Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib

Objective:Currently,pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases(PNELM)receiving surufatinib treatment was unsatisfying.Our objective was to examine the association between radiological characteristics and efficacy/prognosis.Methods:We enrolled patients with liver metastases in the phase III,SANET-p trial(NCT02589821)and obtained contrast-enhanced computed tomography(CECT)images.Qualitative and quantitative parameters including hepatic tumor margins,lesion volumes,enhancement pattern,localization types,and enhancement ratios were evaluated.The progression-free survival(PFS)and hazard ratio(HR)were calculated using Cox’s proportional hazard model.Efficacy was analyzed by logistic-regression models.Results:Among 152 patients who had baseline CECT assessments and were included in this analysis,the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters.In the multivariable analysis of patients receiving surufatinib(N=100),those with higher arterial phase standardized enhancement ratio-peri-lesion(ASER-peri)exhibited longer PFS[HR=0.039;95%confidence interval(95%CI):0.003−0.483;P=0.012].Furthermore,patients with a high enhancement pattern experienced an improvement in the objective response ratio[31.3%vs.14.7%,odds ratio(OR)=3.488;95%CI:1.024−11.875;P=0.046],and well-defined tumor margins were associated with a higher disease control rate(DCR)(89.3%vs.68.2%,OR=4.535;95%CI:1.285−16.011;P=0.019)compared to poorlydefined margins.Conclusions:These pre-treatment radiological features,namely high ASER-peri,high enhancement pattern,and well-defined tumor margins,have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma

Objective： To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma （PDAC）. Methods： Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter （VAChT）, as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields （5×0.785 mm2）. Cut-offvalues were calculated by receiver operating characteristic curve analysis. Results： VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/（5×0.785） mm2, with a median of 18 fibers/（5×0.785） mm2. Patients with parasympathetic neurogenesis 〉 15 fibers/（5×0.785） mm2 were defined as the high-density group （39 patients, 66.1%）, and those with parasympathetic neurogenesis 〈15 fibers/（5×0.785） mm2 as the low-density group （20 patients, 33.9%）. The high-density group had a higher occurrence of tumor budding （P=0.001） and a higher rate of early recurrence （P=0.035）. Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio （HR）=2.45, 95% confidence interval （95% CI）： 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer （AJCC） stage （P=0.010） and tumor budding （P=0.009）. Conclusions： Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC.

Laparoscopic treatment for suspected gallbladder cancer confined to the wall： a 10-year study from a single institution

Objective： Although laparoscopic treatment of gallbladder cancer（GBC） has been explored in the last decade,long-term results are still rare. This study evaluates long-term results of intended laparoscopic treatment for suspected GBC confined to the gallbladder wall, based on our experience over 10 years.Methods： Between August 2006 and December 2015, 164 patients with suspected GBC confined to the wall were enrolled in the protocol for laparoscopic surgery. The process for GBC treatment was analyzed to evaluate the feasibility of computed tomography（CT） and/or magnetic resonance imaging（MRI） combined with frozen-section examination in identifying GBC confined to the wall. Of 159 patients who underwent the intended laparoscopic radical treatment, 47 with pathologically proven GBC were investigated to determine the safety and oncologic outcomes of a laparoscopic approach to GBC.Results： Among the 164 patients, 5 patients avoided further radical surgery because of unresectable disease and12 were converted to open surgery; in the remaining 147 patients, totally laparoscopic treatment was successfully accomplished. Extended cholecystectomy was performed in 37 patients and simple cholecystectomy in 10. The T stages based on final pathology were Tis（n=6）, T1 a（n=2）, T1 b（n=9）, T2（n=26）, and T3（n=4）. Recurrence was detected in 11 patients over a median follow-up of 51 months. The disease-specific 5-year survival rate of these 47 patients was 68.8%, and rose to 85% for patients with a normal cancer antigen 19-9（CA19-9） level.Conclusions： The favorable long-term outcomes demonstrate the feasibility of combined CT/MRI and frozensection examination in the selection of patients with GBC confined to the gallbladder wall, confirm the oncologic safety of laparoscopic treatment in selected GBC patients, and favor measurement of preoperative CA19-9 in the selection of GBCs suitable for laparoscopic treatment.

Using a Nomogram to Preoperatively Predict Distant Metastasis of Pancreatic Neuroendocrine Tumor in Elderly Patients

Objective To establish a nomogram for predicting the distant metastasis risk of pancreatic neuroendocrine tumors(pNETs)in elderly patients.Methods We extracted data of patients with diagnosis of pNETs at age≥65 years old between 1973 and 2015 from the Surveillance,Epidemiology,and End Results(SEER)database.All eligible patients were divided randomly into a training cohort and validation cohort.Uni-and multivariate logistic regression analyses were performed on the training cohort to identify independent factors for distant metastasis.A nomogram was developed based on the independent risk factors using rms packages of R software,and was validated internally by the training cohort and externally by the validation cohort using C-index and calibration curves.Results A total of 411 elderly patients were identified,of which 260 were assigned to training cohort and 151 to validation cohort.Univariate and multivariate logistic regression analyses indicated the tumor site(body/tail of pancreas:odds ratio[OR]=2.282;95%confidence interval[CI]:1.174–4.436,P<0.05),histological grade(poorly differentiated/undifferentiated:OR=2.600,95%CI:1.266–5.339,P<0.05),T stage(T2:OR=8.913,95%CI:1.985–40.010,P<0.05;T3:OR=11.830,95%CI:2.530–55.350,P<0.05;T4:OR=68.650,95%CI:8.020–587.600,P<0.05),and N stage(N1:OR=3.480,95%CI:1.807–6.703,P<0.05)were identified as independent risk factors for distant metastasis of pNETs in elderly.The nomogram exhibited good predicting accuracy,with a C-index of 0.809(95%CI:0.757–0.861)in internal validation and 0.795(95%CI:0.723–0.867)in external validation,respectively.The predicted distant metastasis rates were in satisfactory agreement with the observed values by the calibration curves.Conclusion The nomogram we established showed high discriminative ability and accuracy in evaluation of distant metastasis risk in elderly pNETs patients,and could provide a reference for individualized tumor evaluation and treatment decision in elderly pNETs patients.

Does Prior Cancer Have an Influence on the Survival Outcomes of Patients with Localized Pancreatic Neuroendocrine Tumors?

Objective To investigate the impact of prior non-pancreatic cancer on the survival outcomes of patients with localized pancreatic neuroendocrine tumors(Pan NETs).Methods We reviewed the Surveillance,Epidemiology,and End Results database and selected patients with localized Pan NETs diagnosed between 1973 and 2015.We divided the patients into two groups according to the presence or absence of prior non-pancreatic malignancy.Before and after propensity score matching,we compared the clinicopathological characteristics and studied the overall survival and cancer-specific survival.Results A total of 357(12.9%)of 2778 patients with localized Pan NETs had prior cancer.A total of 1211 cases with only a localized Pan NET and 133 cases with a localized Pan NET and prior cancer had complete data and met the inclusion criteria of the current study.Patients with prior cancer were associated with advanced age(>65 years,57.9%prior cancer vs.31.0%no prior cancer,P<0.001),later year of diagnosis(87.2%vs.80.2%,P=0.049),a higher proportion of poorly differentiated/undifferentiated grade tumors(4.5%vs.1.5%,P=0.025),and a higher proportion of no primary site surgery(19.5%vs.10.4%,P=0.003).Prostate(29.32%),breast(18.05%),other genitourinary and retroperitoneal(16.54%),and gastrointestinal(12.78%)cancers were the most common prior cancer types.Most of the prior cancers(95.49%)were localized and regional,and only 4.51%of the prior cancers were distant.Patients with interval periods between the prior cancer and Pan NET of≤36 months,36-60 months,60-120 months,and>120 months accounted for 33.08%,13.53%,24.06%,and 29.32%of all cases with prior cancers,respectively.Univariate and multivariate Cox proportional hazards analyses were performed.The presence/absence of prior cancers did not impact survival outcomes of patients with localized Pan NETs before and after propensity score matching(PSM).Further subgroups analysis showed that,patients with localized Pan NETs and prior distant cancer had worse cancer-specific survival than patients with prior local/regional cancer or patients without prior cancer(P<0.001).No significant differences in cancerspecific survival were observed in terms of the different sites of the prior cancers and the different interval periods of prior cancers and Pan NETs(P<0.05).Conclusions Patients with localized Pan NETs and a history of prior cancer had survival outcomes that were comparable to those of patients with no history of prior cancer.Patients with localized Pan NETs and prior cancer could be candidates for clinical trials if they satisfy all other conditions;aggressive and potentially curative therapies should be offered to these patients.

Chinese expert consensus on multidisciplinary diagnosis and treatment of pancreatic neuroendocrine liver metastases

Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.