Evaluating the Role of Theranostics in Grade 3 Neuroendocrine Neoplasms

4096 Background: Antiresorptive therapy (ART) with bisphosphonates or denosumab is effective in preventing skeletal-related events (SREs) in patients with bone metastases (BM). In neuroendocrine neoplasms (NEN), BM are a negative prognostic factor, however tend to be asymptomatic and SREs are considered a rare event. The role of ART in preventing SREs in NEN has not been investigated so far. Methods: Retrospective analysis of all patients with bone metastases in the NEN database of the National Center for Tumor Diseases who presented at our center between 12/2012 and 01/2017. Overall survival (OS) from diagnosis of BM as well as time to SRE (TTSRE) were calculated. In patients experiencing an SRE within 1 month after diagnosis (i.e. before efficacy of ART could be assessed), TTSRE was defined as the time to a subsequent SRE. Results: In a total of 513 patients in the database, 108 patients with BM could be identified. Median OS was not reached in a median follow-up of 15.2 months. ART was applied to 42.6 % of patients. OS with or without ART did not differ significantly (p = 0.2538). 28.7 % of patients experienced at least 1 SRE, 20.4 % after more than 1 month. Median TTSRE was 63.8 months with ART and 127.0 months without ART (p = 0.1751). TTSRE was shortened in grade 3 vs. grade 1+2 NEN (172 months vs. not reached, HR 4.058, p = 0.0032), as well as in lytic vs. non-lytic metastases (24.5 vs. not reached, HR 7.319, p < 0.0001), however not significantly different in oligometastatic vs. disseminated bone disease (not reached vs. 63,8 months, HR 1.415, p = 0.4287). Application of ART did not significantly change TTSRE in either of these subgroups. Significant toxicity attributable to ART was observed in 15.2 % of ART patients. Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.

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The prognostic role of morphology and Ki67 in grade 3 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN)

Annals of Oncology ◽

10.1093/annonc/mdy293.013 ◽

2018 ◽

Vol 29 ◽

pp. viii472-viii473

Author(s):

A.R. Hayes ◽

M. Furnace ◽

C. Rundell ◽

R. Shah ◽

G. Muller ◽

...

Keyword(s):

Neuroendocrine Neoplasms ◽

Prognostic Role ◽

Grade 3

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Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms

Endocrine Pathology ◽

10.1007/s12022-021-09676-z ◽

2021 ◽

Author(s):

Stefano La Rosa

Keyword(s):

Diagnostic Criteria ◽

Digestive System ◽

Labelling Index ◽

Differential Diagnoses ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Immunohistochemical Profile ◽

Grade 3

AbstractThe growth in knowledge of the pathogenesis, molecular background, and immunohistochemical profile of neuroendocrine neoplasms (NENs) has led not only to an increased awareness of these diseases but also to several changes of the nomenclature. In particular, the concept and terminology of high-grade (grade 3) NENs and mixed neoplasms have changed considerably over the last 20 years, creating some confusion among pathologists and clinicians. The aim of this review is to elucidate the diagnostic criteria, including the most important differential diagnoses of high-grade NENs and mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs). The role of the Ki67 labelling index and morphology, used to define grade 3 NENs of the digestive system and lungs, is also discussed. The evolution of the concepts and terminology of MiNENs is revised, including the most important differential diagnoses.

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The Role of Ki-67 Index Cut-off of 55% and Differentiation in Redefining NET and NEC for Grade 3 Gastrointestinal Neuroendocrine Neoplasms

Journal of Gastrointestinal Surgery ◽

10.1007/s11605-020-04651-1 ◽

2020 ◽

Vol 24 (10) ◽

pp. 2302-2305

Author(s):

Huiying Shi ◽

Luohai Chen ◽

Lingjun Meng ◽

Qin Zhang ◽

Yuan Lin ◽

...

Keyword(s):

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Grade 3

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Role of immunotherapy in gastro‐enteropancreatic neuroendocrine neoplasms (gep‐nens): Current advances and future directions

Journal of Neuroendocrinology ◽

10.1111/jne.12943 ◽

2021 ◽

Vol 33 (3) ◽

Author(s):

Liu Fang ◽

Dasari Arvind ◽

Afshin Dowlati ◽

Amr Mohamed

Keyword(s):

Neuroendocrine Neoplasms ◽

Future Directions

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MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

Non-Coding RNA ◽

10.3390/ncrna7030038 ◽

2021 ◽

Vol 7 (3) ◽

pp. 38

Author(s):

Alexandra Korotaeva ◽

Danzan Mansorunov ◽

Natalya Apanovich ◽

Anna Kuzevanova ◽

Alexander Karpukhin

Keyword(s):

Mirna Expression ◽

Malignant Tumors ◽

Neuroendocrine Neoplasms ◽

Specific Expression ◽

Clinical Biomarkers ◽

Different Types ◽

Functional Features ◽

First Time ◽

Potential Biomarkers

Neuroendocrine neoplasms (NEN) are infrequent malignant tumors of a neuroendocrine nature that arise in various organs. They occur most frequently in the lungs, intestines, stomach and pancreas. Molecular diagnostics and prognosis of NEN development are highly relevant. The role of clinical biomarkers can be played by microRNAs (miRNAs). This work is devoted to the analysis of data on miRNA expression in NENs. For the first time, a search for specificity or a community of their functional characteristics in different types of NEN was carried out. Their properties as biomarkers were also analyzed. To date, more than 100 miRNAs have been characterized as differentially expressed and significant for the development of NEN tumors. Only about 10% of the studied miRNAs are expressed in several types of NEN; differential expression of the remaining 90% was found only in tumors of specific localizations. A significant number of miRNAs have been identified as potential biomarkers. However, only a few miRNAs have values that characterized their quality as markers. The analysis demonstrates the predominant specific expression of miRNA in each studied type of NEN. This indicates that miRNA’s functional features are predominantly influenced by the tissue in which they are formed.

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Diagnostic and Predictive Role of DLL3 Expression in Gastroenteropancreatic Neuroendocrine Neoplasms

Endocrine Pathology ◽

10.1007/s12022-020-09657-8 ◽

2021 ◽

Author(s):

Chiara Liverani ◽

Alberto Bongiovanni ◽

Laura Mercatali ◽

Federica Pieri ◽

Chiara Spadazzi ◽

...

Keyword(s):

Neuroendocrine Neoplasms ◽

Gastroenteropancreatic Neuroendocrine Neoplasms ◽

Predictive Role

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Double-Balloon Enteroscopy in Detecting Small-Bowel Neuroendocrine Neoplasms: A Single-Center Prospective Study

Digestion ◽

10.1159/000511850 ◽

2020 ◽

pp. 1-9

Author(s):

Roberta Elisa Rossi ◽

Luca Elli ◽

Federica Branchi ◽

Dario Conte ◽

Sara Massironi

Keyword(s):

Small Bowel ◽

Neuroendocrine Neoplasm ◽

Unknown Primary ◽

Neuroendocrine Neoplasms ◽

Double Balloon Enteroscopy ◽

Balloon Enteroscopy ◽

Double Balloon ◽

Diagnostic Role ◽

Positive Results

Background and Aim: Small-bowel neuroendocrine neoplasm (sbNEN) diagnosis has improved with double-balloon enteroscopy (DBE). DBE efficacy in the detection of sbNENs is unknown. We aimed to report the experience at a single referral center for NENs. Methods: All consecutive patients with a suspected sbNEN selected for diagnostic DBE were enrolled. Results: Between 2011 and 2016, 25 patients were referred for a suspected sbNEN. In 15/25 patients, a primary NEN was detected outside the small bowel; in 4, NEN was excluded. After extensive workup, 6 patients (4 males, median age 50 years) underwent DBE (3 anterograde, 2 retrograde, and 1 both; median time: 60 min; median insertion 200 cm). DBE was positive in 3 patients: one had an ileal 2-cm NEN G1, one had an ileal 1.3-cm NEN G1, and one had an ileal 1-cm NEN G2, all surgically removed. Of the 3 other patients, one had a metastatic NEN of unknown primary, the other two had small intestinal NENs, both surgically removed (1.6-cm G1 and G2 NEN). DBE showed a sensitivity of 60% and, in absence of false-positive results, a specificity of 100%. Accuracy resulted 67%. No complications were observed. Conclusions: In line with data from the literature, the present series showed that DBE is a safe and effective procedure in the diagnosis of sbNENs. Further studies are needed to better clarify the diagnostic role of DBE in the neuroendocrine tumor setting and its relationship with other techniques.

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WEE1 Inhibitor: Clinical Development

Current Oncology Reports ◽

10.1007/s11912-021-01098-8 ◽

2021 ◽

Vol 23 (9) ◽

Author(s):

Anthony Kong ◽

Hisham Mehanna

Keyword(s):

Clinical Trials ◽

Tp53 Mutation ◽

Predictive Biomarker ◽

Concurrent Chemotherapy ◽

Clinical Development ◽

Novel Agents ◽

The Novel ◽

Grade 3 ◽

Chemotherapy Agents

Abstract Purpose of Review WEE1 inhibitor has been shown to potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly in p53-mutated or deficient cancer cells although not exclusively. Here, we review the clinical development of WEE1 inhibitor in combination with chemotherapy or radiotherapy with concurrent chemotherapy as well as its combination with different novel agents. Recent Findings Although several clinical trials have shown that WEE1 inhibitor can be safely combined with different chemotherapy agents as well as radiotherapy with concurrent chemotherapy, its clinical development has been hampered by the higher rate of grade 3 toxicities when added to standard treatments. A few clinical trials had also been conducted to test WEE1 inhibitor using TP53 mutation as a predictive biomarker. However, TP53 mutation has not been shown to be the most reliable predictive biomarker and the benefit of adding WEE1 inhibitor to chemotherapy has been modest, even in TP53 biomarker-driven studies. Summary There are ongoing clinical trials testing WEE1 inhibitor with novel agents such as ATR and PAPR inhibitors as well as anti-PDL1 immunotherapy, which may better define the role of WEE1 inhibitor in the future if any of the novel treatment combination will show superior anti-tumor efficacy with a good safety profile compared to monotherapy and/or standard treatment.

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The role of exudation in chronic subdural hematomas

Journal of Neurosurgery ◽

10.3171/jns-07/08/0290 ◽

2007 ◽

Vol 107 (2) ◽

pp. 290-295 ◽

Cited By ~ 31

Author(s):

Mehmet Tokmak ◽

A. Celal Iplikcioglu ◽

Sirzat Bek ◽

Cem Atilla Gökduman ◽

Mustafa Erdal

Keyword(s):

Outer Membrane ◽

Clinical Status ◽

Ct Scans ◽

Subdural Hematomas ◽

The Mean ◽

Grade 3 ◽

Age Range ◽

Exudation Rate

Object Chronic subdural hematomas (SDHs) are a local inflammatory process that causes the formation of a granulation tissue often referred to as the external or outer membrane. This membrane has abnormally permeable macrocapillaries. Therefore, exudation from the macrocapillaries in the outer membrane of chronic SDH may play an important role in the enlargement of chronic SDH. In this study the authors investigated the role of exudation in chronic SDH. Methods The authors examined 24 patients (16 men and eight women; age range 38–86 years [mean age 61.4 years]) with 27 chronic SDHs. The clinical status of the patients was evaluated according to the classification described by Markwalder. The diagnosis was established on computed tomography (CT) scans in all cases. The authors also used the Nomura Classification for judging the lesion's appearance on CT scans. Immediately after the diagnosis, all patients were administered 20 mCi (740 mBq) technetium-99m human serum albumin. Four hours later, blood and SDH samples were taken and radioactivity levels were measured in each. The ratio of activity of the samples taken from chronic SDH to the radioactivity of blood was determined as a percentage and defined as the exudation rate. On the follow-up CT scan obtained on postoperative Day 20, subdural collections thicker than 5 mm were determined to be a reaccumulation. Results The correlations between the exudation rate and age of the patients, clinical grades, CT appearances, and amount of reaccumulation were investigated. In this series the average exudation rate was 13.24% (range 2.05–28.88%). The mean exudation rates according to the clinical grades assigned to patients were as follows: Grade 0, 8.67 ± 5.64% (three patients); Grade 1, 5.07 ± 1.43% (eight patients); Grade 2, 17.87 ± 3.73% (seven patients); and Grade 3, 19.65 ± 7.67% (six patients). Exudation rates in patients with Grades 2 and 3 were significantly higher than those in Grades 0 and 1 (p < 0.05). The mean exudation rates according to the lesion's appearance on CT scans were found as follows: hypodense appearance, 6.55 ± 4.52% (eight patients); isodense appearance, 11.07 ± 6.32% (five patients); hyperdense appearance, 19.47 ± 13.61% (three patients); and mixed-density appearance, 17.40 ± 5.80% (nine patients). The differences among the groups were significant (p < 0.05). The average exudation rate was statistically higher in the patients with reaccumulation (16.30 ± 8.16%) than that in the patients without reaccumulation (9.96 ± 6.84%) (p < 0.05). Conclusions The exudation rate in chronic SDH is correlated with a higher clinical grade (Markwalder Grade 2 or 3), mixed-density CT appearance, and reaccumulation. Therefore, exudation from macrocapillaries in the outer membrane of chronic SDH probably plays an important role in the pathophysiology and the growth of chronic SDH.

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