Genomic Profiling and Molecular Characterisation of Metastatic Urothelial Carcinoma.

The clinical management of metastatic urothelial carcinoma (mUC) is undergoing a major paradigm shift; the integration of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) into the mUC therapeutic strategy has succeeded in improving platinum-based chemotherapy outcomes. Given the expanding therapeutic armamentarium, it is crucial to identify efficacy-predictive biomarkers that can guide an individual patient's therapeutic strategy. We reviewed the literature data on mUC genomic alterations of clinical interest, discussing their prognostic and predictive role.

Lenalidomide arrests cell cycle and modulates PD1-dependent downstream mTOR intracellular signals in melanoma cells.

Despite numerous efforts to define the best therapeutic strategies in advanced melanoma, the response of many patients remains heterogeneous and of short duration. Lenalidomide, an immunomodulating drug, has shown anti-inflammatory, antiangiogenic and anticancer properties in haematological disorders; however, few preclinical data support the rationale for using this drug in melanoma patients. In this study, we investigate lenalidomide's potential role in melanoma by focusing on the in-vitro drug's antiproliferative activity.

Circulating tumor cells from melanoma patients show phenotypic plasticity and metastatic potential in xenograft NOD.CB17 mice.

Background: Innovative therapies have improved the overall survival in melanoma, although a high number of patients still experience disease progression or recurrence. Ex-vivo culture of circulating tumour cells (CTCs) represents a valuable laboratory resource for in-depth characterization of rare cell populations responsible for disease progression.

Methods: CTCs from patients with metastatic melanoma were in-vitro established.

Fertility preservation techniques in cervical carcinoma.

The usefulness of this review is to highlight how a fertility preservation (FP) approach is currently feasible for patients diagnosed with uterine cervical cancer. To this regard, a fertility sparing surgery has just overcome its traditional limits, gained acceptance within the major gynecologic oncology societies thanks to the ability to identify the "ideal" candidates to this conservative treatment. On the other hand, the use of other FPs for oocyte and ovarian cortex cryopreservation is still extremely debated.

Liquid Biopsy in Cervical Cancer: Hopes and Pitfalls.

Cervical cancer (CC) is the fourth most common cancer in women worldwide, with about 90% of cancer-related deaths occurring in developing countries. The geographical influence on disease evolution reflects differences in the prevalence of human papilloma virus (HPV) infection, which is the main cause of CC, as well as in the access and quality of services for CC prevention and diagnosis. At present, the most diffused screening and diagnostic tools for CC are Papanicolaou test and the more sensitive HPV-DNA test, even if both methods require gynecological practices whose acceptance relies on the woman's cultural and religious background.

DEAD-Box Helicase 4 (Ddx4) Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers.

DEAD-Box Helicase 4 (Ddx4) ovarian stem cells are able to differentiate into several cell types under appropriate stimuli. Ddx4 expression has been correlated with poor prognosis of serous ovarian cancer (OC), while the potential role of Ddx4 cells in non-serous epithelial OC (NS-EOC) is almost unexplored. The aim of this study was to demonstrate the presence of Ddx4 cells in NS-EOC and investigate the effect of follicle-stimulating hormone (FSH) on this population.

Dual-procedural separation of CTCs in cutaneous melanoma provides useful information for both molecular diagnosis and prognosis.

Background: Circulating tumor cells (CTCs) have recently emerged as a new dynamic soluble marker for several malignancies including cutaneous melanoma (CM) and are suitable for prognostic evaluations and treatment monitoring. However, to date many limitations still hamper the wide-scale application of CTCs in CM setting, including the lack of standardized methods as well as both low levels and heterogeneity of these cells.

Methods: We developed a protocol for CTC detection in CM based on immune-magnetic sorting to deplete CD45-, CD31- or CD34-positive cells, followed by dielectrophoretic DEPArray separation according to cell morphology and immunophenotype.

Breast cancer: an update on treatment-related infertility.

Breast cancer (BC) is the most common malignancy in women with a significant increasing incidence during the reproductive life. However, based on the newest anti-cancer molecular targeting drugs, successful treatments lead to the disease healing particularly in young patients, thus refreshing their motherhood programs. However, as effect of the BC treatment, a premature depletion of the ovarian follicle reserve occurs in more than one-third of patients resulting in permanent infertility.

In Vitro Generation of Oocytes from Ovarian Stem Cells (OSCs): In Search of Major Evidence.

The existence of ovarian stem cells (OSCs) in women as well as their physiological role in post-menopausal age are disputed. However, accumulating evidence demonstrated that, besides the animal models including primarily mice, even in adult women putative OSCs obtained from ovarian cortex are capable to differentiate in vitro into oocyte-like cells (OLCs) expressing molecular markers typical of terminal stage of oogonial cell lineage. Recent studies describe that, similarly to mature oocytes, the OSC-derived OLCs also contain haploid karyotype.

Dissection of major cancer gene variants in subsets of circulating tumor cells in advanced breast cancer.

Enumeration of circulating tumor cells (CTCs) may reflect the metastatic potential of breast cancer (BC). By using the DEPArray, we investigated CTCs with respect to their epithelial-to-mesenchymal transition phenotype and compared their genomic heterogeneity with tissue biopsies. Seventeen stage IV BC patients were enrolled.

Ddx4 Oogonial Stem Cells in Postmenopausal Women's Ovaries: A Controversial, Undefined Role.

Recent studies support the existence of oogonial stem cells (OSCs) in the ovarian cortex of different mammals, including women.These cells are characterized by small size, membrane expression of DEAD(Asp-Glu-Ala-Asp)-box polypeptide-4 (Ddx4), and stemness properties (such as self-renewal and clonal expansion) as well as the ability to differentiate in vitro into oocyte-like cells. However, the discovery of OSCs contrasts with the popular theory that there is a numerically defined oocyte pool for female fertility which undergoes exhaustion with menopause.

Animal-type melanoma: dog or wolf? A review of the literature and a case report.

The human animal type melanoma (ATM) is a rare subtype of melanoma characterised by the proliferation of pigmented dermal epithelioid and spindled melanocytes. However, this variant of melanoma is still lacking a precise nosography definition and classification for the difficulty to be distinguished from other more common melanocytic lesions, as well as for its peculiar biological behaviour. On the other hand, the contribution of scientific literature to this issue is fragmented and limited to the description of very few cases.

Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology.

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.

In vitro differentiation of human oocyte-like cells from oogonial stem cells: single-cell isolation and molecular characterization.

Study Question: Are the large cells derived from cultured DEAD box polypeptide 4 (DDX4)-positive oogonial stem cells (OSCs), isolated from the ovarian cortex of non-menopausal and menopausal women, oocyte-like cells?

Summary Answer: Under appropriate culture conditions, DDX4-positive OSCs from non-menopausal and menopausal women differentiate into large haploid oocyte-like cells expressing the major oocyte markers growth differentiation factor 9 (GDF-9) and synaptonemal complex protein 3 (SYCP3) and then enter meiosis.

What Is Known Already: The recent reports of OSCs in the ovaries of non-menopausal and menopausal women suggest that neo-oogenesis is inducible during ovarian senescence. However, several questions remain regarding the isolation of these cells, their spontaneous maturation in vitro, and the final differentiation state of the resulting putative oocytes.

pIL6-TRAIL-engineered umbilical cord mesenchymal/stromal stem cells are highly cytotoxic for myeloma cells both in vitro and in vivo.

Background: Mesenchymal/stromal stem cells (MSCs) are favorably regarded in anti-cancer cytotherapies for their spontaneous chemotaxis toward inflammatory and tumor environments associated with an intrinsic cytotoxicity against tumor cells. Placenta-derived or TRAIL-engineered adipose MSCs have been shown to exert anti-tumor activity in both in-vitro and in-vivo models of multiple myeloma (MM) while TRAIL-transduced umbilical cord (UC)-MSCs appear efficient inducers of apoptosis in a few solid tumors. However, apoptosis is not selective for cancer cells since specific TRAIL receptors are also expressed by a number of normal cells.

1,25(OH)2 vitamin D(3) contributes to osteoclast-like trans-differentiation of malignant plasma cells.

1,25-dihydroxyvitamin D (1,25(OH)D) exerts pleiotropic effects including bone turnover and immune system regulation. It inhibits both T and B cell proliferation while decreasing the secretion of inflammatory cytokines and immunoglobulins. 1,25(OH)D also modulates monocyte-macrophage and osteoclast (OC) maturation.

Next-generation Sequencing (NGS) Analysis on Single Circulating Tumor Cells (CTCs) with No Need of Whole-genome Amplification (WGA).

Background: 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.

Characterization of a rare nonpathogenic sequence variant (c.1905C>T) of the dihydropyrimidine dehydrogenase gene (DPYD).

Background: 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.

Methods: We detected in a cancer patient a rare germline synonymous heterozygous variant of DPYD (c.

Extracorporeal shock waves induce osteogenic differentiation of human bone-marrow stromal cells.

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.

Cilengitide restrains the osteoclast-like bone resorbing activity of myeloma plasma cells.

Cilengitide (CLG) is an inhibitor of both αv β3 and αv β5 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 αv β3 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.

Perspective in infertility: the ovarian stem cells.

Infertility is a medical and social condition that affects millions of women worldwide and is today considered so far as a new disease. A considerable progress has been recently pursued in the field of the reproductive medicine and the infertility treatment may account for novel and modern procedures such as in vitro oocyte fertilization, egg donation, pregnancy surrogacy and preimplantation diagnosis. However, great interest has lately been reserved to the ovarian stem cells (OSCs) whose existence in woman ovaries has been proven.

PTHrP produced by myeloma plasma cells regulates their survival and pro-osteoclast activity for bone disease progression.

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.