Summary 15-Deoxy-∆ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) was initially identified as a high affinity natural ligand for the peroxisome proliferator-activated receptor (PPAR)-γ . Recent studies have shown that it has a potent antiinflammatory effect by attenuating the expression of proinflammatory mediators in activated macrophages, mainly through the inhibition of nuclear factor (NF)-κ B-dependent transcription of inflammatory genes. In this study, we investigated the synergistic effect of 15d-PGJ 2 on the expression of LPS-induced chemokine KC mRNA in mouse peritoneal macrophages. The time course of KC mRNA expression in cells stimulated with 15d-PGJ 2 plus LPS simultaneously (15d-PGJ 2 /LPS) showed similar patterns to the cells treated with LPS alone, and 15d-PGJ 2 had no effect on the stability of LPS-induced KC mRNA expression. Although NF-κ B activity in cells treated with LPS was augmented by 15d-PGJ 2 , pyrrolidone dithiocarbamate (PDTC) did not block the synergistic effect of 15d-PGJ 2 on LPS-induced KC mRNA expression. However, the synergistic effect of 15d-PGJ 2 was markedly inhibited when the macrophages were treated with a inhibitor of the mitogen-activated protein kinase (MAPK) signalling pathway, 2 ′ -amino-3 ′ -methoxyflavine (PD98059). Therefore, the mechanism of synergistic action of 15d-PGJ 2 on the expression of LPS-induced KC mRNA in mouse peritoneal macrophages is possibly related to the MAPK signalling pathway, not to NF-κ B activation. These data may contribute to unravelling some of the different mechanisms contrary to the anti-inflammatory effect of 15d-PGJ 2 .
Background: Optical based imaging modalities have shown promise for monitoring tumor response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. In this study, we evaluate whether changes in deoxy-hemoglobin concentration values acquired by a Diffuse Optical Tomography Breast Imaging System (DOTBIS) over different time points are associated with tumor response. Methods: This is a retrospective evaluation of 55 stage II-III BC patients in the neoadjuvant setting who received weekly paclitaxel x 12, followed by dose-dense adriamycin/cyclophosphamide every 2 weeks x 4. The patients were enrolled in this cohort study between 2011 and 2019, and DOTBIS images were acquired from the patient whole breast volume at 6 different time points: at baseline (TP0); two weeks after the first taxane infusion (TP1); after four infusions of taxane (TP2); at the end of the taxane regimen and before starting AC cycle (TP3); after two AC infusions (TP4); and at the end of NAC and before surgery (TP5). ctHHb tumor concentration was measured using low-intensity near-infrared light and normalized by the non-tumor region ctHHb mean value (ctHHbN). In order to evaluate whether pCR status, menopausal status, and molecular subtype classification influence the change of ctHHbN over time, we designed a multilevel mixed-effect statistical model. pCR was defined as no invasive tumor cells from the breast and axillary tissue at surgery (ypT0 ypN0). Results: 20 patients had pCR and 35 were classified as non-pCR. The estimate average ctHHbN for pCR tumors at baseline was 4.02. There was a significant reduction in ctHHbN levels for pCR group at TP1 (-1.31, p = .0001) and TP2 (-1.36, p = .0416). Changes in ctHHbN levels compared to baseline (TP0) values were statistically significant different between pCR and non-pCR at all time points except at the end of the taxane cycle (TP3), Table 1. No significant changes over time were identified between molecular subtypes groups, or between pre- and post-menopausal status. Conclusions: Our study adds to the body of evidence reported for diffuse optical imaging methods applied to breast cancer treatment response. These results show that DOTBIS measured features, such as ctHHbN, change in accordance with pCR status after 2 weeks under NAC, and there are differences in time evolution between the pCR groups. Reduction in ctHHbN levels represents the chemotherapeutic- induced changes in the tumor microvasculature: lower ctHHbN values associate with the reduction in tumor cell proliferation, and consequently in oxygen consumption. Future studies are warranted to evaluate whether early response prediction might determine if earlier treatment changes alter patient outcome. Table 1 - Changes in ctHHbN levels compared to baseline (TP0) values between pCR and non-pCR at all imaging time points. Bold values indicate statistical significance at p <.05 level.Time PointMean Difference ± Std. Errorp-valueTP11.92 ± 0.400.0000TP22.04 ± 0.820.0145TP30.83 ± 1.030.4198TP42.71 ± 0.870.0021TP52.63 ± 0.900.0037 Citation Format: Mirella L Altoe, Kevin Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Monitoring neoadjuvant chemotherapy using diffuse optical tomography breast imaging system [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-10.
Background: Optical based imaging modalities have shown promise for monitoring tumor response to neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC). Patients with triple negative BC (TNBC) who achieve a pathologic complete response (pCR) have improved disease free and overall survival after NAC. In this study, we evaluated whether early changes in diffuse optical tomography breast imaging system (DOTBIS) parameters can predict a pCR. In particular, we studied total hemoglobin concentration (ctHbT) in the tumor region. Methods: This is a retrospective evaluation of 105 stage II-III BC patients enrolled in a prospective cohort study between 2011 and 2019. All patients received standard taxane-based chemotherapy in the neoadjuvant setting and pCR was defined as no invasive tumor cells from the breast and axillary tissue at surgery (ypT0 ypN0). Residual Cancer Burden (RCB) score was also calculated. By imaging the whole breast volume using low intensity near infrared light, we measured tissue concentration of oxy-hemoglobin (ctO2Hb) and deoxy-hemoglobin (ctHHb). After tumor volume segmentation, the mean ctHbT (ctO2Hb+ ctHHb) extracted from the region of interest was normalized by the non-tumor region ctHbT mean value. We conducted an independent-samples t-test to determine if there was a difference in changes in the normalized ctHbT levels at week 4 (w4) between patients with a pCR and non-pCR. A Pearson's correlation assessed for correlation between RCB score and changes in the normalized ctHbT level at w4 compared to baseline. Results: In total, 77 patients had complete data for the analysis. Of these, TNBC accounted for 18% (14/77) of BC cases. DOTBIS data was acquired at baseline for all patients. Twelve patients received weekly paclitaxel x 12, followed by dose-dense adriamycin/cyclophosphamide every 2 weeks x 4, and two received docetaxel/cyclophosphamide every 3 weeks x 6. Ten of 14 TNBC patients were imaged after four weeks of taxane-based NAC (w4). Of the 14 TNBC patients, 6 (43%) achieved pCR. Two patients were classified as RCB-I, 5 as RCB-II, and 1 non-pCR patient without an available RCB. After comparing normalized ctHbT levels at w4 to baseline, NAC was associated with an overall decrease of 28% for the pCR group (n=5) as opposed to an increase of 67% for non-pCR (n=5). The normalized ratio between ctHbT levels measured at w4 and baseline was statistically lower in the pCR group (0.72 ± 0.28) than non-pCR (1.67 ± 0.83) (95% CI, 0.17 to 2.09), p = .043. Changes in the normalized ctHbT levels after 4 weeks of NAC were strongly correlated to RCB score (r = .833, p = .005). Conclusions: This study demonstrates that changes as early as 4 weeks in DOTBIS-measured ctHbT levels in patients with TNBC receiving NAC correlate strongly with pathologic response. If further validated on a larger set, these data could potentially be used to optimize treatment outcomes or improve personalized therapeutic strategies. Citation Format: Mirella L Altoe, Kevin Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Early changes in diffuse optical tomography predicts pathologic complete response to neoadjuvant chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-02.
Background: Optical-based imaging modalities play an important role in assessing breast tissue composition by measuring optical property contrast from endogenous chromophores. The advantages of optical techniques are the use of non-ionizing radiation, ease of use, and relatively low cost. The primary objective of this study is to examine changes in optically derived parameters (i.e., deoxy-hemoglobin concentration, ctHHb) from different breast cancer subtypes under neoadjuvant chemotherapy (NAC), and correlate with tumor pathologic complete response (pCR). Methods: This retrospective study evaluated 89 tumors in total divided into three distinct subtypes: HR+/HER2- (n=34), HER2+ (n=27), and TNBC (n=28). All patients were imaged at baseline, before starting NAC (TP0), and two weeks after receiving one cycle of taxane-based chemotherapy (TP1). HER2+ breast cancer patients also received HER2-target therapy. pCR was defined as complete absence of invasive carcinoma in the breast and lymph node(s) (ypT0/is ypN0 Mx) at the time of surgery. Whole breast volume was imaged by a diffuse optical tomography breast imaging system (DOTBIS) using low-intensity near-infrared light. ctHHb tumor volume concentration was normalized by the non-affected health tissue ctHHb mean value (ctHHbN). For each molecular subgroup, we conducted an independent-samples t-test to determine if there was a difference in ctHHbN levels at TP1 compared to TP0 between patients with a pCR and non-pCR. Significance was assumed at a confidence interval of 95% (α = 0.05). Results: In total, 69 patients were imaged with DOTIBS at both time points, TP0 and TP1. HR+/HER2-, TNBC and HER2+ accounted for 32% (n=23), 37% (n=22) and 30% (n=22), respectively. The ratio between ctHHbN levels measured at TP1 and TP0 was statistically significantly lower in the pCR group than non-pCR for the HER2+ and HR+/HER2- molecular subgroups, Table 1. Conclusion: Aligned to the current practices in breast cancer management based on the characterization of breast cancer subtypes, our work evaluated changes in DOTBIS optically derived features and pCR status for different subtypes. We observed that ctHHbN levels change after two weeks of NAC and these changes are modifiable according to pCR status and are dependent on immunophenotype. Table 1.Ratio between ctHHbN levels measured at TP1 and TP0 between pCR and non-pCR according to different molecular subtypes.Molecular SubtypepCR (mean ± SD )non-pCR (mean ± SD )p-valueHR+/HER2- (n=23)0.77 ± 0.22 (n=6)1.14 ± 0.24 (n=17).01HER2+ (n=24)0.74 ± 0.30 (n=15)1.54 ± 0.98 (n=9).04TNBC (n=22)0.96 ± 0.38 (n=4)1.29 ± 0.37 (n=18).18Bold values indicate statistical significance at p<.05 level. Citation Format: Mirella L Altoe, Kevin M Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Prediction of breast cancer response to neoadjuvant chemotherapy in different biological breast cancer subtypes using diffuse optical tomography [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-04.
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