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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. 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. 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. 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. Hutchison MediPharma.

Background There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. Methods Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. Results A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2–6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3–4 adverse events in 10 patients with available safety data. Conclusions The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

Purpose The purpose of this study is to evaluate the diagnostic efficacy of 68  Ga-NODAGA-LM3 and 68  Ga-DOTA-LM3 and compare them with 68  Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors. Methods Patients were prospectively recruited and equally randomized into two arms: Arm A, patients would undergo a whole-body 68  Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68  Ga-DOTATATE PET/CT scan on the 2nd day; Arm B, patients would undergo a whole-body 68  Ga-DOTA-LM3 PET/CT scan on the 1st day and 68  Ga-DOTATATE PET/CT scan on the 2nd day. Biodistribution in normal organs, lesion detection ability, and tumor uptake were compared between antagonist and agonist in each arm. Results A total of 40 patients with well-differentiated NETs, 20 in each arm, were recruited in the study. 68  Ga-NODAGA-LM3 showed a similar pattern as 68  Ga-DOTATATE, while 68  Ga-DOTA-LM3 demonstrated significantly lower uptake in almost all normal organs compared to 68  Ga-DOTATATE. Both 68  Ga-NODAGA-LM3 and 68  Ga-DOTA-LM3 showed superiority in lesion detection compared to 68  Ga-DOTATATE on lesion-based and patient-based comparison. 68  Ga-NODAGA-LM3 showed a significantly higher tumor uptake (median SUVmax 29.1 versus 21.6, P  < 0.05) and tumor-to-background ratio (median tumor-to-liver ratio 5.0 versus 2.9, P  < 0.05) compared to 68  Ga-DOTATATE. 68  Ga-DOTA-LM3 showed comparable uptake (median SUVmax 16.1 versus 17.8, P  = 0.714) and higher tumor-to-background ratio (median tumor-to-liver ratio 5.2 versus 2.1, P  < 0.05). Conclusion Both 68  Ga-NODAGA-LM3 and 68  Ga-DOTA-LM3 are promising SSTR2 antagonists for neuroendocrine tumors. They demonstrated superiority in diagnostic efficacy compared to agonist 68  Ga-DOTATATE. Trial registration ClinicalTrials.gov identifier: NCT04318561

PurposeTo 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).MethodsThirty-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.ResultsAdministration 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).Conclusion177Lu-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.Trial registrationTreatment 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

Background: There is no clear consensus on second-line chemotherapy for patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of first-line gemcitabine plus nab-paclitaxel (GnP). Objectives: This study aimed to compare the efficacy and safety of oxaliplatin plus S-1 (SOX) versus modified FOLFIRINOX (mFFX) as second-line chemotherapy in this patient population. Design: A retrospective cohort study was conducted. Methods: Patients with advanced PDAC who received second-line SOX or mFFX after GnP failure at Peking Union Medical College Hospital were reviewed. Efficacy (disease control rate (DCR), overall survival (OS), progression-free survival (PFS)), and safety were analyzed. Molecular features were explored in a subgroup using targeted next-generation sequencing (NGS). Results: In total, 113 patients were included (65 SOX, 48 mFFX). The mFFX group had a significantly higher DCR than the SOX group (68.8% vs 40.0%, p = 0.005). Median PFS (4.8 vs 2.4 months, p = 0.001) and OS (10.4 vs 6.1 months, p = 0.001) were significantly longer with mFFX, even after propensity score matching adjustment. However, grade ⩾3 adverse events, particularly severe neutropenia (42.9% vs 13.5%, p = 0.004) and diarrhea (17.1% vs 1.9%, p = 0.031), were more frequent with mFFX. Multivariate analysis confirmed mFFX as an independent predictor for improved PFS (hazard ratio (HR) = 0.52, p = 0.004) and OS (HR = 0.46, p = 0.002). Exploratory NGS analysis in 45 patients suggested ARID1A, INPP4A, NTRK2, and PTPRS alterations may predict poor survival, but did not influence the relative efficacy of either regimen. Conclusion: The mFFX regimen demonstrated superior efficacy over SOX as second-line chemotherapy after GnP failure in advanced PDAC, significantly prolonging PFS and OS. However, this benefit was accompanied by a higher incidence of severe toxicities. Molecular alterations may hold prognostic value but did not guide regimen selection in this study. Plain language summary Comparing two chemotherapy options for advanced pancreatic cancer after initial treatment failure: which works better with manageable side effects? When first-line chemotherapy stops working for advanced pancreatic cancer, doctors need evidence to choose the best next treatment. This study compared two chemotherapy combinations (SOX: S-1 pill + oxaliplatin infusion vs. mFFX: modified four-drug cocktail) in 113 patients whose cancer worsened after standard gemcitabine/nab-paclitaxel treatment. Key findings: Patients receiving mFFX lived nearly twice as long (10.4 vs. 6.1 months average survival) with better short-term disease control (68.8% vs. 40% saw tumor shrinkage/stabilization). However, mFFX caused more severe side effects - 69% vs. 44% experienced significant blood cell drops or diarrhea requiring medical attention. Younger patients (average age 57) tended to receive mFFX more often. Genetic testing revealed four biological markers (ARID1A, INPP4A, NTRK2, PTPRS) that might help predict which patients benefit most from platinum-based therapies like SOX. While mFFX showed stronger anti-cancer effects, its higher toxicity suggests it may be better suited for younger, fitter patients. SOX remains a viable option for those needing gentler treatment. The discovery of potential genetic predictors opens doors for personalized therapy selection in future care. This real-world analysis provides practical guidance for oncologists balancing treatment intensity with patient tolerance in this challenging clinical scenario. Patients should discuss both options’ risks/benefits with their care team based on individual health status and treatment goals.

Background This study assessed the safety, preliminary antitumor activity, and pharmacokinetics of HR070803 (a novel liposomal irinotecan) in combination with 5-FU/LV and oxaliplatin for treatment-naive patients with unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Methods This multicenter, open-label, single-arm, dose-escalation phase 1 study recruited treatment-naive patients aged 18–70 years with unresectable locally advanced or metastatic PDAC. Treatment doses were escalated from 40/60 (HR070803 40 mg/m 2 plus 5-FU/LV and oxaliplatin 60 mg/m 2 ) to 60/60 and 60/85. The primary endpoints were maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary endpoints included safety, preliminary antitumor activity, and pharmacokinetics. Results A total of 41 patients were enrolled, including 6, 17, and 18 patients in the 40/60, 60/60, and 60/85 group, respectively. Only one patient in the 60/60 group experienced dose-limiting toxicities of grade 3 increased alanine aminotransferase and grade 3 increased aspartate aminotransferase, and the MTD was not reached. Adverse events of grade ≥ 3 were reported in 31 (75.6%) patients, with the most common being decreased neutrophil count and increased gamma-glutamyltransferase. No treatment discontinuation occurred owing to adverse events, and there were no treatment-related deaths. The overall response (complete or partial response) rate was 29.3% in the total population. Pharmacokinetic results demonstrated prolonged circulation and slow release of free irinotecan. Conclusions HR070803 plus 5-FU/LV and oxaliplatin demonstrated an acceptable toxicity, good antitumor activity, and favorable pharmacokinetic profile as a first-line treatment for patients with unresectable locally advanced or metastatic PDAC. Based on the comprehensive data obtained during the dose escalation and dose expansion stages, HR070803 60 mg/m 2 plus 5-FU/LV and oxaliplatin 85 mg/m 2 was chosen as the RP2D. Trial registration Clinical trials.gov NCT04796948; registered March 15, 2021.

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.

Objectives To develop a nomogram using pretreatment ultrasound (US) and contrast-enhanced ultrasound (CEUS) to predict the clinical response of neoadjuvant chemotherapy (NAC) in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC). Methods A total of 111 patients with pancreatic ductal adenocarcinoma (PDAC) treated with NAC between October 2017 and February 2022 were retrospectively enrolled. The patients were randomly divided (7:3) into training and validation cohorts. The pretreatment US and CEUS features were reviewed. Univariate and multivariate logistic regression analyses were used to determine the independent predictors of clinical response in the training cohort. Then a prediction nomogram model based on the independent predictors was constructed. The area under the curve (AUC), calibration plot, C-index and decision curve analysis (DCA) were used to assess the nomogram’s performance, calibration, discrimination and clinical benefit. Results The multivariate logistic regression analysis showed that the taller-than-wide shape in the longitudinal plane (odds ratio [OR]:0.20, p  = 0.01) , time from injection of contrast agent to peak enhancement (OR:3.64; p  = 0.05) and Peak tumor / Peak normal (OR:1.51; p  = 0.03) were independent predictors of clinical response to NAC. The predictive nomogram developed based on the above imaging features showed AUCs were 0.852 and 0.854 in the primary and validation cohorts, respectively. Good calibration was achieved in the training datasets, with C-index of 0.852. DCA verified the clinical usefulness of the nomogram. Conclusions The nomogram based on pretreatment US and CEUS can effectively predict the clinical response of NAC in patients with BRPC and LAPC; it may help guide personalized treatment.

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.