Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life.

BACKGROUND: Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear. RESEARCH QUESTION: In the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days? STUDY DESIGN AND METHODS: This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed. RESULTS: Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR [aOR], 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96). INTERPRETATION: In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04505774; URL: www. CLINICALTRIALS: gov.

Patient Factors Associated with High Opioid Consumption after Common Surgical Procedures Following State-Mandated Opioid Prescription Regulations.

BACKGROUND: State regulations have decreased prescribed opioids with more than 25% of patients abstaining from opioids. Despite this, 2 distinct populations of patients exist who consume "high" or "low" amounts of opioids. The aim of this study was to identify factors associated with postoperative opioid use after common surgical procedures and develop an opioid risk score. STUDY DESIGN: Patients undergoing 35 surgical procedures from 7 surgical specialties were identified at a 620-bed tertiary care academic center and surveyed 1 week after discharge regarding opioid use and adequacy of analgesia. Electronic medical record data were used to characterize postdischarge opioids, complications, demographics, medical history, and social factors. High opioid use was defined as >75th percentile morphine milligram equivalents for each procedure. An opioid risk score was calculated from factors associated with opioid use identified by backward multivariate logistic regression analysis. RESULTS: A total of 1,185 patients were enrolled between September 2017 and February 2019. Bivariate analyses revealed patient factors associated with opioid use including earlier substance use (p < 0.001), depression (p = 0.003), anxiety (p < 0.001), asthma (p = 0.006), obesity (p = 0.03), migraine (p = 0.004), opioid use in the 7 days before surgery (p < 0.001), and 31 Clinical Classifications Software Refined classifications (p < 0.05). Significant multivariates included: insurance (p = 0.005), employment status (p = 0.005), earlier opioid use (odds ratio [OR] 2.38 [95% CI 1.21 to 4.68], p = 0.01), coronary artery disease (OR 0.38 [95% CI 0.16 to 0.86], p = 0.02), acute pulmonary embolism (OR 9.81 [95% CI 3.01 to 32.04], p < 0.001), benign breast conditions (OR 3.42 [95% CI 1.76 to 6.64], p < 0.001), opioid-related disorders (OR 6.67 [95% CI 1.87 to 23.75], p = 0.003), mental and substance use disorders (OR 3.80 [95% CI 1.47 to 9.83], p = 0.006), headache (OR 1.82 [95% CI 1.24 to 2.67], p = 0.002), and previous cesarean section (OR 5.10 [95% CI 1.33 to 19.56], p = 0.02). An opioid risk score base was developed with an area under the curve of 0.696 for the prediction of high opioid use. CONCLUSIONS: Preoperative patient characteristics associated with high opioid use postoperatively were identified and an opioid risk score was derived. Identification of patients with a higher need for opioids presents an opportunity for improved preoperative interventions, the use of nonopioid analgesic therapies, and alternative therapies.

Increased histone-DNA complexes and endothelial-dependent thrombin generation in severe COVID-19.

Coagulopathy in severe COVID-19 is common but poorly understood. The purpose of this study was to determine how SARS-CoV-2 infection impacts histone levels, fibrin structure, and endogenous thrombin potential in the presence and absence of endothelial cells. We studied individuals with SARS-CoV-2 infection and acute respiratory distress syndrome at the time of initiation of mechanical ventilation compared to healthy controls. Circulating histone-DNA complexes were elevated in the plasma of COVID-19 patients relative to healthy controls (n=6, each group). Using calibrated automated thrombography, thrombin generation was altered in COVID-19 patient plasma samples. Despite having increased endogenous thrombin potential, patient plasma samples exhibited prolonged lag times and times to peak thrombin in the presence of added tissue factor and PCPS. Strikingly different results were observed when endothelial cells were used in place of tissue factor and PCPS. While healthy control plasma samples did not generate measurable thrombin after 60 min, plasma samples from COVID-19+ patients formed thrombin (mean lag time ~20 min). Consistent with the observed alterations in thrombin generation, clots from COVID-19 subjects exhibited a denser fibrin network, thinner fibers and lower fibrin resolvability. Elevated histones, aberrant fibrin formation, and increased endothelial-dependent thrombin generation may contribute to coagulopathy in COVID-19.

Thrombo-inflammatory biomarkers and D-dimer in a biracial cohort study.

BACKGROUND: Higher D-dimer is a risk factor for cardiovascular diseases and venous thromboembolism. In the general population, D-dimer and other thrombo-inflammatory biomarkers are higher among Black individuals, who also have higher risk of these conditions compared to White people. OBJECTIVE: To assess whether Black individuals have an exaggerated correlation between D-dimer and thrombo-inflammatory biomarkers characteristic of cardiovascular diseases. METHODS: Linear regression was used to assess correlations of 11 thrombo-inflammatory biomarkers with D-dimer in a cross-sectional study of 1068 participants of the biracial Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. RESULTS: Adverse levels of most biomarkers, especially fibrinogen, factor VIII, C-reactive protein, N-terminal pro-B-type natriuretic peptide, and interleukin (IL)-6, were associated with higher D-dimer. Several associations with D-dimer differed significantly by race. For example, the association of factor VIII with D-dimer was more than twice as large in Black compared to White participants. Specifically, D-dimer was 26% higher per standard deviation (SD) higher factor VIII in Black adults and was only 11% higher per SD higher factor VIII in White adults. In Black but not White adults, higher IL-10 and soluble CD14 were associated with higher D-dimer. CONCLUSIONS: Findings suggest that D-dimer might relate to Black/White differences in cardiovascular diseases and venous thromboembolism because it is a marker of amplified thrombo-inflammatory response in Black people. Better understanding of contributors to higher D-dimer in the general population is needed.

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Heparin for Moderately Ill Patients with Covid-19.

BACKGROUND: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. METHODS: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat. RESULTS: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85). CONCLUSIONS: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.

Viscoelastic hemostasis assays in septic, critically ill coronavirus disease 2019 patients: a practical guide for clinicians.

Coronavirus disease 2019 (COVID-19)-associated coagulopathy is unusual, poorly defined and is linked with significant hypercoagulability and microthrombotic and macrothrombotic complications leading to worse outcomes and higher mortality. Conventional coagulation assays do not always actively reflect these derangements and might fail to detect this coagulopathy. Viscoelastic hemostatic assays (VHA) provide a possible tool that adds to conventional coagulation assays in identifying this hypercoagulable state. VHA has been mostly used in surgery and trauma but it's still not well defined in sepsis patients with lack of large randomized trials. Few studies described VHA findings in patients with COVID-19 showing significant hypercoagulability and fibrinolysis shutdown. Clinicians taking care of these patients might have little experience interpreting VHA results. By reviewing the available literature on the use of VHA in sepsis, and the current knowledge on COVID-19-associated coagulopathy we provide clinicians with a practical guide on VHA utilization in patients with COVID-19.

Helicopter Transport Use for Trauma Patients Is Decreasing Significantly Nationwide but Remains Overutilized.

Rapid transfer of trauma patients to a trauma center for definitive management is essential to increase survival. The utilization of helicopter transportation for this purpose remains heavily debated. The purpose of this study was to characterize the trends in helicopter transportations of trauma patients in the United States over the last decade. Subjects with a primary mode of either ground or helicopter transportation were selected from the National Trauma Data Bank datasets 2007 to 2015. Over this period, the proportion of patients transported by a helicopter decreased significantly in a linear fashion from 17 per cent in 2007 to 10.2 per cent in 2015 (P < 0.001). The overall mortality of this population was 7.6 per cent and remained unchanged over the study period (P = 0.545). Almost 3 of 10 subjects (29.4%) transported by a helicopter had an Injury Severity Score <9. The proportion of elderly (>65 years) patients requiring helicopter transportation increased by 69.1 per cent, whereas their associated mortality decreased by 21.5 per cent. The use of a helicopter for the transportation of trauma patients has significantly decreased over the last decade without any significant change in mortality, possibly indicating more effective utilization of available resources. Overtriage of patients with minor injuries remained relatively unchanged.

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regional distribution centers." On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

Visceral pleural invasion does not affect recurrence or overall survival among patients with lung adenocarcinoma ≤ 2 cm: a proposal to reclassify T1 lung adenocarcinoma.

BACKGROUND: T1 (≤ 3 cm) tumors with visceral pleural invasion (VPI) are upstaged to T2a (stage IB) in the TNM classification. We investigated the effect of VPI on the cumulative incidence of recurrence (CIR) and overall survival (OS) of lung adenocarcinoma (ADC) ≤ 2 cm (T1a) and 2 to 3 cm (T1b). METHODS: OS and CIR among patients with or without VPI were examined by tumor size (≤ 2 and 2-3 cm) in 777 patients with node-negative lung ADC ≤ 3 cm who underwent resection. RESULTS: Among patients with tumors ≤ 2 cm, VPI was not associated with either increased CIR (P = .90) or decreased OS (P = .11). Among patients with tumors 2 to 3 cm in size, the presence of VPI was associated with increased CIR (P = .015) and decreased OS (P < .001), even after adjusting for histologic subtype. When stage I lung ADCs ≤ 3 cm were regrouped as either new stage IA (≤ 2 cm with or without VPI, 2-3 cm without VPI) or new stage IB (2-3 cm with VPI), there was a statistically significant difference in 5-year CIR and OS between new stage IA and new stage IB tumors (CIR, 18% vs 40% [P = .004]; OS, 76% vs 51% [P < .001]). CONCLUSIONS: VPI stratifies prognosis in patients with lung ADC 2 to 3 cm but not in those with tumors ≤ 2 cm. Our proposed regrouping of a new stage IB better stratifies patients with poor prognosis, similar to published outcomes in patients with stage II disease, who may benefit from adjuvant chemotherapy.

Safety and stability of retrovirally transduced chimeric antigen receptor T cells.

Evaluation of: Scholler J, Brady TL, Binder-Scholl G et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl Med. 4(132), 132-153 (2012). Adoptive cellular therapy with genetically engineered T cells is predicated on generating effective and persisting T-cell-mediated immunity. Gammaretroviral vector-mediated gene transfer in T cells is the technological basis for promising therapy in both HIV and cancer. Because of concerns over delayed adverse events caused by persisting retroviral vector-engineered cells, the US FDA mandates long-term follow-up of clinical trials. Scholler et al. report FDA-mandated safety data and demonstrate that retrovirally transduced T cells persist in the blood of patients for more than a decade after treatment. These persisting T cells proliferated ex vivo in the presence of antigens and showed no evidence of either insertional oncogenesis or clonal expansion in 11 subjects followed for up to 11 years, supporting the long-term safety and persistence of retrovirally transduced T cells.

FDG-PET SUVmax combined with IASLC/ATS/ERS histologic classification improves the prognostic stratification of patients with stage I lung adenocarcinoma.

BACKGROUND: We investigated the association between the newly proposed International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), and whether the combination of these radiologic and pathologic factors can further prognostically stratify patients with stage I lung adenocarcinoma. METHODS: We retrospectively evaluated 222 patients with pathologic stage I lung adenocarcinoma who underwent FDG-PET scanning before undergoing surgical resection between 1999 and 2005. Patients were classified by histologic grade according to the IASLC/ATS/ERS classification (low, intermediate, or high grade) and by maximum standard uptake value (SUVmax) (low <3.0, high ≥3.0). The cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities. RESULTS: Patients with high-grade histology had higher risk of recurrence (5-year CIR, 29% [n = 25]) than those with intermediate-grade (13% [n = 181]) or low-grade (11% [n = 16]) histology (p = 0.046). High SUVmax was associated with high-grade histology (p < 0.001) and with increased risk of recurrence compared to low SUVmax (5-year CIR, 21% [n = 113] vs. 8% [n = 109]; p = 0.013). Among patients with intermediate-grade histology, those with high SUVmax had higher risk of recurrence than those with low SUVmax (5-year CIR, 19% [n = 87] vs. 7% [n = 94]; p = 0.033). SUVmax was associated with recurrence even after adjusting for pathologic stage (p = 0.037). CONCLUSIONS: SUVmax on FDG-PET correlates with the IASLC/ATS/ERS classification and can be used to stratify patients with intermediate-grade histology, the predominant histologic subtype, into two prognostic subsets.

Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients.

PURPOSE: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biologic function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases. EXPERIMENTAL DESIGN: Human and murine MPM cells with MSLN forced expression and short hairpin RNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples. RESULTS: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, colocalized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n = 139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n = 72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors. CONCLUSIONS: Our data provide evidence elucidating a biologic role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN expressing MPM. As regional invasion is the characteristic feature in MSLN expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target.

A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma.

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.

An in vivo platform for tumor biomarker assessment.

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers--serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response--a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.

Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive, primary pleural malignancy with poor prognosis, hypothesized to originate from a chronic inflammatory state within the pleura. Similar to what has been observed in other solid tumors (melanoma, ovarian and colorectal cancer), clinical and pre-clinical MPM investigations have correlated anti-tumor immune responses with improved survival. As such, a better understanding of the complex MPM tumor microenvironment is imperative in strategizing successful immunotherapies. Herein, we review the immune responses vital to the development and progression of MPM, as well as assess the role of immunomodulatory therapies, highlighting recent pre-clinical and clinical immunotherapy investigations.

Pre-clinical mouse models of primary and metastatic pleural cancers of the lung and breast and the use of bioluminescent imaging to monitor pleural tumor burden.

Malignant pleural disease (MPD) results in an estimated 150,000 cases of malignant pleural effusions (MPE) annually. The most common malignancies associated with MPD are primary malignant pleural mesothelioma (MPM) and metastatic lung cancer, breast cancer, and lymphoma. MPM is a rare, regionally aggressive malignancy whose incidence is increasing secondarily to the latency of disease progression. MPD is characteristic of advanced-stage pleural disease and portends a grave clinical prognosis with a median survival between 3 and 12 months. Preclinical investigations conducted in flank and intraperitoneal tumor models do not fully recapitulate the pleural tumor microenvironment, and the results are not directly translatable to the clinical setting. The protocol described herein provides a mouse model of MPM and MPD from nonhematogenous tumors, resulting in reproducible tumor location, tumor progression, animal survival, and histopathology. Pleural tumor growth in this model resembles the regionally aggressive clinical course and tumor microenvironment of human pleural cancers and provides an optimal animal model to investigate MPD biology and therapies.

Animal models and molecular imaging tools to investigate lymph node metastases.

Lymph node metastasis is a strong predictor of poor outcome in cancer patients. Animal studies of lymph node metastasis are constrained by difficulties in the establishment of appropriate animal models, limitations in the noninvasive monitoring of lymph node metastasis progression, and challenges in the pathologic confirmation of lymph node metastases. In this comprehensive review, we summarize available preclinical animal cancer models for noninvasive imaging and identification of lymph node metastases of non-hematogenous cancers. Furthermore, we discuss the strengths and weaknesses of common noninvasive imaging modalities used to identify tumor-bearing lymph nodes and provide guidelines for their pathological confirmation.

The impact of scoliosis among patients with giant paraesophageal hernia.

BACKGROUND: Kyphoscoliosis is seen in approximately 1.4-15% of the octogenarian population of the US. We hypothesized that patients with kyphoscoliosis are affected with a reduced intra-abdominal volume and progressive laxity of the diaphragmatic hiatal sling musculature leading to an increased risk of hiatal hernia formation and progression over time. METHODS: We retrospectively reviewed the clinical history and roentgenographic data of 320 paraesophageal hernia patients from 2003 to 2007. The prevalence of kyphoscoliosis among this patient cohort and the outcomes of surgical management were compared to paraesophageal hernia patients without kyphoscoliosis. RESULTS: Ninety-three of the 320 patients (29.1%) were found to have significant K/S (mean age 74; 83% female). Laparoscopic repair of paraesophageal hernia with fundoplication was performed in 91% of these patients. There was one death (1.1%; aspiration pneumonia) and 17.2% major postoperative morbidity. Mean length of hospital stay was 8 days (median = 4; range 2-71). Prolonged stays were related mainly to marginal pulmonary status. Kyphoscoliosis was associated with increased peri-operative pulmonary morbidity (16.1%) compared to patients without kyphoscoliosis (7.0%, p = 0.02). CONCLUSION: Kyphoscoliosis may contribute to the development and progression of paraesophageal hernias. Surgeons approaching paraesophageal hernia repair should be aware of the increased pulmonary morbidity and the postoperative care required in managing these patients.