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Pievani A.,Laboratory Of Cellular Therapy G Lanzani | Borleri G.,Laboratory Of Cellular Therapy G Lanzani | Pende D.,Istituto Nazionale per la Ricerca sul Cancro | Moretta L.,Istituto Giannina Gaslini | And 3 more authors.
Blood | Year: 2011

CD3 +CD56 + cytokine-induced killer (CIK) cells display a potent cytolytic activity. The adhesion molecule lymphocyte function-associated antigen-1 plays a crucial role in binding as well as in cytolytic activity of CIK cells against tumor target cells expressing the corresponding ligands. CIK cells express activating natural killer (NK) receptors, including NKG2D, DNAX accessory molecule-1 (DNAM-1), and low levels of NKp30. Cell signaling not only through TCR/CD3 but also through NKG2D, DNAM-1, and NKp30 leads to CIK cell activation resulting in granule exocytosis, cytokine secretion, and cytotoxicity. Antibody blocking experiments showed that DNAM-1, NKG2D, and NKp30 are involved in the TCR-independent tumor cell recognition and killing. Anti-CMV-specific CIK cells could be expanded in standard CIK cultures and mediate both specific, MHC-restricted recognition and TCR-independent NK-like cytolytic activity against leukemic cell lines or fresh leukemic blasts. Antibody blocking of lymphocyte function-associated antigen-1 and DNAM-1 led to significant reduction of both CTL and NK-cell functions, whereas blocking of NKG2D and NKp30 only inhibited NK-like cytotoxicity. Their dual-effector function suggests that CIK cells, when used in a clinical setting, may control both neoplastic relapses and viral infections, 2 frequently associated complications in patients who received a transplant. © 2011 by The American Society of Hematology.


Moretta L.,Istituto Giannina Gaslini | Moretta L.,University of Genoa | Locatelli F.,University of Pavia | Pende D.,Istituto Nazionale per la Ricerca sul Cancro | And 3 more authors.
Blood | Year: 2011

Natural killer (NK) cells are key members of the innate immune system. In a self-environment, they sense and kill target cells lacking major histocompatibility complex class I molecules and release various cytokines on activation. The discovery of human leukocyte antigen (HLA) class I specific inhibitory receptors (including the allotype-specific killer immunoglobulin-like receptors), and of various activating receptors and their ligands, provided the basis for understanding the molecular mechanism of NK-cell activation and function, mainly resulting from the balance between activating and inhibitory signals. In an allogeneic setting, such as T cell-depleted haploidentical hematopoietic stem cell transplantation, NK cells may express inhibitory killer immunoglobulin-like receptors that are not engaged by any of the HLA class I alleles present on allogeneic cells. Such "alloreactive" NK cells greatly contribute both to eradication of leukemia blasts escaping the preparative regimen and to clearance of residual host dendritic cells and T lymphocytes (thus preventing graft-versus-host disease and graft rejection, respectively). Improved prevention of graft-versus-host disease might be achieved by redirecting to lymph nodes adoptively transferred, alloreactive NK cells by inducing CCR7-uptake in vitro. Recent studies suggested that, after immune-suppressive therapy, alloreactive NK cells from an HLA-haploidentical donor may prevent leukemia recurrence also in patients who have not received allogeneic hematopoietic stem cell transplantation. © 2011 by The American Society of Hematology.


Siclari A.,Struttura Complessa di Ortopedia e Traumatologia | Mascaro G.,Servizio di Immunoematologia e Medicina Trasfusionale | Gentili C.,Istituto Nazionale per la Ricerca sul Cancro | Cancedda R.,University of Genoa | Boux E.,Struttura Complessa di Ortopedia e Traumatologia
Clinical Orthopaedics and Related Research | Year: 2012

Background: Bone marrow stimulation techniques in cartilage repair such as drilling are limited by the formation of fibrous to hyaline-like repair tissue. It has been suggested such techniques can be enhanced by covering the defect with scaffolds. We present an innovative approach using a polyglycolic acid (PGA)-hyaluronan scaffold with platelet-rich-plasma (PRP) in drilling. Questions/purposes: We asked whether (1) PRP immersed in a cell-free PGA-hyaluronan scaffold improves patient-reported 1-year outcomes for the Knee injury and Osteoarthritis Score (KOOS), and (2) implantation of the scaffold in combination with bone marrow stimulation leads to the formation of hyaline-like cartilage repair tissue. Patients and Methods: We reviewed 52 patients who had arthroscopic implantation of the PGA-hyaluronan scaffold immersed with PRP in articular cartilage defects of the knee pretreated with Pridie drilling. Patients were assessed by KOOS. At 9 months followup, histologic staining was performed in specimens obtained from five patients to assess the repair tissue quality. Results: The KOOS subscores improved for pain (55 to 91), symptoms (57 to 88), activities of daily living (69 to 86), sports and recreation (36 to 70), and quality of life (38 to 73). The histologic evaluation showed a homogeneous hyaline-like cartilage repair tissue. Conclusions: The cell-free PGA-hyaluronan scaffold combined with PRP leads to cartilage repair and improved patient-reported outcomes (KOOS) during 12 months of followup. Histologic sections showed morphologic features of hyaline-like repair tissue. Long-term followup is needed to determine if the cartilage repair tissue is durable. Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. © 2011 The Association of Bone and Joint Surgeons®.


Grossi F.,Istituto Nazionale per la Ricerca sul Cancro
Drugs | Year: 2012

Disease stabilization after first-line chemotherapy, also known as induction chemotherapy, is defined, according to the Response Evaluation Criteria in Solid Tumours (RECIST), as having neither sufficient shrinkage to qualify as a partial response (PR) nor sufficient increase to qualify as progressive disease (PD). In oncology, stable disease (SD) has often been viewed as an equivocal result and is therefore of unclear clinical value. In SD patients with advanced non-small cell lung cancer (NSCLC)who have already received four cycles of first-line chemotherapy with platinum agents plus a third-generation agent (gemcitabine, vinorelbine, docetaxel or paclitaxel) or pemetrexed, the continuation of the original treatment is not recommended according to the American Society of Clinical Oncology (ASCO) guidelines. The ASCO guidelines recommend maintenance with bevacizumab or cetuximab, as tolerated until progression, only for platinum-based chemotherapy combined with bevacizumab or cetuximab. Several trials and a meta-analysis have, however, suggested a role for maintenance treatment in patients without progression after induction chemotherapy. The National Comprehensive Cancer Network guidelines recently suggested that maintenance therapy may be considered after four to six cycles of induction platinum doublets for patients with tumour responses or SD, and recommended first-line treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutated patients to continue until PD. More recently, two randomized clinical trials that compared pemetrexed or erlotinib with a placebo demonstrated a better overall survival in favour of maintenance therapy. In subgroup analyses for both trials, patients with SD after first-line induction chemotherapy had pronounced survival benefits when erlotinib or pemetrexed maintenance therapy was given, although this result was not achieved in patients with a complete response or PR after induction chemotherapy. The management of patients with SD after first-line chemotherapy is an important issue because only a minority of patients with advanced NSCLC experience tumour shrinkage after standard platinum-based chemotherapy. Many more patients experience either SD or PD. The notion that the prognosis of SD patients varies greatly due to the complexity of SD should, however, be taken into careful consideration for the treatment decision. Therefore, suggestions for the further classification of SD are urgently needed to enable the use of an alternative therapy at an early time. Adis © 2012 Springer International Publishing AG. All rights reserved.


Grant
Agency: Cordis | Branch: FP7 | Program: CSA-CA | Phase: HEALTH-2007-2.4.1-5 | Award Amount: 3.22M | Year: 2008

The project aims to explore, share and collate existing knowledge and practice in each of the key themes identified within the work programme. It aims to reach consensus (based on current practice and available research evidence) on the optimum care to be delivered in the last days of life and gaps in the knowledge base. In addition, it aims to develop innovative ways of addressing gaps in knowledge with the specific aim of improving care for cancer patients in the last days of life. Clearly, such improvements would also impact positively on their informal carers and health professionals delivering the care. Importantly, it aims to do this systematically and collaboratively across Europe and beyond to integrate knowledge from a range of healthcare enviroments and cultures and to avoid duplication of resource and effort.

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