Zirconia Hybrid Dental Implants Influence the Biological Properties of Neural Crest-Derived Mesenchymal Stromal Cells.

Dental implants are regularly employed in tooth replacement, the good clinical outcome of which is strictly correlated to the choice of an appropriate implant biomaterial. Titanium-based implants are considered the gold standard for rehabilitation of edentulous spaces. However, the insurgence of allergic reactions, cellular sensitization and low integration with dental and gingival tissues lead to poor osseointegration, affecting the implant stability in the bone and favoring infections and inflammatory processes in the peri-implant space. These failures pave the way to develop and improve new biocompatible implant materials. CERID dental implants are made of a titanium core embedded in a zirconium dioxide ceramic layer, ensuring absence of corrosion, a higher biological compatibility and a better bone deposition compared to titanium ones. We investigated hDPSCs' biological behavior, i.e., cell adhesion, proliferation, morphology and osteogenic potential, when seeded on both CERID and titanium implants, before and after cleansing with two different procedures. SEM and AFM analysis of the surfaces showed that while CERID disks were not significantly affected by the cleansing system, titanium ones exhibited well-visible modifications after brush treatment, altering cell morphology. The proliferation rate of DPSCs was increased for titanium, while it remained unaltered for CERID. Both materials hold an intrinsic potential to promote osteogenic commitment of neuro-ectomesenchymal stromal cells. Interestingly, the CERID surface mitigated the immune response by inducing an upregulation of anti-inflammatory cytokine IL-10 on activated PBMCs when a pro-inflammatory microenvironment was established. Our in vitro results pave the way to further investigations aiming to corroborate the potential of CERID implants as suitable biomaterials for dental implant applications.

Synergy of Nanotopography and Electrical Conductivity of PEDOT/PSS for Enhanced Neuronal Development.

Biomaterials able to promote neuronal development and neurite outgrowth are highly desired in neural tissue engineering for the repair of damaged or disrupted neural tissue and restoring the axonal connection. For this purpose, the use of either electroactive or micro- and nanostructured materials has been separately investigated. Here, the use of a nanomodulated conductive poly(3,4-ethylendioxithiophene) poly(styrenesulfonate) (PEDOT/PSS) substrate that exhibits instructive topographical and electrical cues at the same time was investigated for the first time. In particular, thin films featuring grooves with sizes comparable with those of neuronal neurites (NanoPEDOT) were fabricated by electrochemical polymerization of PEDOT/PSS on a nanomodulated polycarbonate template. The ability of NanoPEDOT to support neuronal development and direct neurite outgrowth was demonstrated by assessing cell viability and proliferation, expression of neuronal markers, average neurite length, and direction of neuroblastoma N2A cells induced to differentiate on this novel support. In addition to the beneficial effect of the nanogrooved topography, a 30% increase was shown in the average length of neurites when differentiating cells were subjected to an electrical stimulation of a few microamperes for 6 h. The results reported here suggest a favorable effect on the neuronal development of the synergistic combination of nanotopography and electrical stimulation, supporting the use of NanoPEDOT in neural tissue engineering to promote physical and functional reconnection of impaired neural networks.

PEDOT: PSS promotes neurogenic commitment of neural crest-derived stem cells.

Poly (3,4-ethylendioxythiophene) polystyrene sulphonate (PEDOT:PSS) is the workhorse of organic bioelectronics and is steadily gaining interest also in tissue engineering due to the opportunity to endow traditional biomaterials for scaffolds with conductive properties. Biomaterials capable of promoting neural stem cell differentiation by application of suitable electrical stimulation protocols are highly desirable in neural tissue engineering. In this study, we evaluated the adhesion, proliferation, maintenance of neural crest stemness markers and neurogenic commitment of neural crest-derived human dental pulp stem cells (hDPSCs) cultured on PEDOT:PSS nanostructured thin films deposited either by spin coating (SC-PEDOT) or by electropolymerization (ED-PEDOT). In addition, we evaluated the immunomodulatory properties of hDPSCs on PEDOT:PSS by investigating the expression and maintenance of the Fas ligand (FasL). We found that both SC-PEDOT and ED-PEDOT thin films supported hDPSCs adhesion and proliferation; however, the number of cells on the ED-PEDOT after 1 week of culture was significantly higher than that on SC-PEDOT. To be noted, both PEDOT:PSS films did not affect the stemness phenotype of hDPSCs, as indicated by the maintenance of the neural crest markers Nestin and SOX10. Interestingly, neurogenic induction was clearly promoted on ED-PEDOT, as indicated by the strong expression of MAP-2 and ß -Tubulin-III as well as evident cytoskeletal reorganisation and appreciable morphology shift towards a neuronal-like shape. In addition, strong FasL expression was detected on both undifferentiated or undergoing neurogenic commitment hDPSCs, suggesting that ED-PEDOT supports the expression and maintenance of FasL under both expansion and differentiation conditions.

Evaluation of the In Vitro Biocompatibility of PEDOT:Nafion Coatings.

Poly(3,4-ethylenedioxythiophene)-Nafion (PEDOT:Nafion) is emerging as a promising alternative to PEDOT-polystyrene sulfonate (PEDOT:PSS) in organic bioelectronics. However, the biocompatibility of PEDOT:Nafion has not been investigated to date, limiting its deployment toward in vivo applications such as neural recording and stimulation. In the present study, the in vitro cytotoxicity of PEDOT:Nafion coatings, obtained by a water-based PEDOT:Nafion formulation, was evaluated using a primary cell culture of rat fibroblasts. The surface of PEDOT:Nafion coating was characterized by Atomic Force Microscopy (AFM) and water contact angle measurements. Fibroblasts adhesion and morphology was investigated by scanning electron microscopy (SEM) and AFM measurements. Cell proliferation was assessed by fluorescence microscopy, while cell viability was quantified by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), lactate dehydrogenase (LDH) and neutral red assays. The results showed that PEDOT:Nafion coatings obtained by the water dispersion were not cytotoxic, making the latter a reliable alternative to PEDOT:PSS dispersion, especially in terms of chronic in vivo applications.

ROS1 rearrangements are uncommon in biliary tract cancers.

Biliary tract cancers (BTCs) are a pool of diseases with poor prognosis and there is no orphan drug available. Currently, no molecular targets have been tested as druggable oncogenic drivers. C-ros oncogene 1 (ROS1) rearrangements have been previously described in various tumors, including BTCs; however, data regarding their incidence and biological significance are controversial. Therefore, a retrospective multicenter study was performed to assess the incidence of ROS1 rearrangements in BTCs by means of immunohistochemistry and fluorescence in situ hybridization (FISH). The present study failed to demonstrate ROS1 expression in a multicenter series of 150 cases with BTCs and revealed that D4D6 was the most specific clone compared with other ROS1 primary antibodies, namely PA1-30318 and EPMGHR2. Notably, negative results obtained with D4D6 completely matched to data sorted out by FISH analysis, thus confirming a lack of ROS1 gene rearrangements in BTCs and false positive results when PA1-30318 and EPMGHR2 clones were used. These results suggest that ROS1 rearrangements may not be targets for molecular therapy of BTCs with specific inhibitors.

Somatostatin analogs in pregnant patients with neuroendocrine tumor.

Somatostatine analogs (SSAs) are currently indicated in the treatment of acromegaly and neuroendocrine tumors (NETs). Actually, pregnancy in patients with acromegaly and NETs does not represent an exceptional event because reproductive behavior has changed in the last decades and patients with NETs show more frequently long-term survival. The safety profile of SSAs during pregnancy is still controversial. Concerning acromegaly, based on case reports and series, SSAs administration during pregnancy seems to be relatively well tolerated. Concerning patients with NETs, up to date only one patient with NET receiving SSA during pregnancy has been reported in literature. We report two cases of gastroenteropancreatic-NET patients receiving SSA lanreotide for the entire course of their pregnancy, with favorable outcomes for both mothers and babies. Our experience supports the possibility to continue safely SSA lanreotide during pregnancy in patients with NET.

Immune-related adverse events correlate with clinical outcomes in NSCLC patients treated with nivolumab: The Italian NSCLC expanded access program.

OBJECTIVES: The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31-65 % and 2-5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy. MATERIALS AND METHODS: We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis. RESULTS: Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months [95% CI 4.9-7.1] vs 3.0 [95% CI: 2.8-3.2], p < 0.0001) and median overall survival (mOS 16.7 months [95% CI: 13.5-19.9] vs 9.4 [95% CI: 8.4-10.4], p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 [95% CI: 1.22-1.71] p < 0.0001). CONCLUSIONS: This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome.

Effects of a home-based exercise rehabilitation program for cancer survivors.

BACKGROUND: Aerobic and resistance exercises have been promoted recently to improve quality of life in cancer patients. Most cancer survivorship rehabilitation programs consist of supervised exercise programs; however, less data is available on the effects of unsupervised or home-based exercise interventions. The study aimed to compare the physical and physiologic changes in a group of cancer survivors (CS) and a control group of non-cancer, health controls (HC) who participated in individualized home-based aerobic and resistance exercises for 12 months. METHODS: Thirty-three surviving cancer survivors (CS) aged 55.6±3 years were enrolled for 1 year of unsupervised exercise prescription programs. Anthropometric parameters hydration status, fitness, and echocardiographic examination were measured every six month and compared to10 HC (aged 52.6±7.7 years) individuals prior to starting the program (t0) and at 6 (t6) and 12 (t12) months. RESULTS: Among the CS subjects, a significant reductions in waist circumference (t0: 97.5±15.2 cm, t6: 86.6±13.5 cm, t12: 85.8±13.9 cm; P<0.05), body cell mass (t0: 50.9±4.7%, t6: 52.3±4.4%, t12: 53.7±3.7%; P<0.05), and extracellular mass (t0: 49.1±4.7%, t6: 47.6±4.4%, t12: 46.2±3.7%; P<0.05) were observed, as well significant improvements in lower body muscle strength (chair test t0: 13.3±4.1, t6: 14.2±3.5, t12: 15.1±3.2; P<0.05). Changes in functionality and heart function were similar between CS and HC. CONCLUSIONS: Individually-prescribed home-based exercise programs were cost effective, safe and resulted in modest improvements in body composition, strength, and total body water distribution with little to no adverse effect on cardiac function.

Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors.

The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1 (PD-1) and anti-programmed cell death protein ligand 1 (PD-L1) monoclonal antibodies, has opened new scenarios in the management of non-small cell lung cancer (NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry (IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered (tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC.

Osteonecrosis of the Jaw and Angiogenesis inhibitors: A Revival of a Rare but Serous Side Effect.

Osteonecrosis of the jaw (ONJ) is a rare treatment related side effect that was firstly described in 2002 through a case report in metastatic bone cancer patient treated with bisphosphonates (BPs) therapy. ONJ is defined as an eight weeks or longer clinical finding of exposed bone in the oral cavity without response to appropriate therapy. The diagnosis is mainly clinical but often requires a radiological confirmation with an orthopantomography. So it must be made by a dental specialist with sufficient experience on ONJ and requires a detailed anamnestic exploration of comorbidities and treatments history. In particular, ONJ affects a wide number of oncologic patients treated with BPs for bone metastatic cancers and, more recently, with anti-angiogenic drugs. The aim of this this paper is to describe diagnosis and classification of this rare but serious side effect and its pathophysiology. In particular, we provide a detailed description of clinical evidences upon the relationship between anti-angiogenic drugs and ONJ. Considering the evolving of cancer epidemiology with a greater number of cancer surviving patients, this side effect always deserves more attention. We conclude that ONJ must be always carefully investigated and prevented with a multidisciplinary approach involving oncologist, radiation oncologist and skilled dental practitioner when a cancer patient must begin a BP or an antiangiogenic treatment.

First-line treatment of NSCLC with bevacizumab: real world data from an Italian regional based survey.

BACKGROUND: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population. PATIENTS AND METHODS: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany. RESULTS: We evaluated 62 (median age: 63.5 [30-77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2-37] and a median overall survival (OS) of 10.5 [2-39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths. CONCLUSION: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.

Outcome of crizotinib treatment in a young woman with heavily pretreated ROS1-positive lung cancer.

Non-small-cell lung cancer is a term that encompasses a number of subtypes of lung cancer. In recent years, several intracellular pathways have been studied in order to discover a potential target for novel anticancer therapies such as anaplastic lymphoma kinase (ALK) and reactive oxygen species 1 (ROS1). Increased interest in oncologic treatment research has resulted from the observation that ALK- and ROS1-associated tyrosine kinases show molecular analogies in some of their domains. This discovery led to the hypothesis that target therapy against ALK translocation could have efficacy also in ROS1-positive tumors. Crizotinib is an oral tyrosine kinase inhibitor that binds the ALK tyrosine kinase domain, blocking its function. We report the case of a woman with heavily pretreated metastatic lung adenocarcinoma harboring ROS1 positivity who experienced a prolonged and dramatic clinical benefit from crizotinib therapy.

Gallbladder neuroendocrine neoplasm: a case report and critical evaluation of WHO classification.

Gallbladder neuroendocrine neoplasms (GB-NENs) are rare. The majority of GB-NENs are poorly differentiated, with increased mitotic activity and clinically aggressive course. Surgery is the only curative approach and the optimal medical treatment is uncertain. In this report we describe the case of a woman affected by metastatic well differentiated GB-NEN with increased Ki 67. The patient underwent surgical removal of the gallbladder neoplasm and showed disease recurrence with pulmonary and liver metastases. After achieving a partial chemotherapy response, the patient rapidly died due to progressive disease. This case raises important issues. Well differentiated NENs with a high proliferative index are not included as a specific entity in any of the most widely used nomenclature systems. Moreover considering the proliferative index of the disease, it is reasonable to consider the patient a candidate for chemotherapy. Nevertheless, recently published papers raise the possibility that well differentiated NENs and specific proliferative index cutoff can predict low chemosensitivity in patients with highly proliferative neuroendocrine carcinoma.

Complete pathological response in advanced extra-gastrointestinal stromal tumor after imatinib mesylate therapy: a case report.

BACKGROUND: Gastrointestinal stromal tumors are uncommon intra-abdominal tumors. In fewer than 5% of cases, they originate primarily from the mesentery, omentum or peritoneum and these extra-gastrointestinal stromal tumors tend to have characteristics similar to gastrointestinal stromal. CASE REPORT: We report a case of extra-gastrointestinal stromal tumor in a 76-year-old male, Eastern Cooperative Oncology Group (ECOG) performance status of 2. Abdominal Computed Tomography (CT) showed multiple non-homogeneous confluent nodules at the level of the greater omentum and mesentery, involving the bladder and rectum, with additional peritoneal nodules in the upper abdomen. In March 2008, the patient started imatinib mesylate at 400 mg/day. Instrumental examinations showed progressive response until thoracic-abdominal CT in February 2012 which documented a complete response. Follow-up ended in October 2013. Treatment with imatinib, in addition to pathological response, provided clinical benefit, a progressive regression of symptoms and improved the patient's ECOG performance status from 2 to 0.

Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis.

BACKGROUND: Sunitinib malate is an orally bioavailable tyrosine kinase inhibitor that is active against many tyrosine kinase receptors involving crucial pathways in both healthy tissues and malignant tissues. Because its use in clinical practice is quite recent, many of its possible side effects remain unknown. In this report, the authors describe the incidence of new-onset hyperparathyroidism in a cohort of patients with metastatic renal cell carcinoma who received treatment with sunitinib. METHODS: Twenty-six patients who received first-line sunitinib for metastatic renal cell carcinoma were enrolled in this study for a mineral and parathyroid function assessment. Plasma levels of intact parathyroid hormone; serum levels of calcium, phosphorus, 25-hydroxyvitamin D(3), and 1,25-dihydrovitamin D(3); and urinary 24-hour calcium and phosphorus excretion all were measured in each patient. Biochemical evaluations were performed before the beginning of treatment and at the end of each sunitinib treatment period. RESULTS: Eighteen of 26 patients (69.2%) developed hyperparathyroidism with normal serum calcium levels, and 6 of them developed hypophosphatemia. Patients presented with a mean elevation of parathyroid hormone after 2.2 cycles of sunitinib. The levels of 25-OH vitamin D(3) were stable over the course of treatment, whereas 1,25-OH vitamin D(3) levels were increased in 5 hyperparathyroid patients. Those who presenting with elevated parathyroid hormone levels had low or undetectable urinary calcium levels. Parathyroid hormone elevation usually persisted but did not progress during long-term therapy with sunitinib. Permanent treatment interruption resulted in a resolution of hyperparathyroidism. CONCLUSIONS: Hyperparathyroidism developed in an high percentage of patients on sunitinib. Therefore, the authors concluded that sunitinib may affect parathyroid function and bone mineral homeostasis, possibly resulting in abnormal bone remodeling.