Knowledge and attitude of pain management among Italian nurses in intensive care unit: a multicentric descriptive study.

Aim: The main objective of the study was to document the current knowledge and attitudes towards pain management among Italian nurses working in intensive care unit (ICU). Methods: A multicenter cross-sectional study design was carried out. In order to assess the knowledge and attitudes of pain management, the KASRP questionnaire was used. The questionnaire was submitted online through Google Forms platform. Results: A total of 864 nurses completed and returned the study questionnaire (58% were males). The mean of the total correct answers was 31.21 (SD 2.92) out of 40 (total score if all items answered correctly) with range of 22-38. No significant differences were observed with regard to gender (t = 1.875, P = .061). Spearman's correlation test showed a positive significant relationship between knowledge and attitude of pain management and years of ICU experience (r = -.424, P <.001) and between knowledge and attitude of pain management and the attendance of a pain update course in the last 3 years (r= -0.83, P =.014). We haven't found any correlation neither between age and knowledge nor between age and attitude score (r = -0.32, P = .351). Conclusions: This study has shown that Italian ICU nurses have good level of pain management knowledge and attitudes of pain medication. It is recommended to consider pain management in the context of continuing professional development.

Incidence of pain at rest and during nursing procedures in ICU patients: a longitudinal observational study.

AIM: To evaluate pain monitoring in surgical and no-surgical ICU patients and to observe the presence of pain at rest and during nursing procedures. METHODS: A longitudinal, observational study was conducted at an intensive care unit in Italy. Based on the specific conditions of the patient the best rating scale was used (Numerical Rating Scale or the Critical-Care Pain Observation Tool). Two ICU nurses performed pain assessments before and during some nursing procedures that are considered nociceptive. RESULTS: The pain incidence rate in 1,602 days of observation was 0.06 patient/day (59/1000 days of observation). The incidence rate of intense pain was 0.012 patient/day (12/1000 days of observation). Pain at rest was detected in 67 (27.6%) patients. Pain during procedures was found 134 (36.1%) times. In the 96 patients who were in pain the ICU stay (15.4 days + 7.8 vs 11.4 days + 5.6) and the days of mechanical ventilation (13.4 + 7.9 vs 9.7 + 4.9) was increased. Surgical patients had an increased pain risk than non-surgical patients (RR = 2.7, CI = 2.0-3.6; p<.001). CONCLUSIONS: The incidence of pain was recorded in 39.5% of ICU patients. However further studies of larger patient samples are needed.

Root surface alterations following manual and mechanical scaling: A comparative study.

OBJECTIVES: The aim of this study was to investigate the morphological and surface roughness changes in dental root samples following periodontal scaling by hand curette, piezoelectric ultrasonic devices or a combination of these. METHODS: Twenty-four monoradicular teeth extracted as a result of periodontal disease were divided into 4 groups: Group A was treated by piezoelectric ultrasonic scaler Piezon® Master 400; Group P by piezoelectric ultrasonic scaler PiezoSmart® ; Group C using Gracey curette 7/8; Group AC by a combined technique of piezoelectric ultrasonic scaler Piezon® Master 400 and Gracey curette 7/8. The treated samples were then analysed using a white light interferometer and scanning electron microscopy (SEM). RESULTS: Roughness analysis revealed major surface alterations in Group C (Sa  = 24.98 µm); the samples treated using the combined technique (Group AC) showed reduced but still significant alteration (Sa  = 14.48 µm), while samples treated with the piezoelectric ultrasonic devices (Group A and Group P) presented the lowest roughness values (Sa  = 8.99 and Sa  = 4.45 µm, respectively). A significant difference was found between groups C and P (P = 0.036). SEM analysis confirmed the roughness analysis revealing non-homogeneous surfaces in Group C, while a less morphological alteration was noted in the other groups. CONCLUSION: All periodontal devices used in this in vitro study produced a certain degree of surface alteration. Hand curettes appear to have a major impact on surface integrity compared with piezoelectric ultrasonic devices.

Early application of percutaneous vertebroplasty reduces pain without affecting peripheral blood stem cell (PBSC) collection and transplant in newly diagnosed multiple myeloma (MM) patients.

Vertebral fractures occur in over 60% of newly diagnosed multiple myeloma (MM) patients and can cause pain, disability and poor quality of life. Antimyeloma therapy can lead to symptoms improvement, but these effects can take time to be perceived. Application of radiotherapy prior to peripheral blood stem cells (PBSC) mobilisation can impair stem cell collection. Percutaneous vertebroplasty has been proposed as a suitable option to rapidly relieve bone pain from vertebral fractures in MM patients, but, little is known about the effects of this procedure on subsequent PBSC mobilisation, collection and transplant. Eighteen patients (10M/8F, median age 64.5 years) with untreated MM and painful vertebral lesions underwent vertebroplasty prior to proceed to the planned transplant program at our Institution. Forty-one procedures were performed at C2-L5 levels, eight patients were treated at ≥2 levels. Ninety-five per cent of the cases obtained a complete or optimal pain control. All the patients successfully mobilised PBSC (median CD34+ cells = 10.8 × 10(6) /kg) and underwent autologous PBSC transplant; both polymorphonucleates and platelets recovery averaged 11 days. Our data seem to suggest that percutaneous vertebroplasty is useful in newly diagnosed MM patients with painful vertebral fractures as it allows rapid and durable achievement of pain control, without interfering with further treatment.

Boron neutron capture therapy for oral precancer: proof of principle in an experimental animal model.

OBJECTIVES: Field-cancerized tissue can give rise to second primary tumours, causing therapeutic failure. Boron neutron capture therapy (BNCT) is based on biological targeting and would serve to treat undetectable foci of malignant transformation. The aim of this study was to optimize BNCT for the integral treatment for oral cancer, with particular emphasis on the inhibitory effect on tumour development originating in precancerous conditions, and radiotoxicity of different BNCT protocols in a hamster cheek pouch oral precancer model. MATERIALS AND METHODS: Groups of cancerized hamsters were locally exposed to single or double (2 or 4 weeks apart) applications of BNCT at different dose levels, mediated by the boron compounds boronophenylalanine (BPA) or BPA and decahydrodecaborate (GB-10) administered jointly. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumour development from field-cancerized tissue and mucositis were followed for 8 months. RESULTS: A double application (4 weeks apart) of BNCT mediated by GB-10+ BPA at a total dose of 10 Gy in two 5-Gy doses rendered the best therapeutic advantage (63-100% inhibition of tumour development from field-cancerized tissue), minimizing dose-limiting mucositis. CONCLUSION: BNCT can be optimized for the integral treatment for head and neck cancer, considering the implications for field-cancerized tissue.

Mitochondrial electron transport and glycolysis are coupled in articular cartilage.

OBJECTIVE: Although the majority of the adenosine triphosphate (ATP) in chondrocytes is made by glycolysis rather than by oxidative phosphorylation in mitochondria there is evidence to suggest that reactive oxygen species produced by mitochondrial electron transport (ET) help to maintain cellular redox balance in favor of glycolysis. The objective of this study was to test this hypothesis by determining if rotenone, which inhibits ET and blocks oxidant production inhibits glycolytic ATP synthesis. DESIGN: Bovine osteochondral explants were treated with rotenone, an ET inhibitor; or oligomycin an ATP synthase inhibitor; or 2-fluoro-2-deoxy-D-glucose, a glycolysis inhibiter; or peroxide, an exogenous oxidant; or mitoquinone (MitoQ), a mitochondria-targeted anti-oxidant. Cartilage extracts were assayed for ATP, nicotine adenine dinucleotide (NAD+/H), and culture medium was assayed for pyruvate and lactate after 24 h of treatment. Imaging studies were used to measure superoxide production in cartilage. RESULTS: Rotenone and 2-FG caused a significant decline in cartilage ATP (P < 0.001). In contrast, ATP levels were not affected by oligomycin. Peroxide treatment blocked rotenone effects on ATP, while treatment with MitoQ significantly suppressed ATP levels. Rotenone and 2-FG caused a significant decline in pyruvate, but not in lactate production. NADH:NAD+ ratios decreased significantly in both rotenone and 2-FG-treated explants (P < 0.05). Rotenone also significantly reduced superoxide production. CONCLUSIONS: These findings showing a link between glycolysis and ET are consistent with previous reports on the critical need for oxidants to support normal chondrocyte metabolism. They suggest a novel role for mitochondria in cartilage homeostasis that is independent of oxidative phosphorylation.

Circulating cytokines present in the serum of peripheral arterial disease patients induce endothelial dysfunction.

Peripheral arterial disease (PAD) is a chronic condition caused by atherosclerosis and is a severe complication of type 2 diabetes (T2D). We hypothesised that chronic condition of arterial disease engenders inflammation and endothelial damage in response to circulating cytokines released in the blood stream of PAD patients. We explored the levels of circulating cytokines in PAD patients with and without diabetes by multiplex cytokine array compared with non-PAD controls. Serum from PAD patients with or without diabetes showed high levels of VEGF, IFN-gamma, TNF-alpha, MCP-1, and EGF. VEGF levels correlated with TNF-alpha and IFN-gamma, significantly. Endothelial cells (ECs) were exposed to the different altered cytokines to evaluate changes in cell growth, migration and tubule-like formation, displaying impairment on proliferation, migration and tubule formation. Our findings demonstrate that a set of cytokines is significantly increased in the serum of PAD patients. These cytokines act to induce endothelial dysfunction synergistically. VEGF strongly correlated with TNF-alpha and IFN-gamma, opening new therapeutic perspectives.

Inositol activity in oligoasthenoteratospermia--an in vitro study.

BACKGROUND: Oligoasthenoteratospermia, a reduction in motilty and number of spermatozoa and a change in their morphology, is one of the most relevant causes of infertility in men. One of the factors, which may influence male infertility is linked to the production of reactive oxygen species (ROS) by morphologically altered spermatozoa. Spermatozoa are more susceptible than other cell species to the detrimental activity of these chemical compounds. In particular ROS can affect motility, morphology and DNA stability of spermatozoa. AIM: In the present in vitro study the role of a natural substance, inositol, has been investigated as a possible antioxidant agent both for the systemic treatment of male infertility and for the improvement in the in vitro quality of the sperm used for the fertilization applied to medically assisted reproductive procedures. MATERIALS AND METHODS: The collected samples, belonging to subjects suffering from oligoasthenoteratospermia and of healthy subjects were submitted to phase constrast microscopy in order to evaluate spermatozoa motility, treated with inositol 2 mg/ml and then submitted to scansion electron microscopy (SEM) and to transmission electron microscopy (TEM). SEM allowed to study both the surface morphology of the biological samples and the changes induced on them by the treatment with inositol. TEM allowed to study ultrastructural details of the biological samples. RESULTS: In the samples of subjects suffering from oligoasthenoteratospermia the spermatozoa appear entirely covered with an amorphous fibrous material, that gives an excessive viscosity to the seminal fluid, and reduces or avoids cell mobility. The micrographs of these samples show that the mitochondria, in their intermediate tract, appear to be altered with markedly damaged cristae. After treatment with inositol the pathologic samples clearly shows the absence of the amorphous material, perhaps due to a variation in seminal fluid pH. Furthermore, they show the presence of mitochondria morphologically more similar to control specimen mitochondria, with less damage involving mitochondrial cristae. CONCLUSIONS: These preliminary data appear to suggest that inositol, on account of its antioxidant activity, could preferentially aim at the mitochondrium. Further studies are requested to the purpose of better defining the combination between ROS values of the samples, inositol in vitro treatment and oligoasthenoteratospermia.

Shifting from open surgical cut down to ultrasound-guided percutaneous central venous catheterization in children: learning curve and related complications.

PURPOSE: Tunneled indwelling central venous catheters (CVC) are essential in the management of children with cancer, hematological, nephrological disorders and for parenteral nutrition. The aim of this study is to present the experience of a single center of the transition from traditional open surgical cut down procedure (OSC) to ultrasound (US)-guided percutaneous CVC insertion, focusing on learning curve and related complications. METHODS: All CVCs inserted between April 2008 and November 2009 in children at the Gaslini Children Hospital were revised, and data on methods of cannulation, intraoperative and device-related complications and re-intervention were recorded. RESULTS: 194 CVCs were positioned in 188 patients. 128 out of 194 CVCs were positioned through an OSC technique, whereas the remaining 66 CVCs were inserted percutaneously with US guidance. Of the 27 recorded complications, 15 were mechanical events, 7 cases developed infection, whereas the remaining 5 (2.6%) were classified as intraoperative complications. A second surgical procedure was described in 23 (11.8%) cases. CONCLUSION: Shifting from OSC to US-guided percutaneous CVC insertion inevitably involves a challenging learning curve which is generally associated with high complication rates. Complications progressively decrease once a good experience in US guidance and percutaneous technique has been obtained.

Study of the correlation between microfauna and the macrostructure of activated sludge and the efficiency of biological wastewater treatment plants.

Assessment of protozoan populations is an important tool in evaluating the efficiency of activated sludge in the treatment of wastewater. In this process, protozoa play a significant role by grazing on dispersed bacteria, supporting a healthy food web in activated sludge artificial ecosystems. The objective of this study was to verify how the success of the purification process in activated sludge plants, mainly in terms of TSS, BOD, and COD, is related to ciliate protozoa communities and the presence of filamentous bacteria. Samples were collected from five water treatment plants in the Puglia region, in the period May 2007 - April 2008. Microfauna and filamentous bacteria were identified and quantified, and the sludge biotic index calculated. The data show a correlation between the biological components of activated sludge and traditional chemical parameters. Our results indicate that biological analyses represent a valid alternative to traditional chemical testing in assessing the performance of activated sludge systems.

Interaction of vault particles with estrogen receptor in the MCF-7 breast cancer cell.

A 104-kD protein was coimmunoprecipitated with the estrogen receptor from the flowtrough of a phosphocellulose chromatography of MCF-7 cell nuclear extract. mAbs to this protein identified several cDNA clones coding for the human 104-kD major vault protein. Vaults are large ribonucleoprotein particles of unknown function present in all eukaryotic cells. They have a complex morphology, including several small molecules of RNA, but a single protein species, the major vault protein, accounts for >70% of their mass. Their shape is reminiscent of the nucleopore central plug, but no proteins of known function have been described to interact with them. Western blot analysis of vaults purified on sucrose gradient showed the presence of estrogen receptor co-migrating with the vault peak. The AER317 antibody to estrogen receptor coimmunoprecipitated the major vault protein and the vault RNA also in the 20,000 g supernatant fraction. Reconstitution experiments of estrogen receptor fragments with the major vault protein mapped the site of the interaction between amino acids 241 and 280 of human estrogen receptor, where the nuclear localization signal sequences are located. Estradiol treatment of cells increased the amount of major vault protein present in the nuclear extract and coimmunoprecipitated with estrogen receptor, whereas the anti-estrogen ICI182,780 had no effect. The hormone-dependent interaction of vaults with estrogen receptor was reproducible in vitro and was prevented by sodium molybdate. Antibodies to progesterone and glucocorticoid receptors were able to coimmunoprecipitate the major vault protein. The association of nuclear receptors with vaults could be related to their intracellular traffic.

Forum on: the role of recombinant factor VIII in children with severe haemophilia A.

The development of recombinant FVIII (rFVIII) products, fuelled by the need for improved safety of treatment arising from the dramatic widespread blood-borne virus transmission in the 1970-1980s revolutionized the care of children with haemophilia A over the last two decades. The larger availability of perceived safer replacement therapy associated with the introduction of rFVIII products reassured the haemophilia community and there was a strong push in some Western countries to treat haemophilic children only with rFVIII. Moreover, this significantly contributed in the 1990s to the diffusion outside Northern Europe of prophylactic regimens implemented at an early age to prevent bleeding and the resultant joint damage (i.e. primary prophylaxis), together with the possibility of home treatment. These changes led to a substantial improvement of the quality of life of haemophilic children and of their families. The general agreement that primary prophylaxis represents the first-choice treatment for haemophilic children has been recently supported by two randomized controlled trials carried out with rFVIII products, providing evidence on the efficacy of early prophylaxis over on-demand treatment in preserving joint health in haemophilic children. However, the intensity and optimal modalities of implementation of prophylaxis in children, in particular with respect to the issue of the venous access, are still debated. A number of studies also supports the role of secondary prophylaxis in children, frequently used in countries in which primary prophylaxis was introduced more recently. With viral safety now less than an issue and with the more widespread use of prophylaxis able to prevent arthropathy, the most challenging complication of replacement therapy for children with haemophilia remains the risk of inhibitor development. Despite conflicting data, there is no evidence that the type of FVIII concentrate significantly influences the complex multifactorial process leading to anti-FVIII alloantibodies, whereas other treatment-related factors are likely to increase (early intensive treatments due to surgery or severe bleeds) or reduce (prophylaxis) the risk. Although the optimal regimen is still uncertain, eradication of anti-FVIII antibodies by immune tolerance induction (ITI), usually with the same product administered at inhibitor detection, should be the first-choice treatment for all patients with recent onset inhibitors. This issue applies particularly to children, as most patients undergo ITI at an early age, when inhibitors usually appear. The availability of a stable and long-lasting venous access represents a leading problem also in this setting. These and other topics concerning rFVIII treatment of haemophilic children were discussed in a meeting held in Rome on 27 February 2008 and are summarized in this report.

Management and investigation of neonatal thromboembolic events: genetic and acquired risk factors.

Newborns comprise the largest group of children developing thromoboembolic events (TE(S)), due to the peculiarities of their developmental hemostatic system. Moreover, in the sick newborn, especially preterm, numerous acquired perinatal and iatrogenic conditions might result in a disturbance between coagulation and fibrinolysis, leading to thrombus formation. Nevertheless, the contribution of acquired prothrombotic disorders in the pathogenesis of thromboembolic disease in newborns remains poorly defined. Few data are currently available regarding the influence of maternal or fetal genes on thrombotic risk in the fetus and neonate. Ongoing National and International registries are partially answering these questions. The purpose of this review is to evaluate the current knowledge about the role of inherited, acquired perinatal and maternal prothrombotic risk factors in neonatal cerebral nervous system (CNS) thrombotic events and non-CNS thrombotic events.

Incidence of indwelling central venous catheter-related complications using the Sri Paran technique for device fixation in children with cancer.

PURPOSE: Mechanical complications in tunneled indwelling central venous catheters (CVCs) often involve a risk of displacement. Fixation procedures are, therefore, of primary importance. We prospectively evaluated the incidence of CVC-related mechanical and infectious complications observed in devices fixated with the Sri Paran technique. METHODS: All CVCs inserted in children with cancer at our Institution from October 2005 to January 2007 were prospectively monitored for device-related mechanical and infectious complications. The Sri Paran fixation technique was used in all cases. The complication rate per 1,000 days was calculated as 1,000 times the number of complications divided by the total number of catheter days. RESULTS: Ninety-five CVCs were positioned in 84 children. The overall length of observation ranged between 41 and 482 days for a total of 18,618 catheter days. Mechanical complications occurred in 5% of the devices (specific rate 0.27); infections were observed in 6% of the devices (specific rate 0.32). No complications were observed during the first 30 days after CVC insertion. CONCLUSIONS: The results, we obtained with the Sri Paran technique are extremely encouraging. Yet, randomized studies are required to prove these preliminary data.

Geostatistical multimodel approach for the assessment of the spatial distribution of natural background concentrations in large-scale groundwater bodies.

Quantification of the (spatially distributed) natural contributions to the chemical signature of groundwater resources is an emerging issue in the context of competitive groundwater uses as well as water regulation and management frameworks. Here, we illustrate a geostatistically-based approach for the characterization of spatially variable Natural Background Levels (NBLs) of target chemical species in large-scale groundwater bodies yielding evaluations of local probabilities of exceedance of a given threshold concentration. The approach is exemplified by considering three selected groundwater bodies and focusing on the evaluation of NBLs of ammonium and arsenic, as detected from extensive time series of concentrations collected at monitoring boreholes. Our study is motivated by the observation that reliance on a unique NBL value as representative of the natural geochemical signature of a reservoir can mask the occurrence of localized areas linked to diverse strengths of geogenic contributions to the groundwater status. We start from the application of the typical Pre-Selection (PS) methodology to the scale of each observation borehole to identify local estimates of NBL values. The latter are subsequently subject to geostatistical analysis to obtain estimates of their spatial distribution and the associated uncertainty. A multimodel framework is employed to interpret available data. The impact of alternative variogram models on the resulting spatial distributions of NBLs is assessed through probabilistic weights based on model identification criteria. Our findings highlight that assessing possible impacts of anthropogenic activities on groundwater environments with the aim of designing targeted solutions to restore a good groundwater quality status should consider a probabilistic description of the spatial distribution of NBLs. The latter is useful to provide enhanced information upon which one can then build decision-making protocols embedding the quantification of the associated uncertainty.

Intratumoral vs systemic administration of meta-tetrahydroxyphenylchlorin for photodynamic therapy of malignant gliomas: assessment of uptake and spatial distribution in C6 rat glioma model.

Malignant gliomas, with an incidence of 5 cases per 100,000 population per year, represent the most common primary brain tumour. They have an overall survival length of less than 2 years. Many different adjuvant therapies have been developed. Among them, Photodynamic Therapy (PDT), that is based on photochemical reactions between light and tumoral tissue selectively labelled with exogenous photosensitizing agents. Among photosensitizers, m-THPC (Temoporfin), seems to be the most promising one for the treatment of brain tumors, but, unfortunately, it causes problems of high skin photosensitivity. To by-pass this problem, we devised an intratumoral route of administration of this photosensitizer. The aim of this study is to investigate and compare the uptake of m-THPC in brain tumor and normal tissue after systemic and intratumoral administration of the drug. 30 female Wistar rats received m-THPC 12 days after C6 tumor implantation. Temoporfin was administered intratumorally in 24 rats at two different concentrations. 6 rats constituted the control group and received m-THPC by means of an intraperitoneal injection. The brains were extracted at 4 h, 24 h and 96 h after Temoporfin injection. The samples were examined with a confocal laser scanning microscope. All samples showed high fluorescence emission exclusively in the tumour area, without appreciable differences between the samples taken at the different times of sacrifice and the two routes of administration. No fluorescence whatsoever was detected among normal brain tissue surrounding the tumour. The intratumoral route appears to give comparable results to the systemic one, regarding intracellular uptake efficiency and tumour--normal tissue ratio, with the advantage of a much shorter time needed to reach optimal intratumoural concentration--that is just four hours from m-THPC injection.

Deep vein thrombosis: a mininvasive locoregional thrombolytic treatment.

AIM: Locoregional thrombolytic therapy has emerged in the last years as the treatment of choise for iliofemoral deep vein thrombosis, preserving the structural and functional integrity of vein walls. We studied the efficacy and complication rates of direct regional thrombolytic therapy in acute venous thrombosis of lower extremities. METHODS: Between January 2002 and March 2007, 8 selected patients with acute extensive and symptomatic iliofemoral or femoral-popliteal venous thrombosis were treated with flow-direct regional thrombolytic therapy. We used a direct regional infusion of urokinase into the deep venous system ( 100.000 U al presentation, then 75.000 U/ h) from an ipsilateral dorsal foot vein . Simultaneously the superficial venous system was collapsed with elastic limb compression while administering subtherapeutic heparin doses of 300-400 U/h. All patients underwent routine venous duplex imaging at day 1, 2, 30 and after 3, 6 and 12 months. Data including clinical conditions and laboratory values (fibrinogen, hematocrit, haemoglobin, platlets and prothrombin time) were obtained throughout the infusion time. Results. Procedural success was achieved in all patients (100%). Complete recanalization, patency and continence of venous system documented at the echocolorDoppler control, were obtained in 48 hours, with symptom remission. Mean infusion time was 37.5 hours (28-48 hours). Neither major bleeding complications nor pulmonary embolisms occurred during the treatment. At day 30 venous patency and incontinence and long-term symptom resolution were achieved in all patients, as well as at 3, 6 and 12 months. CONCLUSIONS: Loco-regional thrombolytic therapy is safe and effective in selected patients and may become a well-founded alternative in the treatment of acute deep vein thrombosis of lower extremities and in the prevenction of its complications .

Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials.

Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R-CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III-IV. At a median follow-up of 5.1 years, 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4-5 late toxicities. Grade ≤ 3 toxicities were infections (N = 4), thrombosis (N = 1) and neuropathy (N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low.

The physiological role of biogenic amines redox reactions in mitochondria. New perspectives in cancer therapy.

In tumours, polyamines and amine oxidases increase as compared to normal tissues. Cytotoxicity induced by bovine serum amine oxidase (BSAO) and spermine is attributed to H2O2 and aldehydes produced by the reaction. Increasing the incubation temperature from 37 to 42 degrees C enhances cytotoxicity in cells exposed to spermine metabolites. The combination BSAO/spermine prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. Since the tumour cells release endogenous substrates of BSAO, the administration of spermine is not required. Combination with hyperthermia improves the cytocidal effect of polyamines oxidation products. Our findings show that multidrug resistant (MDR) cells are more sensitive to spermine metabolites than their wild-type counterparts, due to an increased mitochondrial activity which induces the generation of intracellular ROS prior to the onset of mitochondrial permeability transition (MPT). It makes this new approach attractive, since the development of MDR is one of the major problems of conventional cancer therapy.