Predictors of Early Hospice or Death in Patients With Inoperable Lung Cancer Treated With Curative Intent.

INTRODUCTION: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT. METHODS AND MATERIALS: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates. RESULTS: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. CONCLUSIONS: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes.

Trimodality therapy for patients with stage III non-small-cell lung cancer: A comprehensive surveillance, epidemiology, and end results analysis.

PURPOSE: Debate exists regarding the optimal management for patients with stage III non-small-cell lung cancer (NSCLC). Recent inclusion of chemotherapeutic data in the Surveillance, Epidemiology, and End Results (SEER) database has made it possible to identify patients with NSCLC who received chemotherapy. We hypothesized that patients with stage III NSCLC experience improved overall survival from trimodality therapy (TMT) versus definitive chemoradiation therapy (CRT) alone. MATERIALS AND METHODS: We analyzed the overall survival of stage III NSCLC patients based on the receipt of TMT versus CRT alone. This included crude and adjusted univariate models as well as crude and doubly robust adjusted multivariable analyses, both utilizing propensity score matching and inverse probability of treatment weighting. Factors included in the multivariable analyses included: age, sex, marital status, income, date of diagnosis, primary site, histology, grade, T stage, N stage, and intended treatment. Planned subset analyses were performed for stage III(N2) patients. RESULTS: Adult patients with stage III NSCLC (N = 9008) from the SEER database were included in our analyses. In our univariate analyses, an overall survival benefit was observed for TMT versus CRT (CrudeHR = 0.58, 95% CI = 0.55-0.61, p < 0.001; AdjHR = 0.58, 95% CI = 0.54-0.61, p < 0.001). This persisted in both crude and doubly robust multivariable analyses (CrudeHR = 0.57, 95% CI = 0.53-0.61, p < 0.001; AdjHR = 0.56, 95% CI = 0.53-0.59, p < 0.001). Patients with stage III(N2) disease also demonstrated a significant benefit to OS with TMT versus CRT alone. CONCLUSION: The significant difference in overall survival seen with TMT suggests this may be an effective treatment approach for select patients.

Receptor-centric solutions for the opioid epidemic: Making the opioid user impervious to overdose death.

This mini-review presents the view that contemporary approaches to stem the tide of opioid overdose deaths are insufficient to make a significant impact. Instead, a focus on the opioid receptor as the ultimate molecular target to directly abolish opioid overdose death is explored. After identifying the key brainstem neurons that control respiration which are inhibited by opioid drugs, genetic techniques targeting the mu opioid receptor are detailed which prevent opioid overdose. This receptor-centric solution for the opioid overdose epidemic can be realized with existing technology and, with sufficient effort, could enter clinical trials within 5 to 10 years.

The Role of Postoperative Radiation Therapy for pN2 Non-small-cell Lung Cancer.

BACKGROUND: The role for postoperative radiation therapy (PORT) for patients with non-small-cell lung cancer (NSCLC) with mediastinal lymph node (LN) involvement (pN2 disease) is controversial. We compared surgery alone with PORT among patients with pN2 NSCLC. We then performed subset analyses to better delineate patients that might benefit from PORT. PATIENTS AND METHODS: We conducted a propensity score (PS)-matched, inverse probability of treatment weighting (IPTW) Surveillance, Epidemiology, and End Results (SEER) analysis of patients with pN2 disease from 1989 to 2016 with surgery alone or PORT. Multiple imputation with chained equations was used for missing LN data. RESULTS: A total of 8631 patients were included in this analysis; 4579 underwent surgery alone, and 4052 underwent PORT. Following PS matching and IPTW, there was no difference in overall survival (OS) (hazard ratio [HR], 0.99; P = .76). However, PORT improved OS among a subset of patients with a LN positive to sampled ratio ≥ 50% (HR, 0.90; P = .01). Moreover, there was a trend towards improved OS among this subset, even with chemotherapy (HR, 0.91; P = .09). CONCLUSION: PORT is not associated with an improvement or detriment in OS for all patients with pN2 NSCLC. However, patients with a positive to sampled LN ratio ≥ 50% may benefit, regardless of chemotherapy status. Nevertheless, PORT will remain the standard of care as we await the results of the ongoing LUNG ART trial.

Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM. METHODS: We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM. RESULTS: 1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 - 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 - 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease. CONCLUSIONS: These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.

Amelioration of Mucositis in Proton Therapy of Fanconi Anemia Fanca-/- Mice by JP4-039.

BACKGROUND/AIM: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice. MATERIALS AND METHODS: Fanca-/- and Fanca+/+ bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and ß-Galactosidase senescence analysis. Fanca-/- and Fanca+/+ mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis. RESULTS: JP4-039 reduced oral cavity ulceration in Fanca-/- mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression. CONCLUSION: JP4-039 protected Fanca-/- and Fanca+/+ cells and mouse oral cavity from both proton and photon radiation.

Induction chemoradiotherapy versus chemotherapy alone for superior sulcus lung cancer.

OBJECTIVES: Although treatment of superior sulcus tumors with induction chemoradiotherapy (CRT) followed by surgery employed in the Intergroup INT-0160 trial is widely adopted as a standard of care, there may be significant associated morbidity and mortality. We describe our experience using standard and alternative induction regimens to assess survival rates and treatment toxicity in these patients. MATERIALS AND METHODS: Electronic medical records of all patients who underwent multimodality treatment including resection of lung cancer invading the superior pulmonary sulcus between 1994 and 2016 were retrospectively reviewed. Multivariable Cox Proportional Hazards model was constructed. RESULTS: Of 102 consecutive patients, 53 (52%) underwent induction CRT, 34 (33%) underwent induction chemotherapy only (Ch) followed by adjuvant radiotherapy, and 15 (15%) underwent no induction therapy followed by adjuvant therapy. There were 2 postoperative deaths (1.9%). To date, 42 patients are alive with a median follow-up 72.5 months. Overall 5-year survival rate was 45.4%. Survival was significantly influenced by age, FEV1, positive resection margins, surgical complications, but not the induction regimen. CRT resulted in higher complete pathological response rate than Ch: 38% vs. 3% (p < 0.001). CRT was associated with higher post-operative re-intubation rate: 13% vs. 0% (p = 0.03). CONCLUSIONS: Our single-institutional experience indicated that while induction CRT produced greater complete pathological response than Ch, it also increased the risk of post-operative complications. With careful patient selection, induction Ch followed by adjuvant radiotherapy may provide comparable survival outcomes to induction CRT. Since induction Ch is associated with lower risk of complications, it may be a particularly desirable choice for patients with impaired performance status.

Improved Survival With Increased Time-To-Radiation and Sequential Chemotherapy After Surgery for pN2 Non-Small-cell Lung Cancer.

BACKGROUND: Currently, the ideal timing for postoperative radiotherapy (PORT) and chemotherapy is unknown. The present study evaluated their relative timing on overall survival (OS) using the National Cancer Database (NCDB). MATERIALS AND METHODS: The NCDB was queried for patients from 2004 to 2012 with resected non-small-cell lung cancer (NSCLC), pathologically involved N2 (pN2) nodes, and negative margins. All patients underwent adjuvant chemotherapy and external beam radiotherapy. The time to radiation (TTR) was determined from the date of surgery to the start of PORT, with the exclusion of those receiving PORT < 4 weeks or > 24 weeks postoperatively. Early and late TTR was dichotomized at 8 weeks after receiver operating characteristic analysis. Multivariate Cox regression analysis was conducted to predict the variables significantly associated with survival. RESULTS: A total of 1629 patients were eligible for analysis. Of the 1629 patients, 703 had received PORT < 8 weeks and 926 had received PORT ≥ 8 weeks postoperatively. The receipt of PORT after 8 weeks was associated with better OS (P = .0044). No significant differences were found in survival in the concurrent group comparing early and later TTR (P = .9119). However, a significant OS benefit was found for sequential chemotherapy with an increased TTR (P = .0045). Older age, male sex, shorter distance traveled, increased nodal positivity, larger tumor size, higher Charlson/Deyo comorbidity score, and early TTR were associated with inferior survival on multivariate analysis. CONCLUSION: A TTR of ≥ 8 weeks with sequential chemotherapy in the setting of PORT was associated with improved survival in patients with NSCLC with pN2 nodes.

Quantitatively Excessive Normal Tissue Toxicity and Poor Target Coverage in Postoperative Lung Cancer Radiotherapy Meta-analysis.

BACKGROUND: A previous meta-analysis (MA) found postoperative radiotherapy (PORT) in lung cancer patients to be detrimental in N0/N1 patients and equivocal in the N2 setting. We hypothesized that treatment plans generated using MA protocols had worse dosimetric outcomes compared to modern plans. PATIENTS AND METHODS: We retrieved plans for 13 patients who received PORT with modern planning. A plan was recreated for each patient using the 8 protocols included in MA. Dosimetric values were then compared between the modern and simulated MA plans. RESULTS: A total of 104 MA plans were generated. Median prescribed dose was 50.4 (range, 50-60) Gy in the modern plans and 53.2 (30-60) Gy in the MA protocols. Median planning volume coverage was 96% (93%-100%) in the modern plans, versus 58% (0%-100%) in the MA plans (P < .001). Internal target volume coverage was 100% (99%-100%) versus 65% (0%-100%), respectively (P < .001). Organs at risk received the following doses: spinal cord maximum dose, 36.8 (4.6-50.4) Gy versus 46.8 (2.9-74.0) Gy (P < .001); esophageal mean dose, 22.9 (5.5-35) Gy versus 30.5 (11.1-52.5) Gy (P = .003); heart V30 (percentage of volume of an organ receiving at least a dose of 30 Gy), 16% (0%-45%) versus 35% (0%-79%) (P = .047); mean lung dose, 12.4 (3.4-24.3) Gy versus 14.8 (4.1-27.4) Gy (P = .008); and lung V20, 18% (4%-34%) versus 25% (8%-67%) (P = .023). CONCLUSION: We quantitatively confirm the inferiority of the techniques used in the PORT MA. Our analysis showed a lower therapeutic ratio in the MA plans, which may explain the poor outcomes in the MA. The findings of the MA are not relevant in the era of modern treatment planning.

The opioid antagonist, ß-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice.

Brain pathologies such as neurodegenerative diseases, infection, traumatic brain injury, and mood disorders produce enormous personal and economic burdens. It is well established that neuroinflammation plays an important role in the etiology and/or manifestation of such disorders. Previously, we discovered that beta-funaltrexamine (ß-FNA) inhibits inflammatory signaling in human astrocytes in vitro, resulting in reduced expression of proinflammatory cytokines/chemokines. The present study examines the effects of peripherally administered ß-FNA on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in vivo. Adult male C57BL/6J mice were administered ß-FNA and were then immediately administered bacterial lipopolysaccharide (LPS). At 24h post-injections, sickness behavior was assessed in an open-field test. Following behavioral analysis plasma and brains were collected. Levels of interleukin-6 (IL-6), interferon-γ inducible protein-10 (CXCL10), and monocyte chemoattractant protein-1 (CCL2) were determined by enzyme-linked immunosorbant assay (ELISA). At 24h post-LPS injection, IL-6, CCL2 and CXCL10 were increased in the plasma, whereas, only CCL2 and CXCL10 were elevated in the brain. ß-FNA significantly inhibited LPS-induced CXCL10 and CCL2 expression in brain, but minimally or not at all in the plasma. LPS-induced sickness behavior, as indicated by a reduction in distance moved, was prevented by ß-FNA. Overall, CXCL10 expression in the brain was most positively and significantly correlated with sickness behavior; whereas, anxiety-like behavior was most positively and significantly correlated with IL-6 and CCL2 levels in the plasma and levels of CXCL10 and CCL2 in the brain. The reduction in sickness behavior may be in part due to decreased chemokine expression in the brain; further examination of the anti-inflammatory and neuroprotective effects of ß-FNA is warranted.

Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides.

It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here, we test this idea by comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. The insensitivity of the delta OR (DOR) to deltorphin was due to variation of a single amino acid, Trp7.35, which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish, and amphibians. The deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides.

The opioid antagonist, ß-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice.

Opioid-immune crosstalk occurs when opioid drugs alter the activity of the immune system. In this study, the opioid antagonist ß-funaltrexamine (ß-FNA) decreases the expression and release of an inflammatory chemokine, interferon-γ inducible protein-10 (CXCL10) from normal human astrocytes stimulated by interleukin 1ß (IL-1ß). ß-FNA decreased CXCL10 by an unknown action that did not involve the mu opioid receptor (MOR). As IL-1ß acts through its receptor to activate NF-κB/MAPK signaling pathways which leads to CXCL10 expression and release, key steps in the IL-1ß signaling pathways were examined following ß-FNA treatment. IL-1ß-induced activation of p38 mitogen-activated protein kinases (p38 MAPK) was inhibited by ß-FNA as shown by decreased p38 MAPK phosphorylation in treated cells. ß-FNA also decreased the levels of activated subunits of NF-κB (p50 and p65) in treated astrocytes. The impact of ß-FNA was also observed in proteins that act to negatively regulate NF-κB signaling. IL-1ß upregulated the expression of A20, a ubiquitin (Ub)-editing enzyme that dampens NF-κB signaling by altering ubiquination patterns on IL-1 receptor second messengers, and the increase in A20 was significantly inhibited by ß-FNA treatment. Inhibition of the Ub-activating enzyme E1 by the inhibitor PYR41 also decreased CXCL10 release, like ß-FNA, and concurrent treatment with both PYR41 and ß-FNA inhibited CXCL10 more than did either agent alone. In mice, lipopolysaccharide-induced CXCL10 expression in the brain was inhibited by treatment with ß-FNA. These findings suggest that ß-FNA exerts an anti-inflammatory action in vitro and in vivo that is MOR-independent and possibly due to the alkylating ability of ß-FNA.

Bioinformatics and evolution of vertebrate nociceptin and opioid receptors.

G protein-coupled receptors (GPCRs) are ancestrally related membrane proteins on cells that mediate the pharmacological effect of most drugs and neurotransmitters. GPCRs are the largest group of membrane receptor proteins encoded in the human genome. One of the most famous types of GPCRs is the opioid receptors. Opioid family receptors consist of four closely related proteins expressed in all vertebrate brains and spinal cords examined to date. The three classical types of opioid receptors shown unequivocally to mediate analgesia in animal models and in humans are the mu- (MOR), delta- (DOR), and kappa-(KOR) opioid receptor proteins. The fourth and most recent member of the opioid receptor family discovered is the nociceptin or orphanin FQ receptor (ORL). The role of ORL and its ligands in producing analgesia is not as clear, with both analgesic and hyperalgesic effects reported. All four opioid family receptor genes were cloned from expressed mRNA in a number of vertebrate species, and there are enough sequences presently available to carry out bioinformatic analysis. This chapter presents the results of a comparative analysis of vertebrate opioid receptors using pharmacological studies, bioinformatics, and the latest data from human whole-genome studies. Results confirm our initial hypotheses that the four opioid receptor genes most likely arose by whole-genome duplication, that there is an evolutionary vector of opioid receptor type divergence in sequence and function, and that the hMOR gene shows evidence of positive selection or adaptive evolution in Homo sapiens.

Phase 2 study of concurrent cetuximab plus definitive thoracic radiation therapy followed by consolidation docetaxel plus cetuximab in poor prognosis or elderly patients with locally advanced non-small cell lung cancer.

BACKGROUND: Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. METHODS AND MATERIALS: Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-"dry" IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). RESULTS: From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board-approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. CONCLUSIONS: Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.

Study of 201 non-small cell lung cancer patients given stereotactic ablative radiation therapy shows local control dependence on dose calculation algorithm.

PURPOSE: Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly correlated with outcomes of lung stereotactic ablative body radiation (SABR). METHODS AND MATERIALS: Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups. RESULTS: Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 [95% confidence interval: 1.18-9.83], Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99GITV = 7.4 Gy, ΔD99PTV = 10.4 Gy, ΔV90GITV = 13.7%, ΔV90PTV = 37.6%, ΔD95PTV = 9.8 Gy, and ΔDISO = 3.4 Gy. GITV = gross internal tumor volume. CONCLUSIONS: Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm.

Normalization of ventilation data from 4D-CT to facilitate comparison between datasets acquired at different times.

PURPOSE: The 4D-CT data used for comparing a patient's ventilation distributions before and after lung radiotherapy are acquired at different times. As a result, an additional variable--the tidal volume (TV)--can alter the results. Therefore, in this paper we propose to normalize the ventilation to the same TV to eliminate that uncertainty. METHODS: Absolute ventilation (AV) data were generated for 6 stereotactic body radiation therapy (SBRT) cases before and after treatment, using the direct geometric algorithm and diffeomorphic morphons deformable image registration (DIR). Each pair of AV distributions was converted to TV-normalized, percentile ventilation (PV) and low-dose well-ventilated-normalized ventilation (LDWV) distributions. The ventilation change was calculated in various dose regions based on the treatment plans using the DIR-registered before and after treatment data sets. The ventilation change based on TV-normalized ventilation was compared with the AV as well as the data normalized by PV and LDWV. RESULTS: AV change may be misleading when the TV differs before and after treatment, which was found to be up to 6.7%. All three normalization methods produced a similar trend in ventilation change: the higher the dose to a region of lung, the greater the degradation in ventilation. In low dose regions (<5 Gy), ventilation appears relatively improved after treatment due to the relative nature of the normalized ventilation. However, the LDWV may not be reliable when the ventilation in the low-dose regions varies. PV exhibited a similar ventilation change trend compared to the TV-normalized in all cases. However, by definition, the ventilation distribution in the PV is significantly different from the original distribution. CONCLUSION: Normalizing ventilation distributions by the TV is a simple and reliable method for evaluation of ventilation changes.

Effects of quantum noise in 4D-CT on deformable image registration and derived ventilation data.

Quantum noise is common in CT images and is a persistent problem in accurate ventilation imaging using 4D-CT and deformable image registration (DIR). This study focuses on the effects of noise in 4D-CT on DIR and thereby derived ventilation data. A total of six sets of 4D-CT data with landmarks delineated in different phases, called point-validated pixel-based breathing thorax models (POPI), were used in this study. The DIR algorithms, including diffeomorphic morphons (DM), diffeomorphic demons (DD), optical flow and B-spline, were used to register the inspiration phase to the expiration phase. The DIR deformation matrices (DIRDM) were used to map the landmarks. Target registration errors (TRE) were calculated as the distance errors between the delineated and the mapped landmarks. Noise of Gaussian distribution with different standard deviations (SD), from 0 to 200 Hounsfield Units (HU) in amplitude, was added to the POPI models to simulate different levels of quantum noise. Ventilation data were calculated using the ΔV algorithm which calculates the volume change geometrically based on the DIRDM. The ventilation images with different added noise levels were compared using Dice similarity coefficient (DSC). The root mean square (RMS) values of the landmark TRE over the six POPI models for the four DIR algorithms were stable when the noise level was low (SD <150 HU) and increased with added noise when the level is higher. The most accurate DIR was DD with a mean RMS of 1.5 ± 0.5 mm with no added noise and 1.8 ± 0.5 mm with noise (SD = 200 HU). The DSC values between the ventilation images with and without added noise decreased with the noise level, even when the noise level was relatively low. The DIR algorithm most robust with respect to noise was DM, with mean DSC = 0.89 ± 0.01 and 0.66 ± 0.02 for the top 50% ventilation volumes, as compared between 0 added noise and SD = 30 and 200 HU, respectively. Although the landmark TRE were stable with low noise, the differences between ventilation images increased with noise level, even when the noise was low, indicating ventilation imaging from 4D-CT was sensitive to image noise. Therefore, high quality 4D-CT is essential for accurate ventilation images.

Β-funaltrexamine inhibits chemokine (CXCL10) expression in normal human astrocytes.

Neuroinflammation is an integral component of neurodegenerative disorders, CNS infection and trauma. Astroglial chemokines, such as CXCL10, are instrumental in neuroinflammatory signaling as well as neurotoxicity. We have utilized proinflammatory-induced CXCL10 expression in normal human astrocytes (NHA) as a model in which to assess the anti-inflammatory actions of the selective, mu-opioid receptor (MOR) antagonist, ß-funaltrexamine (ß-FNA). Interferon (IFN)γ+HIV-1 Tat-induced CXCL10 expression (secreted protein and mRNA) was inhibited by co-treatment with ß-FNA. Neither the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH2 (CTAP) nor the nonselective opioid receptor antagonist, naltrexone inhibited IFNγ+HIV-1 Tat-induced CXCL10 expression. Furthermore, co-treatment with excess CTAP or naltrexone did not prevent ß-FNA mediated inhibition of IFNγ+HIV-1 Tat-induced CXCL10 expression. Additionally, we utilized an inhibitor of NF-κB activation (SN50) to demonstrate that IFNγ+HIV-1 Tat-induced CXCL10 expression is NF-κB-dependent in NHA. Subsequent experiments revealed that ß-FNA did not significantly affect NF-κB activation. Interestingly, we discovered that ß-FNA inhibited p38 activation as indicated by decreased expression of phospho-p38. Together, these findings suggest that the inhibitory actions of ß-FNA are MOR-independent and mediated, in part, via a transcriptional mechanism. These findings add to our understanding of the mechanism by which chemokine expression is inhibited by ß-FNA. In conjunction with future investigations, these novel findings are expected to provide insights into the development of safe and effective treatments for neuroinflammation.