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.

Surgical aspects of small intestinal neuroendocrine tumors

Small intestinal neuroendocrine tumors(NETs)are a heterogeneous group of epithelial tumors with a predominant neuroendocrine differentiation.Although NETs are usually considered rare neoplasms,small intestinal NETs are the most common primary malignancy of the small bowel,with an increasing prevalence worldwide during the course of the past few decades.The indolent nature of these tumors often leads to a delayed diagnosis,resulting in over one-third of patients presenting with synchronous metastases.Primary tumor resection remains the only curative option for this type of tumor.In this review article,the various surgical aspects for the excision of small intestinal NETs are discussed.

Transcatheter arterial chemoembolization for gastrointestinal stromal tumors with liver metastases

AIM:To evaluate the efficacy and safety of transcatheter arterial chemoembolization(TACE) for gastrointestinal stromal tumor(GIST) with liver metastases after the failure of tyrosine kinase inhibitors(TKIs).METHODS:Patients with histologically confirmed CD117-positive GIST with liver metastases who were resistant and/or intolerant to prior imatinib and/or sunitinib and who received TACE for at least one treatment cycle or only best supportive care and TKI reintroduction were eligible for the study.The patients were divided into two groups:those in TACE group received TACE treatment containing 5-20 mL iodized oil and 40-80 mg doxorubicin hydrochloride and TKI reintroduction or best supportive care,those in control group only received TKI reintroduction or best supportive care.The primary end-point was overall survival and the secondary end-points were,progression-free survival(PFS),response rates,and safety.RESULTS:Sixty patients admitted between June 2008 and October 2011 were eligible for this study,including 22 in TACE group and 38 in control group.In the TACE group,12(54.5%) achieved liver partial response,5(22.7%) had stable disease,and 5(22.7%) had liver progressive disease.Disease control rate of liver metastases was 77.3% in the TACE group and 39.5% in the control group.The median liver PFS in TACE group was 47.1 wk(95% CI:23.9-70.3).The median PFS in TACE group was longer than in control group(30.0 wk,95% CI:20.1-39.9 vs 12.9 wk,95% CI:11.9-13.9)(P = 0.0001).The median overall survival in TACE group was also longer than in control group(68.5 wk,95% CI:57.4-79.6 vs 25.7 wk,95% CI:23.2-28.2)(P = 0.0001).TACE treatment significantly reduced the risk of death(hazard ratio:0.109).Patients without extrahepatic metastases treated with TACE had significantly better prognosis.Most of the adverse events were of grade 1 or 2 and tolerable.CONCLUSION:TACE is effective and well tolerated in GIST patients with liver metastases after TKI failure,and it may be an optional treatment for this disease.

Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases

A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography （PET）/computed tomography （CT） demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor （pNET）. According to the latest World Health Organization （WHO, 2013） classification, the tumor was classified as stage IV fimctional G1 pNET. After referral to the multidisciplinary treatment board （MDT）, the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α （IFNα） and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 （1251） seeds implantation therapy, radiofrequency ablation therapy （RFA） or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization （TACE）, RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission （RECIST criteria） with a good quality of life.

Liver-directed therapies for liver metastases from neuroendocrine neoplasms:Can laser ablation play any role?

Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Catheter-based treatments are used in disseminated disease,whereas ablation techniques are usually indicated when the number of LM is limited.Although radiofrequency ablation(RFA)is by far the most used ablative technique,the goal of this opinion review is to explore the potential role of laser ablation(LA)in the treatment of LM from NEN.LA uses thinner needles than RFA,and this is an advantage when the tumors are in at-risk locations.Moreover,the multi-fiber technique enables the use of one to four laser fibers at once,and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter.Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor,sparing the liver parenchyma more than any other liver-directed therapy,and allowing for repeated treatments with low risk of liver failure.A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA,that can play a useful role in the multimodality approach to LM from NEN.

Radical Operation and Everolimus Therapy for Rectal Neuroendocrine Tumor with Liver Metastases: A Case Report with Review of the Literature

Neuroendocrine tumors (NETs) are often misdiagnosed because they can involve any part of the body and have non-specific symptoms. Here, we report a case of a 39-year-old man with rectal neuroendocrine tumor (RNET) and hepatic metastases treated with a combination of radical surgery and Everolimus therapy. The patient complained of abdominal distension, pain, and constipation of one month duration. Enhanced CT scan of the abdomen, colonoscopy and Biopsy findings confirmed the diagnosis of rectal neuroendocrine tumor. As the anatomical structures were clear and the masses seemed to be resectable, we decided to initiate treatment with radical operation and Everolimus therapy. The patient has responded well to the treatment with no evidence of recurrence after 4 years of follow-up. This case is interesting because of the rarity of this neoplasm and its initial misdiagnosis as a giant hepatic carcinoma (hepatoma). It also demonstrates that a combination of curative surgical resection and Everolimus is a good option in a patient with large colorectal neuroendocrine tumors and massive hepatic metastases.

Primary hepatic neuroendocrine tumor with multiple liver metastases:A case report with review of the literature

We herein present a case involving a 41-year-old woman in whom ultrasound examination revealed multiple liver hemangiomas more than 3 years ago.Follow-up ultrasound examination revealed that the masses had significantly increased;the largest was located in the right lobe(about 8.2 cm×7.4 cm×6.0cm).Abdominal multidetector computed tomographyrevealed multiple well-circumscribed,heterogeneous,hypodense masses(largest,6.4 cm×6.3 cm×5.0cm)with significant contrast enhancement during the arterial and portal phases and with contrast washout and peripheral enhancement during the delayed phases.Magnetic resonance images demonstrated multiple well-circumscribed,heterogeneous,hypointense hepatic masses with significant contrast enhancement(largest,6.4 cm×6.5 cm×5.1 cm);multiple enlarged porta lymph nodes;and multiple s l i g h t l y e n l a rg e d re t ro p e r i t o n e a l l y m p h n o d e s.Histological and immunohistochemical examination of the right mass biopsy specimen suggested a malignant neoplasm that had originated from a neuroendocrine cell type(grade 2 well-differentiated neuroendocrine carcinoma).After performing a systemic examination to exclude metastasis from an extrahepatic primary site,we considered that the masses had arisen from a primary hepatic neuroendocrine tumor with multiple liver metastases.The patient underwent transcatheter arterial chemoembolization using a combination of oxaliplatin(150 mg)mixed with one bottle of gelatin sponge particles(560-710μm)and lipiodol(6 m L).Primary neuroendocrine tumors of the liver are extremely rare.This case is interesting because of the rarity of this neoplasm and previous misdiagnosis as multiple liver hemangiomas.Previously reported cases in the literature are also reviewed.

Neuroendocrine liver metastases: Contributions of endoscopy and surgery to primary tumor search

Neuroendocrine tumors (NETs) are diagnosed with increasing frequency and patients often present with liver metastases at the time of diagnosis. Apart from treatment of the metastases, resection of the primary tumor at an early phase is recommended to prevent complications, although it may be difficult to locate, especially in patients with functionally inactive NETs. Small and multifocal tumors in the jejunum and ileum represent a particular challenge. Primary hepatic neuroendocrine carcinoma is extremely rare and is diagnosed only after exclusion of other primary tumors. Therefore, some uncertainty may remain, as small non-hepatic primary tumors may escape detection. Diagnostic work-up in these patients includes biochemical assays and imaging modalities (also comprising specific techniques of scintigraphy and positron emission tomography). This editorial highlights the contributions of endoscopy and operative exploration to the search for the primary tumor. Besides esophagogastro-duodenoscopy, endoscopic ultrasonography, colonoscopy and bronchoscopy, special endoscopic techniques such as balloon enteroscopy or capsule endoscopy are used with growing experience. Compared with balloon enteroscopy, capsule endoscopy is noninvasive and better tolerated, but it cannot localize a lesion precisely and does not allow biopsy or removal of lesions. Before proceeding to surgery, a discussion of the findings by a tumor board should be a standard procedure. Improvements in diagnostic tools have created new perspectives for the detection of obscure primary tumors in patients with neuroendocrine liver metastases, and these searches are best coordinated by a multidisciplinary team.

Current surgical management of pancreatic endocrine tumor liver metastases

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation. CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases.

PRIMARY NEUROENDOCRINE TUMORS OF THE LIVER AND GALLBLADDER

To study Clinico-pathological characters of the neuroendocrine tumors of the liver and gallbladder.MethodsUsing histology, immunohistochemistry and electron microscope, 3 cases of liver and gallbladder were investigated. The primary antibodies including anti-chromogranin A, gastrin, serotonin, insulin, somatostatin, gastrin, pancreatic polypeptide, adreno- corticotropic hormone (ACTH), calcitonin, bombesin, β-human chorionic gonadotropin (β-HCG) were employed to identify the property of tumors.ResultsIn one cases tumor of neuroendocrine carcinoma. In the other two cases tumor were typical carcinoid. In immunohistochemistry study, the tumor cells showed positive reaction to chromagranin A and contained positive cells of gastrin, serotonin, insulin and pancreatic polypaptide. Electronmicroscopy showed the cytoplasm contained dense round granules.ConclusionThe Nuroendocrine tumor of liver and gallbladder is a special type neoplasm with character of histology, immunohistochemistry and electron microscopy. Subject headings neuroendocrine tumor gallbladder liver immunohistochemistry and electron microscopy.

Pancreatic neuroendocrine tumor accompanied with multiple liver metastases

Pancreatic neuroendocrine tumor(P-NET) is rare and slow-growing. Current classifications predict its progno-sis and postoperative recurrence. Curative resection is ideal, although often difficult, because over 80% of pa-tients have unresectable multiple liver metastases and extrahepatic metastasis. Aggressive surgery for liver metastases is important to improve survival. Aggressive or cytoreductive surgery for liver metastases is indi-cated to reduce hormone levels and improve symptoms and prognosis. Liver transplantation was originally con-ceived as an ideal therapy for unresectable liver metas-tases. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with unresectable liver metastases.

Computer planned, image-guided combined resection and ablation for bilobar colorectal liver metastases

For patients with extensive bilobar colorectal liver metastases (CRLM), initial surgery may not be feasible and a multimodal approach including microwave ablation (MWA) provides the only chance for prolonged survival. Intraoperative navigation systems may improve the accuracy of ablation and surgical resection of so-called “vanishing lesions”, ultimately improving patient outcome. Clinical application of intraoperative navigated liver surgery is illustrated in a patient undergoing combined resection/MWA for multiple, synchronous, bilobar CRLM. Regular follow-up with computed tomography (CT) allowed for temporal development of the ablation zones. Of the ten lesions detected in a preoperative CT scan, the largest lesion was resected and the others were ablated using an intraoperative navigation system. Twelve months post-surgery a new lesion (Seg IVa) was detected and treated by trans-arterial embolization. Nineteen months post-surgery new liver and lung metastases were detected and a palliative chemotherapy started. The patient passed away four years after initial diagnosis. For patients with extensive CRLM not treatable by standard surgery, navigated MWA/resection may provide excellent tumor control, improving longer-term survival. Intraoperative navigation systems provide precise, real-time information to the surgeon, aiding the decision-making process and substantially improving the accuracy of both ablation and resection. Regular follow-ups including 3D modeling allow for early discrimination between ablation zones and recurrent tumor lesions.

Pathologic research update of colorectal neuroendocrine tumors

Colorectal neuroendocrine tumors (NETs) originate from neuroendocrine cells in the intestinal tract, and represent a small area within oncology, but one which has provided increasing new data during the past years. Although the World Health Organization has determined clinical and histological features to predict prognosis for such tumors, they may not be valid on an individual basis. We aim to give an overview of the recent findings with regard to pathology, molecular genetics and diagnosis of NETs.

Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies?

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs) frequently present with distant metastases at the time of diagnosis and the liver is the most frequent site of spreading. The early identification of metastatic disease represents a major prognostic factor for GEP-NENs patients. Radical surgical resection, which is feasible for a minority of patients, is considered the only curative option, while the best management for patients with unresectable liver metastases is still being debated. In the last few years, a number of locoregional and systemic treatments has become available for GEP-NEN patients metastatic to the liver. However, to date only a few prospective studies have compared those therapies and the optimal management option is based on clinical judgement. Additionally, locoregional treatments appear feasible and safe for disease control for patients with limited liver involvement and effective in symptoms control for patients with diffuse liver metastases. Considering the lack of randomized controlled trials comparing the locoregional treatments of liver metastatic NEN patients, clinical judgment remains key to set the most appropriate therapeutic pathway. Prospective data may ultimately lead to more personalized and optimized treatments. The present review analyzes all the locoregional therapy modalities(i.e., surgery, ablative treatments and transarterial approach) and aims to provide clinicians with a useful algorithm to best treat GEP-NEN patients metastatic to the liver.

Repeat resection of liver metastases from gastrointestinal stromal tumor

A 44-year-old man, who was diagnosed with a gastrointestinal stromal tumor incidentally during emergency laparotomy for treatment of acute obstruction of small intestine at another hospital in 1999, was referred to our hospital due to a solitary metastasis in the liver in November 2002. A right segmentectomy (Segment 6, Couinaud's system) of liver was carried out. Half and one years later, a recurrent metastasis with involvement of the inferior vena cava was detected in posterior region of the liver. He underwent the third surgery in May 2004. Three another small metastases in greater omentum were found and removed. The tumor in posterior sector of the liver was en bloc resected with portion of involved inferior vena cava and diaphragm. The resected vena cava is repaired primarily through a lateral venorraphy.However, local recurrence was detected one year later, he recieved the fourth surgery in July 2005. He is now in Gleevec therapy. At present, he is in good health and free of recurrence.

Active surveillance in metastatic pancreatic neuroendocrine tumors:A 20-year single-institutional experience

BACKGROUND Pancreatic neuroendocrine tumors(PanNETs)are heterogeneous and indolent;systemic therapy is not essential for every patient with metastatic PanNET.The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis,if the patient has stable disease.However,specific factors that influence surveillance were not mentioned.In addition,data regarding the period of active surveillance in patients with metastatic PanNET are lacking.AIM To specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs(NF-PanNETs).METHODS Seventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled.Time to disease progression(TTP)and time to initiation of systemic therapy were determined.RESULTS Thirty-one(40.8%)patients had recurrent liver disease after R0 resection;45(59.2%)were diagnosed with liver metastasis.The median follow-up period was 42 mo and 90.7%patients were observed to have disease progression.The median TTP(mTTP)was 10 mo.Multivariate analysis showed that the largest axis of the liver metastasis>5 mm(P=0.04),non-resection of the primary tumor(P=0.024),and T3-4 stage(P=0.028)were associated with a shorter TTP.The mTTP in patients with no risk factors was 24 mo,which was significantly longer than that in patients with one(10 mo)or more(6 mo)risk factors(P<0.001).A nomogram with three risk factors showed reasonable calibration,with a C-index of 0.603(95%confidence interval:0.47-0.74).CONCLUSION Active surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors,and other patients progressed rapidly without treatment.Further studies with a larger sample size and a control group are needed.

Liver transplantation as an alternative for the treatment of neuroendocrine liver metastasis: Appraisal of the current evidence

Background:Liver transplantation(LT)for neuroendocrine liver metastases(NELM)is still in debate.Studies comparing LT with liver resection(LR)for NELM are scarce,as patient selection is heterogeneous and experience is limited.The goal of this review was to provide a critical analysis of the evidence on LT versus LR in the treatment of NELM.Data sources:A scoping literature search on LT and LR for NELM was performed with PubMed,including English articles up to March 2023.Results:International guidelines recommend LR for NELM in resectable,well-differentiated tumors in the absence of extrahepatic metastatic disease with superior results of LR compared to systemic or liver-directed therapies.Advanced liver surgery has extended resectability criteria whilst entailing increased perioperative risk and short disease-free survival.In highly selected patients(based on the Milan criteria)with unresectable NELM,oncologic results of LT are promising.Prognostic factors include tumor biology(G1/G2)and burden,waiting time for LT,patient age and extrahepatic spread.Based on low-level evi-dence,LT for low-grade NELM within the Milan criteria resulted in improved disease-free survival and overall survival compared to LR.The benefits of LT were lost in patients beyond the Milan NELM-criteria.Conclusions:With adherence to strict selection criteria especially tumor biology,LT for NELM is becoming a valuable option providing oncologic benefits compared to LR.Recent evidence suggests even stricter selection criteria with regard to tumor biology.

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.

Rare and lacking typical clinical symptoms of liver tumors:Four case reports

BACKGROUND Rare liver tumors(RLTs)have an extremely low likelihood of forming,and some have been recorded only in isolated cases.The lack of normal clinical symptoms in RLTs makes preoperative diagnosis extremely challenging,which results in frequent misinterpretation.The present case report helps enhance our ability to recognize and treat uncommon liver tumor disorders.CASE SUMMARY We describe four distinct examples of rare liver tumor diseases.These cases were all true cases with no conventional clinical signs or imaging findings.In all patients,hepatic occupancy was discovered on physical examination,which raised the preoperative suspicion of hepatic cancer.All tumors were surgically removed,and postoperative histology and immunohistochemistry were performed to confirm the diagnosis.The first patient had primary hepatic fibrosarcoma.The second case involved a primary hepatic neuroendocrine tumors.These two patients had malignant liver tumors,and both had extremely satisfactory surgical outcomes.The third case involved focal hepatic steatosis,and the fourth case involved a single necrotic nodule in the liver.These two patients had benign liver tumors,but they had already undergone surgery and did not require any postoperative care.CONCLUSION The number of patients with RLTs is small,and the clinical and imaging results are vague.Preoperative diagnosis is challenging,and patients are sometimes mistakenly diagnosed with liver cancer,which leads to unnecessary surgical therapy in certain individuals.

Targeted deep sequencing reveals the genetic heterogeneity in well-differentiated pancreatic neuroendocrine tumors with liver metastasis

Background:Pancreatic neuroendocrine tumor is a rare and heterogeneous entity,and approximately half of the patients harbored liver metastasis when initially diagnosed,whose prognosis is dismal.High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor,but the genetic alterations in the metastatic cases remain relatively unclear,which we aimed to study.Methods:Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected.We performed deep sequencing on the exome of 341 tumor-related genes,and compared the differences of genetic alterations between the metastatic and the non-metastatic cases,as well as between the primary and the paired liver metastatic tumors.Results:Sequencing data of 79 samples from 29 pancreatic neuroendocrine tumor patients were included into analysis.A total of 2,471 somatic variants were identified,75.5%of which were considered as low-abundance.NOTCH1 was the most frequently mutated gene,altered in 26(53.1%)pancreatic neuroendocrine tumor samples from 18(62.1%)patients.Compared with the non-metastatic pancreatic neuroendocrine tumors,the metastatic cases were discovered with more single nucleotide variants and copy number variations,indicating the increased genomic instability.In addition,among the paired metastatic cases,the primary and the metastatic lesions shared limited mutated genes.Conclusions:Through the targeted deep sequencing,we identified the intratumor,intraindividual,and interindividual heterogeneity in the pancreatic neuroendocrine tumor patients,particularly in the metastatic cases,bringing potential challenges for the current biopsy strategies in guiding clinical treatments.