Enhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications.

Well-differentiated low-grade lung neuroendocrine tumors (lung carcinoids or LNETs) are histopathologically classified as typical and atypical LNETs, but each subtype is still heterogeneous at both the molecular level and its clinical manifestation. Here, we report genome-wide profiles of primary LNETs' cis-regulatory elements by H3K27ac ChIP-seq with matching RNA-seq profiles. Analysis of these regulatory landscapes revealed three regulatory subtypes, independent of the typical/atypical classification. We identified unique differentiation signals that delineate each subtype. The "proneuronal" subtype emerges under the influence of ASCL1, SOX4, and TCF4 transcription factors, embodying a pronounced proneuronal signature. The "luminal-like" subtype is characterized by gain of acetylation at markers of luminal cells and GATA2 activation and loss of LRP5 and OTP. The "HNF+" subtype is characterized by a robust enhancer landscape driven by HNF1A, HNF4A, and FOXA3, with notable acetylation and expression of FGF signaling genes, especially FGFR3 and FGFR4, pivotal components of the FGF pathway. Our findings not only deepen the understanding of LNETs' regulatory and developmental diversity but also spotlight the HNF+ subtype's reliance on FGFR signaling. We demonstrate that targeting this pathway with FGF inhibitors curtails tumor growth both in vitro and in xenograft models, unveiling a potential vulnerability and paving the way for targeted therapies. Overall, our work provides an important resource for studying LNETs to reveal regulatory networks, differentiation signals, and therapeutically relevant dependencies.

Outcomes of extracranial stereotactic body radiation therapy for induced oligometastatic non-small cell lung cancer on novel systemic therapy.

Background: Stereotactic body radiation therapy (SBRT) is often delivered in patients with oligometastatic disease (OMD). However, the specific subset of patients with polymetastatic non-small cell lung cancer (NSCLC) on novel systemic therapies who develop induced oligopersistant disease (OpersisD) or oligoprogressive disease (OprogD), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) OMD classification, has not been well described. This study explores the outcomes of patients treated with this strategy. Methods: Patients with stage IV NSCLC being treated with osimertinib or immune checkpoint inhibitors (ICIs) who received extracranial SBRT for OpersisD or OprogD were identified in our retrospective analysis. Outcomes reported include progression-free survival (PFS), time to change of systemic treatment (TTCST), overall survival (OS), local control (LC) and treatment-related toxicity. Results: Forty-nine patients received SBRT for OpersisD (34.7%) or OprogD (65.3%) at a median of 5.8 and 15.3 months after start of systemic therapy, respectively. 55.1% received concurrent osimertinib and 44.9% received ICI. Seventy-seven extracranial lesions were treated with various fractionation schemas. At a median of 18.8 months follow-up from first SBRT, LC was achieved in 92.2% of total lesions treated (71). The 1-year OS was 91.7% for OpersisD and 83.3% for OprogD. OpersisD compared to OprogD had a longer median PFS (18.3 vs. 6.1 months) and longer median TTCST (23.6 vs. 13.5 months), median OS was not reached for either cohort. On multivariate analysis, patients treated with osimertinib had shorter PFS (HR: 2.20; 95% CI: 1.01-4.82; P=0.048) and shorter TTCST (HR: 2.83; 95% CI: 1.09-7.33; P=0.032). One patient (2%) experienced grade 3 pneumonitis after SBRT, and no grade 4-5 toxicities were reported with SBRT treatment. Conclusions: This study indicates that SBRT for OpersisD or OprogD in Stage IV NSCLC patients on osimertinib or ICIs is safe, very well tolerated, and may prolong the time before needing a shift in systemic therapy. Further prospective research is needed to validate and expand upon these findings.

The DNA methylome of human vascular endothelium and its use in liquid biopsies.

BACKGROUND: Vascular endothelial cells (VECs) are an essential component of each tissue, contribute to multiple pathologies, and are targeted by important drugs. Yet, there is a shortage of biomarkers to assess VEC turnover. METHODS: To develop DNA methylation-based liquid biopsies for VECs, we determined the methylome of VECs isolated from freshly dissociated human tissues. FINDINGS: A comparison with a human cell-type methylome atlas yielded thousands of loci that are uniquely unmethylated in VECs. These sites are typically gene enhancers, often residing adjacent to VEC-specific genes. We also identified hundreds of genomic loci that are differentially methylated in organotypic VECs, indicating that VECs feeding specific organs are distinct cell types with a stable epigenetic identity. We established universal and lung-specific VEC markers and evaluated their presence in circulating cell-free DNA (cfDNA). Nearly 2.5% of cfDNA in the plasma of healthy individuals originates from VECs. Sepsis, graft versus host disease, and cardiac catheterization are associated with elevated levels of VEC-derived cfDNA, indicative of vascular damage. Lung-specific VEC cfDNA is selectively elevated in patients with chronic obstructive pulmonary disease (COPD) or lung cancer, revealing tissue-specific vascular turnover. CONCLUSIONS: VEC cfDNA biomarkers inform vascular dynamics in health and disease, potentially contributing to early diagnosis and monitoring of pathologies, and assessment of drug activity. FUNDING: This work was supported by the Beutler Research Program, Helmsley Charitable Trust, JDRF, Grail and the DON Foundation (to Y.D.). Y.D holds the Walter & Greta Stiel Chair in heart studies. B.G., R.S., J.M., D.N., T.K., and Y.D. filed patents on cfDNA analysis.

Outcomes of sublobar resection vs lobectomy for invasive clinical stage T1N0 non-small-cell lung cancer: A propensity-match analysis.

BACKGROUND: The role of sub lobar resection (SLR; either segmentectomy or wedge resection) vs lobectomy (LBCT) for invasive clinical stage T1N0 non-small-cell-lung-cancer (NSCLC) has not been fully established yet. AIM: We aimed to characterize the preoperative parameters leading to selecting SLR and compare the overall survival (OS) and disease-free survival (DFS) of these two surgical approaches. METHODS: Clinical data on 162 patients (LBCT-107; SLR-55) were prospectively entered in our departmental database. Preoperative parameters associated with the performance of SLR were identified using univariate and multivariate cox regression analysis. The Kaplan-Meier method was used to compute OS and DFS. Comparison between LBCT and SLR groups and 32 propensity-matched groups was performed using Log-rank test. RESULTS: Median follow-up time for the LBCT and SLR groups was 4.76 (Inter-quartile range [IQR] 2.96 to 8.23) and 3.38 (IQR 2.9 to 6.19) years respectively. OS and DFS rates were similar between the two groups in the entire cohort (OS-LBCT vs SLR P = .853, DSF-LBCT vs SLR P = .653) and after propensity matching (OS-LBCT vs SLR P = .563 DSF-LBCT vs SLR P = .632). Specifically, Two- and five-year OS rates for LBCT and SLR were 90.6.% vs 92.7%, 71.8% vs 75.9% respectively. Independent predictors of selecting for SLR included older age (P < .001), reduced FEV1% (P = .026), smaller tumor size (P = .025), smaller invasive component (P = .021) and higher American Society of Anesthesiology scores (P = .014). CONCLUSIONS: In 162 consecutive and 32 matched cases, SLR and lobar resection had similar overall and disease-free survival rates. SLR may be considered as a reasonable oncological procedure in carefully selected T1N0 NSCLC patients that present with multiple comorbidities and relatively small tumors.

The American Society of Thoracic Surgery Score versus EuroSCORE I and EuroSCORE II in Israeli Patients Undergoing Cardiac Surgery.

BACKGROUND: Recently, Israel established the first national-level adult cardiac surgery database, which was linked to the Society of Thoracic Surgeons (STS). OBJECTIVES: To validate and compare the STS predicted risk of mortality (PROM) to logistic EuroSCORE I (LESI) and EuroSCORE II (ESII) in Israeli patients undergoing cardiac surgery. METHODS: We retrospectively studied 1279 consecutive patients who underwent cardiac surgeries with a calculable PROM. Data were prospectively entered into our database and used to calculate PROM, LESI, and ESII. Scores were normalized and correlated using linear regression and Pearson's test. To examine model calibration, we plotted the total observed versus expected mortality for each score and across five risk-score subgroups. Model discrimination was assessed by measuring the area under the receiver operating curves. RESULTS: The observed 30-day operative mortality was 1.95%. The median (IQ1; IQ3) PROM, LESI, and the ESII scores were 1.45% (0.69; 3.22), 4.54% (2.28; 9.27), and 1.88% (1.18; 3.54), respectively, with observed over expected ratios of 0.63 (95% confidence interval [95%CI] 0.42-0.93), 0.59 (95%CI 0.40-0.87), and 0.24 (95%CI 0.17-0.36), respectively, (STS vs. ESII P = 0.36, STS vs. LESI P = 0.0001). There was good correlation among all scores. All models overestimated mortality. Model discrimination was high and similar for all three scores. Model calibration of the STS, PROM, and ESII were more accurate than the LESI, particularly in higher risk subgroups. CONCLUSIONS: All scores overestimated mortality. In Israeli patients, the STS, PROM, and ESII risk-scores were more reliable metrics than LESI, particularly in higher risk patients.

Matrix metalloproteinase 12 promotes tumor propagation in the lung.

OBJECTIVE: Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. METHODS: We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non-small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. RESULTS: Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. CONCLUSIONS: We suggest that tumor cell-derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.

In the hunt for therapeutic targets: mimicking the growth, metastasis, and stromal associations of early-stage lung cancer using a novel orthotopic animal model.

BACKGROUND: The existing shortage of animal models that properly mimic the progression of early-stage human lung cancer from a solitary confined tumor to an invasive metastatic disease hinders accurate characterization of key interactions between lung cancer cells and their stroma. We herein describe a novel orthotopic animal model that addresses these concerns and consequently serves as an attractive platform to study tumor-stromal cell interactions under conditions that reflect early-stage lung cancer. METHODS: Unlike previous methodologies, we directly injected small numbers of human or murine lung cancer cells into murine's left lung and longitudinally monitored disease progression. Next, we used green fluorescent protein-tagged tumor cells and immuno-fluorescent staining to determine the tumor's microanatomic distribution and to look for tumor-infiltrating immune cells and stromal cells. Finally, we compared chemokine gene expression patterns in the tumor and lung microenvironment. RESULTS: We successfully generated a solitary pulmonary nodule surrounded by normal lung parenchyma that grew locally and spread distally over time. Notably, we found that both fibroblasts and leukocytes are recruited to the tumor's margins and that distinct myeloid cell attracting and CCR2-binding chemokines are specifically induced in the tumor microenvironment. CONCLUSION: Our orthotopic lung cancer model closely mimics the pathologic sequence of events that characterizes early-stage human lung cancer propagation. It further introduces new means to monitor tumor-stromal cell interactions and offers unique opportunities to test therapeutic targets under conditions that reflect early-stage lung cancer. We argue that for such purposes our model is superior to lung cancer models that are based either on genetic induction of epithelial transformation or on ectopic transplantation of malignant cells.

International participation in the Society of Thoracic Surgeons National Database.

In 2011 The Society of Thoracic Surgeons (STS) Workforce on National Databases established the International Database Task Force devoted to expanding participation in the STS National Database internationally. The vision for this initiative was to assist in the globalization of outcomes data and share knowledge, facilitating a worldwide quality collaborative in cardiac surgery. The Department of Cardiothoracic Surgery at Hadassah Medical Center, Jerusalem, Israel, was among the first of several international sites to join the collaborative. This report outlines the rationale behind clinical databases outside of North America submitting data to the STS National Database and reviews the unique challenges and practical steps of integration through experiences by Hadassah Medical Center. Our hope is that this procedural learning will serve as a template to assist future international program integration.

CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential.

Lung cancer is the second most common malignancy and the leading cause of cancer-related death in the western world. Moreover, despite advances in surgery, chemotherapy and radiotherapy, the death rate from lung cancer remains high and the reported overall five-year survival rate is only 15%. Thus, novel treatments for this devastating disease are urgently needed. Chemokines, a family of 48 chemotactic cytokines interacts with their 7 transmembrane G-protein-coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells, which express a relatively restricted repertoire of chemokine and chemokine receptors, utilize and manipulate the chemokine system in a manner that benefits both local tumor growth and distant dissemination. Among the 19 chemokine receptors, CXCR4 is the receptor most widely expressed by malignant tumors and whose role in tumor biology is most thoroughly studied. The chemokine CXCL12, which is the sole ligand of CXCR4, is highly expressed in primary lung cancer as well as in the bone marrow, liver, adrenal glands and brain, which are all sites for lung cancer metastasis. This review focuses on the pathologic role of the CXCR4/CXCL12 axis in NSCLC and on the potential therapeutic implication of targeting this axis for the treatment of NSCLC.

Radical multidisciplinary approach to primary cardiac sarcomas.

OBJECTIVES: Primary cardiac sarcomas are extremely rare, but aggressive, tumours. The median survival with conventional treatment is 6-12 months. Recent data suggest that a radical multidisciplinary approach may improve patient outcome. We sought to evaluate our institutional experience with these tumours. METHODS: A multidisciplinary cardiac tumour programme was established 3 years ago based on the experience and support of our collaborating institution. Treatment consisted of pre- and postoperative chemotherapy, complete (R0) resection of the tumour with structural reconstruction and radiation therapy in selected cases. Left atrial tumours were resected using the cardiac autotransplantation technique. Bovine pericardium was used to reconstruct free-chamber walls or the septum. Valves were replaced by bioprostheses. A variety of autologous, allogeneic and synthetic vascular grafts were used to reconstruct the aorta, pulmonary arteries (PAs) and coronary arteries. RESULTS: Seven patients (3 males), age 51 ± 11 years (35-63), underwent eight operations. Tumour sites were PAs in 2 patients, left atrium in 3, right atrium in 2 and both great vessels in 1. Complete resection was achieved in all cases. There was no operative mortality. Two patients required implantation of a permanent pacemaker. Median survival was 24 months. Three patients died of metastatic disease and 1 sudden death 7, 23, 31 and 33 months after diagnosis. Three patients are alive at 2, 8 and 33 months, in functional Class I or II. One patient developed tumour recurrence and 2 have no evidence of disease. CONCLUSIONS: A radical multidisciplinary approach to cardiac sarcomas consisting of multimodality treatment and complex, technically demanding surgery, is safe and markedly improves (doubling) patient survival.

In vitro and in vivo therapeutic efficacy of CXCR4 antagonist BKT140 against human non-small cell lung cancer.

OBJECTIVES: CXCR4/CXCL12 interactions promote non-small cell lung cancer (NSCLC) growth and dissemination. Furthermore, this axis might promote NSCLC resistance to chemotherapy and/or radiotherapy. Therefore, the CXCR4/CXCL12 axis constitutes an attractive therapeutic target for the treatment of NSCLC. We aimed to characterize the therapeutic efficacy of the novel CXCR4 antagonist BKT140 against human NSCLC. METHODS: We determined the CXCR4 expression in 5 NSCLC cell lines (H358, A549, H460, H1299, and L4). We then tested the colony-forming capacity and proliferation of these cells in the presence of CXCL12 and BKT140. Next, we measured the in vivo growth of A549 and H460 xenografts with or without BKT140 treatment. Finally, we examined, in vitro, the potential antiproliferative effect of BKT140 combined with cisplatin or paclitaxel and after irradiation of NSCLC cells. RESULTS: All tested cell lines expressed CXCR4 and showed increased colony formation in response to CXCL12 stimulation. BKT140 reduced the colony-forming capacity of NSCLC cells. Proliferation assays demonstrated both cytotoxic and cytostatic properties for this peptide. H460 cells were the most sensitive to BKT140 and A549 cells the least. Subcutaneous administration of BKT140 significantly delayed the development of H460 xenografts and showed a similar trend for A549 xenografts. Finally, the antiproliferative effects of BKT140 appears to be additive to those of chemotherapeutic drugs and radiotherapy. CONCLUSIONS: Targeting the CXCL12/CXCR4 axis with BKT140 attenuated NSCLC cells tumor growth and augmented the effects of chemotherapy and radiotherapy. Future research will benefit from delineating the downstream mechanism of BKT140 action and defining BKT140 susceptibility markers.

Extracellular matrix constituents interfere with Newcastle disease virus spread in solid tissue and diminish its potential oncolytic activity.

Advanced melanoma cells, characterized by resistance to chemotherapy, have been shown to be highly sensitive to oncolysis by Newcastle disease virus (NDV). In the present study, we investigated the capacity of NDV to specifically infect and spread into solid tissues of human melanoma and lung carcinoma, in vivo and ex vivo. For this purpose a new model of SCID-beige mice implanted with human melanoma was developed. Surprisingly, the replication competent NDV-MTH and the attenuated, single-cycle replication NDV-HUJ strains, demonstrated a similar oncolytic activity in the melanoma-implanted mice. Further, ex vivo analysis, using organ cultures derived from the melanoma tissues indicated a limited spread of the two NDV strains in the tissue. Extracellular matrix (ECM) molecules, notably heparin sulfate and collagen, were found to limit viral spread in the tissue. This observation was validated with yet another solid tumour of human lung carcinoma. Taken together, the results indicate that the ECM acts as a barrier to virus spread within solid tumour tissues and that this restriction must be overcome to achieve effective oncolysis with NDV.

Involvement of CCR6/CCL20/IL-17 axis in NSCLC disease progression.

OBJECTIVES: Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth. METHODS: A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation. RESULTS: CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P = 0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P = 0.0076, CI 95% 1.52-15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells. CONCLUSION: Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations.

Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation.

OBJECTIVES: Carcinoma-associated fibroblasts are reported to communicate microenvironment-derived signals through chemokine/chemokine receptor interaction, influencing carcinogenesis. We sought to characterize roles of CXCL12/CXCR4 in crosstalk between non-small cell lung cancer epithelial cell and carcinoma-associated fibroblasts and in tumor growth. METHODS: Non-small cell lung cancer tumor samples obtained at surgery and from tumor arrays, as well as primary carcinoma-associated fibroblast and epithelial cell lines generated from fresh tumors, were assessed for CXCL12/CXCR4 expression, tissue localization, and production. Colony assays, extracellular signal-regulated kinase signaling, and chemokine production were measured to assess cancer cell responsiveness to CXCL12 stimulation with or without CXCR4 antagonists. RESULTS: CXCL12 and CXCR4 were detected in all major subtypes of non-small cell lung cancer. CXCL12-expressing carcinoma-associated fibroblasts were mostly located near CXCL12-negative tumor cells, whereas CXCL12-positive tumor cells were mostly surrounded by CXCL12-negative stroma. Intratumoral CXCL12 levels were significantly higher than serum levels. CXCL12 expression correlated with advanced disease stage. In vitro, tumor cell lines produced variable amounts of CXCL12 and expressed high levels of CXCR4. Carcinoma-associated fibroblasts cell lines produced high amounts of CXCL12 and expressed variable levels of CXCR4. Stimulation of non-small cell lung cancer neoplastic cells with CXCL12 increased colony-forming capacity, induced extracellular signal-regulated kinase phosphorylation, and production of the proinflammatory chemokine CCL20. CXCR4 antagonists attenuated these effects. CONCLUSIONS: Interaction between carcinoma-associated fibroblasts and tumor epithelial cells through the CXCL12/CXCR4 axis plays a role in non-small cell lung cancer tumor proliferation, marking this axis as a target for immune intervention.

Infant lungs are preferentially infected by adenovirus and herpes simplex virus type 1 vectors: role of the tissue mesenchymal cells.

BACKGROUND: Adenovirus (AD) and herpes-simplex-virus-1 (HSV-1) have been extensively applied as vectors for gene and cancer therapy in clinical trials. AD5, from which the vector was constructed, is a common respiratory virus that infects mainly infants, yet the reasons for infant sensitivity to infection, other than immunity, are not clear. HSV-1, usually a neurotropic virus, may also cause severe pneumonia or disseminated diseases in infants and immunocompromised patients. METHODS: The tropism of these viruses to different human and mouse lung tissues of newborn and adult was studied in an ex vivo organ culture and it was also applied in vivo using a murine model. RESULTS: The data obtained indicated preferential viral infection of young lung tissues versus adult tissues in organ culture. Further studies indicated that the preferential infection of young tissues was not related to differences in receptor expression or exposure but rather to the different distribution of cell types in these tissues. Murine and human young lungs consist of a relative abundance of mesenchymal cells and these cells were much more susceptible to viral infection compared to adjacent epithelial-pneumocyte cells. These observations were further confirmed using an in vivo model of mouse infection. CONCLUSIONS: The similarity of the human and mouse tissues, with respect to viral vector tropism, validates the mouse model in studies of gene transfer to the lung. Furthermore, the results should facilitate the improved design of gene therapy trials for lung-related diseases in young and adults patients. Copyright © 2011 John Wiley & Sons, Ltd.

Paraganglioma of the mediastinum: challenges in diagnosis and surgical management.

Mediastinal paraganglioms are rare, highly vascularized tumors arising from chromaffin tissue located in the para-aortic ganglia. Tumors tend to invade bordering structures and may also form metastasis. Up to 50% of patients are asymptomatic and diagnosis is incidental. Presenting symptoms are related to catecholamine hypersecretion or to a mass effect. Complete surgical resection remains the standard of care due to malignant potential of the tumor and poor response to chemotherapy or radiation. Strategic location of the tumor in proximity to great vessels, trachea, and recurrent laryngeal nerve poses challenge for the surgeon. We report a case of a 59-year old asymptomatic female who was incidentally diagnosed with a middle mediastinal mass on a positron-emission tomography (PET-CT) scan performed as part of breast cancer surveillance. Complete resection of the tumor was achieved using cardiopulmonary bypass. The patient recovered uneventfully and in a ten-month follow up there is no evidence of recurrence.

Positron emission tomography in interstitial lung disease.

BACKGROUND AND OBJECTIVES: A high rate of glycolysis may reflect the inflammatory activity of interstitial lung disease (ILD). This prospective study investigated whether PET can distinguish IPF, a primarily fibrotic process, from other entities of ILD that have a marked inflammatory component. METHODS: Twenty-one patients referred for surgical lung biopsy because of diffuse ILD underwent PET at the time of the lung biopsy. PET transmission scans were obtained after injecting (18)FDG intravenously. Regions of interest (ROI) were drawn on the lung images, and the standardized uptake value (SUV) was calculated for these ROI. RESULTS: Of the 21 patients studied, 14 had IPF, four had non-specific interstitial pneumonia, and the remaining three patients each had respiratory bronchiolitis-ILD, sarcoidosis and Langerhan's cell histiocytosis. There was no statistically significant difference in the SUV between IPF patients and non-IPF patients (P = 0.26), although patients with IPF tended to have higher SUV. Radiographic changes tended to be more prominent in the lung bases in patients with IPF compared with non-IPF patients; however, the median ratio of SUV measured in the upper fields to the whole lungs in IPF patients was not significantly different compared with the median ratio in non-IPF patients (P = 0.31). CONCLUSION: PET does not allow differentiation of IPF from a non-IPF diffuse interstitial pulmonary process.

Minimally invasive procedures for diagnosis of traumatic right diaphragmatic tears: a method for correct diagnosis in selected patients.

Traumatic rupture of the diaphragm is no longer uncommon. Because of the increasing frequency of motor vehicle accidents, the rate of blunt trauma to the chest and abdomen, which are the most common causes of diaphragmatic rupture, is increased as well. However, the diagnosis is frequently missed or delayed because of the lack of sensitivity and specificity of imaging modalities. Diagnostic laparoscopy is considered a standard tool for penetrating injuries to the left diaphragm and is widely practiced in selected cases. Right diaphragmatic tears, however, are more difficult to diagnose because of the sealing effect of the liver. Blunt abdominal trauma can cause large right diaphragmatic tears, causing liver incarcerations and respiratory compromise, therefore demanding the need for a comparable diagnostic tool. A high index of suspicion, together with knowledge of the mechanism of trauma, is the key factor for the correct diagnosis. Once the diagnosis has been considered, diagnostic laparoscopy and/or diagnostic thoracoscopy should be performed to confirm or rule out this injury. Factors suggestive of a right diaphragmatic tear include newly or progressive elevation of the right diaphragm and respiratory distress without underlining lung injury. The timing of the procedure should be in accordance with the hemodynamic and respiratory status of the patient. This procedure should be performed semielectively if there are no other indications for surgical intervention.

CD4+CXCR4highCD69+ T cells accumulate in lung adenocarcinoma.

The chemokine receptor CXCR4 is involved in the growth and metastasis of tumor cells. However, the expression of its ligand, the chemokine CXCL12, in tumors and its role in regulating the accumulation of immune cells within the tumors is not clear. Using ELISA and immunohistochemistry we found that CXCL12 is expressed in the majority of nonsmall cell lung cancer tissue sections obtained from stage IA to IIB nonsmall cell lung cancer patients undergoing operation. Histopathologic examination of these sections indicated that high CXCL12 expression correlated with increased tumor inflammation. In addition, disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor. Isolation of adenocarcinoma-infiltrating immune cells demonstrated an increase in the percentage of CD4+CD69+CXCR4+ T cells as compared with normal lung tissue. About 30% of these cells expressed the regulatory T cell markers CD25high and FoxP3. The percentage of CD8 T cells within the tumor did not change, however; the percentage of NK and NK T cells was significantly reduced. In correlation with CXCR4 expression, CD4 T cells showed increased migration in response to CXCL12 compared with CD8 T cells and NK cells. Overall, these observations suggest that CXCL12 expression may influence tumor progression by shaping the immune cell population infiltrating lung adenocarcinoma tumors.

Computed tomography screening for lung cancer: applicability of an international protocol in a single-institution environment.

BACKGROUND: The purpose of this study was to assess the applicability of an annual low-dose computed tomography (CT) screening program for lung cancer in a single institution in Israel, which has a relatively lower prevalence of lung cancer compared with other Western countries, and to examine stage distribution of detected lung cancers. PATIENTS AND METHODS: A cohort of 842 former and current smokers underwent baseline low-dose CT screening and a total of 942 annual repeat screenings over a period of 68 months. The definition of positive results on baseline and repeat screening and their diagnostic workup were guided by the common International Early Lung Cancer Action Program protocol. Recommendations for biopsy of suspicious nodules were based on nodule size, nodule growth, non-resolution following antibiotic therapy, and positron emission tomography scan. RESULTS: The test result was positive in 102 of the 842 baseline screenings (12%) and in 45 of the 942 annual repeat screenings (5%), and biopsy was recommended in 12 baseline and 2 annual screenings. Twelve of the 14 cancers diagnosed (86%) were stage I tumors. CONCLUSION: Our study indicates that the adoption of a common international protocol is feasible, even in a very different clinical setting, yielding a high proportion of early-stage lung cancers.