The Impact of Dose Rate on the Tumor Microenvironment Using Flattening-filter-free Beams.

AIMS: Recently, dose delivery technology has rapidly evolved with flattening filter-free beams (FFF), and the biological effects of high dose rates are a matter of interest. We hypothesized that FFF beams at different dose rates obtained with modern linear accelerators have different effects on the TME. MATERIALS AND METHODS: The B16-F10 melanoma syngeneic tumor model was established, and mice were randomized to 2 different doses (2 Gy and 10 Gy) and 3 different dose rates (1 Gy/min, 6 Gy/min, and 14 Gy/min) along with the control group. Euthanasia was performed on the seventh day after RT, and intracardiac blood was collected for a comet assay. Tumors were harvested and examined histomorphologically and immunohistochemically. Statistical analyses were performed using SPSS software version 23 (SPSS Inc., Chicago, IL, USA). RESULTS: The daily growth rate was uniform, and no difference was observed between tumor volumes across all three dose rates for each dose. Deoxyribonucleic acid (DNA) damage in blood mononuclear cells was not affected by dose or dose rate. In the TME histomorphological examination, the number of mitosis is less in the 10 Gy arm, whereas the pleomorphism score was greater. Nevertheless, varying dose rates had no effect on the number of mitosis or the pleomorphism score. The severity of the inflammation, cell densities in the TME, and expression of immunohistochemical markers were comparable across all doses and dose rates. CONCLUSION: In our study involving the B16-F10 syngeneic tumor model, varying dose rates obtained with FFF beams had no effect on tumor volume, blood mononuclear cell DNA damage, or TME parameters. However, in order to fully understand the biological impacts of novel techniques, our study should be validated with alternative preclinical setups.

The prognostic and predictive role of class III ß-Tubulin and hENT1 expression in patients with advanced pancreatic ductal adenocarcinoma.

BACKGROUND: FOLFIRINOX and gemcitabine-nabpaclitaxel (GnP) are standard first-line treatment regimens for advanced pancreatic ductal adenocarcinoma (PDAC). However, currently, there is a lack of predictive biomarkers to aid in the treatment selection. We aimed to explore the prognostic and predictive value of class III ß-Tubulin (TUBB3) and human equilibrative nucleoside transporter 1 (hENT1) expression, which have previously been shown to be associated with taxane and gemcitabine resistance in advanced PDAC. METHODS: We conducted a retrospective analysis of 106 patients with advanced PDAC treated with GnP and/or FOLFIRINOX at our institution. TUBB3 and hENT1 immunohistochemical staining was performed on tumor specimens and subsequently evaluated based on the intensity and percentage of expression. RESULTS: In patients who received the GnP regimen, a high combined score (TUBB3low/hENT1high) was associated with a higher DCR and longer PFS compared to those with intermediate (TUBB3high/hENT1high or TUBB3low/hENT1low) and low score (TUBB3high/hENT1low). In the multivariate analysis, a high combined score was an independent predictor of higher DCR (OR:11.96; 95 % CI:2.61-54.82; p = 0.001) and longer PFS (HR:0.33; 95%CI:0.18-0.60; p < 0.001). However, there was no difference in response rates or PFS based on TUBB3 and hENT1 expression among patients receiving the FOLFIRINOX regimen. CONCLUSION: Our findings indicate that tumor TUBB3 and hENT1 expression may predict the efficacy of the GnP regimen, and low TUBB3 and high hENT1 expression (TUBB3low/hENT1high) are associated with a higher DCR and longer PFS in patients treated with GnP. Evaluating TUBB3 and hENT1 jointly can identify the patients most (as well as least) likely to benefit from GnP chemotherapy.

Defining prognostic parameters of well-differentiated gastric neuroendocrine tumors based on metastatic potential: a two-center experience.

Background: Gastric neuroendocrine tumors [gNETs] are heterogeneous tumors and we are still unable to predict the behavior of these tumors. We aim to define the prognostic parameters of well-differentiated gNETs based on metastatic potential and to evaluate the current classification systems. Patients and methods: We retrospectively retrieved 44 well differentiated gNET cases who underwent radical surgery between 2000-2015 at two tertiary-care centers. Results: Among the 44 well-differentiated gNET patients, 17 (38%) patients had metastatic disease to lymph nodes and/or distant sites, while 27 (62%) were confined to the stomach. Higher risk of metastasis was observed with increasing tumor size, grade, depth of invasion and with type-3 and solitary tumors. 30 (68%) patients had type-1 gNET and 14 (32%) had type-3 gNET. Majority of the type-1 cases (76,6%) were Grade 1 [G1] and type-3 cases (78,5%) were Grade 3 [G3]. Type-1 subgroup had no G3 tumor, and type-3 had no G1. Grade 2 [G2] tumors were more controversial, with metastatic and non-metastatic cases. G2 cases with a >10% Ki67 expression or type-3, had a worse prognosis. Although most of the type-1 gNETs had an indolent course, 6 of 30 (20%) patients had metastatic disease. Metastasizing type-1 gNETs were >10 mm in diameter or extended to/beyond the submucosa. Conclusion: Regarding our results, tumor type, grade, size, focality and depth of invasion are the prognostic parameters for gNETs, based on metastatic potential. Besides these parameters, a two-tiered grading system with a 10% Ki-67 proliferation index cut-off value could be considered for right treatment choice.

Maternal low-quality protein diet exerts sex-specific effects on plasma amino acid profile and alters hepatic expression of methyltransferases in adult rat offspring.

Nutrition during pregnancy and lactation is a critical factor in the development of the offspring. Both protein content and source in maternal diet affect neonatal health, but the long-term effects of maternal low-quality protein diet on the offspring are less clear. This study aimed to examine the effects of maternal low-quality protein diet on offspring's growth, development, circulating metabolites and hepatic expression of methyltransferases. Virgin Wistar rats were mated at 11 weeks of age. Dams were then maintained on either a chow diet with 20% casein as the control group (C), or a low-quality protein diet with 20% wheat gluten as the experimental group (WG) throughout gestation and lactation. After weaning, all offspring were fed a control chow diet until the age of 20 weeks. Male WG offspring had significantly lower body weight and energy intake, whereas female WG offspring had significantly higher body weight and energy intake when compared with controls. Early life exposure to WG diet had no significant effect on circulating metabolites. However, fasting insulin concentrations and homoeostasis model assessment-insulin resistance were decreased in WG male and female offspring. Maternal low-quality protein diet increased plasma aspartic acid, glutamic acid, histidine, cystathione and decreased lysine in male WG offspring. Conversely, the same amino acids were reduced in female WG offspring. Adult offspring exposed to WG diet had significantly upregulated hepatic DNMT3a and DNMT3b expressions. Our study showed that there were differential effects of maternal poor-quality protein diet upon adult offspring's metabolism.

Two markers in predicting the cardiovascular events in patients with polycystic ovary syndrome: increased P-wave and QT dispersion.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a prevalent disease with many potential long-term cardiovascular risks. P-wave dispersion (Pdis) and QT dispersion (QTdis) have been shown to be noninvasive electrocardiographic predictors for development of cardiac arrhythmias. In this study we aimed to search Pdis and QTdis parameters in patients with PCOS. PATIENTS AND METHODS: The study included 82 patients with PCOS and 74 age- and sex-matched healthy controls. Baseline 12-lead electrocardiographic and transthoracic echocardiographic measurements were evaluated. P-wave maximum duration (Pmax), P-wave minimum duration (Pmin), Pdis, QT interval, heart rate-corrected QT dispersion and QTdis were calculated by two cardiologists. RESULTS: Patients wirh PCOS had significantly higher QT dispersion (49.5 ± 14.1 vs. 37.9 ± 12.6 ms, p < 0.001), and P wave dispersion (54.2 ± 11.4 vs. 45.9 ± 10.1 ms, p < 0.001) than the controls. Serum testosterone and estradiol levels was correlated with the Pdis (r = 0.677, p < 0.001 and r = 0.415, p < 0.001 respectively) and QTdis (r = 0.326, p < 0.001 and r = 0.321, p < 0.001 respectively). CONCLUSIONS: Pdis and QTdis are simple and useful electrocardiographic markers which may be used in the prediction of the risk of adverse cardiovascular events in PCOS patients.

Cerebral vasculitis as a major manifestation of rheumatoid arthritis.

OBJECTIVE AND IMPORTANCE: Cerebral vasculitis (CV) is a rare described complication of rheumatoid arthritis (RA). Although the most frequent neurological manifestations of RA are peripheral neuropathy and cervical spinal cord compression due to subluxation of the cervical vertebrae, CV can be seen especially in patients with seropositive and long-standing RA. CLINICAL PRESENTATION: We report two cases of CV associated with RA. Both patients had no extraarticular manifestations and RA clinics were under control. Our first case is a 30-years-old woman with seropositive RA for 15 years who had suddenly onset left facial and upper extremity weakness. In magnetic resonance imaging (MRI) DWI, hyperintensity in frontotemporal region due to acute ischaemia was detected. The new lacuner acute ischaemic lesions in right precentral gyrus, bilateral frontoparietal and corpus callosal region were detected in the control MRI. The cerebral MR angiography and transcranial doppler findings were consistent with CV. The patient responded favourably to pulse methylprednisolone and oral azathiopurine treatments. The second patient is a 52-year-old man who had been RA for 29 years. He admitted to our neurology clinic with speech difficulty and right upper extremity minimal weakness. Magnetic resonance imaging DWI showed left parietooccipital acute ischaemia which was progressed within a week and a new right parietooccipital ischaemia was added. His cerebral MR angiography and cerebral angiography were concordant with CV. The cyclophosphamide therapy was started since the cerebral ischaemia was progressed during pulse methylprednisolone and he responded well to this therapy. CONCLUSION: CV due to RA is an uncommon serious complication which can be life-threatening. Therefore clinicians should be aware of the possibility of CV especially in progressive strokes in RA.

Borderline epithelial ovarian tumors: a single center experience.

AIM: To evaluate the clinical outcomes of the patients treated for borderline ovarian tumor (BOT). MATERIALS AND METHODS: In this retrospective study, records of the patients between November 2001 and December 2012 who underwent surgery and whose final pathological diagnosis were BOT were retrieved. RESULTS: During the study period, 78 patients were diagnosed as BOT. The patho- logical diagnoses of the tumors were serous in 26 (33.3%) and mucinous in 52 patients (66.6 %), respectively. Accuracy of frozen section diagnosis was observed in 63 of 89 patients (70.7%). Sixty-eight women (87.1%) underwent complete staging procedure. According to final pathological diagnoses, Stage IA, IB, and IC were found in 52 (67%), five (6.5%), and seven (9%) patients, respectively. FIGO Stages IIC and IIIC were found in one case in each (1.25%). Remaining 12 patients were classified as unstaged (15%). The median follow-up time was 63 months. The authors observed only one recurrence (1.3%) and that patient died of disease. CONCLUSION: The survival rate in patients with BOTs confined to the ovary is excellent. Surgical staging procedure can be omitted in the patients with grossly apparent Stage I mucinous tumors.

Analyses of atypical glandular cells re-defined by the 2006 Bethesda System: histologic outcomes and clinical implication of follow-up management.

BACKGROUND: To evaluate the histopathology and the long-term follow-up outcome of women who had atypical glandular cells on Pap smears. MATERIALS AND METHODS: All women with atypical glandular cells (AGC) who underwent colposcopic and histopathologic evaluation between January 2005 and October 2010 were reviewed. Patient data were examined up to October 2012, allowing for at least two years of follow-up for all patients. RESULTS: Forty-four women with AGC Pap test underwent histologic follow-up during the study period. Overall, upon reclassification of smears, 35 (79.5%) cases were diagnosed with AGC "not otherwise specified" (NOS) and nine (20.5%) with AGC "favour neoplasia". Seven out of nine patients (77.7%) with AGC "favour neoplasia" had significant pathology. On the other hand, only 11 out of 35 cases (31.4%) with AGC "NOS" had significant pathology. Significant correlation was found between AGC "favour neoplasia" smears and a significant pathology (p: 0.01). Of the 44 patients, 18 (40.9%) had significant pathology. Eight patients (18.2%) had low grade cervical intraepithelial neoplasia (CIN 1), four (9%) had high-grade cervical intraepithelial neoplasia (CIN 2/3), one (2.2%) had microinvasive squamous cell carcinoma of uterine cervix, one (2.2%) had cervical adenocarcinoma in situ, one (2.2%) had cervical adenocarcinoma, one (2.2%) had endometrial adenocarcinoma, and two (4.5%) had endometrial hyperplasia. CONCLUSION: Reporting AGC in the population is clinically significant due to the high prevalence of underlying preinvasive and invasive diseases (40.9%). The subtypes of the AGC category are significant predictor of such lesions.

Nailfold capillary abnormalities are prevalent in sclerodermoid graft-versus-host disease and readily detected with dermatoscopy.

BACKGROUND: Well-recognized videocapillaroscopic patterns have been described in systemic sclerosis (SS). However, no studies have described the capillary abnormalities of sclerodermoid chronic graft-versus-host disease (Scl GVHD) developed after allogeneic haematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES: The aims of this study were to find the characteristics of nailfold capillary changes in Scl GVHD after allo-HSCT. PATIENTS AND METHODS: Eighteen patients affected by Scl GVHD and a control group of 15 patients with lichenoid GVHD were evaluated. Duration and type of sclerodermoid GVHD, Raynaud phenomenon (RP), dysphagia, joint contractures, antinuclear antibodies (ANA), anti-Scl-70 and anticentromere (ACA) antibodies were investigated parameters. A nailfold capillary examination using a standard dermatoscope was performed on all fingers of each subject. RESULTS: Twelve patients were male and six were female with a mean age of 37 +/- 11.6 years. Joint retractions and dysphagia developed in 27.8% and 38.9% of the patients, respectively. Three (16.7%) patients had RP. Autoimmune markers like anti-Scl-70 and ACA were negative in all. Capillaroscopy was abnormal in 15 patients with Scl GVHD. A regular disposition of the capillary loops along with avascular whitish linear areas at the level of the last row, neovascularization with reticular pattern, capillary disorganization, haemorrhages, enlarged capillaries and avascular areas were the main features. No capillary abnormalities were observed in patients with lichenoid GVHD. There was no statistically significant correlation between ANA positivity, RP, joint retractions, dysphagia, extensiveness of Scl GVHD, duration of sclerodermoid lesions and nailfold capillaroscopy analysis. CONCLUSIONS: This study shows the identification of distinct nailfold capillaroscopy patterns in patients with Scl GVHD but it does not confer special risk for any other specific clinical symptoms of the disease.

Electrochemical treatment and operating cost analysis of textile wastewater using sacrificial iron electrodes.

Electrocoagulation (EC) method with iron electrode was used to treat the textile wastewater in a batch reactor. Iron electrode material was used as a sacrificial electrode in monopolar parallel mode in this study. The removal efficiencies of the wastewater by EC were affected by initial pH of the solution, current density, conductivity and time of electrolysis. Under the optimal experimental conditions (initial pH 6.9, current density of 10 mA/cm(2), conductivity of 3,990 microS/cm, and electrolysis time of 10 min), the treatment of textile wastewater by the EC process led to a removal capacity of 78% of chemical oxygen demand (COD) and 92% of turbidity. The energy and electrode consumptions at the optimum conditions were calculated to be 0.7 kWh/kg COD (1.7 kWh/m(3)) and 0.2 kgFe/kg COD (0.5 kgFe/m(3)), respectively. Moreover, the operating cost was calculated as 0.2 euro/kg removed COD or 0.5 euro/m(3) treated wastewater. Zeta potential measurement was used to determine the charge of particle formed during the EC which revealed that Fe(OH)(3) might be responsible for the EC process.

Photocatalytic degradation of Remazol Red F3B using ZnO catalyst.

The photocatalytic degradation of aqueous solution of a commercial azo-reactive textile dye, Remazol Red F3B, has been investigated in a batch slurry reactor, in the presence of ZnO catalyst using two different UV light sources emitting at 254 nm and 365 nm. The effects of various process variables on degradation performance of the process have been investigated. The results showed that decolourization and total organic carbon (TOC) removal are both affected in the same manner by the solution pH in the pH range 6-10, showing maxima at pH 7 and pH 10. They are inversely related to the dye concentration, they increase in power-law with the light intensity. Decolourization is faster with 365 nm UV. TOC removal is not affected by UV wavelength in the initial period up to 20 min, after which it progresses faster under 365 nm UV radiation. These results indicate that the UV wavelength influences especially the degradation rate of the intermediate products generated during the initial period of the photocatalytic process. Finally, catalyst loading affects both efficiencies in the same trend, which are maximized at about 2 g/l catalyst loading.

Myasthenia gravis and lymphoblastic lymphoma involving the thymus: a rare association.

Myasthenia gravis (MG) is an autoimmune neuromuscular junction disease. An association between thymic epithelial neoplasms and MG is well known. However, it is rarely associated with hematologic malignancies. In particular, very few cases of lymphoblastic lymphoma involving the thymus and MG have been reported. Here we report a case T-cell lymphoblastic lymphoma involving the thymus who developed MG after the initial diagnosis. The patient initially presented with a mediastinal mass which was diagnosed as lymphoblastic lymphoma. MG was diagnosed during leukemic relapse in this patient and was based on clinical presentation and neurophysiologic studies including single fiber electromyography (EMG) and repetitive nerve stimulation tests. In contrast to the other cases with such an association, the myasthenic symptoms presented nine months after the diagnosis of lymphoma by thymectomy. The patient had a highly aggressive clinical course and was resistant to various chemotherapy regimens.

Caudal bupivacaine-tramadol combination for postoperative analgesia in pediatric herniorrhaphy.

BACKGROUND: Administration of bupivacaine caudally has been used for postoperative analgesia after urogenital, rectal and lower abdominal surgery in children. Caudal opioids may offer analgesic advantages over bupivacaine alone but have been associated with side effects such as respiratory depression. Tramadol is an analgesic assumed to lack a respiratory depressant effect and has been shown to provide effective, long-lasting analgesia after epidural administration in adults and children. The aim of this study was to determine whether the addition of tramadol to bupivacaine caudally prolongs the duration of analgesia compared with bupivacaine alone, with respect to side effects, and whether caudal tramadol alone provides satisfactory analgesia. METHODS: Sixty boys, aged 12-84 months, undergoing unilateral herniorrhaphy, were allocated randomly to three groups. Children in group B received 0.25% plain bupivacaine 1 ml kg(-1), group BT received an identical local anesthetic dose mixed with tramadol 1.5 mg kg(-1) and group T received caudal tramadol 1.5 mg kg(-1) in 0.9% sodium chloride in the same total volume (1 ml kg(-1)). Pain and demeanour assessments were made 1, 2, 3, 4, 6, 12 and 24 h after recovery from anesthesia with reference to a three-point scale. RESULTS: Analgesia time (time between caudal injection and first administration of analgesic) in group BT (13.5+/-2.2 h) was significantly longer than in the other two groups (P<0.05). In group T, more patients required additional analgesia after surgery than in the other two groups (P<0.05). Pain scores in the three groups were similar up to 4 h after operation but the mean score in group T was higher than groups B and BT 4 and 6 h after operation (P<0.05). Significantly more patients who had received caudal bupivacaine alone or with tramadol had lower pain and demeanour scores during the first 24 h after operation compared with those in the tramadol group. CONCLUSION: Caudal administration of bupivacaine with the addition of tramadol resulted in superior analgesia with a longer period without demand for additional analgesics compared with caudal bupivacaine and tramadol alone without an increase of side effects.

Pulmonary function tests in Parkinson's disease.

Morbidity and mortality are usually caused by respiratory disorders in Parkinson's disease (PD) because of pulmonary functional impairments. The purpose of this study was to determine the effects of PD on ventilatory function and that the use of pulmonary function tests (PFT) may serve as an indicator of PD severity. PFT have been performed in 21 patients with PD (15 non-smoker and six exsmoker with 36.17 +/- 26.54 pack-years of smoking history; mean age 64.67 +/- 10.76 years) and 16 normal age-matched control subjects who never smoked. The clinical disability was indicated by a Hoehn-Yahr (H-Y) scale. MEF25% [maximal flow rate at 25% of remaining forced vital capacity (FVC)] and FEV1 (the volume of air expired during the first second of the FVC) in exsmoker PD group was lower than non-smoker PD group (P < 0.05). The two effort dependent variables' peak expiratory flow (PEF) and the maximal flow rate at 75% of the remaining FVC (MEF75%) percent predicted values were 70.66 +/- 24.15 and 69.05 +/- 24.39 in non-smoker PD group whereas 90.18 +/- 17.24 and 90.00 +/- 18.97% predicted were in control group, respectively (P < 0.05). The maximal voluntary ventilation (MVV) was found to be 52.83 +/- 15.52 and 91.52 +/- 13.80% in PD and control group, respectively (P < 0.0001). MVV was the most effected parameter that was inversely correlated with the PD severity (r=-0.87, P < 0.0001). We concluded that less coordinated and less explosive muscle force has contributed to decrease in PEF and MEF75% values, and MVV decreases in PD as a result of the impaired performance and reduced efficiency during repetitive motor tasks which in part reflects abnormal agonist-antagonist muscle activity. So, spirometric studies may serve as a useful indicator of patients' neurophysiological conditions for the purpose of anticipating and preventing complications because of pulmonary impairment.

Comparison of manually constructed and stapled anastomoses in colorectal surgery. West of Scotland and Highland Anastomosis Study Group.

OBJECTIVE: The authors compared both the initial and the long-term outcomes of patients undergoing stapled and sutured colorectal anastomoses. SUMMARY BACKGROUND DATA: Sutured and stapled large bowel anastomoses are perceived to be equally safe, but concern has been raised about increased rates of tumor recurrence with the use of stapling instruments. METHODS: The outcome of patients with sutured and stapled colorectal anastomoses were compared in a prospective, multicenter, randomized study. Factors affecting long-term outcomes were assessed by both univariate and multivariate analysis. RESULTS: Seven hundred thirty-two patients were recruited. There was a significant increase in radiologic leakage in the sutured group (14.4% vs. 5.2%, p < 0.05), but there was no difference in clinical anastomotic leak rates, morbidity, or postoperative mortality. Tumor recurrence and cancer-specific mortality were higher in the sutured patients (7.5% and 6.7%, respectively) and in patients with anastomotic leaks. CONCLUSIONS: This study shows that suturing or stapling are equally safe in large bowel surgery. However, it also shows a long-term benefit of stapling in colorectal cancer patients.

Early postoperative contrast radiology in the assessment of colorectal anastomotic integrity.

The predictive value and safety of early postoperative radiological assessment of colorectal anastomotic integrity is controversial. In this study, 233 patients with colorectal or left sided colonic anastomoses had water soluble contrast enemas performed in the early postoperative period (mean: day 7 postoperatively, range: days 4-14). A total of 40 radiological leaks were recorded but only 12 of these patients had clinical signs of anastomotic dehiscence. Furthermore, 11 patients who had normal contrast enemas subsequently developed a clinical anastomotic leak. There were therefore 28 (12.0%) false positive and 11 (4.7%) false negative results giving values for the specificity and sensitivity of the radiological investigation of 86.7% and 52.2% respectively. Only 3 patients (1.3%) developed a clinically apparent anastomotic complication following a contrast enema. We conclude that while radiological assessment of distal large bowel anastomoses in the early postoperative period appears to be a safe procedure, it provides little useful clinical information with regard to early postoperative morbidity. Recent work has, however, suggested that radiological anastomotic integrity may be relevant to long term outcome following surgery for colorectal cancer.