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Breast milk is the natural source of nutrition for infants, but while it supports their health, it can also be a potential source of toxic inorganic particulate matter, and this applies to both breast milk and industrially produced milk. The aim of the present study was to evaluate the presence of nanoparticles in both breast milk and formula milk samples. We collected and analyzed, via a new electron scanning microscopic procedure, 19 samples of breast milk from Italian women and 19 formula milk samples produced by different companies. Organic-inorganic agglomerates were detected in 58% of formula and in 63% of breast milk samples, respectively. In addition, a significantly ( p < 0.05) greater size of nanoparticles was observed in formula milk samples. The results, showing the presence of inorganic nanosized particles in breast and artificial milk, may lead to future studies aimed at investigating possible nanosized contamination of milk and identifying early prevention strategies for women and animals involved in the food chain.

Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25-2000 μM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.

Aim: Verify the presence of inorganic nanoparticle entities in brain tissue samples from sudden infant death syndrome (SIDS)/sudden intrauterine unexplained death syndrome (SIUDS) cases. The presence of inorganic debris could be a cofactor that compromises proper brain tissue functionality. Materials & methods: A novel autopsy approach that consists of neuropathological analysis procedures combined with energy dispersive spectroscopy/field emission gun environmental scanning electron microscopy investigations was implemented on 10 SIDS/SIUDS cases, whereas control samples were obtained from 10 cases of fetal/infant death from known cause. Results: Developmental abnormalities of the brain were associated with the presence of foreign bodies. Although nanoparticles were present as well in control samples, they were not associated with histological brain anomalies, as was the case in SIDS/SIUDS. Conclusion: Inorganic particles present in brain tissues demonstrate their ability to cross the hemato-encephalic barrier and to interact with tissues and cells in an unknown yet pathological fashion. This gives a rationale to consider them as cofactors of lethality.

We report, for the first time, the surprising presence of toxic nanoparticles, especially silver, in the brain of a fetus, who died unexpectedly at the end of a regular pregnancy. After an accurate autopsy, including the examination of the fetal annexes, an in-depth anatomopathological study of the nervous system and a search by scanning electron microscopy of nanoparticles in the brain, we highlighted the sequence of events that may have led to this fetal death, triggered primarily by the transition of nanosized xenobiotics from the mother to the fetal bloodstream. From this report emerges the importance of considering the search of nanosubstances in the brain during routine investigations following unexpected and unexplained fetal and infant deaths.

The impact of nanopathology in medicine necessarily involves also the anatomo-pathological diagnostics, because of the current large spread of nanoparticles in the environment and the wide spectrum of correlated human diseases. The main entrance gates of nanoparticles into the body are respiratory inhalation, gastro-intestinal absorption and injection of polluted drugs. In all these cases, their penetration in the lymphatic or blood streams are possible, with subsequent systemic translocation. Different diseases can be generated by nanoparticles exposure, from a direct contact irritation to the onset of granulomatous diseases. Interestingly, they can also act as endocrine disruptors on the autocrine and paracrine systems. At cellular level, nanoparticles can damage the DNA content leading to a subsequent tumorigenesis. In the forensic setting, they can be searched in case of known exposure to inorganic particulate matter or in case of diseases of unknown origin, from granulomatous reactions to foreign inclusions in neoplastic tissues. The combined physical-histopathological studies allow to relate possible environmental/industrial pollution with the pathology and offer a novel tool for forensic investigations, but, overall, they represent new technical evidences for lawyers to present in a court., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rare earth metals (REM) are a group of 17 chemical elements in the periodic table, namely scandium (Sc), yttrium (Y) and the lanthanides. In relation to atomic volume and geological behavior, the lanthanides are further subdivided into light, medium and heavy REM. They find many applications in the technological field; however, their impact on the human health is still conflicting and, for many aspects, unknown. During a research program carried on 113 cases of female breast cancer, immunohistochemically categorized in Her2-positive (29 cases), Her2-negative (57 cases) and triple negative (27 cases), aimed to evaluate the role of environmental particulate in carcinogenesis by elemental microanalysis, for the first time in literature we have detected a REM uptake, in detail europium (Eu), dysprosium (Dy) and praseodymium (Pr), inside the neoplastic cells belonging to a single triple negative breast cancer. Curiously, the woman affected by this form of malignancy had worked in the ceramic industry, a well-known source of REM, during her life, and she was the one and only patient of our series to be dedicated to this activity. The medical repercussions of our findings are here discussed: in fact, a REM detection in only 1 of 113 examined cases seems to exclude active roles in breast carcinogenesis and discloses new possibilities for therapeutic developments in triple negative breast cancer.

Background: Mixed cryoglobulinemia (MC) is a rare multisystem disease whose aetiopathogenesis is not completely understood. Hepatitis C virus (HCV) infection may have a causative role, and genetic and/or environmental factors may also contribute., Aims: To investigate the presence and possible role of environmental agents in MC., Methods: We recruited 30 HCV-infected MC patients with different clinical manifestations and a control group of 30 healthy, sex-/age-matched volunteers. We collected serum samples from each patient and incubated at 4°C for 7 days to obtain cryoprecipitate samples. We used environmental scanning electron microscopy (ESEM) and energy dispersive X-ray spectroscopy microanalysis to verify the presence of microparticles (MPs) and nanoparticles (NPs) in serum and cryoprecipitate samples. We evaluated environmental exposure using a medical and occupational history questionnaire for each subject., Results: MC patients had a significantly higher risk of occupational exposure (OR 5.6; 95% CI 1.84-17.50) than controls. ESEM evaluation revealed a significantly higher concentration, expressed as number of positive spots (NS), of serum inorganic particles in MC patients compared with controls (mean NS 18, SD = 16 versus NS 5.4, SD = 5.1; P < 0.05). Cryoprecipitate samples of MC patients showed high concentrations of inorganic particles (mean NS 49, SD = 19). We found a strong correlation between NS and cryocrit (i.e. percentage of cryoprecipitate/total serum after centrifugation at 4°C) levels (P < 0.001)., Conclusions: In addition to HCV infection, MPs and NPs might play an important role in the aetiopathogenesis of MC., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Among the scientific communities, there is a convergence of results supporting a direct relationship between dysregulated sialylation and poor prognosis in many human cancers. For this reason, we have retrospectively investigated 169 cases of invasive ductal carcinoma of the breast, coming from female patients aged between 31 and 76 years old. The whole series was subdivided into two prognostic groups: the first group consisted of 138 patients, who showed a post-treatment survival time more than 5 years, while the second group was made up by 31 patients, died within 5 years despite of chemotherapy. All the surgical specimens were fixed in 10 % neutral buffered formalin, paraffin embedded and, then, submitted to routinely haematoxylin/eosin staining and to a further histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange), immunohistochemical (ST3GAL5 sialyltransferase, Ki67, c-erbB2, ER, PR) and chemico-elemental characterization. In the 31 cases of breast cancer belonging to the second group, an overexpression of sialomucins and sialyltransferases has been detected. Our results lead us to support that in aggressive chemoresistant breast cancers, the altered expression of sialic acid, due to an uncontrolled sialylation, creates an excessive negative charge on cell membranes, which stimulates repulsion between neoplastic cells and their subsequent access into the blood stream. This event implies an early metastatization and a rapid disease progression with fatal outcome. The early application of Alcian Blue stain on diagnostic biopsies of breast cancer is able to cheaply reveal the sialomucin accumulations, providing for the disease course.

The objective of this study is to examine the toxicity of engineered nanoparticles (NPs) that are dispersed in sea water by using an in vivo model. Because many products of nanotechnology contain NPs and are commonly used and well-established in the market, the accidental release of NPs into the air and water is quite possible. Indeed, at the end of their life cycle, some NPs are inevitably released into waste water and can reach marine ecosystem and affect the organisms there. Although there are few data on the presence of NPs in the marine environment, our awareness of their potential impact on environmental and organismal health is growing. Shallow-water benthonic organisms such as sea urchins provide planktonic larvae as a trophic base for finfish juveniles and are exposed to water from estuaries and precipitation. Such organisms can therefore be directly affected by NPs that are dispersed into those media. We evaluated the effects of exposure to different concentrations of nanosilver, titanium oxide and cobalt NPs on the sperm of the sea urchin Paracentrotus lividus by analyzing the functionality and the morphology and biochemistry of the first developmental stages of the sea urchin. Sperm were exposed to sea water containing suspensions of NPs ranging from 0.0001 mg/L to 1 mg/L. Fertilization ability was not affected, but developmental anomalies were identified in embryos from the gastrula to pluteus stages, including morphological alterations of the skeletal rods. In addition, the enzymatic activity (cholinesterase, ChE) of the larvae was measured. Acetylcholinesterase (AChE) and propionylcholinesterase activity (PrChE) was affected in all of the exposed samples. The results did not vary consistently with the concentration of NP, but controls were significantly different from exposed samples. Exposure of sea urchin to these NPs may cause neurotoxic damage, and the altered ChE activity may be involved in skeletogenic aberrations. In conclusion, the sea urchin represents a suitable and sensitive model for testing the toxicity and effects of engineered NPs that are dispersed in sea water., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Metal nanosolicoparticles are suspected to cause diseases in a number of organisms, including man. In this paper, we report the effects of nanosilver (Ag, 1-20 nm particles) on the early development of the zebrafish, a well-established vertebrate model. Embryos at the midgastrula stage were exposed to concentrations ranging from 100 to 0.001 mg/L to verify the effects on different endpoints: lethality, morphology, expression of cholinergic molecules, and development of the immune system. (1) Relative risk of mortality was exponential in the range between 0.001 and 10 mg/L. Exposure to 100 mg/L caused 100% death of embryos before reaching the tail-bud stage. (2) Developmental anomalies were present in the 72 h larvae obtained from embryos exposed to nanosilver: whole body length, decreased eye dimension, and slow response to solicitation by gentle touch with a needle tip, with a significant threshold at 0.1 mg/L. (3) Dose-dependent inhibition of acetylcholinesterase activity was significant among the exposures, except between 1 mg/L and 10 mg/L. (4) The distribution of CD41+ cells and of CDF/LIF-like immunoreactivity was altered according to the Ag concentration. The possible effect of nanosilver in impairing immune system differentiation through the inhibition of molecules related to the cholinergic system is discussed.

Introduction: Although the causes of sarcoidosis are still unknown, past and current studies have provided evidence that this disease may be associated with occupational exposure to specific environmental agents. We describe a case of sarcoidosis in a dental surgeon with long exposure to inorganic dusts. To the best of our knowledge, this is the first report of this kind in the literature., Case Presentation: At the beginning of 2000, a 52-year-old Caucasian man, who worked as a dental surgeon, presented with shortness of breath during exercise, cough and retrosternal pain. After diagnosis of sarcoidosis, a scanning electronic microscopy with X-ray microanalysis of biopsy specimens was used in order to determine whether the disease could be traced to an occupational environmental agent. Results showed the presence of inorganic dust particles within sarcoidotic granulomas, and demonstrated that the material detected was identical to that found in a powder used by our patient for several years., Conclusions: Although these results cannot be considered as definitive proof, they do however provide strong evidence that this disease may be associated with material used by dental surgeons.

Nanoparticulate materials are produced by industrial processing or engineered for specific biomedical applications. In both cases, their contact with the human body may lead to adverse reactions. Most of the published papers so far have focused on the cytotoxic effects of nanoparticles (NPs). Instead, the present in vitro study investigates the effect of different types of NP on key components of the host response such as clot formation and the inflammatory cells. The different NPs were pre-conditioned with platelet-rich human plasma for 30 min and then incubated with the blood mononuclear cells for 20 hours. The potential of the different NPs to induce clot formation, platelet activation and monocyte/macrophage differentiation was assessed by morphological analysis, immunocytochemistry and biochemical assays. The data showed that nanoparticulate materials based on antimony, silver and nickel were capable of promoting the polymerization of fibrin and the aggregation and fragmentation of platelets, leading to a moderately activated monocyte phenotype. This process was more pronounced in the case of antimony- and silver-based NPs that share a similar size and round-shaped morphology. Conversely, NPs of cobalt, titanium and iron appeared to stimulate cells to acquire a macrophage phenotype able to secrete higher levels of tumour necrosis factor alpha, a pro-inflammatory cytokine. Therefore, the present study provides clear indications about the subtle and adverse effects that the invasion of these materials may produce in the cardiovascular system and in vital organs.

In order to examine the influence that shape and chemistry of different materials have on the incitement of a tissue reaction, we implanted five materials (the two metals Ni and Co, the two ceramics TiO2 and SiO2, and the polymer poly vinyl-chloride) as nanoparticles or bulk, in the dorsal muscles of 50 rats. After 6 or 12 months, rats were euthanized and the implanted materials were excised together with the surrounding tissue. After a first histological evaluation, the specimens were prepared for environmental scanning electron microscopy (ESEM) and for energy dispersive spectroscopy (EDS), in order to analyse the chemical composition of the implanted material after the biological interaction had occurred, and to evaluate the possible corrosion and diffusion of the materials at tissue interface. The results indicate that the metals at nanoscale size have a carcinogenic effect, while the bulk materials only induce a foreign-body reaction. The ESEM observations show a chemical transformation of the materials. Corrosion of the metals and subsequent recombination of the released ions in a sort of organic-inorganic crystals is showed and verified by the EDS analyses. Finally, our hypotheses of the involved pathological mechanism are suggested.

In order to study the pathobiological impact of the nanometre-scale of materials, we evaluated the effects of five different materials as nanoparticulate biomaterials in comparison with bulk samples in contact with living tissues. Five groups out of 10 rats were implanted bilaterally for up to 12 months with materials of the same type, namely TiO2, SiO2, Ni, Co and polyvinyl chloride (PVC), subcutaneously with bulk material on one side of the vertebral column and intramuscularly with nanoparticulate material on the contralateral side. At the end of each implantation time, the site was macroscopically examined, followed by histological processing according to standard techniques. Malignant mesenchymal tumours (pleomorphic sarcomas) were obtained in five out of six cases of implanted Co nanoparticle sites, while a preneoplastic lesion was observed in an animal implanted with Co in bulk form. In the Ni group, all animals rapidly developed visible nodules at the implanted sites between 4 and 6 months, which were diagnosed as rhabdomyosarcomas. Since the ratio of surface area to volume did not show significant differences between the Ni/Co group and the TiO2/SiO2/PVC group, we suggested that the induction of neoplasia was not mediated by physical effects, but was mediated by the well-known carcinogenic impact of Ni and Co. The data from the Co group show that the physical properties (particulate versus bulk form) could have a significant influence on the acceleration of the neoplastic process.

Through an innovative electron microscopy technique, thrombi and fibrotic tissue taken from 14 explanted vena cava filters were observed. Twelve cases showed the presence of micro-and nano-sized inorganic, non biodegradable nor biocompatible particles which did not belong to the metal the device was made of and which could be the sole cause or, more likely, a pre-existing cause for thrombosis. In two cases, those debris activated immunological reactions typical of a foreign body. The presence of inorganic particles in the blood was never detected before and their effects on human health are hardly known. Their thrombogenicity should be added to the Virchow's Triad as a fourth factor and could be the explanation to many of the cases of pulmonary embolism where no thrombotic focus could be demonstrated.

Recent studies give support for a connection between the presence of inorganic particles (of microm and nm size) in different organs and tissues and the development of inflammatory foci, called granulomas. As the potential source of particles (e.g. porcelain dental bridges) and the location of particle detection were topographically far apart, a distribution via the blood stream appears highly probable. Thus, endothelial cells, which line the inner surface of blood vessels, would come into direct contact with these particles, making particle-endothelial interactions potentially pathogenically relevant. The objective of this study was to evaluate the effects that five different nano-scaled particles (PVC, TiO2, SiO2, Co, Ni) have on endothelial cell function and viability. Therefore, human endothelial cells were exposed to different amounts of the above-mentioned particles. Although most particle types are shown to be internalised (except Ni-particles), only Co-particles possessed cytotoxic effects. Furthermore, an impairment of the proliferative activity and a pro-inflammatory stimulation of endothelial cells were induced by exposure to Co- and, to a lesser extent, by SiO2-particles. If a pro-inflammatory stimulation of endothelial cells occurs in vivo, a chronic inflammation could be a possible consequence.

The research deals with new scanning electron microscopic evaluations of the interface between blood and explanted temporary vena cava filters from patients affected by blood disorders. The biological tissues adherent to the filter and the small thrombi formed in vivo were detached from the metallic structure of the device, fixed, dehydrated and prepared for the histological and the electron microscopy. The analyses showed that both samples (thrombus and newly formed tissue) contained foreign, in some cases nano-sized, bodies. The chemistry of these particles was different and varied, and unusual compounds containing non-biocompatible elements like bismuth, lead, wolfram, tungsten were also detected. The interaction between these debris travelling in the blood stream and the blood itself leads to suspect that the formation of the thrombus can originate from these inorganic and inert foreign bodies that act as triggering agent of the blood coagulation.

Pathological colonic tissues were investigated with an Environmental Scanning Electron Microscope technique to verify the presence of inorganic, non-biodegradable pollutants, i.e. micro- and nano-debris of exogenous origin, after debris in liver and kidney had been discovered. In all, 18 samples of colon tissues affected by cancer and Crohn's disease were evaluated and found in all the cases to contain micro- and nano-particles. Their chemistry, detected with an X-ray microprobe, indicated a heterogeneous nature, whereas the size of the particles was homogeneous. Three control samples of healthy, young, cadavers were analysed and showed the absence of debris within the normal, healthy colon mucosa. The study reveals the presence of particulate debris, generally considered as biocompatible, in pathological specimens of human colon. The findings suggest a possible link between the presence of such particles and the underlying pathology in the cases analysed.

An accidental discovery led us to correlate a pathology of "unknown origin" with the presence of micro- and nano-particles of inorganic nature in the human tissues. Bioptic samples of livers and kidneys affected by cryptogenic granulomas were observed through a new type of electron scanning microscope called environmental scanning electron microscope and X-ray-microanalyzed with an energy dispersive system. All the randomly selected samples showed the presence of inorganic samples, sometimes varying in chemical composition, but consistent in size (larger in the liver, smaller in the kidney). This article illustrates the results obtained on randomly picked samples and proposes our new investigative method as an aid to achieve a medical diagnosis. Two more items are discussed: the possible, until now unexplained, origin of a pathology as deriving from the presence of exogenous particles, so a new word "nano-pathology" was developed and, as a consequence, the relativity of the concept of biocompatibility as depending on the size of the material considered and its local concentration. The implications of the discovery are briefly discussed.

Granulomatous reactions caused by foreign bodies have been described in drug abusers, in subjects exposed to occupational pollutants, and more rarely, in association with the use of prosthetic devices. We describe a 62-year-old patient with multiorgan parenchymal granulomatosis caused by inorganic debris of unknown origin. The patient presented with fever, hepatosplenomegaly, progressive cholestasis, and acute renal failure. Liver and kidney biopsies showed the presence of noncaseating epithelioid giant-cell granulomas containing scattered polarizable particles. Similar particles were also present in stools. Studies by innovative scanning electron microscopy and energy-dispersive microanalytical techniques showed that the particles isolated in liver, kidney, and stools were made by feldspars, the main component of porcelain. No occupational or environmental exposure to these materials could be identified in this patient and the only reliable source of the porcelain debris turned out to be constituted by 2 dental bridges evidently worn because of a possible inappropriate construction, malocclusion, and bruxism. The porcelain of the dental prostheses had the same elemental spectrum of the particles isolated from stool specimens and liver-kidney granuloma. After identification of the dental prostheses as the most likely source of ceramic debris, and after their removal, the particles from stool specimens disappeared. The patient was then treated with steroids leading to a remission of the clinical symptoms and a decrease in granulomatous inflammatory reaction in both liver and kidney. This is the first report suggesting that a foreign body systemic granulomatosis can be associated with worn dental prostheses.

Background and Objective: Idarubicin is an effective drug in acute leukemia but its use in non-Hodgkin lymphomas (NHLs) is not yet well established. We evaluated its efficacy in patients with diffuse large cell lymphoma (DLCL) by means of a randomized trial comparing two 12-week regimens (VACOP-B and VICOP-B) which differed only in the anthracycline drug used (doxorubicin vs idarubicin)., Methods: From January 1992 to December 1994, 104 patients aged less than 65 years with de novo advanced stage DLCL were enrolled. Fifty-two patients were treated with VACOP-B (doxorubicin 50 mg/sqm) and 52 with VICOP-B (idarubicin initially 8 mg/sqm and thereafter 10 mg/sqm)., Results: Clinical characteristics of the two groups were not significantly different. One HBsAg+ patient died of hepatic necrosis in the VICOP-B arm, and severe (WHO grade > 2) toxicities occurred in 7 patients treated with VACOP-B and in 5 treated with VICOP-B; the only significant difference was for mucositis (p = 0.02). Complete remission (CR) was obtained in 79% of patients receiving VACOP-B and in 56% (idarubicin 8 mg/sqm) and 75% (idarubicin 10 mg/sqm) of those in the VICOP-B group (p = n.s.). Prognostic factors that negatively affected CR were advanced stage in VACOP, bone marrow infiltration in both schedules. At a median follow-up of two years, overall survival (67% VACOP and 61% VICOP) and disease-free survival (65% and 67%, respectively) were not significantly different., Interpretation and Conclusions: Idarubicin is slightly less toxic than doxorubicin; at a dose of 10 mg/sqm the former is easily tolerated and shows the same efficacy as doxorubicin in the treatment of DLCL.

Background: Elderly patients with acute myeloid leukemia (AML) those refractory to induction chemotherapy and those with so-called secondary leukemia have unfavorable prognoses and require innovative therapeutic approaches. Fludarabine allows an increased accumulation of Ara-CTP in leukemic cells and inhibits DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone results in a synergistic effect., Materials and Methods: From May 1993 to February 1996, fludarabine-containing regimens (FLAG and FLANG) were employed as induction therapy in 51 high-risk AML patients. Diagnosis of AML in 22 patients was preceded by a myelodysplastic syndrome lasting more than six months; 8 of the 29 de novo AML cases (28%) were refractory to previous chemotherapy, 9 (31%) were treated for early relapse, 12 (41%) presented poor prognostic factors at diagnosis. The median age was 64 (range 33-76) years and the FAB subtypes were the following: M0 3, M1 5, M2 28, M4 7, M5 8. Forty-eight per cent of patients showed poor prognosis chromosomal abnormalities. FLAG (24 patients) consisted of both fludarabine 30 mg/sqm over 30 minutes followed 4 hours later by Ara-C 2 g/sqm over 4 hours (for 5 days) and G-CSF 300 micrograms/day administered 12 hours before fludarabine, for a total of 5 doses. FLANG (27 patients) had a shorter duration (3 days), reduced Ara-C dosage (1 g/sqm) and administration of mitoxantrone (10 mg/sqm) at the end of Ara-C infusion., Results: Recovery of both neutrophils (PMN > 0.5 x 10(9)/L) and platelets (Plt > 20 x 10(9)/L) required a median of 16 days from the end of therapy. Overall, 30 patients (59%) achieved CR, 6 (11%) PR and 10 (20%) were refractory; 5 (10%) experienced early death (cerebral hemorrhage or infection). The length of complete response ranged from 2 to 26 months with a median follow-up of 8 months. De novo and secondary AML registered 62 and 54% CR rates, respectively. Eight out of 10 patients refractory to conventional schemes achieved CR (80%) but only 3 out of 10 treated for relapse obtained CR (30%)., Conclusions: FLAG and FLANG showed similar activity and toxicity while proving to be highly effective and relatively well-tolerated treatments for high-risk de novo AML. Secondary leukemias seemed to be responsive as well, but the presence of an unfavorable karyotype alteration lowered the response rate.

Background: Considering the conflicting results of the few reports on geriatric MM patients and the increasing relevance of the problem, we analyzed a series of 113 patients over 64 years of age treated with conventional chemotherapy., Patients and Methods: The median age was 71 (range 65-92). Stage IA, IIA, IIIA and IIIB patients numbered 28, 33, 45 and 7, respectively. The M component was IgG in 73 patients (65%), IgA in 30 (26%), IgD in 3 (3%), light chain in 5 (4%); no monoclonal component was detected in 2 (2%) cases. Sixty-three patients showed symptomatic skeletal disease. Melphalan/prednisone (MP) was the first-line treatment in 84 patients (74%). Patients were grouped according to age (> 64 < or = 74; > or = 75) in order to carry out analysis., Results: Seventy-eight cases (69%) showed a sizable reduction in the tumor mass; objective and partial response was achieved in 57 (50%) and 21 (19%) patients, respectively. Patients with stage I-II disease fared significantly better than stage III patients (median survival: 70 vs 38 months; p = 0.017). Response to first-line treatment correlated with overall survival; patients with responsive or refractory disease had median survival rates of 64 and 20 months, respectively (p = 0.0001)., Conclusions: Neither patients above nor below 75 years of age showed any difference in presentation features or in response to treatment. These results suggest that advanced age should not be considered a major obstacle to active treatment.

The long-term effects of recombinant human erythropoietin (rhEPO) administration in two consecutive cases of paroxysmal nocturnal hemoglobinuria (PNH) with severe anemia are reported. In both patients, a 68-year-old woman and a 66-year-old man, a diagnosis of PNH was made on the basis of severe macrocytic anemia associated with hemoglobinuria, hemosiderinuria and positivity for the sucrose and Ham tests. Subcutaneous treatment with rhEPO, 150 U/Kg body weight daily, was followed in both cases by a progressive increase in hemoglobin concentrations, which thereafter were maintained above 10 g/dL with lower doses of rhEPO and without any relevant side effects for 32 and 29 months of continuous treatment, respectively. A clinical response was observed in spite of elevated baseline serum erythropoietin concentrations, appropriate to the degree of anemia in both patients. These results suggest that rhEPO may be appropriately and safely used in the long-term correction of anemia associated with PNH, and that the response to the pharmacologic doses of rHEPO administered was not dependent on the level of endogenous erythropoietin.

A bioactive glass, S53P4, was implanted as granules subcutaneously in muscles and connective tissue of rabbits, as well as in the mandibular bone of a sheep. After the implantation period of 2-3 months, cross-sections were prepared and studied by scanning electron microscopy and energy dispersive X-ray analysis. The glass reacted essentially in the same way in all types of tissue. The granules consisted of an unreacted core and a reacted layer with a silica-rich and calcium phosphate-rich zone. Large hydroxyapatite crystals were occasionally found on top of the calcium phosphate surface of the granules implanted in soft tissue. On the basis of elemental analysis of the reaction layers it was found that the release of calcium from inside the glass is sufficient to account for the formation of the calcium phosphate surface layer, whereas the release of phosphate from the glass is not sufficient.

The bioactivity of two similar vitreous materials used in the form of granules of 'critical' size was investigated in bone defects in jaws of two sheep. The granules consisted of Hench's Bioglass and another glass with the same chemical composition made in Italy. Two months after implantation, the sheep were killed and elemental analyses carried out on sections of the embedded jaws. The microanalyses for both the glasses showed a diffusion from the granules towards the surrounding tissue of silicon and sodium, and an inverse diffusion (from the surrounding tissue towards the granules) of calcium and phosphorus. The degradation for the Italian glass was slower than for the Bioglass. No significant osteoinduction was seen after that time at the interface of the glass granules or in the bone pocket.

Granules of a glass (A) prepared according to Hench's formula and a new vitreous material for biological applications (AKRA 15) were used for repair of bone defects in the dental field. The behaviour of these materials implanted in holes drilled in sheep's mandibular bone was examined 4, 8, 12 month after implantation. Microradiographic analyses, optical and scanning electron microscopic observations, and X-ray microprobe evaluations were carried out using undecalcified, methacrylate-embedded sections of the jaw containing the granules. After one year the granules of A disappeared, but not important bone growth was observed also in the holes containing AKRA 15. SEM and microprobe showed: disappearance of Na and Si ions at different stages; increase of P and Ca up to 4 month and then decrease, but in different ways in the two glasses; unexpected appearance of K ions after 4 month only in AKRA 15.

Granules of hydroxyapatite (HA) and tricalcium phosphate (TCP) were implanted in separate holes drilled in mandibular bone of sheep to check the bone growth and in vivo behaviour of the materials. The experiment was performed in three sheep, killed respectively at 4, 8, 12 month. Samples of bone with the materials were explanted, microradiographed and sectioned to evaluate the interface under optical and electron scanning electron microscope. The hole, left empty as a reference, showed no full repair; whereas 4 month after implantation the TCP granules induce total repair of the hole. HA granules crumbled and no new bone induction was seen even 12 month after implantation.