It is important to improve the magnitude of dose variation that is caused by the interplay effect. The aim of this study was to investigate the impact of the number of breaths (NBs) to the dose ...variation for VMAT‐SBRT to lung cancer. Data on respiratory motion and multileaf collimator (MLC) sequence were collected from the cases of 30 patients who underwent radiotherapy with VMAT‐SBRT for lung cancer. The NBs in the total irradiation time with VMAT and the maximum craniocaudal amplitude of the target were calculated. The MLC sequence complexity was evaluated using the modulation complexity score for VMAT (MCSv). Static and dynamic measurements were performed using a cylindrical respiratory motion phantom and a micro ionization chamber. The 1 standard deviation which were obtained from 10 dynamic measurements for each patient were defined as dose variation caused by the interplay effect. The dose distributions were also verified with radiochromic film to detect undesired hot and cold dose spot. Dose measurements were also performed with different NBs in the same plan for 16 patients in 30 patients. The correlations between dose variations and parameters assessed for each treatment plan including NBs, MCSv, the MCSv/amplitude quotient (TMMCSv), and the MCSv/amplitude quotient × NBs product (IVS) were evaluated. Dose variation was decreased with increasing NBs, and NBs of >40 times maintained the dose variation within 3% in 15 cases. The correlation between dose variation and IVS which were considered NBs was shown stronger (R2 = 0.43, P < 0.05) than TMMCSv (R2 = 0.32, P < 0.05). The NBs is an important factor to reduce the dose variation. The patient who breathes >40 times during irradiation of two partial arcs VMAT (i.e., NBs = 16 breaths per minute) may be suitable for VMAT‐SBRT for lung cancer.
TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously ...administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302.
The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth.
Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To examine the relationship between local oxygen partial pressure and energy metabolism in the tumor, electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) with ...hyperpolarized 1-
C pyruvate were performed. SCCVII and HT29 solid tumors implanted in the mouse leg were imaged by EPRI using OX063, a paramagnetic probe and
C-MRI using hyperpolarized 1-
C pyruvate. Local partial oxygen pressure and pyruvate metabolism in the two tumor implants were examined. The effect of a single dose of 5-Gy irradiation on the pO
and metabolism was also investigated by sequential imaging of EPRI and
C-MRI in HT29 tumors. A phantom study using tubes filled with different concentration of 1-
C pyruvate, 1-
C lactate, and OX063 at different levels of oxygen confirmed the validity of this sequential imaging of EPRI and hyperpolarized
C-MRI.
studies revealed SCCVII tumor had a significantly larger hypoxic fraction (pO
< 8 mmHg) compared to HT29 tumor. The flux of pyruvate-to-lactate conversion was also higher in SCCVII than HT29. The lactate-to-pyruvate ratio in hypoxic regions (pO
< 8 mmHg) 24 hours after 5-Gy irradiation was significantly higher than those without irradiation (0.76 vs. 0.36) in HT29 tumor. The
study showed an increase in extracellular acidification rate after irradiation. In conclusion, co-imaging of pO
and pyruvate-to-lactate conversion kinetics successfully showed the local metabolic changes especially in hypoxic area induced by radiation therapy.
The purpose of this study was to determine appropriate beam arrangement for volumetric-modulated arc therapy (VMAT)-based stereotactic body radiation therapy (SBRT) in the treatment of patients with ...centrally located lung tumors. Fifteen consecutive patients with centrally located lung tumors treated at our institution were enrolled. For each patient, three VMAT plans were generated using two coplanar partial arcs (CP VMAT), two non-coplanar partial arcs (NCP VMAT), and one coplanar full arc (Full VMAT). All plans were designed to deliver 70 Gy in 10 fractions. Target coverage and sparing of organs at risk (OARs) were compared across techniques. PTV coverage was almost identical for all approaches. The whole lung V10Gy was significantly lower with CP VMAT plans than with NCP VMAT plans, whereas no significant differences in the mean lung dose, V5Gy, V20Gy or V40Gy were observed. Full VMAT increased mean contralateral lung V5Gy by 12.57% and 9.15% when compared with NCP VMAT and CP VMAT, respectively. Although NCP VMAT plans best achieved the dose–volume constraints for mediastinal OARs, the absolute differences in dose were small when compared with CP VMAT. These results suggest that partial-arc VMAT may be preferable to minimize unnecessary exposure to the contralateral lung, and use of NCP VMAT should be considered when the dose–volume constraints are not achieved by CP VMAT.
A 75-year-old man who had undergone left upper lobectomy of the lung exhibited fever and insomnia on postoperative day (POD) 1 and muscle rigidity, autonomic instability, and somnolence on POD2 after ...epidural administration of droperidol and withdrawal of oral etizolam. He had not been known to have any neuromuscular diseases or psychiatric diseases, with the exception of anxiety disorder. Brain computed tomography did not show cerebrovascular disorders. Consultation with a neurologist led to a suspicion of neuroleptic malignant syndrome (NMS). Epidural droperidol was stopped and administration of dantrolene was initiated. These measures, in addition to supportive care, only partially ameliorated the symptoms of the patient, and consciousness disturbance developed; the patient finally became comatose on POD3. However, intravenous diazepam (10 mg) improved his symptoms abruptly. Subsequently, oral administration of lorazepam (1 mg/day) was started, and his symptoms disappeared within 2 days (POD5). Although NMS-like symptoms are rarely seen in clinical practice, some factors may induce it during the perioperative period, such as the administration of dopamine antagonists and the cessation of benzodiazepines. Intravenous diazepam is an effective treatment in cases with suspected gamma-aminobutyric acid (GABA) hypoactivity at the GABA
A
receptor induced by the cessation of benzodiazepines.
Purpose:
To experimentally investigate the effects of variations in respiratory motion during breath-holding (BH) at end-exhalation (EE) on intensity-modulated radiotherapy (BH–IMRT) dose ...distribution using a motor-driven base, films, and an ionization chamber.
Methods:
Measurements were performed on a linear accelerator, which has a 120-leaf independently moving multileaf collimator with 5-mm leaf width at the isocenter for the 20-cm central field. Polystyrene phantoms with dimensions of 40 × 40 × 10 cm were set on a motor-driven base. All gantry angles of seven IMRT plans (a total of 35 fields) were changed to zero, and doses were then delivered to a film placed at a depth of 4 cm and an ionization chamber at a depth of 5 cm in the phantom with a dose rate of 600 MU/min under the following conditions: pulsation from the abdominal aorta and baseline drift with speeds of 0.2 mm/s (BD0.2mm/s) and 0.4 mm/s (BD0.4mm/s). As a reference for comparison, doses were also delivered to the chamber and film under stationary conditions.
Results:
In chamber measurements, means ± standard deviations of the dose deviations between stationary and moving conditions were −0.52% ± 1.03% (range: −3.41–1.05%), −0.07% ± 1.21% (range: −1.88–4.31%), and 0.03% ± 1.70% (range: −2.70–6.41%) for pulsation, BD0.2mm/s, and BD0.4mm/s, respectively. The γ passing rate ranged from 99.5% to 100.0%, even with the criterion of 2%/1 mm for pulsation pattern. In the case of BD0.4mm/s, the γ passing rate for four of 35 fields (11.4%) did not reach 90% with a criterion of 3%/3 mm. The differences in γ passing rate between BD0.2mm/s and BD0.4mm/s were statistically significant for each criterion. Taking γ passing rates of > 90% as acceptable with a criterion of 3%/3 mm, large differences were observed in the γ passing rate between the baseline drift of ≤5 mm and that of >5 mm (minimum γ passing rate: 92.0% vs 82.7%; p < 0.01).
Conclusions:
This study suggested that the baseline drift of >5 mm should be avoided in the BH–IMRT.
Both severe hypokalemia and persistent hypertension are clinical symptoms of hyperaldosteronism. Hyperaldosteronism may occur as a primary or secondary syndrome. Excess ACTH produced ectopically by ...tumors may induce hyperaldosteronism through the mineralocorticoid activity of glucocorticoids that are upregulated by ACTH. Licorice, with the active ingredient glycyrrhiza, is also a well-known inducer of hyperaldosteronism under specific conditions. In this report, we describe a case of severe hypokalemia caused by ectopic ACTH syndrome (EAS) elicited by an intrathoracic carcinoid tumor, which had transformed to produce ACTH during the 6-year clinical course, and was modulated by licorice ingestion. Hypokalemia was not clearly recognized preoperatively but became obvious within 3 h of general anesthesia with epidural blockade. At the end of anesthesia, arterial blood gas analysis indicated severe hypokalemia (K
+
= 1.7 mEq/l) and metabolic alkalosis (pH 7.56, PaCO
2
= 54.9 mmHg, HCO
3
−
= 44.5 mmol/l, BE = 21.8 mmol/l), without any typical symptoms such as muscle weakness or ECG abnormalities. The hypokalemia was resistant to potassium supplementation and persisted for 4 days. Perioperative imbalance between the administration and elimination of potassium and surgical stress might contribute to the rapid exacerbation and induce the clinical manifestation of EAS.
Oxygen imaging techniques, which can probe the spatiotemporal heterogeneity of tumor oxygenation, could be of significant clinical utility in radiation treatment planning and in evaluating the ...effectiveness of hypoxia-activated prodrugs. To fulfill these goals, oxygen imaging techniques should be noninvasive, quantitative, and capable of serial imaging, as well as having sufficient temporal resolution to detect the dynamics of tumor oxygenation to distinguish regions of chronic and acute hypoxia.
No current technique meets all these requirements, although all have strengths in certain areas. The current status of positron emission tomography (PET)-based hypoxia imaging, oxygen-enhanced magnetic resonance imaging (MRI),
F MRI, and electron paramagnetic resonance (EPR) oximetry are reviewed along with their strengths and weaknesses for planning hypoxia-guided, intensity-modulated radiation therapy and detecting treatment response for hypoxia-targeted prodrugs.
Spatial and temporal resolution emerges as a major concern for these areas along with specificity and quantitative response. Although multiple oxygen imaging techniques have reached the investigative stage, clinical trials to test the therapeutic effectiveness of hypoxia imaging have been limited.
Imaging elements of the redox environment besides oxygen by EPR and hyperpolarized MRI may have a significant impact on our understanding of the basic biology of the reactive oxygen species response and may extend treatment possibilities.
Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, ...their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbate's pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation.
To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated that the generation of hydrogen peroxide consumes oxygen, which is offset at later time points by a reduction in oxygen consumption due to hydrogen peroxide's cytotoxic effect.
In vivo, photoacoustic imaging showed pharmacologic ascorbate treatment at sublethal levels triggered a complex, multi-phasic response in tumor oxygenation across both cell lines. Initially, ascorbate generated transient hypoxia within minutes through hydrogen peroxide production, via reactions that consume oxygen. This initial hypoxic phase peaked at around 150 s and then gradually subsided. However, at longer time scales (approximately 300 s) a vasodilation effect triggered by ascorbate resulted in increased blood flow and subsequent reoxygenation. Combining sublethal levels of i. p. Ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549 xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response.
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•Hypoxia targeting drugs like evofosfamide target tumors resistant to radiation and other treatments.•Transiently increasing hypoxia can increase the effectiveness of hypoxia targeting drugs.•Hydrogen peroxide production from ascorbate transiently consumes oxygen.•At longer time scales, ascorbate causes vasodilation reversing the temporary hypoxia.•Ascorbate with evofosfamide significantly slowed tumor growth compared to either treatment alone.
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