Mesialización del sector posterior por la ausencia del primer molar mediante el uso de microimplantes / Mesialization of the posterior sector due to the absence of the first molar through the use of micro-implants

Se presenta un caso clínico de paciente femenina de 16 años, la cual reportó haber perdido su primer molar superior izquierdo por caries dos años atrás. Es una paciente con maloclusión clase II esquelética, mesofacial, perfil recto, clase I molar derecho, ausencia del diente 26, clase I canina derecha y tendencia a clase II canina izquierda, con apiñamiento leve superior e inferior y línea media dental inferior desviada a la izquierda. Se trató mediante el uso de microimplante, con el objetivo de mesializar los dientes 27 y 28 así como mejorar el asentamiento de la clase canina izquierda. Se finalizó de manera exitosa la mesialización de los dientes posteriores superiores izquierdos, estableciendo una adecuada oclusión, eliminando el apiñamiento, logrando una buena guía anterior con líneas medias dentales coincidentes, proporcionando una sonrisa funcional y armoniosa. El propósito de este caso es demostrar que con las herramientas y mecánicas adecuadas además de una buena planificación, se puede lograr el control del anclaje en el movimiento de cierre posterior a falta de un molar ausente, y así lograr establecer una adecuada oclusión.

A clinical case of a 16-year-old female patient is presented, who reported having lost her upper left first molar due to caries two years ago is presented. She is a patient with class II skeletal, mesofacial malocclusion, straight profile, class I right molar, absence of tooth 26, class I right canine and tendency to class II left canine, with mild upper and lower crowding and lower dental midline deviated to the left. It was treated through the use of a microimplant, with the objective of mesializing teeth 27 and 28 as well as improving the settlement of the left canine class. The mesialization of the upper left posterior teeth was successfully completed, establishing adequate occlusion, eliminating crowding, achieving good anterior guidance with coincident dental midlines, providing a functional and harmonious smile. The purpose of this case is to demonstrate that with the appropriate tools and mechanics in addition to good planning, control of the anchorage in the posterior closing movement can be achieved in the absence of an absent molar, and thus achieve adequate occlusion.

Implementation of 3D conformal radiotherapy technology at the National Cancer Centre Mongolia: A successful Asia-Pacific collaborative initiative.

INTRODUCTION: Mongolia has a population of 3.3 million and is classified by the WHO as a lower middle-income country. Cancer is now a major public health issue and one of the leading causes of mortality. Within the framework of an existing national cancer control plan, the National Cancer Centre of Mongolia (NCCM) aimed to implement 3D conformal radiation planning and linac-based treatment delivery. METHODS: In 2018, an opportunity arose for collaboration between the Mongolia Society for Radiation Oncology (MOSTRO), the National Cancer Centre Mongolia (NCCM), the Asia-Pacific Radiation Oncology Special Interest Group (APROSIG) of the Royal Australian and New Zealand College of Radiologists (RANZCR) and the Asia-Pacific Special Interest Group (APSIG) of the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) and radiation therapists (RTTs) from a range of Australian centres. We describe here the results to date of this collaboration. RESULTS: Despite a number of significant technical and practical barriers, successful linac commissioning was achieved in 2019. Key factors for success included a leadership receptive to change management, stable bureaucracy and health systems, as well as a synchronised effort, regional cooperation and mentorship. CONCLUSION: Future directions for ongoing collaborative efforts include a continued focus on education, practical training in radiotherapy planning and delivery and postgraduate education initiatives. Radiotherapy safety and quality assurance remain an ongoing priority, particularly as technological advances are sequentially implemented.

Cautiously optimistic: A survey of radiation oncology professionals' perceptions of automation in radiotherapy planning.

INTRODUCTION: While there is evidence to show the positive effects of automation, the impact on radiation oncology professionals has been poorly considered. This study examined radiation oncology professionals' perceptions of automation in radiotherapy planning. METHOD: An online survey link was sent to the chief radiation therapists (RT) of all Australian radiotherapy centres to be forwarded to RTs, medical physicists (MP) and radiation oncologists (RO) within their institution. The survey was open from May-July 2019. RESULTS: Participants were 204 RTs, 84 MPs and 37 ROs (response rates ∼10% of the overall radiation oncology workforce). Respondents felt automation resulted in improvement in consistency in planning (90%), productivity (88%), quality of planning (57%), and staff focus on patient care (49%). When asked about perceived impact of automation, the responses were; will change the primary tasks of certain jobs (66%), will allow staff to do the remaining components of their job more effectively (51%), will eliminate jobs (20%), and will not have an impact on jobs (6%). 27% of respondents believe automation will reduce job satisfaction. 71% of respondents strongly agree/agree that automation will cause a loss of skills, while only 25% strongly agree/agree that the training and education tools in their department are sufficient. CONCLUSION: Although the effect of automation is perceived positively, there are some concerns on loss of skillsets and the lack of training to maintain this. These results highlight the need for continued education to ensure that skills and knowledge are not lost with automation.

Impact of dosimetric differences between CT and MRI derived target volumes for external beam cervical cancer radiotherapy.

OBJECTIVES: The use of MRI is becoming more prevalent in cervical cancer external beam radiotherapy (RT). The aim of this study was to investigate the impact of dosimetric differences between CT and MRI-derived target volumes for cervical cancer external beam RT. METHODS: An automated planning technique for volumetric modulated arc therapy was developed. Two automated planning plans were generated for 18 cervical cancer patients where planning target volumes (PTVs) were generated based on CT or MRI data alone. Dose metrics for planning target volumes and organs at risk (OARs) were compared to analyse any differences based on imaging modality. RESULTS: All treatment plans were clinically acceptable. Bladder doses (V40) were lower in MRI-based plans (p = 0.04, 53.6 ± 17.2 % vs 60.3 ± 13.1 % for MRI vs CT, respectively). The maximum dose for left iliac crest showed lower doses in CT-based plans (p = 0.02, 47.8 ± 0.7 Gy vs 47.4 ± 0.4 Gy MRI vs CT, respectively). No significant differences were seen for other OARs. CONCLUSIONS: The dosimetric differences of CT- and MRI-based contouring variability for this study was small. CT remains the standard imaging modality for volume delineation for these patients. ADVANCES IN KNOWLEDGE: This is the first study to evaluate the dosimetric implications of imaging modality on target and OAR doses in cervical cancer external beam RT.

Evaluation of the introduction of a 'traffic light protocol' for dose-volume histogram constraints of organs at risk in definitive radiotherapy at Liverpool and Macarthur Cancer Therapy Centres.

INTRODUCTION: Protocols have been developed in our department with recommended dose constraints for organs at risk (OAR) for each tumour site receiving definitive radiotherapy. We have developed a colour coding system to indicate when constraints are meeting objectives (green), have minor variation from planning objectives (yellow) and have major variation from planning objectives (red). We performed a quality audit to assess adherence to the protocol and to determine the rate of acute and subacute toxicities. METHODS: All definitive radiotherapy dose-volume histogram (DVH) reports generated in the first 6 months of 2017 at Liverpool and Macarthur cancer therapy centres were collected. For each radiotherapy group, the overridden dose constraints were evaluated and categorized to red and yellow. For all patients in our data set, follow-up documents/assessments were searched for grade 3 or higher acute or subacute radiotherapy toxicity and compared with those who had overridden dose constraints. RESULTS: There were 210 (34%) plans accepted with at least one major variation and 161 (26%) plans with minor variation. Head and neck group had the most rate of major variations (77%). The best groups in adherence to protocol were lymphoma and breast groups. In general, grade 3 toxicity was observed in 1%, 4% and 9% of patients who were in green, yellow and red categories. Overall, we noted a correlation with grade 3 toxicities between acceptable plans (green) and ones with a minor or major variation (yellow or red) (1% vs. 7% P = 0.0001). CONCLUSION: In conclusion this study showed an increased risk of higher grade toxicities when DVHs were beyond our departmental constraints using a 'Traffic Light System'. With this new colour coding system, we can facilitate auditing of the dose constraints in order to improve the quality of radiotherapy plans and potentially provide benchmarking for reducing toxicities in radiotherapy treatments.

Adapting automated treatment planning configurations across international centres for prostate radiotherapy.

BACKGROUND AND PURPOSE: Automated configurations are increasingly utilised for radiotherapy treatment planning. This study investigates whether automated treatment planning configurations are adaptable across clinics with different treatment planning protocols for prostate radiotherapy. MATERIAL AND METHODS: The study comprised three participating centres, each with pre-existing locally developed prostate AutoPlanning configurations using the Pinnacle3® treatment planning system. Using a three-patient training dataset circulated from each centre, centres modified local prostate configurations to generate protocol compliant treatment plans for the other two centres. Each centre applied modified configurations on validation datasets distributed from each centre (10 patients from 3 centres). Plan quality was assessed through DVH analysis and protocol compliance. RESULTS: All treatment plans were clinically acceptable, based off relevant treatment protocol. Automated planning configurations from Centre's A and B recorded 2 and 18 constraint and high priority deviations respectively. Centre C configurations recorded no high priority deviations. Centre A configurations produced treatment plans with superior dose conformity across all patient PTVs (mean = 1.14) compared with Centre's B and C (mean = 1.24 and 1.22). Dose homogeneity was consistent between all centre's configurations (mean = 0.083, 0.077, and 0.083 respectively). CONCLUSIONS: This study demonstrates that automated treatment planning configurations can be shared and implemented across multiple centres with simple adaptations to local protocols.

Nivolumab in Renal Cell Carcinoma: Current Trends and Future Perspectives.

Targeted agents form the backbone of most therapeutic strategies in advanced renal cell carcinoma (aRCC) but ultimately resistance develops and toxicity often leads to discontinuation of treatment, limiting the clinical benefits of these treatments. Nivolumab, a fully human IgG4 anti-PD-1 antibody, selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and provides a novel therapy option for patients with aRCC. In 2015, the pivotal phase III study CheckMate 025 led to the Food and Drug Administration approval of nivolumab in patients with aRCC who had received prior anti-angiogenic therapy, and in 2017, the phase III study CheckMate 214 showed that combined immunotherapy with nivolumab plus ipilimumab resulted in greater objective response rate and prolonged progression-free survival when compared with sunitinib in intermediate- and poor-risk patients with previously untreated aRCC. Early studies of nivolumab in association with anti-angiogenic therapy have generated enthusiasm and multiple combination trials are ongoing.

Multi-institutional comparison of simulated treatment delivery errors in ssIMRT, manually planned VMAT and autoplan-VMAT plans for nasopharyngeal radiotherapy.

PURPOSE: To quantify the impact of simulated errors for nasopharynx radiotherapy across multiple institutions and planning techniques (auto-plan generated Volumetric Modulated Arc Therapy (ap-VMAT), manually planned VMAT (mp-VMAT) and manually planned step and shoot Intensity Modulated Radiation Therapy (mp-ssIMRT)). METHODS: Ten patients were retrospectively planned with VMAT according to three institution's protocols. Within one institution two further treatment plans were generated using differing treatment planning techniques. This resulted in mp-ssIMRT, mp-VMAT, and ap-VMAT plans. Introduced treatment errors included Multi Leaf Collimator (MLC) shifts, MLC field size (MLCfs), gantry and collimator errors. A change of more than 5% in most selected dose metrics was considered to have potential clinical impact. The original patient plan total Monitor Units (MUs) were correlated to the total number of dose metrics exceeded. RESULTS: The impact of different errors was consistent, with ap-VMAT plans (two institutions) showing larger dose deviations than mp-VMAT created plans (one institution). Across all institutions' VMAT plans the significant errors included; ±5° for the collimator angle, ±5mm for the MLC shift and +1, ±2 and ±5mm for the MLC field size. The total number of dose metrics exceeding tolerance was positively correlated to the VMAT total plan MUs (r=0.51, p<0.001), across all institutions and techniques. CONCLUSIONS: Differences in VMAT robustness to simulated errors across institutions occurred due to planning method differences. Whilst ap-VMAT was most sensitive to MLC errors, it also produced the best quality treatment plans. Mp-ssIMRT was most robust to errors. Higher VMAT treatment plan complexity led to less robust plans.

Investigating the impact of treatment delivery uncertainties on treatment effectiveness for lung SABR.

To quantify the impact of treatment delivery uncertainties on lung stereotactic ablative body radiotherapy (SABR) plans for step-and-shoot intensity-modulated radiotherapy (ssIMRT) and volumetric modulated arc therapy (VMAT). Baseline ssIMRT and VMAT treatment plans were generated for a cohort of 18 lung SABR patients. Modified plans were generated for each baseline plan by systematically varying gantry and collimator angles between - 5 and + 5 degrees, as well as multi-leaf collimator (MLC) leaf position errors of magnitude between 1 and 5 mm in both directions (i.e. leaf banks shifted either in the same (Type 1) or opposite (Type 2) directions). Planning target volume (PTV), spinal cord and healthy lung dose-volume histogram (DVH) metrics were compared between the modified and baseline plans. Collimator and gantry angle uncertainties did not significantly impact any of the PTV DVH metrics considered. MLC shifts of 5 mm resulted in average V95% changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) and average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) for ssIMRT and VMAT plans. Comparatively, MLC shifts of - 2 mm resulted in average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) and average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) for ssIMRT and VMAT plans. ssIMRT gantry angle uncertainties impacted spinal cord DVH metrics the most, with increases in [Formula: see text] of [Formula: see text] occurring for a 1 degree shift. Type 2 MLC modifications impacted all OAR DVH metrics substantially with differences in spinal cord [Formula: see text] (ssIMRT) and healthy lung [Formula: see text] (VMAT) exceeding [Formula: see text] for 5 mm shifts. Uncertainties in MLC leaf positions affected target and OAR DVH metrics more than collimator or gantry angle uncertainties for lung SABR plans. Less patient-to-patient variation occurred from delivery uncertainties in VMAT than ssIMRT.

Standardized screening for periodontitis as an integral part of multidisciplinary management of adults with type 2 diabetes: an observational cross-sectional study of cohorts in the USA and UK.

OBJECTIVE: To determine prevalence and factors predictive of periodontitis by using a standardized assessment model in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed an observational cross-sectional study to determine the burden of periodontitis in adults with type 2 diabetes attending urban, ambulatory referral centers in the USA and UK. Full-mouth probing was performed and periodontitis was diagnosed based on either a low (≥5 mm at ≥1 site) or high pocket probing-depth threshold (≥6 mm at ≥1 site). Results were stratified into a five-stage schema and integrated with other clinical variables into the novel Diabetes Cross-Disciplinary Index to function as a balanced health scorecard. Corresponding demographic and routinely collected health data were obtained and comparisons were made between patients with and without periodontitis. Multivariable logistic regression was performed to identify factors predictive of the presence or absence of periodontitis. RESULTS: Between our two cohorts, 253 patients were screened. Caucasians comprised >90% and Hispanic Americans >75% of the UK and US cohorts, respectively. Males and females were equally distributed; mean age was 53.6±11 years; and 17 (6.7%) were edentulous. Of the 236 dentate patients, 128 (54.2%) had periodontitis by low threshold and 57 (24.2%) by high threshold. Just 17 (7.2%) were periodontally healthy. No significant differences in age, HbA1c, blood pressure, body mass index, low-density lipoprotein cholesterol, or smoking status (all p>0.05) were identified between those with or without periodontitis (regardless of threshold) and none was found to be a significant predictor of disease. CONCLUSIONS: Periodontitis is frequent in adults with type 2 diabetes and all should be screened. Periodontal health status can be visualized with other comorbidities and complications using a novel balanced scorecard that could facilitate patient-clinician communication, shared decision-making, and prioritization of individual healthcare needs.

Dose discrepancy between planning system estimation and measurement in spine stereotactic body radiation therapy: A case report.

Stereotactic body radiation therapy (SBRT) to treat spinal metastases has shown excellent clinical outcomes for local control. High dose gradients wrapping around spinal cord make this treatment technically challenging. In this work, we present a spine SBRT case where a dosimetric error was identified during pre-treatment dosimetric quality assurance (QA). A patient with metastasis in T7 vertebral body consented to undergo SBRT. A dual arc volumetric modulated arc therapy plan was generated on the Pinnacle treatment planning system (TPS) with a 6 MV Elekta machine using gantry control point spacing of 4°. Standard pre-treatment QA measurements were performed, including ArcCHECK, ion chamber in CTV and spinal cord (SC) region and film measurements in multiple planes. While the dose measured at CTV region showed good agreement with TPS, the dose measured to the SC was significantly higher than reported by TPS in the original and repeat plans. Acceptable agreement was only achieved when the gantry control point spacing was reduced to 3°. A potentially harmful dose error was identified by pre-treatment QA. TPS parameter settings used safely in conventional treatments should be re-assessed for complex treatments.

Tumor necrosis factor links chronic obstructive pulmonary disease and K-ras mutant lung cancer through induction of an immunosuppressive pro-tumor microenvironment.

Tumor necrosis factor (TNF) is known as an important regulator of tumor microenvironment and inflammation. TNF levels are markedly elevated in the bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), which is an independent risk factor for lung cancer. We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model (CC-LR mouse). This was associated with a significant increase of neutrophils in BALF, accompanied by a marked increase in TNF level, suggesting a link between COPD, TNF, and lung cancer promotion. Therefore, we first overexpressed TNF in the airway epithelium of CC-LR mice, which promoted lung cancer by ∼2-fold. This was associated with increased numbers of Ki67 and CD31 positive cells in lung tumors of CC-LR/TNF-Tg mice. We also found a robust increase in NF-κB activation, and numbers of neutrophils and myeloid-derived suppressor cells (MDSCs) in lung. Accordingly, we depleted MDSCs in CC-LR/TNF-Tg mice, which lead to significant tumor suppression emphasizing on the role of TNF-induced MDSCs in K-ras induced lung tumorigenesis. Finally, we targeted TNF expression by crossing CC-LR mice with TNF knock-out mice (CC-LR/TNF-KO), which resulted in a significant decrease in lung tumor burden in the absence or presence of COPD-like airway inflammation. Interestingly, there were less MDSCs and lower Ki67 and CD31 expression in the lung of the CC-LR/TNF-KO mice. We conclude that TNF links COPD to lung cancer promotion by induction of an immunosuppressive MDSC response, and subsequent amplification of proliferation and angiogenesis in tumors.

IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer.

Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras-mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL6, and activation of its responsive transcription factor STAT3 in K-ras-mutant lung tumors, which was further amplified by the tumor-enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras-mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL6 using a monoclonal anti-IL6 antibody in a K-ras-mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL6 blockade significantly inhibited lung cancer promotion, tumor cell-intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL6 inhibition reduced expression of protumor type 2 molecules (arginase 1, Fizz 1, Mgl, and IDO), number of M2-type macrophages and granulocytic myeloid-derived suppressor cells, and protumor T-regulatory/Th17 cell responses. This was accompanied by increased expression of antitumor type 1 molecule (Nos2), and antitumor Th1/CD8 T-cell responses. Our study demonstrates that IL6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also reeducates the lung microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces IL6 as a potential druggable target for prevention and treatment of K-ras-mutant lung tumors. Cancer Res; 76(11); 3189-99. ©2016 AACR.

Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals.

Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1ß (IL-1ß), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1ß, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-ß, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.

Investigating the causes for decreased levels of glutathione in individuals with type II diabetes.

Tuberculosis (TB) remains an eminent global burden with one third of the world's population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-ß), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection.

Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase.

BACKGROUND: Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion. Neutrophils are among the first cells to arrive at sites of inflammation, and the increased number of tumor-associated neutrophils is linked to poorer outcome in patients with lung cancer. RESULTS: We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR). This was associated with severe lung neutrophilic influx due to the increased level of neutrophil chemoattractant, KC. To further study the role of neutrophils in lung tumorigenesis, we depleted neutrophils in CC-LR mice using an anti-neutrophil antibody. This resulted in a significant reduction in lung tumor number. We further selectively inhibited the main receptor for neutrophil chemo-attractant KC, CXCR2. Similarly, this resulted in suppression of neutrophil recruitment into the lung of CC-LR mice followed by significant tumor reduction. Neutrophil elastase (NE) is a potent elastolytic enzyme produced by neutrophils at the site of inflammation. We crossed the CC-LR mice with NE knock-out mice, and found that lack of NE significantly inhibits lung cancer development. These were associated with significant reduction in tumor cell proliferation and angiogenesis. CONCLUSION: We conclude that lung cancer promotion by inflammation is partly mediated by activation of the IL-8/CXCR2 pathway and subsequent recruitment of neutrophils and release of neutrophil elastase. This provides a baseline for future clinical trials using the IL-8/CXCR2 pathway or NE inhibitors in patients with lung cancer.

Nontypeable Haemophilus influenzae in chronic obstructive pulmonary disease and lung cancer.

Chronic obstructive pulmonary disease (COPD) is predicted to become the third leading cause of death in the world by 2020. It is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases, most commonly cigarette smoke. Among smokers with COPD, even following withdrawal of cigarette smoke, inflammation persists and lung function continues to deteriorate. One possible explanation is that bacterial colonization of smoke-damaged airways, most commonly with nontypeable Haemophilus influenzae (NTHi), perpetuates airway injury and inflammation. Furthermore, COPD has also been identified as an independent risk factor for lung cancer irrespective of concomitant cigarette smoke exposure. In this article, we review the role of NTHi in airway inflammation that may lead to COPD progression and lung cancer promotion.