A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells.

Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC50 value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1-5 µM) significantly increased TNF-α mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHC-II and CD86 and the mRNA expression of TNF-α, IL-6 and IL-12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs.

Moderately Hypofractionated Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost for Prostate Cancer: Five-Year Toxicity Results From a Prospective Phase I/II Trial.

BACKGROUND: In this phase I/II trial, 5-year physician-assessed toxicity and patient reported quality of life data is reported for patients undergoing moderately hypofractionated intensity modulated radiation therapy (IMRT) for prostate cancer using a simultaneous integrated boost (SIB) and pelvic lymph node (LN) coverage. MATERIALS AND METHODS: Patients with T1-T2 localized prostate cancer were prospectively enrolled, receiving risk group based coverage of prostate ± seminal vesicles (SVs) ± pelvic lymph nodes (LNs). Low risk (LR) received 69.6 Gy/29 fractions to the prostate, while intermediate risk (IR) and high risk (HR) patients received 72 Gy/30fx to the prostate and 54Gy/30fx to the SVs. If predicted risk of LN involvement >15%, 50.4 Gy/30fx was delivered to pelvic LNs. Androgen deprivation therapy was given to IR and HR patients. RESULTS: There were 55 patients enrolled and 49 patients evaluable at a median follow up of 60 months. Included were 11 (20%) LR, 23 (41.8%) IR, and 21 (38.2%) HR patients. Pelvic LN treatment was given in 25 patients (51%). Prevalence rates of late grade 2 GI toxicity at 1, 3, and 5 years was 5.8, 3.9, and 5.8%, respectively, with no permanent grade 3 events. Prevalence rates of late grade 2 GU toxicity at 1, 3, and 5 years rates were 15.4, 7.7, and 13.5%, respectively, with three grade 3 events (5.8%). The biochemical relapse free survival at 5 years was 88.3%. There were no local, regional, or distant failures, with all patients still alive at last follow up. CONCLUSION: Moderate hypofractionation of localized prostate cancer utilizing a SIB technique and LN coverage produces tolerable acute/late toxicity. Given equivalent efficacy between moderate hypofractionation schedules, the optimal regimen will be determined by long-term toxicity reported from both the physician and patient perspective. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT01117935, Date of Registration: 5/6/2010.

Phase 1/2 study of hypofractionated intensity-modulated radiation therapy for prostate cancer including simultaneously integrated boost.

PURPOSE: This study evaluates the safety and efficacy of moderately hypofractionated radiation therapy (RT) with simultaneous integrated boost (HSIB) intensity modulated RT (IMRT) that includes coverage of the seminal vesicles (SVs) and pelvic lymph nodes (LNs). METHODS AND MATERIALS: Men with localized prostate cancer were prospectively enrolled in a phase 1/2 trial to receive HSIB-IMRT to the prostate, ± SV, ± pelvic LN using a risk-based method. Low-risk patients received 69.6 Gy to only the prostate in 29 fractions. Intermediate-risk (IR) and high-risk (HR) patients received 30 fractions with 72 Gy to the prostate, 54 Gy to the SV, and 50.4 Gy to the pelvic LN when risk of LN involvement exceeded 15% by the Roach formula. IR and HR patients received androgen deprivation therapy. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated with patient- and physician-reported surveys. RESULTS: Fifty-five men were enrolled, and 49 had at least 1 year of follow-up with 19.2% low-risk, 40.4% IR, and 40.4% HR disease. The median age was 69 years; median follow-up time was 36.9 months. Twenty-six patients received pelvic nodal HSIB-IMRT. At 2 years, the cumulative incidence of physician-reported late grade 2+ GU and GI toxicity was 32.6% and 18.4% respectively. At 2 years, only 10.2% grade 2+ GU toxicities and 2.0% grade 2+ GI toxicities remained unresolved. At last follow-up, the prevalence of unresolved physician-reported late grade 2+ GU and GI toxicity was 4.1% and 0%. The median patient-reported American Urologic Association-International Prostate Symptom Score fell from 10 at baseline to 7.5 at 2 years. The 3-year biochemical relapse-free survival rate for the cohort was 96%. CONCLUSIONS: HSIB-IMRT with risk-based nodal coverage results in excellent biochemical control. Although the cumulative incidence of physician-reported GU toxicity was higher than anticipated, late GI and GU toxicity was relatively transient.

Variabilities of Magnetic Resonance Imaging-, Computed Tomography-, and Positron Emission Tomography-Computed Tomography-Based Tumor and Lymph Node Delineations for Lung Cancer Radiation Therapy Planning.

PURPOSE: To investigate interobserver delineation variability for gross tumor volumes of primary lung tumors and associated pathologic lymph nodes using magnetic resonance imaging (MRI), and to compare the results with computed tomography (CT) alone- and positron emission tomography (PET)-CT-based delineations. METHODS AND MATERIALS: Seven physicians delineated the tumor volumes of 10 patients for the following scenarios: (1) CT only, (2) PET-CT fusion images registered to CT ("clinical standard"), and (3) postcontrast T1-weighted MRI registered with diffusion-weighted MRI. To compute interobserver variability, the median surface was generated from all observers' contours and used as the reference surface. A physician labeled the interface types (tumor to lung, atelectasis (collapsed lung), hilum, mediastinum, or chest wall) on the median surface. Contoured volumes and bidirectional local distances between individual observers' contours and the reference contour were analyzed. RESULTS: Computed tomography- and MRI-based tumor volumes normalized relative to PET-CT-based volumes were 1.62 ± 0.76 (mean ± standard deviation) and 1.38 ± 0.44, respectively. Volume differences between the imaging modalities were not significant. Between observers, the mean normalized volumes per patient averaged over all patients varied significantly by a factor of 1.6 (MRI) and 2.0 (CT and PET-CT) (P=4.10 × 10-5 to 3.82 × 10-9). The tumor-atelectasis interface had a significantly higher variability than other interfaces for all modalities combined (P=.0006). The interfaces with the smallest uncertainties were tumor-lung (on CT) and tumor-mediastinum (on PET-CT and MRI). CONCLUSIONS: Although MRI-based contouring showed overall larger variability than PET-CT, contouring variability depended on the interface type and was not significantly different between modalities, despite the limited observer experience with MRI. Multimodality imaging and combining different imaging characteristics might be the best approach to define the tumor volume most accurately.

Apparent diffusion coefficient (ADC) change on repeated diffusion-weighted magnetic resonance imaging during radiochemotherapy for non-small cell lung cancer: A pilot study.

OBJECTIVES: Serial diffusion-weighted magnetic resonance imaging (DW-MRI) during radiochemotherapy of non-small cell lung cancer (NSCLC) is analyzed to investigate the apparent diffusion coefficient (ADC) as a potential biomarker for tumor response. METHODS: Ten patients underwent DW-MRI prior to and at three and six weeks during radiochemotherapy. Three methods of contouring primary tumors (PT) were performed to evaluate the impact of tumor heterogeneity on ADC values: PTT: whole tumor volume; PTT-N: PTT-necrosis; PTL: small volume of presumed active tumor with low ADC value. Pretreatment and during-treatment absolute ADC values and ADC value changes were analyzed for PT and involved lymph nodes (LN). RESULTS: ADC values for PTT, PTT-N, PTL and LN increased by 8-14% (PT) and 15% (LN) at three weeks, and 19-26% and 23% at 6 weeks post initial treatment (p=0.04-0.002). Average percent ADC value increase was smaller than tumor volume regression (p=0.06-0.0005). Patients with overall survival <12 months had a lower increase of ADC values compared to longer surviving patients (p=0.008 for PTT). CONCLUSIONS: Significant ADC value increases during radiochemotherapy for non-small cell lung cancer were observed. ADC value change during treatment appears to be an independent marker of patient outcome and warrants further investigation.

Patient-reported outcomes after electron radiation treatment for early-stage palmar and plantar fibromatosis.

PURPOSE: Palmar and plantar fibromatosis (PPF) is a progressive connective tissue disorder of the hand/foot that often leads to debilitating functional impairment. In Europe, orthovoltage radiation therapy (RT) has been demonstrated to prevent local disease progression for up to 80% of patients with early-stage PPF. There are limited data reporting outcomes for populations outside of Europe or using electron RT. METHODS AND MATERIALS: Between 2008 and 2013, 44 early-stage PPF cases received RT. RT fields involved clinically defined targets encompassing involved areas (skin changes, cords, nodules) with at least 1.5-cm margins. En face electrons (6-12 MeV) and bolus (0.5-1 cm) were selected individually. Outcomes are reported for patients who participated in an institutional review board-approved standardized questionnaire and chart review. RESULTS: Thirty-three patients received 66 treatments (45 hands/15 feet and 6 reirradiations). Most frequent dose schemes were 21 Gy (3 Gy in 7 fractions) and 30 Gy (3 Gy in 10 fractions with 6- to 8-week breaks after 15 Gy). Median time to follow-up survey was 31 months. Disease progression at any location within or outside the RT treatment field occurred in 20 of 33 patients (61%). Fourteen of 60 sites (23%) developed in-field progression, but 4 sites were successfully reirradiated with final local control in 50 of 60 sites (83%). RT improved pretreatment symptoms of pain with strain at 30 of 37 sites (81%) and itch/burn sensations at 17 of 21 sites (81%). There were no reported grade ≥2 late toxicities even with reirradiation. Patient reported overall success with treatment was 31 of 33 patients (94%). CONCLUSION: PPF is a progressive disease. En face electron RT is an effective therapy that stabilizes or improves symptoms in the majority of patients. Reirradiation can be considered as a treatment option for in-field progression. Patients report minimal toxicity and a high rate of satisfaction with treatment.

Estimation of optimal b-value sets for obtaining apparent diffusion coefficient free from perfusion in non-small cell lung cancer.

The purpose of this study was to determine optimal sets of b-values in diffusion-weighted MRI (DW-MRI) for obtaining monoexponential apparent diffusion coefficient (ADC) close to perfusion-insensitive intravoxel incoherent motion (IVIM) model ADC (ADCIVIM) in non-small cell lung cancer. Ten subjects had 40 DW-MRI scans before and during radiotherapy in a 1.5 T MRI scanner. Respiratory triggering was applied to the echo-planar DW-MRI with TR ≈ 4500 ms, TE = 74 ms, eight b-values of 0-1000 µs µm(-2), pixel size = 1.98 × 1.98 mm(2), slice thickness = 6 mm, interslice gap = 1.2 mm, 7 axial slices and total acquisition time ≈6 min. One or more DW-MRI scans together covered the whole tumour volume. Monoexponential model ADC values using various b-value sets were compared to reference-standard ADCIVIM values using all eight b-values. Intra-scan coefficient of variation (CV) of active tumour volumes was computed to compare the relative noise in ADC maps. ADC values for one pre-treatment DW-MRI scan of each of the 10 subjects were computed using b-value pairs from DW-MRI images synthesized for b-values of 0-2000 µs µm(-2) from the estimated IVIM parametric maps and corrupted by various Rician noise levels. The square root of mean of squared error percentage (RMSE) of the ADC value relative to the corresponding ADCIVIM for the tumour volume of the scan was computed. Monoexponential ADC values for the b-value sets of 250 and 1000; 250, 500 and 1000; 250, 650 and 1000; 250, 800 and 1000; and 250-1000 µs µm(-2) were not significantly different from ADCIVIM values (p > 0.05, paired t-test). Mean error in ADC values for these sets relative to ADCIVIM were within 3.5%. Intra-scan CVs for these sets were comparable to that for ADCIVIM. The monoexponential ADC values for other sets-0-1000; 50-1000; 100-1000; 500-1000; and 250 and 800 µs µm(-2) were significantly different from the ADCIVIM values. From Rician noise simulation using b-value pairs, there was a wide range of acceptable b-value pairs giving small RMSE of ADC values relative to ADCIVIM. The pairs for small RMSE had lower b-values as the noise level increased. ADC values of a two b-value set-250 and 1000 µs µm(-2), and all three b-value sets with 250, 1000 µs µm(-2) and an intermediate value approached ADCIVIM, with relative noise comparable to that of ADCIVIM. These sets may be used in lung tumours using comparatively short scan and post-processing times. Rician noise simulation suggested that the b-values in the vicinity of these experimental best b-values can be used with error within an acceptable limit. It also suggested that the optimal sets will have lower b-values as the noise level becomes higher.

3D dose verification using tomotherapy CT detector array.

PURPOSE: To evaluate a three-dimensional dose verification method based on the exit dose using the onboard detector of tomotherapy. METHODS AND MATERIALS: The study included 347 treatment fractions from 24 patients, including 10 prostate, 5 head and neck (HN), and 9 spinal stereotactic body radiation therapy (SBRT) cases. Detector sonograms were retrieved and back-projected to calculate entrance fluence, which was then forward-projected on the CT images to calculate the verification dose, which was compared with ion chamber and film measurement in the QA plans and with the planning dose in patient plans. RESULTS: Root mean square (RMS) errors of 2.0%, 2.2%, and 2.0% were observed comparing the dose verification (DV) and the ion chamber measured point dose in the phantom plans for HN, prostate, and spinal SBRT patients, respectively. When cumulative dose in the entire treatment is considered, for HN patients, the error of the mean dose to the planning target volume (PTV) varied from 1.47% to 5.62% with a RMS error of 3.55%. For prostate patients, the error of the mean dose to the prostate target volume varied from -5.11% to 3.29%, with a RMS error of 2.49%. The RMS error of maximum doses to the bladder and the rectum were 2.34% (-4.17% to 2.61%) and 2.64% (-4.54% to 3.94%), respectively. For the nine spinal SBRT patients, the RMS error of the minimum dose to the PTV was 2.43% (-5.39% to 2.48%). The RMS error of maximum dose to the spinal cord was 1.05% (-2.86% to 0.89%). CONCLUSIONS: An excellent agreement was observed between the measurement and the verification dose. In the patient treatments, the agreement in doses to the majority of PTVs and organs at risk is within 5% for the cumulative treatment course doses. The dosimetric error strongly depends on the error in multileaf collimator leaf opening time with a sensitivity correlating to the gantry rotation period.