostaglandin E 2 , even in stimulated cells, although little effect was seen on cyclooxygenase-2 protein levels. Inhibition of proliferation was evident only at doses that exceeded those used in the animal model. CONCLUSION: Inhibition of cyclooxygenase-2 with low-dose celecoxib restricted the growth of lung cancer in this model. This might be mediated by prostaglandin E 2 . Higher doses of celecoxib afforded no additional benefit. Chronic therapy with low-dose cyclooxygenase-2 inhibition has the potential to influence tumor progression in non-small cell lung cancer.

Integrin alpha v beta 3-targeted imaging of lung cancer.

A series of radiolabeled cyclic arginine-glycine-aspartic acid (RGD) peptide ligands for cell adhesion molecule integrin alpha v beta 3-targeted tumor angiogenesis targeting are being developed in our laboratory. In this study, this effort continues by applying a positron emitter 64Cu-labeled PEGylated dimeric RGD peptide radiotracer 64Cu-DOTA-PEG-E[c(RGDyK)]2 for lung cancer imaging. The PEGylated RGD peptide indicated integrin alpha v beta 3 avidity, but the PEGylation reduced the receptor binding affinity of this ligand compared to the unmodified RGD dimer. The radiotracer revealed rapid blood clearance and predominant renal clearance route. The minimum nonspecific activity accumulation in normal lung tissue and heart rendered high-quality orthotopic lung cancer tumor images, enabling clear demarcation of both the primary tumor at the upper lobe of the left lung, as well as metastases in the mediastinum, contralateral lung, and diaphragm. As a comparison, fluorodeoxyglucose (FDG) scans on the same mice were only able to identify the primary tumor, with the metastatic lesions masked by intense cardiac uptake and high lung background. 64Cu-DOTA-PEG-E[c(RGDyK)]2 is an excellent position emission tomography (PET) tracer for integrin-positive tumor imaging. Further studies to improve the receptor binding affinity of the tracer and subsequently to increase the magnitude of tumor uptake without comprising the favorable in vivo kinetics are currently in progress.

Neochordal repair of the posterior mitral leaflet.

BACKGROUND: Myxomatous mitral valve insufficiency is traditionally repaired by posterior leaflet quadrangular resection and reconstruction. A simplified repair technique without leaflet resection is described, and our initial experience is reviewed. METHODS: Thirty-nine consecutive patients with significant mitral regurgitation underwent repair since January 2000 by placement of expanded polytetrafluoroethylene sutures between the leading (coapting) edge of the posterior leaflet and the corresponding papillary muscle. An annuloplasty ring was placed, and no leaflet tissue was resected. Patient medical records were obtained and retrospectively reviewed. RESULTS: Twenty-five men and 14 women (median age, 61 years; range, 40-88 years) had their mitral valve repaired by a variety of surgical approaches, including robotic (18 patients), right thoracotomy (6 patients), and sternal (15 patients). Three patients have required valve replacement: 1 at the initial operation, 1 because of dehiscence of the annuloplasty ring, and 1 after subsequent rupture of a previously normal native chorda. At follow-up (median, 12 months), 92% (33/36) of the remaining patients had an intact mitral repair with no to mild regurgitation, 8.3% (3/36) of patients had moderate regurgitation, and 92% of all patients (36/39) were in New York Heart Association class I. There were no deaths. CONCLUSIONS: Myxomatous mitral regurgitation due to posterior leaflet insufficiency can be repaired without leaflet resection by placement of neochordae. This repair technique is effective and is readily accomplished by traditional and minimally invasive surgical approaches.

Detection of melanomas in patients followed up with total cutaneous examinations, total cutaneous photography, and dermoscopy.

BACKGROUND: Many factors have been identified as important determinants that increase the risk of malignant melanoma (MM) developing. Patients with classic atypical mole syndrome (CAMS) have multiple such factors and are known to be at high risk for MMs developing. OBJECTIVE: We sought to evaluate the risk for newly diagnosed MMs developing in patients with CAMS and in a heterogeneous group of patients at high risk (ie, those with high-risk non-CAMS [HRNCAMS]) who had 1 or more risk factors: personal history of nonmelanoma skin cancers; family history of melanoma; biopsy specimen-confirmed dysplastic nevi; and meeting 1 or 2 of the 3 CAMS criteria. We also aimed to report our experience treating these patients at high risk with annual total cutaneous examination, total cutaneous photography, and dermoscopy. METHODS: Consecutive medical records from a private dermatology practice were reviewed. A total of 258 patients were selected who fulfilled the criteria of having: (1) total cutaneous photography as an aid for follow-up; (2) total cutaneous examination at least once per year; (3) at least 6 months of clinical follow-up; and (4) no personal history of melanomas. A total of 160 patients with CAMS and 98 with HRNCAMS were included in this study. The 10-year risk for MM developing in these 2 cohorts was computed using the Kaplan-Meier method. RESULTS: In the CAMS cohort, 28 new MMs developed in 19 patients resulting in a cumulative 10-year risk of 14% (95% confidence interval: 7-20). In the HRNCAMS cohort, 10 new MMs developed in 9 patients, and the cumulative 10-year risk was 10% (95% confidence interval: 2-17). The difference between the 2 groups was not statistically significant (P=.91). The MMs diagnosed in both cohorts were either in situ or less than 1 mm in Breslow thickness. There were no MM metastases or MM-related deaths in either cohort during a mean follow-up period of 120 months for the CAMS and 98 months for the HRNCAMS group. CONCLUSION: Both the patients with CAMS and HRNCAMS were at very high risk for MMs developing. The combination of total cutaneous photography, total cutaneous examination, and dermoscopy were used in treating our patients. No MM 1 mm or greater in thickness developed during follow-up in either group.