Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.

The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.

Different performance of platform switching in equicrestal position implant: an histological study.

OBJECTIVE: In this study we tested two different type of implant systems that were selected on the basis of differences in macrogeometry of platform switching in order to evaluate the behavior in term of BIC on the platform. MATERIAL AND METHOD: The patients were divided in two groups (Group I and II); group I was composed by 4 patients that each received in the posterior areas of mandible one type A implant (3,6 mm in diameter and 6,5 mm in length GTBPlan1Health Amaro (UD) Italy) one type B implant (4 mm in diameter and 8 mm in length OsseoSpeed Astra Tech, Dentsply Molndal, Sweden). Group II was composed by 3 patients that each received in the posterior areas of jawsbone one type A implant [3,6 mm in diameter and 6,5 mm in length GTB- Plan1Health Amaro, (UD), Italy] one type B implant (4 mm in diameter and 8 mm in length OsseoSpeed Astra Tech, Dentsply Molndal, Sweden). All the implants were placed, by the same operator, in equicrestal position using "one stage" technique with a healing abutment at an adequate gingival height. After 12 weeks of healing all the implants of both groups were harvested with the peri-implant bone tissues. BIC upon platform was calculated considering as implant surface the platform length. RESULTS: Our results showed that the mean percentage of BIC value related to platform surface placed in equicrestal position was higher in patients with type A implant than patients receiving type B implant independently from mandibular or maxillary positions. Moreover the mean percentage of BIC related to platform surface was significantly (p<0.05) higher in Group II/A than Group I/A. CONCLUSIONS: Our data highlights that the particular features of the Bioplatform of Type A implant systems guarantee a higher value of BIC even if the implants were placed equicrestally.

The influence of micro and macro-geometry in term of bone-implant interface in two implant systems: an histomorphometrical study.

OBJECTIVE: Many factors could affect the osseous healing of implants such as surface topography of biomaterial, the status of the bone/implant site, implant loading conditions, surgical technique and implant design. The aim of this study was to analyze the BIC of 2 different implants systems characterized by different micro and macrogeometry, that were placed in the posterior maxillary and mandibular jaws of humans, clinically unloaded and retrieved for histomorphometric analyses after 12 weeks. MATERIAL AND METHOD: The patients were divided in two groups (Group I and II); group I was composed by 4 patients that each received in the posterior areas of mandible one type A implant [GTB-Plan1Health Amaro (UD) Italy] one type B implant (OsseoSpeed Astra Tech, Dentsply Molndal, Sweden). Group II was composed by 3 patients that each received in the posterior areas of jawsbone one type A implant [GTB-Plan1Health Amaro (UD) Italy] one type B implant (OsseoSpeed Astra Tech, Dentsply Molndal, Sweden). After 12 weeks of healing all the implants of both groups were harvested with the peri-implant bone tissues. Osseointegration process was evaluated throughout measurements of BIC. RESULTS: No statistical significance differences were found among the mean percentage of BIC of Group I - type A were 66,51% versus 49,96% in Group I - type B, as well as among the mean percentage of BIC of Group II - type A were 43.7% versus 60.02% in Group II - type B. CONCLUSIONS: Our results highlight that the mean percentage of BIC after 12 weeks from the implants placement without functional loading is not influenced by the composition of the implant surface.

Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients.

This multicenter phase II trial evaluated the safety and efficacy of lenalidomide-prednisone (RP) induction, followed by lenalidomide-melphalan-prednisone (MPR) consolidation and RP maintenance in elderly unfit newly diagnosed myeloma patients. Patients received four 28-day RP induction courses (lenalidomide 25 mg/day on days 1-21 and prednisone 50 mg three times/week), followed by six 28-day MPR consolidation cycles (melphalan 2 mg, prednisone 50 mg three times/week and lenalidomide 10-15 mg/day on days 1-21), and maintenance with lenalidomide (10 mg/day on days 1-21 every 28 days) plus prednisone (25 mg three times/week). Forty-six patients were enrolled. Median age was 75 years, 59% of patients had at least one comorbidity and 35% at least two. Partial response rate was 80%, including 29% very good partial response. Median time to progression was 19.6 months, median progression-free survival was 18.4 months and 2-year overall survival was 80%. At the tolerated consolidation dose (melphalan 25 mg/month and lenalidomide 10 mg/day), the most frequent grade 3 adverse events were neutropenia (36.4%), anemia (12.1%), cutaneous reactions (18.2%) and infections (12.1%). Grade 4 neutropenia occurred in 12.1% of patients. In conclusion, RP induction followed by MPR consolidation and RP maintenance showed a manageable safety profile, and reduced the risk of severe hematological toxicity in unfit elderly myeloma patients.

Comparative assessment of telomere length before and after hematopoietic SCT: role of grafted cells in determining post-transplant telomere status.

Our objective was to characterize the role of grafted cells in determining telomere length (TL) after hematopoietic SCT (HSCT). A total of 20 patients undergoing autografts had PBSC collected after two sequential mobilization courses: TL in the first collection was significantly longer than in the second. For their autografts, 10 patients used PBSC from the first collection and 10 from the second. TL was also investigated before and after HSCT and on the graft in 10 allogeneic HSCT. After autografting, patients receiving PBSC from the first collection had BM TL reflecting that of grafted cells (median bp: 7730 on PBSC vs 7610 on post-HSCT BM, P=NS) and significantly longer than TL of the second collection; analogously, patients autografted with PBSC from the second collection had BM TL reflecting that of grafted cells (7360 on PBSC vs 7120 on post-HSCT BM, P=NS) and significantly shorter compared with the first collection. In the allograft setting, eight patients had their pre-transplant TL significantly shorter than donor PBSC (5960 vs 7110; P=0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P=NS). We conclude that grafted cells have a major role in determining TL after HSCT.

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia.

Telomere length (TL) has been associated with outcome in chronic lymphocytic leukemia (CLL). The aim of this extensive analysis carried out on 401 CLL patients was to assess TL conclusively as a prognostic biomarker. Our study included two cohorts used as learning (191 patients) and blinded validation series (210 patients). A TL cutoff of 5000 bp was chosen by receiver operating characteristic (ROC) analysis and Youden's index in the learning series. In this series, TL< or =5000 bp was independently associated to a worse outcome for both overall survival (OS; 105.5 vs 281 months, P<0.001) and treatment-free survival (TFS; 24.6 vs 73 months, P<0.001). In the blinded validation series, TL< or =5000 bp was confirmed as an independent outcome predictor for OS (79.8 vs not reached, P<0.001) and TFS (15.2 vs 130.8 months, P<0.001). Moreover, TL< or =5000 bp independently predicted the risk of Richter's syndrome (5-year risk: 18.9 vs 6.4%, P=0.016). Within CLL subsets defined by biological predictors, TL consistently identified patient subgroups harboring unfavorable prognosis. These results demonstrate that TL is a powerful independent predictor of multiple outcomes in CLL, and contributes to refine the prognostic assessment of this disease when utilized in combination with other prognostic markers. We thus believe that this prognostic biomarker has the potential for a more widespread use in CLL.

Treating maxillary horizontal atrophies with particulate homologous bone grafts: a case report.

Presentation of a clinical case characterized by an atrophic degeneration in the superior maxilla which is very common to observe in the daily routine and wants to demonstrate the excellent results achieved with bone regeneration procedures by using grafting material of a homologous derivation, in this case of a particulate type. In view of the results in here presented and of those achieved in more than 10 years of clinical experience with homologous material, it can be considered an excellent alternative to the autologous grating procedures; and this also thanks to the clinical and histologic behaviour that this material has previously showed in the orthopedic field. The simplicity of the surgical procedures, the reduced invasivity for the patient and the possibility for the clinician to regenerate even the smaller defects contestually to implants insertion, allow many clinicians to benefit of this technique in their own practices.

Comparing the TiOblast and Osseospeed surfaces. Histomorphometric and histological analysis in humans.

The aim of the present study was to compare two implant surfaces, the TiOblast (Astra Tech) surface, manufactured by blasting the surface and already present in literature and the Osseospeed (Astra Tech) surface, manufactured by blasting and treating the surface with fluoride ions and recently launched onto the market with the modified surfaces of the latest generation. This study is part of a more extensive research project whose protocol required the insertion of 10 couples of implants; thus in the present discussion partial data are being taken into consideration, with an eye at collecting more data in the future, regarding both microscopy and histomorphometric histological analysis on 5 couples of implants. The purpose of the study is to investigate how the modified surfaces of the latest generation can guarantee a greater osseointegration both from a qualitative and quantitative level compared to the surfaces presently used and that they may represent the first example of "bioactivity", that is, an active interaction with the processes of new bone formation and tissue healing.

Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients.

Some evidences suggest that telomere restriction fragment length (TRF-L) is an effective indicator of histopathogenesis in B-cell tumors. As histopathogenesis is relevant for B-cell chronic lymphocytic leukemia (B-CLL) prognosis, TRF-L was assessed by Southern blot in 201 patients and compared to variable immunoglobulin heave chain gene mutational status (VH-MS) and to other known prognostic features. Overall survival (OS), time to first treatment (TTFT) and progression-free survival (PFS) were evaluated. Our results indicate the following: (1) TRF-L is heterogeneous among B-CLL patients (median 6014 bp, range 1465-16 762); (2) TRF-L correlates to VH-MS (r(2)=0.1994, P<0.0001) with VH-mutated patients showing long and VH-unmutated short telomeres; however, 41% of VH-unmutated and 5% of VH-mutated patients did not show this correlation and were thus defined as 'discordant'; (3) TRF-L effectively predicts outcome in terms of TTFT, PFS and OS; (4) VH-unmutated discordant patients have a better clinical outcome than VH-unmutated concordant patients (OS P<0.01, PFS P<0.05) and similar to that of VH-mutated patients (OS, PFS P=NS). Compared to VH-unmutated concordant patients, VH-unmutated discordant patients showed no peculiarity in their immunoglobulin rearrangement nor in their flow cytometry or fluorescence in situ hybridization profile. In conclusion, TRF-L can be helpful to refine prognostication of B-CLL patients, particularly those with a VH-unmutated immunoglobulin sequence.

Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.

The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.

Pituitary function in chronic heart failure in the elderly.

Heart failure is a complex syndrome characterized by the activation of hemodynamic, immunologic and neurohormonal systems, which have beneficial effects in the short run, but will ultimately lead to secondary end-organ damage with worsening of LV remodeling and subsequent cardiac decompensation. A very important role seems to be played by modifications of the pituitary hormone systems. Due to the neurohormonal activation there is an increase in the activity in the renin angiotensin system, in the adrenergic nervous system, and in the cytokine system. In heart failure there is a decrease in many anabolic hormones, such as a decrease of GH and IGF-I, of DHEA/DHEAS with normal or increased F, and a decrease of LH and sex steroids, resulting in an important catabolic drive, capable of contributing to the development of cardiac failure and to sarcopenia and/or cachexia, frequently observed in the advanced stages of the disease. However, these hormone alterations have been described in relatively young patients with chronic heart failure, since the mean age of all the subjects studied was of about 60 yr and none of the studies have specifically addressed this issue in the very old patients, who represent the largest portion of population affected by this pathological condition. The role of hormone replacement therapy needs to be verified in a population of elderly patients with heart failure.