Partial Response Group Research Articles

Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic Graft vs. Host Disease: A Report of Two Phase I/II Trials

Introduction Sclerotic chronic graft vs. host disease (scGVHD) is characterized by progressive skin fibrosis that often causes limited mobility and poor quality of life. Aberrant activation of hedgehog signaling leading to the differentiation of dermal fibroblasts into collagen-releasing myofibroblasts has been implicated in scGVHD. Targeted inhibition with hedgehog pathway inhibitors ameliorate fibrosis in experimental models. Our objective was to determine the safety and efficacy of glasdegib, an oral antagonist of the hedgehog signalling transducer Smoothened (SMO) in adult patients (pts) with refractory scGVHD. Methods Two independent, single-arm, open-label, phase I/II investigator-initiated studies [NCT03415867, Spanish Transplantation and Cellular Therapy Cooperative Group (GETH); NCT04111497, Fred Hutchinson Cancer Center/Huntsman Cancer Institute/Duke University Medical Center (FHD)] were performed. Adults with active scGVHD after ≥1 (FHD) or ≥2 (GETH) lines of prior therapy were enrolled. The GETH trial followed a 3+3 dose-finding strategy, whereas the FHD trial employed a fixed-dose design. Primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in the GETH trial, and safety and tolerability in the FHD trial. Secondary endpoints included efficacy, patient-reported outcomes and biological correlates of response. Glasdegib was administered once daily in continuous 28-day cycles. Individual organs were scored per 2014 NIH cGVHD criteria. A scGVHD partial response (PR) was defined as skin and/or joints score improvement (≥1 point for body surface area [BSA], skin features or joints/fascia scores; ≥2 points for skin/joints tightening or total P-ROM scores) in the absence of worsening in those scores or an increase ≥2 points in the global severity score. Data cut-off was at 12 months from time of glasdegib initiation. Results Twenty (GETH) and 15 (FHD) pts were enrolled who received a median of 4 (range 2-10) and 4 (1-16) prior lines of therapy. The median age was 47 years (range 27-73) and 64 (33-74) in the GETH and FHD studies, respectively. In the GETH trial, 3 pts were included in cohort 1 (50 mg), 3 in cohort 2 (100 mg) and 16 in the expansion cohort (50 mg). All pts in the FHD trial received glasdegib at an initial dose of 50 mg. Frequent treatment-emergent grade (G) ≥2 adverse events (AEs) in the GETH trial included muscle cramps (85%), alopecia (50%) and dysgeusia (35%). Two pts in cohort 2 experienced a DLT (G3 muscle cramps) that resulted in establishment of the MTD at 50 mg. Similarly, G3 muscle cramps were the most frequently reported adverse event (AE) occurring in 33% of pts in the FHD trial. In the FHD study, a pre-specified trial stopping rule was triggered by the emergence of G3 muscle cramps AEs in 5 pts. In the GETH trial, glasdegib dose reductions were undertaken in 10 pts, and 8 pts stopped glasdegib before completion of 12 cycles of therapy. Ten pts remained on treatment beyond 12 months. In the FHD trial, the glasdegib dose was reduced in 5 pts; 12 pts stopped glasdegib before 12 cycles. Two pts remained on treatment for longer than 12 months and one pt remains on glasdegib at 10 months. At the 12-month data cut-off, 9 (45%) pts in the GETH trial achieved a skin BSA score and/or sclerotic features score PR, and 9 (45%) pts had obtained a joints/fascia score response (6 PRs, 3 complete responses). Corresponding findings in the FHD trial were 4 pts (27%; 3 PRs, 1 CR) and 3 pts (20%; 2 PRs, 1 CR). An improvement ≥2 points in the total P-ROM score was observed in 11 (55%) pts in the GETH study and 4 (27%) pts in the FHD study, Additionally, an improvement ≥2 points in the 0-10 skin and/or joint tightening severity scale was reported in 13 (65%) and 4 (31%; 2 pts with missing data) pts in the GETH and FHD trials, respectively. Overall, 13 (65%) pts obtained a scGVHD PR in the GETH trial, with a median time of 2.4 months to response. Likewise, 7 (47%) pts had a scGVHD PR in the FHD group, with a median time of 0.9 months to response. Preliminary correlative studies did not show changes in the distribution of T-cell subpopulations or TCR diversity in the GETH trial. Conclusions Glasdegib demonstrated high rates of clinical activity in heavily pretreated pts with scGVHD, but tolerability was hampered by the emergence of treatment-related muscle cramps. Yet, selected pts derived a sustained benefit from treatment in the absence of limiting toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between serum baseline C1q and IgG levels and the efficacy of combined immunotherapy in patients with esophageal squamous cell carcinoma: a retrospective study

Background To assess the clinical value of serum complement component 1q (C1q) and immunoglobulin G (IgG) levels in predicting the response to combined immunotherapy in patients with esophageal squamous cell carcinoma. Methods We conducted a retrospective study of 44 patients with esophageal squamous cell carcinoma who received combined immunotherapy in our hospital. Serum IgG and C1q levels were collected before and three weeks after immunotherapy treatment, together with other data on clinical and demographic characteristics. Results Twenty seven patients (61.4%) showed partial response (PR), 13 (29.5%) stable disease (SD), and 4 (9.1%) progressive disease (PD). None of the patients presented complete response (CR). The PR group displayed lower IgG and higher C1q levels both before and after immunotherapy than patients showing SD or PD. The IgG reduction (59.3%) and C1q increment (70.3%) in the PR group three weeks post-treatment were significantly larger than those in patients showing SD or PD. Moreover, the pretreatment C1q level and the post-treatment change of C1q levels were strongly associated with the immunotherapy response. Conclusions High pre- and post-treatment C1q levels and reduced post-treatment IgG levels correlate with efficacy of combined immunotherapy in patients with esophageal squamous cell carcinoma. Serum baseline C1q level may predict immunotherapy response in such patients.

THE ROLE OF DIFFUSION-WEIGHTED MR IMAGING IN EVALUATING THE RESPONSE TO STEROID THERAPY IN IDIOPATHIC GRANULOMATOUS MASTITIS LESIONS

Objective: The aim of this study was to investigate the role of diffusion-weighted magnetic resonance imaging (DW MRI) with an apparent diffusion coefficient (ADC) map in evaluating the response to treatment of steroid-treated idiopathic granulomatous mastitis (IGM) lesions. Materials and Methods: This retrospective study included 99 lesions of 58 female patients (average age: 32.91 years; range: 22–55 years) with biopsy-proven IGM. Patients were treated with oral and topical steroids. All pre-treatment and post-treatment MR examinations were evaluated. The maximal size of the masses and nonmass enhancement (NME) lesions were measured. Patients were classified as complete response (CR), partial response (PR), and non-response (NR) according to the dynamic contrast-enhanced (DCE) MR findings after treatment. Results: ADC values of areas occupied by IGM (0.933±0.317x10-3 mm2 /sec) were lower than contralateral normal parenchyma (1.259±0.423x10-3 mm2 /sec). Twenty-two (22.22%) of the lesions were in the NR group, 30 (30.30%) in the PR group, and 47 (47.47%) in the CR group. There was no significant difference between the pre-treatment ADC values in NR, PR, and CR groups (p=0.228). There was a significant difference between the pre-treatment and post-treatment ADC values in the PR groups (p=0.001). Conclusion: DW MR imaging in IGM is a useful method to monitor the response to treatment. However, it is not successful in predicting response to treatment.

Apparent diffusion coefficient histogram analysis for predicting neoadjuvant chemoradiotherapy response in patients with rectal cancer.

PURPOSE This study aimed to retrospectively evaluate the apparent diffusion coefficient (ADC) histograms in predicting chemoradiotherapy (CRT) response in patients with locally advanced rectal cancer (LARC). METHODS A total of 51 patients who underwent surgery in our institution for rectal cancer following neoadjuvant CRT between November 2013 and July 2019 were enrolled. Conventional magnetic resonance (MR) and diffusion-weighted images obtained before and after CRT were evaluated retrospectively. All tumor-containing regions of interests were drawn in 3 selected axial images, and special software for histogram analysis was used to evaluate ADC distribution. ADC cutoff values from post-CRT ADC histogram were calculated from receiver operating characteristic (ROC) analysis for evaluating CRT response. RESULTS In histopathological analysis, 5 patients (9.8%) had minimal response (group 1), 31 patients (60.8%) had partial response (group 2), and 15 patients (29.4%) had complete or almost complete response (group 3). In the ADC histogram, minimum, maximum, 10th, 25th, 50th, 75th, and 90th percentile, mean ADC values, and skewness values of groups 2 and 3 showed significant changes before and after CRT, but no difference was found within group 1 values. The mean, 25th, 50th, 75th percent ADC values after CRT and skewness, and kurtosis values were significantly different between group 1 and group 3. Skewness value from the ADC histogram in postCRT magnetic resonance imaging had the best diagnostic performance with an area under the ROC curve of 0.851 (P =.003) for detecting group 3. The skewness cutoff calculated from the ROC analysis was 0.210 for evaluating CRT response. The sensitivity and specificity of the cut-off value were 100% and 61.4%, respectively. CONCLUSION The ADC histogram analysis seems to have potential application in predicting response to neoadjuvant CRT in patients with locally advanced rectal cancer.

Gut microbiota composition in chemotherapy and targeted therapy of patients with metastatic colorectal cancer.

Studies have reported the effects of the gut microbiota on colorectal cancer (CRC) chemotherapy, but few studies have investigated the association between gut microbiota and targeted therapy. This study investigated the role of the gut microbiota in the treatment outcomes of patients with metastatic CRC (mCRC). We enrolled 110 patients with mCRC and treated them with standard cancer therapy. Stool samples were collected before administering a combination of chemotherapy and targeted therapy. Patients who had a progressive disease (PD) or partial response (PR) for at least 12 cycles of therapy were included in the study. We further divided these patients into anti-epidermal growth factor receptor (cetuximab) and anti-vascular endothelial growth factor (bevacizumab) subgroups. The gut microbiota of the PR group and bevacizumab-PR subgroup exhibited significantly higher α-diversity. The β-diversity of bacterial species significantly differed between the bevacizumab-PR and bevacizumab-PD groups (P = 0.029). Klebsiella quasipneumoniae exhibited the greatest fold change in abundance in the PD group than in the PR group. Lactobacillus and Bifidobacterium species exhibited higher abundance in the PD group. The abundance of Fusobacterium nucleatum was approximately 32 times higher in the PD group than in the PR group. A higher gut microbiota diversity was associated with more favorable treatment outcomes in the patients with mCRC. Bacterial species analysis of stool samples yielded heterogenous results. K. quasipneumoniae exhibited the greatest fold change in abundance among all bacterial species in the PD group. This result warrants further investigation especially in a Taiwanese population.

Complete Response Evaluation of Locally Advanced Rectal Cancer to Neoadjuvant Chemoradiotherapy Using Textural Features Obtained from T2 Weighted Imaging and ADC Maps.

The prediction of pathological responses for locally advanced rectal cancer using magnetic resonance imaging (MRI) after neoadjuvant chemoradiotherapy (CRT) is a challenging task for radiologists, as residual tumor cells can be mistaken for fibrosis. Texture analysis of MR images has been proposed to understand the underlying pathology. This study aimed to assess the responses of lesions to CRT in patients with locally advanced rectal cancer using the first-order textural features of MRI T2-weighted imaging (T2-WI) and apparent diffusion coefficient (ADC) maps. Forty-four patients with locally advanced rectal cancer (median age: 57 years) who underwent MRI before and after CRT were enrolled in this retrospective study. The first-order textural parameters of tumors on T2-WI and ADC maps were extracted. The textural features of lesions in pathologic complete responders were compared to partial responders using Student's t- or Mann-Whitney U tests. A comparison of textural features before and after CRT for each group was performed using the Wilcoxon rank sum test. Receiver operating characteristic curves were calculated to detect the diagnostic performance of the ADC. Of the 44 patients evaluated, 22 (50%) were placed in a partial response group and 50% were placed in a complete response group. The ADC changes of the complete responders were statistically more significant than those of the partial responders (P = 0.002). Pathologic total response was predicted with an ADC cut-off of 1310 x 10-6 mm2/s, with a sensitivity of 72%, a specificity of 77%, and an accuracy of 78.1% after neoadjuvant CRT. The skewness of the T2-WI before and after neoadjuvant CRT showed a significant difference in the complete response group compared to the partial response group (P = 0.001 for complete responders vs. P = 0.482 for partial responders). Also, relative T2-WI signal intensity in the complete response group was statistically lower than that of the partial response group after neoadjuvant CRT (P = 0.006). As a result of the conversion of tumor cells to fibrosis, the skewness of the T2-WI before and after neoadjuvant CRT was statistically different in the complete response group compared to the partial response group, and the complete response group showed statistically lower relative T2-WI signal intensity than the partial response group after neoadjuvant CRT. Additionally, the ADC cut-off value of 1310 × 10-6 mm2/s could be used as a marker for a complete response along with absolute ADC value changes within this dataset.

Stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC).

BackgroundDefinitive chemoradiation is the preferred treatment for cervical esophageal carcinoma (CEC), per the National Comprehensive Cancer Network (NCCN) guidelines. However, in treatment failures, salvage surgery poses significant technical challenges. If non-responders could be identified, prior to chemoradiation, these patients may benefit from primary esophagectomy. Programmed cell death protein 1 (PD-1) inhibitor is widely used and recognized as an effective treatment method in various cancers including esophageal cancer. Therefore, we propose to screen for treatment response to neoadjuvant immunotherapy plus chemotherapy to select patients who are radiosensitive and potential candidates for laryngeal preservation. While non-responders are likely to be insensitive to chemoradiation would be offered radical esophagectomy.MethodsA total of 36 patients with histopathologically-confirmed locally advanced CEC have been enrolled in our study. All participants will receive 2 cycles of induction therapy, which was tislelizumab combined with paclitaxel and carboplatin. Patients will be classified into 3 groups according to their response to induction therapy: a remarkable response (RR) group, limited partial response (LPR) group, and poor response (POR) group. Stratified patients will receive the following follow-up treatments: those in the RR group will receive dCRT, and those in the LPR and POR groups will undergo radical surgery. Then, participants in the RR group will be administrated with tislelizumab alone for 1 year. The choice of postoperative treatment for patients in the LPR and POR groups will depend on the patient’s condition, including chemotherapy, radiotherapy, immunotherapy, or follow-up. The primary endpoint of the study is the 2-year event-free survival (EFS). The secondary endpoints are disease-free survival (DFS), regression-free survival (RFS), objective response rate (ORR), and 5-year overall survival (OS). At the same time, we will assess the patient’s quality of life (QoL).ConclusionsScreening CEC patients after immune-induction therapy combined with chemotherapy using different treatment strategies might lead to improvements in their QoL and OS time. No relevant double-endpoint studies have been reported until now. Our study is the first multicenter, prospective, exploratory study to seek the optimal treatment for locally advanced CEC patients. The results may offer high-level evidence for future CEC treatment.Trial RegistrationChictr.Org identifier: ChiCTR2200057732.

Fear of Recurrence and Somatic Symptom Severity in Multiple Myeloma Patients: An Institution-Based Cross-Sectional Study

Abstract Introduction Psychosocial concerns especially fear of cancer recurrence (FCR) is less commonly addressed among patients with multiple myeloma in India. Myeloma being incurable, an understanding of this problem is essential for adequately addressing them. Objectives To study the prevalence of FCR among patients with multiple myeloma and determine the prevalence of somatic symptoms among patients with multiple myeloma. Materials and Methods A cross-sectional study was performed at our institution among patients with multiple myeloma who had been on treatment for 1 year or more. The study was conducted between July 01 and July 31, 2015. At least 49 patients were required to be recruited into this study to meet its first objective. Patients were administered fear of cancer recurrence inventory (FCRI) questionnaire and Physical Health Questionnaire-15 (PHQ-15) questionnaire. Results Sixty-four patients participated in the study. The median age was 60 years (34–80 years) and majority were females (N = 38, 60%). ISS staging information was available in 53 (83%) patients. Of 53, 24 (45%) were ISS stage 3, 12 (23%) were ISS stage 2 and remaining stage 1. The mean total FCRI score in the study population was 27.95 (SD: 24.5). Moderate to high levels of FCR were seen in 40% (N = 26). Using PHQ-15, 54 (84%) patients had mild or lesser somatic symptom burden. Disease status of patients at the time of this study had a significant statistical association with PHQ-15 scores (mean score in partial response (PR) or more group 6.02 versus 8.00 in less than PR group, p = 0.02). Conclusions Overall, FCR scores and somatic symptom severity were low among our patients with multiple myeloma. However, a significant proportion had moderate to high levels of FCR. Further studies involving larger numbers in a prospective manner required to confirm our findings of fear of cancer recurrence among patients with multiple myeloma.

Arterial enhancement fraction in evaluating the therapeutic effect and survival for hepatocellular carcinoma patients treated with DEB-TACE

BackgroundArterial enhancement fraction (AEF), derived from triphasic CT scans, is considered to indirectly reflect the ratio of hepatic arterial perfusion to total perfusion. The purpose of this study was to retrospectively investigate the relationship between AEF and treatment response and survival in hepatocellular carcinoma (HCC) patients treated with drug-eluting bead (DEB) TACE.MethodsAEF of primary lesion (AEFpre) and residual tumor (AEFpost) in 158 HCC patients were obtained from triphasic liver CT examinations pre- and post-treatment. Wilcoxon-signed rank test was used to compare the AEFpre and AEFpost for different response groups. Survival curves for overall survival (OS) in patients with different AEF were created by using Kaplan-Meier method. Cox regression analyses were used to determine the association between AEF and OS.ResultsThere was no correlation between AEFpre and treatment response. After DEB-TACE, AEFpost was significantly lower than AEFpre either in the partial response group (38.9% vs. 52.7%, p < 0.001) or in the stable disease group (49.3% vs. 52.1%, p = 0.029). In the progression disease group, AEFpost was numerically higher than AEFpre (55.5% vs. 53.0%, p = 0.604). Cox regression analyses showed that risk of death increased in patients with AEFpre > 57.95% (HR = 1.66, p = 0.019) or AEFpost > 54.85% (HR = 2.47, p < 0.001), and the risk reduced in patients with any reduction in tumor AEF (decrease ratio ≥ 0) and with increased AEF but not exceeding the ratio of 0.102 (increase ratio < 0.102) (HR = 0.32, p < 0.001).ConclusionsThe change in AEF of viable tumor is correlated with response of HCC to DEB-TACE. In addition, the AEF could be a helpful predictor in future studies on the embolization treatment for HCC.

Prediction of the therapeutic efficacy of epirubicin combined with ifosfamide in patients with lung metastases from soft tissue sarcoma based on contrast-enhanced CT radiomics features

ObjectiveTo investigate the value of contrast-enhanced computed tomography (CECT) radiomics features in predicting the efficacy of epirubicin combined with ifosfamide in patients with pulmonary metastases from soft tissue sarcoma.MethodsA retrospective analysis of 51 patients with pulmonary metastases from soft tissue sarcoma who received the chemotherapy regimen of epirubicin combined with ifosfamide was performed, and efficacy was evaluated by Recist1.1. ROIs (1 or 2) were selected for each patient. Lung metastases were used as target lesions (86 target lesions total), and the patients were divided into a progression group (n = 29) and a non-progressive group (n = 57); the latter included a stable group (n = 34) and a partial response group (n = 23). Information on lung metastases was extracted from CECT images before chemotherapy, and all lesions were delineated by ITK-SNAP software manually or semiautomatically. The decision tree classifier had a better performance in all radiomics models. A receiver operating characteristic curve was plotted to evaluate the predictive performance of the radiomics model.ResultsIn total, 851 CECT radiomics features were extracted for each target lesion and finally reduced to 2 radiomics features, which were then used to construct a radiomics model. Areas under the curves of the model for predicting lesion progression were 0.917 and 0.856 in training and testing groups, respectively.ConclusionThe model established based on the radiomics features of CECT before treatment has certain predictive value for assessing the efficacy of chemotherapy for patients with soft tissue sarcoma lung metastases.

Arterial spin labeling of nasopharyngeal carcinoma shows early therapy response

ObjectiveThis study aimed to determine the value of arterial spin labeling (ASL) perfusion imaging in assessing the early efficacy of chemoradiotherapy for nasopharyngeal carcinoma (NPC).MethodsFifty-five patients with locoregionally advanced NPC underwent conventional 3.0-T magnetic resonance imaging (MRI) and ASL before and after chemoradiotherapy (prescribed dose reached 40 Gy). Based on the response evaluation criteria for solid tumors (RECIST 1.1), the patients were divided into the partial response and stable disease groups. MRI re-examination was performed one month after chemoradiotherapy completion, and patients were divided into residual and non-residual groups. We investigated inter-group differences in ASL-based tumor blood flow (TBF) parameters (pre-treatment tumor blood flow, post-treatment tumor blood flow, and changes in tumor blood flow, i.e., Pre-TBF, Post-TBF, ΔTBF), correlation between TBF parameters and tumor atrophy rate, and value of TBF parameters in predicting sensitivity to chemoradiotherapy.ResultsThere were differences in Pre-TBF, Post-TBF, and ΔTBF between the partial response and stable disease groups (p < 0.01). There were also differences in Pre-TBF and ΔTBF between the residual and non-residual groups (p < 0.01). Pre-TBF and ΔTBF were significantly correlated with the tumor atrophy rate; the correlation coefficients were 0.677 and 0.567, respectively (p < 0.01). Pre-TBF had high diagnostic efficacies in predicting sensitivity to chemoradiotherapy and residual tumors, with areas under the curve of 0.845 and 0.831, respectively.ConclusionASL permits a noninvasive approach to predicting the early efficacy of chemoradiotherapy for NPC.

Tumour response heterogeneity as a powerful independent predictor of treatment outcome in advanced lung adenocarcinoma: a retrospective analysis

Tumour response heterogeneity to treatment is common across different foci in the same patient with cancer. However, the effect of heterogeneity on clinical outcome remains unclear. Here, we developed a quantitative assessment of tumour response heterogeneity and explored the correlation of tumour response heterogeneity with the clinical outcome. Patients eligible for this retrospective study had advanced lung adenocarcinoma, with 3-10 measured foci, an Eastern Cooperative Oncology Group status of 0-1, and received first-line chemotherapy or targeted therapy. Percent change of the longest diameter in each measurable lesion were assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The tumour response heterogeneity score was the absolute value of the dispersion coefficient of the percentage value of each target lesion. Patients were randomly divided (1:1) into a learning and a validation set. The optimal cutoff value of tumour response heterogeneity score was identified according to progression-free survival information in the discovery cohort. We then confirmed and analysed the correlation of tumour response heterogeneity scores with clinicopathological features in the validation cohort. Next-generation sequencing was used to investigate a potential mechanism linking tumour response heterogeneity scores to clinical outcomes. Data from 174 patients were collected between Jan 1, 2016, and Dec 30, 2020. 101 (58%) patients had been treated with platinum-based doublet chemotherapy and 73 (42%) with targeted therapy. Median follow-up was 19·8 months (IQR 3·71-13·75). In the discovery cohort (n=85), the optimal cutoff point of tumour response heterogeneity score was defined as 0·46. Patients with high tumour response heterogeneity score had worse progression-free survival than patients with low tumour response heterogeneity (median 4·5 months [95% CI 3·6-8·6] vs 15·8 months (12·8-not reached), hazard ratio [HR] 4·43 [95% CI 2·14-9·16]; p<0·0001). In the validation cohort (n=89), high tumour response heterogeneity score was shown to be associated with significantly shorter progression-free survival (median 5·1 months (95% CI 3·5-7·8) vs 12·9 months (10·4-28·7), HR 2·69 [95% CI 1·59-4·55]; p<0·0001). The median value of tumour response heterogeneity score followed the order of progressive disease, stable disease, and partial response (p<0·0001). Patients with high tumour response heterogeneity score had worse overall response rate than patients with low tumour response heterogeneity score (30·0% vs 68·0%; Fisher's exact test p<0·0001). In the overall population (n=174), high tumour response heterogeneity score was further shown to be an independent biomarker for progression-free survival by univariate and multivariate analysis. Moreover, tumour response heterogeneity score was able to further distinguish the outcomes in partial response and stable disease subgroup. In the partial response group, high tumour response heterogeneity score was associated with significantly shorter progression-free survival in the partial response subgroup (HR 2·79 [95% CI 1·24-6·29; p=0·0006) and the stable disease subgroup (HR 2·55 [95% CI 1·44-4·49]; p=0·0015). Compared with low tumour response heterogeneity score, high tumour response heterogeneity score was associated with higher tumour mutation burden and high frequency variation of cell cycle signal pathway. The tumour response heterogeneity score, a novel metric for tumour response heterogeneity, was a powerful independent predictor of outcome in advanced lung adenocarcinoma. The tumour response heterogeneity score further stratified patients with the same RECIST assessment results and could be a useful addition to the RECIST assessment system. Further prospective studies are warranted. National Natural Science Foundation of China (grant 82072565) and Bejing Xisike Clinical Oncology Research Foundation (grant Y-2019AZZD-0386).

Serum IgG4 Concentration Is a Potential Predictive Biomarker in Glucocorticoid Treatment for Idiopathic Retroperitoneal Fibrosis.

Objectives: To evaluate the management and outcome of idiopathic retroperitoneal fibrosis (iRPF) in Japan, and to identify its clinical biomarker. Methods: We retrospectively analyzed 129 patients with iRPF treated between January 2008 and May 2018 at 12 university and related hospitals. Patients treated with glucocorticoid were analyzed to identify a predictive biomarker. These patients were classified into three groups according to overall effectiveness (no change: NC, complete response: CR, and partial response groups: PR), and each parameter was compared statistically. Results: Male–female ratio was 5:1, and median age at diagnosis was 69 (33–86) years. Smoking history was reported in 59.6% of the patients. As treatment, 95 patients received glucocorticoid therapy with an overall response rate of 84%. As a result, serum concentration of IgG4 was significantly decreased in NC group compared with the other two groups (56.6 mg/dL vs. 255 mg/dL, 206 mg/dL, p = 0.0059 and 0.0078). ROC analysis was performed between the nonresponder (NC) and responder groups (CR + PR) to identify the cut-off value of serum IgG4 as a predictive marker. As a result, AUC of 0.793 was confirmed. Conclusions: Pre-treatment serum IgG4 concentration may have potential as a predictive biomarker of steroid treatment.

Abstract 623: NK cells are involved in promoting anti-tumor responses to DPX-peptide immunotherapy

Abstract DPX™ technology is a non-aqueous, immune-educating therapeutic platform that delivers specific instruction to the immune system. Antigenic peptides can be packaged within DPX to elicit a robust and persistent tumor antigen-specific T cell response. Maveropepimut-S (MVP-S), formerly DPX-Survivac, contains 5 peptides derived from the tumor antigen survivin, as well as poly dIdC and a T helper peptide. In clinical trials, MVP-S consistently incites a robust and persistent, survivin-specific immune response and promotes T and B cell infiltration into tumor tissues. Importantly, MVP-S based therapy has provided compelling evidence for clinical benefit in multiple cancer indications, notably DLBCL and ovarian cancer. Herein, we provide the first evidence from clinical and preclinical studies that Natural Killer (NK) cells are involved in the anti-cancer efficacy of DPX-based therapy. We evaluated clinical samples from the DeCidE1 trial in advanced, recurrent ovarian cancer (NCT02785250). RNA-profiling of immune cells within tumor tissue revealed the presence of both activated and resting NK cells. Prior to treatment, activated NK cells were more evident in samples from patients achieving partial response (by RECISTv1.1). A higher percentage of subjects within the partial response group were more likely to maintain or increase resting NK cell infiltration on-treatment. PBMCs obtained prior to and on treatment showed no difference in CD56high and low NK profiles related to clinical benefit, highlighting that these changes in NK cell involvement are specific within tumor tissue. We sought to explore whether NK cells may be involved in DPX-based therapeutic efficacy using the HPV E7 model, C3, implanted in Rag1-/- mice, deficient in T and B cells. Mice were pre-treated with DPX packaged with the HPV E7 49-57 T cell peptide antigen (DPX-R9F) and 16 days later implanted with C3 tumor cells. At 40 days post treatment, 100% of control mice showed C3 tumor growth. By contrast, in the DPX-R9F immunized group, 60% of the mice were tumor free. Moreover, in the remaining 40% of the immunized group, the C3 tumors grew significantly slower than C3 tumors of the control group. Together, these data indicate that immunization with DPX-R9F enabled tumor control even in the absence of T or B cell function. To assess whether tumor control involved NK cells/perforin function, we repeated the experiment in Rag1-/-/Perforin-/- mice. In these mice, DPX-R9F immunization was far less effective than in the Rag1-/- mice, showing that only 20% of immunized mice were tumor free and suggesting that DPX-R9F mediated tumor control was partially dependent upon NK cell/perforin function. Taken together, these results from both clinical/translational studies and preclinical models suggest a distinct role for NK cells, in addition to the previously recognized role for T and B cells, in DPX-mediated immunotherapeutic efficacy. Citation Format: Moamen Bydoun, Daniel Medina-Luna, Brennan Dirk, Jeremy Graff, Olga Hrytsenko, Andrew Makrigiannis. NK cells are involved in promoting anti-tumor responses to DPX-peptide immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 623.

Serum cytokines could be predictors for PD-1 antibody response in advanced HBP cancer.

e16114 Background: According to previous clinical trials and pilot studies, PD1 antibodies might provide favorable long-term survival in combination with chemotherapy for unresectable hepatobiliary and pancreatic (HBP) cancers. We conducted a real-world evaluation of PD1 antibodies in patients with unresectable HBP cancers. We also aimed to explore biomarkers for the early prediction of PD1 antibodies response. Methods: From Jan 2021 to Dec 2021, 48 unresectable HBP cancers were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine. The key eligibility criteria were:(1)histopathologically confirmed advances unresectable HBP cancers; (2)without systematic treatment; (3)¡Ý18 years old; (4)ECOG PS 0 or 1. Clinical decisions were made by multi-disciplinary team (MDT). The treatment efficacy was evaluated by mRECIST. Results: A total of 48 patients were finally included and analyzed, which their baseline characteristics were listed in Table. we assessed the treatment efficacy using the dynamic change of tumor makers. And we observed that tumor markers of progressive disease(PD) group were higher than those of stable disease(SD) and partial response(PR) group. A total of 37 patients with complete biomarker data, were finally included in cytokines and immune response analysis. During the immune checkpoint inhibitors treatment, we detect the trough concentration of serum cytokines(IL-2, IL-4, IL-6, IL-10, IL-16, TNF-¦Á and TIFN-¦Ã). We observed that serum cytokines indexes of PD group were higher than those of SD and PR group. Conclusions: We observed that tumor markers of PD group were higher than those of SD and PR group. The serum cytokines (IL-4, IL-16 and TIFN-¦Ã) may be potential biomarkers for the early prediction of PD1 antibodies response. [Table: see text]

The predictive value of tumor volume reduction ratio on three-dimensional endorectal ultrasound for tumor response to chemoradiotherapy for locally advanced rectal cancer.

BackgroundPreoperative chemoradiotherapy remains part of the standard treatment for patients with locally advanced rectal cancer. Subsequent treatment individualization requires accurate prediction of tumor response to chemoradiotherapy. Three-dimensional endorectal ultrasound (3D-ERUS) can automatically capture and store the images of the rectal wall and rectal cancer with high resolution. In this study, we aimed to assess the correlation and predictive value between tumor volume changes measured on 3D-ERUS and the histopathological tumor response after chemoradiotherapy for patients with locally advanced rectal cancer.MethodsA total of 54 patients with locally advanced rectal cancer who underwent chemoradiotherapy and had complete 3D-ERUS data pre-and post-chemoradiotherapy were enrolled in the study. The tumor volume pre-and post-chemoradiotherapy was measured manually on 3D-ERUS, and the tumor volume reduction ratio was calculated. The histopathological tumor regression grade (TRG) was used to assess tumor response. The differences in volumetry parameters were compared between groups with varying tumor response. The diagnostic efficacy of the tumor volume reduction ratio was evaluated by the receiver operating characteristic (ROC) curve.ResultsThe mean age of all patients was 55.19±12.46 years. The relative proportions of TRG 0–3 were 29.6% (16/54), 16.6% (9/54), 50% (27/54), and 3.8% (2/54), respectively. The median tumor volumes post-chemoradiotherapy in good responders (TRG 0–1, median tumor volume =3.26 cm3) and the complete response group (TRG 0, median tumor volume =2.61 cm3) were smaller than those in poor responders (TRG 2–3, median tumor volume =5.43 cm3) and the partial response group (TRG 1–3, median tumor volume =4.00 cm3), while tumor volume reduction ratios were higher than those of poor responders (79.32% vs. 59.67%) and the partial response group (82.22% vs. 61.64%), with significant differences (all P values <0.05). The ROC curves showed that the cut-off values of the tumor volume reduction ratio to predict good responders and complete response were 67.77% and 72.02%, respectively. The corresponding areas under the curve in the prediction of good responders and complete response were 0.830 and 0.829, respectively.ConclusionsThe tumor volume reduction ratio measured on 3D-ERUS might be a helpful indicator for tumor response in patients with locally advanced rectal cancer.

Efficacy of niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer in phase 3 PRIME study: A subgroup analysis by response to first-line platinum-based chemotherapy.

5551 Background: In PRIME (NCT03709316), niraparib significantly reduced the risk of disease progression or death versus placebo (PBO) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.34–0.60) in Chinese patients (pts) with newly diagnosed, advanced ovarian cancer (OC), regardless of biomarker status. As response to chemotherapy is deemed to be associated with prognosis in OC, this subgroup analysis of the PRIME study aims to better understand niraparib treatment effect in pts based on response to first-line platinum-based chemotherapy (1L CT). Methods: This randomized, double-blind, PBO-controlled, phase 3 trial enrolled adults with newly diagnosed, stage III or IV OC who achieved a complete response (CR) or partial response (PR) to 1L CT and received primary or interval cytoreductive surgery, irrespective of residual disease status after surgery. Pts were randomized (2:1) to receive niraparib or PBO, whose starting doses were individualized based on baseline bodyweight and platelet count, with stratification according to status of germline BRCA mutations (yes or no), tumor homologous recombination status (deficient or proficient), receipt of neoadjuvant chemotherapy (yes or no), and clinical response to 1L CT (CR or PR). This prespecified exploratory analysis reports progression-free survival (PFS) and HRs based on clinical response to 1L CT. The data cut-off date was 30 September 2021. Results: Of the 384 pts randomized, 315 (82.0%) and 69 (18.0%) had a CR (212 niraparib, 103 PBO) or PR (43 niraparib, 26 PBO) to 1L CT, respectively. Baseline characteristics are presented in the Table. The overall PFS median follow-up was 27.5 months. Niraparib significantly extended PFS compared with PBO: the median PFS was 29.4 months for niraparib versus 8.3 months for PBO (HR=0.45; 95% CI, 0.32–0.61; P&lt;0.001) in the CR group and was 19.3 months for niraparib versus 8.3 months for PBO (HR=0.45; 95% CI, 0.23–0.86; P=0.014) in the PR group. Conclusions: In pts with newly diagnosed advanced OC, PFS was substantially prolonged with niraparib versus PBO, regardless of response to chemotherapy and biomarker status. Moreover, pts who achieved a CR appeared to receive larger PFS benefit from niraparib than those with a PR. Clinical trial information: NCT03709316. [Table: see text]

Long-Term Efficacy and Safety of Anlotinib as a Monotherapy and Combined Therapy for Advanced Sarcoma.

ObjectiveTo analyze the effectiveness of the long-term (> 12 months) administration of anlotinib as a monotherapy or combined therapy in patients with advanced sarcomas.MethodsA retrospective analysis was conducted of patients with advanced sarcomas with measurable target lesions since 2018. Twenty-two of the patients had taken anlotinib regularly for > 12 months. The patients’ general information and the drug’s clinical efficacy and toxicity data were collected and statistically analyzed using RECIST 1.1 to measure the target lesions and tumor PFS time as the main endpoints. We used a swimmer plot to observe the drug’s efficacy and duration, and employed a waterfall plot to express the best treatment effect.ResultsThe study included 14 male and 8 female patients, ranging in age from 14 to 75 (mean: 44.82) years. The primary diseases included alveolar soft part sarcoma, synovial sarcoma, leiomyosarcoma, and others. The metastasis sites were the lungs in fifteen cases, lymph nodes in four cases, and multiple sites in three cases. Fourteen patients had previously undergone chemotherapy. The current therapy protocol was oral anlotinib alone for nine cases, combination chemotherapy for nine cases, and combination immunotherapy (anti-PD-1) for four cases. The highest clinical efficacy was complete remission (CR) in four (18.18%) cases, partial response (PR) in five (22.73%) cases, and stable disease in 13 (59.09%) cases, with an odds ratio of response of 40.91%. The mean PFS for the CR, PR, and stable disease groups was 16.50, 14.50, and 29.31 months, respectively (p < 0.05). The main adverse effects included hand-foot syndrome, hypertension, and leukopenia.ConclusionAnlotinib monotherapy or combination therapy can be more effective and safer for certain advanced sarcomas, with more extended maintenance and acceptable side effects. Clinical efficacy at the CR and PR levels might predict the long-term PFS in certain advanced sarcomas.

Impact of Cytoreductive Nephrectomy Following Nivolumab Plus Ipilimumab Therapy for Patients With Advanced Renal Cell Carcinoma.

CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC. Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy. The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR. Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

Expression of miR-106b-5p in children with primary immune thrombocytopenia and its correlation with T cells

To study the expression level of plasma miR-106b-5p in primary immune thrombocytopenia (ITP) and its correlation with the levels of T helper 17 cell (Th17) and regulatory T cell (Treg) and the Th17/Treg ratio. A total of 79 children with ITP (ITP group) and 40 healthy children (control group) were selected as subjects. According to the treatment response, the 79 children with ITP were divided into three groups: complete response (n=40), partial response (n=18), and non-response (n=21). Quantitative real-time PCR was used to measure the expression level of miR-106b-5p. Flow cytometry was used to measure the frequencies of Th17 and Treg, and the Th17/Treg ratio was calculated. The correlation of the expression level of plasma miR-106b-5p with the frequencies of Th17 and Treg and the Th17/Treg ratio was analyzed. Compared with the control group, the ITP group had significantly higher levels of miR-106b-5p, Th17, and Th17/Treg ratio (P<0.05) and a significantly lower level of Treg (P<0.05). After treatment, the ITP group had significant reductions in the levels of miR-106b-5p, Th17, and Th17/Treg ratio (P<0.05) and a significant increase in the level of Treg (P<0.05). Compared with the partial response and non-response groups, the complete response group had significantly lower levels of miR-106b-5p, Th17, and Th17/Treg ratio (P<0.05) and a significantly higher level of Treg (P<0.05). The correlation analysis showed that in the children with ITP, the expression level of plasma miR-106b-5p was positively correlated with the Th17 level and the Th17/Treg ratio (r=0.730 and 0.816 respectively; P<0.001) and was negatively correlated with the Treg level (r=-0.774, P<0.001). A higher expression level of miR-106b-5p and Th17/Treg imbalance may be observed in children with ITP. The measurement of miR-106b-5p, Th17, Treg, and Th17/Treg ratio during treatment may be useful to the evaluation of treatment outcome in children with ITP.