Baculovirus vector-mediated transfer of NIS gene into colon tumor cells for radionuclide therapy

AIM:To investigate the feasibility of radionuclide therapy of colon tumor cells by baculovirus vector-mediated transfer of the sodium/iodide symporter(NIS) gene.METHODS:A recombinant baculovirus plasmid carrying the NIS gene was constructed,and the viruses(BacNIS) were prepared using the Bac-to-Bac system.The infection efficiency in the colon cancer cell line SW1116 of a green fluorescent protein(GFP) expressing baculovirus(Bac-GFP) at different multiplicities of infection(MOI) with various concentrations of sodium butyrate was determined by flow cytometry.An in vitro cytotoxicity assay was also conducted after infection of SW1116 cells with Bac-NIS.Iodine uptake of Bac-NIS infected SW1116 cells and inhibition of this uptake by sodium perchlorate was examined,and the effect of Bac-NISmediated 131 I in killing tumor cells was evaluated by cell colony formation tests.RESULTS:Infection and transgene expression in SW1116with Bac-GFP were significantly enhanced by sodium butyrate,as up to 72% of SW1116 cells were infected with the virus at MOI of 400 and sodium butyrate at 0.5 mmol/L.No obvious cytotoxicity was observed under these conditions.Infection of SW1116 with Bac-NIS allowed uptake of 131 I in these tumor cells,which could be inhibited by sodium perchlorate.The viability of SW1116 cells infected with Bac-NIS was significantly lower than with Bac-GFP,suggesting that NIS gene-mediated 131 I uptake could specifically kill tumor cells.CONCLUSION:Baculovirus vector-mediated NIS gene therapy is a potential approach for treatment of colon cancer.

Perspective of molecular imaging and peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors:where do we stand?

The clinical use of nuclear medicine imaging and therapy in pancreatic neuroendocrine tumors has been greatly strengthened since the approval of ^(68)Ga-DOTATATE and ^(177)Lu-DOTATATE.However,many aspects are still under discussion.In this 2-part article,we aim to collect and discuss current evidence of molecular imaging and peptide receptor radionuclide therapy(PRRT)in pancreatic neuroendocrine tumor.In the first part,we will address some critical aspects of ^(68)Ga-SSAs imaging,including diagnostic efficacy,recurrence detection and follow-up,patient selection for PRRT,and pitfalls in image interpretation.Besides,we will also briefly discuss the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography,special imaging strategy in regard to insulinoma,and the status of radiolabeled somatostatin receptor antagonist.In the second part,we aim to review the current evidence of PRRT in pancreatic neuroendocrine tumor,focusing on efficacy and safety in particular.We will also introduce the recent development of PRRT,including PRRT in high-grade neuroendocrine neoplasms,retreatment PRRT,upfront PRRT,PRRT in the setting of neoadjuvant therapy and conversion therapy,combination therapies with PRRT,PRRT withαradionuclides,and PRRT with antagonists.

Interventional Radionuclide Therapy of Hepatocellular Carcinoma： Assessment of Intratumoral Retention of HPMA Copolymers

To develop new radiopharmaceuticals for the interventional radionuclide therapy of recurrent hepatocellular carcinoma, poly（HPMA）-APMA-DTPA[HPMA=N-（2-hydroxypropyl） methacrylamide; APMA=N-（3-aminopropyl）methacrylamide; DTPA=diethylenetriaminepentaacetic acidl was synthesized by free radical precipitation polymerization in acetone/dimethylsulfoxide with N,N＇-azobis（isobutyronitrile） as the initiator. The copolymers were characterized with nuclear magnetic resonance（NMR） spectroscopy and gel permeation chromatography（GPC, Mn=2.2xl04, Mw/Mn=l.38）. Subsequently, poly（HPMA）-APMA-DTPA was conjugated with 99mTC radionuclide. Prolonged retention of poly（HPMA）-APMA-DTPA conjugate within the tumor tissues was demonstrated by single-photon emission computed tomography computed tomography（SPECT-CT） at 1, 2, 4 and 24 h following intra-tumoral injection of the conjugate to hepatocellular carcinoma xenografts in mice. DTPA-99mTc was also synthesized and characterized for comparison. The data suggest that the poly（HPMA）-APMA-DTPA conjugates might be useful for the interventional radionuclide therapy of recurrent hepatocellular carcinoma in humans.

Successful Treatment with 177Lutetium-Dotatate and Maintenance Octreotide in a Patient with Esthesioneuroblastoma with Central Nervous System Invasion: Case Report and Review of the Literature

This article presents a case of a patient with relapsed esthesioneuroblastoma (ENB), an aggressive rare tumor that arises from the specialized sensory epithelial olfactory cells in the skull base area, which was initially treated with endoscopic surgery, followed by adjuvant radiotherapy. After local relapse, new surgical approaches and subsequent lines of platin-based chemotherapy were performed. A PET-CT with 68GALIUM DOTATATOC (PET-DOTATOC) showed intense uptake of disease, compatible with the presence of somatostatin receptors, in the face, nodes, liver, bones, and meningeal area. Treatment with 4 cycles of 177Lutetium-Dotatate was performed, followed by maintenance octreotide, with a major radiological and clinical response that is lasting more than 1 year after treatment. This article describes a rare case of a skull-base tumor, with multiple recurrences, in which disease control was achieved with a targeted Peptide Receptor Radionuclide Therapy (PRRT) with 177Lutetium-Dotatate, and discusses factors that could influence the incorporation of this form of therapy. Previous case reports proved the potential efficacy of this therapy usually given for low-grade neuroendocrine tumors and will be carefully reviewed.

Advances in medical treatment for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PanNENs)are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years.For patients with locally advanced or distant metastatic PanNENs,systemic treatment options vary due to the different differentiations,grades and stages.The available options for systemic therapy include somatostatin analogs,molecularly targeted agents,cytotoxic chemotherapeutic agents,immune checkpoint inhibitors,and peptide receptor radionuclide therapy.In addition,the development of novel molecularly targeted agents is currently in progress.The sequence of selection between different chemotherapy regimens has been of great interest,and resistance to chemotherapeutic agents is the major limitation in their clinical application.Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents.Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors,and greater therapeutic efficacy may be achieved by emerging radiolabeled peptides.Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity,dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy.Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments.In the future,the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.

Quality of life in patients with gastroenteropancreatic tumours: A systematic literature review

BACKGROUND Gastroenteropancreatic neuroendocrine tumours(GEP-NETs)are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract(GINETs)or the pancreas(P-NETs).They are relatively uncommon,accounting for 2%of all gastrointestinal malignancies.The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy,biological therapies,and peptide receptor radionuclide therapy.Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease.Health-related quality of life(HRQoL)is increasingly important as a concept reflecting the patients’perspective in conjunction with the disease presentation,severity and treatment.AIM To conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019.METHODS The PRISMA guiding principles were applied.MEDLINE,Embase and the Cochrane library were searched.Data extracted from the publications included type of study,patient population data(mid-gut/hind-gut/GI-NET/P-NET),sample size,intervention/comparators,HRQoL instruments,average and data spread of overall and sub-scores,and follow-up time for data collection.RESULTS Forty-three publications met the inclusion criteria.The heterogeneous nature of the different study populations was evident;the percentage of female participants ranged between 30%-60%,whilst average age ranged from 53.8 to 67.0 years.Eight studies investigated GI-NET patients only,six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour.The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30(n=28)with consistent results across studies;the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies.A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms.The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients;it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients’HRQoL.CONCLUSION HRQoL instruments offer a means to monitor patients’general disease condition,disease progression and their physical and mental well-being.Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack,however,validation and a defined minimal clinical important difference specifically for GINET and P-NET patients.

Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed.Unfunctional GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of misdiagnosis.Therefore,many GEP-NEN patients present with later staged tumors.Motivated hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent years.The result of which is great progress in clinical diagnosis and treatment.According to the most recent clinical guidelines,improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas(NECs),which are subclassified into large and small cell NECs.Combining different functional imaging methods facilitates precise diagnosis.The expression of somatostatin receptors helps to predict prognosis.Genetic analyses of mutations affecting death domain associated protein(DAXX),multiple endocrine neoplasia type 1(MEN 1),alpha thalassemia/intellectual disability syndrome X-linked(ATRX),retinoblastoma transcriptional corepressor 1(RB 1),and mothers against decapentaplegic homolog 4(SMAD 4)help distinguishing grade 3 NENs from poorly differentiated NECs.The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.

Evaluation of ^(177)Lu-Dotatate treatment in patients with metastatic neuroendocrine tumors and prognostic factors

BACKGROUND^177Lu peptide receptor radionuclide therapy(PRRT)is a recently approved therapy in Spain that has been demonstrated to be a well-tolerated therapy for positive somatostatin receptor advanced gastroenteropancreatic neuroendocrine tumors.AIM To determine the impact of PRRT on quality of life,radiologic and metabolic response,overall survival,prognostic factors and toxicity.METHODS Thirty-six patients treated with^177Lu-PRRT from 2016 to 2019 were included.The most frequent location of the primary tumor was the gastrointestinal tract(52.8%),pancreas(27.8%),and nongastropancreatic neuroendocrine tumor(11.1%).The liver was the most common site of metastasis(91.7%),followed by distant nodes(50.0%),bone(27.8%),peritoneum(25.0%)and lung(11.1%).Toxicity was evaluated after the administration of each dose.Treatment efficacywas evaluated by two parameters:stable disease and disease progression in response evaluation criteria in solid tumors 1.1 criterion and prognostic factors were tested.RESULTS From 36 patients,55.6%were men,with a median age of 61.1±11.8 years.Regarding previous treatments,55.6%of patients underwent surgery of the primary tumor,100%of patients were treated with long-acting somatostatin analogues,66.7%of patients were treated with everolimus,27.8%of patients were treated with tyrosine kinase inhibitor,and 27.8%of patients were treated with interferon.One patient received radioembolization,three patients received chemoembolization,six patients received chemotherapy.Hematological toxicity was registered in 14 patients(G1-G2:55.5%and G3:3.1%).Other events presented were intestinal suboclusion in 4 cases,cholestasis in 2 cases and carcinoid crisis in 1 case.The median follow-up time was 3 years.Currently,24 patients completed treatment.Nineteen are alive with stable disease,two have disease progression,eight have died,and nine are still receiving treatment.The median overall survival was 12.5 mo(95%confidence interval range:9.8–15.2),being inversely proportional to toxicity in previous treatments(P<0.02),tumor grade(P<0.01)and the presence of bone lesions(P=0.009)and directly proportional with matching lesion findings between Octreoscan and computed tomography pre-PRRT(P<0.01),,primary tumor surgery(P=0.03)and metastasis surgery(P=0.045).In a multivariate Cox regression analysis,a high Ki67 index(P=0.003),a mismatch in the lesion findings between Octreoscan and computed tomography pre-PRRT(P<0.01)and a preceding toxicity in previous treatments(P<0.05)were risk factors to overall survival.CONCLUSION Overall survival was inversely proportional to previous toxicity,tumor grade and the presence of bone metastasis and directly proportional to matching lesion findings between Octreoscan and computed tomography pre-PRRT and primary tumor and metastasis surgery.

Current update on imaging for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(panNEN)are a heterogeneous group of tumors with differing pathological,genetic,and clinical features.Based on clinical findings,they may be categorized into functioning and nonfunctioning tumors.Adoption of the 2017 World Health Organization classification system,particularly its differentiation between grade 3,well-differentiated pancreatic neuroendocrine tumors(panNET)and grade 3,poorly-differentiated pancreatic neuroendocrine carcinomas(panNEC)has emphasized the role imaging plays in characterizing these lesions.Endoscopic ultrasound can help obtain biopsy specimen and assess tumor margins and local spread.Enhancement patterns on computed tomography(CT)and magnetic resonance imaging(MRI)may be used to classify panNEN.Contrast enhanced MRI and diffusion-weighted imaging have been reported to be useful for characterization of panNEN and quantifying metastatic burden.Current and emerging radiotracers have broadened the utility of functional imaging in evaluating panNEN.Fluorine-18 fluorodeoxyglucose positron emission tomography(PET)/CT and somatostatin receptor imaging such as Gallium-681,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–octreotate PET/CT may be useful for improved identification of panNEN in comparison to anatomic modalities.These new techniques can also play a direct role in optimizing the selection of treatment for individuals and predicting tumor response based on somatostatin receptor expression.In addition,emerging methods of radiomics such as texture analysis may be a potential tool for staging and outcome prediction in panNEN,however further investigation is required before clinical implementation.

Acquired hepatocerebral degeneration in a metastatic neuroendocrine tumor long-term survivor——an update on neuroendocrine neoplasm’s treatment:A case report

BACKGROUND Metastatic small bowel low-grade neuroendocrine tumors(NETs)have a good prognosis.Surgery is the only curative treatment;however,this may induce advanced liver disease,particularly in long-term survivor patients.Acquired hepatocerebral degeneration or Parkinsonism in cirrhosis is characterized by rapidly progressive extrapyramidal symptoms in patients with advanced liver disease.CASE SUMMARY A 70-year-old man presented to the emergency department with diminished consciousness and disorientation,and was diagnosed with hepatic encephalopathy.The patient was diagnosed in 1993 with a metastatic small bowel NET,for which he twice underwent hepatic surgery,with metastatic resection in 1993 and a right hepatectomy in 2002 to remove two hepatic metastases.In 2003,the patient started first-line chemotherapy and in 2004 started the first of three consecutive biological treatments,followed by radio-molecular therapy,achieving stable disease for 14 years.Disease progression was identified and he underwent an endoscopic retrograde cholangiopancreatography.However,in 2019 advanced liver disease was identified.We diagnosed the development of acquired hepatocerebral degeneration,an unusual long-term side effect after multiple hepatic procedures.CONCLUSION The importance of regular and ongoing surveillance in long-term NET survivors who undergo hepatic procedures should be integrated into the therapeutic management plan,as some of these negative outcomes could be prevented.

Review of recent advances in medical treatment for neuroendocrine neoplasms:somatostatin analogs and chemotherapy

Neuroendocrine neoplasms(NENs)are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms.There are a number of different types of NENs.They usually arise as advanced and low/intermediate grade only in a minority of cases,as high grade.Treatment depends on which type and may include surgery,interventional radiology,and systemic treatment,including chemotherapy,somatostatin analogs,interferonα2b,peptide receptor radionuclide therapy,and only for pancreatic neuroendocrine tumors,molecular targeted agents,including everolimus and sunitinib.The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy.The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features,such as symptoms and endocrine markers.

Metastatic well-differentiated pancreatic neuroendocrine tumors to the liver: a narrative review of systemic and surgical management

Pancreatic neuroendocrine tumors(PNETs)are a rare group of neoplasms originating from the endocrine pancreas.PNETs are classified as functional or non-functional tumors.PNETs are more often diagnosed at a higher stage with distant metastases or advanced locoregional disease.The majority of individuals with hepatic metastases will ultimately die of liver failure;therefore,the treatment of liver tumor burden is critical to providing a survival impact.While surgical resection remains the only chance of cure for disease confined to the pancreas or for locoregional disease,the treatment of advanced or metastatic PNETs is more complex and often requires a multimodal approach.This review focuses on treatment options for well and moderately differentiated PNETs with metastatic disease to the liver.These include surgery,liver-directed therapies including ablative and intra-arterial therapies,and systemic therapies such as somatostatin analogues,targeted therapies,chemotherapy,and peptide receptor radionuclide therapy.Developing an individualized treatment strategy requires careful assessment of liver tumor burden and predicted biological behavior.Aggressive surgical resection of hepatic metastases secondary to PNET primary tumors is associated with improved survival in multiple retrospective studies.General goals of treatment for metastatic disease include prolonging overall survival and progression free survival,improving quality of life,and control of symptoms.

Systemic treatment of advanced, metastatic, medullary thyroid carcinoma

Medullary thyroid carcinoma(MTC)is a rare endocrine tumor,which arises from thyroid parafollicular C cells.Through its ability to metastasize by blood and lymphatic vessels,it can show a more aggressive clinical behavior than differentiated thyroid cancers.Mutation of RET gene is the main molecular alteration involved in MTC origin.In the case of germline RET mutation,MTC can be inherited in an autosomal dominant way and show three different phenotypes:familial medullary thyroid carcinoma and multiple endocrine neoplasia types IIA and IIB.In addition,in sporadic cases,somatic RET mutation remains the key molecular alteration in most of cases.Total thyroidectomy with prophylactic or therapeutic central compartment lymph nodes dissection is the surgical treatment of choice.Further surgical treatments and local therapies should be used in the case of single or few local or distant metastasis.However,in cases with large metastatic spread of the disease,particularly in those with significant tumor progression,additional systemic treatments are needed.In this review,we discuss the key points of systemic treatment in advanced,metastatic MTC.We provide an update on the main aspects(from biological rationale to clinical experience)of each treatment,focusing our attention on the drugs used in clinical practice in the last years.Finally,we give insights about the emerging treatments from highly selective RET inhibitors to new radionuclide therapy.