Are liver contour and bone fusion comparable to fiducials for IGRT in liver SBRT?

Introduction: Liver stereotactic body radiotherapy (SBRT) is increasingly being used to treat tumours. The purpose of this study was to compare the differences in patient positioning when using implanted fiducials as surrogates compared to alternative methods based on liver contour or bone registration. Material and methods: Eighteen patients treated with SBRT who underwent a fiducial placement procedure were included. Fiducial guidance was our gold standard to guide treatment in this study. After recording the displacements, when fusing the planning CT and CBCT performed in the treatment unit using fiducials, liver contour and bone reference, the differences between fiducials and liver contour and bone reference were calculated. Data from 88 CBCT were analyzed. The correlation between the displacements found with fiducials and those performed based on the liver contour and the nearest bone structure as references was determined. The mean, median, variance, range and standard deviation of the displacements with each of the fusion methods were obtained. µ, Æ©, and σ values and margins were obtained. Results: Lateral displacements of less than 3 mm with respect to the gold standard in 92% vs. 62.5% of cases using liver contour and bone references, respectively, with 93.2% vs. 65.9% in the AP axis and SI movement in 69.3% vs. 51.1%. The errors µ, σ and Æ© of the fusions with hepatic contour and bone reference in SI were 0.26 mm, 4 mm and 3 mm, and 0.8 mm, 5 mm and 3 mm respectively. Conclusion: Our study showed that displacements were smaller with the use of hepatic contour compared to bone reference and comparable to those obtained with the use of fiducials in the lateral, AP and SI motion axes. This would justify that hepatic contouring can be a guide in the treatment of patients in the absence of fiducials.

Application of discrete cosine transform to assess the effect of tumor motion variations on the definition of ITV in lung and liver SBRT.

PURPOSE: To use Discrete Cosine Transform to include tumor motion variations on ITV definition of SBRT patients. METHODS: Data from 66 patients was collected. 2D planar fluoroscopy images (FI) were available for 54 patients. Daily CBCT projections (CBCTp) from 29 patients were employed to measure interfraction amplitude variability. Systematic amplitude variations were obtained from 17 patients with data from both FI and CBCTp. Tumor motion curves obtained from FI were characterized with a Cosine model (CM), based on cosine functions to the power of 2, 4 or 6, and DCT. Performance of both models was evaluated by means of R2 coefficient and by comparing their results on Internal Target Volume (ITV) margins against those calculated from original tumor motion curves. Amplitude variations from CBCTp, as well as estimations of baseline shift variations were added to the DCT model to account for their effect on ITV margins. RESULTS: DCT replicated tumor motion curves with a mean R2 values for all patients of 0.86, 0.91 and 0.96 for the lateral (LAT), anterior-posterior (AP) and cranio-caudal (CC) directions respectively. CM yielded worst results, with R2 values of 0.64, 0.61 and 0.74 in the three directions. Interfraction amplitude variation increased ITV margins by a 9%, while baseline shift variability implied a 40% and 80-100% increase for normalized values of baseline shift of 0.2 and 0.4 respectively. CONCLUSIONS: Probability distribution functions of tumor positions can be successfully characterized with DCT. This permits to include tumor motion variablilities obtained from patient population into patient specific ITVs.

Brain metastases: Single-dose radiosurgery versus hypofractionated stereotactic radiotherapy: A retrospective study.

BACKGROUND: Radiosurgery is employed for the treatment of brain metastases. The aim of this study is to evaluate the efficacy and tolerability of single-dose radiosurgery (SRS) compared to hypofractionated stereotactic radiotherapy (hFSRT). MATERIALS AND METHODS: Between 2004 and 2018, we analyzed treatments of 97 patients with 135 brain metastases. Fifty-six patients were treated with SRS, and 41 patients were treated with hFSRT. Median dose was 16 Gy (12-20 Gy) for the SRS group and 30 Gy in 5-6 fractions for the hFSRT group. hFSRT was used for larger lesions and lesions located near critical structures. Kaplan-Meier curves were constructed for overall survival (OS) and local control (LC). RESULTS: Median age was 64 years (range, 32-89 years). Median survival was 10 months (1-68 months). With a median follow-up of 10 months, no significant differences in OS between groups were found (P=0.21). LC for all patients was 67%. Local progression-free survival (LPFS) at 6 months and 1 year was 71% and 60% for the SRS group, respectively, and 80% and 69% for the hFSRT group, respectively (P=0.93). Although hFSRT was used for larger lesions and lesions in adverse locations, LPFS was not inferior compared to lesions treated with SRS. We observed acute toxicity grade 1-2 in 25 patients (25.8%). Late complications were observed in 11 patients (11.3%). Acute and late toxicity was similar in the SRS- and hFSRT-treated patients (P=0.63 and P=0.11, respectively). Brain recurrence occurred in 37.5% and 14.6% in the hFSRT and SRS group, respectively (P=0.06). CONCLUSIONS: Since patients treated with hFSRT exhibited similar survival and LPFS rates without differences in toxicity compared to those treated with SRS, hFSRT can be beneficial, particularly for patients with brain metastases. RELEVANCE FOR PATIENTS: Hypofractionated schemes in stereotactic radiosurgery offers treatment alternatives to patients with large lesions or lesions near critical structures.

Effectiveness and toxicity of helical tomotherapy for patients with locally recurrent nasopharyngeal carcinoma

Purpose. We assessed therapeutic outcomes of reirradiation with helical tomotherapy (HT) for locoregional recurrent nasopharyngeal carcinoma (LRNPC) patients. Methods and materials. Treatment outcomes were evaluated retrospectively in 17 consecutive LRNPC patients receiving HT between 2006 and 2012. Median age was 57 years and most patients (n = 13) were male. Simultaneous systemic therapy was applied in 5 patients. Initial treatment covered the gross tumor volume with a median dose of 70 Gy (60–81.6 Gy). Reirradiation was confined to the local relapse region with a median dose of 63 Gy (50–70.2 Gy), resulting in a median cumulative dose of 134 Gy (122–148.2 Gy). The median time interval between initial and subsequent treatment was 42 months (11–126). Results. The median follow-up for the entire cohort was 23 and 35 months for survivors. Three patients (18 %) developed both local and distant recurrences and only one patient (6 %) suffered from isolated local recurrence. Two-year actuarial DFS and LC rates were 74 and 82 %, respectively. Two-year OS rate was 79 %. Acute and late grade 2 toxicities were observed in 8 patients (47 %). No patient experienced late grade ≥3 toxicity. Late toxicity included fibrosis of skin, hypoacusia, dysphagia, and xerostomia. Patients with higher Karnofsky performance status scores associated with a lower risk of mortality (HR 0.85, p = 0.015). Conclusion. Reirradiation with HT in patients with LRNPC is feasible and yields encouraging results in terms of local control and overall survival with acceptable toxicity (AU)

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Effectiveness and toxicity of helical tomotherapy for patients with locally recurrent nasopharyngeal carcinoma.

PURPOSE: We assessed therapeutic outcomes of reirradiation with helical tomotherapy (HT) for locoregional recurrent nasopharyngeal carcinoma (LRNPC) patients. METHODS AND MATERIALS: Treatment outcomes were evaluated retrospectively in 17 consecutive LRNPC patients receiving HT between 2006 and 2012. Median age was 57 years and most patients (n = 13) were male. Simultaneous systemic therapy was applied in 5 patients. Initial treatment covered the gross tumor volume with a median dose of 70 Gy (60-81.6 Gy). Reirradiation was confined to the local relapse region with a median dose of 63 Gy (50-70.2 Gy), resulting in a median cumulative dose of 134 Gy (122-148.2 Gy). The median time interval between initial and subsequent treatment was 42 months (11-126). RESULTS: The median follow-up for the entire cohort was 23 and 35 months for survivors. Three patients (18 %) developed both local and distant recurrences and only one patient (6 %) suffered from isolated local recurrence. Two-year actuarial DFS and LC rates were 74 and 82 %, respectively. Two-year OS rate was 79 %. Acute and late grade 2 toxicities were observed in 8 patients (47 %). No patient experienced late grade ≥3 toxicity. Late toxicity included fibrosis of skin, hypoacusia, dysphagia, and xerostomia. Patients with higher Karnofsky performance status scores associated with a lower risk of mortality (HR 0.85, p = 0.015). CONCLUSION: Reirradiation with HT in patients with LRNPC is feasible and yields encouraging results in terms of local control and overall survival with acceptable toxicity.

SU-E-T-290: Dosimetric Verification of Helical Tomotherapy against Experimental Measurements for Head and Neck Treatments.

PURPOSE: To verify a Tomotherapy plan for a typical head and neck treatment against experimental measurements. METHODS: The treatment plan for a head and neck case was generated by the Tomotherapy treatment planning system (TPS) to deliver ∼70 Gy in 33 sessions to the contoured PTV. The plan was calculated on a CIRS ATOM anthropomorphic phantom that provides a grid spacing of 3×3 cm2 holes to accommodate thermoluminescent detectors (TLD). The plan was verified against experimental measurements carried out by 7 LiF:Mg,Ti (TLD-700) TLD. Up to 20 locations were selected within the irradiated region and three detectors were used simultaneously at each point to decrease the statistical uncertainty. TLD locations were labeled in the planning system and dose comparisons between TPS prediction and experimental measurements were performed in terms of absolute dose to water for a single fraction. We examined the dose from (i) the corresponding 3.5MV Tomo-scan alone and (ii) the complete treatment. TLD-700 were found to fulfill the requirements of reproducibility, linearity and flat energy response in a previous study. In particular, TLD energy response was previously checked for 6 MV flattening filter free and conventional radiation beams under reference conditions. RESULTS: Doses derived from the TPS were in most cases in good agreement (4% on average) with TLD dose measurements within TLD statistical uncertainties (about 3%). Larger discrepancies up to 7% were found for points close to complex tissue inhomogeneities, such as bony structures. Dose from the scanning procedure alone is about 1 % of the dose per fraction. CONCLUSIONS: This work indicates that dose delivery plans created with Tomotherapy TPS are accurate for head and neck tumor localizations.

Evolving architectural patterns in microbial colonies development.

Semithin sections of colonies of three ATCC strains (Staphylococcus aureus, Escherichia coli, and Candida albicans) showed that their internal structure had specific patterns that evolved over the time. These patterns generally were defined by the presence of different layers composed of microorganisms with variable population densities and dead cells. The observed structures in this study could be explained as a particular form of biofilm with an air-semisolid interface.

Cefditoren versus ceftazidime in inducer-substrate combinations for the evaluation of AmpC production in a disc approximation test.

OBJECTIVE: To evaluate cefditoren in inducer-substrate combinations to screen for AmpC induction. METHODS: 100 clinical isolates (25 P. aeruginosa, 25 E. cloacae, 14 M. morganii, 13 S. marcescens, 12 C. freundii, 7 P. rettgeri, and 4 E. aerogenes) were tested by the Kirby-Bauer disc approximation method using cefditoren and ceftazidime discs as substrates, and cefditoren and imipenem discs as inducers. RESULTS: None of the strains showed induction of AmpC with cefditoren-ceftazidime as inducer-substrate combination. Imipenem-cefditoren as inducer-substrate combination was not useful for evaluating strains of P. aeruginosa since no inhibition zones surrounding the cefditoren disc were found. Among evaluable enterobacteria (those showing substrate inhibition zone), inducible Amp C was detected in 48 out of 63 (76.2%) with cefditoren, and in 33 out of 68 (48.5%) isolates with ceftazidime as substrate. Significantly (p=0.013) higher number of AmpC producers were detected with cefditoren versus ceftazidime (76.2% vs. 48.5%), due to the differences found for E. cloacae (72.8% vs. 21.7%; p=0.0009) and S. marcescens (100% vs. 54.5%; p=0.03). Higher mean reductions of diameters around substrate discs were found for cefditoren (4.17 mm) vs. ceftazidime (3.79 mm), reaching statistical significance (p<0.05) for indol-positive proteae: M. morganii (5.32 mm vs. 3.92 mm) and P. rettgeri (3.47 mm vs. 2.64 mm). CONCLUSION: Cefditoren showed no induction capability, and when used as substrate (with imipenem as inducer) it offered detection rates of AmpC inducible enterobacteria higher than the imipenem-ceftazidime combination, mainly for Enterobacter spp. and Serratia spp., with higher diameter reductions for indol-positive proteae.

Exposure-response analysis of tigecycline in pharmacodynamic simulations using different size inocula of target bacteria.

This study explored tigecycline exposure-bacterial responses in pharmacodynamic simulations (in vitro kinetic model) using different inocula. One meticillin-resistant vancomycin-heteroresistant Staphylococcus aureus, one Enterococcus faecium and one extended-spectrum beta-lactamase-producing Escherichia coli with equal tigecycline minimum inhibitory concentrations/minimum bactericidal concentrations (MICs/MBCs) (0.12/0.25 microg/mL) were used. A computerised pharmacodynamic bicompartmental model simulated three tigecycline twice-daily dosing regimens over 48h: 50mg (100mg loading dose); 100mg; and 150 mg. Areas under bacterial growth curves were calculated, and differences between the growth curve used as control and the killing curve of bacteria exposed to tigecycline (ABBC) were determined. With standard inocula [ca. 1 x 10(6)colony-forming units (CFU)/mL], linear increases in area under the concentration-time curve (AUC)/MIC (25.6 for 50mg, 53.76 for 100mg and 79.52 for 150 mg) produced linear increases in activity against Gram-positive organisms (mean ABBCs of 120.60, 143.20 and 195.80 log CFU x h/mL for S. aureus and of 95.75, 172.55 and 216.90 log CFUxh/mL for E. faecium, respectively), with the activity of the 150 mg regimen being significantly higher (P<0.01) than that of the other two regimens. ABBCs obtained with the 100mg regimen using standard inocula were similar to those obtained with the 150 mg regimen when using high inocula (ca. 1 x 10(7)CFU/mL). Against E. coli, the highest dosing regimen was required to obtain significant antibacterial activity compared with control (mean ABBCs of 145.75 log CFU x h/mL with standard inocula and 63.33 log CFU x h/mL with high inocula). An increase in tigecycline dosing appears to be an interesting therapeutic option to maximise antibacterial activity owing to its linear pharmacokinetics and pharmacodynamics, especially when severe infections with high bacterial load are suspected.

Influence of media and testing methodology on susceptibility to tigecycline of Enterobacteriaceae with reported high tigecycline MIC.

The tigecycline susceptibility of six different Enterobacteriaceae strains with reported high tigecycline MICs was determined in quintuplicate by four methodologies using Mueller-Hinton agar and broth from six manufacturers. The MICs determined by Etest were a >or=1-fold dilution lower than those determined by broth microdilution and agar dilution, with the highest modal values given by agar dilution. The highest modal MICs were obtained using Oxoid medium, and the lowest inhibition zone values (disc diffusion) were obtained using Oxoid and bioMérieux media. The lowest MICs were obtained by Etest using Difco or Merck media.

In vitro killing activity of crevicular concentrations of tinidazole plus common oral antibiotics against high-density mixed inocula of periodontal pathogens in strict anaerobic conditions.

BACKGROUND: Odontogenic infections are polymicrobial. This study explores the in vitro killing activity by concentrations similar to those found in crevicular fluid of tinidazole in combination with amoxicillin/clavulanic acid, clindamycin and levofloxacin against four groups of high-density mixed inocula of anaerobes (Prevotella buccae, Fusobacterium nucleatum, and Veillonella spp.) and facultative (Capnocytophaga spp. and Streptococcus spp.) isolates of periodontal pathogens. METHODS: Killing curves were assessed under strict anaerobic conditions with antibiotics alone and in combination with tinidazole at concentrations similar to those achieved in crevicular fluid against approximately 10(7) colony forming units (CFU)/ml inoculum (1:1:1:1:1 proportion of the five bacterial isolates) of the four bacterial groups. Group 1 did not include beta-lactamase-producing strains; groups 2, 3, and 4 included one, two, and three beta-lactamase-producing strains, respectively. RESULTS: In single-drug experiments, at 48 hours, tinidazole alone did not show significant killing of the entire bacterial population, whereas reductions in the initial inocula > or =2.09 log(10) CFU/ml with clindamycin, > or =3.26 log(10) CFU/ml with amoxicillin/clavulanic acid, and > or =3.83 log(10) CFU/ml with levofloxacin were obtained. When combined with tinidazole, reductions were significantly higher for all antibiotics: > or =5.28 log(10) CFU/ml with clindamycin, > or =4.78 log(10) CFU/ml with amoxicillin/clavulanic acid, and > or =6.17 log(10) CFU/ml with levofloxacin. CONCLUSION: In addition to its high activity against anaerobic periodontal pathogens, tinidazole offered synergism with other antibiotics against the large strict anaerobic subpopulation and the small facultative subpopulation of a high-density mixed inocula of odontogenic pathogens under strict anaerobic conditions, similar to those of odontogenic infections.

Bactericidal activity of daptomycin versus vancomycin in the presence of human albumin against vancomycin-susceptible but tolerant methicillin-resistant Staphylococcus aureus (MRSA) with daptomycin minimum inhibitory concentrations of 1-2microg/mL.

This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC)=0.5/16, 1/32, 2/32 and 1/32microg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4microg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations (C(max)) (65.70/98.60microg/mL) and trough concentrations (C(min)) (7.90/9.13microg/mL) in the presence and absence of a physiological human albumin concentration (4g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C(max) (41.45/8.18microg/mL) and C(min) (4.98/0.76microg/mL). Vancomycin C(max) and C(min) concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C(max) and C(min). C(max) was rapidly bactericidal (< or =4h) with >5 log(10) reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C(max). C(min) exhibited similar final colony counts at 0h and 24h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at < or =4h for strains with an MIC of 1microg/mL and ca. 2 logCFU/mL reduction at < or =6h for strains with an MIC of 2microg/mL. This activity was significantly higher than the activity of the free C(min) fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.

Tinidazole inhibitory and cidal activity against anaerobic periodontal pathogens.

The in vitro activity of tinidazole against anaerobic periodontal pathogens (25 Prevotella buccae, 18 Prevotella denticola, 10 Prevotella intermedia, 6 Prevotella melaninogenica, 5 Prevotella oralis, 10 Fusobacterium nucleatum and 8 Veillonella spp.) was determined by agar dilution. MIC(90) values (minimum inhibitory concentration for 90% of the organisms) were 8 microg/mL for Veillonella spp., 4 microg/mL for P. intermedia, 2 microg/mL for P. buccae, 1 microg/mL for Fusobacterium spp. and 0.5 microg/mL for other Prevotella spp. Cidal activity was studied by killing curves with tinidazole and amoxicillin (alone and in combination) at concentrations similar to those achieved in crevicular fluid (41.2 microg/mL tinidazole and 14.05 microg/mL amoxicillin) against an inoculum of ca. 10(7)colony-forming units/mL of four bacterial groups, each one composed of four different strains of the following periodontal isolates: Prevotella spp., Fusobacterium spp. and Veillonella spp. (anaerobes) and one amoxicillin-susceptible Streptococcus spp. (facultative) in a proportion of 1:1:1:1. When only beta-lactamase-negative Prevotella or Fusobacterium strains were tested, significantly higher reductions were found with amoxicillin (>4 log reduction at 48 h) versus controls. The presence of beta-lactamase-positive Prevotella spp. or F. nucleatum strains rendered amoxicillin inactive (no reductions at 48 h), with no differences from controls. Amoxicillin+tinidazole produced >3 log reduction at 24h and >4 log reduction at 48 h regardless of the presence or not of beta-lactamase-positive strains. The presence in crevicular fluid of beta-lactamases produced by beta-lactamase-positive periodontal pathogens may have ecological and therapeutic consequences since it may protect beta-lactamase-negative periodontal pathogens from amoxicillin treatment. In vitro, tinidazole offered high antianaerobic activity against beta-lactamase-positive and -negative periodontal pathogens, avoiding amoxicillin inactivation.

Beta-lactam activity against penicillin-resistant Streptococcus pneumoniae strains exhibiting higher amoxicillin versus penicillin minimum inhibitory concentration values: an in vitro pharmacodynamic simulation.

BACKGROUND: Activity of simulated serum concentrations after oral therapy with 400 mg cefditoren pivoxil b.i.d., 500 mg cefuroxime axetil b.i.d. and 875/125 mg amoxicillin/clavulanic acid b.i.d. and t.i.d. regimens was explored over 24 h against Streptococcus pneumoniae. METHODS: Computerized pharmacodynamic simulations were performed against strains with penicillin/amoxicillin/cefuroxime/cefditoren minimum inhibitory concentrations (MICs, microg/ml) and serotypes: strain 1 (0.25/0.12/1/0.12; serotype 6A), strain 2 (2/4/ 2/0.25; serotype 6B), strain 3 (4/16/4/0.5; serotype 14), and strain 4 (4/16/8/1; serotype 14). RESULTS: Bactericidal activity (> or =3 log(10) reduction) at 12 and 24 h was obtained against all strains with cefditoren, against strains 1 and 2 with cefuroxime and amoxicillin/clavulanic acid t.i.d., but only against strain 1 with amoxicillin/clavulanic acid b.i.d.. Bactericidal activity at 24 h was related to T > MIC of >30% dosing interval, 1.7-2.0 log(10) reductions with T > MIC of 20-30%, and <1 log(10) reduction or regrowth with T > MIC of 0%. CONCLUSIONS: It is difficult to achieve pharmacodynamic coverage and bactericidal activity by physiological concentrations of oral beta-lactams against penicillin-resistant pneumococcal strains exhibiting higher amoxicillin versus penicillin MICs. Cefditoren may offer alternatives.

Cidal activity of oral third-generation cephalosporins against Streptococcus pneumoniae in relation to cefotaxime intrinsic activity.

This study explores the killing kinetics within 12 h of four oral third-generation cephalosporins against ten Streptococcus pneumoniae strains exhibiting cefotaxime minimum inhibitory concentrations (MICs) from 0.03 to 2 microg/ml. Killing curves were performed with concentrations achievable in serum after standard doses (0.015-4 microg/ml). Reductions of 90% were achieved with all compounds at serum-achievable concentrations for strains exhibiting cefotaxime MIC < or = 0.5 microg/ml. Against strains with cefotaxime MIC > or = 1 microg/ml, only cefditoren reached a 90% reduction with concentrations of 0.5-1 microg/ml doses. At 4 microg/ml, cefditoren and cefotaxime reached 99.9% reduction in seven of the ten strains studied. At serum-achievable concentrations, cefdinir and cefixime were not bactericidal against strains exhibiting cefotaxime MIC > or = 0.25 microg/ml and > or = 0.5 microg/ml, respectively. Cefditoren showed the best killing kinetic profiles and this observation may be important when choosing an oral third-generation cephalosporin as initial or sequential therapy.

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