Promising targetable biomarkers in pancreatic neuroendocrine tumours.

INTRODUCTION: In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development. AREAS COVERED: We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs. EXPERT OPINION: Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors.

Lung carcinoids with high proliferative activity: Further support for the identification of a new tumor category in the classification of lung neuroendocrine neoplasms.

Highly proliferative lung carcinoids (HPLC) have been recently reported but information about this subset remains scarce. OBJECTIVES: Clinical and pathological data of 630 patients with lung carcinoids (LC) referred to Gustave Roussy Institute (GR) and European Institute of Oncology (IEO) were retrospectively reviewed to select HPLC and analyze their frequency, behavior and compare their outcome to conventional LC with Ki-67 ≤ 20 % and mitotic count (MC)≤10/2 mm2. MATERIALS AND METHODS: Selection criteria were: diagnosis of LC confirmed by local pathologist, and available clinical and follow-up data. Patients with Ki-67 > 20 % and/or MC > 10/ 2 mm2 in primary or metastatic specimens were identified as HPLC. RESULTS: 30/514 patients (6%) met the selection criteria of HPLC. Based on primary tumor evaluation, 22/25 (88 %) were classified as atypical carcinoids (AC). Median MC was 4.5/2 mm2 (1-11) 6/2 mm2 (3-15) in primary tumors and metastasis, respectively. Median Ki-67 was respectively 23 % (15-65) and 25 % (8-60). Recurrence rate was 66 % (12/18) in HPLC and 9 % (33/352) in conventional LC. Median RFS was 24 (10-NR) months in HPLC, 288 (141-NR) months in LC with Ki-67 index≤5 % and NR (148-NR) months in LC with Ki-67 6-20% (p < 001). Median OS was 203 (83-NR) months in LC with Ki-67 index≤5%, 101 (79-NR) months in LC with Ki-67 index 6-20 % and 53 (39-NR) months in HPLC (p = 002). Among 20 metastatic patients with HPLC, median PFS under platinum-based chemotherapy, everolimus, alkylating-based chemotherapy, FOLFOX and PRRT was 5.1 (95 % CI 0.7-9.4), 12.1(95 %CI 0.3-24), 6.8 (95 % CI 0-14.9), 10.2 (95 % CI 0.4-19.9) and 14.2 months (95 % CI 0-30) respectively. Best response was stable disease (SD) under platinum-based chemotherapy and partial response (PR) under alkylating-based chemotherapy and FOLFOX. CONCLUSION: This study confirms the existence and rarity of HPLC. Their characteristics and clinical behavior are more similar to LC rather than neuroendocrine carcinomas (NECs), suggesting that this entity could be managed accordingly.

Detecting the shape of anisotropic gold nanoparticles in dispersion with single particle extinction and scattering.

The shape and size of nanoparticles are important parameters affecting their biodistribution, bioactivity, and toxicity. The high-throughput characterisation of the nanoparticle shape in dispersion is a fundamental prerequisite for realistic in vitro and in vivo evaluation, however, with routinely available bench-top optical characterisation techniques, it remains a challenging task. Herein, we demonstrate the efficacy of a single particle extinction and scattering (SPES) technique for the in situ detection of the shape of nanoparticles in dispersion, applied to a small library of anisotropic gold particles, with a potential development for in-line detection. The use of SPES paves the way to the routine quantitative analysis of nanoparticles dispersed in biologically relevant fluids, which is of importance for the nanosafety assessment and any in vitro and in vivo administration of nanomaterials.

Treatments for colorectal liver metastases: A new focus on a familiar concept.

A major challenge for the management of advanced-colorectal-cancer is the multidisciplinary approach required for the treatment of liver metastases. Reducing the burden of liver metastases with liver-directed therapy has an important impact on both survival and health-related quality of life. This paper debates the rationale and current liver-directed approaches for colorectal liver metastases based on the evidence of literature and new clinical trials. Surgery is the gold standard, when feasible, and it's the main treatment goal for patients with potentially-resectable disease as a means of prolonging progression-free survival. Better tumor response rates with modern systemic therapy mean that more unresectable patients are now down-staged for radical resection following conversion therapy but for other patients, additional procedures are needed. In multiple unilobar disease, when the projected remnant liver is <30% of the total liver, portal embolization or selective-internal-radiation-therapy (SIRT) can induce hypertrophy of the healthy liver, leading to resectability. In multiple bilobar disease, in situ destruction of non-resectable lesions by minimally invasive techniques may be associated with liver resection to achieve potential curative intent. Other palliative liver-directed approaches, such as SIRT or intra-hepatic chemotherapy (HAI), which are associated with higher response rates, may also have role in down-staging patients for resection. Until recently, such technologies have not been validated in prospective controlled trials. However in the light of new Phase 3 data for SIRT as well as for HAI combined with modern therapies or radiofrequency ablation in the first- and second-line setting, the clinical value of these treatments needs to be re-appraised.

Single particle optical extinction and scattering allows real time quantitative characterization of drug payload and degradation of polymeric nanoparticles.

The behavior of nanoparticles in biological systems is determined by their dimensions, size distribution, shape, surface chemistry, density, drug loading and stability; the characterization of these parameters in realistic conditions and the possibility to follow their evolution in vitro and in vivo are, in most of the cases, far from the capabilities of the standard characterization technologies. Optical techniques such as dynamic light scattering (DLS) are, in principle, well suited for in line characterization of nanoparticle, however their fail in characterizing the evolution of nanoparticle in solution where change in particle dimension and density is present. Here we present an in-line optical technique based on single particle extinction and scattering (SPES) overcoming the limitations typical of DLS and allowing for the efficient characterization of nanoparticle polydispersity, index of refraction and degradation dynamics in solution. Using SPES, we characterized the evolution of PLGA nanoparticles with different structures and drug payloads in solution and we compared the results with DLS. Our results suggest that SPES could be used as a process analytical technology for pharmaceutical nanoparticle production.

Pseudonecrotizing fasciitis due to dialysate and air leak in a peritoneal dialysis patient.

Necrotizing fasciitis is a serious, rapidly progressive infection of subcutaneous tissue and fascia. While free intraperitoneal air is known to occur in peritoneal dialysis patient, dissection of this air into the abdominal wall mimicking the subcutaneous emphysema of necrotizing fasciitis has not previously been reported. We herein report the first case of pseudonecrotizing fasciitis due to dialysate fluid and air leak in a patient on peritoneal dialysis and discuss features differentiating this process from true necrotizing fasciitis.

Cell surface glycosaminoglycans in normal and leukemic leukocytes.

The intracellular and extracellular glycosaminoglycans (GAGs) of peripheral leukocytes in normal subjects and leukemic patients were characterized by electrophoresis and enzyme sensitivity. Normal peripheral granulocytes (PMN) are very rich in trypsin removable surface GAGs, while none are present on the surface of leukemic cells in acute myeloid leukemia. The intracellular and extracellular GAGs have also been analysed in the pig and compared to normal pig bone marrow haematopoietic cells. Mysenchymal cells cultured in vitro from marrow matrix and peripheral endothelial cells have also been studied. The results suggest that the exposure of cell surface chondroitin sulphate A is an important step involved in the peripheralisation of PMN.

Intercellular glycosaminoglycans in normal and neoplastic tissues.

Intercellular glycosaminoglycans have been isolated from normal and neoplastic mammalian tissues. They have been characterized by cellulose acetate electrophoresis and by chemical and enzymatic degradation. The electrophoretic pattern of the intercellular glycosaminoglycans is tissue specific. Furthermore, the electrophoretic patterns of all spontaneous neoplasias analyzed differ significantly from patterns obtained from the tissues of origin.

Surface glycosaminoglycans and calcium distribution in 3T3 cells.

Resting 3T3 cells have relatively more sulphated glycosaminoglycans and Ca2+ in their cell coat than do growing or SV40-virus-transformed cells. It is suggested that the different Ca2+-binding capacity controls cellular activities by affecting the distribution of Ca2+ between the intra- and ecto-cellular compartments.