Full-thickness closure in breast-conserving surgery: the impact on radiotherapy target definition for boost and partial breast irradiation. A multimodality image evaluation.

BACKGROUND: During breast-conserving surgery (BCS), surgeons increasingly perform full-thickness closure (FTC) to prevent seroma formation. This could potentially impair precision of target definition for boost and accelerated partial breast irradiation (APBI). The purpose of this study was to investigate the precision of target volume definition following BCS with FTC among radiation oncologists, using various imaging modalities. METHODS: Twenty clinical T1-2N0 patients, scheduled for BCS involving clip placement and FTC, were included in the study. Seven experienced breast radiation oncologists contoured the tumor bed on computed tomography (CT), magnetic resonance imaging (MRI) and fused CT-MRI datasets. A total of 361 observer pairs per image modality were analyzed. A pairwise conformity among the generated contours of the observers and the distance between their centers of mass (dCOM) were calculated. RESULTS: On CT, median conformity was 44 % [interquartile range (IQR) 28-58 %] and median dCOM was 6 mm (IQR 3-9 mm). None of the outcome measures improved when MRI or fused CT-MRI were used. In two patients, superficial closure was performed instead of FTC. In these 14 image sets and 42 observer pairs, median conformity increased to 70 %. CONCLUSIONS: Localization of the radiotherapy target after FTC is imprecise, on both CT and MRI. This could potentially lead to a geographical miss in patients at increased risk of local recurrence receiving a radiation boost, or for those receiving APBI. These findings highlight the importance for breast surgeons to clearly demarcate the tumor bed when performing FTC.

A Prospective Study of Magnetic Resonance Imaging-guided Focal Salvage High-dose-Rate Brachytherapy for Radiorecurrent Prostate Cancer: Updated Results of 30 Patients.

PURPOSE: Limited prospective data on focal salvage high-dose-rate (HDR) prostate brachytherapy is available. We sought to explore the toxicities, health-related quality of life (HRQoL), and efficacy of focal salvage HDR brachytherapy in a prospective clinical trial. This report presents the updated results of previously published data. METHODS AND MATERIALS: Patients with locally recurrent prostate cancer after previous external beam radiation therapy and/or brachytherapy were enrolled. Patients received magnetic resonance imaging (MRI)-guided, ultrasound-based focal HDR brachytherapy delivered over 2 fractions of 13.5 Gy delivered 1 to 2 weeks apart. Androgen deprivation therapy (ADT) was not used. RESULTS: Thirty patients were treated between 2012 and 2019. At a median follow-up time of 39 months, the 3-year biochemical failure-free rate was 61.8% (95% confidence interval, 44.0%-86.6%), and the 3-year ADT/salvage therapy-free rate was 86.0% (95% confidence interval, 74.1%-99.8%). Seventeen patients experienced subsequent biochemical failure, 9 received ADT and/or further local salvage, and no patients died of prostate cancer. Of the 28 patients who had posttreatment MRI, 26 had a local treatment response. No acute grade ≥3 genitourinary/gastrointestinal toxicity was observed. One temporary late grade 3 genitourinary toxicity event occurred, but no late grade ≥3 gastrointestinal toxicity was seen. No significant decline in urinary or bowel HRQoL was observed. CONCLUSIONS: Focal salvage HDR brachytherapy has a favorable side effect profile, no significant decline in HRQoL, and the 3-year biochemical control rates are in line with those of other salvage options. Early MRI response at the treated site is common, but does not preclude subsequent biochemical failure.

Dosimetric evaluation of sucrose and granulated cane sugar in the therapeutic dose range.

Granulated cane sugar has been used as a dosimetric material to report dose in high dose accidental irradiations. The purpose of this study was to assess whether clinical dosimetry is also plausible with such a commonly available material. The behavior of cane sugar was explored with respect to therapeutically relevant radiation quantities (dose, dose rate) and qualities (energy, radiation type) as well as under different temperature conditions. The stability of the signal postirradiation was also measured. Absorbed dose was measured by spectrophotometric readout of a ferrous ammonium sulfate xylenol orange (FX)-sugar solution in 10 cm path length cells. A visible color change was produced as a function of dose when the irradiated sugar samples were dissolved in FX solution (10% dilution by mass). A comparison of the optical absorbance spectra and dose response of cane sugar with analytical grade sucrose was done to establish a benchmark standard from which subsequent dosimetry measurements can be validated. The response of the sugar dosimeter read at 590 nm was found to be linear over the dose range of 100-2000 cGy, independent of energy (6-18 MV) and of the average dose rate (100-500 cGy/min). The readout of sugar samples irradiated with mixed photon and electron fields was also shown to be independent of radiation type (photons and electrons). Sugar temperature (20-40 degrees C) during irradiation did not affect dose estimates, making it a promising dosimeter for in vivo dosimetry, particularly in cases where the dosimeter must remain in contact with the patient for an extended period of time. Sugar can be used as an integrating dosimeter, since it exhibits no fractionation effects. Granulated cane sugar is cost effective, safe, soft tissue equivalent, and can be used under various experimental conditions, making it a suitable dosimeter for some radiotherapy applications.

Image-guided cervix high-dose-rate brachytherapy treatment planning: does custom computed tomography planning for each insertion provide better conformal avoidance of organs at risk?

PURPOSE: Intracavitary high-dose-rate (HDR) brachytherapy (BT) for cervical cancer involves multiple applicator insertions. Our study addresses whether customized three-dimensional plans generated for the first insertion (using computed tomography [CT] planning) can be applied to subsequent insertions without significant changes in dose distributions if identical applicators are used. METHODS AND MATERIALS: Twenty-seven patients were treated with external-beam radiotherapy, platinum-based chemotherapy, and HDR BT. Either tandem and ovoids (TO, n=12) or tandem and ring (TR, n=15) applicators were used, based on clinical indications. Postimplant CT scans were acquired and custom plans generated for each insertion. Dose parameters for organs at risk (OARs) from the second insertion were retrospectively compared to those that would have been delivered using the initial plan. RESULTS: Overall, we observed a significant increase (p<0.038) in dose to International Commission on Radiation Units and Measurement points and 2cm(3) volumes of bladder and rectum when a single plan was used. The sigmoid and small bowel exhibited a more variable increase in dose. Applicator-specific results revealed a significant increase (p<0.030) to dose points and volumes for the rectum and bladder for TR applicators. Conversely, dose values from the more flexible TO did not show any significant trend, exhibiting large interpatient variations. CONCLUSIONS: A duplication of planned dwell times and positions from one insertion to the next does not duplicate dose distributions in HDR cervix applications. A single plan used for an entire course of BT can result in significant increases to OAR doses for TR and unpredictable OAR doses for TO applicators. Treatment plans should be tailored for each insertion to reflect current applicator and anatomical geometry.

Optimization of high-dose-rate cervix brachytherapy applicator placement: the benefits of intraoperative ultrasound guidance.

PURPOSE: To promote efficient workflow for image-guided high-dose-rate (HDR) brachytherapy (BT) for cervix cancer by implementing intraoperative ultrasound (US) guidance for placement and optimization of intrauterine applicators. We sought to establish this as part of routine radiation oncology practice without radiology consultation. METHODS AND MATERIALS: Thirty-five consecutive insertions were performed in 21 women between July 2006 and March 2007. Cervical dilation, tandem selection and insertion were guided by transabdominal US. Final tandem position following vaginal applicator insertion was also confirmed by US. Computed tomography (CT) imaging was used for treatment planning and to assess perforation and applicator suitability for each patient anatomy. RESULTS: Intrauterine tandem insertion was successfully guided by US in the majority of procedures (34/35). CT imaging confirmed accurate placement within the uterine canal in each case, compared with a historic institutional perforation rate of 10%. Visualizing patient anatomy during insertion altered the selection of tandem length and angle in 49% of cases, resulting in improved applicator matching to anatomy. Average insertion time significantly decreased from 34 to 26 minutes (p=0.01). Requests for assistance from gynecologic surgical oncology declined from 38% to 5.7% of procedures. CONCLUSIONS: Intraoperative US guidance for cervix BT has been successfully implemented with staff and equipment from radiation oncology. Using US during every insertion has led to improved applicator selection and placement while decreasing procedure time and reducing out of department consultations. These changes have eliminated repeat insertions due to unfavorable applicator placement (as revealed on postoperative CT), thus improving department efficiency and quality of patient care.

Bone-composition imaging using coherent-scatter computed tomography: assessing bone health beyond bone mineral density.

Quantitative analysis of bone composition is necessary for the accurate diagnosis and monitoring of metabolic bone diseases. Accurate assessment of the bone mineralization state is the first requirement for a comprehensive analysis. In diagnostic imaging, x-ray coherent scatter depends upon the molecular structure of tissues. Coherent-scatter computed tomography (CSCT) exploits this feature to identify tissue types in composite biological specimens. We have used CSCT to map the distributions of tissues relevant to bone disease (fat, soft tissue, collagen, and mineral) within bone-tissue phantoms and an excised cadaveric bone sample. Using a purpose-built scanner, we have measured hydroxyapatite (bone mineral) concentrations based on coherent-scatter patterns from a series of samples with varying hydroxyapatite content. The measured scatter intensity is proportional to mineral density in true g/cm3. Repeated measurements of the hydroxyapatite concentration in each sample were within, at most, 2% of each other, revealing an excellent precision in determining hydroxyapatite concentration. All measurements were also found to be accurate to within 3% of the known values. Phantoms simulating normal, over-, and under-mineralized bone were created by mixing known masses of pure collagen and hydroxyapatite. An analysis of the composite scatter patterns gave the density of each material. For each composite, the densities were within 2% of the known values. Collagen and hydroxyapatite concentrations were also examined in a bone-mimicking phantom, incorporating other bone constituents (fat, soft tissue). Tomographic maps of the coherent-scatter properties of each specimen were reconstructed, from which material-specific images were generated. Each tissue was clearly distinguished and the collagen-mineral ratio determined from this phantom was also within 2% of the known value. Existing bone analysis techniques cannot determine the collagen-mineral ratio in intact specimens. Finally, to demonstrate the in situ potential of this technique, the mineralization state of an excised normal cadaveric radius was examined. The average collagen-mineral ratio of the cortical bone derived from material-specific images of the radius was 0.53+/-0.04, which is in agreement with the expected value of 0.55 for healthy bones.

Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases.

Mutant, activated ras oncogenes are found in many human cancers. Experimental studies have shown that Ras enhances metastatic ability in several cell types. However, the biological mechanisms by which Ras contributes to metastasis remain poorly understood. Our goal was to determine which steps in the formation of macroscopic metastases were affected by Ras. Green fluorescent protein-transfected NIH 3T3 and T24 H-ras-transformed (PAP2) fibroblasts were injected via mesenteric vein to target mouse liver. The proportion of cells that survived at each step of the metastatic process (at 60 min to 14 days after injection) were quantified. We found that Ras did not enhance the ability of cells to extravasate from liver sinusoids or to survive as solitary undivided cells in liver tissue. Furthermore, we found that a subset of cells from both cell lines initiated growth to form micrometastases by day 3. Only micrometastases formed by ras-transformed cells, however, persisted to form macroscopic metastases by day 14, whereas most NIH 3T3 micrometastases disappeared. We investigated this difference in maintenance of developing metastases by quantifying apoptosis and proliferation within the micrometastases. PAP2 metastases had a significantly higher proportion of proliferating cells as compared with apoptosing cells, whereas NIH 3T3 metastases had low proliferation and high apoptosis levels. Whereas the ability of Ras to induce vascular endothelial growth factor has suggested one way that Ras might affect metastatic ability (through induction of angiogenesis), our study provides in vivo evidence for a direct role for Ras in maintenance of metastatic growth via a shift in proliferation/apoptosis balance to favor metastatic growth.

Analysis of urinary stone components by x-ray coherent scatter: characterizing composition beyond laboratory x-ray diffractometry.

Monoenergetic x-ray diffraction (XRD) analysis is an established standard for the assessment of urinary stone composition. The inherent low energy of x-rays used (8 keV), however, restricts penetration depth and imposes a requirement for small powdered samples. A technique capable of producing detailed information regarding component structural arrangements in calculi non-destructively would provide clearer insights into causes of formation and subsequent growth and allow the selection of more appropriate courses of therapy. We describe a new method based on the detection of coherent scatter (CS) in stone components using polyenergetic x-rays (70 kVp) from diagnostic equipment. While the higher energy allows the analysis of intact calculi, the polyenergetic source causes an angular broadening of measured CS patterns. We show that it is possible to relate the polyenergetic (CS) and monoenergetic (XRD) measurements through a superposition integral of the monoenergetic XRD cross-section with a function representative of the polyenergetic spectrum used in CS. Experimentally acquired diffractometry cross-sections of the seven major urinary stone components were subjected to this operation, revealing good agreement of diffraction features with CS. Therefore, our CS analysis is sensitive to stone component structure, similar to conventional XRD analysis. This indicates that CS analysis can be used as a basis to classify urinary calculi by composition. The potential of identifying stone components non-destructively was demonstrated from a tomographic CS analysis of a stone-mimicking phantom. Tomographic composition maps were generated from CS patterns, showing the structural arrangement of multiple stone components within the phantom. CS analysis has the ability to detect components in the presence of many others. The ability to perform CS measurements in intact calculi would allow for the identification of stone structures critical to patient metaprophylaxis.

Laboratory coherent-scatter analysis of intact urinary stones with crystalline composition: a tomographic approach.

Knowledge of urinary stone composition and structure provides important insights in guiding treatment and preventing recurrence. No current method can successfully provide information relating structure and composition of intact stones. We are developing a tomographic technique that uses measures of coherently scattered diagnostic x-rays to yield stone composition. Coherent-scatter (CS) properties depend on molecular structure and are, therefore, sensitive to material composition. Powdered, amorphous or polycrystalline materials with no significant orientation produce circularly symmetric CS patterns. However, in materials with preferred crystallite orientation, like urinary stones, bright spots in CS patterns are observed. This compromises a composition analysis based on comparing CS measurements from calculi to a library of CS signatures from powdered chemicals. We show that a computed tomographic reconstruction of CS measurements using filtered backprojection (CSCT) effectively eliminates bright spots and yields CS patterns equivalent to powdered materials. This allows for direct comparison with a powdered chemical reference library to establish composition. Validation is achieved through a tomographic CS analysis of an aluminium (Al) rod phantom. Much like calculi, CS patterns from a solid polycrystalline Al rod exhibit diffraction spots, absent in the ring-like Al powder CS pattern. We show that the reconstructed Al CS cross-section is equivalent to its powdered counterpart and results in clearly defined composition images. The potential of CSCT to identify stone composition is demonstrated through images of intact stones deemed chemically pure by infrared spectroscopy. Computed tomographic reconstruction of CS signals allowed the generation of composition maps, showing the distribution of stone components. These images provide strong evidence that current laboratory techniques risk missing critical stone components due to inadequate sampling. This is of particular importance since follow-up treatments are based on these composition analyses. CS analysis can distinguish common stone components and can provide topographic composition maps of intact stones. Such details offer invaluable clinical information regarding stone formation, treatment and follow-up, and thus support the development of CS analysis as a laboratory stone analysis technique.

Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer.

PURPOSE: To quantify differences in treatment delivery efficiency and dosimetry between step-and-shoot intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) for prostate treatment. METHODS AND MATERIALS: Twenty-five prostate cancer patients were selected retrospectively for this planning study. Treatment plans were generated for: prostate alone (n = 5), prostate + seminal vesicles (n = 5), prostate + seminal vesicles + pelvic lymph nodes (n = 5), prostate bed (n = 5), and prostate bed + pelvic lymph nodes (n = 5). Target coverage, dose homogeneity, integral dose, monitor units (MU), and sparing of organs at risk (OAR) were compared across techniques. Time required to deliver each plan was measured. RESULTS: The dosimetric quality of IMRT, VMAT, and HT plans were comparable for target coverage (planning target volume V95%, clinical target volume V100% all >98.7%) and sparing of organs at risk (OAR) for all treatment groups. Although HT resulted in a slightly higher integral dose and mean doses to the OAR, it yielded a lower maximum dose to all OAR examined. VMAT resulted in reductions in treatment times over IMRT (mean = 75%) and HT (mean = 70%). VMAT required 15-38% fewer monitor units than IMRT over all treatment volumes, with the reduction per fraction ranging from 100-423 MU from the smallest to largest volumes. CONCLUSIONS: VMAT improves efficiency of delivery for equivalent dosimetric quality as IMRT and HT across various prostate cancer treatment volumes in the intact and postoperative settings.

Three-dimensional image-based planning for cervix brachytherapy with bilateral hip prostheses: a solution using MVCT with helical tomotherapy.

PURPOSE: We present a method of three-dimensional image-based planning for cervix high-dose-rate (HDR) brachytherapy for patients with bilateral metal hip prostheses using megavoltage computed tomography (MVCT) imaging. METHODS AND MATERIALS: Two patients with bilateral metal hip prostheses were treated with our standard HDR brachytherapy fractionation and critical structure tolerance limits for cervical cancer. MVCT imaging was used for treatment planning because of artifacts present in kilovoltage computed tomography (kVCT), which did not allow visualization of the organs of interest. RESULTS: The MVCT images provided adequate contrast to allow the contouring of organs at risk and the digitization of HDR applicators. HDR brachytherapy treatment planning was successfully accomplished based on MVCT images for 2 patients with bilateral metal hip prostheses. CONCLUSIONS: Using MVCT imaging eliminated streak artifacts, which improved the image quality for treatment planning. MVCT offers an option for three-dimensional planning for cervix brachytherapy in patients with bilateral hip prostheses.

Establishing composition and structure of intact urinary calculi by x-ray coherent scatter for clinical laboratory investigations.

PURPOSE: Current urinary stone analysis techniques are limited in their abilities to simultaneously characterize composition and structure. Laboratory techniques such as IRS and x-ray diffractometry require small powdered samples for analysis, rendering composition results dependent on the choice of sample and its preparation. We investigated the application of x-ray CS analysis to identify topographic urinary stone composition ex vivo. CS is essentially a transmission based x-ray diffractometry method that depends on molecular structure and, therefore, can distinguish different compounds. Diagnostic x-ray equipment facilitates the examination of structural arrangements of minerals in intact calculi. MATERIALS AND METHODS: Tomographic images of intact calculi CS properties were acquired with a purposely built scanner. Composition is extracted from CS by fitting a library of common pure stone component CS signatures to those of the unknown sample in each image pixel. Two zones per stone were isolated (powdered) for IRS composition analysis for comparison with CS maps at these locations. Each stone was also independently analyzed for bulk composition by IRS analysis. RESULTS: CS composition maps revealed the spatial arrangement of minerals in intact calculi. IRS results showed good agreement with CS in the selected regions of interest. Bulk composition by IRS was noted to miss some important stone components, indicating that the choice of sample may skew composition results. CONCLUSIONS: CS from diagnostic x-rays can be used to identify structure and composition in mixed urinary calculi nondestructively. The tissue specific CS images presented support the development of CS analysis as a means of identifying stone composition characteristics in the laboratory.