The Recent Development of Luteolin-loaded Nanocarrier in Targeting Cancer.

INTRODUCTION: Luteolin (LUT), a naturally occurring flavonoid found in vegetables, fruits, and herbal medicines, has been extensively studied for its pharmacological activities, including anti-proliferative and anticancer effects on various cancer lines. It also exhibits potent antioxidant properties and pro-apoptotic activities against human cancers. However, its therapeutic potential is hindered by its poor solubility in water (5 µg/ml at 45°C) and low bioavailability. This research on the development of luteolin-loaded nanocarrier aims to overcome these limitations, thereby opening up new possibilities in cancer treatment. METHODS: This paper covers several nanoformulations studied to increase the solubility and bioavailability of LUT. The physicochemical characteristics of the nanoformulation that influence luteolin's solubility and bioavailability have been the subject of more in-depth investigation. Furthermore, it examines how LUT's anti-inflammatory and antioxidant properties aid in lessening the side effects of chemotherapy. RESULTS: Most nanoformulations, including phytosomes, lipid nanoparticles, liposomes, protein nanoparticles, polymer micelles, nanoemulsions, and metal nanoparticles, have shown promising results in improving the solubility and bioavailability of LUT. This is a significant step forward in enhancing the therapeutic potential of LUT in cancer treatment. Furthermore, the study found that LUT's ability to scavenge free radicals can significantly reduce the side effects of cancer treatment, further highlighting its potential to improve patient outcomes. CONCLUSION: Nanoformulations, because of their unique surface and physiochemical properties, improve the solubility and bioavailability of LUT. However, poor in-vitro and in-vivo correlation and scalability of nanoformulations need to be addressed to achieve good clinical performance of LUT in oncology.

Local delivery of methotrexate/glycyrrhizin-loaded hyaluronic acid nanofiber for the management of oral cancer.

The challenges in treating oral cancer include the limited effectiveness and systemic side effects of conventional chemotherapy and radiation therapy. Hyaluronic acid (HA) based Glycyrrhizin (GL) and Methotrexate (MT) loaded localized delivery systems, specifically nanofiber (NF) based platforms, were developed to address these challenges. The electrospinning method was used for the successful fabrication of a homogenous NF membrane and characterized for morphology, drug entrapment efficiency, tensile strength, and ex-vivo mucoadhesive study. Also, it was evaluated for in-vitro drug release profile, ex-vivo drug permeability, in-vitro anti-inflammatory, apoptosis assay by MTT and flow, and against specific cell lines in order to determine their potential for therapeutic use. Superior tensile breaking force (50 g), mucoadhesive strength of 153 gm/cm2, drug permeability, and releasing properties of designed NF, making them perfect requirements for oral cavity delivery. The anticancer potential of MT in the MTT assay and flow cytometry analysis was significantly increased in oral epidermal carcinoma cell (KB cell) for drug-loaded NF with 63.97 ± 1.99 % apoptosis, at 24 h. With these incorporated, GL with MT in NF had an anti-inflammatory potential, also demonstrated in-vitro and in-vivo. In the Ehrlich Ascites Carcinoma (EAC) induced mice model, the optimal formulation's shows better potential for tumor regression when comparing the developed NF formulation to the drugs. Experimental results show that by lowering mucositis-related inflammation and enhancing the effectiveness of oral cancer treatment, a developed nanofiber-based local drug delivery system offers a feasible strategy for managing oral cancer.

Novel Drug Delivery Approaches for the Localized Treatment of Cervical Cancer.

Cervical cancer (CC) is the fourth leading cancer type in females globally. Being an ailment of the birth canal, primitive treatment strategies, including surgery, radiation, or laser therapy, bring along the risk of infertility, neonate mortality, premature parturition, etc. Systemic chemotherapy led to systemic toxicity. Therefore, delivering a smaller cargo of therapeutics to the local site is more beneficial in terms of efficacy as well as safety. Due to the regeneration of cervicovaginal mucus, conventional dosage forms come with the limitations of leaking, the requirement of repeated administration, and compromised vaginal retention. Therefore, these days novel strategies are being investigated with the ability to combat the limitations of conventional formulations. Novel carriers can be engineered to manipulate bioadhesive properties and sustained release patterns can be obtained thus leading to the maintenance of actives at therapeutic level locally for a longer period. Other than the purpose of CC treatment, these delivery systems also have been designed as postoperative care where a certain dose of antitumor agent will be maintained in the cervix postsurgical removal of the tumor. Herein, the most explored localized delivery systems for the treatment of CC, namely, nanofibers, nanoparticles, in situ gel, liposome, and hydrogel, have been discussed in detail. These carriers have exceptional properties that have been further modified with the aid of a wide range of polymers in order to serve the required purpose of therapeutic effect, safety, and stability. Further, the safety of these delivery systems toward vital organs has also been discussed.

Chemometric profiling and anti-arthritic activity of aerial parts of Glinus oppositifolius (L.) Aug. DC.

ETHNOPHARMACOLOGICAL RELEVANCE: Glinus oppositifolius (L.) Aug. DC. belongs to the family Molluginaceae, an annual prostrate herb traditionally used to treat inflammations, arthritis, malarial, wounds, fevers, diarrhoea, cancer, stomach discomfort, jaundice, and intestinal parasites. However, the anti-arthritic activity of the aerial part has still not been reported. AIM OF THE STUDY: To investigate the antioxidant and anti-arthritic activity of G. oppositifolius in Complete Freund's Adjuvant (CFA) induced rats. MATERIALS AND METHODS: The dried aerial parts of this plant material were defatted with n-hexane and extracted by methanol using a soxhlet apparatus. The in vitro anti-arthritic activity of methanolic extract of G. oppositifolius (MEGO) was evaluated in protein denaturation, membrane stabilization, and inhibition of proteinase assay at 25, 50, 100, 200, and 400 µg/ml concentrations. Female Wistar rats were immunized sub-dermally into the right hind paw with 0.1 ml of CFA. Rats were administered with MEGO at doses of 200 and 400 mg/kg once daily for fourteen days after arthritis induction. Assessment of arthritis was performed by measuring paw diameter, arthritic index, arthritic score, body weight, organ weight, and hematological and biochemical parameters, followed by the analysis of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1-beta (IL-1ß), cyclooxygenase-2 (COX-2), interleukin 13 (IL-13) and interleukin 10 (IL-10) and histopathological study. In vivo antioxidant effect was investigated in enzymatic assays. The presence of phytoconstituents was analyzed by Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS), respectively. In silico molecular docking study of the compounds was carried out against COX-2, IL-1ß, IL-6, and TNF-α using AutoDock 4.2 and BIOVIA-Discovery Studio Visualizer software. RESULTS: MEGO's in vitro anti-arthritic activity showed dose-dependent inhibition of protein denaturation, membrane stabilization, and proteinase inhibition, followed by significant in vivo anti-arthritic activity. The rats treated with MEGO showed tremendous potential in managing arthritis-like symptoms by restoring hematological, biochemical, and histological changes in CFA-induced rats. MEGO (200 and 400 mg/kg) showed a significant alleviation in the levels of hyper expressed inflammatory mediators (TNF-α, IL-1ß, and IL-6) and oxidative stress (SOD, CAT, GSH, and LPO) in CFA-induced rats. Spergulagenin-A as identified by LC-MS analysis, exhibited the highest binding affinity against COX-2 (-8.6), IL-1ß (7.2 kcal/mol), IL-6 (-7.4 kcal/mol), and TNF-α (-6.5 kcal/mol). CONCLUSIONS: Provided with the comprehensive investigation, methanolic extract of G. oppositifolius against arthritic-like condition is a proof of concept that revalidates its ethnic claim. The presence of Spergulagenin-A might be responsible for the anti-arthritic activity.

Radiation therapy margin reduction for patients with localized prostate cancer: A prospective study of the dosimetric impact and quality of life.

OBJECTIVES: To investigate the impact of reducing Clinical Target Volume (CTV) to Planning Target Volume (PTV) margins on delivered radiation therapy (RT) dose and patient reported quality-of-life (QOL) for patients with localized prostate cancer. METHODS: Twenty patients were included in a single institution IRB-approved prospective study. Nine were planned with reduced margins (4 mm at prostate/rectum interface, 5 mm elsewhere), and 11 with standard margins (6/10 mm). Cumulative delivered dose was calculated using deformable dose accumulation. Each daily CBCT dataset was deformed to the planning CT (pCT), dose was computed, and accumulated on the resampled pCT using a parameter-optimized, B-spline algorithm (Elastix, ITK/VTK). EPIC-26 patient reported QOL was prospectively collected pre-treatment, post-treatment, and at 2-, 6-, 12-, 18-, 24-, 36-, 48-, and 60-month follow-ups. Post -RT QOL scores were baseline corrected and standardized to a [0-100] scale using EPIC-26 methodology. Correlations between QOL scores and dosimetric parameters were investigated, and the overall QOL differences between the two groups (QOLMargin-reduced -QOLcontrol ) were calculated. RESULTS: The median QOL follow-up length for the 20 patients was 48 months. Difference between delivered dose and planned dose did not reach statistical significance (p > 0.1) for both targets and organs at risk between the two groups. At 4 years post-RT, standardized mean QOLMargin-reduced -QOLcontrol were improved for Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, and Sexual EPIC domains by 3.5, 14.8, 10.2, and 16.1, respectively (higher values better). The control group showed larger PTV/rectum and PTV/bladder intersection volumes (7.2 ± 5.8, 18.2 ± 8.1 cc) than the margin-reduced group (2.6 ± 1.8, 12.5 ± 8.3 cc), though the dose to these intersection volumes did not reach statistical significance (p > 0.1) between the groups. PTV/rectum intersection volume showed a moderate correlation (r = -0.56, p < 0.05) to Bowel EPIC domain. CONCLUSIONS: Results of this prospective study showed that margin-reduced group exhibited clinically meaningful improvement of QOL without compromising the target dose coverage.

Gastroretentive Drug Delivery System in Cancer Chemotherapy.

BACKGROUND: Chemotherapy for stomach cancer often includes several side effects. The primary reasons for the failure of such treatment approaches are low drug concentrations in target tissues and a short stomach residence time. OBJECTIVE: Gastroretentive controlled drug delivery systems improves the therapeutic performance of chemotherapeutic drugs following oral administration because of the longer gastric retention time. The goal of this study was to find suitable gastroretentive formulations that might be used for the localized treatment of stomach cancer. METHODS: The purpose of this study is to summarize current advances in gastro-retentive drug administration for oral chemotherapy, with a focus on floating, mucoadhesive, and swellable systems. This article also discusses the potentials and limitations of existing gastroretentive drug delivery systems used in cancer chemotherapy. RESULTS: Due to increased stomach retention and modified drug release properties, gastroretentive controlled drug delivery systems improve the therapeutic performance of anti-cancer drugs used to treat stomach cancer. CONCLUSION: Gastroretentive drug delivery systems appear to be a promising carrier for localized chemotherapy with smaller doses and better patient compliance. However, selection of drug candidates, drugfood interactions and chemotherapy-induced gastric discomfort remain the key characteristics that must be addressed to improve treatment outcomes.

PVP-microneedle array for drug delivery: mechanical insight, biodegradation, and recent advances.

Microneedle arrays are micron-sized needles usually attached to a supporting base or patch facilitated drug delivery for systemic effects. Polyvinylpyrrolidone (PVP) is a lactam polymer containing an internal amide linkage. Because of its versatility and biocompatibility, it has been widely utilized to treat several skin, bone and eye problems. Due to its specific and unique properties, the researchers realize its utility as a polymer of tremendous potential. PVP-based dissolvable microneedles have widely been utilized as a carrier for delivering DNAs, proteins, vitamins, and several biological macromolecules transdermally. However, it does not get biodegraded into the body. Therefore, the presence of its fragments in the body post-treatment needs proper justification. The adequate justification for the fate of the fragment's end products in the body will allow even better utilization of PVP. This review analyses and illustrates various experimental findings to highlight the most recent advancements and applications of PVP microneedles in drug delivery systems and cosmetology and the potential for PVP microneedles in treating dermal and systemic disorders. This review presents the expected mode of PVP biodegradation in aqueous and soil environments as a waste material, its inertness, biocompatibility, and the importance of PVP as a fabricating material, pharmaceutical uses, and non-toxic profile.

Chitosan as a potential biomaterial for the management of oral mucositis, a common complication of cancer treatment.

Oral mucositis is a serious issue in patients receiving oncological therapies. Mucosal protectants considered to be one of the preferred choices used in the management of mucositis. However, the protective efficacy of currently available mucosal protectants has been significantly compromised due to poor retention, lack of lubrication, poor biodegradability, and inability to manage secondary complications. Chitosan is a promising material for mucosal applications due to its beneficial biomedical properties. Chitosan is also anti-inflammatory, anti-microbial, and capable of scavenging free radicals, makes it a good candidate for the treatment of oral mucositis. Additionally, chitosan's amino polysaccharide skeleton permits a number of chemical alterations with better bioactive performance. This article provides a summary of key biological properties of chitosan and its derivatives that are useful for treating oral mucositis. Current literature evidence shows that Chitosan has superior mucosal protective properties when utilised alone or as delivery systems for co-encapsulated drugs.

Trends in iron oxide nanoparticles: a nano-platform for theranostic application in breast cancer.

Breast cancer (BC) is the deadliest malignant disorder globally, with a significant mortality rate. The development of tolerance throughout cancer treatment and non-specific targeting limits the drug's response. Currently, nano therapy provides an interdisciplinary area for imaging, diagnosis, and targeted drug delivery for BC. Several overexpressed biomarkers, proteins, and receptors are identified in BC, which can be potentially targeted by using nanomaterial for drug/gene/immune/photo-responsive therapy and bio-imaging. In recent applications, magnetic iron oxide nanoparticles (IONs) have shown tremendous attention to the researcher because they combine selective drug delivery and imaging functionalities. IONs can be efficaciously functionalised for potential application in BC therapy and diagnosis. In this review, we explored the current application of IONs in chemotherapeutics delivery, gene delivery, immunotherapy, photo-responsive therapy, and bio-imaging for BC based on their molecular mechanism. In addition, we also highlighted the effect of IONs' size, shape, dimension, and functionalization on BC targeting and imaging. To better comprehend the functionalization potential of IONs, this paper provides an outline of BC cellular development. IONs for BC theranostic are also reviewed based on their clinical significance and future aspects.Graphical Abstract[Formula: see text].

Current Breast cancer treatment resists due to the development of drug tolerance throughout cancer treatment and non-specific drug targeting.Magnetic IONs are being utilised for the therapy and bio-imaging of breast cancer by targeting overexpressed biomarkers, proteins, and receptors in breast cancer progression.Physical properties of IONs, such as size, shape, and dimensions, also alter their therapeutic and imaging responses.Iron oxide nanoparticles can be efficaciously functionalised based on breast cancer molecular mechanisms for potential application in breast cancer drug delivery, gene delivery, immunotherapy, photo responsive therapy, and bio-imaging.

Nanotherapeutics approaches to overcome P-glycoprotein-mediated multi-drug resistance in cancer.

Multidrug resistance (MDR) in cancer chemotherapy is a growing concern for medical practitioners. P-glycoprotein (P-gp) overexpression is one of the major reasons for multidrug resistance in cancer chemotherapy. The P-gp overexpression in cancer cells depends on several factors like adenosine triphosphate (ATP) hydrolysis, hypoxia-inducible factor 1 alpha (HIF-1α), and drug physicochemical properties such as lipophilicity, molecular weight, and molecular size. Further multiple exposures of anticancer drugs to the P-gp efflux protein cause acquired P-gp overexpression. Unique structural and functional characteristics of nanotechnology-based drug delivery systems provide opportunities to circumvent P-gp mediated MDR. The primary mechanism behind the nanocarrier systems in P-gp inhibition includes: bypassing or inhibiting the P-gp efflux pump to combat MDR. In this review, we discuss the role of P-gp in MDR and highlight the recent progress in different nanocarriers to overcome P-gp mediated MDR in terms of their limitations and potentials.

How does CBCT reconstruction algorithm impact on deformably mapped targets and accumulated dose distributions?

PURPOSE: We performed quantitative analysis of differences in deformable image registration (DIR) and deformable dose accumulation (DDA) computed on CBCT datasets reconstructed using the standard (Feldkamp-Davis-Kress: FDK_CBCT) and a novel iterative (iterative_CBCT) CBCT reconstruction algorithms. METHODS: Both FDK_CBCT and iterative_CBCT images were reconstructed for 323 fractions of treatment for 10 prostate cancer patients. Planning CT images were deformably registered to each CBCT image data set. After daily dose distributions were computed, they were mapped to planning CT to obtain deformed doses. Dosimetric and image registration results based CBCT images reconstructed by two algorithms were compared at three levels: (A) voxel doses over entire dose calculation volume, (B) clinical constraint results on targets and sensitive structures, and (C) contours propagated to CBCT images using DIR results based on three algorithms (SmartAdapt, Velocity, and Elastix) were compared with manually delineated contours as ground truth. RESULTS: (A) Average daily dose differences and average normalized DDA differences between FDK_CBCT and iterative_CBCT were ≤1 cGy. Maximum daily point dose differences increased from 0.22 ± 0.06 Gy (before the deformable dose mapping operation) to 1.33 ± 0.38 Gy after the deformable dose mapping. Maximum differences of normalized DDA per fraction were up to 0.80 Gy (0.42 ± 0.19 Gy). (B) Differences in target minimum doses were up to 8.31 Gy (-0.62 ± 4.60 Gy) and differences in critical structure doses were 0.70 ± 1.49 Gy. (C) For mapped prostate contours based on iterative_CBCT (relative to standard FDK_CBCT), dice similarity coefficient increased by 0.10 ± 0.09 (p < 0.0001), mass center distances decreased by 2.5 ± 3.0 mm (p < 0.00005), and Hausdorff distances decreased by 3.3 ± 4.4 mm (p < 0.00015). CONCLUSIONS: The new iterative CBCT reconstruction algorithm leads to different mapped volumes of interest, deformed and cumulative doses than results based on conventional FDK_CBCT.

Recent Advances in Herbal Nanomedicines for Cancer Treatment.

Cancer continues to be one of the deadliest diseases that adversely impacts the large population of the world. A stack of scientific documents reflects a huge number of potent plant-based anticancer drugs such as curcumin (CUR), podophyllotoxin, camptothecin (CPT), vincristine, vinblastine, paclitaxel (PTX), etc. that have been integrated into the modern practice of cancer treatment. The demand for natural products raises exponentially as they are generally considered to be safe, and devoid of critical toxic effects at the therapeutic dose when compared to their synthetic counterparts. Despite rising interest towards the potent phytoconstituents, formulation developer faces various challenges in drug development processes such as poor water solubility, low bioavailability, marginal permeability, and nonspecific drug delivery at the target site, etc. Further, adverse drug reaction and multidrug resistance are other critical issues that need to be addressed. Nanomedicines owing to their unique structural and functional attributes help to fix the above challenges for improved translational outcomes. This review summarises the prospects and challenges of a nanotechnology-based drug delivery approach for the delivery of plant-based anticancer drugs.

Dendrimer grafted albumin nanoparticles for the treatment of post cerebral stroke damages: A proof of concept study.

Stroke is the second largest disease of mortality. The biggest hurdle in designing effective brain drug delivery systems is offered by the blood-brain barrier (BBB), which is highly impermeable to many drugs. Albumin nanoparticles (NP) have gained attention due to their multiple ligand binding sites and long circulatory half-life. Citicoline (CIT) is reported to enhance the acetylcholine secretion in the brain and also helps in membrane repair and regeneration. However, the poor BBB permeation of CIT results in lower levels of CIT in the brain. This demands the development of a suitable delivery platform to completely realize the therapeutic benefit of CIT in stroke therapy. This investigation reports the synthesis and characterization of second generation (2.0 G) dendrimer Amplified Albumin (dAA) biopolymer by FTIR, MALDI-TOF, and surface charge (mV). Further, the synthesized biopolymer has been utilized to develop a CIT nanoformulation using a commercially translatable one-pot process. Release of CIT from biopolymer was performed within an acetate buffer at pH 5 and Phosphate buffer at pH 7.4. Further, we investigated the ability of biopolymer to permeate BBB by in vitro permeability assay in bEnd.3 cells. MTT assay of CIT-dAA-NP, CIT-ANP, and 2.0 G PAMAM dendrimers was performed in bEnd.3 cells. Therapeutic efficacy of the synthesized biopolymer was determined by VEGF gene expression within an in vitro hypoxia model in PC12 cells. Thus, this investigation resulted in biopolymers that can be used to deliver any therapeutic agent by altering the permeability of the BBB. Also, cationization by dendrimer grafting is one such strategy that may be used to cationize any other negatively charged polymer, such as albumin. The synthesized biopolymer is not limited to deliver molecules to the brain, but can also be used to increase the loading of negatively-charged drug molecules, siRNA, or any other oligonucleotide.

Improvements in CBCT Image Quality Using a Novel Iterative Reconstruction Algorithm: A Clinical Evaluation.

PURPOSE: This study aimed to evaluate the clinical utility of a novel iterative cone beam computed tomography (CBCT) reconstruction algorithm for prostate and head and neck (HN) cancer. METHODS AND MATERIALS: A total of 10 patients with HN and 10 patients with prostate cancer were analyzed. For each patient, raw CBCT acquisition data were used to reconstruct images with a currently available algorithm (FDK_CBCT) and novel iterative algorithm (Iterative_CBCT). Quantitative contouring variation analysis was performed using structures delineated by several radiation oncologists. For prostate, observers contoured the prostate, proximal 2 cm seminal vesicles, bladder, and rectum. For HN, observers contoured the brain stem, spinal canal, right-left parotid glands, and right-left submandibular glands. Observer contours were combined to form a reference consensus contour using the simultaneous truth and performance level estimation method. All observer contours then were compared with the reference contour to calculate the Dice coefficient, Hausdorff distance, and mean contour distance (prostate contour only). Qualitative image quality analysis was performed using a 5-point scale ranging from 1 (much superior image quality for Iterative_CBCT) to 5 (much inferior image quality for Iterative_CBCT). RESULTS: The Iterative_CBCT data sets resulted in a prostate contour Dice coefficient improvement of approximately 2.4% (P = .029). The average prostate contour Dice coefficient for the Iterative_CBCT data sets was improved for all patients, with improvements up to approximately 10% for 1 patient. The mean contour distance results indicate an approximate 15% reduction in mean contouring error for all prostate regions. For the parotid contours, Iterative_CBCT data sets resulted in a Hausdorff distance improvement of approximately 2 mm (P < .01) and an approximate 2% improvement in Dice coefficient (P = .03). The Iterative_CBCT data sets were scored as equivalent or of better image quality for 97.3% (prostate) and 90.0% (HN) of the patient data sets. CONCLUSIONS: Observers noted an improvement in image uniformity, noise level, and overall image quality for Iterative_CBCT data sets. In addition, expert observers displayed an improved ability to consistently delineate soft tissue structures, such as the prostate and parotid glands. Thus, the novel iterative reconstruction algorithm analyzed in this study is capable of improving the visualization for prostate and HN cancer image guided radiation therapy.

Elevated C-reactive protein and posttraumatic stress pathology among survivors of the 9/11 World Trade Center attacks.

BACKGROUND: Systemic inflammation has emerged as a promising marker and potential mechanism underlying post-traumatic stress disorder (PTSD). The relationship between posttraumatic stress pathology and systemic inflammation has not, however, been consistently replicated and is potentially confounded by comorbid illness or injury, common complications of trauma exposure. METHODS: We analyzed a large naturalistic cohort sharing a discrete physical and mental health trauma from the destruction of the World Trade Center (WTC) towers on September 11, 2001 (n = 641). We evaluated the relationship between multiple physical and mental health related indices collected through routine evaluations at the WTC Environmental Health Center (WTC EHC), a treatment program for community members exposed to the disaster. C-Reactive Protein (CRP), a marker of systemic inflammation, was examined in relation to scores for PTSD, PTSD symptom clusters (re-experiencing, avoidance, negative cognitions/mood, arousal), depression and anxiety, while controlling for WTC exposures, lower respiratory symptoms, age, sex, BMI and smoking as potential risks or confounders. RESULTS: CRP was positively associated with PTSD severity (p < 0.001), trending toward association with depression (p = 0.06), but not with anxiety (p = 0.27). CRP was positively associated with re-experiencing (p < 0.001) and avoidance (p < 0.05) symptom clusters, and trended toward associations with negative cognitions/mood (p = 0.06) and arousal (p = 0.08). CONCLUSIONS: In this large study of the relationship between CRP and posttraumatic stress pathology, we demonstrated an association between systemic inflammation and stress pathology (PTSD; trending with depression), which remained after adjusting for potentially confounding variables. These results contribute to research findings suggesting a salient relationship between inflammation and posttraumatic stress pathology.

Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers.

Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5-20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5-20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5-20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD.

Do Sociodemographic Factors Influence Outcome in Prostate Cancer Patients Treated With External Beam Radiation Therapy?

OBJECTIVES: The purpose of this study was to analyze the prognostic significance of sociodemographic factors on biochemical control (bNED) and overall survival (OS) in patients with prostate cancer. METHODS: Prostate cancer patients treated with definitive external beam radiation therapy (EBRT)±hormone therapy from 1997 to 2006 were analyzed in this IRB-approved study. Patient demographics, treatment (Tx), and clinical outcome were obtained from electronic medical records. Median household income (mHHI) at the census block group level was obtained from the 2000 census data. Data on disease and Tx parameters included Gleason score, pre-Tx prostate-specific antigen (PSA), T stage, year of Tx, EBRT dose, and use of hormone therapy. Patients were categorized as having low-risk, intermediate-risk, or high-risk disease. Sociodemographic factors included age, race, marital status, and mHHI. Biochemical failure was defined as nadir PSA+2 ng/mL. OS was based on death from any cause. RESULTS: A total of 788 consecutive patients were studied with a median follow-up of 7 years (range, 0.4 to 15 y). African Americans comprised 48% of the patients, whereas 46% of patients were white and 6% were other races. Whites had an average mHHI of $60,190 compared with $36,917 for African Americans (P<0.001). After multivariable modeling, only radiation dose was predictive for bNED (P=0.004) or OS (P=0.008). No sociodemographic factors were predictive for either outcome. Higher radiation dose predicted for better biochemical control and OS. CONCLUSIONS: This analysis suggests that sociodemographic factors are not important prognostic factors in determining outcome after EBRT for prostate cancer.

Contouring variability of human- and deformable-generated contours in radiotherapy for prostate cancer.

This study was designed to evaluate contouring variability of human-and deformable-generated contours on planning CT (PCT) and CBCT for ten patients with low-or intermediate-risk prostate cancer. For each patient in this study, five radiation oncologists contoured the prostate, bladder, and rectum, on one PCT dataset and five CBCT datasets. Consensus contours were generated using the STAPLE method in the CERR software package. Observer contours were compared to consensus contour, and contour metrics (Dice coefficient, Hausdorff distance, Contour Distance, Center-of-Mass [COM] Deviation) were calculated. In addition, the first day CBCT was registered to subsequent CBCT fractions (CBCTn: CBCT2-CBCT5) via B-spline Deformable Image Registration (DIR). Contours were transferred from CBCT1 to CBCTn via the deformation field, and contour metrics were calculated through comparison with consensus contours generated from human contour set. The average contour metrics for prostate contours on PCT and CBCT were as follows: Dice coefficient-0.892 (PCT), 0.872 (CBCT-Human), 0.824 (CBCT-Deformed); Hausdorff distance-4.75 mm (PCT), 5.22 mm (CBCT-Human), 5.94 mm (CBCT-Deformed); Contour Distance (overall contour)-1.41 mm (PCT), 1.66 mm (CBCT-Human), 2.30 mm (CBCT-Deformed); COM Deviation-2.01 mm (PCT), 2.78 mm (CBCT-Human), 3.45 mm (CBCT-Deformed). For human contours on PCT and CBCT, the difference in average Dice coefficient between PCT and CBCT (approx. 2%) and Hausdorff distance (approx. 0.5 mm) was small compared to the variation between observers for each patient (standard deviation in Dice coefficient of 5% and Hausdorff distance of 2.0 mm). However, additional contouring variation was found for the deformable-generated contours (approximately 5.0% decrease in Dice coefficient and 0.7 mm increase in Hausdorff distance relative to human-generated contours on CBCT). Though deformable contours provide a reasonable starting point for contouring on CBCT, we conclude that contours generated with B-Spline DIR require physician review and editing if they are to be used in the clinic.

Deformable image registration based automatic CT-to-CT contour propagation for head and neck adaptive radiotherapy in the routine clinical setting.

PURPOSE: To evaluate the clinical potential of deformable image registration (DIR)-based automatic propagation of physician-drawn contours from a planning CT to midtreatment CT images for head and neck (H&N) adaptive radiotherapy. METHODS: Ten H&N patients, each with a planning CT (CT1) and a subsequent CT (CT2) taken approximately 3-4 week into treatment, were considered retrospectively. Clinically relevant organs and targets were manually delineated by a radiation oncologist on both sets of images. Four commercial DIR algorithms, two B-spline-based and two Demons-based, were used to deform CT1 and the relevant contour sets onto corresponding CT2 images. Agreement of the propagated contours with manually drawn contours on CT2 was visually rated by four radiation oncologists in a scale from 1 to 5, the volume overlap was quantified using Dice coefficients, and a distance analysis was done using center of mass (CoM) displacements and Hausdorff distances (HDs). Performance of these four commercial algorithms was validated using a parameter-optimized Elastix DIR algorithm. RESULTS: All algorithms attained Dice coefficients of >0.85 for organs with clear boundaries and those with volumes >9 cm(3). Organs with volumes <3 cm(3) and/or those with poorly defined boundaries showed Dice coefficients of ∼ 0.5-0.6. For the propagation of small organs (<3 cm(3)), the B-spline-based algorithms showed higher mean Dice values (Dice = 0.60) than the Demons-based algorithms (Dice = 0.54). For the gross and planning target volumes, the respective mean Dice coefficients were 0.8 and 0.9. There was no statistically significant difference in the Dice coefficients, CoM, or HD among investigated DIR algorithms. The mean radiation oncologist visual scores of the four algorithms ranged from 3.2 to 3.8, which indicated that the quality of transferred contours was "clinically acceptable with minor modification or major modification in a small number of contours." CONCLUSIONS: Use of DIR-based contour propagation in the routine clinical setting is expected to increase the efficiency of H&N replanning, reducing the amount of time needed for manual target and organ delineations.

Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer.

PURPOSE: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. METHODS AND MATERIALS: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. RESULTS: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. CONCLUSIONS: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.