Effects of environmental concentrations of the fragrance amyl salicylate on the mediterranean mussel Mytilus galloprovincialis.

Amyl salicylate (AS) is a fragrance massively used as a personal care product and following the discharged in wastewaters may end up in the aquatic environment representing a potential threat for the ecosystem and living organisms. AS was recently detected in water of the Venice Lagoon, a vulnerable area continuously subjected to the income of anthropogenic chemicals. The lagoon is a relevant area for mollusc farming, including the Mediterranean mussels (Mytilus galloprovincialis) having an important economic and ecological role. Despite high levels of AS occurred in water of the Lagoon of Venice, no studies investigated the possible consequences of AS exposures on species inhabiting this ecosystem to date. For the first time, we applied a multidisciplinary approach to investigate the potential effects of the fragrance AS on Mediterranean mussels. To reach such a goal, bioaccumulation, cellular, biochemical, and molecular analyses (RNA-seq and microbiota characterization) were measured in mussels treated for 7 and 14 days with different AS Venice lagoon environmental levels (0.1 and 0.5 µg L-1). Despite chemical investigations suggested low AS bioaccumulation capability, cellular and molecular analyses highlighted the disruption of several key cellular processes after the prolonged exposures to the high AS concentration. Among them, potential immunotoxicity and changes in transcriptional regulation of pathways involved in energy metabolism, stress response, apoptosis and cell death regulations have been observed. Conversely, exposure to the low AS concentration demonstrated weak transcriptional changes and transient increased representation of opportunistic pathogens, as Arcobacter genus and Vibrio aestuarianus. Summarizing, this study provides the first overview on the effects of AS on one of the most widely farmed mollusk species.

The effects of glyphosate and AMPA on the mediterranean mussel Mytilus galloprovincialis and its microbiota.

Glyphosate, the most widely used herbicide worldwide, targets the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) enzyme in the shikimate pathway found in plants and some microorganisms. While the potential for glyphosate to induce a broad range of biological effects in exposed organisms has been demonstrated, the global molecular mechanisms of toxicity and potential effects in bacterial symbionts remain unclear, in particular for ecologically important marine species such as bivalve molluscs. Here, the effects of glyphosate (GLY), its degradation product aminomethylphosphonic acid (AMPA), and a mixture of both (MIX) on the mussel M. galloprovincialis were assessed in a controlled experiment. For the first time, next generation sequencing (RNA-seq and 16S rRNA amplicon sequencing) was used to evaluate such effects at the molecular level in both the host and its respective microbiota. The results suggest that the variable capacity of bacterial species to proliferate in the presence of these compounds and the impairment of host physiological homeostasis due to AMPA and GLY toxicity may cause significant perturbations to the digestive gland microbiota, as well as elicit the spread of potential opportunistic pathogens such as Vibrio spp.. The consequent host-immune system activation identified at the molecular and cellular level could be aimed at controlling changes occurring in the composition of symbiotic microbial communities. Overall, our data raise further concerns about the potential adverse effects of glyphosate and AMPA in marine species, suggesting that both the effects of direct toxicity and the ensuing changes occurring in the host-microbial community must be taken into consideration to determine the overall ecotoxicological hazard of these compounds.

Analysis of the Trend Over Time of High-Urgency Liver Transplantation Requests in Italy in the 4-Year Period 2014-2017.

BACKGROUND: The national protocol for the handling of high-urgency (HU) liver organ procurement for transplant is administered by the Italian National Transplant Center. In recent years, we have witnessed a change in requests to access the program. We have therefore evaluated their temporal trend, the need to change the access criteria, the percentage of transplants performed, the time of request satisfaction, and the follow-up. METHODS: We analyzed all the liver requests for the HU program received during the 4-year period of 2014 to 2017 for adult recipients (≥18 years of age): all the variables linked to the recipient or to the donor and the organ transplants are registered in the Informative Transplant System as established by the law 91/99. In addition, intention to treat (ITT) survival rates were compared among 4 different groups: (1) patients on standard waiting lists vs (2) patients on urgency waiting lists, and (3) patients with a history of transplant in urgency vs (4) patients with a history of transplant not in urgency. RESULTS: Out of the 370 requests included in the study, 291 (78.7%) were satisfied with liver transplantation. Seventy-nine requests (21.3%) have not been processed, but if we consider only the real failures, this percentage falls to 13.1% and the percentage of satisfied requests rises to 86.9%. The average waiting period for liver transplantation (LT) is 1.7 days and most requests (74%) are met in less than 24 hours, if we consider the hours between the registration of the request and the donor reporting . The percentage of late retransplantations is 2.1%. The clinical indication for HU-LT that appears to improve over time is hepatic artery thrombosis (82.5%). The overall 1-year patient survival is 68.3%. The overall 1-year graft survival, performed on all the patients, is 89% and all the indications for HU-LT appear to go well over time with an average survival rate greater than 85%. CONCLUSIONS: The indications for HU-LT are changing according to the changes in the hepatologic field in recent years. The centralized management of requests has proven to be successful in optimizing responses. Urgent LT is confirmed to be lifesaving in its timeliness.

Colonization and infection due to carbapenemase-producing Enterobacteriaceae in liver and lung transplant recipients and donor-derived transmission: a prospective cohort study conducted in Italy.

OBJECTIVES: A prospective cohort study was conducted in Italy in order to describe the microbiologic aspects of colonization/infection by carbapenemase-producing Enterobacteriaceae (CPE) in donors and recipients of lung and liver transplants and the possible CPE transmission from donors to recipients. METHODS: Between 15 January 2014 and 14 January 2015, all recipients of solid organ transplants (SOT) at ten lung and eight liver transplantation centres and the corresponding donors were enrolled. Screening cultures to detect CPE were performed in donors, and screening and clinical cultures in recipients with a 28-day microbiologic follow-up after receipt of SOT. Detection of carbapenemase genes by PCR, genotyping by multilocus sequence typing, and pulsed-field gel electrophoresis and whole-genome sequencing were performed. RESULTS: Of 588 screened donors, 3.4% were colonized with CPE. Of the liver first transplant recipients (n = 521), 2.5% were colonized before receipt of SOT and 5% acquired CPE during follow-up. CPE colonization was higher in lung first transplant recipients (n = 111, 2.7% before SOT and 14.4% after SOT). CPE infections occurred in 1.9% and 5.3% of liver or lung recipients, respectively. CPE isolates were mostly Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae belonging to CG258. Three events of donor-recipient CPE transmission, confirmed by whole-genome sequencing and/or pulsed-field gel electrophoresis, occurred in lung recipients: two involving K. pneumoniae sequence type 512 and one Verona integron-encoded metallo-ß-lactamase (VIM)-producing Enterobacter aerogenes. CONCLUSIONS: This study showed a low risk of donor-recipient CPE transmission, indicating that donor CPE colonization does not necessarily represent a contraindication for donation unless colonization regards the organ to be transplanted. Donor and recipient screening remains essential to prevent CPE transmission and cross-infection in transplantation centres.

Hepatitis C Virus Positive Patients on the Waiting List for Liver Transplantation: Turnover and Characteristics of the Population on the Eve of the Therapeutic Revolution With Direct-Acting Antivirals.

INTRODUCTION: Antivirals direct acting (DAA) for hepatitis C virus (HCV) have brought a revolution in the field of transplantation. It is likely to think that in the future patients on the waiting list for liver transplantation (LT) will no longer be registered for HCV-related cirrhosis but for liver disease from other causes. On the eve of this change, we show a snapshot of the Italian waiting list for LT. METHODS: From October 1, 2012 to September 30, 2013, we estimated the total number of patients on the liver waiting list as intention to treat (ITT), the number of incident cases, and the delistings, particularly in the HCV positive (HCV+) population. Gender, median age, etiology and prognosis of liver disease, presence of hepatocellular carcinoma (HCC), reason for delisting, mean waiting time for LT, and rate of death on waiting list were evaluated. RESULTS: In the time period, there were 517 new patients who were HCV+ (median age, 53 years): 255 (49.3%) mono-infected with HCV, 236 (45.7%) co-infected with HCV and hepatitis B virus (HBV), 11 (2.1%) co-infected with HCV and human immunodeficiency virus (HIV), and 15 (2.9%) co-infected with HCV, HBV, and HIV. The median model for end-stage liver disease (MELD) score at listing was 17 and HCC was present in 206 (39.8%) cases. HCV+ patients delisted were 442 (61.9%), 355 (80.3%) for LT. The mean waiting time to transplantation was 1.9 months; the percentage of death was 7.6%. CONCLUSIONS: This snapshot of the waiting list for LT in the year before the advent of DAA drugs will allow us to assess whether and how they will change the waiting list for LT when we start to look at the impact of new therapies on the waiting list.

A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation.

Bruton's tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel isoform abundantly expressed in colon carcinoma cell lines and tumour tissue samples. p65BTK protein is expressed, through heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent and internal ribosome entry site-driven translation, from a transcript containing an alternative first exon in the 5'-untranslated region, and is post-transcriptionally regulated, via hnRNPK, by the mitogen-activated protein kinase (MAPK) pathway. p65BTK is endowed with strong transforming activity that depends on active signal-regulated protein kinases-1/2 (ERK1/2) and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Moreover, p65BTK inhibition affects growth and survival of colon cancer cells. Our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach.

Deaths with acute cerebral lesions in ICU: does the number of potential organ donors depend on predictable factors?

BACKGROUND: As the potentiality of deceased organ donation mostly depends on the number of brain deaths (BDs), the aim of this study is to quantify rates and probabilities of BD declaration in Italy. METHODS: Deaths with acute cerebral lesion (ACLDs) in the Italian ICUs have been prospectively collected. A total of 27,490 ACDLs occurred in 5 years. Age, gender, etiology, timing of death and ICU Region have been utilized for multivariate analysis. RESULTS: The global ratio of BD declarations to ACLDs was 39.9%. The rates of ACLDs, BD declarations and actual donors were 93.5, 37.3 and 19.7 pmp respectively. Wide variability resulted among Regions, with 148.2 ACLDs, 77.8 BD declarations and 42 donors pmp as benchmark. The probability of being BD declared was significantly higher in stroke compared with head injury (OR 1.6, P<0.001) and in females (OR 1.5, P<0.001), with half the Regions missing around 50% of BD declarations compared with the benchmark, particularly in elderly patients. CONCLUSION: Predictable factors associated with BD declaration can be identified in ACLD management. Positive factors leading to the identification of potential organ donors, i.e., the capacity of declaring BD in all the patients fulfilling BD criteria irrespective of age and etiology, could be captured in the best performing regions and reproduced throughout the Country. The implementation of simple indicators based on prospective ACLD monitoring, i.e. the declared BDs to ACLDs in ICU ratio, may be helpful in achieving efficiency targets and reliable comparisons of outcomes in the identification of BD potential organ donors.

Chronic obstructive pulmonary disease: the Disability Adjusted Life Years in northern Italy.

AIM: The DALY measure represents a new tool for improving the capacity of local health unit to assess population health needs and priorities. Our study aimed to increase the validity of the Disability Adjusted Life Years (DALY), by incorporating local estimates of the disease incidence and applying population-specific disability weights. METHODS: This is a prospective cohort study enrolling subjects aged 45+ years, first-time admitted to the hospital with principal diagnosis of 490-492, 496 ICD IX-CM codes and followed for one year to evaluate the vital status. A subset was administered the Saint George Respiratory Questionnaire to estimate the distribution of the chronic obstructive pulmonary disease (COPD)-related disability. RESULTS: Estimates of total DALY (per 1000) for COPD varied between 2.1 to 3.4 years among men and between 1.0 to 2.3 years among women; percentages of years of life lost due to a premature mortality were between 60 and 70%. CONCLUSION: The DALY represents a new tool for improving the capacity to assess population health needs and priorities. Policy makers owning such a further element of evaluation may be better oriented in allocating resources for COPD among the different health care chapters: prevention, emergency, chronicity and rehabilitation.

Mg(++)-induced endothelial cell migration: substratum selectivity and receptor-involvement.

The activation of endothelial cells during angiogenesis requires cell spreading and migration. These processes are influenced by extracellular signals such as chemoattractants from the local microenvironment. We have shown previously that transmembrane Ca++ influx is necessary for motility and cell spreading, thus we hypothesized that the extracellular divalent cations Mg++ and Ca++ may regulate human umbilical vein endothelial cell (HUVEC) spreading and act as chemoattractants. Studies demonstrated that extracellular Mg++ induced a statistically better spread phenotype when cells were plated on multiple extracellular matrix substrata; Ca++ promoted cell spreading only on vitronectin. Mg++ but not Ca++ acted as a potent chemoattractant when HUVEC migrated on gelatin- and type IV collagen- but not on vitronectin-coated filters. A checkerboard analysis of migration showed that Mg++ induces both chemokinetic and chemotactic migration peaking at 0.1 and 10 mM, respectively. An equivalent effect of oligomycin was seen on motility to Mg++ or to vascular endothelial growth factor (VEGF) in extracellular Mg(++)-free conditions, ruling out an exclusive role for Mg++ as a migration energy producer. The Mg(++)-stimulated chemotaxis was inhibited > 60% by pertussis toxin, d-erythrosphingosine, and tyrphostin B48, but unaffected by cholera toxin exposure. These data suggest that Mg(++)-induced chemotaxis may be promoted through a Gi protein-coupled receptor pathway with a requirement for protein kinase C activity and protein tyrosine phosphorylation. Thus, Mg++ may be a newly recognized receptor-mediated chemoattractant for endothelial cells.

Quantitative multiparametric immunophenotyping in acute lymphoblastic leukemia: correlation with specific genotype. I. ETV6/AML1 ALLs identification.

The t(12;21)(p13;q22) fusion gene is the most frequent genetic lesion described in precursor B cell acute lymphoblastic leukemia (ALL) of childhood occurring in a quarter of cases. This gene rearrangement is associated with a good outcome presenting a high response rate to chemotherapy. In spite of its potential clinical relevance, the t(12;21) translocation usually goes undetected with conventional cytogenetic procedures. In the present study we utilized an objective flow cytometric approach (multiparametric quantitative analysis) for the phenotypic characterization of this type of ALL. We studied a total of 74 precursor B-ALL children, including 21 t(12;21)+ and 53 t(12;21)- cases. Our results show that the t(12;21)(p13;q22)+ ALLs display a higher intensity of CD10 (P = 0.0016) and HLADR (P = 0.005) expression together with lower levels of the CD20 (P = 0.01), CD45 (P = 0.01), CD135 (P = 0.003) and CD34 (P = 0.03) antigens as compared to the t(12;21) cases. Moreover, as regards CD34 expression, we observed a more heterogeneous antigen expression within individual patients with higher coefficients of variation (median of 202 vs 88, P = 0.0001). A multi-variate analysis disclosed that with the immunophenotypic approach used identification of t(12;21)+ cases can be achieved with a sensitivity of 86% and a specificity of 100%. We conclude that childhood precursor B-ALL carrying the t(12;21) translocation display characteristic phenotypic features which could provide a rapid, simple, sensitive and specific screening method to select for those cases that should undergo confirmatory molecular analysis.

Interferon treatment of chronic hepatitis C in patients cured of pediatric malignancies.

BACKGROUND AND OBJECTIVE: Chronic hepatitis C was a frequent complication in patients treated for malignancy until the introduction of anti-HCV screening tests for blood donors. The association between chronic hepatitis C and progression to cirrhosis and hepatocellular carcinoma has been reported in about 20% and 5% of patients, respectively, within 20-30 years of infection. In adult patients, interferon has proved to be effective in decreasing the abnormal values of transaminases and the level of HCV viremia. Our purpose was to assess efficacy of and tolerance to interferon in a group of young patients who had acquired HCV infection during a period of chemotherapy. DESIGN AND METHODS: Interferon-a (IFN) was administered to 26 adolescents and young adults (13 males, age range 17-36 years; median age 24) with chronic hepatitis C, including 4 with hepatitis B virus co-infection, who had been treated for leukemia or solid tumor 5 to 19 years before joining this trial. Patients were treated with natural IFN alpha at a dose of 4 MU/m(2) thrice weekly for 12 months and followed up for another 6 months thereafter. RESULTS: Nine patients stopped treatment during the first 6 months because of side effects (2 cases) or lack of response. At the end of the trial, 8 (31%) cases had responded, with alanine amino-transferase normalization and clearance of hepatitis C virus (HCV) RNA. A sustained response was only documented in 15% of cases, however, irrespective of any hepatitis B virus co-infection. The 2 patients with HCV genotype 2 were both responders, whereas only 8% of those with genotype 1 responded. INTERPRETATION AND CONCLUSIONS: These data show that the efficacy of IFN in this series of young patients is similar to that reported for otherwise healthy adults with hepatitis C. Patients with genotype 2 are strong candidates for IFN treatment while other therapeutic strategies should be designed for patients with HCV genotype 1.

High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma.

PURPOSE: The European Collaborative MMT4-91 trial was conducted as a prospective nonrandomized study to evaluate the potential benefit of high-dose melphalan as consolidation of first complete remission in children with stage IV rhabdomyosarcoma. PATIENTS AND METHODS: Fifty-two patients in complete remission after six courses of chemotherapy received "megatherapy": 42 received melphalan alone, whereas 10 received melphalan in combination with etoposide, carboplatin/etoposide, or thiotepa/busulfan and etoposide. The outcome of this group of patients was compared with that observed in 44 patients who were also in complete remission after six courses of identical chemotherapy (plus surgery or radiotherapy) but went on to receive a total of up to 12 courses of conventional chemotherapy (four cycles). No differences were found between the two groups regarding clinical characteristics, chemotherapy received before complete remission, or response to chemotherapy. In particular, there was no significant difference between the groups for site of primary tumor, histologic subtype, age at presentation, presence of bone or bone marrow metastases, or number of metastases. RESULTS: The 3-year event-free survival (EFS) and overall survival (OS) rates were 29.7% and 40%, respectively, for those receiving high-dose melphalan or other multiagent high-dose regimens and 19.2% and 27.7%, respectively, for those receiving standard chemotherapy. The difference was not statistically significant (P =.3 and P =.2 for EFS and OS, respectively). There was a significant prolongation in the time from the last day of high-dose chemotherapy or the end of chemotherapy cycle 4 to the time of relapse in those receiving megatherapy (168 days for patients receiving megatherapy v 104 days for those receiving standard therapy; P =.05). CONCLUSION: The addition of a high-dose alkylating agent to consolidation therapy may have prolonged progression-free survival in this poor-risk patient group, but it did not significantly improve the ultimate outcome.

Regulation of the RhoA pathway in human endothelial cell spreading on type IV collagen: role of calcium influx.

We have shown that nonvoltage-operated Ca(2+) entry regulates human umbilical vein endothelial cell adhesion, migration, and proliferation on type IV collagen. We now demonstrate a requirement for Ca(2+) influx for activation of the RhoA pathway during endothelial cell spreading on type IV collagen. Reorganization of actin into stress fibers was complete when the cells where fully spread at 90 minutes. No actin organization into stress fibers was seen in endothelial cells plated on type I collagen, indicating a permissive effect of type IV collagen. CAI, a blocker of nonvoltage-operated Ca(2+) channels, prevented development of stress fiber formation in endothelial cells on type IV collagen. This permissive effect was augmented by Ca(2+) influx, as stimulated by 0. 5 microM thapsigargin or 0.1 microM ionomycin, yielding faster development of actin stress fibers. Ca(2+) influx and actin rearrangement in response to thapsigargin and ionomycin were abrogated by CAI. Activated, membrane-bound RhoA is a substrate for C3 exoenzyme which ADP-ribosylates and inactivates RhoA, preventing actin stress fiber formation. Pretreatment of endothelial cells with C3 exoenzyme prevented basal and thapsigargin-augmented stress fiber formation. While regulation of Ca(2+) influx did not alter RhoA translocation, it reduced in vitro ADP-ribosylation of RhoA (P(2)<0. 05), suggesting Ca(2+) influx is needed for RhoA activation during spreading on type IV collagen; no Ca(2+) regulated change in RhoA was seen in HUVECs spreading on type I collagen matrix. Blockade of Ca(2+) influx of HUVEC spread on type IV collagen also reduced tyrosine phosphorylation of p190Rho-GAP and blocked thapsigargin-enhanced binding of p190Rho-GAP to focal adhesion kinase. Thus, Ca(2+) influx is necessary for RhoA activation and for linkage of the RhoA/stress fiber cascade to the focal adhesion/focal adhesion kinase pathway during human umbilical vein endothelial cell spreading on type IV collagen.

Endothelial cell spreading on type IV collagen and spreading-induced FAK phosphorylation is regulated by Ca2+ influx.

The interaction of endothelial cells with their basement membrane and local stroma is highly regulated. The observation that CAI, an inhibitor of Ca++ influx, inhibited human umbilical vein endothelial cell (HUVEC) adhesion suggested that Ca++ influx was a regulator of HUVEC-matrix interaction. Exposure of HUVEC cells to CAI or SK&F 96365, another Ca++ influx inhibitor, selectively blocked spreading but not attachment on type IV collagen but not type I collagen. Ca++ influx blockade also prevented spreading-induced FAK phosphorylation and kinase activity and secondary paxillin phosphorylation. No inhibitory effect was observed when the cells spread on type I collagen. The inhibitory effect of CAI on spreading and spreading-associated FAK phosphorylation and kinase activity was reversible. These data indicate that HUVEC cells have a selective requirement for Ca++ influx for spreading and downstream signaling on basement membrane type IV collagen.

Peripheral blood stem cell collection and transplantation in paediatric malignancies: a monocentric experience.

Thirty-seven patients underwent peripheral blood stem cell (PBSC) collection from May 1994 to May 1997. Twenty-five were males and 12 were females, the median age at collection was 11.5 years (range 1-27.4) and the median weight was 38 kg (range 9-80). As mobilising chemotherapy, cyclophosphamide, etoposide, doxorubicin and cytosine arabinoside were the drugs most frequently used in association with G-CSF for a total of 47 courses. Sixty-one aphereses were performed with a median collection of CD34+ and CFU-GM cells/kg of 3.6 x 10(6) (range 0.6-31.8) and 24.4 x 10(4) (range 0.1-1260), respectively. Minimal residual disease (MRD) was found in five of the 30 investigated aphereses. Twenty-one of the 37 patients underwent high-dose chemotherapy with autologous stem cell rescue: in seven the stem cell source was peripheral blood and bone marrow. The median duration of hospitalization was 18 days for the PBSC group and 23 days for the PBSC/ABMT group. Overall survival was 78.7% at a median follow-up of 18 months (range 2-31) and the DFS was 52% without difference depending on stem cell source. Compared to a historical group of ABMT patients, the PBSC group showed a statistical advantage in terms of neutrophils and platelet engraftment, blood and platelet requirements, and length of hospitalization. PBSC collection is a feasible procedure also in the paediatric setting providing that vascular access is adequate. As already reported, PBSC transplant results in faster engraftment and shorter hospitalization that could allow a better utilization of health financial resources. The question whether the source of stem cells could influence transplant outcome would require a prospective randomised study.

Veno-occlusive disease of the liver in children treated for Wilms tumor.

INTRODUCTION: Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. METHODS: To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) +/- other drugs +/- radiotherapy according to surgical stage and histology. RESULTS: Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during preoperative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6-180 days using supportive therapy only. CONCLUSIONS: (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patients.

Second malignant neoplasms in patients treated on SIOP Wilms tumour studies and trials 1, 2, 5, and 6.

The incidence of second malignant neoplasms (SMNs) was investigated among 1,988 patients with complete data, enrolled in the SIOP Wilms tumor trials and studies 1, 2, 5, and 6, treated between September 1971 and October 1987. By the end of 1992, eight SMNs were documented, whereas only 1.3 were expected (standardized incidence ratio [SIR] = 4.15; 95% CI = 1.79, 8.17). The risk increases in the first 10 years from diagnosis, while no apparent excess of risk is observed in the subsequent periods. This finding however is difficult to interpretdue to the low statistical power. The cumulative incidence of a second cancer observed at 15 years after Wilms tumor diagnosis was 0.65%. Six SMNs were registered in the cohort of patients treated in the SIOP studies 1, 2 and 5 (999 cases) compared to the two cases observed in the SIOP6 cohort (989 cases). If the suggested reduced incidence of second cancers between SIOP1-5 and SIOP6 patient cohorts is confirmed by longer follow-up, it might reflect changes in the treatment protocols.