Peritoneal metastases in patients with neuroendocrine neoplasms: a challenging site of metastases with clinical and prognostic implications.

PURPOSE: Peritoneal metastases (PM) of neuroendocrine neoplasm (NEN) origin are identified with increasing frequency and exert a significant effect on quality of life and clinical status of the patients. The aim of this study was to identify the characteristics and the prognostic significance of PM in patients with NENs. METHODS: A retrospective analysis of the data of patients from two tertiary referral centers was performed. We defined a control group of age- and gender-matched NEN patients with comparable stage IV disease but no PM. RESULTS: We analysed 70 patients (41 females) with PM. Small intestine was the most common primary NEN site (87.1%). PM prevalence was 10.3%. Forty-four patients presented with synchronous PM, whereas 26 developed metachronous PM. The majority of patients had other concomitant metastases (50 hepatic, 6 lung and 12 bone metastases). Twelve patients developed intestinal obstruction. After PM diagnosis, 76% of patients received treatment with somatostatin analogues while six patients (8.6%) were treated with peptide receptor radionuclide therapy (PRRT). The median progression-free survival (PFS) in the PRRT-treated group was 15 months (95% CI 2-28). Median overall survival (OS) in the PM group was 142 months [95% CI 71-213] while it was not reached in the control group. CONCLUSION: Peritoneal metastases show low prevalence among NEN patients and are most likely to develop in patients with small intestinal NENs and advanced metastatic disease. The presence of PM does seem to be associated with a negative prognostic impact on OS of NEN patients and their identification and prompt treatment is of major importance.

A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility.

BACKGROUND: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS: Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification (chi-square = 180, OR = 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%. CONCLUSION: NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.

A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood.

BACKGROUND: The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy-liquid biopsy-to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). PATIENTS AND METHODS: A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data. RESULTS: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%-96% with a mean DOR of 5 853, +LR of 195, and -LR of 0.06. The NETest was 84.5%-85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%-97.8%. As an interventional/response biomarker, the accuracy was 93.7%-97.4%. The pooled AUC for the NETest was 0.954 ± 0.005, with a z-statistic of 175.06 (P < 0.001). CONCLUSIONS: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines.

A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms.

BACKGROUND: The aim of this study was to compare mitotic count (MC) and Ki-67 proliferation index as prognostic markers in pancreatic and midgut neuroendocrine neoplasms (NENs). METHODS: Two hundred eighty-five patients with metastatic NENs were recruited. Concordance between histological grade according to either Ki-67 or MC as defined by the European Neuroendocrine Tumour Society guidelines was assessed and the prognostic significance of Ki-67 or MC were evaluated. RESULTS: There was a discrepancy of 44 and 38% in grade assignment when using Ki-67 or MC in pancreatic and midgut NENs, respectively. In multivariate analysis, grade using Ki-67, but not MC, was a significant prognostic factor in determining overall survival (hazard ratios: midgut G2 2.34, G3 15.1, pancreas G2 2.08, G3 11.3). The prognostic value of Ki-67 was improved using a modified classification (hazard ratios: midgut G2 3.02, for G3 22.1, pancreas G2 5.97, G3 33.8). CONCLUSION: There is a lack of concordance between Ki-67 and MC in assigning tumour grade. Grade according to Ki-67 was a better prognostic marker than MC for metastatic pancreatic and midgut NENs. We suggest that Ki-67 alone should be used for grading pancreatic and midgut NENs and that the current threshold for classifying G1/G2 tumours should be revised from 2 to 5%.

ENETS standardized (synoptic) reporting for endoscopy in neuroendocrine tumors.

Despite efforts from various endoscopy societies, reporting in the field of endoscopy remains extremely heterogeneous. Harmonisation of clinical practice in endoscopy has been highlighted by application of many clinical practice guidelines and standards pertaining to the endoscopic procedures and reporting are underlined. The aim of the proposed "standardised reporting" is to (1) facilitate recognition of gastrointestinal neuroendocrine neoplasms (NEN) on initial endoscopy, (2) to enable interdisciplinary decision making for treatment by a multidisciplinary team, (3) to provide a basis for a standardised endoscopic follow-up which allows detection of recurrence or progression reliably, (4) to make endoscopic reports on NEN comparable between different units, and (5) to allow research collaboration between NEN centres in terms of consistency of their endoscopic data. The ultimate goal is to improve disease management, patient outcome and reduce the diagnostic burden on the side of the patient by ensuring the highest possible diagnostic accuracy and validity of endoscopic exams and possibly interventions.

Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours.

BACKGROUND: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen. METHOD: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m(-2)), cisplatin (70 mg m(-2)) and streptozocin (1000 mg m(-2)) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival. RESULTS: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3-4 toxicity was neutropaenia (28% patients) but grade 3-4 infection was rare (7%). The most frequent non-haematological grade 3-4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and alpha-fetoprotein. CONCLUSIONS: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.

Two-dimensional electrophoretic analysis of nuclear matrix proteins in human colon adenocarcinoma.

The aim of the present study was to observe possible qualitative and quantitative expression differences between nuclear matrix proteins (NMPs) of human colon adenocarcinoma and their mirror biopsies, using the technique of two-dimensional gel electrophoresis, in order to identify the existence of specific NMP fingerprints for colon cancer. Colon tissues were examined ultrastructurally and NMPs were isolated biochemically, by serial extraction of lipids, soluble proteins, DNA, RNA, and intermediate filaments and were separated according to their isoelectric point (pI) and their molecular weight (MW) by high-resolution two-dimensional electrophoresis (2D). By comparing the 2D electropherograms of colon cancer tissues and mirror biopsy tissues we observed qualitative and quantitative expression differences between their NMPs but also a differentiation of NMP composition between the stages of malignancy. Moreover, despite the similarities between mirror biopsy samples, a highlight percentage of exception was observed. Electrophoretic results provided in this study demonstrated that the examined NMPs could be further investigated as potential markers for detection of colorectal cancer in an early stage, for the assessment of the disease progression, as well as useful tools for individual therapy and for preventing a possible recurrence of cancer and metastasis.

Management of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs).

Neuroendocrine tumors (NETs) are relatively rare neoplasms that often present as diagnostic dilemmas due to obscure or non-specific symptoms. The ability of carcinoid tumors to cause clinical symptoms by secretion of hormones or biogenic amines is best recognised in the form of the carcinoid syndrome. Although generally slow growing, a significant minority demonstrate aggressive tumor growth. Ten-twenty percent of pancreatic NETs may be associated with hereditary disorders such as multiple endocrine neoplasia-1 (MEN-1) and less frequently, Von Hippel Lindau, which should be considered in the investigation and management of these patients. A small percentage of NETs are associated with co-existing synchronous non-carcinoid neoplasm. The aim of this paper was to review the optimal management in patients with NETs. The therapeutic options which are reviewed, including the use of somatostatin analogues, the role of surgery, the use of chemotherapy, biotherapy using interferon, peptide receptor targeted therapy. In addition, the challenging interventional management of liver metastases is discussed, including the role of hepatic-artery embolization, radiofrequency ablation and the place of orthotoptic liver transplantation in selected patients. Authors have focused on the newest therapeutic modalities, e.g., radionuclide peptide receptor targeted therapy with Yttrium-90 and Lutetium-177, the newest somatostatin analogues such as pasireotide and angiogenic inhibitors. In conclusion, with the increasing number of investigative procedures and therapeutic options available to diagnose and treat carcinoid tumors, it is vital to have a multidisciplinary approach. Furthermore, additional scientific research and controlled clinical trials are needed to determine the efficacy of the many treatment options, which for these rare tumors can only be achieved by collaboration.

Major postoperative complications after pancreatic resection for P-NETS are not associated to earlier recurrence.

BACKGROUND: The oncological impact of surgical complications has been studied in visceral and pancreatic cancer. AIM: To investigate the impact of complications on tumour recurrence after resections for pancreatic neuroendocrine tumours. METHODS: We have retrospectively analysed 105 consecutive resections performed at the Royal Free London Hospital from 1998 to 2014, and studied the long-term outcome of nil-minor (<3) versus major (≥3) Clavien-Dindo complications (CD) on disease-free (DFS) and overall survival (OS). RESULTS: The series accounted for 41 (39%) pancreaticoduodenectomies, two (1.9%) central, 48 (45.7%) distal pancreatectomies, eight (7.6%) enucleations, four (3.8%) total pancreatectomies. Sixteen (15.2%) were extended to adjacent organs, 13 (12.3%) to minor liver resections. Postoperative complications presented in 43 (40.1%) patients; CD grade 1 or 2 in 23 (21.9%), grades ≥3 in 20 (19%). Among 25 (23.8%) pancreatic fistulas, 14 (13.3%) were grades B or C. Thirty-four (32.4%) patients developed exocrine, and 31 (29.5%) endocrine insufficiency. Seven patients died during a median 27 (0-175) months follow up. Thirty-day mortality was 0.9%. OS was 94.1% at 5 years. Thirty tumours recurred within 11.7 (0.8-141.5) months. DFS was 44% at 5 years. At univariate analysis, high-grade complications were not associated with shorter DFS (p = 0.744). At multivariate analysis, no parameter was independent predictor for DFS or OS. The comparison of nil-minor versus major complications showed no DFS difference (p = 0.253). CONCLUSION: From our series, major complications after P-NETs resection are not associated to different disease recurrence; hence do not require different follow up or adjuvant regimens.

Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel).

BACKGROUND: Somatostatin analogues are the mainstay of therapy for malignant carcinoid syndrome. There is clear evidence that the once monthly intramuscular formulation, Octreotide LAR, controls symptoms of carcinoid syndrome, and recent data also suggests an antitumour effect. There is limited data on prolonged release Lanreotide (Somatuline Autogel, Ipsen Pharma Biotech, Signes, France) and no long-term data to date. AIM: To present long-term results of prolonged release Lanreotide in a large cohort of patients with malignant carcinoid syndrome, assessing clinical and objective response and tolerance. METHODS: Seventy six patients with metastatic midgut neuroendocrine tumours and carcinoid syndrome were included in this 9-year retrospective study. Clinical response was based on symptom score with radiological assessment based on RECIST (Response Evaluation Criteria In Solid Tumours). RESULTS: Data were available in 69 patients. Ninety four percent achieved symptomatic response at first follow-up visit. Forty six percent had loss of symptomatic response, but 44% of these achieved control with an increase in dose of prolonged release Lanreotide. Overall, symptoms were well controlled throughout the study period with prolonged release Lanreotide alone in 74% of patients. Twenty six percent required additional treatment despite good initial response. Only 30% demonstrated radiological progression. Eleven patients who were switched from Octreotide LAR had return of symptomatic control. No significant adverse effects were experienced. CONCLUSIONS: Prolonged release Lanreotide provides good symptomatic control of diarrhoea and flushing as well as tumour stability in patients with malignant carcinoid syndrome.

Review article: future therapies for management of metastatic gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are relatively uncommon tumours that occur anywhere within the gastrointestinal tract. The prevalence of GEP NETs is estimated to be 35 per 100 000 population. Patients often present with metastatic disease and consequently, palliative treatments form the mainstay of therapy. AIM: To review the current and novel therapeutic options for management of GEP NETs. METHODS: Searches for all studies related to GEP NETs, NETs and carcinoid tumours in Medline and abstracts from international meetings. RESULTS: Somatostatin analogues remain the first line therapy for management of symptoms of GEP NETs and may have anti-proliferative action. New somatostatin analogues with different somatostatin receptor affinity have been developed. Radionuclide peptide receptor therapy is established in patients with positive somatostatin scintigraphy. A number of new agents and targeted therapies are currently being evaluated in a phase I and II studies and these include angiogenic inhibitors, mammalian target of rapamycin inhibitors and immune therapies. CONCLUSIONS: A number of nonsurgical therapies are available for management of gastroenteropancreatic neuroendocrine tumours. It is hoped, the development of some of these promising novel therapies will expand the therapeutic armamentarium.

Surgical management and palliative treatment in bronchial neuroendocrine tumours: a clinical study of 45 patients.

Bronchial neuroendocrine tumours account for 1-2% of all lung cancers; they are thought to arise from the neuroendocrine cells located in the bronchial mucosa. The majority of the literature available comprises surgical series and there is a scarcity of data available for the management of patients with inoperable disease. We present a series of 45 patients referred to our institution from 1998 to 2006, with a mean follow-up of 54 months. Histological diagnosis from our department was available for 39 patients, with the remainder having had histological assessment performed previously. Typical carcinoid was present in 25 cases, atypical in 9 cases, large cell neuroendocrine carcinoma in 4 and 1 case of small cell lung carcinoma. All patients were staged at time of initial diagnosis with CT scan, in addition Octreoscans were performed when appropriate. Twenty-six of these 45 cases had unresectable disease, whilst the remainder were treated with surgical resection. Initial therapy with surgical resection was performed in 19 patients, 2 of whom had undergone neo-adjuvant chemotherapy. Recurrence occurred in 7 (36.8%), average duration of disease-free survival post-surgery was 61 months. Chemotherapy was first line therapy in five cases, four achieved disease stabilization and one case had progressive disease. Somatostatin analogues were used as first line therapy in six patients, for symptom control and anti-tumour effect. Peptide receptor radionuclide therapy, with Yttrium-90 DOTA-Octreotate, was given in two cases, both of whom achieved disease stabilization for 9-12 months respectively. There was a significant difference between Stage 4 and Stage 1 disease at presentation and survival. In conclusion curative surgical resection is treatment of choice, however, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy offers palliation improving both symptoms and mortality.

Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR.

BACKGROUND: Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. AIM: To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome. METHODS: A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria. RESULTS: Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted. CONCLUSIONS: Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described.