Paternal prescription medication before conception: A retrospective cohort study of all births in Denmark 1997-2017.

AIM: To study what medication fathers are being prescribed in the months preceding conception. METHODS: A retrospective cohort study of Danish national registries, comprising all births in Denmark 1997-2017 (1.3 million births). Time trends and absolute levels of paternal prescription medication in the 6 months prior to conception were assessed. While all medications were examined (N = 1335), we focused on the main medication groups, medications that have increased in use over time, and medications for which previous evidence exists of an effect on sperm quality. RESULTS: The average number of prescriptions increased over the study period (from 0.75 prescriptions to 0.82 per birth). Polypharmacy (three or more prescriptions) increased from less than 8% to 10% of fathers. The use of pain medication, proton-pump inhibitors, selective serotonin reuptake inhibitors and some inhalants have all increased markedly over the last 20 years. CONCLUSIONS: Potential harm to the offspring done by paternal medication may present an increasing problem. As paternal medication exposure is increasing, examination of generational effects, such as major birth defects, is necessary.

Successful mobilization of PBSCs predicts favorable outcomes in multiple myeloma patients treated with novel agents and autologous transplantation.

Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes. However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34(+) cell yields as compared with TD (9.75 vs 10.76 × 10(6) CD34(+) cells/kg, P=0.220). For poor mobilizers (<4 × 10(6) CD34(+) cells/kg), 5-year rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for successful mobilizers (TTP:17 vs 48%, P<0.0001; PFS: 16 vs 46%, P<0.0001; OS: 50 vs 80%, P<0.0001). These differences were retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD, irrespective of the number of harvested CD34(+) cells. The number of collected PBSCs predicted better outcomes after auto-SCT and VTD overcame the negative impact of a poor stem cell mobilization.

Survival, Continence and Potency (SCP) recovery after radical retropubic prostatectomy: a long-term combined evaluation of surgical outcomes.

OBJECTIVE: To offer a comprehensive account of surgical outcomes on a defined series of patients treated with radical retropubic prostatectomy (RRP) for prostate cancer in a single European Center after 5-year minimum follow-up according to the Survival, Continence and Potency (SCP) system. MATERIAL AND METHODS: We evaluated our Institutional database of patients who underwent RRP from November 1995 to September 2008. Oncological and functional outcomes were reported according to the recently proposed SCP system. RESULTS: The 5- and 10-year biochemical recurrence-free survival rates were 80.1% and 55.8%, respectively. At the end of follow-up, 611 (78.5%) patients were fully continent (C0), 107 (13.8%) used 1 pad for security (C1) and 60 (7.7%) patients were incontinent (C2). Of the 112 patients who underwent nerve-sparing RRP, 22 (19.6%) were fully potent without aids (P0), 13 (11.6%) were potent with assumption of PDE-5 inhibitors (P1) and 77 (68.8%) experienced erectile dysfunction (P2). The combined SCP outcomes were reported together only in 95 (12.2%) evaluable patients. In patients preoperatively continent and potent, who received a nerve-sparing and did not require adjuvant therapy, oncological and functional success was attained by 29 (30.5%) patients. In the subgroup of 508 patients not evaluable for potency recovery, oncological and continence outcomes were obtained in 357 patients (70.3%). CONCLUSION: Survival, Continence and Potency (SCP) classification offer a comprehensive report of surgical results, even in those patients who do not represent the best category, thus allowing to provide a much more accurate evaluation of outcomes after RP.

Tiempo de isquemia caliente y complicaciones postoperatorias después de la nefrectomía parcial de carcinoma de células renales / Warm ischemia time and postoperative complications after partial nephrectomy for renal cell carcinoma

Objetivo: Evaluar las correlaciones entre puntuaciones PADUA y RENAL, TIC y complicaciones postoperatorias en una cohorte de pacientes que se sometieron a cirugía de conservación de nefronas por elección abierta o mínimamente invasiva para el carcinoma de células renales. Material y métodos: Analizamos 96 pacientes consecutivos que fueron sometidos a nefrectomía parcial por carcinoma de células renales entre 2004 y 2013 en nuestra institución. La prueba de Spearman se utilizó para comparar variables categóricas. Para todos los análisis estadísticos un valor de p < 0,05 de 2 caras se consideró estadísticamente significativo. Resultados: La mediana de puntuación PADUA (RI) fue de 7 (7-8) y la puntuación RENAL mediana (RI) fue de 7 (6-8). La mediana de tiempo de isquemia caliente (RI) fue de 14 min (8-20). Se encontraron complicaciones postoperatorias de grado bajo y alto en 27 (28,1%) y 6 (6,3%) pacientes, respectivamente. Las categorías de grupos de riesgo de PADUA se correlacionaron significativamente con TIC > 20 min y las complicaciones postoperatorias de alto grado, respectivamente (p = 0,04), independientemente del abordaje quirúrgico. Las categorías de grupos de riesgo RENAL predijeron significativamente más tiempo de pinzamiento hiliar en nuestra cohorte (p = 0,04), pero no se encontraron correlaciones estadísticamente significativas con las complicaciones postoperatorias de alto grado. Conclusiones: En nuestra serie retrospectiva las puntuaciones nefrométricas demostraron predecir significativamente mayor tiempo de isquemia caliente y mayores complicaciones postoperatorias, especialmente en aquellos pacientes con tumores renales más difíciles y complejos. Por lo tanto, al planificar realizar la nefrectomía parcial los urólogos deberían utilizar ampliamente estas herramientas completas

Objective: To evaluate the correlations between PADUA and RENAL scores, WIT and postoperative complications in a cohort of patients who underwent elective open or minimally invasive nephron sparing surgery for renal cell carcinoma. Materials and methods: We analyzed 96 consecutive patients who underwent partial nephrectomy for renal cell carcinoma between 2004 and 2013 at our Institution. The Spearman test was used to compare categorical variables. For all statistical analyses, a two-sided p < 0.05 was considered statistically significant. Results: The median (IQR) PADUA score was 7 (7-8) and the median (IQR) RENAL score was 7 (6-8). The median (IQR) warm ischemia time was 14 min (8-20). Low grade and high grade postoperative complications were found in 27 (28.1%) and 6 (6.3%) patients, respectively. PADUA risk group categories significantly correlated with WIT > 20 min and high grade postoperative complications, respectively (p = 0.04), regardless of the surgical approach. RENAL risk group categories significantly predicted longer hilar clamping time in our cohort (p = 0.04), but no statistically significant correlations with high grade postoperative complications were found. Conclusions: In our retrospective series nephrometric scores demonstrated to significantly predict longer warm ischemia time and higher postoperative complications, especially in those patients with more challenging and complex renal tumors. Therefore, when planning to perform partial nephrectomy, urologists should widely use these comprehensive tools

Warm ischemia time and postoperative complications after partial nephrectomy for renal cell carcinoma.

OBJECTIVE: To evaluate the correlations between PADUA and RENAL scores, WIT and postoperative complications in a cohort of patients who underwent elective open or minimally invasive nephron sparing surgery for renal cell carcinoma. MATERIAL AND METHODS: We analyzed 96 consecutive patients who underwent partial nephrectomy for renal cell carcinoma between 2004 and 2013 at our Institution. The Spearman test was used to compare categorical variables. For all statistical analyses, a two-sided P < .05 was considered statistically significant. RESULTS: The median (IQR) PADUA score was 7 (7-8) and the median (IQR) RENAL score was 7 (6-8). The median (IQR) warm ischemia time was 14 min (8-20). Low grade and high grade postoperative complications were found in 27 (28.1%) and 6 (6.3%) patients, respectively. PADUA risk group categories significantly correlated with WIT > 20 minutes and high grade postoperative complications, respectively (P = .04), regardless of the surgical approach. RENAL risk group categories significantly predicted longer hilar clamping time in our cohort (P = .04), but no statistically significant correlations with high grade postoperative complications were found. CONCLUSIONS: In our retrospective series nephrometric scores demonstrated to significantly predict longer warm ischemia time and higher postoperative complications, especially in those patients with more challenging and complex renal tumors. Therefore, when planning to perform partial nephrectomy, urologists should widely use these comprehensive tools.

Intensification of GVHD prophylaxis with low-dose ATG-F before allogeneic PBSC transplantation from HLA-identical siblings in adult patients with hematological malignancies: results from a retrospective analysis.

Several studies have shown that chronic GVHD (cGVHD) is more frequent in patients receiving transplants from PBSC than in those receiving BM. In the setting of PBSC-unrelated transplants, the addition of anti-T-cell globulin (ATG) has shown a significant decrease in incidence/severity of cGVHD, without an increase in relapses or infections. However, no prospective data are yet available in the sibling setting. We retrospectively analyzed the effects of intensification of standard GVHD prophylaxis (CsA+MTX) by the addition of low-dose ATG in 245 patients receiving a transplant from HLA-identical sibling. From 1996 to 2001, patients received PBSC as the preferred source (group 2), and then ATG was added before transplant (group 3) because of a high cGVHD rate. Patients receiving BM in the same time period were analyzed as a control group (group 1). The incidence of grade III-IV acute GVHD and cGVHD was not significantly different in the three groups, but extensive cGVHD was highest in group 2 (38%) compared with group 3 (21%) or group 1 (28%; P=0.03). OS, TRM and time to relapse/progression were similar in the three groups. Our analysis shows that adding ATG to PBSC sibling allogeneic transplants can lower cGVHD, without an increase of relapse. Further prospective studies are needed to confirm these findings.

Comparison of two methods for cardiac output measurement in critically ill patients.

BACKGROUND: The aim of recent haemodynamic monitoring has been to obtain continuous and reliable measures of cardiac output (CO) and indices of preload responsiveness. Many of these methods are based on the arterial pressure waveform analysis. The aim of our study was to assess the accuracy of CO measurements obtained by FloTrac/Vigileo, software version 1.07 and the new version 1.10 (Edwards Lifesciences LLC, Irvine, CA, USA), compared with CO measurements obtained by bolus thermodilution by pulmonary artery catheterization (PAC) in the intensive care setting. METHODS: In 21 critically ill patients (enrolled in two University Hospitals), requiring invasive haemodynamic monitoring, PAC and FloTrac/Vigileo transducers connected to the arterial pressure line were placed. Simultaneous measurements of CO by two methods (FloTrac/Vigileo and thermodilution) were obtained three times a day for 3 consecutive days, when possible. The level of concordance between the two methods was assessed by the procedure suggested by Bland and Altman. RESULTS: One hundred and forty-one pairs of measurements (provided by thermodilution and by both 1.07 and 1.10 FloTrac/Vigileo versions) were obtained in 21 patients (seven of them were trauma patients) with a mean (sd) age of 59 (16) yr. The Pearson product moment coefficient was 0.62 (P<0.001). The bias was -0.18 litre min(-1). The limits of agreement were 4.54 and -4.90 litre min(-1), respectively. CONCLUSIONS: Our data show a poor level of concordance between measures provided by the two methods. We found an underestimation of CO values measured with the 1.07 software version of FloTrac for supranormal values of CO. The new software (1.10) has been improved in order to correct this bias; however, its reliability is still poor. On the basis of our data, we can therefore conclude that both software versions of FloTrac/Vigileo did not still provide reliable estimation of CO in our intensive care unit setting.

Elucidating the role of matrix stiffness in 3D cell migration and remodeling.

Reductionist in vitro model systems which mimic specific extracellular matrix functions in a highly controlled manner, termed artificial extracellular matrices (aECM), have increasingly been used to elucidate the role of cell-ECM interactions in regulating cell fate. To better understand the interplay of biophysical and biochemical effectors in controlling three-dimensional cell migration, a poly(ethylene glycol)-based aECM platform was used in this study to explore the influence of matrix cross-linking density, represented here by stiffness, on cell migration in vitro and in vivo. In vitro, the migration behavior of single preosteoblastic cells within hydrogels of varying stiffness and susceptibilities to degradation by matrix metalloproteases was assessed by time-lapse microscopy. Migration behavior was seen to be strongly dependent on matrix stiffness, with two regimes identified: a nonproteolytic migration mode dominating at relatively low matrix stiffness and proteolytic migration at higher stiffness. Subsequent in vivo experiments revealed a similar stiffness dependence of matrix remodeling, albeit less sensitive to the matrix metalloprotease sensitivity. Therefore, our aECM model system is well suited to unveil the role of biophysical and biochemical determinants of physiologically relevant cell migration phenomena.

The addition of plerixafor is safe and allows adequate PBSC collection in multiple myeloma and lymphoma patients poor mobilizers after chemotherapy and G-CSF.

We report 13 multiple myeloma (MM) or lymphoma patients who were failing PBSC mobilization after disease-specific chemotherapy and granulocyte-CSF (G-CSF), and received plerixafor to successfully collect PBSCs. Patients were considered poor mobilizers when the concentration of PB CD34(+) cells was always lower than 10 cells/µL, during the recovery phase after chemotherapy and/or were predicted to have inadequate PBSC collection to proceed to autologous transplantation. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to three consecutive days, while continuing G-CSF, 10-11 h before the planned leukapheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a 4.7 median fold-increase in the number of circulating CD34(+) cells after plerixafor as compared with baseline CD34(+) cell concentration (from a median of 6.2 (range 1-12) to 21.5 (range 9-88) cells/µL). All patients collected >2 × 10(6) CD34(+) cells/kg in 1-3 leukaphereses. In all, 5/13 patients have already undergone autograft with plerixafor-mobilized PBSCs, showing a rapid and durable hematological recovery. Our results suggest that the pre-emptive addition of plerixafor to G-CSF after chemotherapy is safe and may allow the rescue of lymphoma and MM patients, who need autologous transplantation but are failing PBSC mobilization.

Central nervous system infectious complications early after liver transplantation.

Infectious complications contribute to significant patient morbidity and mortality in orthotopic liver transplant (OLT) recipients. Early central nervous system (CNS) involvement (within the first month after OLT) by infectious disease is essentially set off by aggressive surgical procedures, severe morbid conditions of the pretransplant period, initial graft dysfunction, permanence of intravascular catheters, and prolonged mechanical ventilation. The type and severity of CNS infection may be determined by many factors, such as posttransplant adverse events; prolonged or repeated surgery with massive intraoperative transfusions, net state of immunosuppression, recurrence of infections by immunomodulating viruses, and retransplantation. Bacteria, viruses, and fungi can spread to the CNS just as they affect the abdomen, blood stream, respiratory tract, urine, drainages, etc. Because immunosuppressive drugs may modify the clinical presentation of CNS infections, it is very important to maintain vigilance and attend to minor neurologic symptoms. Special attention should therefore be given to cerebral investigation in patients with prolonged pulmonary contamination, unresponsive fever, and heavy corticosteroid therapy, primarily when they became disoriented, develop seizures, or exhibit focal neurologic signs. Clinical response to medical therapy may sometimes be poor because of chronic encapsulation of the pathogen, development of resistance, and/or catastrophic hemorrhagic complications.

Hemodynamic profile of portopulmonary hypertension.

Portopulmonary hypertension (PPHTN) refers to the development of pulmonary arterial hypertension in the setting of portal hypertension with or without chronic hepatic failure. This syndrome is characterized by marked alternations of pulmonary vascular tone and obstruction of pulmonary arterial blood flow. An increased pulmonary blood flow, which is a hallmark of the hyperdynamic circulation of cirrhotic patients, seems to be present in almost all patients who develop PPHTN. The elevations of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) along with the transpulmonary gradient (TPG) have been considered in diagnosing PPHTN. Only a high TPG reflects the severity of obstruction to pulmonary blood flow and differentiates an elevated PAP with concomitant elevated PVR from the situation where the increase in PAP is due only to the hyperdynamic flow and elevated volume. A considerable risk for cardiovascular death arises when PAP increases significantly; this may occur in rapidly evolving syndromes, in very advanced disease, or during a complicated liver transplantation. The distinction between PPHTN and elevated PAP in the context of a hyperdynamic state is of great importance; a PAP increase of hyperkinetic origin, as opposed to PPHTN, is apparently not associated with a high risk for adverse effects during and following liver transplantation.

Noninvasive ventilation in postoperative care of lung transplant recipients.

Noninvasive positive pressure ventilation (NIPPV), which provides consolidated treatment of both acute and chronic respiratory failure, is increasingly being used in the postoperative care of lung transplant patients. Graft- and patient-related respiratory insufficiency requiring mechanical ventilation are common features in the postoperative period; they may persist for hours to days. Prolonged intubation, particularly in these immunocompromised patients, has been considered one of the main predisposing factors for developing nosocomial pneumonia. It has been associated with increased length of intensive care unit (ICU) stay as well. Noninvasive mechanical ventilation is nowadays an attractive choice to shorten weaning time and avoid reintubation following lung transplantation. Rapid extubation plus prompt NIPPV application is a useful strategy for lung recipients who do not completely fulfill the criteria for safe extubation. Unloading respiratory muscles, decreasing respiratory rate and sensation of dyspnea, improving ventilation/perfusion abnormalities, decreasing the heart rate, and improving hemodynamics are among the recognized benefits. Adding a noninvasive inspiratory support plus positive end-expiratory pressure (PEEP) to lung transplant recipients has been helpful to prevent airway injury and infections, avoiding the need for reintubation in cases of extubation failure, facilitating nocturnal sedation, treating the post-reimplantation syndrome and postoperative phrenic nerve dysfunction, and preventing reintubation in cases of readmission to the ICU. In our practice, the helmet system has emerged as the preferred interface; in cases of dyshomogeneous dorsobasal lung infiltrates, it allows effective ventilatory support in the prone position as well.

Bone marrow histology in marginal zone B-cell lymphomas: correlation with clinical parameters and flow cytometry in 120 patients.

BACKGROUND: Among marginal zone lymphomas (MZLs), bone marrow (BM) involvement features are well established in the splenic marginal zone lymphoma (SMZL); few data are available for extranodal marginal zone lymphoma (EMZL) and nodal marginal zone lymphoma (NMZL). PATIENTS AND METHODS: Incidence and patterns of histologic BM involvement are studied in 120 MZL patients (48 SMZL, 59 EMZL, 13 NMZL) at onset and during follow-up; relationships between clinical features, BM histology and flow cytometry (FC) are analyzed. RESULTS: At diagnosis, BM involvement occurs in 90% SMZL, 22% EMZL and 54% NMZL (P<0.0001); at reevaluation, incidence raises to 96% in SMZL and 34% in EMZL. Concordance between histology and FC is found in 87% of cases; most discordant cases have positive histology but negative FC. SMZL and EMZL show a nodular BM infiltration; the interstitial pattern is frequent in NMZL (P<0.0001); sinusoidal localization is typical of SMZL, frequent in NMZL and occasional in EMZL (P=0.0001). Stage, leukemic disease, B symptoms, more than one extranodal involved site, splenomegaly, elevated beta2-microglobulin, serum monoclonal component, International Prognostic Index (IPI) and age-adjusted IPI are directly related to BM infiltration. CONCLUSIONS: The different prevalence of BM involvement in MZL subtypes reflects their heterogeneous dissemination modalities; histology seems more sensible than FC to detect BM infiltration; development of BM involvement during follow-up is typical of EMZL.

Activated recombinant protein C in septic shock early after liver transplantation: a case report.

Severe infectious diseases after liver transplant are associated with high risk of multiorgan failure and mortality. Septic shock is difficult to manage in this setting since it is often unresponsive to conventional aggressive therapy. Adjuvant therapies have been proposed in association with full combination treatment to sustain the failing organs and improve outcomes in severe sepsis. Recombinant human activated protein C drotrecogin alfa, Xigris) has been occasionally administered to treat posttransplant sepsis to modulate and downregulate the complex network of inflammatory and coagulopathic processes. Herein we have reported on a patient who was given drotrecogin alfa 15 days following liver transplant for acute septic shock originating from a nosocomially acquired pneumonia. Recombinant activated drotrecogin alfa, associated with conventional aggressive treatment, was efficacious to revert the life-threatening "slippery slope" of vasoplegia and uncontrolled diffuse inflammation.

Microbiologic contamination of intraoperative blood salvaged during liver transplantation.

Bacterial contamination is one of the potential risks of blood salvage and reinfusion during orthotopic liver transplantation (OLT) because cell-saver machines lack antibacterial protection devices. This study was designed to analyze the potential bacterial contamination of blood salvaged during OLT; a secondary end point was to evaluate whether reinfusion of potentially contaminated blood may have been responsible for clinically manifested infective complications in the same patient. After induction of anesthesia, a blood sample was drawn from the central venous catheter (CVC) immediately after its positioning, to exclude potential coexisting hematic contamination of the recipient. During the procedure, 2 other samples of salvaged blood were collected for bacteriological analysis. Twenty-six of 38 samples of salvaged blood were positive for microorganisms, whereas 12 did not reveal the presence of infectious agents. In 19 of 26 positive samples, Staphylococcus species (73%) were isolated with only 2 of 38 samples drawn from CVC being contaminated. Candida Albicans was cultured in 2 samples. The high percentage (73%) of coagulase-negative Staphylococci indicates that blood contamination could have been caused by microorganisms from the air or suctioned from contact surfaces and the surgical field. Although almost 70% of processed and reinfused units tested positive for microbes, none of the postoperative blood cultures (at day 1 and day 3) revealed growth of the same species, not even in the 2 patients who had positive CVC cultures after induction of anesthesia.

Anesthetic concerns in lung transplantation for severe pulmonary hypertension.

Lung transplantation has become a consolidated treatment for patients with severe pulmonary hypertension (PH). Several difficulties are encountered during the procedure in such candidates, who are still recognized as more severely affected by perioperative morbility and mortality than those undergoing lung transplantation for other diseases. Right ventricular (RV) enlargement with tricuspid regurgitation, small left ventricle (LV) with an asymmetric hypetrophic wall, interventricular septal shift toward the left, with ventricular stiffness and diastolic incompetence, are typical preoperative echocardiographic findings of end-stage PH. A smooth induction and tracheal intubation will help prevent hypertensive crisis in highly susceptible candidates. Uncompensated vasodilatation or myocardial depression caused by anesthetics and mechanical ventilation may be responsible for acute RV dysfunction associated with low systemic blood pressure. Resuscitation and emergency adoption of cardiopulmonary by-pass (CPB) has been described for near-fatal anesthesia induction. Cardiovascular instability can develop after institution of one-lung ventilation and pulmonary artery clamping. An acute increase in pulmonary pressure results in a decrease in RV ejection fraction and then in acute RV failure. Interdependence of the right and left ventricles occurs such that RV function can alter LV function. Early detection of impending circulatory and/or respiratory deterioration is warranted to prevent an irreversible decline in cardiac output, resulting in hazardous cardiac arrest. Inhaled nitric oxide represents the first choice for treatment of PH and RV failure associated with systemic hypotension during lung transplantation. Intraoperative situations requiring CPB must be identified before development of systemic shock, which represents a late ominous sign of RV failure.

Cerebral blood flow in fulminant hepatitis.

Fulminant hepatic failure (FHF) is often complicated with cerebral edema, intracranial hypertension, and coma. Cytotoxic and vasogenic factors have been recognized in the etiology of cerebral edema. One of the main causes seems to be the accumulation of glutamine in astrocytes, which is produced from ammonia and the excitatory neurotransmitter glutamate. Ammonia is detoxified within the brain in astrocytes, where it increases the osmotic pressure for water. Ammonia-induced astrocytic water accumulation seems to act as an integrative trigger for the development of intracranial hypertension. While cerebral blood flow is sometimes reduced in the first stage of FHF, as compensatory cerebral vasoconstriction to reduce mean arterial pressure, it later increases as hyperammonemia decreases cerebral arteriolar tone. Despite vasodilation in the systemic and splanchnic beds at early stages of the disease, cerebral vessel resistance may increase, so that cerebral perfusion pressure may be preserved. When cerebral vascular tone is no longer effective in the course of illness, vasodilation gradually develops and rapidly becomes poorly responsive to carbon dioxide stimulation, which signifies loss of autoregulatory tone and cerebral hyperemia develops. Prolonged excessive flow may lead to brain swelling, vasogenic edema, and intracerebral hemorrhage. Brain edema further aggravates the critically reduced cerebral perfusion and is responsible for the high mortality.

Short- and long-term haematological surveillance of healthy donors of allogeneic peripheral haematopoietic progenitors mobilized with G-CSF: a single institution prospective study.

Healthy allogeneic donors, who were treated with G-CSF and underwent peripheral blood haematopoietic precursor collection at our Institution, were enrolled in a short- and long-term haematological surveillance protocol for a 5--7--year period. To date, 94 donors have been assessed with a mean follow-up of 30 months (4--84); for 30 subjects, the follow-up is >or=48 months. During G-CSF administration, 23/94 donors showed a significant platelet count decrease from the baseline. Pre-apheresis platelet decrement correlated with the total G-CSF dose administered, baseline platelet level and donor age. Normal platelet counts returned within 4--8 months. PMN and/or lymphocyte lower values were observed in 55/94 donors 2 weeks after G-CSF administration, with mean drops from the baseline of 40 and 36% for PMN and lymphocytes, respectively. The PMN decrease correlated inversely with donor age, as younger donors were more affected than older ones, whereas the lymphocyte decrease correlated directly with the total blood volumes processed in the apheresis courses, in particular for donors subjected to large volume leukaphereses. Long-term observation showed moderate neutrophil reduction (25% count drop from the baseline) in four of the 30 donors observed for four years or more. 14 donors showed persistent, slight lymphocytopenia (mean drop of 13%) until the third year, with recovery in the fourth year of follow-up.

Precipitation casting of polycaprolactone for applications in tissue engineering and drug delivery.

Microporous materials have been produced by gradual precipitation from solutions of poly(epsilon-caprolactone) (PCL) in acetone induced by solvent extraction across a semi-permeable PCL membrane which is formed in situ at the polymer solution/non-solvent interface. Microparticulates of hydroxyapatite and inulin polysaccharide, respectively, were incorporated in precipitation cast PCL matrices to illustrate potential applications in hard tissue repair and macromolecular drug release. Microporous PCL and HA filled PCL materials were found to provide a favourable surface for attachment and growth of primary human osteoblasts in cell culture. The in vitro degradation characteristics of microporous PCL and inulin/PCL materials in PBS at 37 degrees C were monitored over 45 months. Microporous PCL demonstrated zero weight loss, minor changes in molecular weight characteristics and a fairly constant indentation resistance of around 1 MN/m2. Inulin-loaded PCL materials exhibited a total weight loss of approximately 17% after 12 months in PBS. The indentation resistance decreased by 50% from an initial value of 28 MN/m2 in the first 2 months and then remained stable. Precipitation cast materials based on PCL are expected to be useful for formulating long-term, controlled release devices for bioactive molecules such as growth factors and hormones and extended-residence supports for cell growth and tissue development.

Double reinforcement with fludarabine/high-dose cytarabine enhances the impact of autologous stem cell transplantation in acute myeloid leukemia patients.

Reinforced chemotherapy based on a double high-dose consolidation regimen could be a different way to enhance in vivo purging prior to autologous stem cell transplantation (auto-SCT) in acute myeloid leukemia (AML). We investigated the impact on outcome of auto-SCT after two different strategies of early intensification performed after an identical induction regimen in adult patients with AML. Between January 1993 and December 1998, 140 consecutive AML patients were enrolled in a program consisting of an identical anthracycline-based induction (ICE) and two different consolidation regimens: one cycle, cytarabine-based (single-NOVIA: 91 patients); two cycles, fludarabine-based (double-FLAN: 49 patients). Seventy out of 91 patients received single-NOVIA consolidation: 60 underwent a transplantation procedure (allogeneic bone marrow transplantation (allo-BMT):16 patients; auto-SCT: 44). Thirty-five out of 49 patients received double-FLAN consolidation: 31 underwent a transplantation procedure (allo-BMT: 10; auto-SCT: 21). The double consolidation regimen was well-tolerated with only minor side-effects. Median follow-up observation time for surviving patients was 38 months (range, 17-71) for the double-FLAN consolidation group and 70 months (range: 48-93) for the single-NOVIA consolidation group. Among the patients who received auto-SCT, the double consolidation strategy produced a superior disease-free survival curve at 36 months (78.6% (95%CI: 59.4-97.8) vs 47.7% (95%CI: 33-62.4)) compared with the single-NOVIA group. This difference was confirmed when the patients were analyzed for intention to treat (P = 0.04). In addition, the double-FLAN consolidation group showed a superior overall survival and lower relapse rate (P = 0.02). We conclude that the double-FLAN reinforcement strategy is safe and enhances the clinical impact of auto-SCT for AML patients in first complete remission. It may provide specific clinical benefit for patients undergoing auto-SCT.