Early Pathological Response Research Articles

MRI-based tumor shrinkage patterns after early neoadjuvant therapy in breast cancer: correlation with molecular subtypes and pathological response after therapy

BackgroundMRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze the relationship between TSP after early NAT and pathological response after therapy in different molecular subtypes.MethodsWe prospectively enrolled participants with invasive ductal breast cancers who received NAT and performed pretreatment DCE-MRI from September 2020 to August 2022. Early-stage MRIs were performed after the first (1st-MRI) and/or second (2nd-MRI) cycle of NAT. Tumor shrinkage patterns were categorized into four groups: concentric shrinkage, diffuse decrease (DD), decrease of intensity only (DIO), and stable disease (SD). Logistic regression analysis was performed to identify independent variables associated with pathologic complete response (pCR), and stratified analysis according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype.Results344 participants (mean age: 50 years, 113/345 [33%] pCR) with 345 tumors (1 bilateral) had evaluable 1st-MRI or 2nd-MRI to comprise the primary analysis cohort, of which 244 participants with 245 tumors had evaluable 1st-MRI (82/245 [33%] pCR) and 206 participants with 207 tumors had evaluable 2nd-MRI (69/207 [33%] pCR) to comprise the 1st- and 2nd-timepoint subgroup analysis cohorts, respectively. In the primary analysis, multivariate analysis showed that early DD pattern (OR = 12.08; 95% CI 3.34–43.75; p < 0.001) predicted pCR independently of the change in tumor size (OR = 1.37; 95% CI 0.94–2.01; p = 0.106) in HR+/HER2− subtype, and the change in tumor size was a strong pCR predictor in HER2+ (OR = 1.61; 95% CI 1.22–2.13; p = 0.001) and triple-negative breast cancer (TNBC, OR = 1.61; 95% CI 1.22–2.11; p = 0.001). Compared with the change in tumor size, the SD pattern achieved a higher negative predictive value in HER2+ and TNBC. The statistical significance of complete 1st-timepoint subgroup analysis was consistent with the primary analysis.ConclusionThe diffuse decrease pattern in HR+/HER2− subtype and stable disease in HER2+ and TNBC after early NAT could serve as additional straightforward and comprehensible indicators of treatment response.Trial registration: Trial registration at https://www.chictr.org.cn/. Registration number: ChiCTR2000038578, registered September 24, 2020.

Stereotactic MR-guided adaptive radiotherapy (SMART) for primary rectal cancer: evaluation of early toxicity and pathological response.

The purpose of this study is to measure the effects of stereotactic MR-guided adaptive radiotherapy (SMART) for rectal cancer patients in terms of early toxicity and pathological response. For this prospective pilot study, patients diagnosed with locally advanced rectal cancer (LARC) with positive lymph node clinical staging underwent SMART on rectal lesion and mesorectum using hybrid MR-Linac (MRIdian ViewRay). Dose prescription at 80% isodose for the rectal lesion and mesorectum was 40 Gy (8 Gy/fr) and 25 Gy (5 Gy/fr), respectively, delivered on 5 days (3 fr/week). Response assessment by MRI was performed 3 weeks after SMART, then patients fit for surgery underwent total mesorectal excision. Primary endpoint was evaluation of adverse effect of radiotherapy. Secondary endpoint was pathological complete response rate. Early toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). From October 2020 to January 2022, twenty patients underwent rectal SMART. No grade 3-5 toxicity was recorded. Twelve patients were eligible for total mesorectal excision (TME). Mean interval between the completion of SMART and surgery was 4 weeks. Pathological downstaging occurred in all patients; rate of pathological complete response (pCR) was 17%. pCR occurred with a prolonged time to surgery (> 7 weeks). To our knowledge, this is the first study to use stereotactic radiotherapy for primary rectal cancer. SMART for rectal cancer is well tolerated and effective in terms of tumor regression, especially if followed by delayed surgery.

Prediction of pathological response grading for esophageal squamous carcinoma after neoadjuvant chemoradiotherapy based on MRI imaging using PDX.

To confirm the efficacy of magnetic resonance-diffusion weighted imaging (MR-DWI) in esophageal squamous cell carcinoma (ESCC) early pathological response prediction and assessment to neoadjuvant chemoradiotherapy (nCRT) using patient-derived xenografts (PDXs). PDX-bearing mice were randomly divided into two groups: the experimental group receiving cisplatin combined with radiotherapy, whereas the control group receiving normal saline. MRI scans were performed in treatment groups in the before, middle, and end of treatment. The correlations between tumor volumes, ADC values and tumor pathological response at different time nodes were explored. Then, expression of proliferation marker and apoptotic marker were detected using immunohistochemistry, and apoptosis rate was detected by TUNEL assay to further verify the results observed in the PDX models. The ADC values of the experimental group were significantly higher than the control group in the both middle and end stage of treatment (all P< 0.001), however, significant difference was only observed in tumor volume at the end stage of treatment (P< 0.001). Furthermore, the △ADCmid-pre in our study may able to identify tumors with or without pCR to nCRT at an early stage, due to these changes were prior to the changes of tumor volume after treatment. Finally, TUNEL results also showed that the apoptosis rate of the experiment groups increased the most in the middle stage of treatment, especially the groups with pCR, but the highest apoptosis rate occurred in the end of the treatment. Further, the two PDX models with pCR exhibited the highest levels of apoptotic marker (Bax), and lowest levels of proliferation marker (PCNA and Ki-67) in the both middle and end stage of the treatment. ADC values could be used to determine the tumor's response to nCRT, especially in the middle stages of treatment and before the tumor tissue morphology changes, and further, the ADC values were consistent with the potential biomarkers reflecting histopathological changes. Therefore, we suggest that radiation oncologists could refer to the ADC values in the middle stages of treatment when predicting the tumor histopathological response to n CRT in patients with ESCC.

Quantitative Diffusion-Weighted Imaging Analyses to Predict Response to Neoadjuvant Immunotherapy in Patients with Locally Advanced Head and Neck Carcinoma.

Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. 32 patients with stage II-IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01-0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor's regression (p = 0.04, p = 0.02). Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation.

Altered Cellular Protein Quality Control System Modulates Cardiomyocyte Function in Volume Overload-Induced Hypertrophy.

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system.

Dynamic alteration in SULmax predicts early pathological tumor response and short-term prognosis in non-small cell lung cancer treated with neoadjuvant immunochemotherapy.

Introduction: Biomarkers predicting tumor response to neoadjuvant immunochemotherapy in non-small cell lung cancer (NSCLC) are still lacking despite great efforts. We aimed to assess the effectiveness of the immune PET Response Criteria in Solid Tumors via SULmax (iPERCIST-max) in predicting tumor response to neoadjuvant immunochemotherapy and short-term survival in locally advanced NSCLC. Methods: In this prospective cohort study, we calculated SULmax, SULpeak, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their dynamic percentage changes in a training cohort. We then investigated the correlation between alterations in these parameters and pathological tumor responses. Subsequently, iPERCIST-max defined by the proportional changes in the SULmax response (△SULmax%) was constructed and internally validated using a time-dependent receiver operating characteristic (ROC) curve and the area under the curve (AUC) value. A prospective cohort from the Sun Yat-Sen University Cancer Center (SYSUCC) was also included for external validation. The relationship between the iPERCIST-max responsiveness and event-free survival in the training cohort was also investigated. Results: Fifty-five patients with NSCLC were included in this study from May 2019 to December 2021. Significant alterations in post-treatment SULmax (p < 0.001), SULpeak (p < 0.001), SULmean (p < 0.001), MTV (p < 0.001), TLG (p < 0.001), and tumor size (p < 0.001) were observed compared to baseline values. Significant differences in SULpeak, SULmax, and SULmean between major pathological response (mPR) and non-mPR statuses were observed. The optimal cutoff values of the SULmax response rate were −70.0% and −88.0% using the X-tile software. The univariate and multivariate binary logistic regression showed that iPERCIST-max is the only significant key predictor for mPR status [OR = 84.0, 95% confidence interval (CI): 7.84–900.12, p < 0.001]. The AUC value for iPERCIST-max was 0.896 (95% CI: 0.776–1.000, p < 0.001). Further, external validation showed that the AUC value for iPERCIST-max in the SYSUCC cohort was 0.889 (95% CI: 0.698–1.000, p = 0.05). Significantly better event-free survival (EFS) in iPERCIST-max responsive disease (31.5 months, 95% CI 27.9–35.1) than that in iPERCIST-max unresponsive disease (22.2 months, 95% CI: 17.3–27.1 months, p = 0.024) was observed. Conclusion: iPERCIST-max could better predict both early pathological tumor response and short-term prognosis of NSCLC treated with neoadjuvant immunochemotherapy than commonly used criteria. Furthermore, large-scale prospective studies are required to confirm the generalizability of our findings.

Contrast-free MRI quantitative parameters for early prediction of pathological response to neoadjuvant chemotherapy in breast cancer.

To assess early changes in synthetic relaxometry after neoadjuvant chemotherapy (NAC) for breast cancer and establish a model with contrast-free quantitative parameters for early prediction of pathological response. From March 2019 to January 2021, breast MRI were performed for a primary cohort of women with breast cancer before (n = 102) and after the first (n = 93) and second (n = 90) cycle of NAC. Tumor size, synthetic relaxometry (T1/T2 relaxation time [T1/T2], proton density), and ADC were obtained, and the changes after treatment were calculated. Prediction models were established by multivariate logistic regression; evaluated with discrimination, calibration, and clinical application; and compared with Delong tests, net reclassification (NRI), and integrated discrimination index (IDI). External validation was performed from February to June 2021 with an independent cohort of 35 patients. In the primary cohort, all parameters changed after early treatment. Synthetic relaxometry decreased to a greater degree in major histologic responders (MHR, Miller-Payne G4-5) compared with non-MHR (Miller-Payne G1-3). A model combining ADC after treatment, changes in T1 and tumor size, and cancer subtype achieved the highest AUC after the first (primary/validation cohort, 0.83/0.82) and second cycles (primary/validation cohort, 0.85/0.84). No difference of AUC (p ≥ 0.27), NRI (p ≥ 0.31), and IDI (p ≥ 0.32) was found between models with different cycles and size-measured sequences. Model calibration and decision curves demonstrated a good fitness and clinical benefit, respectively. Early reduction in synthetic relaxometry indicated pathological response to NAC. Contrast-free T1 and ADC combined with size and cancer subtype predicted effectively pathological response after one NAC cycle. • Synthetic MRI relaxometry changed after early neoadjuvant chemotherapy, which demonstrated pathological response for mass-like breast cancers. • Contrast-free quantitative parameters including T1 relaxation time and apparent diffusion coefficient, combined with tumor size and cancer subtype, stratified major histologic responders. • A contrast-free model predicted an early pathological response after the first treatment cycle of neoadjuvant chemotherapy.

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

SummaryThe kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.

Abstract PS3-02: Radiologic review to refine selection of candidates for de-escalation of neoadjuvant therapy

Abstract PurposeIn the on-going I-SPY2 TRIAL, participants receive 12 cycles of weekly paclitaxel with or without addition of experimental agents for 12 weeks (first regimen), followed by 4 cycles of anthracycline-cyclophosphamide (AC, second regimen) prior to surgery. A de-escalation strategy currently being introduced in I-SPY2 will give patients the option to skip AC if it is highly likely that they have achieved early pathologic complete response (pCR) at the inter-regimen time point (12 weeks). To guide selection of candidates for this option, a prediction model combining subtype-specific MRI predictive probabilities with mid-treatment percutaneous core biopsy pathology has been developed. The combined model predicts a patient as early pCR if the MRI model based on a quantitative measure of functional tumor volume predicts a high likelihood of pCR, and pathology determines that there are no invasive cancer cells detected in the mid-treatment core biopsy. This study was performed to develop radiologic criteria for post-selection review to further reduce the possibility for incorrect de-escalation recommendation. MethodsA review of 87 I-SPY2 patients with serial MRI and inter-regimen core biopsy identified 25 patients where both the subtype specific MRI model and at least 2 of 11 I-SPY2 pathologists predicted early pCR. One radiologist retrospectively reviewed MRIs at pre-treatment and inter-regimen for the 25 patients in a blinded fashion, and labeled the presence of residual disease on MRI at inter-regimen as follows: rank 0, no residual disease; rank 1, possible residual disease; rank 2, obvious residual disease.To evaluate the accuracy of selecting candidates for de-escalation of neoadjuvant therapy (i.e. predicting patients with early pCR at inter-regimen), surgical pathology of pCR after the completion of NAC (both first and second regimens) was defined as a surrogate “truth” in this study. Positive predictive value (PPV) and sensitivity for the combined MRI-pathology model were computed for all pathologist pairs. After adding qualitative radiologic review, patients labeled as rank 2 were excluded from the candidates with predicted early pCR by the combined MRI-pathology model. PPV and sensitivity before and after radiologic review were compared. ResultsThe 25 patients included 21 patients that ultimately achieved pCR, and 4 patients that did not. Radiologic review of the inter-regimen MRI for these patients classified their MRIs as 20% (5/25) rank 0 (no residual disease), 36% (9/25) rank 1 (possible residual disease), and 44% (11/25) rank 2 (obvious residual disease). Most (3/4) non-pCR patients were classified rank 2, however one (1/4) was assessed rank 0. Eight of the 21 pCR patients (38%) were classified as having obvious residual disease on inter-regimen MRI. Without radiologic review, the combined MRI-pathology model predicted pCR with a mean PPV of 92% (range 83-100%) and a mean sensitivity of 91% (range 76-100%). When patients labeled as rank 2 by radiologic review were excluded from candidates with predicted early pCR, PPV increased to 99% (range 93-100%) at the expense of lower sensitivity of 59% (range 52-62%). Conclusion In this study, elimination of rank 2 lesions resulted in substantial improvement in PPV (92% to 99%) with a consequent reduction in sensitivity from 91% to 59%. Notably, none of the rank 1 lesions, where diagnostic interpretation was less certain, were found to be non-pCR at surgery. High PPV is essential to ensure high accuracy and safety in directing early pCR patients to therapy de-escalation. These findings will be further validated in continuing studies and radiologic re-review will be included in the de-escalation strategy for omission of AC in the I-SPY2 TRIAL. Citation Format: Natsuko Onishi, Wen Li, Sara J Venters, Denise M Wolf, David C Newitt, Elissa R Price, Jessica Gibbs, Barbara LeStage, the I-SPY 2 Pathology Working Group, the I-SPY 2 Imaging Working Group, the I-SPY 2 Consortium, William F Symmans, Nola M Hylton. Radiologic review to refine selection of candidates for de-escalation of neoadjuvant therapy [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 PS3-02.

Early prediction of neoadjuvant treatment outcome in locally advanced breast cancer using parametric response mapping and radial heterogeneity from breast MRI.

Early prediction of nonresponse is essential in order to avoid inefficient treatments. To evaluate if parametrical response mapping (PRM)-derived biomarkers could predict early morphological response (EMR) and pathological complete response (pCR) 24-72 hours after initiation of chemotherapy treatment and whether concentric analysis of nonresponding PRM regions could better predict response. This was a retrospective analysis of prospectively acquired cohort, nonrandomized, monocentric, diagnostic study. Sixty patients were initially recruited, with 39 women participating in the final cohort. A 1.5T scanner was used for MRI examinations. Dynamic contrast-enhanced (DCE)-MR images were acquired at baseline (timepoint 1, TP1), 24-72 hours after the first chemotherapy (TP2), and after the end of anthracycline treatment (TP3). PRM was performed after fusion of T1 subtraction images from TP1 and TP2 using an affine registration algorithm. Pixels with an increase of more than 10% of their value (PRMdce+) were corresponding nonresponding regions of the tumor. Patients with a decrease of maximum diameter (%dDmax) between TP1 and TP3 of more than 30% were defined as EMR responders. pCR patients achieved a residual cancer burden score of 0. T-test, receiver operating characteristic (ROC) curves, and logistic regression were used for the analysis. PRM showed a statistical difference between pCR response groups (P < 0.01) and AUC of 0.88 for the prediction of non-pCR. Logistic regression analysis demonstrated that PRMdce+ and Grade II were significant (P < 0.01) for non-pCR prediction (AUC = 0.94). Peripheral tumor region demonstrated higher performance for the prediction of non-pCR (AUC = 0.85) than intermediate and central zones; however, statistical comparison showed no significant difference. PRM could be predictive of non-pCR 24-72 hours after initiation of chemotherapy treatment. Moreover, the peripheral region showed increased AUC for non-pCR prediction and increased signal intensity during treatment for non-pCR tumors, information that could be used for optimal tissue sampling. 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1403-1411.

278P - Correlation between radiologic complete response (rCR) in contrast-enhanced magnetic resonance imaging (CE-MRI) after neoadjuvant chemotherapy for early breast cancer and pathologic complete response and their impact in recurrence-free survival

BackgroundPatients with early breast cancer (EBC) achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) have a favorable prognosis. Breast surgery and more chemotherapy treatment might be avoided in patients in whom the presence of residual tumor can be ruled out with high confidence. We investigated the diagnostic accuracy of contrast enhanced MRI (CE-MRI) in predicting pCR and long-term outcome after NACT. MethodsPatients with EBC, who had undergone CE-MRI before and after NACT, were retrospectively analyzed (n=421), and regarding to the absence (radiologic complete remission; rCR) or presence (no-rCR) of residual contrast enhancement. ResultsOverall rCR and pCR rates were 35% (147/421) and 36% (154/421), respectively. We found a total of 70% (101/144) of rCR corresponded to a pCR (meaning the positive predictive value - PPV). In contrast, in 80% (219/272) of patients, residual tumor observed on MRI was pathologically confirmed (meaning the negative predictive value - NPV). Sensitivity to detect a pCR was 65% (101/154), while specificity to detect residual tumor and accuracy were 83% (219/262); and 76% (320/421), respectively. The PPV was significantly lower in luminal compared to HER2 positive and triple negative tumors (10/34 = 29 % vs. 50/62 = 81% and 41/48 = 85% respectively). The concordance between rCR and pCR was moderate (Cohen’s kappa − 0.5) but with low level in luminal tumors (Coheńs Kappa – 0.3). In multivariate analysis both assessments were significantly associated with disease free survival (rCR : HR:0,344 P=0.001; pCR : HR : 0,154 P=0.000), but not in luminal tumors (rCR : HR:0,813 P=0.692; pCR : HR : 0,326 P=0.275). ConclusionsThe accuracy of preoperative CE-MRI to predict pCR after NACT for EBC is moderate but in luminal tumors did not accurately predict pCR. However, rCR was strongly associated with favorable RFS, especially in HER2 positive and triple negative breast cancer tumors. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract P6-02-02: Near-infrared spectral tomography (NIRST): A prognostic assessment tool for predicting residual cancer burden (RCB) during neoadjuvant chemotherapy (NAC) in breast cancer (BC)

Abstract Background: NIRST, a noninvasive imaging with no ionizing radiation, has been found to be prognostic as a tool to monitor early pathologic response to NAC in BC using biophysical properties of the tumor compared with normal breast tissue. We aim to establish NIRST indicators as early surrogates of treatment response and to evaluate its potential as a predictive tool in treatment decisions. Methods: 27 women with locally advanced BC undergoing NAC were enrolled in this pilot study. NIRST imaging was performed pre-treatment, after cycle 1 and 2, at the mid-point of NAC, and at the conclusion of NAC prior to surgery. Biophysical data including oxy- and deoxy-hemoglobin, water, lipid, and scatter components were obtained at these time points. To minimize inter-subject variability due to breast density and its effects on the NIRST data, statistical analysis was conducted using ratios of obtained biophysical data to pretreatment average of the contralateral normal breast tissue. Residual Cancer Burden (RCB) index was used to evaluate residual disease after treatment with NAC. RCB scores and classes were determined in 24 of the 27 surgical tissue specimens and these were compared to the NIRST data. RCB data for 3 patients were excluded: 2 patients had undergone positive excisional lymph node biopsy prior to NAC and 1 patient had surgery at an outside hospital. Results: Of the 27 patients, 7 had triple negative BC and 13 had HER-2 positive BC. The change in total hemoglobin (ΔHb-T %) after the first cycle of NAC when compared to the pre-treatment total hemoglobin was determined to be the best predicting factor for RCB (p-value &amp;lt;0.001). The Pearson correlation coefficient was calculated for both RBC class and RBC score (0.7 and 0.6). The significance of the correlation coefficient was evaluated using two-sided t-test and the resulting P-values of 0.006 and 0.001 respectively demonstrate that these correlations are statistically significant. Summary of the NIRST biophysical data and the correlating RCBPatientAgeERPRHer2RCB ScoreHbT -ΔHbT-pre136+-+0-139.933.30251---0-43.532.53341+++0-42.281.89430---0-43.061.59552---0-42.541.71663+++0-151.883.12760--+0-46.471.59852---0-42.721.96966--+0-110.022.471039--+0-9.091.101171+-+0-13.331.501252++-4.12153.201.581362++-3.7475.741.531470--+1.931100.521.631553++-3.4447.831.181641+++4.18929.841.511756+++4.44459.001.471850++-4.008-41.112.181954---3.05011.111.802063++-2.90020.001.502149---0.78026.321.902257++-1.8505.881.702347++-3.600-7.692.602470---3.10047.061.70 Conclusions: We have demonstrated a statistically significant correlation between ΔHb-T % after the first cycle of NAC and the RCB. These findings suggest the potential of using NIRST as an early assessment tool to evaluate response to NAC in BC patients and warrant further evaluation in a larger study. Citation Format: Batukbhai B, Jiang S, Bernhardt EB, Muller K, Cao X, Gui J, DiFlorio-Alexander RM, Chamberlin MD, Schwartz GN, Paulsen KD, Pogue BW, Kaufman PA. Near-infrared spectral tomography (NIRST): A prognostic assessment tool for predicting residual cancer burden (RCB) during neoadjuvant chemotherapy (NAC) in breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-02.

Soluble tumour necrosis factor receptor I is a promising early indicator of complicated clinical outcome in patients following severe trauma.

Post-traumatic mortality rates are still very high and show an increasing tendency. Early identification of patients at high risk of severe complications has a significant impact on treatment outcomes. The aim of the study was to better understand the early pathological inflammatory response to injury and infection, and to determine the usefulness of the assessment of TNF-α and sTNFR1 concentrations in the peripheral blood as early indicators of severe post-traumatic complications. The study was carried out in a group of 51 patients after trauma, treated in the ED, including 32 patients who met the inclusion criteria for immunological analysis. Patients were divided into two groups using the ISS scale (A ISS ≥ 20, B ISS < 20). The highest TNF-α and sTNFR1 concentrations in both groups were recorded at admission and were significantly higher in group A compared to group B (A vs. B TNF-α 2.46 pg/ml vs. 1.78 pg/ml; sTNFR1 1667.5 pg/ml vs. 875.2 p < 0.005). The concentration of sTNFR1 in patients with severe complications was significantly higher compared to patients without complications and preceded clinical symptoms of complications (C+ vs. C– 1561.5 pg/ml vs. 930.6 pg/ml, p < 0,005). The high diagnostic sensitivity calculated from the ROC curves was found for the concentrations of both cytokines: TNF-α (AUC = 0.91, p = 0.004) and sTNFR1 (AUC = 0.86, p = 0.011). Elevated levels of sTNFR1, determined in the peripheral blood shortly after injury, are significantly associated with the occurrence of later complications, which in some patients lead to death. In contrast, high levels of TNF-α shortly after injury are associated with mortality.

Can Multi-Parametric MR Based Approach Improve the Predictive Value of Pathological and Clinical Therapeutic Response in Breast Cancer Patients?

The potential of total choline (tCho), apparent diffusion coefficient (ADC) and tumor volume, both individually and in combination of all these three parameters (multi-parametric approach), was evaluated in predicting both pathological and clinical responses in 42 patients with locally advanced breast cancer (LABC) enrolled for neoadjuvant chemotherapy (NACT). Patients were sequentially examined by conventional MRI; diffusion weighted imaging and in vivo proton MR spectroscopy at 4 time points (pre-therapy, after I, II, and III NACT) at 1.5 T. Miller Payne grading system was used for pathological assessment of response. Of the 42 patients, 24 were pathological responders (pR) while 18 were pathological non-responders (pNR). Clinical response determination classified 26 patients as responders (cR) while 16 as non-responders (cNR). tCho and ADC showed significant changes after I NACT, however, MR measured tumor volume showed reduction only after II NACT both in pR and cR. After III NACT, the sensitivity to detect responders was highest for MR volume (83.3% for pR and 96.2% for cR) while the specificity was highest for ADC (76.5% for pR and 100% for cR). Combination of all three parameters exhibited lower sensitivity (66.7%) than MR volume for pR prediction, however, a moderate improvement was seen in specificity (58.8%). For the prediction of clinical response, multi-parametric approach showed 84.6% sensitivity with 100% specificity compared to MR volume (sensitivity 96.2%; specificity 80%). Kappa statistics demonstrated substantial agreement of clinical response with MR volume (k = 0.78) and with multi-parametric approach (k = 0.80) while moderate agreement was seen for tCho (k = 0.48) and ADC (k = 0.46). The values of k for tCho, MR volume and ADC were 0.31, 0.38, and 0.18 indicating fair, moderate, and slight agreement, respectively with pathological response. Moderate agreement (k = 0.44) was observed between clinical and pathological responses. Our study demonstrated that both tCho and ADC are strong predictors of assessment of early pathological and clinical responses. Multi-parametric approach yielded 100% specificity in predicting clinical response. Following III NACT, MR volume emerged as highly suitable predictor for both clinical and pathological assessments. PCA demonstrated separate clusters of pR vs. pNR and cR vs. cNR at post-therapy while with some overlap at pre-therapy.

18FDG-PET-CT identifies histopathological non-responders after neoadjuvant chemotherapy in locally advanced gastric and cardia cancer: cohort study

BackgroundPathologic response to neoadjuvant chemotherapy (neoCTX) is a prognostic factor in many cancer types, and early prediction would help to modify treatment. In patients with gastric and esophagogastric junction (AEG) cancer, the accuracy of FDG PET-CT to predict early pathologic response after neoadjuvant chemotherapy (neoCTX) is currently not known.MethodsFrom a consecutive cohort of 72 patients, 44 patients with resectable, locally-advanced gastric cancer or AEG Siewert type II and III received neoCTX after primary staging with endoscopic ultrasound, PET-CT and laparoscopy. Overall, 14 patients did not show FDG uptake, and the remaining 30 were restaged by PET-CT 14 days after the first cycle of neoCTX. Metabolic response was defined as decrease of tumor standardized uptake value (SUV) by ≥35%. Major pathologic regression was defined as less than 10% residual tumor cells.ResultsMetabolic response after neoCTX was detected in 20/30 (66.7%), and non-response in 10/30 (33.3%) patients. Among metabolic responders, n = 10 (50%) showed major and n = 10 (50%) minor pathologic regression. In non-responders, n = 9 (90%) had minor and 1 (10%) a major pathologic regression. This resulted in a sensitivity of 90.9%, specificity 47.3%, positive predictive value 50%, negative predictive value 90% and accuracy of 63.3%.ConclusionResponse PET-CT after the first cycle of neoCTX does not accurately predict overall pathologic response. However, PET-CT reliably detects non-responders, and identifies patients who should either immediately proceed to resection or receive a modified multimodality therapy.Trial registrationThe trial was registered and approved by local ethics committee PB_2016–00769.

TU‐D‐207B‐05: Intra‐Tumor Partitioning and Texture Analysis of DCE‐MRI Identifies Relevant Tumor Subregions to Predict Early Pathological Response of Breast Cancer to Neoadjuvant Chemotherapy

Purpose:To predict early pathological response of breast cancer to neoadjuvant chemotherapy (NAC) based on quantitative, multi‐region analysis of dynamic contrast enhancement magnetic resonance imaging (DCE‐MRI).Methods:In this institution review board‐approved study, 35 patients diagnosed with stage II/III breast cancer were retrospectively investigated using DCE‐MR images acquired before and after the first cycle of NAC. First, principal component analysis (PCA) was used to reduce the dimensionality of the DCE‐MRI data with a high‐temporal resolution. We then partitioned the whole tumor into multiple subregions using k‐means clustering based on the PCA‐defined eigenmaps. Within each tumor subregion, we extracted four quantitative Haralick texture features based on the gray‐level co‐occurrence matrix (GLCM). The change in texture features in each tumor subregion between pre‐ and during‐NAC was used to predict pathological complete response after NAC.Results:Three tumor subregions were identified through clustering, each with distinct enhancement characteristics. In univariate analysis, all imaging predictors except one extracted from the tumor subregion associated with fast wash‐out were statistically significant (p&lt; 0.05) after correcting for multiple testing, with area under the ROC curve or AUCs between 0.75 and 0.80. In multivariate analysis, the proposed imaging predictors achieved an AUC of 0.79 (p = 0.002) in leave‐one‐out cross validation. This improved upon conventional imaging predictors such as tumor volume (AUC=0.53) and texture features based on whole‐tumor analysis (AUC=0.65).Conclusion:The heterogeneity of the tumor subregion associated with fast wash‐out on DCE‐MRI predicted early pathological response to neoadjuvant chemotherapy in breast cancer.

¹⁸F-FDG PET/CT in the early prediction of pathological response in aggressive subtypes of breast cancer: review of the literature and recommendations for use in clinical trials.

Early assessment of response to neoadjuvant chemotherapy (NAC) might be helpful in avoiding the toxicity of ineffective chemotherapy and allowing refinement of treatment. We conducted a review of the literature regarding the applicability of (18)F-FDG PET/CT to the prediction of an early pathological response in different subgroups of breast cancer. Clinical research in this field has intensified in the last few years. Early studies by various groups have shown the potential of (18)F-FDG PET/CT in the early assessment of response to NAC. However, interim PET/CT in breast cancer has not yet gained wide acceptance compared to its use in other settings such as lymphomas. This is in part due to a lack of consensus that early evaluation of response can be used to direct change in therapy in the neoadjuvant breast cancer setting, and only limited data showing that response-adaptive therapy leads to improved outcomes. However, one major element that has hampered the use of (18)F-FDG PET/CT in directing neoadjuvant therapy is its evaluation in populations with mixed subtypes of breast cancer. However, major improvements have occurred in recent years. Pilot studies have highlighted the need for considering breast cancer subtype and the type of treatment, and have offered criteria for the use of PET/CT for the early prediction of response in specific settings. (18)F-FDG PET/CT has considerable potential for the early prediction of pathological complete response to NAC in aggressive subtypes such as triple-negative or HER2-positive breast cancers. The results of a multicentre trial that used early metabolic response on (18)F-FDG PET/CT as a means to select poor responders to adapt neoadjuvant treatment have recently been published. Other trials are ongoing or being planned.

Role of conventional and diffusion weighted MRI in predicting treatment response after low dose radiation and chemotherapy in locally advanced carcinoma cervix

Background and purposeTo assess the diagnostic performance of conventional and diffusion weighted (DWI) magnetic resonance imaging (MRI) in predicting response in locally advanced cervical cancer. Materials and methodsTotal 24 patients with stage IIB–IIIB squamous cell carcinoma cervix were treated with initial two cycles of paclitaxel and carboplatin and concurrent low dose radiotherapy prior to standard chemoradiation. Response was assessed clinically and radiologically after 3weeks of initial treatment. Volumetric and functional parameters derived from conventional and diffusion weighted MRI, due to treatment were measured. ResultsSignificant reduction of GTV was noted in MRI (54cm3 vs. 11cm3, p<0.01) and DWI (44cm3 vs. 6cm3, p<0.01, ΔADC=0.49×10−3mm2/sec, p<0.01) after treatment. Tumor volume reduction rate (TVRR) in DWI was significantly higher in pathological good responders (p=0.03). In this group both mean post treatment apparent diffusion coefficient (ADC) value and ΔADC were significantly higher (p=0.01 and p=0.03). ADC was a good predictor for pathological response (area under receiver operating characteristic curve (ROC) 0.814). ConclusionTVRR (DWI) and ΔADC can be used as a predictor of early pathological response. Complete response based on DWI, could be a useful predictor of long term disease control.

Lung pathogenicity of European genotype 3 strain porcine reproductive and respiratory syndrome virus (PRRSV) differs from that of subtype 1 strains

Porcine reproductive and respiratory syndrome (PRRS) is difficult to control due to a high mutation rate of the PRRS virus (PRRSV) and the emergence of virulent strains. The objective of this study was to analyse early and late pathological responses in the respiratory tract after infection with the European PRRSV subtype 3 strain Lena in comparison to two European PRRSV subtype 1 strains: Belgium A and Lelystad-Ter Huurne (LV). For each virus strain, groups of twelve pigs were inoculated, and four pigs per group were euthanized at days 3, 7 and 35 post-infection (p.i.) for consecutive examination. Infection with strain Lena resulted in a more severe disease than with the subtype 1 strains, an inflammatory response within the first week of infection with expression of IL-1α in the lung and lymph node, and an influx of neutrophils and monocytes in bronchoalveolar lavage fluid (BALF). Infection with strain Belgium A or LV resulted in mild or no pathology within the first week of infection, but inflammatory cell influx in the lung interstititium was increased at the end of the experiment at day 35 p.i. At five weeks p.i., all strains induced a higher percentage of cytotoxic T cells and higher levels of IFN-γ producing cells in BALF. This might have contributed to clearance of virus. In general, subtype 3 strain Lena induced a stronger early inflammatory response which led to more severe clinical disease and pathology. On the other hand, this may have supported an enhanced or faster clearance of virus in tissues, compared to subtype 1 strains.

Gender-Related Differences in Pathological and Clinical Tumor Response Based on Immunohistochemical Proteins Expression in Rectal Cancer Patients Treated with Short Course of Preoperative Radiotherapy

BackgroundPrognostic value of pretreatment expression of proteins in rectal cancer for early pathological tumor response (pTR), clinical tumor response (CTR) to preoperative radiotherapy (RT), and the potential difference between these parameters depending on patient gender is not established. Material and MethodsOne hundred eleven patients were treated with short preoperative course of RT (SCRT) with 5 Gy dose per fraction during 5 days, followed by surgery 3 to 53 days (mean, 21 days) later. Expression of CD34, Ki-67, GLUT-1, Ku70, BCL-2, and P53 proteins was assessed immunohistochemically. ResultsThere were 76 men and 35 women. There were 27, 69, and 15 clinical tumor-node-metastasis (cTNM) tumor stages I, II, and III, respectively. Significant differences in Ki-67, GLUT-1, Ku 70, and BCL-2 expressions between male and female tumors were observed for pathological TNM (pTNM) stage and grade. Association between proteins expression and pTNM, pTR, and CTR was analyzed separately for short (≤15 days) and long (>15 days) break between RT and surgery and males and female patients. For SCRT with short break, no protein was significantly related to pTNM; for pTR, higher Ki-67 and lower BCL-2 expression were correlated with pTR. In the male subgroup, BCL-2 overexpression was predictive. For SCRT with long break, none of the proteins was predictive for pTR, but Ki-67, Ku70 (in female subgroup), and BCL-2 expressions were positively correlated with pTNM. BCL-2 overexpression was associated with CTR in the females only. ConclusionIn SCRT, long break in the treatment should be avoided because correlation between Ki-67, KU70, and BCL-2 expressions and pTNM after RT might indicate tumor progression.