Assessment Of Chemotherapy Response Research Articles

Intratumoral Heterogeneity Assessment of the Extracellular Bone Matrix and Immune Microenvironment in Osteosarcoma Using Digital Imaging to Predict Therapeutic Response

The assessment of chemotherapy response in osteosarcoma (OS) based on the average percentage of viable cells is limited, as it overlooks the spatial heterogeneity of tumor cell response (foci of resistant cells), immune microenvironment, and bone microarchitecture. Despite the resulting positive classification for response to chemotherapy, some patients experience early metastatic recurrence, demonstrating that our conventional tools for evaluating treatment response are insufficient. We studied the interactions between tumor cells, immune cells (lymphocytes, histiocytes, and osteoclasts), and bone extracellular matrix (ECM) in 18 surgical resection samples of OS using multiplex and conventional immunohistochemistry (IHC: CD8, CD163, CD68, and SATB2), combined with multiscale characterization approaches in territories of good and poor response (GRT/PRT) to treatment. GRT and PRT were defined as subregions with <10% and ≥10% of viable tumor cells, respectively. Local correlations between bone ECM porosity and density of immune cells were assessed in these territories. Immune cell density was then correlated to overall patient survival. Two patterns were identified for histiocytes and osteoclasts. In poor responder patients, CD68 osteoclast density exceeded that of CD163 histiocytes but was not related to bone ECM load. Conversely, in good responder patients, CD163 histiocytes were more numerous than CD68 osteoclasts. For both of them, a significant negative local correlation with bone ECM porosity was found (P < .01). Moreover, in PRT, multinucleated osteoclasts were rounded and intermingled with tumor cells, whereas in GRT, they were elongated and found in close contact with bone trabeculae. CD8 levels were always low in metastatic patients, and those initially considered good responders rapidly died from their disease. The specific recruitment of histiocytes and osteoclasts within the bone ECM, and the level of CD8 represent new features of OS response to treatment. The associated prognostic signatures should be integrated into the therapeutic stratification algorithm of patients after surgery.

Update on FDG-PET in pediatric lymphoma.

Lymphoma represent the third most common malignant disease in childhood and adolescence. They are divided into pediatric Hodgkin lymphoma (P-HL) and pediatric non-Hodgkin lymphoma (P-NHL). In P-HL, excellent cure rates are achieved through combined modality treatment using chemotherapy and radiotherapy. For more than 20 years, FDG-PET has been an integral part of the treatment and guides its intensity through improved staging and precise assessment of chemotherapy response. In P-NHL, good cure rates are achieved with chemotherapy alone. At present FDG-PET plays only a subordinate role in the treatment setting. Its potential to contribute to treatment management is far from being fully utilised. In this article, the current status of FDG-PET in pediatric lymphoma is presented in detail. The core elements are the sections on staging and response assessment. In addition, challenges and pitfalls are discussed and future developments are outlined.

Relationship between Serum Vascular Endothelial Growth Factor-A Levels and Response to Chemotherapy in Cervical Cancer

Introduction: cervical cancer ranks second in gynecological cancer worldwide. 62-82 % of cervical cancer patients present at an advanced stage and respond poorly to treatment. Assessment of chemotherapy response requires examination of the biomarker Vascular endothelial growth factor-A (VEGF-A), which is the main regulator of the abnormal angiogenesis process. Objectives: this study aims to analyze the relationship between serum VEGF-A levels and the response to neoadjuvant chemotherapy in cervical cancer patients. Methods: this research is Quasi-Experimental, pretest and posttest without control. Total sample: 30 stages IIIB cervical cancer patients underwent a pretest before cisplatin chemotherapy by measuring cervical lesions using ultrasound and serum VEGF-A levels using ELISA. 3 weeks after the third cycle of chemotherapy, a posttest examination is carried out like the pretest examination. Results: the results showed a significant reduction in serum VEGF-A levels and cervical lesion diameter after chemotherapy (p=0,032), (p=0,000). In response to neoadjuvant chemotherapy, 21 patients responded negatively, and 9 responded positively. High levels of VEGF-A before chemotherapy gave a negative response (p=0,042) and low levels of VEGF-A after chemotherapy gave a positive response (p=0,049). Conclusions: this study concludes that there is a relationship between high serum VEGF-A levels before chemotherapy with a negative response and low serum VEGF-A levels after chemotherapy with a positive response in cervical cancer patients

National trends in neoadjuvant chemotherapy utilization for cT1-2 N0 triple negative breast cancer: Did the CREATE-X trial impact treatment patterns?

e12599 Background: Neoadjuvant chemotherapy (NAC) for operable breast cancer allows for in-vivo assessment of chemotherapy response with survival and therapeutic implications. In 2017, the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial demonstrated significant improvement in survival with the addition of adjuvant capecitabine in patients with triple negative breast cancer (TNBC) and residual disease after NAC. These results provided the rationale for NAC even in early stage TNBC. The aim of this study was to assess U.S. national rates of NAC utilization in early-stage node-negative TNBC patients before and after the release of CREATE-X and to assess factors associated with receiving NAC vs adjuvant chemotherapy (AC). Methods: The National Cancer Database was queried for women with cT1-2N0M0 TNBC from 2014–19. NAC utilization was collected and categorized as 2014-15 (pre-CREATE-X), 2016-17 (transition yrs), and 2018-19 (post-CREATE-X). Those who did not receive chemotherapy were excluded. NAC use over time was analyzed via multivariable logistic regression (MLR). Clinical and demographic factors associated with NAC vs AC utilization were assessed using ANOVA, Chi-squared, and Fisher Exact tests. A MLR model was used to determine predictors of receipt of NAC vs AC. Results: 55,633 women were treated from 2014-19: 26.9% with NAC, 52.4% with AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71yrs, respectively, p &lt; 0.01). Most had cT1c (32.7%, n = 18,190) or cT2 (41.95%, n = 23,331) tumors and 99% had invasive ductal pathology. NAC utilization significantly increased over time, 19.5% (n = 3,465 of 17,777) in 2014-15, 27.1% (n = 5,140 of 18,985) in 2016-17, and 33.6% (n = 6,337 of 18,871) in 2018-19 (p &lt; 0.01). On MLR analysis, increased use of NAC was associated with younger age ( &lt; 50yrs), non-Hispanic white patients, having no comorbidities, having a cT2 tumor, grade 2 disease, and care at an academic or integrated network cancer program (p &lt; 0.05 for all). Patients with Medicare and Medicaid insurance were less likely to receive NAC (p &lt; 0.01). Patients who traveled &gt; 60 miles to their treating facility were more likely to receive NAC (p &lt; 0.01). Conclusions: From 2014–19, NAC utilization increased for patients with cT1-2N0M0 TNBC coinciding with the release of the CREATE-X results. Findings demonstrate the significance of the multidisciplinary oncology team in developing individualized treatment plans based on emerging clinical trial evidence. Racial, socioeconomic, and access disparities were observed in NAC utilization and warrants further investigation and interventions to ensure equitable care. [Table: see text]

Abbreviated Versus Full-Protocol MRI for Breast Cancer Neoadjuvant Chemotherapy Response Assessment: Diagnostic Performance by General and Breast Radiologists.

BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually (p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.

Prognostic value of the completeness of the metabolic response in patients with diffused large B-cell lymphoma

The currently used prognostic factors for long-term results of standard treatment of diffuse large B-cell lymphoma (DLBCL) are not clear enough to predict outcomes. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim 18 F-FDG PET/CT after first-line treatment in patients with DLBCL. One hundred-eighty patients with DLBCL underwent baseline and interim 18 F-FDG PET/CT scans after 4 cycles of R-CHOP during the period of 2015–2020 at the N. N. Alexandrov National Cancer Centre of Belarus. Interim 18 F-FDG PET/ CT findings were retrospectively correlated to the progression-free survival (PFS) using the Kaplan–Meier analysis. The metabolic response was assessed according Deauville criteria: PET-negative – Deauville 1–2, PET-positive – Deauville 3–5. The International prognostic index (IPI) was used for risk stratification. After 4 cycles of chemotherapy, PET-positive lesions were found in 76 patients and negative scans – in 104 patients. Survival analyses showed highly significant relationships between early interim 18 F-FDG PET/CT imaging and PFS (p &lt; 0.001). For PET-negative patients, the 7-year PFS rate was 91.1 %, for PET-positive patients it is 41.2 %. 5-year PFS rates for PET-negative patients with IPI scores 0–1, 2–3 and 4–5 were 97.5, 93.4 and 66.7 %, respectively. For PET-positive patients, 5-year PFS rates in the same subgroups were 55.6, 50.6 and 23.1 %, respectively. Early interim 18 F-FDG PET/CT imaging is a predictor of PFS in DLBCL. An early assessment of chemotherapy response with 18 F-FDG PET/CT scans may provide useful information on selection of patients for escalated therapeutic strategies.

Deep Learning–Based Objective and Reproducible Osteosarcoma Chemotherapy Response Assessment and Outcome Prediction

Osteosarcoma is the most common primary bone cancer, whose standard treatment includes pre-operative chemotherapy followed by resection. Chemotherapy response is used for prognosis and management of patients. Necrosis is routinely assessed after chemotherapy from histology slides on resection specimens, where necrosis ratio is defined as the ratio of necrotic tumor/overall tumor. Patients with necrosis ratio ≥90% are known to have a better outcome. Manual microscopic review of necrosis ratio from multiple glass slides is semiquantitative and can have intraobserver and interobserver variability. In this study, an objective and reproducible deep learning-based approach was proposed to estimate necrosis ratio with outcome prediction from scanned hematoxylin and eosin whole slide images (WSIs). To conduct the study, 103 osteosarcoma cases with 3134 WSIs were collected. Deep Multi-Magnification Network was trained to segment multiple tissue subtypes, including viable tumor and necrotic tumor at a pixel level and to calculate case-level necrosis ratio from multiple WSIs. Necrosis ratio estimated by the segmentation model highly correlates with necrosis ratio from pathology reports manually assessed by experts. Furthermore, patients were successfully stratified to predict overall survival with P = 2.4 × 10-6 and progression-free survival with P = 0.016. This study indicates that deep learning can support pathologists as an objective tool to analyze osteosarcoma from histology for assessing treatment response and predicting patient outcome.

Staging and chemotherapy response assessment of bladder cancer using hybrid deep machine learning model on CT scan images.

e16550 Background: Improved computational power and modern algorithms have generated significant interest in radiomics for cancer diagnosis and staging. Here we assess the performance of deep learning (DL) models as a means for feature extraction in combination with supervised machine learning (ML) algorithms for accurate staging and chemotherapy response assessment of bladder cancer. Methods: Deidentified grayscale CT images from bladder cancer patients scheduled to undergo radical cystectomy were included in this retrospective study. These images were manually annotated with two regional masks (normal region and cancer region). Five DL models- namely, AlexNet, GoogleNet, InceptionV3, ResNet-50, and XceptionNet pre-trained on the ImageNet dataset, a public dataset, were then fine-tuned on our bladder CT scan data to extract features. Through feature selection process, the subset of the features was used to build ML classifiers for classification. The classification was performed using five different ML classifiers, namely k-Nearest Neighbor (KNN), Naïve-Bayes (NB), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and Decision Tree (DT). The classification task was performed with 10-fold cross-validation, and each of the experiments contained a different but not mutually exclusive subset of samples. The evaluation metrics include accuracy, sensitivity, specificity, precision, and F1-score. Results: A total of 200 deidentified grayscale CT images of 100 patients with histologically proven bladder cancer, were included in this study. For experiment (1) normal vs. cancer, the LDA classifier on XceptionNet based features provides the best performance with an accuracy of 86.07%, sensitivity of 96.75%, specificity of 69.65%, precision of 83.07%, and F1-score of 89.39%. For experiment (2) non-muscle invasive Cancer (NMIBC) vs. muscle invasive bladder cancer (MIBC), the LDA classifier on XceptionNet based features provided the best performance with an accuracy of 79.72%, sensitivity of 66.62%, specificity of 87.39%, precision of 75.58%, and F1-score of 70.81%. For experiment (3) T0 lesion vs. MIBC, the LDA classifier on XceptionNet based features provides the best performance with an accuracy of 74.96%, sensitivity of 80.51%, specificity of 70.22%, precision of 69.78%, and F1-score of 74.73%. Conclusions: Our proposed model has shown good results in differentiating normal vs cancer and promising performance in differentiating T0 vs MIBC after chemotherapy treatment. We are expanding our dataset to further improve the performance in differentiating T0 vs MIBC. In addition, we will investigate the applicability of GAN for data augmentation to address data limit. We believe the hybrid DL and ML framework may facilitates radiologists' decisions and clinical decision-making in patients with bladder cancer.

Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA.

Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p &lt; 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.

Identification and Quantification of Iron Metabolism Landscape on Therapy and Prognosis in Bladder Cancer.

The morbidity of bladder cancer (BLCA) is high and has gradually elevated in recent years. BLCA is also characterized by high recurrence and high invasiveness. Due to the drug resistance and lack of effective prognostic indicators, the prognosis of patients with BLCA is greatly affected. Iron metabolism is considered to be a pivot of tumor occurrence, progression, and tumor microenvironment (TME) in tumors, but there is little research in BLCA. Herein, we used univariate COX regression analysis to screen 95 prognosis-related iron metabolism-related genes (IMRGs) according to transcription RNA sequencing and prognosis information of the Cancer Genome Atlas (TCGA) database. TCGA-BLCA cohort was clustered into four distinct iron metabolism patterns (C1, C2, C3, and C4) by the non-negative matrix factorization (NMF) algorithm. Survival analysis showed that C1 and C3 patterns had a better prognosis. Gene set variant analysis (GSVA) revealed that C2 and C4 patterns were mostly enriched in carcinogenic and immune activation pathways. ESTIMATE and single sample gene set enrichment analysis (ssGSEA) also confirmed the level of immune cell infiltration in C2 and C4 patterns was significantly elevated. Moreover, the immune checkpoint genes in C2 and C4 patterns were observably overexpressed. Studies on somatic mutations showed that the tumor mutation burden (TMB) of C1 and C4 patterns was the lowest. Chemotherapy response assessment revealed that C2 pattern was the most sensitive to chemotherapy, while C3 pattern was the most insensitive. Then we established the IMRG prognosis signature (IMRGscore) by the least absolute shrinkage and selection operator (LASSO), including 13 IMRGs (TCIRG1, CTSE, ATP6V0A1, CYP2C8, RNF19A, CYP4Z1, YPEL5, PLOD1, BMP6, CAST, SCD, IFNG, and ASIC3). We confirmed IMRGscore could be utilized as an independent prognostic indicator. Therefore, validation and quantification of iron metabolism landscapes will help us comprehend the formation of the BLCA immunosuppressive microenvironment, guide the selection of chemotherapeutic drugs and immunotherapy, and predict the prognosis of patients.

Changes in apparent diffusion coefficient and pathological response in colorectal liver metastases after preoperative chemotherapy.

The pathological response to preoperative chemotherapy of colorectal liver metastases (CRLMs) is predictive of long-term prognosis after liver resection. Accurate preoperative assessment of chemotherapy response could enable treatment optimization. To investigate whether changes in lesion-apparent diffusion coefficient (ADC) measured with diffusion-weighted magnetic resonance imaging (MRI) can be used to assess pathological treatment response in patients with CRLMs undergoing preoperative chemotherapy. Patients who underwent liver resection for CRLMs after preoperative chemotherapy between January 2011 and December 2019 were retrospectively included if they had undergone MRI before and after preoperative chemotherapy on the same 1.5-T MRI scanner with diffusion-weighted imaging with b-values 50, 400, and 800 s/mm2. The pathological chemotherapy response was assessed using the tumor regression grade (TRG) by AJCC/CAP. Lesions were divided into two groups: pathological responding (TRG 0-2) and non-responding (TRG 3). The change in lesion ADC after preoperative chemotherapy was compared between responding and non-responding lesions. A total of 27 patients with 49 CRLMs were included, and 24/49 lesions showed a pathological chemotherapy response. After chemotherapy, ADC increased in both pathological responding (pretreatment ADC: 1.26 [95% confidence interval (CI)=1.06-1.37] vs. post-treatment ADC: 1.33 [95% CI=1.13-1.56] × 10-3 mm2/s; P = 0.026) and non-responding lesions (1.12 [95% CI=0.980-1.21] vs. 1.20 [95% CI=1.09-1.43] × 10-3 mm2/s; P = 0.018). There was no difference in median relative difference in ADC after chemotherapy between pathological responding and non-responding lesions (15.8 [95% CI=1.42-26.3] vs. 7.17 [95% CI=-4.31 to 31.2]%; P = 0.795). Changes in CRLM ADCs did not differ between pathological responding and non-responding lesions.

T1 mapping as a surrogate marker of chemotherapy response evaluation in patients with osteosarcoma

ObjectivesTo characterize baseline T1 values of tumors, measure changes after the course of chemotherapy, and evaluate its potential as a marker of response assessment in patients with osteosarcoma. Materials and MethodsA total of 35 patients (male:female = 27:8; age = 17.9 ± 6 years; metastatic:localized = 11:24) with biopsy-proven osteosarcoma were analyzed prospectively. All patients underwent magnetic resonance imaging before neoadjuvant chemotherapy (NACT) (baseline) and after NACT completion (follow-up), followed by surgery and histopathological evaluation. Histopathological necrosis served as the gold standard for assessing chemotherapy response (responder: ≥50% necrosis and non-responder: <50% necrosis). Three-dimensional spoiled gradient recalled echo images were acquired with varying flip angles (50, 100, 200, and 300) using a 1.5 Tesla scanner. T1 values were estimated in healthy muscle tissue and tumors at baseline and follow-up, and the relative percentage changes after NACT (ΔT1) were evaluated, and histogram analysis was performed to characterize the T1 value of the tumor and predict the NACT response using the Pearson correlation coefficient (r) and receiver operating characteristic curve analysis. ResultsAt baseline, a significantly higher T1-mean (830.96 ± 193.88 msec versus 683.29 ± 210.00 msec; p = 0.003) and lower T1-skewness (0.86 ± 1.66 versus 1.60 ± 1.55; p = 0.02) were observed in osteosarcoma than healthy tissue. Responder:non-responder ratio was 13:22. At baseline, a significantly higher T1-mean (936.14 ± 193.17 msec versus 768.82 ± 169.25 msec; p = 0.018) and lower T1-skewness (-0.17 ± 0.85 versus 1.47 ± 1.73; p = 0.003) were observed among responders, than non-responders. After NACT, ΔT1 in tumor was significantly higher among responders than non-responders (-27.22 ± 12.17% versus −15.70 ± 18.99%; p = 0.034). ΔT1-mean and ΔT1-skewness after NACT were moderately correlated (r = − 0.4, p = 0.030; r = 0.4, p = 0.011) with histopathological necrosis. For predicting NACT response, T1-mean and T1-skewness jointly produced an area under the curve (AUC) = 0.80 at baseline, and ΔT1-mean and ΔT1-skewness jointly produced AUC = 0.76 after NACT. ConclusionThe mean and skewness of T1 values in osteosarcoma are potential non-invasive imaging markers for chemotherapy response assessment.

Angiogenesis versus Metabolic Imaging in Locally Advanced Breast Cancer Patients - A Comparative Study.

Purpose:The comparison of angiogenesis imaging (Ga-68-DOTA-Arginine-Glycine-Aspartic Acid [RGD]) positron emission tomography/computed tomography [PET/CT]) with metabolic imaging (F-18 fluorodeoxyglucose [FDG] PET/CT) in primary staging and response assessment to neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC) patients.Methods:In this prospective study, 85 female patients with LABC were subjected to two PET/CT studies (Ga-68-DOTA-RGD2 and F-18 FDG) within 1 week of each other. Thirty patients had repeat studies 4 weeks after completing eight cycles of NACT. Response assessment was done by RECIST 1.1 criteria.Results:Ga-68-DOTA-RGD2 and F-18 FDG uptake in the primary tumor were seen in all patients. Ipsilateral axillary and internal mammary lymph nodes were detected in 77 (90.5%) versus 80 (94.1%) and 22 (25.8%) versus 27 (31.7%) patients on Ga-68-DOTA-RGD2 and F-18 FDG scans, respectively. Ipsilateral supra-clavicular lymph nodes and skeletal lesions were noted in 17 (20%) versus 21 (24.7%) patients and 23 (27.0%) versus 24 (28.2%) patients on Ga-68-DOTA-RGD2 versus F-18 FDG studies, respectively. However, the Ga-68-DOTA-RGD2 did not show uptake in F-18 FDG avid liver lesions (LLs) in 10 patients, adrenal lesion in one patient, mediastinal lymph nodes in 2 patients, lung nodules, and pleural soft-tissue deposits, each in one patient. In response assessment, 23 and 25 patients had concordance with RECIST1.1 criteria on F-18 FDG and Ga-68-DOTA-RGD2 scans, respectively. However, there were discordant results in four patients on Ga-68-DOTA-RGD2 scan and two patients on F-18 FDG scans.Conclusion:Metabolic imaging is better in primary staging and chemotherapy response assessment than angiogenesis imaging in LABC patients. The latter may miss the metastatic soft-tissue deposits, adrenal, and LLs.

Clonal Progression during First Course of Chemotherapy in Acute Myeloid Leukemia Suboptimal Responders Heralds Reinduction Failure and Early Death

INTRODUCTIONOptimal response to induction chemotherapy for acute myeloid leukemia (AML) is achievement of complete remission (CR) and minimal residual disease (MRD) negativity. Suboptimal responses include achievement of CR but MRD positivity (CRMRD+ patients) as well as failure to achieve CR. The prospect is bleak, especially in the latter group, but intensified treatment can cure some of these. Careful deliberation of patient fitness, drug toxicities and level of residual disease is required prior to choice of reinduction therapy. HYPOTHESISWe hypothesized that by studying clonal architecture changes during AML treatment, subclonal development or progression would add another dimension to the chemotherapy response assessment beyond that of merely a quantitative reduction in blasts or a given MRD marker. PATIENTS AND METHODS25 uniformly treated (“3+7” like) AML patients were included, 7 CRMRD+ (flow cytometry-determined MRD levels between 0.02% and 1%), and 18 who did not achieve CR after the first course of chemotherapy, of whom 17 received reinduction chemotherapy. Median time from diagnosis to CR evaluation after first course of chemotherapy: 33 days (range: 20-74 days)For the CRMRD+ patients; MRD cells from bone marrow samples taken after 1st treatment course were isolated using a FACSAria III based on the appropriate leukemia associated phenotype determined at diagnosis.All samples were analyzed using a 26-gene panel (ASXL1, BCOR, CALR, CBL, CSNK1A1, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2) . Furthermore, CSFR3, GATA1, PTPN11 and WT1 were analyzed in the group who did not achieve CR. The TruSeq Custom Amplicon kit was used for library prep and samples were sequenced using the MiSeq instrument. RESULTSIn the CRMRD+ group clonal architecture in unsorted diagnosis samples were compared to clonal architecture in the FACS products. In 3 informative cases, a development in the clonal architecture was seen. In two cases, a subclone positive for TET2 only persisted even if the fully mutated clones of the patients (one TET2 +/ NRAS +, one TET2 +/ NPM1 +/ IDH2 +) disappeared. Both patients relapsed. In the third patient; a IDH2 + SRSF2 + clone persisted, a IDH2 + SRSF2 + BCOR + clone disappeared. In the remaining 4 patients no mutations were detected in the FACS product.For the group of patients not in CR clonal architecture development between diagnosis and regeneration after first course of chemotherapy could be studied in 16/18 cases. Two cases were negative for all aberrations tested. 9/16 cases were clonally stable, displaying a reduction in mutation load comparable to leukemic burden reduction. In the remaining 7 cases, clonal development was seen: In 4 cases, one or more subclones were selectively eradicated leaving the more resistant clones. NPM1 was the only marker that was eradicated in more than one clone (n=2) and TET2 was the only marker that persisted in more than one clone (n=2). In 3/7 cases subclones emerged during chemotherapy; a WT1 + NRAS + clone in a NRAS + background, a SETBP1 + TET2 + ASXL1 + RUNX1 + clone in an RUNX1 + background and a DNMT3A + NPM1 + clone in a NPM1 + background. The 2-year survival of patients who received further chemotherapy was significantly different in the three groups (Clonally stable (n=9): 0.58, clonal architecture development but no emerging subclones (n=4): 0.25, AMLs with emerging subclones (n=3): 0 (last patient died after 224 days), P = 0.01 (Log-rank test)). CONCLUSIONThis study provides proof of the concept of subclonal architecture changes even in patients with minute amounts of residual leukemia (CRMRD+ group) and we were able to study the subclonal architecture changes in three of these patients.In patients not reaching CR, clonal architecture development was a rather common occurrence (7/16 cases). In three patients we observed that not only did a subclone resist chemotherapy, it grew during treatment. Even in this small study, this finding proved to be a significant marker of ultimate treatment failure.If corroborated in larger studies, we envisage that an approach like the one applied here can assist physicians' decisions in the choice of further treatment in patients experiencing suboptimal response to induction chemotherapy. DisclosuresMeggendorfer:MLL Munich Leukemia Laboratory: Employment. Koch:Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Circulating tumor DNA is a sensitive marker for routine monitoring of treatment response in advanced colorectal cancer

Accurate assessment of chemotherapy response provides the means to terminate ineffective treatment, trial alternative drug regimens or schedules and reduce dose to minimize toxicity. Here, we have compared circulating tumor DNA (ctDNA) with carcinoembryonic antigen (CEA) for the cycle by cycle assessment of chemotherapy response in 30 patients with metastatic colorectal cancer. CtDNA (quantified using individualized digital droplet PCR (ddPCR) assays) and CEA levels were determined immediately prior to each chemotherapy cycle over time periods ranging from 42-548 days (average of 10 time points/patient). Twenty-nine/thirty (97%) patients had detectable ctDNA compared with 83% whose tumors were CEA-positive (>5 ng/ml) during the monitoring course. Over the course of treatment, 20 disease progression events were detected by computed tomography; ctDNA predicted significantly more of these events than CEA (16 (80%) versus 6 (30%), respectively; P-value = 0.004). When progression was detected by both ctDNA and CEA, the rise in ctDNA occurred significantly earlier than CEA (P-value = 0.046). Partial responses to chemotherapy were also detected more frequently by ctDNA, although this was not significant (P-value = 0.07). In addition, another 28 colorectal cancer patients who underwent potentially curative surgery and showed no evidence of residual disease were monitored with ctDNA for up to 2 years. Clinical relapse was observed in 6/28 (21%) patients. Four out of 6 of these patients showed a significant increase in ctDNA at or prior to relapse. Overall, ctDNA analyses were able to be performed in a clinically relevant timeline and were a more sensitive and responsive measure of tumor burden than CEA.

The role of volumetric method in the assessment of chemotherapy response and predicting survival in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a pleural tumor with high mortality rate and short-term survival expectancy after diagnosis. Assessment of the response to chemotherapy, which is the first choice in treatment of MPM, is important for the transition to alternative chemotherapy protocols and immunotherapy. There is no clarity in the response to chemotherapy treatment. Our study aims to compare the assessment of chemotherapy response using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and volumetric measurements and to correlate with median survival. Thirty-two patients (16 females and 16 males) were included in the study, and their ages ranged from 28 to 78 years. Chemotherapy response was determined by both mRECIST and volumetric approach. Tumor volume was measured by linear interpolation and semi-automatic segmentation. Log-rank multiple cutoff analysis was used to determine appropriate cutoff values of volumetric response criteria. According to both mRECIST and volumetric approach, median survival times in partial response, stable disease, and progressive disease groups were 24, 15, and 9 months, respectively. The survival times of the three groups were different (logrank: 17.76; P < 0.001) by mRECIST. The survival of the progressive disease group was shorter than that of the other groups (logrank: 18.91; P < 0.001) by volumetric approach. In the assessment of chemotherapy response, even though classifications obtained according to the mRECIST criteria and volumetric measurements are statistically compatible, we think that the measurement of the volumetric values will increase the standardization. In our study, threshold values for volumetric measurements were determined; however, these values should be supported by large-scale multicenter studies.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study

BackgroundIt is estimated that around 15–30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy.It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs.MethodsIn this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3–4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8–10 Dutch hospitals. The first patient was included in February 2020.DiscussionPatient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated.Trial registrationThis study has been registered in the Netherlands Trial Register (NL8177) at 11–26-2019, https://www.trialregister.nl/trial/8177. The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Computed tomography texture analysis for assessment of chemotherapy response of Hodgkin lymphoma.

The aim of this study was to test the hypothesis that computed tomography texture analysis (CTTA) is accurate for response assessment of Hodgkin lymphoma (HL).A total of 100 patients with HL were identified. CTTA in baseline and interim staging was performed generating volume of interests in lymphoma tissue from which CTTA features including 1st, 2nd, and higher order textural features were extracted. Baseline and interim 2-deoxy-fluor-glucose positron emission tomography results were used to determine therapy response and compared to CTTA in terms of patient outcome.At interim, 1st-order features yielded a significant drop (e.g., entropy of heterogeneity, P = .01) or a significant rise (deviation, P < .001), whereas 2nd and higher order features decreased (e.g., entropy of co-occurrence matrix, P < .001). Patients achieving complete remission at end of treatment had a significantly lower entropy of heterogeneity at baseline and interim compared to patients achieving partial remission (P < .05).CT textural features change in parallel to metabolic therapy response, and are therefore a feasible diagnostic tool for a more accurate response assessment of HL.

Phase 2 Study of Dose-Reduced Consolidation Radiation Therapy in Diffuse Large B-Cell Lymphoma

To evaluate the feasibility of reducing the dose of consolidation radiation therapy (RT) in diffuse large B-cell lymphoma. This phase 2 study enrolled patients with diffuse large B-cell lymphoma, not otherwise specified and primary mediastinal (thymic) large B-cell lymphoma in complete response on positron emission tomography-computed tomography imaging after ≥4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen. Consolidation RT used a dose of 19.5 to 20Gy. The primary endpoint was 5-year freedom from local recurrence. Sixty-two patients were enrolled between 2010 and 2016. Stage distribution was as follows: I to II (n=49, 79%) and III to IV (n=13, 21%). Bulky disease (defined as ≥7.5cm or ≥10cm) was present in 23 (40%) and 16 (28%) patients, respectively. Chemotherapy was R-CHOP (then list the drugs) in 58 (94%) and R-EPOCH (then list the drugs) in 4 (6%) with a median of 6 cycles. With a median follow-up of 51months, 7 patients developed disease progression (6 outside the RT field, 1 within the RT field). Freedom from local recurrence at 5years was 98% (90% lower confidence bound, 88%). Progression-free and overall survival at 5years were 83% and 90%, respectively. With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., positron emission tomography-computed tomography), the dose of RT in combined modality treatment programs may potentially be reduced to 20Gy. This achieves excellent local control with the potential to decrease acute and long-term side effects.

The effect of low insurance reimbursement on quality of care for non-small cell lung cancer in China: a comprehensive study covering diagnosis, treatment, and outcomes

BackgroundThe insurance reimbursement rate of medical cost affects the quality and quantity of health services provided in China. The nature of this relationship, however, has not been reliably described in the field of non-small cell lung cancer (NSCLC). The objective of the current study was to examine the impact of low reimbursement rates of medical costs on diagnosis, treatment and outcomes among patients with NSCLC.MethodsWe examined care of 2643 NSCLC patients and we divided the study cohort into a high reimbursement rate group and a low reimbursement rate group. The impact of reimbursement rates of medical costs on quality of care of NSCLC patients were examined using logistic regression and generalized linear models.ResultsCompared with patients insured with high reimbursement rate, patients insured through lower reimbursement rate programs were less likely to benefit from early detection and treatment services. Delayed detection was more common in low reimbursement group and they were less likely to be recommended for adjuvant chemotherapy, or to receive adjuvant chemotherapy and postoperative radiation therapy and they had lower odds to receipt chemotherapy response assessment. However, low reimbursement rate group had lower rate of in-hospital mortality and metastases.ConclusionsLow reimbursement rate mainly negatively influenced the diagnosis and treatment of NSCLC. Reducing the gap in reimbursement rate between the three health insurance schemes should be a focus of equalizing access to care and improving the level of medical compliance and finally improving quality of care of NSCLC.