Progressive bone loss, resulting in both osteoporosis and osteomalacia, is a frequent long-term complication in cancer patients undergoing common anti-tumor treatment programs. Monitoring of bone health by both imaging techniques and biochemical markers measurement, is useful in preventing the severe skeleton default.

Cellular therapies represent an emerging field in oncology. Several studies support the efficacy of cell-based immunotherapies for different solid tumors. Recent approaches, however, have been optimized in using adult stem cells, genetically modified to produce cytotoxic molecules for fighting cancer. In this review, we focused major preclinical and clinical results in this fascinating field of cell-based strategies against cancer.

Diagnostic and therapeutic approaches to non small cell lung cancer (NSCLC), especially adenocarcinoma, have recently undergone dramatic evolution according to the tremendous amount of molecular data collected on this cancer. In fact, the application of oncogenomics has identified novel molecular subtypes of NSCLC and led the way to diagnostic criteria based on the expression of specific genetic alterations that can provide prognostic and specific indications to the molecular targeted therapies. In NSCLC, several genes show "driver" molecular alterations that confer oncogenic potential to progenitor cells through the enrollment of metabolic pathways critical for cell proliferation and tumor development. On the other hand, clinical management of NSCLC with small molecules has undoubtedly provided optimistic results with both a significant increase in overall survival and reduction in therapy-related toxicity including relative complications. Thus, pharmacogenomics, as the newest tool for using the targeted therapy represents the most innovative approach for treatment of this cancer once the molecular aberrations are identified. In particular, the relative mutational status of several driver genes including EGFR, ALK, ROS1 and others, is directly correlated to a better response to thyrosin-kinase inhibitors. Furthermore, other therapeutic strategies with inhibitors of angiogenic receptors, PARP, histone-deacetylase, PI3K and HSP90, are intensively studied in pre-clinical models as well as in clinical trials for a potential adoption in clinical practice. The introduction of more advanced techniques for molecular profiling also allows to identify pathogenic variants of many other genes involved in the progression of lung adenocarcinoma with the aim to develop novel molecular targets for pharmacological research. In this review, we will revisit the current applications of oncogenomics in the diagnosis and treatment of this tumor.

In tumors characterized by a high osteotropism, such as multiple myeloma, the measurement of bone metabolism markers is helpful in monitoring both severity and prognosis of the skeletal disease. Here, we review the pathophysiology of these markers including tartrate resistant acid phosphatase (TRAcP), which appears highly specific and closely related to the extent of myeloma bone lesions.

Objective. This study examined whether obesity is characterized by higher 24 h mean pulse pressure (24 h mean SBP-24 h mean DBP) and whether free thyroid hormones (FT3 and FT4) have a relationship with 24 h mean pulse pressure. Methods. A total of 231 euthyroid overweight and obese patients, 103 women and 128 men, aged 18–68 yrs, normotensive (n = 69) or with recently developed hypertension (n = 162), never treated with antihypertensive drugs, were investigated. Fasting insulin, TSH, FT3, FT4, glucose, and lipid serum concentrations were measured.Waist circumference was measured as an indirect parameter of central fat accumulation. Ambulatory blood pressure monitoring (ABPM) was performed. Results. 24 h mean pulse pressure (PP) showed a significant positive correlation with BMI (P < 0.001), waist circumference (P < 0.001), and FT3 (P < 0.001) and insulin serum levels (P < 0.05). When a multivariate analysis was performed, and 24 h PP was considered as the dependent variable, and waist circumference, FT3, insulin, male sex, and age as independent parameters, 24 h mean PP maintained a significant association only with waist circumference (P < 0.001) and FT3 levels (P < 0.05). Conclusion. Our results suggest that FT3 per se may contribute to higher pulse pressure in obese subjects.

Adenocarcinoma of the ceruminous glands is a rare malignancy arising from the glands of the external auditory canal. In most patients it is usually diagnosed as locally advanced disease with a major obstacle for radical surgery. Here, we describe two cases of patients suffering of sudden hearing loss and ipsilateral facial hemiparesis due to tumors arising from the ceruminous glands with primary intracranial involvement and subsequent middle ear infiltration. The patient with localadvanced disease underwent surgery followed by adjuvant treatment, whereas the other patient with advanced disease only to palliative therapy. However, both of them received volumetric-modulated arc radiotherapy (VMAT) resulting in complete remission as adjuvant treatment in the first patients while extending the survival as palliation in the second one. Thus, VMAT appears a suggested approach in this tumor which management is still poorly defined.

Autophagy occurs in tumor cells acquiring cytotoxic drug resistance and its activation may impair their susceptibility to apoptosis in response to apoptogen agents. We investigated the pro-apoptotic effect of dexamethasone (Dex) on MM cell lines (U266, INA-6, LR5-8226, LIG, and MCC2) and primary malignant plasma cells from naïve and refractory/relapsed patients. We evaluated the transcriptional and ultrastructural events leading to autophagy by measuring Beclin-1 and p62 levels and transmission electronic microscopy. Autophagy was inhibited by hydroxychloroquine (HCQ), whereas the ability of Dex-resistant MM cells to recover the susceptibility to apoptosis was measured. A direct relationship between autophagy and Beclin-1 or LC3/Atg8 levels was observed, whereas their mRNAs were inversely correlated to p62 expression. Starvation strongly activated autophagy by inducing cellular, transcriptional, and ultrastructural modifications that were reversed by HCQ. Taken together, these data suggest that autophagy is a potential mechanism leading to drug resistance in MM, and suggest Beclin-1 and p62 as early markers of cell susceptibility to apoptosis. The combination of HCQ with novel agents may thus be considered to improve the therapeutic response in relapsed/resistant MM patients.

Melphalan has been a mainstay of multiple myeloma (MM) therapy for many years. However, following treatment with this alkylator, malignant plasma cells usually escape both apoptosis and cell cycle control, and acquire drug-resistance resulting in tumor progression. Bendamustine is being used inMMpatients refractory to conventional DNA-damaging agents, although the mechanisms driving this lack of cross-resistance are still undefined. Here, we investigated the molecular pathway of bendamustine-induced cell death in melphalan-sensitive and melphalan-resistant MM cell lines. Bendamustine affected cell survival resulting in secondary necrosis, and prompted cell death primarily through caspase-2 activation. Also, bendamustine blocked the cell cycle in the G2/M phase and induced micronucleation, erratic chromosome spreading and mitotic spindle perturbations in melphalan-resistant MM cells. In these cells, both Aurora kinase A (AURKA) and Polo-like kinase-1 (PLK-1), key components of the spindle-assembly checkpoint,were down-regulated following incubationwith bendamustine, whereas levels of Cyclin B1 increased as a consequence of the prolonged mitotic arrest induced by the drug. These findings indicate that, at least in vitro, bendamustine drives cell death by promoting mitotic catastrophe in melphalan-resistantMMcells. Hence, activation of this alternative pathway of cell death may be a novel approach to the treatment of apoptosis-resistant myelomas.

Multiple myeloma (MM) is a hematologic malignancy whose progression may account for uncontrolled osteoclastogenesis promoted by the malignant plasma cells within the marrow microenvironment. Osteoclasts are multinucleated cells derived from the fusion of myeloid progenitors such as monocytes/macrophages, in response to specific differentiation factors released within the marrow niche, that are significantly deregulated in MM. In this malignancy DC-STAMP, a major fusogen protein enrolled by pre-osteoclasts, is highly expressed by peripheral macrophages, whereas dendritic cells and myeloma plasma cells show high fusogenic susceptibility and under specific conditions transdifferentiate to osteoclasts. In particular, the malignant plasma cells, besides altered ploidy, expression of cancer stem cell phenotype and high metastasizing capability, are able to express phenotypic markers of osteclasts, namely the proteolytic enzymes for the bone matrix, and to activate the β3 transcriptional pathway leading to ERK1/2 phosphorylation and initiation of the bone resorbing activity. Thus, based on the imbalanced osteoclast formation and activity that involve cells constitutively uncommitted to osteoclast differentiation, both homotypic and heterotypic cell fusions in myeloma marrow microenvironment represent a major pathogenetic event that drives the development and progression of the skeleton devastation typical of the myeloma bone disease.

In the era of precision medicine, the suitability of fluoropyrimidine therapies in clinical oncology can be checked by pharmacogenetic investigations of single patients, thus optimizing resources and indicating the appropriate drugs to personalize their chemotherapy. For example, the presence of dihydropyrimidine dehydrogenase gene (DPYD) polymorphisms in cancer patients may lead to adverse effects when adopting fluoropyrimidine-based therapies.

Cilengitide (CLG) is an inhibitor of both avb3 and avb5 integrins, with a defined anti-tumour effect in glioblastoma. Pre-clinical studies demonstrate its ability to restrain the bone resorbing property of metastatic osteotropic tumours and we have previously shown that the disablement of avb3 in multiple myeloma (MM) plasma cells results in exhaustion of their in vitro osteoclast (OC)-like activity on bone substrate. Here, we investigated the effect of CLG on this functional property of MM cells. Both avb3 and avb5 were measured on primary marrow MM cells from 19 patients, and the effect of CLG on proliferation, apoptosis and adhesion was investigated in parallel with MM cell lines and OCs from healthy donors. In addition, the effect of CLG on the capability of malignant plasma cells to produce erosive lacunae on calcium phosphate was explored in relation to the activation of intracellular kinases of molecular pathways of both integrins. Ultrastructural microscopy was used to evaluate the morphological changes in MM cells due to the effect of CLG on cell adhesion. The data from our study demonstrate that CLG restrains the bone resorbing function of MM cells by disabling their adhesion properties. Further investigations in preclinical studies of osteotropic tumours are warranted.

Bortezomib and Lenalidomide have been shown to be effective in the control of multiple myeloma (MM) progression. We have investigated their role in the in vitro expression of Osterix by primary osteoblast cultures from MM patients and found that Osterix RNA was constitutively down-regulated in these cells. Treatment of osteoblasts with Bortezomib resulted in an increase of Osterix RNA and in enhanced activity of both BMP-2 and Runx2. Instead, Lenalidomide was unable to modify Osterix transcription. These findings provide additional evidence suggesting that, at least in vitro, Bortezomib promotes the osteoblast maturation whereas Lenalidomide is ineffective. (C) 2009 Elsevier Ltd. All rights reserved.

The crosstalk of myeloma cells with accessory cells drives the expansion of malignant plasma cell clones and the hyperactivation of osteoclastogenesis that occurs in multiple myeloma (MM). These reciprocal interactions promote defective dendritic cell (DC) function in terms of antigen processing, clearance of tumor cells, and efficacy of the immune response. Thus, myeloma cells exert immune suppression that explains, at least in part, the failure of therapeutic approaches, including DC vaccination. Impairment of DCs depends on high bone marrow levels of cytokines and adhesion molecules that affect both maturation and expression of costimulatory molecules by DCs. Moreover, DCs share with osteoclasts (OCs) a common ontogenetic derivation from the monocyte lineage, and thus may undergo OC-like transdifferentiation both in vitro and in vivo. Immature DCs (iDCs) induce clonogenic growth of malignant plasma cells while displaying OC-like features, including the ability to resorb bone tissue once cultured with myeloma cells. This OC-like transdifferentiation of iDCs is dependent on the activation of both the receptor activator of nuclear factor kappa B (RANK)-RANK ligand (RANK-L) and CD47-thrombospondin (TSP)-I axes, although interleukin 17-producing T helper-17 clones within the bone microenvironment may also take part in this function. Therefore, iDCs allied with malignant plasma cells contribute to MM osteoclastogenesis, although other molecules released by tumor cells may independently contribute to the bone-resorbing machinery. The Oncologist 2011;16:1040-1048

Applications of laser therapy in biostimulation and healing injured tissues are widely described in medical literature. The present study focuses on the effects of laser irradiation on the growth rate and differentiation of human osteoblast-like cells seeded on titanium or zirconia surfaces. Cells were laser irradiated with low therapeutical doses at different intervals and the effects of irradiation were evaluated at each time-point. After 3 hours lasered cells showed an enhanced mitogen activity compared to non-lasered control cells and a higher alkaline phosphatase activity, marker of bone formation. At the same time, the mRNA of RUNX2 and OSTERIX, two genes involved in osteoblast differentiation, showed a clear decrease in lasered cells. This reached the lowest value 6 to 12 hours after irradiation, after which the transcripts started to increase, indicating that the laser treatment did promote the osteogenic potential of growth-induced cells. These results indicate that Low Level Laser Treatment (LLLT) stimulates osteogenic cell proliferation

Background: Breast cancer (BC) cells secrete soluble factors that accelerate osteoclast (OC) differentiation, leading to the formation of osteolytic bone metastases. In the BOLERO-2 trial, BC patients with bone involvement who received Everolimus had a delayed tumor progression in the skeleton as a result of direct OC suppression through the inhibition of mTOR, in addition to the general suppressor effect on the cancer cells. Here, we explored the effect of Everolimus, as mTOR inhibitor, on the pro-OC paracrine activity of BC cells. Methods: Both MDA-MB-231 and MCF-7 BC cell lines were incubated with sub-lethal amounts of Everolimus, and their conditioned supernatants were assessed for their capacity to differentiate OCs from PBMC from healthy donors, as well as to interfere with their bone resorbing activity shown on calcium phosphate slices. We also measured the mRNA levels of major pro-OC factors in Everolimus-treated BC cells and their secreted levels by ELISA, and evaluated by immunoblotting the phosphorylation of transcription factors enrolled by pathways cooperating with the mTOR inhibition. Finally, the in vivo pro-OC activity of these cells was assessed in SCID mice after intra-tibial injections. Results: We found that Everolimus significantly inhibited the differentiation of OCs and their in vitro bone-resorbing activity, and also found decreases of both mRNA and secreted pro-OC factors such as M-CSF, IL-6, and IL-1β, whose lower ELISA levels paralleled the defective phosphorylation of NFkB pathway effectors. Moreover, when intra-tibially injected in SCID mice, Everolimus-treated BC cells produced smaller bone metastases than the untreated cells. Conclusions: mTOR inhibition in BC cells leads to a suppression of their paracrine pro-OC activity by interfering with the NFkB pathway; this effect may also account for the delayed progression of bone metastatic disease observed in the BOLERO-2 trial. Keywords: BOLERO-2 trial, Breast cancer cells, mTOR, Osteoclastogenesis, Everolimus

The effects of treatment with shock waves (SW) on osteoblastic cells have already been described. Furthermore, the effects of treatment with SW are also determined by the contextual stimulation of other cell lines, in particular of mesenchymal cells. This is the first experimental study of stimulation of a human mesenchymal stem cell line, taken from bone marrow, using SW (electromagnetic device), with two energy levels. The results showed a significant increase in expression of the main osteoblastic differentiation genes: BMP2, alkaline phosphatase, osteocalcin, COL1A1, RUNX2. The monitoring within 96 hours demonstrated a progressive increase of cell adhesion and an intense cell proliferation at 48 h. The differentiation response and proliferation of stem cells after treatment with SW shows that this therapy is an effective method of regenerative medicine.

Recently, genetically modified mesenchymal stem cells (MSCs) have been exploited to deliver anti-cancer bio-drugs directly within the tumour mass. Here, we explored whether adipose-derived MSCs (AD-MSCs), engineered to express the pro-apoptotic ligand TRAIL (also known as TNFSF10), kill multiple myeloma (MM) cells and migrate towards MM cells in vitro. Different MM cell lines were assessed for their sensitivity to recombinant human (rh) TRAIL alone and in combination with the proteasome inhibitor bortezomib, which was shown to enhance the effect of rhTRAIL. TRAIL(+) -AD-MSCs were co-cultured with bortezomib-pretreated MM cells and their killing activity was evaluated in presence or absence of caspase inhibition. AD-MSC migration towards media conditioned by both myeloma cells and myeloma bone fragments was also investigated. Despite moderate MM cell sensitivity to rhTRAIL, TRAIL(+) -AD-MSCs in combination with bortezomib significantly induced myeloma cell death. This effect was associated with caspase-8 activation and abrogated by capsase inhibition. On the other hand, co-culture experiments were performed to evaluate whether unmodified AD-MSCs affect myeloma cell growth in vitro. AD-MSCs appeared ineffective on myeloma cell growth and showed migratory capacity towards MM cells in vitro. These data emphasize the anti-myeloma activity of TRAIL-engineered AD-MSCs and provide support for a future model of a cell-based approach against MM.

Lenalidomide (LEN) is a structural analogue of Thalidomide and is currently considered a promising compound among immunomodulatory drugs. Following the demonstration of its potent anti-angiogenic, anti-inflammatory, and antineoplastic effects in preclinical models, LEN has emerged as an interesting option for the management of selective hematologic malignancies and may also have a possible role in certain solid tumors as well. It is currently approved in the second-line therapy of multiple myeloma (MM) as well as in myelodysplastic syndrome characterized by 5q minus abnormalities. LEN has been found to be effective in the treatment of both of these conditions and to possess a manageable toxicity profile. In MM, a number of ongoing clinical trials are defining its role in the treatment of newly diagnosed disease as well as in maintenance therapy. Combination approaches pretransplant have shown great promise. Its role in the management of relapsed and refractory disease is now well established. Its long-term tolerability profile appears favorable although an increased risk in new malignancies in patients receiving LEN as maintenance post-stem cell transplant warrants some caution, with follow-up studies being important in determining the long-term implications of this observation.

Over the last decades, the concept of precision medicine has dramatically renewed the field of medical oncology; the introduction of patient-tailored therapies has significantly improved all measurable outcomes. Liquid biopsy is a revolutionary technique that is opening previously unexpected perspectives. It consists of the detection and isolation of circulating tumor cells, circulating tumor DNA and exosomes, as a source of genomic and proteomic information in patients with cancer. Many technical hurdles have been resolved thanks to newly developed techniques and next-generation sequencing analyses, allowing a broad application of liquid biopsy in a wide range of settings. Initially correlated to prognosis, liquid biopsy data are now being studied for cancer diagnosis, hopefully including screenings, and most importantly for the prediction of response or resistance to given treatments. In particular, the identification of specific mutations in target genes can aid in therapeutic decisions, both in the appropriateness of treatment and in the advanced identification of secondary resistance, aiming to early diagnose disease progression. Still application is far from reality but ongoing research is leading the way to a new era in oncology. This review summarizes the main techniques and applications of liquid biopsy in cancer.

Low vitamin D levels have been associated with autoimmune disorders and, then, with the Hashimoto's autoimmune thyroiditis (AT), the most common autoimmune disease. Obesity is characterized by lower vitamin D levels and higher risk to develop autoimmune diseases. The aim of the study was to examine the possibility of an association between AT and decreased 25(OH) vitamin D (25(OH)D) levels in a cohort of otherwise healthy overweight and obese subjects.

The crosstalk of melanoma cells with components of the microenvironment promotes malignant cell proliferation and spread to distant tissues. Although the major pathogenetic events have already been elucidated, the mechanisms that drive the metastatic behavior of tumor cells are still undefined. MicroRNAs (miRNAs) are small non-coding RNAs that control post-transcriptional gene expression through interconnected kinases upstream of functional genes involved in tumor progression. Here, we review the biological relevance of melanoma-related miRNAs and focus on their potential role in propagating signals that may cause tumor microenvironment rearrangements, as well as disablement of the immune system and melanoma cell proliferation.

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder characterized by an accumulation of cells sharing the major phenotypic features of cutaneous Langerhans cells. Given its variable clinical evolution, ranging from self-limiting lesions to multisystemic forms with a poor prognosis, in the last decades it has been debated whether LCH might not have a neoplastic rather than an inflammatory nature. However, although the fundamental events underlying the pathogenesis of LCH are still elusive, recent advances have strikingly improved our understanding of the disease. In particular, the identification of multiple interplays between LCH cells and their tumor microenvironment, along with the recognition of the lesional cytokine storm as a key determinant of LCH progression, has substantiated new opportunities for devising targeted therapeutic approaches. Strikingly, the detection of the rapidly accelerated fibrosarcoma isoform BV600E gain-of-function mutation as a genetic alteration recurring in more than 50% of patients has fueled the paradoxical picture of LCH as a tumor of the antigen-presenting cells that can evade rejection by the immune system.Thus, new evidence regarding the ontogeny of LCH cells, as well as a better understanding of the putative immune system frustrating strategy in LCH, may help to define the precise pathogenesis.

Isolation and genotyping of circulating tumor cells (CTCs) is gaining an increasing interest by clinical researchers in oncology not only for investigative purposes, but also for concrete application in clinical practice in terms of diagnosis, prognosis and decision treatment with targeted therapies. For the mutational analysis of single CTCs, the most advanced biotechnology methodology currently available includes the combination of whole genome amplification (WGA) followed by next-generation sequencing (NGS). However, the sequence of these molecular techniques is time-consuming and may also favor operator-dependent errors, related to the procedures themselves that, as in the case of the WGA technique, might affect downstream molecular analyses.

: Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and prostaglandin E2, insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development. The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies.

BACKGROUND: Renal sinus fat (RSF) has been recognized as a risk factor for arterial hypertension. This study was addressed to examine whether also para- and perirenal fat accumulation is associated to higher 24-h mean systolic (SBP) and/or diastolic blood pressure (DBP) levels in overweight and obese subjects. METHODS: A cohort of 42 overweight and obese patients, 29 women and 13 men, aged 25-55 years, not treated with any kind of drug, was examined. Body mass index (BMI), waist circumference (WC), fasting insulin and glucose serum levels, insulin resistance (assessed by using the homeostasis model assessment [HOMAIR]), and 24-h aldosterone urine levels were measured. Ambulatory blood pressure monitoring (ABPM) was measured with 15 min intervals from 7.0 a.m. to 11.0 a.m. and with 30 min intervals from 23.0 to 7.0 for consecutive 24 h, starting from 8:30 AM. Measurement of para- and perirenal fat thickness was performed by ultrasounds by a duplex Doppler apparatus. RESULTS: Para- and perirenal ultrasonographic fat thickness (PUFT) was significantly and positively correlated with WC (p < 0.01), insulin (p < 0.01), HOMAIR (p < 0.01), and 24-h mean DBP levels (p < 0.05). 24-h mean DBP was also significantly and positively correlated with 24-h aldosterone urine concentrations (p < 0.001). A multivariate analysis by multiple linear regression was performed; the final model showed that the association of 24-h mean DBP as dependent variable with PUFT (multiple R = 0.34; p = 0.026) and daily aldosterone production (multiple R = 0.59; p = 0.001) was independent of other anthropometric, hormone and metabolic parameters. DISCUSSION AND CONCLUSIONS: This study shows a positive independent association between PUFT and mean 24-h diastolic blood pressure levels in overweight and obese subjects, suggesting a possible direct role of PUFT in increasing daily diastolic blood pressure.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are characterized by mutations of KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) or PDGFRA (platelet-derived growth factor receptor α) that may be efficiently targeted by tyrosine kinase inhibitors (TKI). Notwithstanding the early responsiveness to TKI, the majority of GISTs progress, imposing the need for alternative therapeutic strategies. DOG1 (discovered on GIST-1) shows a higher sensitivity as a diagnostic marker than KIT, however its prognostic role has been little investigated. METHODS: We evaluated DOG1 expression by immunohistochemistry (IHC) in 59 patients with GISTs, and correlated its levels with clinical and pathological features as well as mutational status. Kaplan-Meier analysis was also applied to assess correlations of the staining score with patient recurrence-free survival (RFS). RESULTS: DOG1 was expressed in 66 % of CD117(+) GISTs and highly associated with tumor size and the rate of wild-type tumors. Kaplan-Meier survival analysis showed that a strong DOG1 expression demonstrated by IHC correlated with a worse 2-year RFS rate, suggesting its potential ability to predict GISTs with poor prognosis. CONCLUSIONS: These findings suggest a prognostic role for DOG1, as well as its potential for inclusion in the criteria for risk stratification.

The goal of cancer pharmacogenomics is to obtain benefit from personalized approaches of cancer treatment and prevention. Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and targets, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. Although a considerable amount of new targeted agents have been designed based on a finely understanding of molecular alterations in cancer, a wide gap between pharmacogenomic knowledge and clinical application still persists. This review focuses on the relevance of mutational analyses in predicting individual response to antitumor therapy, in order to improve the translational impact of genetic information on clinical practice.

A group of 608 apparently healthy patients, 136 men and 472 women, either overweight or obese, aged 18-69 years, were examined. BMI, waist circumference, fasting blood glucose (FBG), insulin, and complement 3 (C3) serum levels were measured; the homeostasis model assessment (HOMAIR) was used to evaluate insulin resistance; and physical activity was quantified by a questionnaire. Results: HOMAIR showed a positive correlation with BMI (r: 0.478, p < 0.001), waist circumference (r: 0.487, p < 0.001), and C3 (r: 0.445, p < 0.001). Moreover, it was significantly associated with gender (F Fisher = 22.12, p < 0.001), and the mean HOMAIR levels were significantly different among the three groups of physical activity, with the lowest level of insulin resistance at the highest level of physical activity (F=7,31, p < 0.001). A multiple regression analysis was carried out with HOMAIR as the dependent variable and gender, age, BMI, waist circumference, C3 and the level of physical activity as independent variables (fitted model: F = 41.24, P<0.001, R2 = 0.328). HOMAIR maintained an independent association with C3 (β = 0.678, P<0.001), sex (β = 0.189, P<0.001), BMI (β = 0.637, P<0.01), and age (β = -0.004, P<0.05). Conclusions: This study of a cohort of overweight and obese subjects has shown that insulin resistance (dependent variable) is positively associated with C3 serum levels, independently of age, gender, anthropometric parameters and physical activity, suggesting that higher C3 serum levels may directly increase insulin resistance in obesity.

A cohort of 66 healthy overweight and obese patients, 53 women and 13 men were examined. Waist circumference and fasting 25(OH)D, insulin, glucose, lipid (cholesterol, HDL cholesterol, and triglyceride), C-reactive protein (CRP), and complement 3 (C, and 4 (C serum concentrations were measured. Insulin resistance was assessed by the homeostasis model assessment (HOMA. Results. 25(OH)D levels showed a significant negative correlation with BMI (P < 0.01), waist circumference (P < 0.05), fasting insulin (P < 0.01), HOMA(P < 0.01), triglycerides (P < 0.01), CRP (P < 0.01), C(P < 0.05), and C(P < 0.05). Multiple regression analyses were performed with 25(OH)D as the dependent variable and BMI (or waist circumferences), fasting insulin (or HOMA, triglycerides, and CRP (or Cor C as independent variables. Only insulin or HOMAmaintained a significant independent association with 25(OH)D levels, whereas vitamin D did not maintain a significant independent association with CRP or Cor Cconcentrations. Conclusions. The present study, performed in overweight and obese subjects, shows that 25(OH)D levels are negatively associated with inflammatory parameters such as CRP and Cand Clevels, but not independently of BMI, body fat distribution, insulin levels, or insulin resistance. Our results suggest that hyperinsulinemia and/or insulin resistance are directly responsible for decrease of 25(OH)D levels in obesity.

To promote their survival and progression in the skeleton, osteotropic malignancies of breast, lung, and prostate produce parathyroid hormone–related protein (PTHrP), which induces hypercalcemia. PTHrP serum elevations have also been described in multiple myeloma (MM), although their role is not well defined. When we investigated MM cells from patients and cell lines, we found that PTHrP and its receptor (PTH‐R1) are highly expressed, and that PTHrP is secreted both as a full‐length molecule and as small subunits. Among these subunits, the mid‐region, including the nuclear localization sequence (NLS), exerted a proliferative effect because it was accumulated in nuclei of MM cells surviving in starvation conditions. This was confirmed by increased transcription of several genes enrolled in proliferation and apoptosis control. PTHrP was also found to stimulate PTH‐R1 inMMcells. PTH‐R1’s selective activation by the full‐length PTHrP molecule or the NH2‐terminal fragment resulted in a significant increase of intracellular Ca2þ influx, cyclic adenosine monophosphate (cAMP) content, and expression of receptor activator of NF‐kB ligand (RANKL) and monocyte chemoattractant protein‐1 (MCP‐1). Our data definitely clarify the role of PTHrP in MM. The PTHrP peptide is functionally secreted by malignant plasma cells and contributes to MM tumor biology and progression, both by intracrine maintenance of cell proliferation in stress conditions and by autocrine or paracrine stimulation of PTH‐R1, which in turn reinforces the production of osteoclastogenic factors.

Objective: The study aim was to compare C3 levels with the common carotid artery intima-media thickness (CCAIMT) in subjects of both genders, with a wide range of BMI, independently of age, gender, and abdominal obesity. Method: 140 euthyroid, mainly overweight/obese subjects (age 18-30 years) were examined. BMI, waist circumference, blood pressure, fasting insulin, glucose, lipids, C3 and C-reactive protein serum concentrations, and insulin resistance degree (estimated by homeostasis model assessment for insulin resistance (HOMAIR)) were measured. Results: CCA-IMT was positively (p < 0.001) correlated with BMI, waist circumference, systolic and diastolic blood pressures, HOMAIR, and insulin, CRP, and C3 serum levels. The multiple linear regression analysis showed that only male gender and waist circumference maintained an independent relation with the CCA-IMT. Conclusion: This study suggests that central fat accumulation and male gender independently increase the thickness of the arterial wall, whereas inflammation and inflammatory markers do not have an independent effect on this parameter.

Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated.

We present the final results of a Phase II study that evaluated safety and efficacy of lenalidomide in combination with rituximab in 39 patients with recurrent small lymphocytic lymphoma (N=18), marginal zone lymphoma (N=8), or lymphoplasmacytic lymphoma (N=13). Patients received oral doses of lenalidomide 20 mg once daily on days 1-21 and rituximab 375 mg/m2 on day 14 of each 28-day course. Patients received up to 6 courses. The overall response was 54%, with a complete response of 21%. At 2 years, progression free survival, duration of remission, and overall survival were 45%, 76%, and 78%, respectively. The evaluation of treatment response by histology showed an overall response rates of 75%, 46%, and 50%, in marginal zone, lymphoplasmacytic and small lymphocytic lymphoma, respectively. Histology-based estimates of remission durations at 2 years were 100%, 100%, and 51% for marginal zone, lymphoplasmacytic, and small lymphocytic lymphomas, respectively. A log rank test showed that the marginal zone and lymphoplasmacytic lymphoma curves were marginally significantly different from the small lymphocytic lymphoma curve. Our results demonstrated that patients with recurrent marginal zone and lymphoplasmacytic lymphomas that responded to the combination treatment had long-lasting responses. Of note, no other studies have published the effects of this combination treatment on patients with relapsed lymphoplasmacytic lymphoma. Our findings showed a mild, predictable, and manageable toxicity profile. Confirmation of these results in Phase III trials will facilitate moving towards a chemotherapy-free approach in the management of indolent non-Hodgkin lymphoma. ClinicalTrials.gov; Identifier: NCT01830478.

Recent advances in understanding the biologic mechanisms underlying cancer development have driven the design of new therapeutic approaches, termed 'targeted therapies', that selectively interfere with molecules or pathways involved in tumor growth and progression. Inactivation of growth factors and their receptors on tumor cells as well as the inhibition of oncogenic tyrosine kinase pathways and the inhibition of molecules that control specific functions in cancer cells constitute the main rational bases of new cancer treatments tailored for individual patients. Small-molecule inhibitors and monoclonal antibodies are major components of these targeted approaches for a number of human malignancies. As the studies of the bio-molecular features of cancer progress, new exciting strategies have arisen, such as targeting cancer stem cells that drive tumor relapses or the selective induction of apoptosis in malignant cells. This article primarily focuses on the biologic bases of the new cancer drugs and summarizes their mechanisms of action, the clinical evidence of their anti-cancer effectiveness as well as the rationale for their use in clinical practice.

One of the great challenges of cancermedicine is to develop effective treatments for bonemetastatic cancer.Most patients with advanced solid tumorswill develop bone metastasis andwill suffer fromskeletal related events associated with this disease. Although some therapies are available to manage symptoms derived from bone metastases, an effective treatment has not been developed yet. The mammalian target of rapamycin (mTOR) pathway regulates cell growth and survival. Alterations in mTOR signaling have been associated with pathological malignancies, including bone metastatic cancer. Inhibition of mTOR signalingmight therefore be a promising alternative for bonemetastatic cancermanagement. This review summarizes the current knowledge onmTOR pathway signaling in bone tissue and provides an overview on the known effects of mTOR inhibition in bone cancer, both in in vitro and in vivo models.

Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross-talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-kappaB/receptor activator of nuclear factor-kappaB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1alpha/chemokine receptor for macrophage inflammatory protein-1alpha axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-beta, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease.

The urokinase receptor (uPAR) exerts essential functions in the pathophysiology of cancers and therefore constitutes an important drug target. In order to generate efficient drugs against uPAR, a new approach includes chimeric proteins associating one molecular address to specifically target uPAR and one bacterial or plant toxin that will eventually kill the tumoural cell. Using this frame, several recombinant toxins have been designed namely DTAT, DTAT13, EGFATFKDEL 7 mut, and ATF-SAP. As molecular address, all of these fusion proteins use the amino-terminal fragment of urokinase that binds with high affinity to uPAR through its growth factor domain (GFD). The various toxin moieties were derived from either diphtheria toxin, Pseudomonas exotoxin A (PE38), or saporin. In this review, we describe the rational, design, production and therapeutic anti-cancer potential of these chimeric toxins.

A great debate in literature exists nowadays on the role of uric acid as a marker of cardiovascular and metabolic organ damage or a risk factor for cardiovascular and metabolic disease.