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.

Radiosensitising Effects of Metformin Added to Concomitant Chemoradiotherapy with Cisplatin in Cervical Cancer.

AIMS: The role of metformin on the radiosensitising effect of cisplatin is not clear. Here we investigated the radiosensitising effect of metformin alone and combined with cisplatin in HeLa cells, as well as the implications of the adenosine monophosphate-activated protein kinase (AMPK) pathway on the radiosensitising effect. MATERIALS AND METHODS: HeLa cells were treated with ionising radiation, metformin, cisplatin, A769662 (AMPK activator) and dorsomorphin (AMPK inhibitor) or in combination. A cell proliferation assay, Western blot and flow cytometry were carried out. RESULTS: Metformin potentiated cisplatin cytotoxicity when administered 4 h before ionising radiation. Although the radiosensitising effects of metformin and cisplatin alone were observed, which is more apparent at high ionising radiation doses, the metformin-cisplatin combination did not increase the radiosensitivity of cisplatin at any ionising radiation dose. Dorsomorphin alone significantly decreased cell proliferation and potentiated the radiosensitising effects of cisplatin with ionising radiation. Administration of A769662 24 h prior to cisplatin treatment resulted in an increased AMPK level that yielded resistance to cisplatin, but this effect was not observed in HeLa cells concomitantly treated with A769662 and cisplatin. CONCLUSIONS: Modulation of AMPK may have a role in cervical cancer treatment. Increased AMPK levels result in higher sensitivity to ionising radiation but causes resistance to cisplatin. Dorsomorphin is proven to be a potent radiosensitising agent. The use of metformin alone may be an option as a radiosensitiser during high-dose ionising radiation (e.g. intracavitary brachytherapy).

Two injection digital block versus single subcutaneous palmar injection block for finger lacerations.

PURPOSE: We aimed to compare two digital nerve block techniques in patients due to traumatic digital lacerations. METHODS: This was a randomized-controlled study designed prospectively in the emergency department of a university-based training and research hospital. Randomization was achieved by sealed envelopes. Half of the patients were randomised to traditional (two-injection) digital nerve block technique while single-injection digital nerve block technique was applied to the other half. Score of pain due to anesthetic infiltration and suturing, onset time of total anesthesia, need for an additional rescue injection were the parameters evaluated with both groups. Epinephrin added lidocaine hydrochloride preparation was used for the anesthetic application. Visual analog scale was used for the evaluation of pain scores. Outcomes were compared by using Mann-Whitney U test and Student t-test. RESULTS: Fifty emergency department patients ≥18 years requiring digital nerve block were enrolled in the study. Mean age of the patients was 33 (min-max: 19-86) and 39 (78 %) were male. No statistically significant difference was found between the two groups in terms of our main parameters; anesthesia pain score, suturing pain score, onset time of total anesthesia and rescue injection need. CONCLUSION: Single injection volar digital nerve block technique is a suitable alternative for digital anesthesias in emergency departments.

Can initial lactate levels predict the severity of unintentional carbon monoxide poisoning?

INTRODUCTION: Accidental carbon monoxide (CO) intoxication is a major cause of unintentional poisoning. This study aimed to determine the value of initial lactate levels in patients with CO poisoning and to evaluate its utilization in the emergency department (ED). METHODS: A retrospective cross-sectional study was carried out among patients with CO intoxication, who were admitted to the ED between April 1, 2011 and April 1, 2012. The study data were extracted from a hospital database system using International Classification of Diseases-10 diagnosis codes. The patients were analyzed according to lactate levels, carboxyhemoglobin (COHb) levels, electrocardiographic manifestations, and clinical features at admission to the ED. RESULTS: A total of 74 patients with CO poisoning were enrolled in this study. The average COHb value of the patients was 21.5 ± 13.9%. A total of 50 patients (67.6%) received normobaric oxygen treatment and 24 patients (32.4%) received hyperbaric oxygen (HBO) treatment. The patients who received HBO treatment had increased lactate levels compared with patients receiving normobaric oxygen treatment (2.3 mmol/L vs. 1.0 mmol/L, p < 0.001). The lactate levels were positively correlated with COHb values (r = 0.738, p < 0.001). We determined that a lactate level of 1.85 mmol/L has a sensitivity of 70.8% and a specificity of 78.0% to predict the HBO treatment needed in CO poisoning. CONCLUSION: In evaluating patients with CO poisoning, an initial lactate level could be taken into consideration as an adjunctive parameter of severity, together with the clinical criteria and levels of COHb.

Assessment of human papilloma viral load of archival cervical intraepithelial neoplasia by real-time polymerase chain reaction in a Turkish population.

The purpose of this study was to determine the existence, and viral load of human papilloma virus (HPV) subtypes 16 and 18 in paraffinized cervical intraepithelial neoplasia (CIN) samples by real-time polymerase chain reaction (RT-PCR). Overall 94 women were included. Of these patients 47 (50%) had CIN I, 27 (28.8%) had CIN II, and 20 (21.2%) had CIN III. HPV positivity for these three groups were 4.2%, 14.8% and 45%, respectively. HPV positivity in CIN III patients was significantly higher than CIN I (OR = 18.41, 95% CI 3.00-145.73; p < 0.001), and CIN II patients (OR = 4.70, 95% CI 1.00-23.76; p = 0.05). The difference between CIN I and II was not significant (p = 0.18). Viral loads were 10(2), and 10(4) copy/ml for two CIN I patients; 10(2), 10(3), and 10(5) for three CIN II patients; and 10(2), 10(3), 10(4), 10(4), 10(5), 10(5), and 10(6) copy/ml for eight patients with CIN III. Viral load of the remaining one patient could not be assessed. No significant variance was noted among the groups with respect to viral load (p = 0.73). RT-PCR had important advantages of detecting, typing, and quantifying at the same time. Although HPV positivity was increased significantly by the degree of lesions, this relation was not observed for viral load.

Pro-inflammatory cytokine response of the fluid contents of spermatoceles and epididymal cysts.

The aim of the study was to determine the cellular contents and concentrations of interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in fluids of patients with spermatocele or epididymal cyst. Twenty-five symptomatic patients, 14 with epididymal cysts and 11 with spermatoceles, were included in the study. Fluids were obtained during surgical excision of the cysts and cytological smears were stained with May-Gruenwald-Giemsa to establish cell components. The concentrations of IL-6, IL-8 and TNF-alpha were measured by chemiluminescent immunometric assay. Cytological analysis of the fluids demonstrated various sperm forms ranging from immature germ cells to degenerated spermatozoa without inflammatory cells such as neutrophils and macrophages. The concentrations (mean+/- SEM, pg/mg protein) of IL-6, IL-8 and TNF-alpha were 13.52 +/- 1.40, 22.20 +/- 2.43, 3.51 +/- 1.43 in spermatocele fluids and 5.76 +/- 0.48, 11.57 +/- 1.89, 2.53 +/- 0.41 in epididymal cyst fluids. Both IL-6 and IL-8 concentrations in the spermatocele group were higher than in the epididymal cyst group (P < 0.0001). There were no differences in TNF-alpha concentrations between the groups (P > 0.05). These findings indicate that local production of pro-inflammatory cytokines is involved in cyst formation. The presence of immunologic activation in these fluids advocates a policy of selective surgical intervention in patients with spermatocele or epididymal cyst.

Doxazosin: a new cytotoxic agent for prostate cancer?

OBJECTIVE: To determine the sensitivity of drug-resistant prostate cancer cell lines to doxazosin-mediated cell death, and the effects of combining doxazosin and chemotherapeutic agents on these cell lines. Materials and methods The cytotoxic effect of doxazosin was initially evaluated in the prostate carcinoma cell lines DU145 and PC-3. Doxazosin was combined either with adriamycin, etoposide or paclitaxel after its cytotoxic effects were detected in these cell lines. The tetrazolium dye (MTT) assay and trypan blue dye-exclusion tests were used to determine drug-mediated cytotoxicity. Experiments were performed at least three times and representative data are presented. RESULTS: Both cell lines were sensitive to doxazosin-mediated cytotoxicity and the maximum cytotoxicity was achieved after 72 h. While cell death increased with increasing concentrations of doxazosin, 60 micromol/L doxazosin killed more than half of the cells in these cell lines. The combination of doxazosin with both adriamycin and etoposide resulted in significant synergistic cytotoxic activity at subtoxic concentrations of the drugs. Interestingly, the combination of doxazosin and paclitaxel resulted in antagonistic activity. CONCLUSION: Doxazosin-mediated cytotoxicity in the drug-resistant human prostate carcinoma cell lines was confirmed. Combinations of doxazosin with either adriamycin and etoposide, but not paclitaxel, had synergistic cytotoxic activity in these tumour cell lines. These results suggest that doxazosin could be a new cytotoxic agent, either used alone or combined, in the treatment of prostate cancer.

Intracavernosal adrenalin injection in priapism.

Prolonged erection is a rare problem in urology but it must be treated effectively. The most common etiological factor is intracavernosal vasoactive agent injection for diagnosis or treatment of erectile dysfunction. The aim of this study was to evaluate the efficacy of intracavernosal adrenalin injection alone in the treatment of priapism. Nineteen patients with prolonged erection were evaluated. Seventeen out of the 19 prolonged erections were due to intracavernosal vasoactive agent injection and the remaining two were idiopathic. In all cases 2 ml adrenalin (1/100 000) was injected in each cavernosal body. In the patients who did not respond to the first injection, repeated adrenalin injections were performed at 20 min intervals. Blood pressure and heart rate were monitored during the injections. Detumescence was achieved in ten (53%) patients after the first injection. Repeated adrenalin injections (2-5 injections) were required in nine patients and eight (42%) of them achieved detumescence. Only one (5%) patient who had 26-h prolonged erection could not achieve detumescence. There was no significant difference in blood pressure and heart rate during the monitoring of the patients when compared to the initial values. No standard treatment method has yet been described for prolonged erection. Repeated aspirations and irrigations for treatment of prolonged erection are problematical applications both for patients and urologist. Intracavernosal adrenalin injection alone can be used with high efficacy and safety for the treatment of prolonged erection especially in patients with a short duration of erection.

Results of extracorporeal shock wave lithotripsy in the pediatric age group.

OBJECTIVE: In this study we aimed to show the efficacy of extracorporeal shock wave lithotripsy (ESWL) for urinary stone disease in the pediatric age group and to evaluate the complications encountered after the treatment. METHODS: 67 children with 109 stones underwent ESWL, using a Dornier MPL 9000 lithotriptor. Styrofoam boards were used to protect the lungs. KUB and chest radiographs were taken on the day after treatment. If stone-free status was achieved, the patient was followed with ultrasonography and urine analysis every 6 months for 2 years. If fragments < 4 mm were present, follow-up was repeated every 3 months. RESULTS: Stone size ranged from 0.5 to 3.5 cm. 71 renoureteral units underwent a total of 129 ESWL sessions. Retreatment was required in 28 patients. The mean number of sessions per unit was 1.8. A stone-free status was achieved in 60 renoureteral units. The overall success rate was 88.6%. The composition of the stone was mixed calcium oxalate and phosphate in the majority of the patients. Auxiliary procedures used were push-back, ureteroscopic stone removal, and open surgery. Hematuria, colics and fever over 38 degrees C were the complications encountered after the treatment. CONCLUSIONS: ESWL is the first-line treatment for renal and upper ureteral calculi. However, larger stones which will require several ESWL sessions and consecutively increased number of shock waves are best treated with percutaneous nephrolithotomy plus ESWL. Patients with congenital anomalies necessitating surgical reconstruction are the best candidates for operation.

Detection of metastatic bone lesions in patients with prostate carcinoma: 99Tcm-monoclonal antibody imaging.

Bone scintigraphy has been shown to be sensitive in determining bone involvement in patients with malignancy, but it does not allow the assessment of bone marrow lesions in early disease. The aim of this study was to detect bone marrow invasion using 99Tcm-labelled monoclonal antigranulocyte antibody (AgMoAb) in patients with prostate carcinoma. We studied 56 patients whose mean (+/- S.D.) age was 67 +/- 7 years. The mean prostate-specific antigen level was 6.1 ng ml-1 (normal range 0-5 ng ml-1). Twelve patients were in stage A, 16 in stage B, 17 in stage C and 11 in stage D. Six patients had been receiving chemotherapy and four patients radiotherapy before scanning. Bone scans were obtained 2 h after the intravenous injection of 555 MBq 99Tcm-methylene diphosphonate (99Tcm-MDP). Within a week, bone marrow imaging was performed 4 and 24 h after the injection of 555 MBq 99Tcm-AgMoAb. Metastatic bone lesions were detected on the 99Tcm-MDP scans of 14/56 (25%) patients, of whom one was in stage A, two in stage B, four in stage C and seven in stage D. Hypoactive lesions in bone marrow were detected in 25/56 (45%) patients, of whom two were in stage A, five in stage B, seven in stage C and 11 in stage D. Bone marrow metastases were confirmed in six patients by computed tomography (CT) and magnetic resonance imaging (MRI) and in two patients by marrow aspiration biopsy. A false-positive immune scintigram was found in three patients previously receiving radiotherapy or chemotherapy. We suggest that 99Tcm-AgMoAb scintigraphy is a sensitive procedure for the detection of bone marrow lesions. However, the reason for false-positive and false-negative results should be considered and CT, MRI and marrow biopsy should be performed when clinically necessary.

Anti-bacterial activity of the fluid contents of spermatoceles and epididymal cysts.

OBJECTIVE: To show that the fluids obtained from spermatoceles and epididymal cysts are not infected, even though they may be present for long periods, and that these fluids have bactericidal activity. MATERIALS AND METHODS: Sixteen patients, 13 with a spermatocele and three with an epididymal cyst, were included in the study. Protein, glucose, chloride, inorganic phosphorus, calcium and magnesium contents were measured and cultures of the fluids were carried out. Bactericidal activity against the Escherichia coli NTCC 10418 clone was tested in different dilutions. RESULTS: Biochemical analysis showed that the protein, glucose and ionic content of the fluids was lower than that of serum, except for chloride. Microbiological cultures were negative for all samples. A significant bactericidal effect was obtained with 1/1 dilution and no reproduction was seen with this dilution. CONCLUSION: These findings indicate that the fluids within spermatoceles and epididymal cysts do not become infected under normal circumstances.