Is noncoplanar plan more robust to inter-fractional variations than coplanar plan in treating bilateral HN tumors with pencil-beam scanning proton beams?

PURPOSE: Noncoplanar plans (NCPs) are commonly used for proton treatment of bilateral head and neck (HN) malignancies. NCP requires additional verification setup imaging between beams to correct residual errors of robotic couch motion, which increases imaging dose and total treatment time. This study compared the quality and robustness of NCPs with those of coplanar plans (CPs). METHODS AND MATERIALS: Under an IRB-approved study, CPs were created retrospectively for 10 bilateral HN patients previously treated with NCPs maintaining identical beam geometry of the original plan but excluding couch rotations. Plan robustness to the inter-fractional variation (IV) of both plans was evaluated through the Dose Volume Histograms (DVH) of weekly quality assurance CT (QACT) sets (39 total). In addition, delivery efficiency for both plans was compared using total treatment time (TTT) and beam-on time (BOT). RESULTS: No significant differences in plan quality were observed in terms of clinical target volume (CTV) coverage (D95) or organ-at-risk (OAR) doses (p > 0.4 for all CTVs and OARs). No significant advantage of NCPs in the robustness to IV was found over CP, either. Changes in D95 of QA plans showed a linear correlation (slope = 1.006, R2  > 0.99) between NCP and CP for three CTV data points (CTV1, CTV2, and CTV3) in each QA plan (117 data points for 39 QA plans). NCPs showed significantly higher beam delivery time than CPs for TTT (539 ± 50 vs. 897 ± 142 s; p < 0.001); however, no significant differences were observed for BOT. CONCLUSION: NCPs are not more robust to IV than CPs when treating bilateral HN tumors with pencil-beam scanning proton beams. CPs showed plan quality and robustness similar to NCPs while reduced treatment time (∼6 min). This suggests that CPs may be a more efficient planning technique for bilateral HN cancer proton therapy.

Evaluation of intrafraction couch shifts for proton treatment delivery in head-and-neck cancer patients: Toward optimal imaging frequency.

PURPOSE: Treatment planning for head-and-neck (H&N) cancer, in particular oropharynx, nasopharynx, and paranasal sinus cases, at our center requires noncoplanar proton beams due to the complexity of the anatomy and target location. Targeting accuracy for all beams is carefully evaluated by using image guidance before delivering proton beam therapy (PBT). In this study, we analyzed couch shifts to evaluate whether imaging is required before delivering each field with different couch angles. METHODS: After the Institutional Review Board approval, a retrospective analysis was performed on data from 28 H&N patients treated with PBT. Each plan was made with two-to-three noncoplanar and two-to-three coplanar fields. Cone-beam computed tomography and orthogonal kilovoltage (kV) images were acquired for setup and before delivering each field, respectively. The Cartesian (longitudinal, vertical, and lateral) and angular (pitch and roll) shifts for each field were recorded from the treatment summary on the first two fractions and every subsequent fifth fraction. A net magnitude of the three-dimensional (3D) shift in Cartesian coordinates was calculated, and a 3D vector was created from the 6 degrees of freedom coordinates for transforming couch shifts in the system coordinate to the beam's-eye view. RESULTS: A total of 3219 Cartesian and 2146 angular shift values were recorded for 28 patients. Of the Cartesian shifts, 2069 were zero (64.3%), and 1150 (35.7%) were nonzero (range, -7 to 11 mm). Of the angular shifts, 1034 (48.2%) were zero, and 1112 (51.8%) were nonzero (range, -3.0° to 3.2°). For 17 patients, the couch shifts increased toward the end of the treatment course. We also found that patients with higher body mass index (BMI) presented increased net couch shifts (p < 0.001). With BMI < 27, all overall net shift averages were <2 mm, and overall maximum net shifts were <6 mm. CONCLUSIONS: These results confirm the need for orthogonal kV imaging before delivering each field of H&N PBT at our center, where a couch rotation is involved.

Comparison of the dosimetric accuracy of proton breast treatment plans delivered with SGRT and CBCT setups.

PURPOSE: To compare the dosimetric accuracy of surface-guided radiation therapy (SGRT) and cone-beam computed tomography (CBCT) setups in proton breast treatment plans. METHODS: Data from 30 patients were retrospectively analyzed in this IRB-approved study. Patients were prescribed 4256-5040 cGy in 16-28 fractions. CBCT and AlignRT (SGRT; Vision RT Ltd.) were used for treatment setup during the first three fractions, then daily AlignRT and weekly CBCT thereafter. Each patient underwent a quality assurance CT (QA-CT) scan midway through the treatment course to assess anatomical and dosimetric changes. To emulate the SGRT and CBCT setups during treatment, the planning CT and QA-CT images were registered in two ways: (1) by registering the volume within the CTs covered by the CBCT field of view; and (2) by contouring and registering the surface surveyed by the AlignRT system. The original plan was copied onto these two datasets and the dose was recalculated. The clinical treatment volume (CTV): V95% ; heart: V25Gy , V15Gy , and mean dose; and ipsilateral lung: V20Gy , V10Gy , and V5Gy , were recorded. Multi and univariate analyses of variance were performed to assess the differences in dose metric values between the planning CT and the SGRT and CBCT setups. RESULTS: The CTV V95% and lung V20Gy , V10Gy , and V5Gy dose metrics were all significantly (p < 0.01) lower on the QA-CT in both the CBCT and SGRT setup. The differences were not clinically significant and were, on average, 1.4-1.6% lower for CTV V95% and 1.8%-6.0% lower for the lung dose metrics. When comparing the lung and CTV V95% dose metrics between the CBCT and SGRT setups, no significant difference was observed. This indicates that the SGRT setup provides similar dosimetric accuracy as CBCT. CONCLUSION: This study supports the daily use of SGRT systems for the accurate dose delivery of proton breast treatment plans.

Impact of bowel and rectum air on target dose with robustly optimized intensity-modulated proton therapy plans.

PURPOSE: Pelvic target dose from intensity-modulated proton therapy (IMPT) is sensitive to patient bowel motion. Robustly optimized plans in regard to bowel filling may improve the dose coverage in the treatment course. Our purpose is to investigate the effect of air volume in large and small bowel and rectum on target dose from IMPT plans. METHODS AND MATERIAL: Data from 17 cancer patients (11 prostate, 3 gynecologic, 2 colon, and 1 embryonal rhabdomyosarcoma) with planning CT (pCT) and weekly or biweekly scanned quality assurance CTs (QACTs; 82 QACT scans total) were studied. Air in bowels and rectum traversed by proton pencil beams was contoured. The robust treatment plan was made by using 3 CT sets: the pCT set and 2 virtual CT sets that were copies of pCT but in which the fillings of bowels and rectum were overridden to be either air or muscle. Each plan had 2-5 beams with a mean of 3 beams. Targets in the pCT were mapped to the QACTs by deformable image registration, and the dose in QACTs was calculated. Dose coverage (D99 and D95) and correlations between dose coverage and changes in air volume were analyzed. The significance of the correlation was analyzed by t test. RESULTS: Mean changes of D99 in QACTs were within 3% of those in the pCT for all prostate and colon cases but >3% in 2 of the 3 gynecologic cases and in the embryonal rhabdomyosarcoma case. Of these three cases with mean change of D99 > 3%, air volume may be the main cause in 2. For the prostate cases, correlation coefficients were <0.7 between change in air volume and change in D99 and D95, because other anatomy changes also contributed to dose deviation. Correlation coefficients in the non-prostate cases were >0.9 between D99 change and rectum and between D95 change and small bowel, indicating a greater effect of the air volume on target dose. CONCLUSION: The air volume may still have an important effect on target dose coverage in treatment plans using 3 CT sets, particularly when the air is traversed by multiple beams.

Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.

INTRODUCTION: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance. METHODS: Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy. RESULTS: Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression. CONCLUSIONS: Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.

Docetaxel radiosensitizes castration-resistant prostate cancer by downregulating CAV-1.

PURPOSE: Docetaxel (DXL), a noted radiosensitizer, is one of the few chemotherapy drugs approved for castration-resistant prostate cancer (CRPC), though only a fraction of CRPCs respond to it. CAV-1, a critical regulator of radioresistance, has been known to modulate DXL and radiation effects. Combining DXL with radiotherapy may create a synergistic anticancer effect through CAV-1 and improve CRPC patients' response to therapy. Here, we investigate the effectiveness and molecular characteristics of DXL and radiation combination therapy in vitro. MATERIALS AND METHODS: We used live/dead assays to determine the IC50 of DXL for PC3, DU-145, and TRAMP-C1 cells. Colony formation assay was used to determine the radioresponse of the same cells treated with radiation with/without IC50 DXL (4, 8, and 12 Gy). We performed gene expression analysis on public transcriptomic data collected from human-derived prostate cancer cell lines (C4-2, PC3, DU-145, and LNCaP) treated with DXL for 8, 16, and 72 hours. Cell cycle arrest and protein expression were assessed using flow cytometry and western blot, respectively. RESULTS: Compared to radiation alone, combination therapy with DXL significantly increased CRPC death in PC3 (1.48-fold, p < .0001), DU-145 (1.64-fold, p < .05), and TRAMP-C1 (1.13-fold, p < .05) at 4 Gy of radiation. Gene expression of CRPC treated with DXL revealed downregulated genes related to cell cycle regulation and upregulated genes related to immune activation and oxidative stress. Confirming the results, G2/M cell cycle arrest was significantly increased after treatment with DXL and radiation. CAV-1 protein expression was decreased after DXL treatment in a dose-dependent manner; furthermore, CAV-1 copy number was strongly associated with poor response to therapy in CRPC patients. CONCLUSIONS: Our results suggest that DXL sensitizes CRPC cells to radiation by downregulating CAV-1. DXL + radiation combination therapy may be effective at treating CRPC, especially subtypes associated with high CAV-1 expression, and should be studied further.

Cone-Beam CT Images as an Indicator of QACT During Adaptive Proton Therapy of Extremity Sarcomas.

Purpose: Periodic quality assurance CTs (QACTs) are routine in proton beam therapy. In this study, we tested whether the necessity for a QACT could be determined by evaluating the change in beam path length (BPL) on daily cone-beam CT (CBCT). Patients and Methods: In this Institutional Review Board-approved study, we retrospectively analyzed 959 CBCT images from 78 patients with sarcomas treated with proton pencil-beam scanning. Plans on 17 QACTs out of a total of 243 were clinically determined to be replanned for various reasons. Daily CBCTs were retrospectively analyzed by automatic ray-tracing of each beam from the isocenter to the skin surface along the central axis. A script was developed for this purpose. Patterns of change in BPL on CBCT images were compared to those from adaptive planning using weekly QACTs. Results: Sixteen of the 17 adaptive replans showed BPL changes ≥4 mm for at least 1 of the beams on 3 consecutive CBCT sessions. Similarly, 43 of 63 nonadaptively planned patients had BPL changes <4 mm for all of the beams. A new QACT criterium of a BPL change of any beam ≥4 mm on 3 consecutive CBCT sessions resulted in a sensitivity of 94.1% and a specificity of 68.3%. Had the BPL change been used as the QACT predictor, a total of 37 QACTs would have been performed rather than 243 QACTs in clinical practice. Conclusion: The use of BPL changes on CBCT images represented a significant reduction (85%) in total QACT burden while maintaining treatment quality and accuracy. QACT can be performed only when it is needed, but not in a periodic manner. The benefits of reducing QACT frequency include reducing imaging dose and optimizing patient time and staff resources.

The evaluation of NIR-absorbing porphyrin derivatives as contrast agents in photoacoustic imaging.

Six free base tetrapyrrolic chromophores, three quinoline-annulated porphyrins and three morpholinobacteriochlorins, that absorb light in the near-IR range and possess, in comparison to regular porphyrins, unusually low fluorescence emission and (1)O2 quantum yields were tested with respect to their efficacy as novel molecular photo-acoustic imaging contrast agents in a tissue phantom, providing an up to ∼2.5-fold contrast enhancement over that of the benchmark contrast agent ICG. The testing protocol compares the photoacoustic signal output strength upon absorption of approximately the same light energy. Some relationships between photophysical parameters of the dyes and the resulting photoacoustic signal strength could be derived.

Multimodal Imaging of Pancreatic Cancer Microenvironment in Response to an Antiglycolytic Drug.

Lipid metabolism and glycolysis play crucial roles in the progression and metastasis of cancer, and the use of 3-bromopyruvate (3-BP) as an antiglycolytic agent has shown promise in killing pancreatic cancer cells. However, developing an effective strategy to avoid chemoresistance requires the ability to probe the interaction of cancer drugs with complex tumor-associated microenvironments (TAMs). Unfortunately, no robust and multiplexed molecular imaging technology is currently available to analyze TAMs. In this study, the simultaneous profiling of three protein biomarkers using SERS nanotags and antibody-functionalized nanoparticles in a syngeneic mouse model of pancreatic cancer (PC) is demonstrated. This allows for comprehensive information about biomarkers and TAM alterations before and after treatment. These multimodal imaging techniques include surface-enhanced Raman spectroscopy (SERS), immunohistochemistry (IHC), polarized light microscopy, second harmonic generation (SHG) microscopy, fluorescence lifetime imaging microscopy (FLIM), and untargeted liquid chromatography and mass spectrometry (LC-MS) analysis. The study reveals the efficacy of 3-BP in treating pancreatic cancer and identifies drug treatment-induced lipid species remodeling and associated pathways through bioinformatics analysis.

Proton beam therapy can achieve lower vertebral bone marrow dose than photon beam therapy during chemoradiation therapy of esophageal cancer.

Chemoradiation therapy plays an important role in both the neoadjuvant and definitive management of esophageal cancer (EC). Prior studies have suggested that advanced planning techniques can better spare organs at risk including the heart. Although multiple toxicities can result from esophageal radiotherapy, one less studied acute toxicity is that of myelosuppression, which can result, in part, from the combination of chemotherapy and incidental radiotherapy administration to the vertebral bodies (VBs), which abut the posterior aspect of the esophagus, especially in the lower thoracic esophagus. Traditionally, VB bone marrow doses are not accounted during EC radiation therapy planning. We sought to compare the doses to VBs between proton and photon radiation therapy as part of chemoradiation therapy for EC treatment. By reducing doses to the vertebrae, radiation therapy can decrease treatment-related myelosuppression, which can avoid delays or chemotherapy dose reductions in therapy, which likely affect long-term patient survival. Dose constraints are not routinely employed for bone marrow in radiation treatment planning. In our previous work, we identified thresholds to avoid grade ≥3 leukopenia, including VB V10Gy, VB V20Gy, and a mean VB dose (MVD) of 18.8 Gy. Herein we perform a retrospective dosimetric planning study comparing passive- or double-scattering proton beam therapy (PS-PBT), volumetric-modulated arc therapy (VMAT) (photon-based), and intensity-modulated radiation therapy (IMRT) (photon-based) in 25 patients with locally advanced EC who were treated originally with photon RT at our institution between 2011 and 2016. The aforementioned dose constraints were included in the retrospective planning process for PS-PBT, VMAT, and IMRT to determine the feasibility of achieving these VB constraints while maintaining reasonable target coverage and planned, consistent constraints to other organs at risk including lungs, spinal cord, and stomach. PS-PBT plans were found to achieve lower doses for VB V10Gy, V20Gy, and MVD than VMAT and static IMRT plans while achieving the same target coverage. PS-PBT resulted in lower organs at risk dosimetric parameters than the photon plans, with p < 0.0001. Student's paired t-test p-values in favor of proton therapy's ability to spare organs were as follows: for PS-PBT vs VMAT and PS-PBT vs IMRT in mean doses for lung, liver, and VB and VB V10Gy and VB V20Gy were all <0.001 (Bonferroni corrected α=0.017). One-way ANOVA found that VB doses (VB V10Gy, VB V20Gy, and MVD) were significantly lower for proton therapy (p < 0.006) among the 3 planning techniques.

Variation of V105% between pre- and postmerged subfields in field-in-field hypofractionated breast radiotherapy plans.

Hypofractionated whole-breast irradiation has emerged as a viable alternative to conventional fractionation. In the field-in-field forward planning technique, a merged plan with 2 to 4 segmental fields is the final plan delivered to the machine. As per the ASTRO guidelines for the hypofractionation regimen, the volume of breast tissue receiving V105% of the prescription dose should be less than 200 cc. However, we have noticed substantial changes to this volume (change in V105% between -55 cc and + 47.1 cc) after merging the subfields. This study compares the V105% of 29 breast plans before and after merging the subfields.

In vivo longitudinal imaging of RNA interference-induced endocrine therapy resistance in breast cancer.

Endocrine therapy resistance in breast cancer is a major obstacle in the treatment of patients with estrogen receptor-positive (ER+) tumors. Herein, we demonstrate the feasibility of longitudinal, noninvasive and semiquantitative in vivo molecular imaging of resistance to three endocrine therapies by using an inducible fluorescence-labeled short hairpin RNA (shRNA) system in orthotopic mice xenograft tumors. We employed a dual fluorescent doxycycline (Dox)-regulated lentiviral inducer system to transfect ER+ MCF7L breast cancer cells, with green fluorescent protein (GFP) expression as a marker of transfection and red fluorescent protein (RFP) expression as a surrogate marker of Dox-induced tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) knockdown. Xenografted MCF7L tumor-bearing nude mice were randomized to therapies comprising estrogen deprivation, tamoxifen or an ER degrader (fulvestrant) and an estrogen-treated control group. Longitudinal imaging was performed by a home-built multispectral imaging system based on a cooled image intensified charge coupled device camera. The GFP signal, which corresponds to number of viable tumor cells, exhibited excellent correlation to caliper-measured tumor size (P << .05). RFP expression was substantially higher in mice exhibiting therapy resistance and strongly and significantly (P < 1e-7) correlated with the tumor size progression for the mice with shRNA-induced PTEN knockdown. PTEN loss was strongly correlated with resistance to estrogen deprivation, tamoxifen and fulvestrant therapies.

Vertebral body irradiation during chemoradiation therapy for esophageal cancer contributes to acute bone marrow toxicity.

BACKGROUND: Hematologic toxicity (HT) commonly occurs during chemoradiation therapy (CRT) for esophageal cancer. We sought to determine radiation doses that correlate with declines in blood counts due to vertebral body (VB) irradiation during CRT. METHODS: We analyzed 53 esophageal cancer patients who were treated with weekly neoadjuvant carboplatin, paclitaxel and RT with weekly complete blood counts (CBC) available during treatment. HTs were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Dose volume histogram (DVH) parameters of Vx, defined as percentage of entire bony vertebra (body, pedicles, laminae, processes) receiving at least x Gy of radiation, were collected for VB V5 (VBV5), VBV10-VBV60 in increments of 10, and mean vertebral dose (MVD). Linear and logistic regressions were performed to identify associations between leukopenia nadirs and DVH parameters. Receiver operator curves identified thresholds to avoid grade ≥3 leukopenia. RESULTS: A proportion of 32.1% of patients (n=17) developed grade 3 leukopenia and 5.7% (n=3) developed grade 4 leukopenia. VBV5, VBV10, VBV20, VBV30, and MVD were significantly associated with worsening leukopenia on univariate and multivariate analysis. Associations with leukopenia were not seen with VBV40 and VBV50 DVH values. Thresholds to avoid grade ≥3 leukopenia were VBV10 <49.1%, VBV20 <45.6%, and MVD <17.2 Gy. CONCLUSIONS: VBV5, VBV10, VBV20, VBV30 associate with leukopenia during CRT for esophageal cancer patients. Improved radiation sparing of the VB may decrease HT and may improve tolerability of concurrent chemotherapy and allow for intensification of systemic therapy during RT.

Wavelet-based characterization of spectral fluctuations in normal, benign, and cancerous human breast tissues.

Fluorescence intensity fluctuations in the visible wavelength regime in normal, benign, and cancerous human breast tissue samples are studied through wavelet transform. The analyses have been carried out in unpolarized, parallel and perpendicularly polarized channels, for optimal tissue characterization. It has been observed that polarized fluorescence data, particularly the perpendicular components, differentiate various tissue types quite well. Wavelet transform, because of its ability for multiresolution analysis, provides the ideal tool to separate and characterize fluctuations in the fluorescence spectra at different scales. We quantify these differences and find that the fluctuations in the perpendicular channel of the cancerous tissues are more randomized as compared to their normal counterparts. Furthermore, for cancerous tissues, the same is very well described by the normal distribution, which is not the case for normal and benign samples. It has also been observed that, up to a certain point, fluctuations at larger scales are more sensitive to tissue types. The differences in the average, low-pass wavelet coefficients of normal, cancerous, pericanalicular, and intracanalicular benign tissues are also pointed out.

Recovery of turbidity free fluorescence from measured fluorescence: an experimental approach.

Fluorescence from fluorophores embedded in a turbid medium like biological tissue gets strongly modulated by the wavelength dependent absorption and scattering properties of tissue. This makes it extremely difficult to extract valuable biochemical information from tissue which is present in the intrinsic line shape and intensity of fluorescence from tissue fluorophores. We present an experimental approach to remove the distorting effect of scattering and absorption on intrinsic fluorescence of fluorophores embedded in a turbid medium like tissue. The method is based on simultaneous measurement of polarized fluorescence and polarized elastic scattering spectra from a turbid medium. The polarized fluorescence normalized by the polarized elastic scattering spectra (in the wavelength range of fluorescence emission) was found to be free from the distorting effect of absorption and scattering properties of the medium. The applicability range of this technique to recover intensity and line shape information of intrinsic fluorescence has been investigated by carrying out studies on a variety of tissue phantoms having different absorption and scattering properties. The results obtained show that this technique can be used to recover intrinsic line shape and intensity information of fluorescence from fluorophores embedded in a scattering medium for the range of optical transport parameters typically found in biological tissue.

Targeting pancreatic cancer with magneto-fluorescent theranostic gold nanoshells.

AIM: We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase-associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. MATERIALS & METHODS: Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the near-infrared (NIR) dye indocyanine green, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1-derived xenografts in nude mice. RESULTS: Anti-NGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2-weighted MRI with higher tumor contrast than can be obtained using long-circulating, but nontargeted, PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. CONCLUSION: TGNS with embedded NIR and magnetic resonance contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy.

Characteristic spectral features of the polarized fluorescence of human breast cancer in the wavelet domain.

Wavelet transform of polarized fluorescence spectra of human breast tissues is found to localize spectral features that can reliably differentiate normal and malignant tissue types. The intensity differences of parallel and perpendicularly polarized fluorescence spectra are subjected to investigation, since they are relatively free of diffusive background. A number of parameters, capturing spectral variations and subtle changes in the diseased tissues in the visible wavelength regime, are clearly identifiable in the wavelet domain. These manifest both in the average low-pass and high frequency high-pass wavelet coefficients.

Imaging tumor oxyhemoglobin and deoxyhemoglobin concentrations with ultrasound-guided diffuse optical tomography.

We present an ultrasound (US)-guided diffuse optical tomography for mapping tumor deoxyhemoglobin (deoxyHb) and oxyhemoglobin (oxyHb) concentrations in blood phantoms and in in-vivo patients. Because oxyHb and deoxyHb respond differently at different wavelengths, four laser diodes of wavelengths 740 nm, 780 nm, 808 nm and 830 nm were used in the study. Tumor model experiments were performed using phantoms of different hemoglobin oxygen saturations (14%-89%) representing hemoglobin oxygenation in tissue. Targets of different sizes and located at different depths were used to validate the accuracy of oxygen saturation estimation. The absolute deviations between the estimated hemoglobin oxygen saturations obtained from reconstructed absorption maps and oxygen measurements obtained using a pO2 electrode were less than 8% over the measured range of oxygen saturation. An inhomogeneous concentric blood phantom of deoxygenated center core and oxygenated outer shell was imaged and deoxyHb and oxyHb maps revealed corresponding distributions which correlated well with inhomogeneous deoxy- and oxy- distributions frequently seen in breast cancers. Clinical examples are given to demonstrate the utility of US-guided optical tomography in mapping heterogeneous deoxyHb and oxyHb distributions in breast cancers.

Artifact reduction method in ultrasound-guided diffuse optical tomography using exogenous contrast agents.

In diffuse optical tomography (DOT), a typical perturbation approach requires two sets of measurements obtained at the lesion breast (lesion or target site) and a contra-lateral location of the normal breast (reference site) for image reconstruction. For patients who have a small amount of breast tissue, the chest-wall underneath the breast tissue at both sites affects the imaging results. In this group of patients, the perturbation, which is the difference between measurements obtained at the lesion and reference sites, may include the information of background mismatch which can generate artifacts or affect the reconstructed quantitative absorption coefficient of the lesion. Also, for patients who have a single breast due to prior surgery, the contra-lateral reference is not available. To improve the DOT performance or overcome its limitation, we introduced a new method based on an exogenous contrast agent and demonstrate its performance using animal models. Co-registered ultrasound was used to guide the lesion localization. The results have shown that artifacts caused by background mismatch can be reduced significantly by using this new method.