Neoplasms

Symptoms and General Pathology

All Conditions

Gland and Hormone Related Diseases

Rare Diseases

Neoplasm Metastasis

Neuroendocrine Tumors

Endocrine Gland Neoplasms

Lymphatic Metastasis

Neoplastic Processes

Endocrine System Diseases

Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Non Functioning Pancreatic Endocrine Tumor

Stefano Partelli, MD, PhD

Pancreatic Neuroendocrine Neoplasms (PanNEN) are a heterogeneous group of neoplasms that arise from the endocrine cells of the pancreatic gland. Non-functioning (NF-PanNEN) represents the most common forms and do not produce syndromes due to hormonal hypersecretion. Several prognostic factors have been demonstrated for NF-PanNEN. The presence of nodal metastasis and lymph node ratio are widely considered predictors of disease-free survival and even the number of positive nodes has been found to be associated with recurrence. In addition to traditional imaging exams, diagnostic work-up should include a Positron Emission Tomography/CT with 68Ga labeled somatostatin analogues, which have shown a high sensitivity and specificity while 18F-FDG PET can be associated for evaluating the possible presence of a high-grade component. Moreover, pancreatic endoscopic ultrasound (EUS) is usually part of the preoperative staging both for imaging details and cytological sampling. Therefore an accurate identification of nodal metastases preoperatively may have important implications for the extent of surgical resection and lymphadenectomy and even for a prognostic outcome.

In this study the investigators will evaluate prospectively the accuracy of these diagnostic exams in detecting the lymph node status. Patients with sporadic NF-PanNEN who are candidates for surgical resection will undergo CE-CT scan, 68Ga DOTATOC (and eventually 18F-FDG) PET/MRI and EUS with FNA/B. Reference standard for defining the presence of nodal metastases is represented by pathological examination on the specimen.

The study is designed as a prospective monocentric observational cohort study. The primary endpoint of the study is to assess the accuracy of preoperative diagnostic procedures in terms of sensitivity and specificity in detecting nodal metastases in sporadic NF-PanNEN as determined by pathological examination on the specimen.

Patients with a suspect of a sporadic NF-PanNEN will be considered for the study at the time of the first visit. All consecutive patients who will meet inclusion criteria, after informed consent, will be included. The preoperative work-up will be performed in our center. All the examinations required for this study are necessary for the correct preoperative staging, representing the standard diagnostic work-up in patients with PanNEN. Computed tomography (CT) images will be obtained by multiphase technique. Non-enhanced, arterial and portal phase images will be obtained in all the patients. Computed tomography (CT) images will be obtained by multiphase technique. Non-enhanced, late arterial and portal phase images will be obtained in all the patients as well. Every lymph nodal finding with short-axis diameter \>1cm or with pathological contrast enhancement will be considered as pathological. Pancreatic endoscopic ultrasound (EUS) is a relatively recent endoscopic technique which combines the high-frequency ultrasound technology with the direct endoscopic vision, permitting a sensitive evaluation of pancreatic lesions (from the stomach or the duodenum), an accurate vascular staging and the assessment of pathologic lymph nodes related to the tumor. Nodes larger than 1 cm, with well demarked and/or rounded margins and with typical echoic/elastographic features will be reported as metastatic. Moreover, the additive value of EUS is the possibility to sample pancreatic masses and lymph nodes with a fine needle aspiration (FNA), to obtain a cytological diagnosis. A PET/MRI with 68Ga-DOTATOC is also necessary for the staging of the disease. A 18F-FDG PET will be performed according to the clinician's discretion, especially in the presence of large lesions and/or liver metastases.

As soon as the preoperative assessment will be completed, a surgical resection will be proposed to the patient according to the international guidelines on the management of NF-PanNEN. A standard pancreatic resection will be performed according to the site and the extension of the lesion. Nodes will be classified according to the Japanese classification of the biliary tract cancers. The extension of lymphadenectomy will be related to the type of pancreatic resection.

LN that will be resected apart from the pancreatic specimen, will be sent for pathological examination in a separated cup labelled by the surgeon. In case of preoperative detection of nodal involvement in a station not included in the standard lymphadenectomy, the nodes in this station will be resected to confirm or not the radiological finding. Reference standard for defining the presence of nodal metastases will be represented by the pathological examination.

All data regarding the clinical aspect, the radiological reports and the pathological exam will be fully available only to the surgeon. Radiologist, nuclear medicine physician, and pathologist will be blinded to the radiological findings.

Several retrospective studies 11-12 reported a prevalence of nodal metastases in PanNEN of about 40%, in case of tumors \> 2 cm. No data have been found on the sensitivity and specificity of the various examinations in detecting nodal involvement. Given this prevalence and assuming a good accuracy based on this institute experience, the simple size required to assess the sensitivity and specificity of the methods was found to be of 150 patients, considering a 95% confidence interval with a margin of error of 10%.

A descriptive analysis will be performed of the data obtained. The aim will be to evaluate the sensitivity, the specificity and the positive and negative predictive values of the preoperative staging (CE-CT scan, EUS, 68Ga DOTATOC/18F-FDG PET/MRI). The comparison between the exams in terms of prediction of the nodal status will be calculated with the McNemar test. A logistic regression model will be used to assess the risk of nodal positivity at the pathological report when the preoperative imaging demonstrates the features of nodal metastases. OR and 95% confidence interval will be calculated. The statistical correlation between the risk of nodal positivity at the pathological report and some preoperative variables will be evaluated with the chi-square test and ROC curves analysis.

Diagnostic Accuracy of Preoperative Diagnostic Procedure in the Assessment of Lymph Node Metastases by NF-PanNENs

Diagnostic Accuracy of 68Gallium Positron Emission Tomography/ Magnetic Resonance Imaging (68Ga PET/MRI), Endoscopic Ultrasound (EUS) and Computed Tomography in the Assessment of Lymph Node Metastases by Nonfunctioning Pancreatic Neuroendocrine Neoplasms

The primary endpoint of the study is to assess the accuracy of preoperative diagnostic procedures in terms of sensitivity and specificity in detecting nodal metastases in sporadic NF-PanNEN

The secondary outcomes include the assessment of the prognostic role of nodal involvement on disease/progression free survival in patients who undergo a pancreatic resection for a Non-functioning Pancreatic Neoplasms.

This secondary outcome include the evaluation of other possible variables that can be associated with the risk of nodal metastases such as preoperative dimension in mm of the PanNEN, location, features at the imaging, standard uptake value (SUV).

IRCCS San Raffaele

Principal Investigator

Advised surveillance strategy consists of imaging studies (MR or EUS or US), every 6 months for the first two years and yearly thereafter for five years in the absence of significant changes on imaging or symptoms appearance. During surveillance, a high-quality imaging technique (MRI or CT) is mandatory at least every 12 months. Determination of CgA during follow-up is at physician's discretion. During follow-up, the treating physician is responsible for patient management and decision-making.

Timing and type of resection will be established by the treating physician. Follow up strategy after surgery consists of imaging studies (MR or CT), every 6 months for the first two years and yearly thereafter for five years. An high-quality imaging technique (MRI or CT) is mandatory at least every 12 months. Determination of CgA during follow-up is at physician's discretion. During follow-up, the treating physician is responsible for patient management and decision-making. Date of surgery does not change the timing of follow up which starts from the date of enrolment.

Patients will be submitted to radiological imaging studies (CT scan and/or MRI and/ or 68Gallium PET/CT and/or Octreoscan and/or EUS+FNAand/or Octreoscan and/or EUS+FNA) at diagnosis, and then every 6 months for the first two years and yearly thereafter for five years in the absence of significant changes on imaging or symptoms appearance. Every 12 months (or 6 months for patients with Ki67\> 2%) a high quality imaging (CT scan or MRI) is required.

Radiological imaging studies

quality of life and the perceived burden of surveillance or follow-up after surgery for participants, will be investigated by administrating HADS questionnaire and EORTC QLQ-C30 (version 3) and EORTC QLQ-GI.NET21 Module.

Quality of Life Assessment

Massimo Falconi, Professor

Stefano Partelli, MD PhD

Francesca Muffatti, MD

The aim of the study is to evaluate the most appropriate management of sporadic asymptomatic non-functioning pancreatic neuroendocrine neoplasms (NF-PNEN) ≤ 2 cm. P NF-PNEN management will be decided at the hospital and all therapeutics decision will be decided/coordinated by the treating physician.

Patients will be either submitted to surgical resection or to active surveillance.

In the last decade a dramatic increase in diagnosis of small, incidentally discovered, NF-PNEN was observed. Various study indicates the safety of a conservative management for this lesion and the The European Neuroendocrine Tumor Society (ENETS) proposed a "wait and see" approach for small NF-PNEN.

Indications for surgery include the presence of a localized NF-PNEN in the absence of distant metastases as curative resection of these tumors is associated with favourable prognosis especially for low grade.

In the last decade a dramatic increase in diagnosis of small, incidentally discovered, NF-PNEN was observed.Moreover, other investigators observed a clear relationship between the tumor diameter and low risk of malignancy and systemic progression.

In particular, a tumor size ≤ 2 cm seems to be associated with a negligible risk of disease recurrence and with a very low incidence of aggressive features such as lymph node involvement.On this basis, the European Neuroendocrine Tumor Society (ENETS) proposed a "wait and see" approach for small NF-PNEN when incidentally discovered. Since then, various series evaluated the safety of a conservative management for small, sporadic, incidentally diagnosed, NF-PNEN.

After a median follow-up of 28-45 months, all the studies confirmed that an intensive surveillance for incidental and small NF-PNEN is safe in selected cases.

Nevertheless, available data are based only on retrospective series with a significant heterogeneity of inclusion criteria and different tumor diameter cut-off and the appropriate management of this entities (surveillance versus surgery) is still a matter of debate.

Asymptomatic Small Pancreatic Endocrine Neoplasms.

A Prospective Evaluation of the Management of Sporadic Asymptomatic Nonfunctioning Pancreatic Neuroendocrine Neoplasms ≤ 2 cm

The primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgical resection group) or death from disease.

The secondary end point is to evaluate the frequency of asymptomatic sporadic NF-PNEN ≤ 2 cm among overall sporadic NF-PNEN. Participating centers are required to give yearly the number of patients with NF-PNEN referred to their institution.

Morbidity and mortality of patients submitted to surgical resection

Number of patients submitted to surgery andh type of surgical procedures.

NF-PNEN evolution, in terms of development of symptoms, tumour growth, development of distant metastases and secondary pancreatic duct dilatation.

The perceived burden of surveillance or follow-up after surgery for participants, as assessed by questionnaires regarding attitude towards surveillance and general anxiety and depression (Hospital Anxiety and Depression scale, HADS). Quality of Life will be investigated, by filling in EORTC QLQ-C30 (version 3) and EORTC QLQ-GI.NET21 Module.

full Professor

Digestive System Diseases

Recurrence

Adenoma

Adenoma, Islet Cell

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neoplasms, Glandular and Epithelial

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Neuroepithelioma

Pancreatic Cancer

The plasma level of chromogranin A (CgA) was measured in enrolled patients who was diagnosed as PNET in preoperative condition.After surgical resection, the CgA level was only measured in the the patient with PNET. In the PNET group, the CgA level was regularly checked in a 3, 6, 12, and 24 months after surgical resection.

Chromogranin A

Songcheol Kim, MD PhD

Chromogranin A (CgA) is a glycoprotein with a molecular weight of 49 to 52 kDa produced by chromaffin cells of the adrenal medulla, enterochromaffin-like (ECL) cells, and endocrine cells of the stomach and pancreas, and it is the precursor to several functional peptides including vasostatin and pancreastatin.

Importantly, CgA can be measured in the serum or plasma or detected within the secretory vesicles as a general diagnostic biomarker for neuroendocrine tumors (NETs), and plasma CgA levels also provide information regarding tumor burden and response to treatment. It has a sensitivity and specificity between 27% and 81%.

Some studies have noted an association between CgA concentrations and tumor location or degree of differentiation. It has also been proposed that plasma CgA levels are more frequently elevated in well-differentiated tumors compared with poorly differentiated tumors of the midgut. Some other clinical series have provided evidence of an association between plasma CgA levels and the extent of disease, tumor burden, or presence of metastases, and high baseline levels of CgA are suggestive of a poor prognosis.

However, there exist still controversies the effectiveness of serum CgA levels on diagnostic relevance, treatment response after surgical resection or sandostatin analog, clinicopathologic features of pancreatic neuroendocrine tumors (PNETs).

To date, moreover, a precise association between CgA levels and survival has not been clearly demonstrated, although a number of studies suggest that this relationship may exist. There, especially, is no relevant data on value of serum CgA level for clinical usefulness in Korean population.

An interventional, prospective, multi center pilot study to assess the clinical relevance of CgA levels in patients with PNET as performed in current clinical practice.

There will be a measurement of CgA levels at baseline (preoperative measures after consent) and afterwards, in 3, 6, 12, and 24 months after resection. Immunoradiometric assay (IRMA, normal values: \< 100 ng/mL) will be used.

The collection of blood samples will proceed as detailed below:

Extraction of samples for serum collection:

7 ml of blood without anticoagulants will be allowed to sit for 30 min at room temperature before the serum is separated by centrifugation (3500 rpm). The serum will be stored at -20ºC

Assessments: Baseline (preoperative measures after consent), 3,6, 12, and 24 months

Clinical parameters: weight, height, performance status, vital signs including blood pressure, clinical signs and symptoms, survival data

Blood biochemical parameters: Sodium, potassium, calcium, glucose, urea, creatinina, bilirubin, alkaline phosphatase, aspartate transaminase (AST), and alanine transaminase (ALT).

Computed tomography (CT) : preoperative condition, and 3,6,12,24 months after resection.

Clinical Effectiveness of Serum Chromogranin A Levels on Diagnostic of Pancreatic Neuroendocrine Tumors

Clinical Effectiveness of Serum Chromogranin A (CgA) Levels on Diagnostic Relevance, Response After Surgical Resection and Recurrence of Pancreatic Endocrine Tumors (PET)

In the PNET group, the plasma level of CgA was regularly measured.

In the PNET group, the plasma level of CgA was regularly checked to follow up the status of disease progression.

In the PNET group, the CT was regularly checked to follow up the status of disease progression.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Diagnostic Accuracy of Preoperative Diagnostic Procedure in the Assessment of Lymph Node Metastases by NF-PanNENs	NCT03918759	Non Functioning...		18 Years -	IRCCS San Raffaele
Asymptomatic Small Pancreatic Endocrine Neoplasms.	NCT03084770	Non Functioning...	Radiological im... Quality of Life...	18 Years -	IRCCS San Raffaele
Asymptomatic Small Pancreatic Endocrine Neoplasms.	NCT03084770	Non Functioning...	Radiological im... Quality of Life...	18 Years -	IRCCS San Raffaele
Clinical Effectiveness of Serum Chromogranin A Levels on Diagnostic of Pancreatic Neuroendocrine Tumors	NCT02759718	Non Functioning...	Chromogranin A	19 Years - 80 Years	Asan Medical Center

Spots Global Cancer Trial Database for non functioning pancreatic endocrine tumor