Search

Contrast-enhanced ultrasound (CEUS) is a promising imaging modality in predicting the efficacy of neoadjuvant chemotherapy for pancreatic cancer, a tumor with high mortality. In this study, we proposed a deep-learning-based strategy for analyzing CEUS videos to predict the prognosis of pancreatic cancer neoadjuvant chemotherapy. Pre-trained convolutional neural network (CNN) models were used for binary classification of the chemotherapy as effective or ineffective, with CEUS videos collected before chemotherapy as the model input, and with the efficacy after chemotherapy as the reference standard. We proposed two deep learning models. The first CNN model used videos of ultrasound (US) and CEUS (US+CEUS), while the second CNN model only used videos of selected regions of interest (ROIs) within CEUS (CEUS-ROI). A total of 38 patients with strict restriction of clinical factors were enrolled, with 76 original CEUS videos collected. After data augmentation, 760 and 720 videos were included for the two CNN models, respectively. Seventy-six-fold and 72-fold cross-validations were performed to validate the classification performance of the two CNN models. The areas under the curve were 0.892 and 0.908 for the two models. The accuracy, recall, precision and F1 score were 0.829, 0.759, 0.786, and 0.772 for the first model. Those were 0.864, 0.930, 0.866, and 0.897 for the second model. A total of 38.2% and 40.3% of the original videos could be clearly distinguished by the deep learning models when the naked eye made an inaccurate classification. This study is the first to demonstrate the feasibility and potential of deep learning models based on pre-chemotherapy CEUS videos in predicting the efficacy of neoadjuvant chemotherapy for pancreas cancer.

Purpose:No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs.Patients and Methods:Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1).Results:Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9–34] and 15% (95% CI, 6–31), disease control rates were 91% (95% CI, 77–97) and 92% (95% CI, 79–98), and median progression-free survival was 21.2 months (95% CI, 15.9–24.8) and 13.4 months (95% CI, 7.6–19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%).Conclusions:Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.

Supplementary Tables Table S1. Pharmacokinetic parameters for surufatinib in patients following dosing of 300 mg, QD Table S2. Association between baseline biomarker levels and PFS

Supplementary Figure

BACKGROUND The purpose of this study was to compare survival outcomes in patients with perineural invasion (PNI)-positive laryngeal squamous cell carcinoma (LSCC) and patients with PNI-negative LSCC. METHODS A total of 1,272 patients with LSCC, diagnosed between 2008 and 2017, were included in this study. LSCC Patients with and without PNI were matched based on possible confounding factors. Survival analysis was performed using Kaplan-Meier estimates and the Cox proportional hazards model. RESULTS Of the 1,272 LSCC patients, 118 (9.28%) were positive for PNI. Compared to PNI-negative patients, PNI-positive LSCC patients had significantly worse overall survival (OS) (p = 0.017), disease-specific survival (DSS) (p = 0.034) and recurrence-free survival (RFS) (p = 0.002). After pair matching, cohorts consisted of 118 patients in the PNI-positive group and 118 in the PNI-negative group. Significantly increased risk of OS (HR, 2.17; 95% confidence interval [CI], 1.29-3.61, p = 0.003), DSS (HR, 2.07; 95% CI, 1.32-3.24, p = 0.004) and RFS (HR, 2.65; 95% CI, 1.59-4.40, p

Tongtong Zhou,1,2,&ast; Li Tan,1,&ast; Yang Gui,1 Jing Zhang,1 Xueqi Chen,1 Menghua Dai,3 Mengsu Xiao,1 Qing Zhang,1 Xiaoyan Chang,4 Qun Xu,5 Chunmei Bai,6 Yuejuan Cheng,6 Qiang Xu,3 Xue Wang,7 Hua Meng,1 Wanying Jia,1 Ke Lv,1 Yuxin Jiang1 1Department of Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Ultrasound, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People’s Republic of China; 6Department of Medical Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 7Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke Lv; Yuxin JiangDepartment of Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaTel/Fax +86 10-69155493; +86 10-69155491Email lvke@163.com; yuxinjiangxh@163.comObjective: Investigate the CEUS enhancement patterns of PDAC and analyse correlations between the CEUS enhancement pattern and both the degree of tumour tissue differentiation and overall survival (OS).Methods: The study included 56 patients with locally advanced PDAC, performed conventional ultrasound and CEUS, and analysed characteristics of the CEUS enhancement patterns. In addition, clinical data, such as serum level of CA19-9, TNM stage were collected, and patients’ survival times were followed up. TICs of dynamic CEUS images were acquired using image processing software to obtain the peak, TP, sharpness, and AUC. Correlations of the CEUS enhancement patterns of PDAC with the degree of differentiation of tumour tissue and OS were quantitatively analysed, as were the correlations of the TIC parameters and CEUS enhancement patterns with OS.Results: Enhancement in the arterial phase included iso-enhancement (30.3%) and hypo-enhancement (69.6%), and was not significantly correlated with sex, age at disease onset, or lesion size. Also was not significantly correlated with tumour tissue differentiation. Clear survival times were obtained for 50 patients during follow-up, and the median survival time was significantly longer for the patients with iso-enhancement than hypo-enhancement. Among the TIC parameters, peaktumour, sharpnesstumour, AEsharpness, and REsharpness differed significantly between the group with iso-enhancement and hypo-enhancement (p < 0.05).Conclusion: The CEUS enhancement patterns of PDAC in the arterial phase include iso-enhancement and hypo-enhancement. Enhancement pattern was not significantly correlated with the degree of differentiation of tumour tissue, but patient survival time differed significantly between the two enhancement patterns, with longer survival for patients with iso-enhancement.Keywords: contrast-enhanced ultrasound, pancreatic ductal adenocarcinoma, survival time, enhancement pattern, time-intensity curve

Pancreatic neuroendocrine tumor (pNET) is the most common subset (31.5%) of gastroenteropancreatic neuroendocrine tumor in China. Based on real-world data from a single center, the present study aimed to evaluate the influence of clinical characteristics, medical treatment and surgery on the survival of non-functional metastatic G2 pNET. In total, 114 metastatic non-functional G2 pNET patients, who were treated and followed up in the Department of Medical Oncology, Peking Union Medical College Hospital (PUMCH) from 2001 until 2019, were analyzed retrospectively. The primary endpoint, overall survival (OS), was calculated from the date of diagnosis to the date of death. The second endpoint, progression-free survival (PFS), was calculated from the date of diagnosis to the date of disease progression. Statistical data were analyzed to evaluate the effects of a clinical characteristic, medical treatment and surgery on OS and PFS. Sixty-nine (60.5%) patients were male and 87 (76.3%) were aged 60 years. The liver was the most common metastatic organ, with a total of 84 cases (73.7%). With respect to surgery, 32 (28.1%) patients underwent radical surgery and 37 (32.5%) underwent palliative surgery. Survival analysis showed that the 5-year and 10-year survival rates were 79.36% and 70.0%, respectively. Univariate and multivariate Cox regression analyses suggested that both radical (p .001/.003) and palliative surgery (p .001/.002) significantly prolonged OS, as revealed by the Kaplan-Meier test (p .001). Subgroup analysis showed that palliative resection also significantly improves the prognosis in patients with multiple liver metastases. However, the first-line systemic anti-tumor therapy option showed no statistical differences in the present study. Overall, patients with non-functional metastatic G2 pNET receiving palliative or radical surgery demonstrated significantly better survival. Prospective clinical trials are suggested to validate our findings.

This study aimed to evaluate the safety and efficacy of multiple cycles of 177Lu-DOTA-Evans blue (EB)-TATE peptide receptor radionuclide therapy (PRRT) at escalating doses in neuroendocrine tumors (NETs). Methods: Thirty-two NET patients were randomly divided into 3 groups and treated with escalating doses. Group A received 1.17 ± 0.09 GBq/cycle; group B, 1.89 ± 0.53 GBq/cycle; and group C, 3.97 ± 0.84 GBq/cycle. The treatment was planned for up to 3 cycles. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Treatment response was evaluated according to the European Organisation for Research and Treatment of Cancer criteria and modified PERCIST. Results: Administration of PRRT was well tolerated, without life-threatening adverse events (CTCAE grade 4). CTCAE grade 3 hematotoxicity was recorded in 1 patient (16.6%) in group B (thrombocytopenia) and 3 patients (21.4%) in group C (thrombocytopenia in 3, anemia in 1). CTCAE grade 3 hepatotoxicity (elevated aspartate aminotransferase) was recorded in 1 patient in group A (8.3%) and 1 patient in group C (7.1%). No nephrotoxicity was observed. According to the criteria of the European Organisation for Research and Treatment of Cancer, the overall disease response rates were similar in groups A, B, and C (50.0%, 50.0%, and 42.9%, respectively), and the overall disease control rates were higher in groups B (83.3%) and C (71.5%) than in group A (66.7%). According to modified PERCIST, a lower disease response rate but a similar disease control rate were found. When a comparable baseline SUVmax ranging from 15 to 40 was selected, the percentage change in SUVmax increased slightly in group A (2.1% ± 40.8%) but decreased significantly in groups B and C (-38.7% ± 10.0% and -14.7% ± 20.0%, respectively) after the first PRRT (P = 0.001) and decreased in all 3 groups after the third PRRT (groups A, B, and C: -6.9% ± 42.3%, -49.2% ± 30.9%, -11.9% ± 37.9%, respectively; P = 0.044). Conclusion: Dose escalations of up to 3.97 GBq/cycle seem to be well tolerated for 177Lu-DOTA-EB-TATE. 177Lu-DOTA-EB-TATE doses of 1.89 and 3.97 GBq/cycle were effective in tumor control and more effective than 1.17 GBq/cycle.

Background Pancreatic neuroendocrine tumors (pNET) are rare and heterogeneous. New biomarkers are needed for better predicting the prognosis and for providing individualized treatment. Versican (VCAN) plays an important role in tumorigenesis. Therefore, we plan to investigate the role of VCAN in pNET prognosis. Method The clinical and pathological data of pNET patients who underwent surgery between 2005 and 2010 were collected and evaluated. Radiologic tumor assessments with contrast computed tomography or magnetic resonance imaging were performed at baseline and follow up. The radiologic response was classified according to the RECIST 1.1 criteria. VCAN expression was assessed by immunohistochemical staining (IHC). Result Among 155 pNET patients, 112 (72.3%) pNET patients were VCAN positive, and 43 (27.7%) were negative. Positive expression of VCAN in pNET was significantly associated with a longer disease-free survival (DFS) compared with VCAN negative pNET (p = 0.038, HR 0.462, 95% CI 0.218–0.978). Subgroup analysis showed that VCAN positive expression was associated with a longer DFS in the G1 subgroup (p = 0.031, HR 0.124, 95% CI 0.013–1.193), the tumor size>2 cm subgroup (p = 0.047, HR 0.458, 95% CI 0.207–1.012) and the NF-pNET subgroup (p = 0.003, HR 0.274, 95% CI 0.112–0.673). Multivariable analysis showed that VCAN negative expression, G2 and tumor size>2 cm were independent factors of poor prognosis of pNET (p = 0.041, p Conclusion Our data indicate that VCAN positive expression may serve as an independent factor of predicting DFS in pNET; its expression in pNET tissues was correlated with a longer DFS.

To evaluate the safety and efficacy of 177Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue, at escalating doses, was used to increase tumor retention in patients with progressive metastatic neuroendocrine tumors (NETs). Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: group A (n = 6, 43 ± 12 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTATATE as controls; group B (n = 7, 55 ± 7 years) administered approximately 1.11 GBq (30 mCi) 177Lu-DOTA-EB-TATE; group C (n = 6, 55 ± 10 years) administered approximately 1.85 GBq (50 mCi) 177Lu-DOTA-EB-TATE; group D (n = 14, 50 ± 10 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0. 68Ga-DOTATATE PET/CT were performed at baseline and 2–3 months after treatment for response evaluation. Administration was well tolerated. No CTC 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity was observed during or after treatment in groups A–C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ% = − 17.4 ± 29.3%) and group D (Δ% = − 15.1 ± 39.1%), but greatly increased in group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). Referring to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in groups A, B, C, and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ% = − 7.3 ± 24.5%) (P = 0.214), significant decrease in group C (Δ% = − 34.9 ± 12.4%) (P = 0.001), and in group D (Δ% = − 17.9 ± 19.7%) (P = 0.012) as compared with group A with increased SUVmax (Δ% = 8.4 ± 48.8%). SUVmax significantly decreased in the EBTATE groups (groups B–D combined) (Δ% = − 19.0 ± 21.5%) as compared with the TATE group (P = 0.045). 177Lu-DOTA-EB-TATE is well tolerated and is more effective than 177Lu-DOTATATE. Both 1.85 GBq (50 mCi) and 3.7 GBq (100 mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of 177Lu-DOTA-EB-TATE treatment and longer follow-up is warranted. Treatment Using 177Lu-DOTA-EB-TATE in Patients with Advanced Neuroendocrine Tumors (NCT03478358). URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4

The focus of this study was to investigate the effects of luxS, a key regulatory gene of the autoinducer-2 (AI-2) quorum sensing (QS) system, on the biofilm formation and biocontrol efficacy against Ralstonia solanacearum by Paenibacillus polymyxa HY96-2. luxS mutants were constructed and assayed for biofilm formation of the wild-type (WT) strain and luxS mutants of P. polymyxa HY96-2 in vitro and in vivo. The results showed that luxS positively regulated the biofilm formation of HY96-2. Greenhouse experiments of tomato bacterial wilt found that from the early stage to late stage postinoculation, the biocontrol efficacy of the luxS deletion strain was the lowest with 50.70 ± 1.39% in the late stage. However, the luxS overexpression strain had the highest biocontrol efficacy with 75.66 ± 1.94% in the late stage. The complementation of luxS could restore the biocontrol efficacy of the luxS deletion strain with 69.84 ± 1.09% in the late stage, which was higher than that of the WT strain with 65.94 ± 2.73%. Therefore, we deduced that luxS could promote the biofilm formation of P. polymyxa HY96-2 and further promoted its biocontrol efficacy against R. solanacearum.

(68)Ga-DOTA-JR11 is a somatostatin receptor subtype 2–specific antagonist used for PET/CT imaging. The purpose of this study was to compare (68)Ga-DOTA-JR11 and (68)Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. Methods: Patients with histologically proven, metastatic or unresectable, well-differentiated neuroendocrine tumors were prospectively recruited to this study. Each patient received an intravenous injection of (68)Ga-DOTATATE (155 ± 52 MBq) on the first day and (68)Ga-DOTA-JR11 (148 ± 52 MBq) on the second day. Whole-body PET/CT scans were performed at 40–60 min after injection on the same scanner. Physiologic normal-organ uptake, lesion numbers, and lesion uptake were compared. Results: Thirty-one patients were prospectively enrolled in the study. The SUV(max) of the spleen, renal cortex, adrenal glands, pituitary glands, stomach wall, normal liver parenchyma, small intestine, pancreas, and bone marrow was significantly lower on (68)Ga-DOTA-JR11 than on (68)Ga-DOTATATE PET/CT (P < 0.001). (68)Ga-DOTA-JR11 detected significantly more liver lesions (552 vs. 365, P = 0.001) but fewer bone lesions (158 vs. 388, P = 0.016) than (68)Ga-DOTATATE. The target-to-background ratio of liver lesions was significantly higher on (68)Ga-DOTA-JR11 (7.7 ± 5.4 vs. 3.4 ± 2.0, P < 0.001). (68)Ga-DOTA-JR11 and (68)Ga-DOTATATE PET/CT showed comparable results for primary tumors and lymph node metastases on both patient-based and lesion-based comparisons. Conclusion: (68)Ga-DOTA-JR11 performs better in detecting liver metastases, with a better tumor-to-background ratio, whereas (68)Ga-DOTATATE may outperform (68)Ga-DOTA-JR11 in the detection of bone metastases. However, the lower somatostatin receptor subtype 2 affinity of (68)Ga-DOTA-JR11 than of (177)Lu-DOTA-JR11 may limit its role as a diagnostic pair for the theranostic approach with (177)Lu-DOTA-JR11.

To investigate the health-related quality of life (HRQoL) of patients who had neuroendocrine tumors (NETs) from SANET trials.Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo. HRQoL questionnaires, including the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-G.I.NET21, were collected. The prespecified HRQoL outcome was the mean change of scores from baseline to the last available visit for each domain. Time until definitive deterioration (TUDD) was defined as the time from randomization to deterioration of ≥10 points from baseline in domain score, disease progression, or death.370 patients were enrolled and randomly assigned to surufatinib (n = 242) or placebo (n = 128). No significant difference in mean scores change from baseline to the last available visit was observed for QLQ-C30 and QLQ- G.I.NET21 domains, with the exception of diarrhea. The mean score of diarrhea increased 11.7 points from baseline in the surufatinib arm and decreased 1.2 points in the placebo arm, and the between-group difference was 12.9 points. Compared with placebo, surufatinib treated patients had a significantly longer TUDD for dyspnea (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.39-0.86; P = 0.0058) and a significantly shorter TUDD for diarrhea (HR 2.91; 95% CI, 1.66-5.10; P 0.0001). There were no significant differences in TUDD for the remaining domains of QLQ-C30 and G.I.NET-21.HRQoL was similar in patients treated with surufatinib and placebo except for diarrhea. The preservation of HRQoL supports surufatinib as a treatment option for NETs.ClinicalTrials.gov: NCT02589821, NCT02588170.

1398 Introduction: New SiPM PET scanner hardware is widening the range of imaging performance between old and new generation scanners. New advanced reconstructions result in generally higher contrast images, and higher reconstructed resolution is achievable but with a noise penalty that impacts both quantitative accuracy and reproducibility. The choice as to how to optimally acquire and reconstruct PET images for a given PET/CT system is complex and unclear. We believe there would be value in creating and sharing a comprehensive library of well-curated, standardized, PET/CT scanner model-specific phantom images data sets with associated analyses. This has potential to benefit both the clinical and clinical trial enterprises as well as providing well-characterized image datasets to entities developing imaging segmentation and analysis software. Described below is a prototype phantom-based approach to standardly and fully characterize a particular PET/CT scanner model’s 1) reconstructed resolution, 2) noise properties, 3) recovery coefficient (RC) performance, and 4) image quality across a broad range of reconstructions. The method employs three currently available commercial phantoms, a prototype phantom, and publicly available analysis software. Results are preliminarily presented on four PET/CT platforms, but is intended to ultimately include all PET/CT systems. Methods: In this prototype performance measurement paradigm, the GE Discovery MI, Siemens Vision 600, Siemens mCT, and Siemens TruePoint are characterized. Four phantoms were used: the 20 cm uniform phantom, standard NEMA IQ phantom, a modified (12 sphere) NEMA IQ Phantom, and CTN Oncology Phantom. Acquisitions and analyses were performed as shown in Table 1. The number and types of reconstructions performed cover the full clinical range of reconstruction parameter sets, including advanced reconstructions. Analyses were performed with the publicly available online automated SNMMI Phantom Analysis Tool (PAT) http://snmmi.org/PAT, except for the modified NEMA 12 sphere phantom. Axial and radial resolution were measured on the DMI (42 different reconstruction parameter sets), Vision (48), mCT (48) and TruePoint (18) using the uniform phantom1. RC curves were generated using high statistics data (30 min/bed) using recommended CTN and EARL fills for the CTN and NEMA phantoms, respectively. Clinical statistic RC curves were generated for all systems and reconstructions using 17 replicate 4-minute/bed acquisitions (decay corrected) of the 12 sphere NEMA phantom to assess reproducibility of clinically relevant SUV measurements. NEMA noise and image roughness measurements were made using the CTN and modified NEMA phantom data collected with clinically relevant counts.Lesion detection and image quality measures were manually performed using a Likert scale on the 2 image quality features available in the CTN Oncology phantom. Results: Data was successfully collected, reconstructed, and analyzed for the 4 PET/CT systems, resulting in 2500 total phantom datasets for the 4 systems. Axial and Radial reconstructed resolution were successfully measured using PAT for all scanners and reconstructions (Fig 1). The 17 replicate 4-minute scans enabled generation of RC curves (SUVmax, SUVpeak, SUVmean) with associated standard deviation of the measurements to assess reproducibility and bias as a function of reconstruction. These RC curves acquired with clinically relevant counts can be compared to the RC curves generated with the high statistic, lower noise 30 min/bed acquisitions from the CTN and NEMA phantoms. Conclusion: A prototype performance measurement paradigm for PET/CT scanners has been tested and appears to generate meaningful quantitative information that could inform both clinical practice and clinical trials. Image sets, metadata, and analysis have been uploaded to an SNMMI administered platform for sharing.1Lodge et al. JNM 2018, 59(11) 1768-1775

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a poor prognosis. In resectable PDAC, the recurrence rate is still high even when surgery and adjuvant chemotherapy (CT) are applied. Regional lymph node metastasis and positive margins are associated with higher recurrence risk and worse survival. Adjuvant radiotherapy has been explored, but its efficacy remains controversial. In recent years, some characteristics have been reported to stratify patients who may benefit from adjuvant chemoradiation (CRT), such as lymph node metastasis and margin status. Adjuvant chemotherapy followed by chemoradiation (CT-CRT) was also proposed. A total of 266 patients with resectable PDAC who have lymph node metastasis or R1 resection after surgery were enrolled. In multivariate Cox regression analyses, pancreatic body or tail tumor location (HR 0.433, pvs. 21.4% in the CT and CT-CRT group, respectively). However, no significant differences in disease-free survival among these two groups were observed.

Background The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC). Methods Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8–10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA. Results A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6–26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70–50.69; P = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29–15.70; P = 0.0008). Conclusions Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information.

This study aimed to evaluate the safety and efficacy of multiple cycles of (177)Lu-DOTA-Evans blue (EB)-TATE peptide receptor radionuclide therapy (PRRT) at escalating doses in neuroendocrine tumors (NETs). Methods: Thirty-two NET patients were randomly divided into 3 groups and treated with escalating doses. Group A received 1.17 ± 0.09 GBq/cycle; group B, 1.89 ± 0.53 GBq/cycle; and group C, 3.97 ± 0.84 GBq/cycle. The treatment was planned for up to 3 cycles. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Treatment response was evaluated according to the European Organisation for Research and Treatment of Cancer criteria and modified PERCIST. Results: Administration of PRRT was well tolerated, without life-threatening adverse events (CTCAE grade 4). CTCAE grade 3 hematotoxicity was recorded in 1 patient (16.6%) in group B (thrombocytopenia) and 3 patients (21.4%) in group C (thrombocytopenia in 3, anemia in 1). CTCAE grade 3 hepatotoxicity (elevated aspartate aminotransferase) was recorded in 1 patient in group A (8.3%) and 1 patient in group C (7.1%). No nephrotoxicity was observed. According to the criteria of the European Organisation for Research and Treatment of Cancer, the overall disease response rates were similar in groups A, B, and C (50.0%, 50.0%, and 42.9%, respectively), and the overall disease control rates were higher in groups B (83.3%) and C (71.5%) than in group A (66.7%). According to modified PERCIST, a lower disease response rate but a similar disease control rate were found. When a comparable baseline SUV(max) ranging from 15 to 40 was selected, the percentage change in SUV(max) increased slightly in group A (2.1% ± 40.8%) but decreased significantly in groups B and C (−38.7% ± 10.0% and −14.7% ± 20.0%, respectively) after the first PRRT (P = 0.001) and decreased in all 3 groups after the third PRRT (groups A, B, and C: −6.9% ± 42.3%, −49.2% ± 30.9%, −11.9% ± 37.9%, respectively; P = 0.044). Conclusion: Dose escalations of up to 3.97 GBq/cycle seem to be well tolerated for (177)Lu-DOTA-EB-TATE. (177)Lu-DOTA-EB-TATE doses of 1.89 and 3.97 GBq/cycle were effective in tumor control and more effective than 1.17 GBq/cycle.

e16210 Background: Due to the rarity, research on gastric neuroendocrine carcinoma (NEC) is limited. The treatment has been extrapolated from small-cell lung cancer (SCLC) data. However, a previous study found gastric NECs had a genetic feature characterized by a lower frequency of RB1 mutations than SCLC. Several studies also showed RB1mutation or loss of Rb expression could predict the efficacy of SCLC treatment in NEC. Our study investigated a subtyping method by p53 and Rb immunohistochemistry (IHC) staining in gastric NEC, which might help identify patients responding to SCLC treatment. Methods: Patients with gastric NEC who underwent radical surgery in Peking Union Medical College Hospital (PUMCH) from 2013 to 2021 were identified. The expression of Rb, p53, PD-L1 and CD8 T cell infiltration were accessed by IHC stain. The mutations of RB1 and TP53, tumor mutation burden (TMB), and microsatellite instability (MSI) were detected by whole-exom sequencing (WES). Fisher’s exact test and Mann–Whitney test were used to detect differences between groups. Spearman's test was used to detect correlations between variables. Kaplan-Meier and Cox hazards methods were applied to the survival analysis. Samples of gastric adenocarcinoma, gastric neuroendocrine tumor (NET), and SCLC were also included. Results: A total of 41 patients with gastric NEC were included. WES was carried out in 28 patients. TP53 mutation was detected in 14 patients. RB1 mutation was detected in 1 patient. A classification method based on gene mutation was not able to be further investigated. In IHC of 41 patients, 46.2% showed Rb expression absence. 68.4% had abnormal p53 expression. 39 patients were classified based on IHC results. Patients with both abnormal expression of p53 and Rb were defined as SCLC-like type, accounting for 38.5%.The remaining patients were defined as non-SCLC-like type. SCLC-like gastric NEC had an increased number of lymph nodes metastasis (P = 0.001) and higher TNM stage (P < 0.001). The SCLC-like group's overall survival (OS) was significantly lower than the non-SCLC-like group (P = 0.023). Classification based on p53 and Rb expression was an independent predictor of OS (P = 0.021), HR = 4.690, 95%CI (1.263, 17.421). The classification results of gastric NEC were significantly different from those in gastric NET(P = 0.001), gastric adenocarcinoma(P = 0.002), but not in SCLC(P = 0.464). In 39 classified patients, the positive rate of PD-L1 expression was 23.1%; CD8 T cells high infiltration (>25 % of the stromal area) was 46.7%; the median TMB was 4.9 Muts/MB, and MSI was not detected. There was no significant difference in the expression of immunotherapy-related markers between the two types. Conclusions: Our study revealed subtypes of gastric NEC based on p53 and Rb expression with different prognoses. Further research on the treatment efficacy predictive role of this subtyping method is warranted.

e15000 Background: Metastatic pheochromocytoma / paraganglioma (MPP) are rare while the prognosis was poor and the efficacy for current therapy was unsatisfactory. Anlotinib is a multikinase inhibitor targeting tumor angiogenesis and growth. Currently, there is no study evaluating the efficacy and safety of anlotinib in MPP pts. Methods: This is a prospective, single-arm phase 2 trial (NCT 04860700). Pts with histologically or radiologically confirmed MPP were enrolled. Main other inclusion criteria were 18-75 years old and ECOG PS 0-2. Anlotinib (8-12mg, QD) were given orally from d1 to d14 every 21 days until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included biochemical (catecholamine levels) response rate (BRR), progression-free survival (PFS) and safety. Results: 10 pts with MPP were enrolled and tumor response were evaluated in 6 patients. All these 6 patients had objective radiological evidence of progression within 6 months before enrollment. Tumor shrinkage was observed in 4 pts, 1 achieved partial response (PR) and 3 achieved stable disease (SD). The ORR was 16.7% (1/6). For 1 patient (p-1) with no measurable lesions, the pathological lymph nodes shrunk obviously and the rapid progression of bone metastatic lesion was well controlled. Among all 6 pts, catecholamine levels were obviously decreased in 4 pts, achieving a BRR of 67%. 1 patient who developed blindness at right eye caused by the progression of intracranial metastasis after chemotherapy had recovered the vision after anlotinib treatment. At the data cutoff date on February 1st, 2022, 1 patient terminated anlotinib since obvious elevation of catecholamine level and others were still in treatment with no radiographic disease progression. The median treatment duration was 7.5 cycles. The details of efficacy result were listed in table below. Overall, treatment of anlotinib blocked the rapid disease progression and achieved a durable disease control. The most common treatment-related adverse event (TRAE) was hypertension (5/6), which was well controlled, other TRAEs occurred in > 1 pts included grade 1 or 2 proteinuria (2/6) and palmar-plantar erythrodysesthesia syndrome (2/6). Conclusions: The preliminary results of this study indicated that anlotinib is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. Clinical trial information: NCT04860700. [Table: see text]

Background: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy is the first line diagnostic tool used in the evaluation of solid pancreatic masses with high sensitivity and specificity prior to the surgery. Mixed ductal-neuroendocrine neoplasms of the pancreas are rare entity consisting of both ductal adenocarcinoma and neuroendocrine neoplasms, with each component representing at least 30%. Methods: We performed a retrospective analysis of patients with a diagnosis of pancreatic mixed ductal adenocarcinoma and neuroendocrine neoplasms by EUS-FNA specimens at Peking Union Medical College Hospital between 2010-2019 and presented a review of the literature.Results: A total of 3 cases (1 male and 2 females) were evaluated, aged 46, 38 and 62 years, and presented with 3-cm, 2.3-cm and 1.8-cm pancreatic masses, respectively. All the patients presented with abdominal pain and underwent EUS-FNA biopsy. FNA smears revealed a mixture of ductal adenocarcinoma and neuroendocrine neoplasms, identified by immunohistochemistry. According to Ki-67 proliferation index and mitotic count, the tumor grades of the neuroendocrine component were classified as NET G2 in 2 cases (cases 2 and 3) and NEC in 1 (case 1). All of the patients received adjuvant therapy. The diagnosis of patient 1 was confirmed on surgical excision, and she died 5 months after surgery due to hepatic metastases. The other two patients did not undergo surgery, but achieved long – term survival of 3 and 5 years, respectively. To date, 34 cases of pancreatic mixed ductal adenocarcinoma and neuroendocrine neoplasms have been reported in the English language literature including our present three cases. Among them, 5 of 12 patients who underwent preoperative biopsy were diagnosed as combined ductal adenocarcinoma and neuroendocrine neoplasms, of which 3 surgical resection specimens available were identified as mixed ductal-neuroendocrine neoplasms.Conclusion: We suggest that EUS-FNA biopsy is the most effective method for rapid evaluation of pancreatic mixed ductal-neuroendocrine neoplasms with high sensitivity, which is important to determine the most optimum therapy. If the tumor grades of the neuroendocrine component were classified as NET G2 by EUS-FNA biopsy, we propose appropriate adjuvant therapy rather than surgery.

We present a case with a pancreatic neuroendocrine tumor and extensive tumor thrombosis in portal venous system. The tumor was first identified on contrast-enhanced CT and later confirmed using Ga-DOTATATE and Ga-NODAGA-LM3 PET/CT. Both tracers demonstrated similar pattern with higher tumor affinity and tumor-to-background ratio using Ga-NODAGA-LM3.

Summary Background Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. Methods SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov , NCT02589821 . Findings Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3–19·4) in the surufatinib group and 11·1 months (5·7–35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5–13·8) for surufatinib versus 3·7 months (2·8–5·6) for placebo (hazard ratio 0·49, 95% CI 0·32–0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. Interpretation Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. Funding Hutchison MediPharma.