Accuracy of dose-volume metric calculation for small-volume radiosurgery targets.

PURPOSE: For stereotactic radiosurgery (SRS), accurate evaluation of dose-volume metrics for small structures is necessary. The purpose of this study was to compare the DVH metric capabilities of five commercially available SRS DVH analysis tools (Eclipse, Elements, Raystation, MIM, and Velocity). METHODS: DICOM RTdose and RTstructure set files created using MATLAB were imported and evaluated in each of the tools. Each structure set consisted of 50 randomly placed spherical targets. The dose distributions were created on a 1-mm grid using an analytic model such that the dose-volume metrics of the spheres were known. Structure sets were created for 3, 5, 7, 10, 15, and 20 mm diameter spheres. The reported structure volume, V100% [cc], and V50% [cc], and the RTOG conformity index and Paddick Gradient Index, were compared with the analytical values. RESULTS: The average difference and range across all evaluated target sizes for the reported structure volume was - 4.73%[-33.2,0.2], 0.11%[-10.9, 9.5], -0.39%[-12.1, 7.0], -2.24%[-21.0, 1.3], and 1.15%[-15.1,0.8], for TPS-A through TPS-E, respectively. The average difference and range for the V100%[cc] (V20Gy[cc]) was - 0.4[-24.5,9.8], -2.73[-23.6, 1.1], -3.01[-23.6, 0.6], -3.79[-27.3, 1.3], and 0.26[-6.1,2.6] for TPS-A through TPS-E, respectively. For V50%[cc](V10Gy[cc]) in TPS-A through TPS-E the average and ranger were - 0.05[-0.8,0.4], -0.18[-1.2, 0.5], -0.44[-1.4, 0.3], -0.26[-1.8, 2.6], and 0.09[-1.4,2.7]. CONCLUSION: This study expanded on the previously published literature to quantitatively compare the DVH analysis capabilities of software commonly used for SRS plan evaluation and provides freely available and downloadable analytically derived set of ground truth DICOM dose and structure files for the use of radiotherapy clinics. The differences between systems highlight the need for standardization and/or transparency between systems, especially when evaluating plan quality for multi-institutional clinical trials.

Incorporating biological modeling into patient-specific plan verification.

PURPOSE: Dose-volume histogram (DVH) measurements have been integrated into commercially available quality assurance systems to provide a metric for evaluating accuracy of delivery in addition to gamma analysis. We hypothesize that tumor control probability and normal tissue complication probability calculations can provide additional insight beyond conventional dose delivery verification methods. METHODS: A commercial quality assurance system was used to generate DVHs of treatment plan using the planning CT images and patient-specific QA measurements on a phantom. Biological modeling was performed on the DVHs produced by both the treatment planning system and the quality assurance system. RESULTS: The complication-free tumor control probability, P+ , has been calculated for previously treated intensity modulated radiotherapy (IMRT) patients with diseases in the following sites: brain (-3.9% ± 5.8%), head-neck (+4.8% ± 8.5%), lung (+7.8% ± 1.3%), pelvis (+7.1% ± 12.1%), and prostate (+0.5% ± 3.6%). CONCLUSION: Dose measurements on a phantom can be used for pretreatment estimation of tumor control and normal tissue complication probabilities. Results in this study show how biological modeling can be used to provide additional insight about accuracy of delivery during pretreatment verification.

Characterizing a deformable registration algorithm for surface-guided breast radiotherapy.

PURPOSE: Surface-guided radiation therapy (SGRT) is a nonionizing imaging approach for patient setup guidance, intra-fraction monitoring, and automated breath-hold gating of radiation treatments. SGRT employs the premise that the external patient surface correlates to the internal anatomy, to infer the treatment isocenter position at time of treatment delivery. Deformations and posture variations are known to impact the correlation between external and internal anatomy. However, the degree, magnitude, and algorithm dependence of this impact are not intuitive and currently no methods exist to assess this relationship. The primary aim of this work was to develop a framework to investigate and understand how a commercial optical surface imaging system (C-RAD, Uppsala, Sweden), which uses a nonrigid registration algorithm, handles rotations and surface deformations. METHODS: A workflow consisting of a female torso phantom and software-introduced transformations to the corresponding digital reference surface was developed. To benchmark and validate the approach, known rigid translations and rotations were first applied. Relevant breast radiotherapy deformations related to breast size, hunching/arching back, distended/deflated abdomen, and an irregular surface to mimic a cover sheet over the lower part of the torso were investigated. The difference between rigid and deformed surfaces was evaluated as a function of isocenter location. RESULTS: For all introduced rigid body transformations, C-RAD computed isocenter shifts were determined within 1 mm and 1˚. Additional translational shifts to correct for rotations as a function of isocenter location were determined with the same accuracy. For yaw setup errors, the difference in shift corrections between a plan with an isocenter placed in the center of the breast (BrstIso) and one located 12 cm superiorly (SCFIso) was 2.3 mm/1˚ in lateral direction. Pitch setup errors resulted in a difference of 2.1 mm/1˚ in vertical direction. For some of the deformation scenarios, much larger differences up to 16 mm and 7˚ in the calculated shifts between BrstIso and SCFIso were observed that could lead to large unintended gaps or overlap between adjacent matched fields if uncorrected. CONCLUSIONS: The methodology developed lends itself well for quality assurance (QA) of SGRT systems. The deformable C-RAD algorithm determined accurate shifts for rigid transformations, and this was independent of isocenter location. For surface deformations, the position of the isocenter had considerable impact on the registration result. It is recommended to avoid off-axis isocenters during treatment planning to optimally utilize the capabilities of the deformable image registration algorithm, especially when multiple isocenters are used with fields that share a field edge.

Risk of metachronous recurrence after endoscopic submucosal dissection of esophageal squamous cell carcinoma.

Development of endoscopic submucosal dissection (ESD) improves the en bloc resection rate of superficial esophageal squamous cell carcinoma (SESCC). Although the background mucosa after ESD remains malignant potential, esophageal (sub)circumferential ESD, in cases where the mucosal defect is greater than three-fourths of the circumference, might induce refractory stricture, and it may disturb early detection of the recurrence. Therefore, we aimed to elucidate whether the patients treated by (sub)circumferential ESD for SESCC may remain at risk of metachronous recurrence. In a single-center retrospective study, we collected data from 154 consecutive patients who were treated with curative ESD for SESCC from 2002 to 2013 and followed by surveillance for longer than 12 months. Metachronous recurrence was defined as histologically proven SESCC at other site of the ESD scar or abnormal nodal swelling was detected later than 12 months after ESD. The primary endpoint was to identify the risk of metachronous recurrence using multivariate analyses. The secondary endpoint was to investigate difference in clinical pathological features between patients with and without the recurrence. The overall rate of metachronous recurrence was 14.9% during 40.5 median months after the initial ESD. 24.1% and 9.0% of overall metachronous recurrence were observed in patients treated with (sub)circumferential ESD and non-subcircumferential ESD, respectively, despite no significant difference in their observation duration. After the application of a stepwise regression model that included all variants, a Cox proportional hazards regression model identified (sub)circumferential ESD as the only risk for the recurrence (hazard ratio (HR): 1.48, 95% confidence intervals (CI): 1.04-2.08, P = 0.028). The cumulative recurrence rate revealed a significant difference between patients treated by (sub)circumferential ESD and those by nonsubcircumferential ESD (HR: 3.094, 95% CI: 1.33-7.52, P = 0.009), despite no significant difference in their cause-specific survival. Additionally, the session numbers of the follow-up endoscopy until the detection of metachronous recurrence after the non-subcircumferential ESD were significantly less than those after the (sub)circumferential ESD (7.8 ± 1.8 vs. 15.2 ± 1.5 P = 0. 005), despite no significant difference in their cancer-free duration. In conclusion, we demonstrated that patients treated by curative (sub)circumferential ESD for SESCC might be high risk for metachronous recurrence. Therefore, we should establish a risk-stratified surveillance program after (sub)circumferential ESD and preventive strategies for post-ESD stricture.

Identification of a high-risk group for low-dose aspirin-induced gastropathy by measuring serum pepsinogen in H. pylori-infected subjects.

BACKGROUND: We recently demonstrated in humans that the extent of low-dose aspirin (LDA)-induced gastropathy was directly related to the individual gastric acid secretion level. We also established reliable cutoff serum pepsinogen (PG) values to predict gastric acid secretion status. In this study, we investigated the clinical usefulness of measuring the serum pepsinogen values for identifying a high-risk group for gastric mucosal injury among chronic LDA users. METHODS: One hundred long-term LDA users were enrolled in this analysis. Serum from each subject was subjected to determination of H. pylori status and measurement of pepsinogen values. According to our recent report, a PG I value ≥ 50 ng/mL was defined as estimated hyperchlorhydria in H. pylori-negative subjects, while a PG I/II ≥ 3.3 was defined as estimated hyperchlorhydria in H. pylori-positive subjects. The grade of gastric mucosal injury was assessed endoscopically, and multiple logistic regression analyses were used to estimate the risk. RESULTS: Estimated hyperchlorhydria was a strong independent risk for intensive gastric mucosal injury with an OR (95% CI): 34.0 (4.5-259) and for gastric ulcer with an OR (95% CI): 10.2 (1.8-58.3) in H. pylori-positive subjects, while it was not a significant risk in H. pylori-negative subjects. The association persisted even after excluding those with conventional risks for LDA-gastropathy such as ulcer histories. CONCLUSION: Using simple serum measurement of H. pylori antibody and pepsinogen concentrations, an extremely high-risk group for LDA-induced gastropathy could be extracted, and these patients should become a therapeutic target for prevention of LDA-induced gastropathy.

Resistance training does not have an effect on cognition or related serum biomarkers in nonagenarians: a randomized controlled trial.

The aim of this randomized controlled trial was to determine the effects of 8-week exercise-intervention on cognition and related serum biochemical markers in nonagenarians. We also studied the effects of a 4-week training cessation ('detraining') period on our study variables. Participants were randomly allocated to a standard-care (control) or intervention (exercise) group [n=20 (16 women)/group]. The intervention focused on supervised, light-to-moderate-intensity aerobic and resistance exercises (mainly leg press), and included 3 weekly sessions. Cognitive status was determined by the mini-mental state examination and geriatric depression scale. We analysed proteins with reported relation with mechanisms behind cognition changes such as serum levels of angiotensin converting enzyme, amyloid-precursor protein, epidermal growth factor, brain-derived neural factor and tumor necrosis factor. No significant change (P>0.05) in any of the variables studied was found following the exercise intervention compared with the standard-care group. Similarly, no significant changes (P>0.05) were observed following the detraining period compared with the standard-care group. Overall changes after the exercise intervention in serum biomarkers were not associated with changes in functional capacity and cognitive measures. An 8-week exercise intervention focusing on resistance exercises neither benefits cognitive function nor affects the levels of the serum proteins analysed in nonagenarians.

Reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin-induced gastropathy.

BACKGROUND: Gastric mucus is considered to play an essential role in gastric mucosal defense mechanisms, especially when irritants are present in the stomach. AIM: To investigate the relationship between low-dose aspirin-induced gastropathy and gastric secretory function, especially gastric mucus secretion, in healthy volunteers. METHODS: Thirty male, asymptomatic, Helicobacter pylori pylori-negative healthy volunteers were asked to take 100 mg of enteric-coated aspirin (Bayaspirin) once a day for 10 days. Endoscopic examination was performed before and 3 and 10 days after drug administration. The extent of endoscopically assessed gastric mucosal injury was semi-quantitatively evaluated according to the modified Lanza score. The pentagastrin-stimulated gastric juice was collected for 10 min during the endoscopic examination and subjected to analysis for gastric acid (mEq/10 min) or mucus (mg hexose/10 min) output. RESULTS: Overall, the 10-day aspirin treatment significantly increased gastric mucus secretion from 0.8 (interquartile range 1.7) to 1.6 (1.6) mg hexose/10 min (P < 0.05), with a concomitant and significant decrease in the gastric acid/mucus ratio from 4.3 (5.2) to 2.9 (4.7) (P < 0.01). Subsequent analysis of two subgroups of volunteers categorized according to their endoscopic status ("severe gastropathy" vs. "modest gastropathy") revealed that changes in gastric secretory parameters occurred exclusively in those subjects without severe gastric injury; there was no alteration in these parameters in subjects with severe gastric injury. CONCLUSIONS: The results of this study suggest that the reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin-induced gastropathy. In some individuals, such a response may be insufficient to prevent the development of severe mucosal injury and even ulcers and their complications.

Serious laryngeal edema during endoscopic resection for squamous cell carcinoma of the esophagus.

The detection of early esophageal squamous cell carcinoma (ESCC) in patients following radiotherapy for squamous cell carcinoma of the head and neck (HNSCC) has increased with the development of endoscopic technologies. The aim of the current case - control study was to elucidate the risk factors of serious laryngeal edema, a lethal complication that occurs during endoscopic resection for ESCC. Among 184 consecutive patients who were treated by endoscopic resection for ESCC between January 2009 and May 2012, five of 22 patients with a history of radiotherapy for HNSCC suffered from serious laryngeal edema, which was not observed in patients who had not undergone radiotherapy. The susceptibility to serious laryngeal edema in patients with a history of radiotherapy followed by neck dissection for HNSCC was significantly greater than those without such histories. Despite the limited number of cases, we suggest that previous radiotherapy followed by neck dissection for HNSCC might be a predictive factor for serious laryngeal edema during endoscopic resection.

ACE and ACTN3 genes and muscle phenotypes in nonagenarians.

We studied the association of ACE and ACTN3 polymorphisms with skeletal muscle phenotypes (i. e. upper and lower body muscular strength and functional tests) in Spanish nonagenarian subjects [n=41, 33 women, 8 men, age: 90-97 years]. Mean values of the study phenotypes were not significantly different (all P>0.05) between ACE and ACTN3 genotypes. The analyses of the combined effects between genotypes ( ACE DD & ACTN3 RR/RX vs. ACE II/ID & ACTN3 XX) did not yield any significant difference. Our data suggest that, in the elderly, the influence of genetic factors on muscle phenotype traits is not reducible to a few single polymorphisms, including ACE and ACTN3 variants.

Reactive nitrogen oxide species induce dilatation of the intercellular space of rat esophagus.

OBJECTIVE: Dilatation of the intercellular space (DIS) of the esophageal epithelium is recognized as one of the earliest histological changes in gastroesophageal reflux disease patients. At the human gastroesophageal junction, reactive nitrogen oxide species (RNOS) are generated luminally through the entero-salivary re-circulation of dietary nitrate. In cases with gastroesophageal reflux, the site of luminal RNOS generation may shift to the distal esophagus. The aim of this study was to investigate whether luminal RNOS exposure could be involved in the pathogenesis of DIS. MATERIAL AND METHODS: Rat esophageal mucosa was studied with an Ussing chamber model. On the luminal side of the chamber, RNOS were generated by the acidification of physiologic concentrations of sodium nitrite (1.0 or 5.0 mM). Esophageal barrier function was assessed by means of electrophysiological transmembrane resistance and membrane permeability by means of (3)H-mannitol flux. The dimensions of the intercellular spaces were assessed by using transmission electron microscopy. RESULTS: Administration of acid plus sodium nitrite induced DIS of the esophageal epithelium, and this ultrastructural morphological change was accompanied by a concomitant decrease in the transmembrane resistance and an increase in the epithelial permeability. The DIS induced by luminal RNOS was also confirmed in an in vivo exposure model. CONCLUSIONS: The present animal study indicates that the RNOS generated by the acidification of salivary nitrite in the presence of refluxed gastric acid in the esophagus could be a luminal factor that is responsible for the induction of DIS. Further studies are warranted to investigate the clinical relevance of the present findings to the human situation.

Gastric hyposecretion in esophageal squamous-cell carcinomas.

Recently, gastric fundic atrophy is reported to be an independent risk factor for esophageal squamous-cell carcinoma (ESCC). The aim of this study is to investigate the acid secretory level in ESCC in a case-control study. From April 2004 to March 2008, 100 consecutive subjects with early ESCC and 100 age- and sex-matched asymptomatic controls were prospectively enrolled. Gastrin-stimulated acid output was assessed by endoscopic gastrin test. Conditional regression analyses were used to adjust for other potential confounders. Multivariate analyses revealed a strong association between profound hypochlorhydria and ESCC with odds ratio (95% confidence interval): 6.0 (1.9-18.4). The association remained significant after adjusting for the effect of gastric atrophy as a covariate. The association became stronger as the ESCC developed more distal site of the esophagus. This study indicates that profound hypochlorhydria is a strong independent risk factor for ESCC even after adjusting for the influence of gastric atrophy.

In vitro antimicrobial and cytotoxic activities of leaves and flowers extracts from Lippia alba.

The research was conducted to investigate the in vitro antimicrobial and cytotoxic activities of leaves and flowers extract extracted from Lippia alba. Disc diffusion technique was used for in vitro antibacterial and antifungal screening. Zones of inhibition were observed in disc diffusion for antibacterial screening against 4 Gram-positive pathogenic and 6 Gram-negative pathogenic bacteria. Among crude extracts chloroform extract showed good activity against all test organisms. A Large zone of inhibition was observed (18 mm) against Vibrio parahaemolyticus. In antifungal screening, the compound showed mild to moderate zones of inhibition against four tested organisms. A Large zone of inhibition was observed against Aspergillus niger (13 mm). Cytotoxic activities of crude extracts were determined using Brine shrimp lethality Bioassay and LC50 values of standard Vincristin sulphate as positive control, n-hexane and crude ethanol extracts were found to be 5, 15 and 20 microg mL(-1), respectively.

Disruption of gastric barrier function by luminal nitrosative stress: a potential chemical insult to the human gastro-oesophageal junction.

OBJECTIVE: The human gastro-oesophageal junction is exposed to abundant amounts of luminal reactive nitrogen oxide species (RNOS) derived from the enterosalivary re-circulation of dietary nitrate. The aim of this study is to investigate the direct effects of luminal RNOS on the adjacent gastric barrier function using an ex vivo chamber model. METHODS: A chamber model in which the rat gastric mucosal membrane was mounted between the two halves of a chamber was designed to simulate the microenvironment of the lumen and the adjacent mucosa of the gastro-oesophageal junction. On the mucosal side of the chamber, RNOS were generated by the acidification of physiological concentrations of sodium nitrite. The epithelial barrier function was evaluated by electrophysiological transmembrane resistance, and membrane permeability with [3H]mannitol flux. The expression of occludin was evaluated by immunohistochemistry and immunoblotting. Dinitrosyl dithiolato iron complex (DNIC) was also measured by means of electron paramagnetic resonance spectroscopy to confirm the diffusion of RNOS from the mucosal lumen into the mounted mucosa. RESULTS: The administration of acidified nitrite to the mucosal lumen caused both a decrease in transmembrane resistance and an increase in epithelial permeability, suggesting a disturbance of the gastric barrier function. These changes were accompanied by a derangement of the expression of occludin. The diffusion of luminal RNOS into the mounted membrane was confirmed by showing the generation of DNIC within the tissue. CONCLUSIONS: Simulating the microenvironment of the human gastro-oesophageal junction, this study demonstrated that RNOS generated luminally at the human gastro-oesophageal junction can derange the barrier function of the adjacent tissue by disrupting the tight junction.

Fe-S cluster proteins are intracellular targets for nitric oxide generated luminally at the gastro-oesophageal junction.

In human, high concentrations of nitric oxide are generated at the gastro-oesophageal junction through entero-salivary recirculation of dietary nitrate. Nitric oxide is known to have a high affinity for Fe-S cluster proteins. The aim of this study is to investigate whether nitric oxide arising from the lumen diffuses into the adjacent tissue where it can interact with Fe-S proteins both in a rat animal model and human. An electron paramagnetic resonance detectable complex, dinitrosyl dithiolato iron complex (DNIC), was used as a biomarker for the interaction between Fe-S proteins and nitric oxide. The generation of the complex was evaluated in resected gastric tissue of nitrite-administered rat or biopsy specimens from human after nitrate ingestion. The activity of aconitase, one of the Fe-S cluster proteins, was also determined. The signal of the complex was observed at the rat gastro-oesophageal junction where luminal generation of nitric oxide from nitrite was maximal, and the intensity increased in a dose- and time-dependent manner. The appearance of the complex was accompanied by a significant inhibition of the aconitase activity at that site. The complex appeared in biopsy specimens from the gastro-oesophageal junction in three of five men after nitrate ingestion. Since DNIC is considered to be a decomposition product when Fe-S cluster proteins interact with nitric oxide, the appearance of the signal provides direct evidence that nitric oxide arising from the lumen can destroy such proteins. DNIC formation may represent the cellular mechanism responsible for the high prevalence of disease at the gastro-oesophageal junction.

An exploratory study of buprenorphine use in Bangladesh: a note.

A pilot study was carried out in Bangladesh during August and September, 1995, using a "snowball" technique with 30 male multiple drug users in order to investigate buprenorphine use, characteristics of the users, their reasons for its use and the drug's effects.

Pulmonary venous velocity patterns in mitral stenosis.

Pulmonary venous (PV) velocities obtained by transthoracic echocardiography are used to assess diastolic function. The systolic/diastolic (S/D) PV velocity ratio is increased with impaired early diastolic filling and decreased with elevated mean left atrial pressure (LAP). Mitral stenosis (MS) is characterized by impaired filling and elevated LAP. We hypothesized that the S/D ratio would be increased in MS except in severe MS with high LAP, in which the S/D ratio would be decreased. Patients with isolated MS who underwent transthoracic echocardiography were studied. The PV S/D ratio was compared in mild (n = 18), moderate (n = 16), and severe (n = 7) MS. There was no characteristic PV pattern, with each category showing a wide range of S/D ratios (mild, S/D ratio = 1.42 +/- 0.56; moderate, S/D ratio = 1.19 +/- 0.59, and severe, S/D ratio = 1.33 +/- 0.53) (mean +/- SD). Furthermore, there was no relationship between the S/D ratio and any index of severity of MS. There is no characteristic PV velocity pattern in MS.